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Publisher: Elsevier   (Total: 3177 journals)

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Showing 1 - 200 of 3177 Journals sorted alphabetically
Academic Pediatrics     Hybrid Journal   (Followers: 39, SJR: 1.655, CiteScore: 2)
Academic Radiology     Hybrid Journal   (Followers: 26, SJR: 1.015, CiteScore: 2)
Accident Analysis & Prevention     Partially Free   (Followers: 105, SJR: 1.462, CiteScore: 3)
Accounting Forum     Hybrid Journal   (Followers: 28, SJR: 0.932, CiteScore: 2)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 42, SJR: 1.771, CiteScore: 3)
Achievements in the Life Sciences     Open Access   (Followers: 7)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 6)
Acta Astronautica     Hybrid Journal   (Followers: 448, SJR: 0.758, CiteScore: 2)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 2)
Acta Biomaterialia     Hybrid Journal   (Followers: 30, SJR: 1.967, CiteScore: 7)
Acta Colombiana de Cuidado Intensivo     Full-text available via subscription   (Followers: 3)
Acta de Investigación Psicológica     Open Access   (Followers: 2)
Acta Ecologica Sinica     Open Access   (Followers: 11, SJR: 0.18, CiteScore: 1)
Acta Histochemica     Hybrid Journal   (Followers: 5, SJR: 0.661, CiteScore: 2)
Acta Materialia     Hybrid Journal   (Followers: 326, SJR: 3.263, CiteScore: 6)
Acta Mathematica Scientia     Full-text available via subscription   (Followers: 5, SJR: 0.504, CiteScore: 1)
Acta Mechanica Solida Sinica     Full-text available via subscription   (Followers: 9, SJR: 0.542, CiteScore: 1)
Acta Oecologica     Hybrid Journal   (Followers: 12, SJR: 0.834, CiteScore: 2)
Acta Otorrinolaringologica (English Edition)     Full-text available via subscription  
Acta Otorrinolaringológica Española     Full-text available via subscription   (Followers: 2, SJR: 0.307, CiteScore: 0)
Acta Pharmaceutica Sinica B     Open Access   (Followers: 2, SJR: 1.793, CiteScore: 6)
Acta Poética     Open Access   (Followers: 4, SJR: 0.101, CiteScore: 0)
Acta Psychologica     Hybrid Journal   (Followers: 26, SJR: 1.331, CiteScore: 2)
Acta Sociológica     Open Access   (Followers: 1)
Acta Tropica     Hybrid Journal   (Followers: 7, SJR: 1.052, CiteScore: 2)
Acta Urológica Portuguesa     Open Access  
Actas Dermo-Sifiliograficas     Full-text available via subscription   (Followers: 3, SJR: 0.374, CiteScore: 1)
Actas Dermo-Sifiliográficas (English Edition)     Full-text available via subscription   (Followers: 2)
Actas Urológicas Españolas     Full-text available via subscription   (Followers: 3, SJR: 0.344, CiteScore: 1)
Actas Urológicas Españolas (English Edition)     Full-text available via subscription   (Followers: 1)
Actualites Pharmaceutiques     Full-text available via subscription   (Followers: 7, SJR: 0.19, CiteScore: 0)
Actualites Pharmaceutiques Hospitalieres     Full-text available via subscription   (Followers: 3)
Acupuncture and Related Therapies     Hybrid Journal   (Followers: 8)
Acute Pain     Full-text available via subscription   (Followers: 15, SJR: 2.671, CiteScore: 5)
Ad Hoc Networks     Hybrid Journal   (Followers: 11, SJR: 0.53, CiteScore: 4)
Addictive Behaviors     Hybrid Journal   (Followers: 18, SJR: 1.29, CiteScore: 3)
Addictive Behaviors Reports     Open Access   (Followers: 9, SJR: 0.755, CiteScore: 2)
Additive Manufacturing     Hybrid Journal   (Followers: 12, SJR: 2.611, CiteScore: 8)
Additives for Polymers     Full-text available via subscription   (Followers: 23)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 193, SJR: 4.09, CiteScore: 13)
Advanced Engineering Informatics     Hybrid Journal   (Followers: 12, SJR: 1.167, CiteScore: 4)
Advanced Powder Technology     Hybrid Journal   (Followers: 17, SJR: 0.694, CiteScore: 3)
Advances in Accounting     Hybrid Journal   (Followers: 9, SJR: 0.277, CiteScore: 1)
Advances in Agronomy     Full-text available via subscription   (Followers: 17, SJR: 2.384, CiteScore: 5)
Advances in Anesthesia     Full-text available via subscription   (Followers: 30, SJR: 0.126, CiteScore: 0)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 2)
Advances in Applied Mathematics     Full-text available via subscription   (Followers: 12, SJR: 0.992, CiteScore: 1)
Advances in Applied Mechanics     Full-text available via subscription   (Followers: 12, SJR: 1.551, CiteScore: 4)
Advances in Applied Microbiology     Full-text available via subscription   (Followers: 24, SJR: 2.089, CiteScore: 5)
Advances In Atomic, Molecular, and Optical Physics     Full-text available via subscription   (Followers: 15, SJR: 0.572, CiteScore: 2)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4, SJR: 2.61, CiteScore: 7)
Advances in Botanical Research     Full-text available via subscription   (Followers: 1, SJR: 0.686, CiteScore: 2)
Advances in Cancer Research     Full-text available via subscription   (Followers: 35, SJR: 3.043, CiteScore: 6)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 9, SJR: 1.453, CiteScore: 2)
Advances in Catalysis     Full-text available via subscription   (Followers: 5, SJR: 1.992, CiteScore: 5)
Advances in Cell Aging and Gerontology     Full-text available via subscription   (Followers: 5)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 14)
Advances in Chemical Engineering     Full-text available via subscription   (Followers: 29, SJR: 0.156, CiteScore: 1)
Advances in Child Development and Behavior     Full-text available via subscription   (Followers: 11, SJR: 0.713, CiteScore: 1)
Advances in Chronic Kidney Disease     Full-text available via subscription   (Followers: 11, SJR: 1.316, CiteScore: 2)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 26, SJR: 1.562, CiteScore: 3)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 20, SJR: 1.977, CiteScore: 8)
Advances in Computers     Full-text available via subscription   (Followers: 14, SJR: 0.205, CiteScore: 1)
Advances in Dermatology     Full-text available via subscription   (Followers: 15)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 13)
Advances in Digestive Medicine     Open Access   (Followers: 12)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 7)
Advances in Drug Research     Full-text available via subscription   (Followers: 26)
Advances in Ecological Research     Full-text available via subscription   (Followers: 44, SJR: 2.524, CiteScore: 4)
Advances in Engineering Software     Hybrid Journal   (Followers: 29, SJR: 1.159, CiteScore: 4)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 8)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 52, SJR: 5.39, CiteScore: 8)
Advances in Exploration Geophysics     Full-text available via subscription   (Followers: 1)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 9)
Advances in Food and Nutrition Research     Full-text available via subscription   (Followers: 67, SJR: 0.591, CiteScore: 2)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 17)
Advances in Genetics     Full-text available via subscription   (Followers: 21, SJR: 1.354, CiteScore: 4)
Advances in Genome Biology     Full-text available via subscription   (Followers: 11, SJR: 12.74, CiteScore: 13)
Advances in Geophysics     Full-text available via subscription   (Followers: 7, SJR: 1.193, CiteScore: 3)
Advances in Heat Transfer     Full-text available via subscription   (Followers: 26, SJR: 0.368, CiteScore: 1)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 11, SJR: 0.749, CiteScore: 3)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 26)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 3, SJR: 0.193, CiteScore: 0)
Advances in Immunology     Full-text available via subscription   (Followers: 37, SJR: 4.433, CiteScore: 6)
Advances in Inorganic Chemistry     Full-text available via subscription   (Followers: 10, SJR: 1.163, CiteScore: 2)
Advances in Insect Physiology     Full-text available via subscription   (Followers: 2, SJR: 1.938, CiteScore: 3)
Advances in Integrative Medicine     Hybrid Journal   (Followers: 6, SJR: 0.176, CiteScore: 0)
Advances in Intl. Accounting     Full-text available via subscription   (Followers: 3)
Advances in Life Course Research     Hybrid Journal   (Followers: 9, SJR: 0.682, CiteScore: 2)
Advances in Lipobiology     Full-text available via subscription   (Followers: 1)
Advances in Magnetic and Optical Resonance     Full-text available via subscription   (Followers: 8)
Advances in Marine Biology     Full-text available via subscription   (Followers: 21, SJR: 0.88, CiteScore: 2)
Advances in Mathematics     Full-text available via subscription   (Followers: 15, SJR: 3.027, CiteScore: 2)
Advances in Medical Sciences     Hybrid Journal   (Followers: 9, SJR: 0.694, CiteScore: 2)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 6)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 5, SJR: 1.158, CiteScore: 3)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 25)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 8)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 7, SJR: 0.182, CiteScore: 0)
Advances in Nanoporous Materials     Full-text available via subscription   (Followers: 5)
Advances in Oncobiology     Full-text available via subscription   (Followers: 2)
Advances in Organ Biology     Full-text available via subscription   (Followers: 2)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 18, SJR: 1.875, CiteScore: 4)
Advances in Parallel Computing     Full-text available via subscription   (Followers: 7, SJR: 0.174, CiteScore: 0)
Advances in Parasitology     Full-text available via subscription   (Followers: 5, SJR: 1.579, CiteScore: 4)
Advances in Pediatrics     Full-text available via subscription   (Followers: 27, SJR: 0.461, CiteScore: 1)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 19)
Advances in Pharmacology     Full-text available via subscription   (Followers: 17, SJR: 1.536, CiteScore: 3)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 9, SJR: 0.574, CiteScore: 1)
Advances in Phytomedicine     Full-text available via subscription  
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3, SJR: 0.109, CiteScore: 1)
Advances in Plant Biochemistry and Molecular Biology     Full-text available via subscription   (Followers: 11)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 6)
Advances in Porous Media     Full-text available via subscription   (Followers: 5)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 19)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20, SJR: 0.791, CiteScore: 2)
Advances in Psychology     Full-text available via subscription   (Followers: 68)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 6, SJR: 0.371, CiteScore: 1)
Advances in Radiation Oncology     Open Access   (Followers: 2, SJR: 0.263, CiteScore: 1)
Advances in Small Animal Medicine and Surgery     Hybrid Journal   (Followers: 3, SJR: 0.101, CiteScore: 0)
Advances in Space Biology and Medicine     Full-text available via subscription   (Followers: 6)
Advances in Space Research     Full-text available via subscription   (Followers: 433, SJR: 0.569, CiteScore: 2)
Advances in Structural Biology     Full-text available via subscription   (Followers: 5)
Advances in Surgery     Full-text available via subscription   (Followers: 13, SJR: 0.555, CiteScore: 2)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 37, SJR: 2.208, CiteScore: 4)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 20)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 15)
Advances in Virus Research     Full-text available via subscription   (Followers: 6, SJR: 2.262, CiteScore: 5)
Advances in Water Resources     Hybrid Journal   (Followers: 54, SJR: 1.551, CiteScore: 3)
Aeolian Research     Hybrid Journal   (Followers: 6, SJR: 1.117, CiteScore: 3)
Aerospace Science and Technology     Hybrid Journal   (Followers: 388, SJR: 0.796, CiteScore: 3)
AEU - Intl. J. of Electronics and Communications     Hybrid Journal   (Followers: 8, SJR: 0.42, CiteScore: 2)
African J. of Emergency Medicine     Open Access   (Followers: 6, SJR: 0.296, CiteScore: 0)
Ageing Research Reviews     Hybrid Journal   (Followers: 12, SJR: 3.671, CiteScore: 9)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 488, SJR: 1.238, CiteScore: 3)
Agri Gene     Hybrid Journal   (Followers: 1, SJR: 0.13, CiteScore: 0)
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 18, SJR: 1.818, CiteScore: 5)
Agricultural Systems     Hybrid Journal   (Followers: 32, SJR: 1.156, CiteScore: 4)
Agricultural Water Management     Hybrid Journal   (Followers: 45, SJR: 1.272, CiteScore: 3)
Agriculture and Agricultural Science Procedia     Open Access   (Followers: 4)
Agriculture and Natural Resources     Open Access   (Followers: 3)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 58, SJR: 1.747, CiteScore: 4)
Ain Shams Engineering J.     Open Access   (Followers: 5, SJR: 0.589, CiteScore: 3)
Air Medical J.     Hybrid Journal   (Followers: 8, SJR: 0.26, CiteScore: 0)
AKCE Intl. J. of Graphs and Combinatorics     Open Access   (SJR: 0.19, CiteScore: 0)
Alcohol     Hybrid Journal   (Followers: 12, SJR: 1.153, CiteScore: 3)
Alcoholism and Drug Addiction     Open Access   (Followers: 12)
Alergologia Polska : Polish J. of Allergology     Full-text available via subscription   (Followers: 1)
Alexandria Engineering J.     Open Access   (Followers: 2, SJR: 0.604, CiteScore: 3)
Alexandria J. of Medicine     Open Access   (Followers: 1, SJR: 0.191, CiteScore: 1)
Algal Research     Partially Free   (Followers: 11, SJR: 1.142, CiteScore: 4)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 2)
Allergologia et Immunopathologia     Full-text available via subscription   (Followers: 1, SJR: 0.504, CiteScore: 1)
Allergology Intl.     Open Access   (Followers: 5, SJR: 1.148, CiteScore: 2)
Alpha Omegan     Full-text available via subscription   (SJR: 3.521, CiteScore: 6)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 11, SJR: 0.201, CiteScore: 1)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 54, SJR: 4.66, CiteScore: 10)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 6, SJR: 1.796, CiteScore: 4)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 6, SJR: 1.108, CiteScore: 3)
Ambulatory Pediatrics     Hybrid Journal   (Followers: 5)
American Heart J.     Hybrid Journal   (Followers: 58, SJR: 3.267, CiteScore: 4)
American J. of Cardiology     Hybrid Journal   (Followers: 67, SJR: 1.93, CiteScore: 3)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 47, SJR: 0.604, CiteScore: 1)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 13)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 14, SJR: 1.524, CiteScore: 3)
American J. of Human Genetics     Hybrid Journal   (Followers: 37, SJR: 7.45, CiteScore: 8)
American J. of Infection Control     Hybrid Journal   (Followers: 29, SJR: 1.062, CiteScore: 2)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 37, SJR: 2.973, CiteScore: 4)
American J. of Medicine     Hybrid Journal   (Followers: 50)
American J. of Medicine Supplements     Full-text available via subscription   (Followers: 3, SJR: 1.967, CiteScore: 2)
American J. of Obstetrics and Gynecology     Hybrid Journal   (Followers: 272, SJR: 2.7, CiteScore: 4)
American J. of Ophthalmology     Hybrid Journal   (Followers: 66, SJR: 3.184, CiteScore: 4)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 5, SJR: 0.265, CiteScore: 0)
American J. of Orthodontics and Dentofacial Orthopedics     Full-text available via subscription   (Followers: 6, SJR: 1.289, CiteScore: 1)
American J. of Otolaryngology     Hybrid Journal   (Followers: 25, SJR: 0.59, CiteScore: 1)
American J. of Pathology     Hybrid Journal   (Followers: 32, SJR: 2.139, CiteScore: 4)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 28, SJR: 2.164, CiteScore: 4)
American J. of Surgery     Hybrid Journal   (Followers: 39, SJR: 1.141, CiteScore: 2)
American J. of the Medical Sciences     Hybrid Journal   (Followers: 12, SJR: 0.767, CiteScore: 1)
Ampersand : An Intl. J. of General and Applied Linguistics     Open Access   (Followers: 7)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.144, CiteScore: 3)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 67, SJR: 0.138, CiteScore: 0)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 25, SJR: 0.411, CiteScore: 1)
Anales de Cirugia Vascular     Full-text available via subscription   (Followers: 1)
Anales de Pediatría     Full-text available via subscription   (Followers: 3, SJR: 0.277, CiteScore: 0)
Anales de Pediatría (English Edition)     Full-text available via subscription  
Anales de Pediatría Continuada     Full-text available via subscription  
Analytic Methods in Accident Research     Hybrid Journal   (Followers: 5, SJR: 4.849, CiteScore: 10)
Analytica Chimica Acta     Hybrid Journal   (Followers: 44, SJR: 1.512, CiteScore: 5)
Analytica Chimica Acta : X     Open Access  
Analytical Biochemistry     Hybrid Journal   (Followers: 217, SJR: 0.633, CiteScore: 2)
Analytical Chemistry Research     Open Access   (Followers: 13, SJR: 0.411, CiteScore: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 14)
Anesthésie & Réanimation     Full-text available via subscription   (Followers: 2)
Anesthesiology Clinics     Full-text available via subscription   (Followers: 25, SJR: 0.683, CiteScore: 2)
Angiología     Full-text available via subscription   (SJR: 0.121, CiteScore: 0)
Angiologia e Cirurgia Vascular     Open Access   (Followers: 1, SJR: 0.111, CiteScore: 0)
Animal Behaviour     Hybrid Journal   (Followers: 230, SJR: 1.58, CiteScore: 3)
Animal Feed Science and Technology     Hybrid Journal   (Followers: 7, SJR: 0.937, CiteScore: 2)
Animal Reproduction Science     Hybrid Journal   (Followers: 7, SJR: 0.704, CiteScore: 2)

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Similar Journals
Journal Cover
Acta Pharmaceutica Sinica B
Journal Prestige (SJR): 1.793
Citation Impact (citeScore): 6
Number of Followers: 2  

  This is an Open Access Journal Open Access journal
ISSN (Print) 2211-3843 - ISSN (Online) 2211-3835
Published by Elsevier Homepage  [3177 journals]
  • Develop a 3D neurological disease model of human cortical glutamatergic
           neurons using micropillar-based scaffolds

    • Abstract: Publication date: Available online 23 March 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Cheng Chen, Xin Dong, Kaiheng Fang, Fang Yuan, Yao Hu, Min Xu, Yu Huang, Xixiang Zhang, Danjun Fang, Yan LiuEstablishing an effective three-dimensional (3D) in vitro culture system to better model human neurological diseases is desirable, since the human brain is a 3D structure. Here, we demonstrated the development of a polydimethylsiloxane (PDMS) pillar-based 3D scaffold that mimicked the 3D microenvironment of the brain. We utilized this scaffold for the growth of human cortical glutamatergic neurons that were differentiated from human pluripotent stem cells. In comparison with the 2D culture, we demonstrated that the developed 3D culture promoted the maturation of human cortical glutamatergic neurons by showing significantly more MAP2 and less Ki67 expression. Based on this 3D culture system, we further developed an in vitro disease-like model of traumatic brain injury (TBI), which showed a robust increase of glutamate-release from the neurons, in response to mechanical impacts, recapitulating the critical pathology of TBI. The increased glutamate-release from our 3D culture model was attenuated by the treatment of neural protective drugs, memantine or nimodipine. The established 3D in vitro human neural culture system and TBI-like model may be used to facilitate mechanistic studies and drug screening for neurotrauma or other neurological diseases.Graphical abstractBased on a polydimethylsiloxane (PDMS) pillar-based 3D scaffold, more mature and higher proportion of human cortical neurons was achieved. This study provided an in vitro disease-like model of traumatic brain injury, which would facilitate mechanistic studies and drug screening for neurotrauma or other neurological diseases.Graphical abstract for this article
       
  • Matrine attenuates oxidative stress and cardiomyocyte apoptosis in
           doxorubicin-induced cardiotoxicity via maintaining AMPKα/UCP2 pathway

    • Abstract: Publication date: Available online 16 March 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Can Hu, Xin Zhang, Wenying Wei, Ning Zhang, Haiming Wu, Zhenguo Ma, Lingli Li, Wei Deng, Qizhu TangOxidative stress and cardiomyocyte apoptosis are involved in the pathogenesis of doxorubicin (DOX)-induced cardiotoxicity. Matrine is well-known for its powerful anti-oxidant and anti-apoptotic capacities. Our present study aimed to investigate the effect of matrine on DOX-induced cardiotoxicity and try to unearth the underlying mechanisms. Mice were exposed with DOX to generate DOX-induced cardiotoxicity or normal saline as control. H9C2 cells were used to verify the effect of matrine in vitro. DOX injection triggered increased generation of reactive oxygen species (ROS) and excessive cardiomyocyte apoptosis, which were significantly mitigated by matrine. Mechanistically, we found that matrine ameliorated DOX-induced uncoupling protein 2 (UCP2) downregulation, and UCP2 inhibition by genipin could blunt the protective effect of matrine on DOX-induced oxidative stress and cardiomyocyte apoptosis. Besides, 5′-AMP-activated protein kinase α2 (Ampkα2) deficiency inhibited matrine-mediated UCP2 preservation and abolished the beneficial effect of matrine in mice. Besides, we observed that matrine incubation alleviated DOX-induced H9C2 cells apoptosis and oxidative stress level via activating AMPKα/UCP2, which were blunted by either AMPKα or UCP2 inhibition with genetic or pharmacological methods. Matrine attenuated oxidative stress and cardiomyocyte apoptosis in DOX-induced cardiotoxicity via maintaining AMPKα/UCP2 pathway, and it might be a promising therapeutic agent for the treatment of DOX-induced cardiotoxicity.Graphical abstractMatrine attenuated oxidative stress and cardiomyocyte apoptosis in DOX-induced cardiotoxicity via maintaining AMPKα/UCP2 pathway, and it might be a promising therapeutic agent for the treatment of DOX-induced cardiotoxicity.Graphical abstract for this article
       
  • Targeting the untargetable KRAS in cancer therapy

    • Abstract: Publication date: Available online 6 March 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Pingyu Liu, Yijun Wang, Xin LiRAS is one of the most well-known proto-oncogenes. Its gain-of-function mutations occur in approximately 30% of all human cancers. As the most frequently mutated RAS isoform, KRAS is intensively studied in the past years. Despite its well-recognized importance in cancer malignancy, continuous efforts in the past three decades failed to develop approved therapies for KRAS mutant cancer. KRAS has thus long been considered to be undruggable. Encouragingly, recent studies have aroused renewed interest in the development of KRAS inhibitors either directly towards KRAS or against the crucial steps required for KRAS activation. This review summarizes the most recent progress in the exploration of KRAS-targeted anticancer strategies and hopefully provides useful insights for the field.Graphical abstractContinuous efforts in the past three decades failed to develop approved therapies for KRAS mutant cancer. Encouragingly, recent progress in the development of KRAS inhibitors either directly towards mutant KRAS or against the crucial steps required for KRAS activation may bring breakthrough for this long-pursued undruggable target.Graphical abstract for this article
       
  • Targeting slug-mediated non-canonical activation of c-Met to overcome
           chemo-resistance in metastatic ovarian cancer cells

    • Abstract: Publication date: Available online 2 March 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Linlin Chang, Yan Hu, Yingying Fu, Tianyi Zhou, Jun You, Jiamin Du, Lin Zheng, Ji Cao, Meidan Ying, Xiaoyang Dai, Dan Su, Qiaojun He, Hong Zhu, Bo YangMetastasis-associated drug resistance accounts for high mortality in ovarian cancer and remains to be a major barrier for effective treatment. In this study, SKOV3/T4, a metastatic subpopulation of ovarian cancer SKOV3 cells, was enriched to explore potential interventions against metastatic-associated drug resistance. Quantitative genomic and functional analyses were performed and found that slug was significantly increased in the SKOV3/T4 subpopulation and contributed to the high resistance of SKOV3/T4. Further studies showed that slug activated c-Met in a ligand-independent manner due to elevated levels of fibronectin and provoked integrin α V function, which was confirmed by the significant correlation of slug and p-Met levels in 121 ovarian cancer patient samples. Intriguingly, c-Met inhibitor(s) exhibited greatly enhanced anti-cancer effects in slug-positive ovarian cancer models both in vitro and in vivo. Additionally, IHC analyses revealed that slug levels were highly correlated with reduced survival of ovarian cancer patients. Taken together, this study not only uncovers the critical roles of slug in drug resistance in ovarian cancer but also highlights a promising therapeutic strategy by targeting the noncanonical activation of c-Met in slug-positive ovarian cancer patients with poor prognosis.Graphical abstractIn order to overcome chemotherapy resisitance in metastatic ovarian cancer patients, we enriched a metastatic subpopulation of SKOV3 cells to explore the mechanisms underlying metastatic-associated drug resistance. Quantitative genomic and functional analyses uncover the critical roles of slug in metastatic-associated drug resistance, which can be overcome by c-Met inhibitor(s) both in vitro and in vivo.Graphical abstract for this article
       
  • Cholesterol-tuned liposomal membrane rigidity directs tumor penetration
           and anti-tumor effect

    • Abstract: Publication date: Available online 2 March 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Hangyi Wu, Miaorong Yu, Yunqiu Miao, Shufang He, Zhuo Dai, Wenyi Song, Yuan Liu, Sha Song, Ejaj Ahmad, Dongkai Wang, Yong GanRecently, liposomes have been widely used in cancer therapeutics, but their anti-tumor effects are suboptimal due to limited tumor penetration. To solve this problem, researchers have made significant efforts to optimize liposomal diameters and potentials, but little attention has been paid to liposomal membrane rigidity. Herein, we sought to demonstrate the effects of cholesterol-tuned liposomal membrane rigidity on tumor penetration and anti-tumor effects. In this study, liposomes composed of hydrogenated soybean phospholipids (HSPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2000) and different concentrations of cholesterol were prepared. It was revealed that liposomal membrane rigidity decreased with the addition of cholesterol. Moderate cholesterol content conferred excellent diffusivity to liposomes in simulated diffusion medium, while excessive cholesterol limited the diffusion process. We concluded that the differences of the diffusion rates likely stemmed from the alterations in liposomal membrane rigidity, with moderate rigidity leading to improved diffusion. Next, the in vitro tumor penetration and the in vivo anti-tumor effects were analyzed. The results showed that liposomes with moderate rigidity gained excellent tumor penetration and enhanced anti-tumor effects. These findings illustrate a feasible and effective way to improve tumor penetration and therapeutic efficacy of liposomes by changing the cholesterol content, and highlight the importance of liposomal membrane rigidity.Graphical abstractLiposomes with tunable rigidity were constructed conveniently by varying the contents of cholesterol. It is revealed that liposomes with moderate rigidity gained improved tumor penetration and enhanced anti-tumor effects compared to their soft and hard counterparts.Graphical abstract for this article
       
  • Dual-targeting and microenvironment-responsive micelles as a gene delivery
           system to improve the sensitivity of glioma to radiotherapy

    • Abstract: Publication date: March 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 2Author(s): Xiuxiu Jiao, Yuan Yu, Jianxia Meng, Mei He, Charles Jian Zhang, Wenqian Geng, Baoyue Ding, Zhuo Wang, Xueying DingDbait is a small double-stranded DNA molecule that has been utilized as a radiosensitizer to enhance the sensitivity of glioma to radiotherapy (RT). However, there is no effective drug delivery system to effectively overcome the bloodbrain barrier (BBB). The aim of this study was to develop a gene delivery system by using the BBB and glioma dual-targeting and microenvironment-responsive micelles (ch-Kn(s-s)R8-An) to deliver Dbait into glioma for RT. Angiopep-2 can target the low-density lipoprotein receptor-related protein-1 (LRP1) that is overexpressed on brain capillary endothelial cells (BCECs) and glioma cells. In particular, due to upregulated matrix metalloproteinase 2 (MMP-2) in the tumor microenvironment, we utilized MMP-2-responsive peptides as the enzymatically degradable linkers to conjugate angiopep-2. The results showed that ch-Kn(s-s)R8-An micelles maintained a reasonable size (80–160 nm) with a moderate distribution and a decreased mean diameter from the cross-linking as well as exhibited low critical micelle concentration (CMC) with positive surface charge, ranging from 15 to 40 mV. The ch-K5(s-s)R8-An/pEGFP showed high gene transfection efficiency in vitro, improved uptake in glioma cells and good biocompatibility in vitro and in vivo. In addition, the combination of ch-K5(s-s)R8-An/Dbait with RT significantly inhibited the growth of U251 cells in vitro. Thus, ch-K5(s-s)R8-An/Dbait may prove to be a promising gene delivery system to target glioma and enhance the efficacy of RT on U251 cells.Graphical abstractUsing Dbait as a radiosensitizer, dual-targeting and microenvironment-responsive micelle is developed as a gene delivery system to improve sensitivity of glioma to radiotherapy (RT). The micelle can effectively target glioma and further penetrate into the core of the tumor through exposing R8 to deliver Dbait into glioma cells.fx1
       
  • Cytotoxic and antibacterial polyketide-indole hybrids synthesized from
           indole-3-carbinol by Daldinia eschscholzii

    • Abstract: Publication date: March 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 2Author(s): Liping Lin, Nan Jiang, Huimin Wu, Yaning Mei, Jie Yang, Renxiang TanTwo skeletally undescribed polyketide-indole hybrids (PIHs), named indolchromins A and B, were generated from indole-3-carbinol (I3C) in the fungal culture (Daldinia eschscholzii). The indolchromin structures were elucidated mainly by their 1D and 2D NMR spectra with the former confirmed by the single-crystal X-ray crystallographic analysis. Each indolchromin alkaloid was chirally separated into four isomers, whose absolute configurations were assigned by comparing the recorded circular dichroism (CD) spectra with the electronic CD (ECD) curves computed for all optional stereoisomers. Furthermore, the indolchromin construction pathways in fungal culture were clarified through enzyme inhibition, precursor feeding experiment, and energy calculation. The cascade reactions, including decarboxylative Claisen condensation catalyzed by 8-amino-7-oxononanoate synthase (AONS), C(sp3)-H activation, double bond migration, and Michael addition, all undergone compatibly during the fungal cultivation. In an MIC range of 1.3–8.6 μmol/L, (2S,4R)- and (2R,4S)-indolchromin A and (2R,4S)-indolchromin B are inhibitory against Clostridium perfringens, Clostridium difficile, Veillonella sp., Bacteroides fragilis, and Streptococcus pyogenes. (2R,4S)-Indolchromin A and (2S,4S)-indolchromin B were cytotoxic against the human breast cancer cell line MDA-MB-231 with IC50 values of 27.9 and 131.2 nmol/L, respectively, with the former additionally active against another human breast cancer cell line MCF-7 (IC50 94.4 nmol/L).Graphical abstractSkeletally undescribed polyketide-indole hybrids with potent antibacterial and cytotoxic properties, were characterized from the indole-3-carbinol (I3C) exposed fungal culture. The chirality–bioactivity relationship was facilitated by fractionating and bio-evaluating all indolchromin stereoisomers, whose absolute configurations were established by pairing their recorded CD spectra with those computed for all options.fx1
       
  • Discovery of a series of dimethoxybenzene FGFR inhibitors with
           5H-pyrrolo[2,3-b]pyrazine scaffold: structure–activity relationship,
           crystal structural characterization and in vivo study

    • Abstract: Publication date: March 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 2Author(s): Peng Wei, Bo Liu, Ruifeng Wang, Yinglei Gao, Lanlan Li, Yuchi Ma, Zhiwei Qian, Yuelei Chen, Maosheng Cheng, Meiyu Geng, Jingkang Shen, Dongmei Zhao, Jing Ai, Bing XiongGenomic alterations are commonly found in the signaling pathways of fibroblast growth factor receptors (FGFRs). Although there is no selective FGFR inhibitors in market, several promising inhibitors have been investigated in clinical trials, and showed encouraging efficacies in patients. By designing a hybrid between the FGFR-selectivity-enhancing motif dimethoxybenzene group and our previously identified novel scaffold, we discovered a new series of potent FGFR inhibitors, with the best one showing sub-nanomolar enzymatic activity. After several round of optimization and with the solved crystal structure, detailed structureactivity relationship was elaborated. Together with in vitro metabolic stability tests and in vivo pharmacokinetic profiling, a representative compound (35) was selected and tested in xenograft mouse model, and the result demonstrated that inhibitor 35 was effective against tumors with FGFR genetic alterations, exhibiting potential for further development.Graphical abstractWith the guidance of the crystal structure, we discovered a series of selective FGFR inhibitors bearing 5H-pyrrolo[2,3-b]pyrazine scaffold. After considerable efforts to improve the metabolic stability and pharmacokinetic properties, finally, we obtained a potent and active compound 35 showing in vivo efficacy in xenograft mouse model.fx1
       
  • Design, synthesis and biological evaluation of chalcone analogues with
           novel dual antioxidant mechanisms as potential anti-ischemic stroke agents
           

    • Abstract: Publication date: March 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 2Author(s): Jiabing Wang, Lili Huang, Chanchan Cheng, Ge Li, Jingwen Xie, Mengya Shen, Qian Chen, Wulan Li, Wenfei He, Peihong Qiu, Jianzhang WuScavenging reactive oxygen species (ROS) by antioxidants is the important therapy to cerebral ischemia-reperfusion injury (CIRI) in stroke. The antioxidant with novel dual-antioxidant mechanism of directly scavenging ROS and indirectly through antioxidant pathway activation may be a promising CIRI therapeutic strategy. In our study, a series of chalcone analogues were designed and synthesized, and multiple potential chalcone analogues with dual antioxidant mechanisms were screened. Among these compounds, the most active 33 not only conferred cytoprotection of H2O2-induced oxidative damage in PC12 cells through scavenging free radicals directly and activating NRF2/ARE antioxidant pathway at the same time, but also played an important role against ischemia/reperfusion-related brain injury in animals. More importantly, in comparison with mono-antioxidant mechanism compounds, 33 exhibited higher cytoprotective and neuroprotective potential in vitro and in vivo. Overall, our findings showed compound 33 could emerge as a promising anti-ischemic stroke drug candidate and provided novel dual-antioxidant mechanism strategies and concepts for oxidative stress-related diseases treatment.Graphical abstractChalcone analogue 33 conferred protection of PC12 cells against H2O2 insult with novel dual-antioxidant mechanism of directly scavenging reactive oxygen species (ROS) and indirectly through antioxidant pathway activation, and the effect of 33 was more pronounced than that of mono-antioxidant mechanism compounds after MCAO and BCAO in animals.fx1
       
  • LSD1 inhibition suppresses the growth of clear cell renal cell carcinoma
           via upregulating P21 signaling

    • Abstract: Publication date: March 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 2Author(s): Liangsong Zhu, Jianfeng Wang, Wen Kong, Jiwei Huang, Baijun Dong, Yiran Huang, Wei Xue, Jin ZhangHistone lysine-specific demethylase 1 (LSD1) has been implicated in the disease progression of several types of solid tumors. This study provides the first evidence showing that LSD1 overexpression occurred in 62.6% (224/358) of clear cell renal cell carcinomas (ccRCC). LSD1 expression was associated with the progression of ccRCC, as indicated by TNM stage (P=0.006), especially tumor stage (P=0.017) and lymph node metastasis (P=0.030). High LSD1 expression proved to be an independent prognostic factor for poor overall survival (P
       
  • The epigallocatechin gallate derivative Y6 reverses drug resistance
           mediated by the ABCB1 transporter both in vitro and in vivo

    • Abstract: Publication date: March 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 2Author(s): Yan Wen, Ruiqiang Zhao, Pranav Gupta, Yingfang Fan, Yunkai Zhang, Zhenguang Huang, Xiaohui Li, Yuangang Su, Lijuan Liao, Yu-An Xie, Donghua Yang, Zhe-Sheng Chen, Gang LiangPreviously, we reported that Y6, a new epigallocatechin gallate derivative, is efficacious in reversing doxorubicin (DOX)--mediated resistance in hepatocellular carcinoma BEL-7404/DOX cells. In this study, we evaluated the efficacy of Y6 in reversing drug resistance both in vitro and in vivo by determining its effect on the adenosine triphosphate-binding cassette protein B1 transporter (ABCB1 or P-glycoprotein, P-gp). Our results showed that Y6 significantly sensitized cells overexpressing the ABCB1 transporter to anticancer drugs that are ABCB1 substrates. Y6 significantly stimulated the adenosine triphosphatase activity of ABCB1. Furthermore, Y6 exhibited a higher docking score as compared with epigallocatechin gallate inside the transmembrane domain of ABCB1. In addition, in the nude mouse tumor xenograft model, Y6 (110 mg/kg, intragastric administration), in combination with doxorubicin (2 mg/kg, intraperitoneal injection), significantly inhibited the growth of BEL-7404/DOX cell xenograft tumors, compared to equivalent epigallocatechin gallate. In conclusion, Y6 significantly reversed ABCB1-mediated multidrug resistance and its mechanisms of action may result from its competitive inhibition of the ABCB1 drug efflux function.Graphical abstractY6, an epigallocatechin gallate derivative, reverses ABCB1-mediated multidrug resistance in vitro and in vivo, and the reversal effect of Y6 is significantly greater than epigallocatechin gallate.fx1
       
  • SHP2 inhibition triggers anti-tumor immunity and synergizes with PD-1
           blockade

    • Abstract: Publication date: March 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 2Author(s): Mingxia Zhao, Wenjie Guo, Yuanyuan Wu, Chenxi Yang, Liang Zhong, Guoliang Deng, Yuyu Zhu, Wen Liu, Yanhong Gu, Yin Lu, Lingdong Kong, Xiangbao Meng, Qiang Xu, Yang SunTyrosine phosphatase SHP2 is a promising drug target in cancer immunotherapy due to its bidirectional role in both tumor growth promotion and T-cell inactivation. Its allosteric inhibitor SHP099 is known to inhibit cancer cell growth both in vitro and in vivo. However, whether SHP099-mediated SHP2 inhibition retards tumor growth in vivo via anti-tumor immunity remains elusive. To address this, a CT-26 colon cancer xenograft model was established in mice since this cell line is insensitive to SHP099. Consequently, SHP099 minimally affected CT-26 tumor growth in immuno-deficient nude mice, but significantly decreased the tumor burden in CT-26 tumor-bearing mice with intact immune system. SHP099 augmented anti-tumor immunity, as shown by the elevated proportion of CD8+IFN-γ+ T cells and the upregulation of cytotoxic T-cell related genes including Granzyme B andPerforin, which decreased the tumor load. In addition, tumor growth in mice with SHP2-deficient T-cells was markedly slowed down because of enhanced anti-tumor responses. Finally, the combination of SHP099 and anti-PD-1 antibody showed a higher therapeutic efficacy than either monotherapy in controlling tumor growth in two colon cancer xenograft models, indicating that these agents complement each other. Our study suggests that SHP2 inhibitor SHP099 is a promising candidate drug for cancer immunotherapy.Graphical abstractThe SHP2 allosteric inhibitor, SHP099, is a promising drug candidate for cancer immunotherapy. SHP2 inhibition both enhances and normalizes anti-tumor immunity, and the combination of SHP099 and anti-PD-1 is a potentially robust therapeutic strategy for cancer control.fx1
       
  • Glycyrrhetinic acid binds to the conserved P-loop region and interferes
           with the interaction of RAS-effector proteins

    • Abstract: Publication date: March 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 2Author(s): Yuan Zhang, Zhihua Wang, Xiaoyao Ma, Shengnan Yang, Xueyan Hu, Jin Tao, Yuanyuan Hou, Gang BaiMembers of the RAS proto-oncogene superfamily are indispensable molecular switches that play critical roles in cell proliferation, differentiation, and cell survival. Recent studies have attempted to prevent the interaction of RAS/GTP with RAS guanine nucleotide exchange factors (GEFs), impair RAS-effector interactions, and suppress RAS localization to prevent oncogenic signalling. The present study aimed to investigate the effect of the natural triterpenoic acid inhibitor glycyrrhetinic acid, which is isolated from the roots of Glycyrrhiza plant species, on RAS stability. We found that glycyrrhetinic acid may bind to the P-loop of RAS and alter its stability. Based on our biochemical tests and structural analysis results, glycyrrhetinic acid induced a conformational change in RAS. Meanwhile, glycyrrhetinic acid abolishes the function of RAS by interfering with the effector protein RAF kinase activation and RAS/MAPK signalling.Graphical abstractGlycyrrhetinic acid binds to the conserved P-loop region of RAS protein, induces a conformational change, and alters its stability. Meanwhile, glycyrrhetinic acid abolishes the function of RAS by interfering with the effector protein RAF kinase activation and RAS/MAPK signalling.fx1
       
  • Hypocrellin A-based photodynamic action induces apoptosis in A549 cells
           through ROS-mediated mitochondrial signaling pathway

    • Abstract: Publication date: March 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 2Author(s): Shanshan Qi, Lingyuan Guo, Shuzhen Yan, Robert J. Lee, Shuqin Yu, Shuanglin ChenOver recent decades, many studies have reported that hypocrellin A (HA) can eliminate cancer cells with proper irradiation in several cancer cell lines. However, the precise molecular mechanism underlying its anticancer effect has not been fully defined. HA-mediated cytotoxicity and apoptosis in human lung adenocarcinoma A549 cells were evaluated after photodynamic therapy (PDT). A temporal quantitative proteomics approach by isobaric tag for relative and absolute quantitation (iTRAQ) 2D liquid chromatography with tandem mass spectrometric (LC–MS/MS) was introduced to help clarify molecular cytotoxic mechanisms and identify candidate targets of HA-induced apoptotic cell death. Specific caspase inhibitors were used to further elucidate the molecular pathway underlying apoptosis in PDT-treated A549 cells. Finally, down-stream apoptosis-related protein was evaluated. Apoptosis induced by HA was associated with cell shrinkage, externalization of cell membrane phosphatidylserine, DNA fragmentation, and mitochondrial disruption, which were preceded by increased intracellular reactive oxygen species (ROS) generations. Further studies showed that PDT treatment with 0.08 µmol/L HA resulted in mitochondrial disruption, pronounced release of cytochrome c, and activation of caspase-3, -9, and -7. Together, HA may be a possible therapeutic agent directed toward mitochondria and a promising photodynamic anticancer candidate for further evaluation.Graphical abstractHypocrellin A-mediated oxidative injury induced by light emitting diode irradiation triggers mitochondrial membrane potential changes and dysfunction, then mitochondrial cytochrome c release and caspase activation, which consequently lead to apoptosis. The study demonstrated hypocrellin A may be a possible therapeutic anticancer agent directed toward mitochondria.fx1
       
  • Recent progress and challenges in screening and characterization of UGT1A1
           inhibitors

    • Abstract: Publication date: March 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 2Author(s): Xia Lv, Yangliu Xia, Moshe Finel, Jingjing Wu, Guangbo Ge, Ling YangUridine-diphosphate glucuronosyltransferase 1A1 (UGT1A1) is an important conjugative enzyme in mammals that is responsible for the conjugation and detoxification of both endogenous and xenobiotic compounds. Strong inhibition of UGT1A1 may trigger adverse drug/herb–drug interactions, or result in metabolic disorders of endobiotic metabolism. Therefore, both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have recommended assaying the inhibitory potential of drugs under development on the human UGT1A1 prior to approval. This review focuses on the significance, progress and challenges in discovery and characterization of UGT1A1 inhibitors. Recent advances in the development of UGT1A1 probes and their application for screening UGT1A1 inhibitors are summarized and discussed in this review for the first time. Furthermore, a long list of UGT1A1 inhibitors, including information on their inhibition potency, inhibition mode, and affinity, has been prepared and analyzed. Challenges and future directions in this field are highlighted in the final section. The information and knowledge that are presented in this review provide guidance for rational use of drugs/herbs in order to avoid the occurrence of adverse effects via UGT1A1 inhibition, as well as presenting methods for rapid screening and characterization of UGT1A1 inhibitors and for facilitating investigations on UGT1A1ligand interactions.Graphical abstractStrong inhibition of UGT1A1 may not only trigger clinical adverse drug/herb–drug interactions (D/HDI), but also result in metabolic disorders via modulation of endobiotic metabolism. This review focuses on the significance, progress and challenges in the discovery and characterization of UGT1A1 inhibitors, as well as the recent advances in the development of UGT1A1 probe substrates for screening and characterization of UGT1A1 inhibitors.fx1
       
  • Marine sponges of the genus Stelletta as promising drug sources: chemical
           and biological aspects

    • Abstract: Publication date: March 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 2Author(s): Qihao Wu, Bastien Nay, Min Yang, Yeke Ni, Hong Wang, Ligong Yao, Xuwen LiMarine sponges of the genus Stelletta are well known as rich sources of diverse and complex biologically relevant natural products, including alkaloids, terpenoids, peptides, lipids, and steroids. Some of these metabolites, with novel structures and promising biological activities, have attracted a lot of attention from chemists seeking to perform their total synthesis in parallel to intensive biological studies towards new drug leads. In this review, we summarized the distribution of the chemically investigated Stelletta sponges, the isolation, synthesis and biological activities of their secondary metabolites, covering the literature from 1982 to early 2018.Graphical abstractMarine sponges of the genus Stelletta are well known as rich sources of diverse and complex natural products with novel structures and broad biological activities, which have attracted a lot of attention from chemists seeking to perform their total synthesis in parallel to intensive biological studies towards new drug leads. In this review, we summarize the chemical and biological aspects of Stelletta sponges as promising drug sources.fx1
       
  • Small molecules for fat combustion: targeting obesity

    • Abstract: Publication date: March 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 2Author(s): Jingxin Liu, Yitao Wang, Ligen LinObesity is increasing in an alarming rate worldwide, which causes higher risks of some diseases, such as type 2 diabetes, cardiovascular diseases, and cancer. Current therapeutic approaches, either pancreatic lipase inhibitors or appetite suppressors, are generally of limited effectiveness. Brown adipose tissue (BAT) and beige cells dissipate fatty acids as heat to maintain body temperature, termed non-shivering thermogenesis; the activity and mass of BAT and beige cells are negatively correlated with overweight and obesity. The existence of BAT and beige cells in human adults provides an effective weight reduction therapy, a process likely to be amenable to pharmacological intervention. Herein, we combed through the physiology of thermogenesis and the role of BAT and beige cells in combating with obesity. We summarized the thermogenic regulators identified in the past decades, targeting G protein-coupled receptors, transient receptor potential channels, nuclear receptors and miscellaneous pathways. Advances in clinical trials were also presented. The main purpose of this review is to provide a comprehensive and up-to-date knowledge from the biological importance of thermogenesis in energy homeostasis to the representative thermogenic regulators for treating obesity. Thermogenic regulators might have a large potential for further investigations to be developed as lead compounds in fighting obesity.Graphical abstractBrown adipose tissue (BAT) and beige cells dissipates fatty acids as heat, termed non-shivering thermogenesis, which has emerged as a potential therapeutically way to treat obesity. The current review provides a comprehensive and up-to-date of knowledge from the biological importance of thermogenesis to the representative thermogenic regulators for treating obesity.fx1
       
  • Repurposing vitamin D for treatment of human malignancies via targeting
           tumor microenvironment

    • Abstract: Publication date: March 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 2Author(s): Xu Wu, Wei Hu, Lan Lu, Yueshui Zhao, Yejiang Zhou, Zhangang Xiao, Lin Zhang, Hanyu Zhang, Xiaobing Li, Wanping Li, Shengpeng Wang, Chi Hin Cho, Jing Shen, Mingxing LiTumor cells along with a small proportion of cancer stem cells exist in a stromal microenvironment consisting of vasculature, cancer-associated fibroblasts, immune cells and extracellular components. Recent epidemiological and clinical studies strongly support that vitamin D supplementation is associated with reduced cancer risk and favorable prognosis. Experimental results suggest that vitamin D not only suppresses cancer cells, but also regulates tumor microenvironment to facilitate tumor repression. In this review, we have outlined the current knowledge on epidemiological studies and clinical trials of vitamin D. Notably, we summarized and discussed the anticancer action of vitamin D in cancer cells, cancer stem cells and stroma cells in tumor microenvironment, providing a better understanding of the role of vitamin D in cancer. We presently re-propose vitamin D to be a novel and economical anticancer agent.Graphical abstractSupplementation of vitamin D is associated with reduced cancer risk and favorable prognosis. Vitamin D not only suppresses cancer cells and cancer stem cells, but also regulates tumor microenvironment, demonstrating the promise of the benefit of vitamin D in cancer prevention and treatment.fx1
       
  • Bioactive A-ring rearranged limonoids from the root barks of Walsura
           robusta

    • Abstract: Publication date: Available online 1 March 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Faliang An, Xiaobing Wang, Minghua Yang, Jun Luo, Lingyi KongScreening active natural products, rapid identification, and accurate isolation are of great important for modern natural lead compounds discovery1. We herely reported the isolation of seven new neotecleanin-type liminoids (1‒7), seven new limonoids with 5-oxatricyclo[5.4.0.11, 4]hendecane ring system (8‒14), and two new precursors (15‒16) together with four known limonoids (17‒20) from the root barks of Walsura robusta. Their structures, including their absolute configurations, were elucidated based on analyses of HR-ESI-MS, 1D/2D NMR, ECD spectrum calculations and single-crystal X-ray diffraction techniques. Compounds 2, 8, 9, 11, 13, 14, 18 showed significant anti-inflammatory activities in LPS-induced RAW 264.7 cell line, BV2 microglial cells, and Propionibacterium acnes-stimulated THP-1 human monocytic cells. Walrobsin M (11) exhibited anti-inflammatory activity with IC50 value of 7.96 ± 0.36 μmol/L, and down-regulated phosphorylation levels of ERK and p38 in a dose-dependent manner.Graphical abstractTwenty A/B spiro-type limonoids (1‒20) including seven new neotecleanin-type liminoids (1‒7), seven novel limonoids (8‒14) with 5-oxatricyclo[5.4.0.11, 4]hendecane ring system, and two key precursors (15‒16) were isolated from the root barks of Walsura robusta. Walrobsin M (11) significantly inhibited inflammatory activity with IC50 value of 7.96 μmol/L, and down-regulated phosphorylation levels of ERK and p38 in a dose-dependent manner.Graphical abstract for this article
       
  • Highlights of the 2nd International Symposium on Tribbles and Diseases:
           tribbles tremble in therapeutics for immunity, metabolism, fundamental
           cell biology and cancer

    • Abstract: Publication date: March 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 2Author(s): The Tribbles (TRIB) family of pseudokinase proteins has been shown to play key roles in cell cycle, metabolic diseases, chronic inflammatory disease, and cancer development. A better understanding of the mechanisms of TRIB pseudokinases could provide new insights for disease development and help promote TRIB proteins as novel therapeutic targets for drug discovery. At the 2nd International Symposium on Tribbles and Diseases held on May 7‒9, 2018 in Beijing, China, a group of leading Tribbles scientists reported their findings and ongoing studies about the effects of the different TRIB proteins in the areas of immunity, metabolism, fundamental cell biology and cancer. Here, we summarize important and insightful overviews from 4 keynote lectures, 13 plenary lectures and 8 short talks that took place during this meeting. These findings may offer new insights for the understanding of the roles of TRIB pseudokinases in the development of various diseases.Graphical abstractThis is a meeting report of the 2nd International Symposium on Tribbles and Diseases held May 7‒9, 2018 in Beijing, China. A group of speakers reported their recent findings and disseminated ongoing studies about Tribbles proteins related to immunity, metabolism, fundamental cell biology, cancer, and discussed potential implications for target therapy.Graphical abstract for this article
       
  • Redox-sensitive prodrug nanoassemblies based on linoleic acid-modified
           docetaxel to resist breast cancers

    • Abstract: Publication date: March 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 2Author(s): Meng Li, Liwen Zhao, Tao Zhang, Yue Shu, Zhonggui He, Yan Ma, Dan Liu, Yongjun WangProdrug nanoassemblies, which can refrain from large excipients, achieve higher drug loading and control drug release, have been placed as the priority in drug delivery system. Reasoning that glutathione (GSH) and reactive oxygen species (ROS) are highly upgraded in tumor tissues which makes them attractive targets for drug delivery system, we designed and synthetized a novel prodrug which utilized mono thioether bond as a linker to bridge linoleic acid (LA) and docetaxel (DTX). This mono thioether-linked conjugates (DTX-S-LA) could self-assemble into nanoparticles without the aid of much excipients. The mono thioether endowed the nanoparticles redox sensitivity resulting in specific release at the tumor tissue. Our studies demonstrated that the nanoassemblies had uniform particle size, high stability and fast release behavior. DTX-S-LA nanoassemblies outperformed DTX solution in pharmacokinetic profiles for it had longer circulation time and higher area under curve (AUC). Compared with DTX solution, the redox dual-responsive nanoassemblies had comparable cytotoxic activity. Besides, the antitumor efficacy was evaluated in mice bearing 4T1 xenograft. It turned out this nanoassemblies could enhance anticancer efficacy by increasing the dose because of higher tolerance. Overall, these results indicated that the redox sensitivity nanoassemblies may have a great potential to cancer therapy.Graphical abstractA novel prodrug was designed and synthetized which utilized mono thioether bond as a linker to bridge linoleic acid and docetaxel. This redox sensitive conjugate could self-assemble into nanoparticles which had excellent physical stability, strong cytotoxic activity, prolonged circulation time and enhanced anticancer efficacy.fx1
       
  • Theranostic nanoparticles with tumor-specific enzyme-triggered size
           reduction and drug release to perform photothermal therapy for breast
           cancer treatment

    • Abstract: Publication date: March 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 2Author(s): Rui Liu, Chuan Hu, Yuanyuan Yang, Jingqing Zhang, Huile GaoAlthough progress has been indeed made by nanomedicines, their efficacies for cancer treatment remain low, consequently leading to failures in translation to clinic. To improve the drug delivery efficiency, nanoparticles need to change size so as to fully utilize the enhanced permeability and retention (EPR) effect of solid tumor, which is the golden principle of nanoparticles used for cancer treatment. Herein, we employed cationic small-sized red emission bovine serum albumin (BSA) protected gold nanocluster (AuNC@CBSA, 21.06 nm) to both load indocyanine green (ICG) and act as imaging probe to realize theranostic. Then AuNC@CBSA-ICG was fabricated with negatively charged hyaluronic acid (HA) to form AuNC@CBSA-ICG@HA, which was about 200 nm to easily retain at tumor site and could be degraded by tumor-specific hyaluronidase into small nanoparticles for deep tumor penetration. The HA shell also endowed AuNC@CBSA-ICG@HA with actively targeting ability and hyaluronidase-dependent drug release. Furthermore, the quenching and recovery of fluorescence revealed the interaction between ICG and carrier, which was essential for the investigation of pharmacokinetic profiles. No matter in vitro or in vivo, AuNC@CBSA-ICG@HA showed markedly anti-tumor effect, and could suppress 95.0% of tumor growth on mice breast cancer model. All results demonstrated AuNC@CBSA-ICG@HA was potential for breast cancer therapy.Graphical abstractThe simply-constructed size-reducible AuNC@CBSA-ICG@HA could be degraded by tumor-specific hyaluronidase into small particles for deep penetration and drug release in tumor region, thus homogeneously distributing in tumor and locally releasing therapeutic agents. The investigations of double locations of carrier and drug provided many opportunities for AuNC@CBSA@HA loading other drugs.fx1
       
  • Transformative hyaluronic acid-based active targeting supramolecular
           nanoplatform improves long circulation and enhances cellular uptake in
           cancer therapy

    • Abstract: Publication date: March 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 2Author(s): Lu Zhong, Lu Xu, Yanying Liu, Qingsong Li, Dongyang Zhao, Zhenbao Li, Huicong Zhang, Haotian Zhang, Qiming Kan, Yongjun Wang, Jin Sun, Zhonggui HeHyaluronic acid (HA) is a natural ligand of tumor-targeted drug delivery systems (DDS) due to the relevant CD44 receptor overexpressed on tumor cell membranes. However, other HA receptors (HARE and LYVE-1) are also overexpressing in the reticuloendothelial system (RES). Therefore, polyethylene glycol (PEG) modification of HA-based DDS is necessary to reduce RES capture. Unfortunately, pegylation remarkably inhibits tumor cellular uptake and endosomal escapement, significantly compromising the in vivo antitumor efficacy. Herein, we developed a Dox-loaded HA-based transformable supramolecular nanoplatform (Dox/HCVBP) to overcome this dilemma. Dox/HCVBP contains a tumor extracellular acidity-sensitive detachable PEG shell achieved by a benzoic imine linkage. The in vitro and in vivo investigations further demonstrated that Dox/HCVBP could be in a "stealth" state at blood stream for a long circulation time due to the buried HA ligands and the minimized nonspecific interaction by PEG shell. However, it could transform into a "recognition" state under the tumor acidic microenvironment for efficient tumor cellular uptake due to the direct exposure of active targeting ligand HA following PEG shell detachment. Such a transformative concept provides a promising strategy to resolve the dilemma of natural ligand-based DDS with conflicting two processes of tumor cellular uptake and in vivo nonspecific biodistribution.Graphical abstractThe transformative CD44-targeted hyaluronic acid (HA) supramolecular nanoplatform would keep the "stealth" state in the blood stream due to the buried HA and the reduced interaction with biosystem by PEG shell. Then the nanoparticles could transform into the "recognition" state for improving cellular uptake via HA-mediated endocytosis after removing the "stealth" PEG layer and exposing the buried HA ligands at the tumor microenvironment pHe.fx1
       
  • Biosynthesis of clinically used antibiotic fusidic acid and identification
           of two short-chain dehydrogenase/reductases with converse
           stereoselectivity

    • Abstract: Publication date: March 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 2Author(s): Zhiqin Cao, Shaoyang Li, Jianming Lv, Hao Gao, Guodong Chen, Takayoshi Awakawa, Ikuro Abe, Xinsheng Yao, Dan HuFusidic acid is the only fusidane-type antibiotic that has been clinically used. However, biosynthesis of this important molecule in fungi is poorly understood. We have recently elucidated the biosynthesis of fusidane-type antibiotic helvolic acid, which provides us with clues to identify a possible gene cluster for fusidic acid (fus cluster). This gene cluster consists of eight genes, among which six are conserved in the helvolic acid gene cluster except fusC1 and fusB1. Introduction of the two genes into the Aspergillus oryzae NSAR1 expressing the conserved six genes led to the production of fusidic acid. A stepwise introduction of fusC1 and fusB1 revealed that the two genes worked independently without a strict reaction order. Notably, we identified two short-chain dehydrogenase/reductase genes fusC1 and fusC2 in the fus cluster, which showed converse stereoselectivity in 3-ketoreduction. This is the first report on the biosynthesis and heterologous expression of fusidic acid.Graphical abstractFusidane-type antibiotics, represented by fusidic acid, helvolic acid and cephalosporin P1, are a group of fungi-derived triterpenoid antibiotics. Here, we firstly identified the biosynthetic gene cluster of the clinically used fusidic acid and characterized its full biosynthetic pathway using a combinational biosynthetic approach. Notably, we identified two short-chain dehydrogenase/reductase FusC1 and FusC2 with converse stereoselectivity in 3-ketoreduction.fx1
       
  • Aspirin alleviates endothelial gap junction dysfunction through inhibition
           of NLRP3 inflammasome activation in LPS-induced vascular injury

    • Abstract: Publication date: Available online 28 February 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Xing Zhou, Yanjiao Wu, Lifeng Ye, Yunting Wang, Kaimin Zhang, Lingjun Wang, Yi Huang, Lei Wang, Shaoxiang Xian, Yang Zhang, Yang ChenThe loss of endothelial connective integrity and endothelial barrier dysfunction can lead to increased vascular injury, which is related to the activation of endothelial inflammasomes. There are evidences that low concentrations of aspirin can effectively prevent cardiovascular diseases. We hypothesized that low-dose aspirin could ameliorate endothelial injury by inhibiting the activation of NLRP3 inflammasomes and ultimately prevent cardiovascular diseases. Microvascular endothelial cells were stimulated by lipopolysaccharide (2 μg/mL) and administrated by 0.1–2 mmol/L aspirin. The wild type mice were stimulated with LPS (100 μg/kg/day), and 1 h later treated with aspirin (12.5, 62.5, or 125 mg/kg/day) and dexamethasone (0.0182 mg/kg/day) for 7 days. Plasma and heart were harvested for measurement of ELISA and immunofluorescence analyses. We found that aspirin could inhibit NLRP3 inflammasome formation and activation in vitro in dose-dependent manner and has correlation between the NLRP3 inflammasome and the ROS/TXNIP pathway. We also found that low-concentration aspirin could inhibit the formation and activation of NLRP3 inflammasome and restore the expression of the endothelial tight junction protein zonula occludens-1/2 (ZO1/2). We assume that aspirin can ameliorate the endothelial layer dysfunction by suppressing the activation of NLRP3 inflammasome.Graphical abstractAspirin inhibits the ROS–TXNIP signaling pathway to suppress NLRP3 inflammasome, thereby inhibits the activation of HMGB1–RAGE axis and eventually restores the tight junction proteins and permeability.fx1
       
  • Kinsenoside attenuates osteoarthritis by repolarizing macrophages through
           inactivating NF-κB/MAPK signaling and protecting chondrocytes

    • Abstract: Publication date: Available online 26 February 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Feng Zhou, Jingtian Mei, Xiuguo Han, Hanjun Li, Shengbing Yang, Minqi Wang, Linyang Chu, Han Qiao, Tingting TangThe objective was to investigate the effect of kinsenoside (Kin) treatments on macrophage polarity and evaluate the resulting protection of chondrocytes to attenuate osteoarthritis (OA) progression. RAW264.7 macrophages were polarized to M1/M2 subtypes then administered with different concentrations of Kin. The polarization transitions were evaluated with quantitative real-time polymerase chain reaction (qRT-PCR), confocal observation and flow cytometry analysis. The mechanism of Kin repolarizing M1 macrophages was evaluated by western blot. Further, macrophage conditioned medium (CM) and IL-1β were administered to chondrocytes. In vivo, micro-CT scanning and histological observations were conducted on anterior cruciate ligament transection (ACLT) mice with or without Kin treatment. We found that Kin repolarized M1 macrophages to the M2 phenotype. Mechanistically, Kin inhibited the phosphorylation of IκBα, which further reduced the downstream phosphorylation of p65 in nuclear factor-κB (NF-κB) signaling. Moreover, Kin inhibited mitogen-activated protein kinases (MAPK) signaling molecules p-JNK, p-Erk and p-p38. Additionally, Kin attenuated macrophage CM and IL-1β-induced chondrocyte damage. In vivo, Kin reduced the infiltration of M1 macrophages, promoted M2 macrophages in the synovium, inhibited subchondral bone destruction and reduced articular cartilage damage induced by ACLT. All the results indicated that Kin is an effective therapeutic candidate for OA treatment.Graphical abstractLPS and IFN-γ induce the polarization of M0 macrophages to the M1 phenotype, which can be suppressed by Kin. Conversely, IL-4, IL-10, and IL-13 promote the polarization of anti-inflammatory M2-type macrophages. Moreover, Kin could promote p-STATA6, which is an important transcription factor for M2 macrophages polarization. Kin repolarizes M1 macrophages to the M2 phenotype by inhibiting the phosphorylation of IκBα and further reducing downstream phosphorylation of p65. Moreover, Kin inhibits p-JNK, p-Erk and p-p38 in MAPK signaling pathway. M1 type macrophages highly release pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α, whereas Kin could decrease macrophage conditioned medium and IL-1β-stimulated chondrocyte damage.Graphical abstract for this article
       
  • Improvement in affinity and thermostability of a fully human antibody
           against interleukin-17A by yeast-display technology and CDR grafting

    • Abstract: Publication date: Available online 22 February 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Wei Sun, Zhaona Yang, Heng Lin, Ming Liu, Chenxi Zhao, Xueying Hou, Zhuowei Hu, Bing CuiMonoclonal antibodies (mAbs) are widely used in many fields due to their high specificity and ability to recognize a broad range of antigens. IL-17A can induce a rapid inflammatory response both alone and synergistically with other proinflammatory cytokines. Accumulating evidence suggests that therapeutic intervention of IL-17A signaling offers an attractive treatment option for autoimmune diseases and cancer. Here, we present a combinatorial approach for optimizing the affinity and thermostability of a novel anti-hIL-17A antibody. From a large naïve phage-displayed library, we isolated the anti-IL-17A mAb 7H9 that can neutralize the effects of recombinant human IL-17A. However, the modest neutralization potency and poor thermostability limit its therapeutic applications. In vitro affinity optimization was then used to generate 8D3 by using yeast-displayed random mutagenesis libraries. This resulted in four key amino acid changes and provided an approximately 15-fold potency increase in a cell-based neutralization assay. Complementarity-determining regions (CDRs) of 8D3 were further grafted onto the stable framework of the huFv 4D5 to improve thermostability. The resulting hybrid antibody 9NT/S has superior stabilization and affinities beyond its original antibody. Human fibrosarcoma cell-based assays and in vivo analyses in mice indicated that the anti-IL-17A antibody 9NT/S efficiently inhibited the secretion of IL-17A-induced proinflammatory cytokines. Therfore, this lead anti-IL-17A mAb might be used as a potential best-in-class candidate for treating IL-17A related diseases.Graphical abstractAnti-IL-17A antibodies were initially developed from a naïve fully human antibody library. The candidate was further affinity-matured by constructing a library of yeast-displayed single-chain Fv (scFv) mutants and thermostability-improved by CDR grafting. The lead anti-IL-17A mAb 9NT/S might be used as a potential best-in-class candidate for treating IL-17A related diseases.Graphical abstract for this article
       
  • Silibinin ameliorates hepatic lipid accumulation and oxidative stress in
           mice with non-alcoholic steatohepatitis by regulating CFLAR-JNK pathway

    • Abstract: Publication date: Available online 22 February 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Yayun Liu, Wei Xu, Ting Zhai, Jiaojiao You, Yong ChenNon-alcoholic steatohepatitis (NASH) is a chronic metabolic syndrome and the CFLAR-JNK pathway can reverse the process of NASH. Although silibinin is used for the treatment of NASH in clinical, its effect on CFLAR-JNK pathway in NASH remains unclear. This study aimed to investigate the effect of silibinin on CFLAR-JNK pathway in NASH models both in vivo and in vitro. The in vivo study was performed using male C57BL/6 mice fed with methionine– choline-deficient diet and simultaneously treated with silibinin for 6 weeks. The in vitro study was performed by using mouse NCTC-1469 cells which were respectively pretreated with oleic acid plus palmitic acid, and adenovirus-down Cflar for 24 h, then treated with silibinin for 24 h. After the drug treatment, the key indicators involved in CFLAR-JNK pathway including hepatic injury, lipid metabolism and oxidative stress were determined. Silibinin significantly activated CFLAR and inhibited the phosphorylation of JNK, up-regulated the mRNA expression of Pparα, Fabp5, Cpt1α, Acox, Scd-1, Gpat and Mttp, reduced the activities of serum ALT and AST and the contents of hepatic TG, TC and MDA, increased the expression of NRF2 and the activities of CAT, GSH-Px and HO-1, and decreased the activities and expression of CYP2E1 and CYP4A in vivo. These effects were confirmed by the in vitro experiments. Silibinin prevented NASH by regulating CFLAR-JNK pathway, and thereby on one hand promoting the β-oxidation and efflux of fatty acids in liver to relieve lipid accumulation, and on the other hand inducing antioxidase activity (CAT, GSH-Px and HO-1) and inhibiting pro-oxidase activity (CYP2E1 and CYP4A) to relieve oxidative stress.Graphical abstractSilibinin could regulate CFLAR-JNK pathway to ameliorates hepatic lipid accumulation, insulin resistence and oxidative stress in C57BL/6 mice treated by methionine- and choline-deficient diet, and NCTC-1469 cells treated by the mixture of oleic acid and palmitic acid and and adenovirus-down Cflar.Graphical abstract for this article
       
  • Cilastatin protects against imipenem-induced nephrotoxicity via inhibition
           of renal organic anion transporters (OATs)

    • Abstract: Publication date: Available online 18 February 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Xiaokui Huo, Qiang Meng, Changyuan Wang, Yanna Zhu, Zhihao Liu, Xiaodong Ma, Xiaochi Ma, Jinyong Peng, Huijun Sun, Kexin LiuImipenem is a carbapenem antibiotic. However, Imipenem could not be marketed owing to its instability and nephrotoxicity until cilastatin, an inhibitor of renal dehydropeptidase-I (DHP-I), was developed. In present study, the potential roles of renal organic anion transporters (OATs) in alleviating the nephrotoxicity of imipenem by cilastatin were investigated in vitro and in rabbits. Our results indicated that imipenem and cilastatin were substrates of hOAT1 and hOAT3. Cilastatin inhibited hOAT1/3-mediated transport of imipenem with IC50 values comparable to the clinical concentration, suggesting the potential to cause a clinical drug–drug interaction (DDI). Moreover, imipenem exhibited hOAT1/3-dependent cytotoxicity, which was alleviated by cilastatin and probenecid. Furthermore, cilastatin and probenecid ameliorated imipenem-induced rabbit acute kidney injury, and reduced the renal secretion of imipenem. Cilastatin and probenecid inhibited intracellular accumulation of imipenem and sequentially decreased the nephrocyte toxicity in rabbit primary proximal tubule cells. Renal OATs, besides DHP-I, was also the target of interaction between imipenem and cilastatin, and contributed to the nephrotoxicity of imipenem. This therefore gives in part the explanation about the mechanism by which cilastatin protected against imipenem-induced nephrotoxicity. Thus, OATs can potentially be used as a therapeutic target to avoid the renal adverse reaction of imipenem in clinic.Graphical abstractRenal OATs, for the first time, were identified to facilitate the transport and nephrotoxicity of imipenem, which could be abolished by cilastatin partly through OATs inhibition.fx1
       
  • Ablation of gut microbiota alleviates obesity-induced hepatic steatosis
           and glucose intolerance by modulating bile acid metabolism in hamsters

    • Abstract: Publication date: Available online 16 February 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Lulu Sun, Yuanyuan Pang, Xuemei Wang, Qing Wu, Huiying Liu, Bo Liu, George Liu, Min Ye, Wei Kong, Changtao JiangSince metabolic process differs between humans and mice, studies were performed in hamsters, which are generally considered to be a more appropriate animal model for studies of obesity-related metabolic disorders. The modulation of gut microbiota, bile acids and the farnesoid X receptor (FXR) axis is correlated with obesity-induced insulin resistance and hepatic steatosis in mice. However, the interactions among the gut microbiota, bile acids and FXR in metabolic disorders remained largely unexplored in hamsters. In the current study, hamsters fed a 60% high-fat diet (HFD) were administered vehicle or an antibiotic cocktail by gavage twice a week for four weeks. Antibiotic treatment alleviated HFD-induced glucose intolerance, hepatic steatosis and inflammation accompanied with decreased hepatic lipogenesis and elevated thermogenesis in subcutaneous white adipose tissue (sWAT). In the livers of antibiotic-treated hamsters, cytochrome P450 family 7 subfamily B member 1 (CYP7B1) in the alternative bile acid synthesis pathway was upregulated, contributing to a more hydrophilic bile acid profile with increased tauro-β-muricholic acid (TβMCA). The intestinal FXR signaling was suppressed but remained unchanged in the liver. This study is of potential translational significance in determining the role of gut microbiota-mediated bile acid metabolism in modulating diet-induced glucose intolerance and hepatic steatosis in the hamster.Graphical abstractIn the antibiotic-treated hamsters, hepatic CYP7B1-mediated alternative bile acid synthesis was activated. In hamsters, intestinal TβMCA accumulated and secondary bile acid levels were downregulated after gut microbiota depletion. Gut microbiota depletion-derived bile acid modulation results in intestinal FXR suppression and improvements of metabolic disorders in HFD-fed hamsters.fx1
       
  • Cardamonin from a medicinal herb protects against LPS-induced septic shock
           by suppressing NLRP3 inflammasome

    • Abstract: Publication date: Available online 14 February 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Zhilei Wang, Guang Xu, Yuan Gao, Xiaoyan Zhan, Nan Qin, Shubin Fu, Ruisheng Li, Ming Niu, Jiabo Wang, Youping Liu, Xiaohe Xiao, Zhaofang BaiAberrant activation of NLRP3 inflammasome has been implicated in the pathogenesis of diverse inflammation-related diseases, and pharmacological molecules targeting NLRP3 inflammasome are of considerable value to identifying potential therapeutic interventions. Cardamonin (CDN), the major active ingredient of the traditional Chinese medicinal herb Alpinia katsumadai, has exerted an excellent anti-inflammatory activity, but the mechanism underlying this role is not fully understood. Here, we show that CDN blocks canonical and noncanonical NLRP3 inflammasome activation triggered by multiple stimuli. Moreover, the suppression of CDN on inflammasome activation is specific to NLRP3, not to NLRC4 or AIM2 inflammasome. Besides, the inhibitory effect is not dependent on the expression of NF-κB-mediated inflammasome precursor proteins. We also demonstrate that CDN suppresses the NLRP3 inflammasome through blocking ASC oligomerization and speckle formation in a dose-dependent manner. Importantly, CDN improves the survival of mice suffering from lethal septic shock and attenuates IL-1β production induced by LPS in vivo, which is shown to be NLRP3 dependent. In conclusion, our results identify CDN as a broad-spectrum and specific inhibitor of NLRP3 inflammasome and a candidate therapeutic drug for treating NLRP3 inflammasome-driven diseases.Graphical abstractCardamonin is a broad-spectrum inhibitor of NLRP3 inflammasome triggered by multiple stimuli. Moreover, the suppression of cardamonin on inflammasome activation is specific to NLRP3, not to NLRC4 or AIM2 inflammasome. Importantly, cardamonin improves the survival of mice suffering from LPS-induced lethal endotoxic shock, which is shown to be NLRP3 dependent.fx1
       
  • Updated developments on molecular imaging and therapeutic strategies
           directed against necrosis

    • Abstract: Publication date: Available online 13 February 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Dongjian Zhang, Meng Gao, Qiaomei Jin, Yicheng Ni, Jian ZhangCell death plays important roles in living organisms and is a hallmark of numerous disorders such as cardiovascular diseases, sepsis and acute pancreatitis. Moreover, cell death also plays a pivotal role in the treatment of certain diseases, for example, cancer. Noninvasive visualization of cell death contributes to gained insight into diseases, development of individualized treatment plans, evaluation of treatment responses, and prediction of patient prognosis. On the other hand, cell death can also be targeted for the treatment of diseases. Although there are many ways for a cell to die, only apoptosis and necrosis have been extensively studied in terms of cell death related theranostics. This review mainly focuses on molecular imaging and therapeutic strategies directed against necrosis. Necrosis shares common morphological characteristics including the rupture of cell membrane integrity and release of cellular contents, which provide potential biomarkers for visualization of necrosis and necrosis targeted therapy. In the present review, we summarize the updated joint efforts to develop molecular imaging probes and therapeutic strategies targeting the biomarkers exposed by necrotic cells. Moreover, we also discuss the challenges in developing necrosis imaging probes and propose several biomarkers of necrosis that deserve to be explored in future imaging and therapy research.Graphical abstractThis review describes the updated joint efforts to develop necrosis imaging probes and therapeutic strategies through targeting the biomarkers exposed by necrotic cells as well as discusses current challenges and possible future research directions.fx1
       
  • MCC1019, a selective inhibitor of the Polo-box domain of Polo-like kinase
           1 as novel, potent anticancer candidate

    • Abstract: Publication date: Available online 10 February 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Sara Abdelfatah, Angela Berg, Qi Huang, Li Jun Yang, Sami Hamdoun, Anette Klinger, Henry J. Greten, Edmond Fleischer, Thorsten Berg, Vincent K.W. Wong, Thomas EfferthPolo-like kinase (PLK1) has been identified as a potential target for cancer treatment. Although a number of small molecules have been investigated as PLK1 inhibitors, many of which showed limited selectivity. PLK1 harbors a regulatory domain, the Polo box domain (PBD), which has a key regulatory function for kinase activity and substrate recognition. We report on 3-bromomethyl-benzofuran-2-carboxylic acid ethyl ester (designated: MCC1019) as selective PLK1 inhibitor targeting PLK1 PBD. Cytotoxicity and fluorescence polarization-based screening were applied to a library of 1162 drug-like compounds to identify potential inhibitors of PLK1 PBD. The activity of compound MC1019 against the PLK1 PBD was confirmed using fluorescence polarization and microscale thermophoresis. This compound exerted specificity towards PLK1 over PLK2 and PLK3. MCC1019 showed cytotoxic activity in a panel of different cancer cell lines. Mechanistic investigations in A549 lung adenocarcinoma cells revealed that MCC1019 induced cell growth inhibition through inactivation of AKT signaling pathway, it also induced prolonged mitotic arrest—a phenomenon known as mitotic catastrophe, which is followed by immediate cell death via apoptosis and necroptosis. MCC1019 significantly inhibited tumor growth in vivo in a murine lung cancer model without affecting body weight or vital organ size, and reduced the growth of metastatic lesions in the lung. We propose MCC1019 as promising anti-cancer drug candidate.Graphical abstractMCC1019 is a novel anticancer candidate that selectively targets PLK1. It mediates G2/M cell cycle arrest and cell death through induction of apoptosis and necroptosis. Inhibition of PLK1 downstream effectors like spindle assembly check points and cell growth pathway was well characterized. In vivo models revealed inhibition of tumor growth and metastasis.fx1
       
  • Multifunctional polymeric micelle-based chemo-immunotherapy with immune
           checkpoint blockade for efficient treatment of orthotopic and metastatic
           breast cancer

    • Abstract: Publication date: Available online 31 January 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Jiaojie Wei, Yang Long, Rong Guo, Xinlei Liu, Xian Tang, Jingdong Rao, Sheng Yin, Zhirong Zhang, Man Li, Qin HeImmunotherapy has become a highly promising paradigm for cancer treatment. Herein, a chemo-immunotherapy was developed by encapsulating chemotherapeutic drug doxorubicin (DOX) and Toll-like receptor 7 agonist imiquimod (IMQ) in low molecular weight heparin (LMWH)-d-α-tocopheryl succinate (TOS) micelles (LT). In this process, LMWH and TOS were conjugated by ester bond and they were not only served as the hydrophilic and hydrophobic segments of the carrier, but also exhibited strong anti-metastasis effect. The direct killing of tumor cells mediated by DOX-loaded micelles (LT-DOX) generated tumor-associated antigens, initiating tumor-specific immune responses in combination with IMQ-loaded micelles (LT-IMQ). Furthermore, the blockade of immune checkpoint with programmed cell death ligand 1 (PD-L1) antibody further elevated the immune responses by up-regulating the maturation of DCs as well as the ratios of CD8+ CTLs/Treg and CD4+ Teff/Treg. Therefore, such a multifunctional strategy exhibited great potential for inhibiting the growth of orthotopic and metastatic breast cancer.Graphical abstractChemotherapeutic doxorubicin (DOX) and immune adjuvant imiquimod (IMQ) were respectively encapsulated in LT micelles (LT-DOX/LT-IMQ) to initiate tumor apoptosis and anti-tumor immune response. However, the PD-L1/PD-1 axis impairs the T cell responses. Therefore, anti-PD-L1 was combined with LT-DOX/LT-IMQ to relieve the suppression and further promote the anti-tumor responses.fx1
       
  • In vitro and in vivo activity of d-serine in combination with β-lactam
           antibiotics against methicillin-resistant Staphylococcus aureus

    • Abstract: Publication date: Available online 31 January 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Qing Wang, Yuemeng Lv, Jing Pang, Xue Li, Xi Lu, Xiukun Wang, Xinxin Hu, Tongying Nie, Xinyi Yang, Yan Q. Xiong, Jiandong Jiang, Congran Li, Xuefu YouAs d-amino acids play important roles in the physiological metabolism of bacteria, combination of d-amino acids with antibiotics may provide synergistic antibacterial activity. The aim of the study was to evaluate in vitro and in vivo activity of d-serine alone and in combination with β-lactams against methicillin-resistant Staphylococcus aureus (MRSA) strains, and to explore the possible sensitization mechanisms. The activity of d-serine, β-lactams alone and in combinations was evaluated both in vitro by standard MICs, time–kill curves and checkerboard assays, and in vivo by murine systemic infection model as well as neutropenic thigh infection model. An in vitro synergistic effect was demonstrated with the combination of d-serine and β-lactams against MRSA standard and clinical strains. Importantly, the combinations enhanced the therapeutic efficacy in the animal models as compared to β-lactam alone groups. Initial mechanism study suggested possible revision of d-alanine-d-alanine residue to d-alanine-d-serine in peptidoglycan by adding of d-alanine in the medium, which may cause decreased affinity to PBPs during transpeptidation. In conclusion, d-serine had synergistic activity in combination with β-lactams against MRSA strains both in vitro and in vivo. Considering the relatively good safety of d-serine alone or in combination with β-lactams, d-serine is worth following up as new anti-MRSA infection strategies.Graphical abstractIn this study, the authors found that d-serine had synergistic activity with β-lactams (represented by oxacillin and meropenem) against MRSA strains both in vitro and in vivo, demonstrated by results in MIC determination/checkerboard assay, time–kill curve analysis, murine systemic infection model and neutropenic thigh infection model.fx1
       
  • Aurone derivatives as Vps34 inhibitors that modulate autophagy

    • Abstract: Publication date: Available online 30 January 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Guodong Li, Joshua William Boyle, Chung-Nga Ko, Wu Zeng, Vincent Kam Wai Wong, Jian-Bo Wan, Philip Wai Hong Chan, Dik-Lung Ma, Chung-Hang LeungWe report in this study the identification of a natural product-like antagonist (1a) of Vps34 as a potent autophagy modulator via structure-based virtual screening. Aurone derivative 1a strongly inhibited Vps34 activity in cell-free and cell-based assays. Significantly, 1a prevents autophagy in human cells induced either by starvation or by an mTOR inhibitor. In silico modeling and kinetic data revealed that 1a could function as an ATP-competitive inhibitor of Vps34. Moreover, it suppressed autophagy in vivo and without inducing heart or liver damage in mice. 1a could be utilized as a new motif for more selective and efficacious antagonists of Vps34 for the potential treatment of autophagy-related human diseases.Graphical abstractWe identified aurone derivative 1a as an ATP-competitive inhibitor of Vps34 inhibitor. 1a prevented autophagy in human cells induced either by starvation or by an mTOR inhibitor. In vivo examination showed that 1a was able to promote p62 accumulation without affecting the morphology of mice heart and liver.fx1
       
  • Up-regulation of glycolipid transfer protein by bicyclol causes
           spontaneous restriction of hepatitis C virus replication

    • Abstract: Publication date: Available online 29 January 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Meng-Hao Huang, Hu Li, Rong Xue, Jianrui Li, Lihua Wang, Junjun Cheng, Zhouyi Wu, Wenjing Li, Jinhua Chen, Xiaoqin Lv, Qiang Li, Pei Lan, Limin Zhao, Yongfeng Yang, Zonggen Peng, Jiandong JiangBicyclol is a synthetic drug for hepatoprotection in clinic since 2004. Preliminary clinical observations suggest that bicyclol might be active against hepatitis C virus (HCV) with unknown mechanism. Here, we showed that bicyclol significantly inhibited HCV replication in vitro and in hepatitis C patients. Using bicyclol as a probe, we identified glycolipid transfer protein (GLTP) to be a novel restrictive factor for HCV replication. The GLTP preferentially bound host vesicle-associated membrane protein-associated protein-A (VAP-A) in competition with the HCV NS5A, causing an interruption of the complex formation between VAP-A and HCV NS5A. As the formation of VAP-A/NS5A complex is essential for viral RNA replication, up-regulation of GLTP by bicyclol reduced the level of VAP-A/NS5A complex and thus inhibited HCV replication. Bicyclol also exhibited an inhibition on HCV variants resistant to direct-acting antiviral agents (DAAs) with an efficacy identical to that on wild type HCV. In combination with bicyclol, DAAs inhibited HCV replication in a synergistic fashion. GLTP appears to be a newly discovered host restrictive factor for HCV replication, Up-regulation of GLTP causes spontaneous restriction of HCV replication.Graphical abstractTreatment of the HCV-infected Huh7.5 cells with bicyclol decreased the level of miR-449b and thus induced the expression of glycolipid transfer protein (GLTP). The up-regulated GLTP preferentially bound host cofactor vesicle-associated membrane protein-associated protein-A (VAP-A) in competition with the HCV NS5A, causing a decrease of the HCV replicative complex level of VAP-A/NS5A, and thus inhibited HCV replication.fx1
       
  • Regulation of microbiota-GLP1 axis by Sennoside A (SA) in diet-induced
           obese mice

    • Abstract: Publication date: Available online 29 January 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Jiamei Le, Xiaoying Zhang, Weiping Jia, Yong Zhang, Juntao Luo, Yongning Sun, Jianping YeSennoside A (SA) is a bioactive component of Chinese herbal medicines with an activity of irritant laxative, which is often used in the treatment of constipation and obesity. However, its activity remains unknown in the regulation of insulin sensitivity. In this study, SA impact on insulin sensitivity was tested in high fat diet (HFD)-induced obese mice through dietary supplementation. At a dosage of 30 mg/kg/day, SA improved insulin sensitivity in the mice after 8-week treatment as indicated by HOMA-IR (homeostatic model assessment for insulin resistance) and glucose tolerance test (GTT). SA restored plasma level of glucagon-like peptide 1 (GLP1) by 90% and mRNA expression of Glp1 by 80% in the large intestine of HFD mice. In the mechanism, SA restored the gut microbiota profile, short chain fatty acids (SCFAs), and mucosal structure in the colon. A mitochondrial stress was observed in the enterocytes of HFD mice with ATP elevation, structural damage, and complex dysfunction. The mitochondrial response was induced in enterocytes by the dietary fat as the same responses were induced by palmitic acid in the cell culture. The mitochondrial response was inhibited in HFD mice by SA treatment. These data suggest that SA may restore the function of microbiota–GLP1 axis to improve glucose metabolism in the obese mice.Graphical abstractSA activity was found in the improvement of insulin sensitivity in diet-induced obesity mice through restoration of blood level of glucagon-like peptide 1. SA induced Glp1 gene expression in L-cells of the colon tissue, which was associated with improvement of dysbiosis, short chain fatty acid abundance and mitochondrial function of L-cells.Graphical abstract for this article
       
  • GLUT1-mediated effective anti-miRNA21 pompon for cancer therapy

    • Abstract: Publication date: Available online 28 January 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Qin Guo, Chao Li, Wenxi Zhou, Xinli Chen, Yu Zhang, Yifei Lu, Yujie Zhang, Qinjun Chen, Donghui Liang, Tao Sun, Chen JiangOncogenic microRNAs are essential components in regulating the gene expression of cancer cells. Especially miR21, which is a major player involved of tumor initiation, progression, invasion and metastasis in several cancers. The delivery of anti-miR21 sequences has significant potential for cancer treatment. Nevertheless, since anti-miR21 sequences are extremely unstable and they need to obtain certain concentration to function, it is intensely difficult to build an effective delivery system for them. The purpose of this work is to construct a self-assembled glutathione(GSH)-responsive system with tumor accumulation capacity for effective anti-miR21 delivery and cancer therapy. A novel drug delivery nanosphere carrying millions of anti-miR21 sequences was developed through the rolling circle transcription (RCT) method. GSH-responsive cationic polymer polyethyleneimine (pOEI) was synthesized to protect the nanosphere from degradation by Dicer or other RNase in normal cells and optimize the pompon-like nanoparticle to suitable size. Dehydroascorbic acid (DHA), a targeting molecule, which is a substrate of glucose transporter 1 (GLUT 1) and highly expressed on malignant tumor cells, was connected to pOEI through PEG, and then the polymer was used for contracting a RNA nanospheres into nanopompons. The anti-miR21 nanopompons showed its potential for effective cancer therapy.Graphical abstractPreparation process, GLUT1-mediated transport and GSH-responsive drug release of DHA-targeting anti-miRNA21 nanopompons were reported. Nanopomponswere first obtained by rolling transformation transcription (RCT) and condensed by tumor-targteing pOEI-PEG-DHA.fx1
       
  • Red blood cell membrane-camouflaged nanoparticles: a novel drug delivery
           system for antitumor application

    • Abstract: Publication date: Available online 24 January 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Qing Xia, Yongtai Zhang, Zhe Li, Xuefeng Hou, Nianping FengErythrocytes (red blood cells, RBCs) are the most abundant circulating cells in the blood and have been widely used in drug delivery systems (DDS) because of their features of biocompatibility, biodegradability, and long circulating half-life. Accordingly, a “camouflage” comprised of erythrocyte membranes renders nanoparticles as a platform that combines the advantages of native erythrocyte membranes with those of nanomaterials. Following injection into the blood of animal models, the coated nanoparticles imitate RBCs and interact with the surroundings to achieve long-term circulation. In this review, the biomimetic platform of erythrocyte membrane-coated nano-cores is described with regard to various aspects, with particular focus placed on the coating mechanism, preparation methods, verification methods, and the latest anti-tumor applications. Finally, further functional modifications of the erythrocyte membranes and attempts to fuse the surface properties of multiple cell membranes are discussed, providing a foundation to stimulate extensive research into multifunctional nano-biomimetic systems.Graphical abstractIn this review, the biomimetic platform of erythrocyte membrane-coated nano-cores is described with regard to coating mechanism, preparation methods, verification methods, and the latest anti-tumor applications. Finally, further functional modifications of the erythrocyte membranes and attempts to fuse the surface properties of multiple cell membranes are discussed.fx1
       
  • Inhibition of FOXO3a/BIM signaling pathway contributes to the protective
           

    • Abstract: Publication date: Available online 24 January 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Junke Song, Wen Zhang, Jinhua Wang, Haiguang Yang, Qimeng Zhou, Haigang Wang, Li Li, Guanhua DuSalvianolic acid A (SalA) is an effective compound extracted from traditional Chinese medicine Salvia miltiorrhiza Bunge. The Forkhead box O3a (FOXO3a) signaling pathway plays crucial roles in the modulation of ischemia-induced cell apoptosis. However, no information about the regulatory effect of SalA on FoxO3a is available. To explore the anti-cerebral ischemia effect and clarify the therapeutic mechanism of SalA, SH-SY5Y cells and Sprague-Dawley rats were applied, which were exposed to oxygen glucose deprivation/reoxygenation (OGD/R) and middle cerebral artery occlusion/reperfusion (MCAO/R) injuries, respectively. The involved pathway was identified using the specific inhibitor LY294002. Results showed that SalA concentration-dependently inhibited OGD/R injury triggered cell viability loss. SalA reduced cerebral infarction, lowered brain edema, improved neurological function, and inhibited neuron apoptosis in MCAO/R rats, which were attenuated by the treatment of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) specific inhibitor LY294002. SalA time- and concentration-dependently upregulated the phosphorylation levels of protein kinase B (AKT) and its downstream protein FOXO3a. Moreover, the nuclear translocation of FOXO3a was inhibited by SalA both in vivo and in vitro, which was also reversed by LY294002. The above results indicated that SalA fought against ischemia/reperfusion damage at least partially via the AKT/FOXO3a/BIM pathway.Graphical abstractThe regulatory effect of salvianolic acid A (SalA) on FOXO3a/BIM signaling was studied in ischemia/reperfusion (I/R) injury. Results showed that inhibition of FOXO3a/BIM signaling through the phosphorylation of AKT contributed to the protective effect of SalA against I/R injury both in vivo and in vitro.fx1
       
  • Development of precision medicine approaches based on inter-individual
           variability of BCRP/ABCG2

    • Abstract: Publication date: Available online 15 January 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Liming Chen, Jose E. Manautou, Theodore P. Rasmussen, Xiao-bo ZhongPrecision medicine is a rapidly-developing modality of medicine in human healthcare. Based on each patient׳s unique characteristics, more accurate dosages and drug selection can be made to achieve better therapeutic efficacy and less adverse reactions in precision medicine. A patient׳s individual parameters that affect drug transporter action can be used to develop a precision medicine guidance, due to the fact that therapeutic efficacy and adverse reactions of drugs can both be affected by expression and function of drug transporters on the cell membrane surface. The purpose of this review is to summarize unique characteristics of human breast cancer resistant protein (BCRP) and the genetic variability in the BCRP encoded gene ABCG2 in the development of precision medicine. Inter-individual variability of BCRP/ABCG2 can impact choices and outcomes of drug treatment for several diseases, including cancer chemotherapy. Several factors have been implicated in expression and function of BCRP, including genetic, epigenetic, physiologic, pathologic, and environmental factors. Understanding the roles of these factors in controlling expression and function of BCRP is critical for the development of precision medicine based on BCRP-mediated drug transport.Graphical abstractThis review summarizes multiple factors, including genetic, epigenetic, physiologic, pathologic, and environmental factors, which have been reported to affect ABCG2 expression or BCRP function. Understanding how these factors affect BCRP function is critical for the development of precision medicine approaches to achieve optimized therapeutic effects and minimize adverse effects when prescribing specific drugs to patients.fx1
       
  • Menthol-modified casein nanoparticles loading 10-hydroxycamptothecin for
           glioma targeting therapy

    • Abstract: Publication date: Available online 11 January 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Caifang Gao, Jianming Liang, Ying Zhu, Chengli Ling, Zhekang Cheng, Ruixiang Li, Jing Qin, Weigen Lu, Jianxin WangChemotherapy outcomes for the treatment of glioma remains unsatisfactory due to the inefficient drug transport across the bloodbrain barrier (BBB) and insufficient drug accumulation in the tumor region. Although many approaches, including various nanosystems, have been developed to promote the distribution of chemotherapeutics in the brain tumor, the delivery efficiency and the possible damage to the normal brain function still greatly restrict the clinical application of the nanocarriers. Therefore, it is urgent and necessary to discover more safe and effective BBB penetration and glioma-targeting strategies. In the present study, menthol, one of the strongest BBB penetration enhancers screened from traditional Chinese medicine, was conjugated to casein, a natural food protein with brain targeting capability. Then the conjugate self-assembled into the nanoparticles to load anti-cancer drugs. The nanoparticles were characterized to have appropriate size, spheroid shape and high loading drug capacity. Tumor spheroid penetration experiments demonstrated that penetration ability of menthol-modified casein nanoparticles (M-CA-NP) into the tumor were much deeper than that of unmodified nanoparticles. In vivo imaging further verified that M-CA-NPs exhibited higher brain tumor distribution than unmodified nanoparticles. The median survival time of glioma-bearing mice treated with HCPT-M-CA-NPs was significantly prolonged than those treated with free HCPT or HCPT-CA-NPs. HE staining of the organs indicated the safety of the nanoparticles. Therefore, the study combined the advantages of traditional Chinese medicine strategy with modern delivery technology for brain targeting, and provide a safe and effective approach for glioma therapy.Graphical abstractChemotherapy for the treatment of glioma remains to be unsatisfactory due to inefficient drug transport across the bloodbrain barrier and insufficient accumulation in the tumor region. The prepared menthol-modified casein nanoparticles combined the advantages of traditional Chinese medicine strategy with modern drug delivery technology for brain tumor.fx1
       
  • Safety and photochemotherapeutic application of poly(γ-glutamic
           acid)-based biopolymeric nanoparticle

    • Abstract: Publication date: Available online 11 January 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Dongyoon Kim, Quoc-Viet Le, Young Bong Kim, Yu-Kyoung OhThe safety of nanomaterials, a crucial consideration for clinical translation, is enhanced by using building blocks that are biologically nontoxic. Here, we used poly(γ-glutamic acid) (γ-PGA) and dopamine as building blocks of polymeric nanomaterials for carrying hydrophobic anticancer drugs. The introduction of phenylalanine onto γ-PGA enabled the resulting amphiphilic derivative of γ-PGA acid to self-assemble in the presence of the anticancer drug paclitaxel (PTX) to form PTX-encapsulated micelles. The surfaces of PTX-loaded micelles were then coated with polymerized dopamine (PDA). The PDA-coated, amphiphilic γ-PGA-based micelles (AM) carrying PTX (PDA/AM/P) exerted near-infrared-responsive photothermal effects. Near-infrared irradiation of cancer cells treated with PDA/AM/P nanoparticles produced a greater anticancer effect than that observed in other treatment groups, indicating a synergistic effect. Intravenous administration of PDA/AM/P completely ablated tumors and prevented their recurrence. Notably, the in vivo safety profile of PDA/AM/P nanoparticles allowed PTX to be delivered at a 3.6-fold higher dose than was possible with PTX solubilized in surfactant, and circumvented the side effects of the surfactant. These results support the multifunctional potential of PDA/AM for the delivery of various hydrophobic drugs and imaging dyes for safe translation of nanomaterials into the clinic.Graphical abstractThe safety of nanomaterials was enhanced using poly(γ-glutamic acid) and dopamine as building blocks. Amphiphilic phenylalanine derivative of poly(γ-glutamic acid) formed a core nanomaterials with hydrophobic paclitaxel inside. The polydopamine-coated and paclitaxel-loaded amphiphilic poly(γ-glutamic acid)-based nanoparticles exerted near-infrared-responsiveness and provided synergistic photothermal chemotherapeutic effect.fx1
       
  • Multifunctional oral delivery systems for enhanced bioavailability of
           therapeutic peptides/proteins

    • Abstract: Publication date: Available online 10 January 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Ying Han, Zhonggao Gao, Liqing Chen, Lin Kang, Wei Huang, Mingji Jin, Qiming Wang, You Han BaeIn last few years, therapeutic peptides/proteins are rapidly growing in drug market considering their higher efficiency and lower toxicity than chemical drugs. However, the administration of therapeutic peptides/proteins is mainly limited in parenteral approach. Oral therapy which was hampered by harsh gastrointestinal environment and poorly penetrating epithelial barriers often results in low bioavailability (less than 1%–2%). Therefore, delivery systems that are rationally designed to overcome these challenges in gastrointestinal tract and ameliorate the oral bioavailability of therapeutic peptides/proteins are seriously promising. In this review, we summarized various multifunctional delivery systems, including lipid-based particles, polysaccharide-based particles, inorganic particles, and synthetic multifunctional particles that achieved effective oral delivery of therapeutic peptides/proteins.Graphical abstractThis review summarized various multifunctional delivery systems, including lipid-based particles, polysaccharide-based particles, inorganic particles, and synthetic multifunctional particles that achieved effective oral delivery of therapeutic peptides/proteins.fx1
       
  • Upregulation of miR-489-3p and miR-630 inhibits oxaliplatin uptake in
           renal cell carcinoma by targeting OCT2

    • Abstract: Publication date: Available online 8 January 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Lu Chen, Le Chen, Zhiyuan Qin, Jinxiu Lei, Sheng Ye, Kui Zeng, Hua Wang, Meidan Ying, Jianqing Gao, Su Zeng, Lushan YuRenal cell carcinoma (RCC) is one of the most common malignant tumors affecting the urogenital system, accounting for 90% of renal malignancies. Traditional chemotherapy options are often the front-line choice of regimen in the treatment of patients with RCC, but responses may be modest or limited due to resistance of the tumor to anticarcinogen. Downregulated expression of organic cation transporter OCT2 is a possible mechanism underlying oxaliplatin resistance in RCC treatment. In this study, we observed that miR-489-3p and miR-630 suppress OCT2 expression by directly binding to the OCT2 3′-UTR. Meanwhile, via 786-O-OCT2-miRNAs stable expression cell models, we found that miRNAs could repress the classic substrate 1-methyl-4-phenylpyridinium (MPP+), fluorogenic substrate N,N-dimethyl-4-(2-pyridin-4-ylethenyl) aniline (ASP+), and oxaliplatin uptake by OCT2 both in vitro and in xenografts. In 33 clinical samples, miR-489-3p and miR-630 were significantly upregulated in RCC, negatively correlating with the OCT2 expression level compared to that in adjacent normal tissues, using tissue microarray analysis and qPCR validation. The increased binding of c-Myc to the promoter of pri-miR-630, responsible for the upregulation of miR-630 in RCC, was further evidenced by chromatin immunoprecipitation and dual-luciferase reporter assay. Overall, this study indicated that miR-489-3p and miR-630 function as oncotherapy-obstructing microRNAs by directly targeting OCT2 in RCC.Graphical abstractMiR-489-3p, c-Myc and miR-630 mediate OCT2 downregulation in RCC cells. MiR-489-3p and miR-630 is abnormally upregulated in RCC samples and exosomes, suppressing OCT2 expression by directly binding to the OCT2 3′-UTR. The increased binding of c-Myc to the promoter of pri-miR-630, contributes to the upregulation of miR-630 in RCC.fx1
       
  • Development of the triazole-fused pyrimidine derivatives as highly potent
           and reversible inhibitors of histone lysine specific demethylase 1
           (LSD1/KDM1A)

    • Abstract: Publication date: Available online 5 January 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Zhonghua Li, Lina Ding, Zhongrui Li, Zhizheng Wang, Fengzhi Suo, Dandan Shen, Taoqian Zhao, Xudong Sun, Junwei Wang, Ying Liu, Liying Ma, Bing Zhao, Pengfei Geng, Bin Yu, Yichao Zheng, Hongmin LiuHistone lysine specific demethylase 1 (LSD1) has been recognized as an important modulator in post-translational process in epigenetics. Dysregulation of LSD1 has been implicated in the development of various cancers. Herein, we report the discovery of the hit compound 8a (IC50 = 3.93 μmol/L) and further medicinal chemistry efforts, leading to the generation of compound 15u (IC50 = 49 nmol/L, and Ki = 16 nmol/L), which inhibited LSD1 reversibly and competitively with H3K4me2, and was selective to LSD1 over MAO-A/B. Docking studies were performed to rationalize the potency of compound 15u. Compound 15u also showed strong antiproliferative activity against four leukemia cell lines (OCL-AML3, K562, THP-1 and U937) as well as the lymphoma cell line Raji with the IC50 values of 1.79, 1.30, 0.45, 1.22 and 1.40 μmol/L, respectively. In THP-1 cell line, 15u significantly inhibited colony formation and caused remarkable morphological changes. Compound 15u induced expression of CD86 and CD11b in THP-1 cells, confirming its cellular activity and ability of inducing differentiation. The findings further indicate that targeting LSD1 is a promising strategy for AML treatment, the triazole-fused pyrimidine derivatives are new scaffolds for the development of LSD1/KDM1A inhibitors.Graphical abstractA series of triazole-pyrimidine derivatives were designed and synthesized as LSD1 inhibitors based on the hit compound 8a from our in-house compound library. Among them, compound 15u was identified as the most potent, selective and reversible LSD1 inhibitor, and also demonstrated excellent cellular inhibitory activities against AML cell lines.fx1
       
  • Orthogonal assays for the identification of inhibitors of the
           single-stranded nucleic acid binding protein YB-1

    • Abstract: Publication date: Available online 3 January 2019Source: Acta Pharmaceutica Sinica BAuthor(s): AlexanderJ. Trevarton, Yan Zhou, Dehua Yang, Gordon W. Rewcastle, Jack U. Flanagan, Antony Braithwaite, Peter R. Shepherd, Cristin G. Print, Ming-Wei Wang, Annette LashamWe have previously shown that high expression of the nucleic acid binding factor YB-1 is strongly associated with poor prognosis in a variety of cancer types. The 3-dimensional protein structure of YB-1 has yet to be determined and its role in transcriptional regulation remains elusive. Drug targeting of transcription factors is often thought to be difficult and there are very few published high-throughput screening approaches. YB-1 predominantly binds to single-stranded nucleic acids, adding further difficulty to drug discovery. Therefore, we have developed two novel screening assays to detect compounds that interfere with the transcriptional activation properties of YB-1, both of which may be generalizable to screen for inhibitors of other nucleic acid binding molecules. The first approach is a cell-based luciferase reporter gene assay that measures the level of activation of a fragment of the E2F1 promoter by YB-1. The second approach is a novel application of the AlphaScreen system, to detect interference of YB-1 interaction with a single-stranded DNA binding site. These complementary assays examine YB-1 binding to two discrete nucleic acid sequences using two different luminescent signal outputs and were employed sequentially to screen 7360 small molecule compounds leading to the identification of three putative YB-1 inhibitors.Graphical abstractNovel AlphaScreen and luciferase reporter gene assays for the discovery of novel small-molecule inhibitors of the transcription factor YB-1 were developed and applied in a collection of 7360 compounds. Finally, three putative YB-1 inhibitors were yielded.fx1
       
  • Drug nanoclusters formed in confined nano-cages of CD-MOF: dramatic
           enhancement of solubility and bioavailability of azilsartan

    • Abstract: Publication date: January 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 1Author(s): Yuanzhi He, Wei Zhang, Tao Guo, Guoqing Zhang, Wei Qin, Liu Zhang, Caifen Wang, Weifeng Zhu, Ming Yang, Xiaoxiao Hu, Vikramjeet Singh, Li Wu, Ruxandra Gref, Jiwen ZhangTremendous efforts have been devoted to the enhancement of drug solubility using nanotechnologies, but few of them are capable to produce drug particles with sizes less than a few nanometers. This challenge has been addressed here by using biocompatible versatile γ-cyclodextrin (γ-CD) metal-organic framework (CD-MOF) large molecular cages in which azilsartan (AZL) was successfully confined producing clusters in the nanometer range. This strategy allowed to improve the bioavailability of AZL in Sprague–Dawley rats by 9.7-fold after loading into CD-MOF. The apparent solubility of AZL/CD-MOF was enhanced by 340-fold when compared to the pure drug. Based on molecular modeling, a dual molecular mechanism of nanoclusterization and complexation of AZL inside the CD-MOF cages was proposed, which was confirmed by small angle X-ray scattering (SAXS) and synchrotron radiation-Fourier transform infrared spectroscopy (SR-FTIR) techniques. In a typical cage-like unit of CD-MOF, three molecules of AZL were included by the γ-CD pairs, whilst other three AZL molecules formed a nanocluster inside the 1.7 nm sized cavity surrounded by six γ-CDs. This research demonstrates a dual molecular mechanism of complexation and nanoclusterization in CD-MOF leading to significant improvement in the bioavailability of insoluble drugs.Graphical abstractThe solubility and bioavailability of AZL loaded in CD-MOF have been significantly improved to 340-fold and 9.7-fold, respectively, compared with the raw API. A dual molecule mechanism of complexation and nanoclusterization was first proposed and experimentally verified.fx1
       
  • Intestinal uptake of barley protein-based nanoparticles for
           β-carotene delivery

    • Abstract: Publication date: January 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 1Author(s): Guangyu Liu, Ying Zhou, Lingyun ChenOur previous study introduced a barley protein microparticle for encapsulation of hydrophobic drug/nutraceutical, which could release nanoparticles upon gastric digestion and deliver encapsulated compound to a simulated intestinal environment intact. This work focused on evaluating the potential of liberated nanoparticles to improve the absorption of encapsulated compounds (e.g., β-carotene) using in vitro Caco-2 cell and ex vivo small intestine models. Nanoparticles obtained from gastric digestion of barley protein microparticles had a spherical shape and an average size of 351 nm. Nanoparticles showed low cytotoxicity in Caco-2 cells and their cellular uptake was dependent on time, concentration and temperature. In a Caco-2 cell monolayer model, significantly greater uptake and transport of β-carotene were observed when it was delivered by nanoparticles (15%), compared to free β-carotene suspension (2.6%). In an ex vivo rat jejunum model, nanoparticles showed the capacity to retain in small intestinal tissue. Approximately 2.24 and 6.04 μg nanoparticle were able to permeate through each cm2 intestinal tissue and translocate to the serosal side after 60 and 90 min, respectively. Results from this study demonstrated the absorption improving effect of the barley protein nanoparticles and suggested their potential as vehicles for hydrophobic compounds.Graphical abstractBarley protein microparticles could protect encapsulated compounds and prevent nanoparticles from aggregation during storage. Barley protein nanoparticles can be liberated from microparticles upon gastric digestion and demonstrate absorption improving effect in both Caco-2 cell and rat jejunum models. These vehicles show significant potential in the delivery of hydrophobic compounds.fx1
       
  • Selenium-layered nanoparticles serving for oral delivery of phytomedicines
           with hypoglycemic activity to synergistically potentiate the antidiabetic
           effect

    • Abstract: Publication date: January 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 1Author(s): Wenji Deng, Huan Wang, Baojian Wu, Xingwang ZhangDiabetes mellitus (DM) remains a great challenge in treatment due to pathological complexity. It has been proven that phytomedicines and natural medicines have prominent antidiabetic effects. This work aimed to develop selenium-layered nanoparticles (SeNPs) for oral delivery of mulberry leaf and Pueraria Lobata extracts (MPE), a group of phytomedicines with significant hypoglycemic activities, to achieve a synergic antidiabetic effect. MPE-loaded SeNPs (MPE-SeNPs) were prepared through a solvent diffusion/in situ reduction technique and characterized by particle size, ζ potential, morphology, entrapment efficiency (EE) and drug loading (DL). The resulting MPE-SeNPs were 120 nm around in particle size with EE of 89.38% for rutin and 90.59% for puerarin, two marker components in MPE. MPE-SeNPs exhibited a slow drug release and good physiological stability in the simulated digestive fluid. After oral administration, MPE-SeNPs produced significant hypoglycemic effects both in the normal and diabetic rats. Ex vivo intestinal imaging and cellular examinations demonstrated that MPE-SeNPs were provided with outstanding intestinal permeability and transepithelial transport aptness. It was also revealed that MPE-SeNPs could alleviate the oxidative stress, improve the pancreatic function, and promote the glucose utilization by adipocytes. Our study provides new insight into the use of integrative nanomedicine containing phytomedicines and selenium for DM treatment.Graphical abstractSelenium-layered nanoparticles (SeNPs) were developed by self-assembly/in situ reduction technique to orally deliver mulberry leaf and Pueraria Lobata extracts (MPE) and enhanced antidiabetic efficacy was achieved through the synergy between selenium and hypoglycemic phytomedicines.fx1
       
  • Preparation and characterization of multimodal hybrid organic and
           inorganic nanocrystals of camptothecin and gold

    • Abstract: Publication date: January 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 1Author(s): Christin P. Hollis, Alan K. Dozier, Barbara L. Knutson, Tonglei LiWe demonstrate a novel inorganic-organic crystalline nanoconstruct, where gold atoms were imbedded in the crystal lattices as defects of camptothecin nanocrystals, suggesting its potential use as simultaneous agents for cancer therapy and bioimaging. The incorporation of gold, a potential computed tomography (CT) contrast agent, in the nanocrystals of camptothecin was detected by transmission electron microscope (TEM) and further quantified by energy dispersive X-ray spectrometry (EDS) and inductively coupled plasma-optical emission spectrometers (ICP-OES). Due to gold's high attenuation coefficient, only a relatively small amount needs to be present in order to create a good noise-to-contrast ratio in CT imaging. The imbedded gold atoms and clusters are expected to share the same biological fate as the camptothecin nanocrystals, reaching and accumulating in tumor site due to the enhanced permeation and retention (EPR) effect.Graphical abstractGold atoms and clusters were integrated physically into the crystal lattices as defects of camptothecin nanocrystals to achieve potential applications of concurrent bioimaging and anticancer therapy.fx1
       
  • The effects of pH, surfactant, ion concentration, coformer, and molecular
           arrangement on the solubility behavior of myricetin cocrystals

    • Abstract: Publication date: January 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 1Author(s): Shuzhen Ren, Mingyu Liu, Chao Hong, Guowen Li, Jiabin Sun, Jianying Wang, Lei Zhang, Yan XiePharmaceutical cocrystals are a promising technology that can be used to improve the solubility of poor aqueous compounds. The objective of this study was to systematically investigate the solubility of myricetin (MYR) cocrystals, including their kinetic solubility, thermodynamic solubility, and intrinsic dissolution rate (IDR). The effects of pH, surfactant, ion concentration, and coformers on the cocrystal solubility were evaluated. Furthermore, single crystal structures of MYR, myricetin–isonicotinamide (MYR–INM) and myricetin–caffeine (MYR–CAF) cocrystals were analyzed to discuss the possible reasons for the enhancement of cocrystal solubility from the perspective of the spatial structure. The results indicated that the kinetic solubility of MYR cocrystals was modulated by pH and cocrystal coformer (CCF) ionization in buffer solution, while it primarily depended on the CCF solubility in pure water. In addition, the solubility of MYR cocrystals was increased in a concentration dependent fashion by the surfactant or ion concentration. The thermodynamic solubility of MYR–INM (1:3) cocrystals decreased with the increases of the pH value of the dissolution media. The IDR of MYR cocrystals was faster than that of MYR in the same medium and extremely fast in pH 4.5 buffer. The improved solubility of MYR cocrystals was probably related to the alternate arrangements of MYR and INM/CAF molecules and increased intermolecular distance. The present study provides some references to investigate the solubility behavior of pharmaceutical cocrystals.Graphical abstractThe myricetin (MYR) cocrystals solubility was systematically elucidated by investigating its kinetic solubility, thermodynamic solubility, and intrinsic dissolution rate. The improved solubility of MYR cocrystals was probably related to the alternate arrangements of MYR and isonicotinamide/caffeine (INM/CAF) molecules and increased intermolecular distance.fx1
       
  • Emerging transporter-targeted nanoparticulate drug delivery systems

    • Abstract: Publication date: January 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 1Author(s): Hongyan Su, Yan Wang, Shuo Liu, Yue Wang, Qian Liu, Guangxuan Liu, Qin ChenTransporter-targeted nanoparticulate drug delivery systems (nano-DDS) have emerged as promising nanoplatforms for efficient drug delivery. Recently, great progress in transporter-targeted strategies has been made, especially with the rapid developments in nanotherapeutics. In this review, we outline the recent advances in transporter-targeted nano-DDS. First, the emerging transporter-targeted nano-DDS developed to facilitate oral drug delivery are reviewed. These include improvements in the oral absorption of protein and peptide drugs, facilitating the intravenous-to-oral switch in cancer chemotherapy. Secondly, the recent advances in transporter-assisted brain-targeting nano-DDS are discussed, focusing on the specific transporter-based targeting strategies. Recent developments in transporter-mediated tumor-targeting drug delivery are also discussed. Finally, the possible transport mechanisms involved in transporter-mediated endocytosis are highlighted, with special attention to the latest findings of the interactions between membrane transporters and nano-DDS.Graphical abstractThe recent trends in transporter-targeted nano-DDS is reviewed: (i) the emerging transporter-targeted nano-DDS developed to facilitate oral drug delivery; (ii) the recent advances in transporter-assisted brain-targeting nano-DDS; (iii) recent developments in transporter-mediated tumor-targeting drug delivery; and (iv) the possible transport mechanisms involved in the transporter-mediated endocytosis.fx1
       
  • Adapting liposomes for oral drug delivery

    • Abstract: Publication date: January 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 1Author(s): Haisheng He, Yi Lu, Jianping Qi, Quangang Zhu, Zhongjian Chen, Wei WuLiposomes mimic natural cell membranes and have long been investigated as drug carriers due to excellent entrapment capacity, biocompatibility and safety. Despite the success of parenteral liposomes, oral delivery of liposomes is impeded by various barriers such as instability in the gastrointestinal tract, difficulties in crossing biomembranes, and mass production problems. By modulating the compositions of the lipid bilayers and adding polymers or ligands, both the stability and permeability of liposomes can be greatly improved for oral drug delivery. This review provides an overview of the challenges and current approaches toward the oral delivery of liposomes.Graphical abstractDespite the success of parenteral liposomes, oral delivery of liposomes is impeded by various barriers such as instability, poor permeability and mass production difficulties. By modulating bilayer compositions and decorating with polymers or ligands, both the stability and permeability of liposomes can be greatly improved, bettering liposomes for oral delivery.fx1
       
  • Advances in coamorphous drug delivery systems

    • Abstract: Publication date: January 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 1Author(s): Qin Shi, Sakib M. Moinuddin, Ting CaiIn recent years, the coamorphous drug delivery system has been established as a promising formulation approach for delivering poorly water-soluble drugs. The coamorphous solid is a single-phase system containing an active pharmaceutical ingredient (API) and other low molecular weight molecules that might be pharmacologically relevant APIs or excipients. These formulations exhibit considerable advantages over neat crystalline or amorphous material, including improved physical stability, dissolution profiles, and potentially enhanced therapeutic efficacy. This review provides a comprehensive overview of coamorphous drug delivery systems from the perspectives of preparation, physicochemical characteristics, physical stability, in vitro and in vivo performance. Furthermore, the challenges and strategies in developing robust coamorphous drug products of high quality and performance are briefly discussed.Graphical abstractfx1
       
  • Application of flash nanoprecipitation to fabricate poorly water-soluble
           drug nanoparticles

    • Abstract: Publication date: January 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 1Author(s): Jinsong Tao, Shing Fung Chow, Ying ZhengNanoparticles are considered to be a powerful approach for the delivery of poorly water-soluble drugs. One of the main challenges is developing an appropriate method for preparation of drug nanoparticles. As a simple, rapid and scalable method, the flash nanoprecipitation (FNP) has been widely used to fabricate these drug nanoparticles, including pure drug nanocrystals, polymeric micelles, polymeric nanoparticles, solid lipid nanoparticles, and polyelectrolyte complexes. This review introduces the application of FNP to produce poorly water-soluble drug nanoparticles by controllable mixing devices, such as confined impinging jets mixer (CIJM), multi-inlet vortex mixer (MIVM) and many other microfluidic mixer systems. The formation mechanisms and processes of drug nanoparticles by FNP are described in detail. Then, the controlling of supersaturation level and mixing rate during the FNP process to tailor the ultrafine drug nanoparticles as well as the influence of drugs, solvent, anti-solvent, stabilizers and temperature on the fabrication are discussed. The ultrafine and uniform nanoparticles of poorly water-soluble drug nanoparticles prepared by CIJM, MIVM and microfluidic mixer systems are reviewed briefly. We believe that the application of microfluidic mixing devices in laboratory with continuous process control and good reproducibility will be benefit for industrial formulation scale-up.Graphical abstractFlash nanoprecipitation (FNP) via mixing devices, such as confined impinging jets mixer (CIJM), multi-inlet vortex mixer (MIVM) and microfluidic mixer systems could tailor drug nanoparticles with various properties by controlling the mixing rate and supersaturation level during the FNP process, as well as the parameters of APIs, solvent, anti-solvent, stabilizers and temperature.fx1
       
  • Editorial: Persistent endeavors for the enhancement of dissolution and
           oral bioavailability

    • Abstract: Publication date: January 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 1Author(s): Wei Wu, Yi Lu, Jianping Qi
       
  • Editor Profiles: Guest Editors of Special Issue on Enhancement of
           Dissolution and Oral Bioavailability of Poorly Water-soluble Drugs

    • Abstract: Publication date: January 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 1Author(s): Wei Wu, Yi Lu, Jianping Qi
       
  • Novel fluorescent probes of 10-hydroxyevodiamine: autophagy and
           apoptosis-inducing anticancer mechanisms

    • Abstract: Publication date: January 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 1Author(s): Shuqiang Chen, Guoqiang Dong, Shanchao Wu, Na Liu, Wannian Zhang, Chunquan ShengNatural product evodiamine and its derivatives represent a promising class of multi-target antitumor agents. However, the clinical development of these compounds has been hampered by a poor understanding of their antitumor mechanisms. To tackle this obstacle, herein, novel fluorescent probes were designed to elucidate the antitumor mode of action of 10-hydroxyevodiamine. This compound was proven to be distributed in the mitochondria and lysosomes and to act by autophagy and apoptosis mechanisms.Graphical abstractNovel fluorescent probes were designed to elucidate the antitumor mode of action of 10-hydroxyevodiamine, which was proven to be distributed in the mitochondria and lysosomes and acted by autophagy and apoptosis mechanisms.fx1
       
  • Pharmacometabolomic prediction of individual differences of
           gastrointestinal toxicity complicating myelosuppression in rats induced by
           irinotecan

    • Abstract: Publication date: January 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 1Author(s): Yiqiao Gao, Wei Li, Jiaqing Chen, Xu Wang, Yingtong Lv, Yin Huang, Zunjian Zhang, Fengguo XuPharmacometabolomics has been already successfully used in toxicity prediction for one specific adverse effect. However in clinical practice, two or more different toxicities are always accompanied with each other, which puts forward new challenges for pharmacometabolomics. Gastrointestinal toxicity and myelosuppression are two major adverse effects induced by Irinotecan (CPT-11), and often show large individual differences. In the current study, a pharmacometabolomic study was performed to screen the exclusive biomarkers in predose serums which could predict late-onset diarrhea and myelosuppression of CPT-11 simultaneously. The severity and sensitivity differences in gastrointestinal toxicity and myelosuppression were judged by delayed-onset diarrhea symptoms, histopathology examination, relative cytokines and blood cell counts. Mass spectrometry-based non-targeted and targeted metabolomics were conducted in sequence to dissect metabolite signatures in predose serums. Eventually, two groups of metabolites were screened out as predictors for individual differences in late-onset diarrhea and myelosuppression using binary logistic regression, respectively. This result was compared with existing predictors and validated by another independent external validation set. Our study indicates the prediction of toxicity could be possible upon predose metabolic profile. Pharmacometabolomics can be a potentially useful tool for complicating toxicity prediction. Our findings also provide a new insight into CPT-11 precision medicine.Graphical abstractMass spectrometry-based non-targeted and targeted metabolomics were conducted in sequence to screen the exclusive biomarkers in predose serums. Based on the pharmacometabolomic analysis, two prediction models were constructed to predict gastrointestinal toxicity and myelosuppression of CPT-11 simultaneously, followed by verification of relevant chemotherapeutic toxicity evaluation indexes.fx1
       
  • Efficient lung cancer-targeted drug delivery via a
           nanoparticle/MSC system

    • Abstract: Publication date: January 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 1Author(s): Xusheng Wang, Haiyan Chen, Xiaowei Zeng, Wenpeng Guo, Yu Jin, Shan Wang, Ruiyun Tian, Yanjiang Han, Ling Guo, Jimin Han, Yaojiong Wu, Lin MeiLow targeting efficiency limits the applications of nanoparticles in cancer therapy. The fact that mesenchymal stem cells (MSC) trapped in the lung after systemic infusion is a disadvantage for cell therapy purposes. Here, we utilized MSC as lung cancer-targeted drug delivery vehicles by loading nanoparticles (NP) with anti-cancer drug. MSC showed a higher drug intake capacity than fibroblasts. In addition, MSC showed predominant lung trapping in both rabbit and monkey. IR-780 dye, a fluorescent probe used to represent docetaxel (DTX) in NP, delivered via MSC accumulated in the lung. Both in vitro MSC/A549 cell experiments and in vivo MSC/lung cancer experiments validated the intercellular transportation of NP between MSC and cancer cells. In vivo assays showed that the MSC/NP/DTX drug delivery system exerted primary tumor inhibition efficiency similar to that of a NP/DTX drug system. Collectively, the MSC/NP drug delivery system is promising for lung-targeted drug delivery for the treatment of lung cancer and other lung-related diseases.Graphical abstractIn this study, MSCs were used as lung targeted delivery vehicles by loading nanoparticles that carrying anti-cancer drug. The high efficiency of lung targeting of MSCs was validated in different animals, and this system efficiently inhibited primary lung tumor growth with lower dose of anti-cancer drug.fx1
       
  • Deep learning for in vitro prediction of pharmaceutical
           formulations

    • Abstract: Publication date: January 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 1Author(s): Yilong Yang, Zhuyifan Ye, Yan Su, Qianqian Zhao, Xiaoshan Li, Defang OuyangCurrent pharmaceutical formulation development still strongly relies on the traditional trial-and-error methods of pharmaceutical scientists. This approach is laborious, time-consuming and costly. Recently, deep learning has been widely applied in many challenging domains because of its important capability of automatic feature extraction. The aim of the present research is to apply deep learning methods to predict pharmaceutical formulations. In this paper, two types of dosage forms were chosen as model systems. Evaluation criteria suitable for pharmaceutics were applied to assess the performance of the models. Moreover, an automatic dataset selection algorithm was developed for selecting the representative data as validation and test datasets. Six machine learning methods were compared with deep learning. Results showed that the accuracies of both two deep neural networks were above 80% and higher than other machine learning models; the latter showed good prediction of pharmaceutical formulations. In summary, deep learning employing an automatic data splitting algorithm and the evaluation criteria suitable for pharmaceutical formulation data was developed for the prediction of pharmaceutical formulations for the first time. The cross-disciplinary integration of pharmaceutics and artificial intelligence may shift the paradigm of pharmaceutical research from experience-dependent studies to data-driven methodologies.Graphical abstractDeep learning with the automatic data splitting algorithm and the evaluation criteria suitable for pharmaceutical formulation data was firstly developed for the prediction of pharmaceutical formulations.fx1
       
  • Interaction between human serum albumin and cholesterol-grafted
           polyglutamate as the potential carriers of protein drugs

    • Abstract: Publication date: January 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 1Author(s): Xiangxue Lyu, Qiufen Zhang, Dehai Liang, Yanbin HuangCurrently there is no successful platform technology for the sustained release of protein drugs. It seems inevitable to specifically develop new materials for such purpose, and hence the understanding of protein–material interactions is highly desirable. In this study, we synthesized cholesterol-grafted polyglutamate (PGA-g-Chol) as a hydrophobically-modified polypeptide, and thoroughly characterized its interaction with a model protein (human serum albumin) in the aqueous solution by using circular dichroism, fluorescence methods, and light scattering. With the protein concentration fixed at 5 μmol/L, adding PGA-g-Chol polymers into the solution resulted in continuous blue shift of the protein fluorescence (from 339 to 332 nm), until the polymer molar concentration reached the same value as the protein. In contrast, the un-modified polyglutamate polymers apparently neither affected the protein microenvironment nor formed aggregates. Based on the experimental data, we proposed a physical picture for such protein–polymer systems, where the polymer first bind with the protein in a 1:1 molar ratio via a fraction of their hydrophobic pendant cholesterol resides along the polymer chain. In this protein/polymer complex, there are excess unbound cholesterol residues. As the polymer concentration increases, the polymers form multi-polymer aggregates around 200 nm in diameter via the same hydrophobic cholesterol residues. The protein/polymer complex also participate in the aggregation via their excess cholesterol residues, and consequently the proteins are encapsulated into the nanoparticles. The encapsulation was also found to increase the thermal stability of the model protein.Graphical abstractA physical picture is proposed for the interactions between proteins and hydrophobically-modified polypeptide, which can be a platform material for sustained release of protein drugs. The polymers form complexes with proteins via the hydrophobic interactions, and these protein-bound polymers self-assemble with other polymers to form nano-sized particles.fx1
       
  • Exploring the utility of the Chasing Principle: influence of drug-free
           SNEDDS composition on solubilization of carvedilol, cinnarizine and R3040
           in aqueous suspension

    • Abstract: Publication date: January 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 1Author(s): ScheylaDaniela Siqueira Jørgensen, Thomas Rades, Huiling Mu, Kirsten Graeser, Anette MüllertzThis study assessed the influence of the composition of drug-free SNEDDS co-dosed with aqueous suspensions of carvedilol (CAR), cinnarizine (CIN) or R3040 on drug solubilization in a two-compartment in vitro lipolysis model. Correlation of drug logP or solubility in SNEDDS with drug solubilization during in vitro lipolysis in the presence of drug-free SNEDDS was assessed. SNEDDS with varying ratios of soybean oil:Maisine 35-1 (1:1, w/w) and Kolliphor RH40, with ethanol at 10% (w/w) were used. SNEDDS were named F65, F55 and F20 (numbers refer to the percentage of lipids) and aqueous suspensions without drug-free SNEDDS (F0) were also analyzed. While the ranking order of drug solubilization was F65=F55=F20>F0 for CAR; F65=F55>F20>F0 for CIN and F65=F55=F20>F0 for R3040 - with higher CAR solubilization than for R3040 and CIN - the ranking of Seq of CAR, CIN and R3040 in SNEDDS was F65F55>F20, respectively. Therefore, the composition of SNEDDS influenced the solubilization of CIN, but not CAR and R3040. Furthermore, high Seq in SNEDDS did not reflect high drug solubilization. As CAR (logP 3.8) showed higher solubilization than CIN (logP 5.8) and R3040 (logP 10.4), a correlation between drug logP and drug solubilization was observed.Graphical abstractThis study assessed the influence of the composition of drug-free SNEDDS co-dosed with aqueous suspensions of carvedilol, cinnarizine or R3040 on drug solubilization in a two-compartment in vitro lipolysis model.fx1
       
  • Cordycepin promotes browning of white adipose tissue through an
           AMP-activated protein kinase (AMPK)-dependent pathway

    • Abstract: Publication date: January 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 1Author(s): Guihong Qi, Yue Zhou, Xiaopo Zhang, Jiaqi Yu, Xin Li, Xiaoxue Cao, Chongming Wu, Peng GuoAbstractObesity is a worldwide epidemic. Promoting browning of white adipose tissue (WAT) contributes to increased energy expenditure and hence counteracts obesity. Here we show that cordycepin (Cpn), a natural derivative of adenosine, increases energy expenditure, inhibits weight gain, improves metabolic profile and glucose tolerance, decreases WAT mass and adipocyte size, and enhances cold tolerance in normal and high-fat diet-fed mice. Cpn markedly increases the surface temperature around the inguinal WAT and turns the inguinal fat browner. Further investigations show that Cpn induces the development of brown-like adipocytes in inguinal and, to a less degree, epididymal WAT depots. Cpn also increases the expression of uncoupling protein 1 (UCP1) and other thermogenic genes in WAT and 3T3-L1 differentiated adipocytes, in which AMP-activated protein kinase (AMPK) plays an important role. Our results provide novel insights into the function of Cpn in regulating energy balance, and suggest a potential utility of Cpn in the treatment of obesity.Graphical AbstractCordycepin increases energy expenditure via promoting white adipose tissue browning in mice, in which AMPK activation may play an important role.fx1
       
  • Development of carrier-free nanocrystals of poorly water-soluble drugs by
           exploring metastable zone of nucleation

    • Abstract: Publication date: January 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 1Author(s): Xiaoting Ren, Jianping Qi, Wei Wu, Zongning Yin, Tonglei Li, Yi LuThere has been increasing interest in research and development of nanocrystals for the delivery of poorly water-soluble drugs that can be directly produced from solution. Compared with traditional carrier-based or encapsulation designs, drug nanocrystals circumvent possible side-effects due to carrier polymers and poor stability issues associated with encapsulation. The production of carrier-free nanocrystals requires careful control of nucleation and thus a thorough understanding of the relevant solution's metastable zone. A solution may stay supersaturated without forming any nuclei and become metastable. The maximal degree of supersaturation is known as the metastable zone width. When nucleation is triggered directly from the metastable zone, it helps to produce homogeneous nuclei leading to uniform nanocrystals. Herein, we report a study in which the solubility and metastable limit of paclitaxel (PTX) in ethanol aqueous solution were measured at 40 °C. A wide range of metastable compositions were studied to prepare carrier-free PTX nanocrystals with particle size smaller than 250 nm and PDI less than 0.25. Compared with the raw material, dissolution rate of PTX nanocrystals was significantly increased. The study enables production of high-quality drug nanocrystals for treating patients.Graphical abstractA solution may stay supersaturated without forming any nuclei and become metastable. When nucleation is triggered directly from the metastable zone, it helps to produce homogeneous nuclei leading to uniform carrier-free nanocrystals. Avoiding disadvantages related to the carrier materials, carrier-free nanocrystals offer numerous benefits for drug delivery.fx1
       
  • Supersaturated polymeric micelles for oral silybin delivery: the role of
           the Soluplus–PVPVA complex

    • Abstract: Publication date: January 2019Source: Acta Pharmaceutica Sinica B, Volume 9, Issue 1Author(s): Chunliu Zhu, Shuang Gong, Jinsong Ding, Miaorong Yu, Ejaj Ahmad, Yi Feng, Yong GanIncreasing the degree of supersaturation of drugs and maintaining their proper stability are very important in improving the oral bioavailability of poorly soluble drugs by a supersaturated drug delivery system (SDDS). In this study, we reported a complex system of Soluplus–Copovidone (Soluplus–PVPVA) loaded with the model drug silybin (SLB) that could not only maintain the stability of a supersaturated solution but also effectively promote oral absorption. The antiprecipitation effect of the polymers on SLB was observed using the solvent-shift method. In addition, the effects of the polymers on absorption were detected by cellular uptake and transport experiments. The mechanisms by which the Soluplus–PVPVA complex promotes oral absorption were explored by dynamic light scattering, transmission electron microscopy, fluorescence spectra and isothermal titration calorimetry analyses. Furthermore, a pharmacokinetic study in rats was used to demonstrate the advantages of the Soluplus–PVPVA complex. The results showed that Soluplus and PVPVA spontaneously formed complexes in aqueous solution via the adsorption of PVPVA on the hydrophilic-hydrophobic interface of the Soluplus micelle, and the Soluplus–PVPVA complex significantly increased the absorption of SLB. In conclusion, the Soluplus–PVPVA complex is a potential SDDS for improving the bioavailability of hydrophobic drugs.Graphical abstractThe study reported a supersaturated complex, formed by Soluplus and PVPVA, for oral silybin (SLB) delivery. The adsorption of PVPVA on the hydrophilic-hydrophobic interface of the Soluplus micelle endowed the complex with the ability to maintain proper stability of SLB supersaturated solution, and thus improved the oral bioavailability of SLB.fx1
       
  • Small interfering RNA delivery to the neurons near the amyloid plaques for
           improved treatment of Alzheimer׳s disease

    • Abstract: Publication date: Available online 30 December 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Qian Guo, Xiaoyao Zheng, Peng Yang, Xiaoying Pang, Kang Qian, Pengzhen Wang, Shuting Xu, Dongyu Sheng, Liuchang Wang, Jinxu Cao, Wei Lu, Qizhi Zhang, Xinguo JiangGene therapy represents a promising treatment for the Alzheimer׳s disease (AD). However, gene delivery specific to brain lesions through systemic administration remains big challenge. In our previous work, we have developed an siRNA nanocomplex able to be specifically delivered to the amyloid plaques through surface modification with both CGN peptide for the blood–brain barrier (BBB) penetration and QSH peptide for β-amyloid binding. But, whether the as-designed nanocomplex could indeed improve the gene accumulation in the impaired neuron cells and ameliorate AD-associated symptoms remains further study. Herein, we prepared the nanocomplexes with an siRNA against β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), the rate-limiting enzyme of Aβ production, as the therapeutic siRNA of AD. The nanocomplexes exhibited high distribution in the Aβ deposits-enriched hippocampus, especially in the neurons near the amyloid plaques after intravenous administration. In APP/PS1 transgenic mice, the nanocomplexes down-regulated BACE1 in both mRNA and protein levels, as well as Aβ and amyloid plaques to the level of wild-type mice. Moreover, the nanocomplexes significantly increased the level of synaptophysin and rescued memory loss of the AD transgenic mice without hematological or histological toxicity. Taken together, this work presented direct evidences that the design of precise gene delivery to the AD lesions markedly improves the therapeutic outcome.Graphical abstractIn this study, the nanocomplexes were prepared with an siRNA against β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), the rate-limiting enzyme of Aβ production, as the therapeutic siRNA of Alzheimer's disease (AD).fx1
       
  • Neutrophil-mimicking therapeutic nanoparticles for targeted chemotherapy
           of pancreatic carcinoma

    • Abstract: Publication date: Available online 26 December 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Xi Cao, Ying Hu, Shi Luo, Yuejing Wang, Tao Gong, Xun Sun, Yao Fu, Zhirong ZhangDue to the critical correlation between inflammation and carcinogenesis, a therapeutic candidate with anti-inflammatory activity may find application in cancer therapy. Here, we report the therapeutic efficacy of celastrol as a promising candidate compound for treatment of pancreatic carcinoma via naïve neutrophil membrane-coated poly(ethylene glycol) methyl ether-block-poly(lactic-co-glycolic acid) (PEG-PLGA) nanoparticles. Neutrophil membrane-coated nanoparticles (NNPs) are well demonstrated to overcome the blood pancreas barrier to achieve pancreas-specific drug delivery in vivo. Using tumor-bearing mice xenograft model, NNPs showed selective accumulations at the tumor site following systemic administration as compared to nanoparticles without neutrophil membrane coating. In both orthotopic and ectopic tumor models, celastrol-loaded NNPs demonstrated greatly enhanced tumor inhibition which significantly prolonged the survival of tumor bearing mice and minimizing liver metastases. Overall, these results suggest that celastrol-loaded NNPs represent a viable and effective treatment option for pancreatic carcinoma.Graphical abstractNeutrophil membrane-coated nanoparticles (NNPs) have been developed to overcome the blood–pancreas barrier to achieve site-specific drug delivery.fx1
       
  • Secalonic acid D induces cell apoptosis in both sensitive and
           ABCG2-overexpressing multidrug resistant cancer cells through upregulating
           c-Jun expression

    • Abstract: Publication date: Available online 21 December 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Hong Zhang, Liyan Huang, Liyang Tao, Jianye Zhang, Fang Wang, Xu Zhang, Liwu FuSecalonic acid D (SAD) could inhibit cell growth in not only sensitive cells but also multidrug resistant (MDR) cells. However, the molecular mechanisms need to be elucidated. Here, we identified that SAD possessed potent cytotoxicity in 3 pairs of MDR and their parental sensitive cells including S1-MI-80 and S1, H460/MX20 and H460, MCF-7/ADR and MCF-7 cells. Furthermore, SAD induced cell G2/M phase arrest via the downregulation of cyclin B1 and the increase of CDC2 phosphorylation. Importantly, JNK pathway upregulated the expression of c-Jun in protein level and increased c-Jun phosphorylation induced by SAD, which was linked to cell apoptosis via c-Jun/Src/STAT3 pathway. To investigate the mechanisms of upregulation of c-Jun protein by SAD, the mRNA expression level and degradation of c-Jun were examined. We found that SAD did not alter the mRNA level of c-Jun but inhibited its proteasome-dependent degradation. Taken together, these results implicate that SAD induces cancer cell death through c-Jun/Src/STAT3 signaling axis by inhibiting the proteasome-dependent degradation of c-Jun in both sensitive cells and ATP-binding cassette transporter sub-family G member 2 (ABCG2)-mediated MDR cells.Graphical abstractSecalonic acid D (SAD) activates JNK to phosphorylate c-Jun and prevents c-Jun protein from degradation. SAD serves as a c-Jun agonist to induce cell apoptosis through SRC/STAT3 signaling and other possible pathways (FasL, BIM, caspase-3, etc).fx1
       
  • Prussian blue nanosphere-embedded in situ hydrogel for photothermal
           therapy by peritumoral administration

    • Abstract: Publication date: Available online 17 December 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Jijun Fu, Bo Wu, Minyan Wei, Yugang Huang, Yi Zhou, Qiang Zhang, Lingran DuTo establish an injectable hydrogel containing prussian blue (PB) nanospheres for photothermal therapy against cancer, PB nanospheres were prepared by one-pot synthesis and the thermosensitive Pluronic F127 was used as the hydrogel matrix. The PB nanospheres and the hydrogel were characterized by shape, particle size, serum stability, photothermal performance upon repeated 808 nm laser irradiation, as well as the rheological features. The effect of the PB nanospheres and the hydrogel were evaluated qualitatively and quantitatively in 4T1 mouse breast cancer cells. The retention, photothermal efficacy, therapeutic effects and systemic toxicity of the hydrogel were assessed in a tumor-bearing mouse model. The PB nanospheres had a diameter of about 150 nm and exhibited satisfactory serum stability, photo-heat convert ability and repeated laser exposure stability. The hydrogel encapsulation did not negatively influence the above features of the photothermal agent. The nanosphere-containing hydrogel showed a phase transition at body temperature and, as a result, a long retention time in vivo. The photothermal agent-embedded hydrogel displayed promising photothermal therapeutic effects in the tumor-bearing mouse model with little-to-no systemic toxicity after peritumoral administration.Graphical abstractThis study developed an in situ hydrogel containing PB nanospheres to treat breast cancer. The injectable hydrogel shows an excellent tumor curing effect and biocompatibility. The PB nanospheres were eliminated through the urine.Graphical abstract for this article
       
  • Guidance for the clinical evaluation of traditional Chinese
           medicine-induced liver injury Issued by China Food and Drug Administration
           

    • Abstract: Publication date: Available online 14 December 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Xiaohe Xiao, Jianyuan Tang, Yimin Mao, Xiuhui Li, Jiabo Wang, Chenghai Liu, Kewei Sun, Yong'an Ye, Zhengsheng Zou, Cheng Peng, Ling Yang, Yuming Guo, Zhaofang Bai, Tingting He, Jing Jing, Fengyi Li, Na An
       
  • Bioengineered miR-27b-3p and miR-328-3p modulate drug metabolism and
           disposition via the regulation of target ADME gene expression

    • Abstract: Publication date: Available online 11 December 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Xin Li, Ye Tian, Mei-Juan Tu, Pui Yan Ho, Neelu Batra, Ai-Ming YuDrug-metabolizing enzymes, transporters, and nuclear receptors are essential for the absorption, distribution, metabolism, and excretion (ADME) of drugs and xenobiotics. MicroRNAs participate in the regulation of ADME gene expression via imperfect complementary WatsonCrick base pairings with target transcripts. We have previously reported that Cytochrome P450 3A4 (CYP3A4) and ATP-binding cassette sub-family G member 2 (ABCG2) are regulated by miR-27b-3p and miR-328-3p, respectively. Here we employed our newly established RNA bioengineering technology to produce bioengineered RNA agents (BERA), namely BERA/miR-27b-3p and BERA/miR-328-3p, via fermentation. When introduced into human cells, BERA/miR-27b-3p and BERA/miR-328-3p were selectively processed to target miRNAs and thus knock down CYP3A4 and ABCG2 mRNA and their protein levels, respectively, as compared to cells treated with vehicle or control RNA. Consequently, BERA/miR-27b-3p led to a lower midazolam 1′-hydroxylase activity, indicating the reduction of CYP3A4 activity. Likewise, BERA/miR-328-3p treatment elevated the intracellular accumulation of anticancer drug mitoxantrone, a classic substrate of ABCG2, hence sensitized the cells to chemotherapy. The results indicate that biologic miRNA agents made by RNA biotechnology may be applied to research on miRNA functions in the regulation of drug metabolism and disposition that could provide insights into the development of more effective therapies.Graphical abstractA novel RNA biotechnology was used to produce bioengineered miRNA agents (BERA), namely BERA/miR-27b-3p and BERA/miR-328-3p, which were selectively processed to target miR-27-3p and -328-3p to modulate the expression of CYP3A4 enzyme and ABCG2 transporter, respectively, in human cells, and subsequently alter cellular drug metabolism and disposition capacity.fx1
       
  • Overcoming chemotherapy resistance via simultaneous drug-efflux
           circumvention and mitochondrial targeting

    • Abstract: Publication date: Available online 29 November 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Minglu Zhou, Lijia Li, Lian Li, Xi Lin, Fengling Wang, Qiuyi Li, Yuan HuangMultidrug resistance (MDR) has been considered as a huge challenge to the effective chemotherapy. Therefore, it is necessary to develop new strategies to effectively overcome MDR. Here, based on the previous research of N-(2-hydroxypropyl)methacrylamide (HPMA) polymer–drug conjugates, we designed an effective system that combined drug-efflux circumvention and mitochondria targeting of anticancer drug doxorubicin (Dox). Briefly, Dox was modified with mitochondrial membrane penetrating peptide (MPP) and then attached to (HPMA) copolymers (P-M-Dox). Our study showed that macromolecular HPMA copolymers successfully bypassed drug efflux pumps and escorted Dox into resistant MCF-7/ADR cells via endocytic pathway. Subsequently, the mitochondria accumulation of drugs was significantly enhanced with 11.6-fold increase by MPP modification. The excellent mitochondria targeting then resulted in significant enhancement of reactive oxygen species (ROS) as well as reduction of adenosine triphosphate (ATP) production, which could further inhibit drug efflux and resistant cancer cell growth. By reversing Dox resistance, P-M-Dox achieved much better suppression in the growth of 3D MCF-7/ADR tumor spheroids compared with free Dox. Hence, our study provides a promising approach to treat drug-resistant cancer through simultaneous drug efflux circumvention and direct mitochondria delivery.Graphical abstractFree Dox that enters cells by diffusion was vulnerable to P-gp efflux. On the contrary, P-M-Dox that enters cells by endocytosis can effectively evade P-gp efflux pump on the cell membrane. Then, P-M-Dox responsively releases MPP modified doxorubicin (M-Dox) in the lysosomal acidic environment, and eventually achieves excellent mitochondria targeting for elevating reactive oxygen species (ROS) generation and minimizing ATP production, thereby killing drug-resistant tumor cells through simultaneous drug efflux circumvention and direct mitochondria delivery.fx1
       
  • Combined obeticholic acid and apoptosis inhibitor treatment alleviates
           liver fibrosis

    • Abstract: Publication date: Available online 27 November 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Jiyu Zhou, Ningning Huang, Yitong Guo, Shuang Cui, Chaoliang Ge, Qingxian He, Xiaojie Pan, Guangji Wang, Hong Wang, Haiping HaoObeticholic acid (OCA), the first FXR-targeting drug, has been claimed effective in the therapy of liver fibrosis. However, recent clinical trials indicated that OCA might not be effective against liver fibrosis, possibly due to the lower dosage to reduce the incidence of the side-effect of pruritus. Here we propose a combinatory therapeutic strategy of OCA and apoptosis inhibitor for combating against liver fibrosis. CCl4-injured mice, d-galactosamine/LPS (GalN/LPS)-treated mice and cycloheximide/TNFα (CHX/TNFα)-treated HepG2 cells were employed to assess the effects of OCA, or together with IDN-6556, an apoptosis inhibitor. OCA treatment significantly inhibited hepatic stellate cell (HSC) activation/proliferation and prevented fibrosis. Elevated bile acid (BA) levels and hepatocyte apoptosis triggered the activation and proliferation of HSCs. OCA treatment reduced BA levels but could not inhibit hepatocellular apoptosis. An enhanced anti-fibrotic effect was observed when OCA was co-administrated with IDN-6556. Our study demonstrated that OCA inhibits HSCs activation/proliferation partially by regulating BA homeostasis and thereby inhibiting activation of HSCs. The findings in this study suggest that combined use of apoptosis inhibitor and OCA at lower dosage represents a novel therapeutic strategy for liver fibrosis.Graphical abstractElevated bile acids (BAs) and hepatocyte apoptosis trigger activation/proliferation of hepatic stellate cells, and ultimately promoted the development fibrosis. Treatment of obeticholic acid, a FXR agonist, reduces BA levels but could not inhibit hepatocellular apoptosis. Combined use of apoptosis inhibitor and FXR agonist represents a novel strategy for liver fibrosis.fx1
       
  • Combinatorial mutation on the β-glycosidase specific to
           7-β-xylosyltaxanes and increasing the mutated enzyme production by
           engineering the recombinant yeast

    • Abstract: Publication date: Available online 27 November 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Jing-Jing Chen, Xiao Liang, Fen Wang, Yan-Hua Wen, Tian-Jiao Chen, Wan-Cang Liu, Ting Gong, Jin-Ling Yang, Ping ZhuTaxol is a “blockbuster” antitumor drug produced by Taxus species with extremely low amount, while its analogue 7-β-xylosyl-10-deacetyltaxol is generally much higher in the plants. Both the fungal enzymes LXYL-P1−1 and LXYL-P1−2 can convert 7-β-xylosyl-10-deacetyltaxol into 10-deacetyltaxol for Taxol semi-synthesis. Of them, LXYL-P1−2 is twice more active than LXYL-P1−1, but there are only 11 significantly different amino acids in terms of the polarity and acidic-basic properties between them. In this study, single and multiple site-directed mutations at the 11 sites from LXYL-P1−1 to LXYL-P1−2 were performed to define the amino acids with upward bias in activities and to acquire variants with improved catalytic properties. Among all the 17 mutants, E12 (A72T/V91S) was the most active and even displayed 2.8- and 3-fold higher than LXYL-P1−2 on β-xylosidase and β-glucosidase activities. The possible mechanism for such improvement was proposed by homology modeling and molecular docking between E12 and 7-β-xylosyl-10-deacetyltaxol. The recombinant yeast GS115-P1E12-7 was constructed by introducing variant E12, the molecular chaperone gene pdi and the bacterial hemoglobin gene vhb. This engineered yeast rendered 4 times higher biomass enzyme activity than GS115-3.5K-P1−2 that had been used for demo-scale fermentation. Thus, GS115-P1E12-7 becomes a promising candidate to replace GS115-3.5K-P1−2 for industrial purpose.Graphical abstractThe combinatorial mutation strategy was employed to increase the β-glycosidase activity, and the mutant E12 with the highest enzyme activity was obtained. The E12 production in the yeast was further improved by co-expressing the molecular chaperone PDI (protein disulfide isomerase) and the Vitreoscilla hemoglobin under the promoter PAOX1. This engineered yeast can be used for the biocatalysis of 7-β-xylosyl-10-deacetyltaxol to 10-deacetyltaxol for Taxol semi-synthesis.fx1
       
  • Chrysophanol protects against doxorubicin-induced cardiotoxicity by
           suppressing cellular PARylation

    • Abstract: Publication date: Available online 1 November 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Jing Lu, Jingyan Li, Yuehuai Hu, Zhen Guo, Duanping Sun, Panxia Wang, Kaiteng Guo, Dayue Darrel Duan, Si Gao, Jianmin Jiang, Junjian Wang, Peiqing LiuThe clinical application of doxorubicin (DOX) in cancer chemotherapy is limited by its life-threatening cardiotoxic effects. Chrysophanol (CHR), an anthraquinone compound isolated from the rhizome of Rheum palmatum L., is considered to play a broad role in a variety of biological processes. However, the effects of CHR׳s cardioprotection in DOX-induced cardiomyopathy is poorly understood. In this study, we found that the cardiac apoptosis, mitochondrial injury and cellular PARylation levels were significantly increased in H9C2 cells treated by Dox, while these effects were suppressed by CHR. Similar results were observed when PARP1 activity was suppressed by its inhibitors 3-aminobenzamide (3AB) and ABT888. Ectopic expression of PARP1 effectively blocked this CHR׳s cardioprotection against DOX-induced cardiomyocyte injury in H9C2 cells. Furthermore, pre-administration with both CHR and 3AB relieved DOX-induced cardiac apoptosis, mitochondrial impairment and heart dysfunction in Sprague–Dawley rat model. These results revealed that CHR protects against DOX-induced cardiotoxicity by suppressing cellular PARylation and provided critical evidence that PARylation may be a novel target for DOX-induced cardiomyopathy.Graphical abstractCHR protected against doxorubicin (DOX)-induced cardiomyocytes apoptosis, mitochondrial injury and heart dysfunction by suppressing cellular PARylation in vitro and in vivo.fx1
       
 
 
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