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Publisher: Elsevier   (Total: 3162 journals)

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Showing 1 - 200 of 3162 Journals sorted alphabetically
A Practical Logic of Cognitive Systems     Full-text available via subscription   (Followers: 9)
AASRI Procedia     Open Access   (Followers: 15)
Academic Pediatrics     Hybrid Journal   (Followers: 33, SJR: 1.655, CiteScore: 2)
Academic Radiology     Hybrid Journal   (Followers: 23, SJR: 1.015, CiteScore: 2)
Accident Analysis & Prevention     Partially Free   (Followers: 95, SJR: 1.462, CiteScore: 3)
Accounting Forum     Hybrid Journal   (Followers: 25, SJR: 0.932, CiteScore: 2)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 36, SJR: 1.771, CiteScore: 3)
Achievements in the Life Sciences     Open Access   (Followers: 5)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 7)
Acta Astronautica     Hybrid Journal   (Followers: 411, SJR: 0.758, CiteScore: 2)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 2)
Acta Biomaterialia     Hybrid Journal   (Followers: 27, SJR: 1.967, CiteScore: 7)
Acta Colombiana de Cuidado Intensivo     Full-text available via subscription   (Followers: 2)
Acta de Investigación Psicológica     Open Access   (Followers: 3)
Acta Ecologica Sinica     Open Access   (Followers: 10, SJR: 0.18, CiteScore: 1)
Acta Haematologica Polonica     Free   (Followers: 1, SJR: 0.128, CiteScore: 0)
Acta Histochemica     Hybrid Journal   (Followers: 3, SJR: 0.661, CiteScore: 2)
Acta Materialia     Hybrid Journal   (Followers: 249, 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: 1, SJR: 1.793, CiteScore: 6)
Acta Poética     Open Access   (Followers: 4, SJR: 0.101, CiteScore: 0)
Acta Psychologica     Hybrid Journal   (Followers: 27, SJR: 1.331, CiteScore: 2)
Acta Sociológica     Open Access   (Followers: 1)
Acta Tropica     Hybrid Journal   (Followers: 6, 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: 6, SJR: 0.19, CiteScore: 0)
Actualites Pharmaceutiques Hospitalieres     Full-text available via subscription   (Followers: 3)
Acupuncture and Related Therapies     Hybrid Journal   (Followers: 6)
Acute Pain     Full-text available via subscription   (Followers: 14, SJR: 2.671, CiteScore: 5)
Ad Hoc Networks     Hybrid Journal   (Followers: 11, SJR: 0.53, CiteScore: 4)
Addictive Behaviors     Hybrid Journal   (Followers: 16, SJR: 1.29, CiteScore: 3)
Addictive Behaviors Reports     Open Access   (Followers: 8, SJR: 0.755, CiteScore: 2)
Additive Manufacturing     Hybrid Journal   (Followers: 9, SJR: 2.611, CiteScore: 8)
Additives for Polymers     Full-text available via subscription   (Followers: 22)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 148, SJR: 4.09, CiteScore: 13)
Advanced Engineering Informatics     Hybrid Journal   (Followers: 11, SJR: 1.167, CiteScore: 4)
Advanced Powder Technology     Hybrid Journal   (Followers: 17, SJR: 0.694, CiteScore: 3)
Advances in Accounting     Hybrid Journal   (Followers: 8, SJR: 0.277, CiteScore: 1)
Advances in Agronomy     Full-text available via subscription   (Followers: 12, SJR: 2.384, CiteScore: 5)
Advances in Anesthesia     Full-text available via subscription   (Followers: 28, 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: 10, SJR: 0.992, CiteScore: 1)
Advances in Applied Mechanics     Full-text available via subscription   (Followers: 11, SJR: 1.551, CiteScore: 4)
Advances in Applied Microbiology     Full-text available via subscription   (Followers: 23, SJR: 2.089, CiteScore: 5)
Advances In Atomic, Molecular, and Optical Physics     Full-text available via subscription   (Followers: 14, 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: 2, SJR: 0.686, CiteScore: 2)
Advances in Cancer Research     Full-text available via subscription   (Followers: 32, SJR: 3.043, CiteScore: 6)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 8, 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: 3)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 12)
Advances in Chemical Engineering     Full-text available via subscription   (Followers: 27, SJR: 0.156, CiteScore: 1)
Advances in Child Development and Behavior     Full-text available via subscription   (Followers: 10, SJR: 0.713, CiteScore: 1)
Advances in Chronic Kidney Disease     Full-text available via subscription   (Followers: 10, SJR: 1.316, CiteScore: 2)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 29, SJR: 1.562, CiteScore: 3)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 19, 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: 12)
Advances in Digestive Medicine     Open Access   (Followers: 9)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 5)
Advances in Drug Research     Full-text available via subscription   (Followers: 25)
Advances in Ecological Research     Full-text available via subscription   (Followers: 44, SJR: 2.524, CiteScore: 4)
Advances in Engineering Software     Hybrid Journal   (Followers: 28, SJR: 1.159, CiteScore: 4)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 7)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 44, 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: 58, SJR: 0.591, CiteScore: 2)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 16)
Advances in Genetics     Full-text available via subscription   (Followers: 16, SJR: 1.354, CiteScore: 4)
Advances in Genome Biology     Full-text available via subscription   (Followers: 8, SJR: 12.74, CiteScore: 13)
Advances in Geophysics     Full-text available via subscription   (Followers: 6, SJR: 1.193, CiteScore: 3)
Advances in Heat Transfer     Full-text available via subscription   (Followers: 21, SJR: 0.368, CiteScore: 1)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 12, SJR: 0.749, CiteScore: 3)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 22)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 2, SJR: 0.193, CiteScore: 0)
Advances in Immunology     Full-text available via subscription   (Followers: 36, SJR: 4.433, CiteScore: 6)
Advances in Inorganic Chemistry     Full-text available via subscription   (Followers: 8, 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: 8, 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: 9)
Advances in Marine Biology     Full-text available via subscription   (Followers: 17, SJR: 0.88, CiteScore: 2)
Advances in Mathematics     Full-text available via subscription   (Followers: 11, SJR: 3.027, CiteScore: 2)
Advances in Medical Sciences     Hybrid Journal   (Followers: 6, SJR: 0.694, CiteScore: 2)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 4, SJR: 1.158, CiteScore: 3)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 22)
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: 3)
Advances in Oncobiology     Full-text available via subscription   (Followers: 1)
Advances in Organ Biology     Full-text available via subscription   (Followers: 1)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 17, 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: 24, SJR: 0.461, CiteScore: 1)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 11)
Advances in Pharmacology     Full-text available via subscription   (Followers: 16, SJR: 1.536, CiteScore: 3)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 8, 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: 9)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 5)
Advances in Porous Media     Full-text available via subscription   (Followers: 5)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 18)
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: 62)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 6, SJR: 0.371, CiteScore: 1)
Advances in Radiation Oncology     Open Access   (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: 395, 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: 10, SJR: 0.555, CiteScore: 2)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 33, SJR: 2.208, CiteScore: 4)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 17)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 13)
Advances in Virus Research     Full-text available via subscription   (Followers: 5, SJR: 2.262, CiteScore: 5)
Advances in Water Resources     Hybrid Journal   (Followers: 46, SJR: 1.551, CiteScore: 3)
Aeolian Research     Hybrid Journal   (Followers: 6, SJR: 1.117, CiteScore: 3)
Aerospace Science and Technology     Hybrid Journal   (Followers: 340, 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: 11, SJR: 3.671, CiteScore: 9)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 448, SJR: 1.238, CiteScore: 3)
Agri Gene     Hybrid Journal   (Followers: 1, SJR: 0.13, CiteScore: 0)
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 17, SJR: 1.818, CiteScore: 5)
Agricultural Systems     Hybrid Journal   (Followers: 31, SJR: 1.156, CiteScore: 4)
Agricultural Water Management     Hybrid Journal   (Followers: 42, SJR: 1.272, CiteScore: 3)
Agriculture and Agricultural Science Procedia     Open Access   (Followers: 3)
Agriculture and Natural Resources     Open Access   (Followers: 3)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 57, SJR: 1.747, CiteScore: 4)
Ain Shams Engineering J.     Open Access   (Followers: 5, SJR: 0.589, CiteScore: 3)
Air Medical J.     Hybrid Journal   (Followers: 6, SJR: 0.26, CiteScore: 0)
AKCE Intl. J. of Graphs and Combinatorics     Open Access   (SJR: 0.19, CiteScore: 0)
Alcohol     Hybrid Journal   (Followers: 11, SJR: 1.153, CiteScore: 3)
Alcoholism and Drug Addiction     Open Access   (Followers: 9)
Alergologia Polska : Polish J. of Allergology     Full-text available via subscription   (Followers: 1)
Alexandria Engineering J.     Open Access   (Followers: 1, 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: 9, SJR: 0.201, CiteScore: 1)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 52, SJR: 4.66, CiteScore: 10)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 4, SJR: 1.796, CiteScore: 4)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 4, SJR: 1.108, CiteScore: 3)
Ambulatory Pediatrics     Hybrid Journal   (Followers: 6)
American Heart J.     Hybrid Journal   (Followers: 50, SJR: 3.267, CiteScore: 4)
American J. of Cardiology     Hybrid Journal   (Followers: 54, SJR: 1.93, CiteScore: 3)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 45, SJR: 0.604, CiteScore: 1)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 10)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 14, SJR: 1.524, CiteScore: 3)
American J. of Human Genetics     Hybrid Journal   (Followers: 34, SJR: 7.45, CiteScore: 8)
American J. of Infection Control     Hybrid Journal   (Followers: 28, SJR: 1.062, CiteScore: 2)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 34, SJR: 2.973, CiteScore: 4)
American J. of Medicine     Hybrid Journal   (Followers: 46)
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: 208, SJR: 2.7, CiteScore: 4)
American J. of Ophthalmology     Hybrid Journal   (Followers: 63, 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: 28, 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: 38, 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: 62, SJR: 0.138, CiteScore: 0)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 17, SJR: 0.411, CiteScore: 1)
Anales de Cirugia Vascular     Full-text available via subscription  
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: 43, SJR: 1.512, CiteScore: 5)
Analytical Biochemistry     Hybrid Journal   (Followers: 175, SJR: 0.633, CiteScore: 2)
Analytical Chemistry Research     Open Access   (Followers: 11, SJR: 0.411, CiteScore: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 11)
Anesthésie & Réanimation     Full-text available via subscription   (Followers: 2)
Anesthesiology Clinics     Full-text available via subscription   (Followers: 23, 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: 192, SJR: 1.58, CiteScore: 3)

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Journal Cover
Acta Pharmaceutica Sinica B
Journal Prestige (SJR): 1.793
Citation Impact (citeScore): 6
Number of Followers: 1  

  This is an Open Access Journal Open Access journal
ISSN (Print) 2211-3843 - ISSN (Online) 2211-3835
Published by Elsevier Homepage  [3162 journals]
  • Serum and glucocorticoid inducible protein kinases (SGKs): a potential
           target for cancer intervention

    • Abstract: Publication date: Available online 5 July 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Rajesh Basnet, Grace Qun Gong, Chenyao Li, Ming-Wei Wang The serum and glucocorticoid inducible protein kinase (SGK) family members share similar structure, substrate specificity and function with AKT and signal downstream of the phosphatidylinositol 3-kinase (PI3K) signalling pathway. They regulate a range of fundamental cellular processes such as cell proliferation and survival, thereby playing an important role in cancer development. This perspective intends to give an overview on the involvement of SGKs (particularly SGK3) in cancer progression, and compares the actions of SGK3 and AKT in cell cycle regulation, oncogenic signalling, and the potential as a therapeutic target for cancer.Graphical abstractGraphical abstract for this article
       
  • Efficacy of inverso isomer of CendR peptide on tumor tissue penetration

    • Abstract: Publication date: Available online 30 June 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Ruifeng Wang, Qing Shen, Xue Li, Cao Xie, Weiyue Lu, Songli Wang, Jing Wang, Dongli Wang, Min Liu The dense extracellular matrix and high interstitial fluid pressure of tumor tissues prevent the ability of anti-tumor agents to penetrate deep into the tumor parenchyma for treatment effects. C-end rule (CendR) peptides can enhance the permeability of tumor blood vessels and tumor tissues via binding to neuropilin-1 (NRP-1), thus aiding in drug delivery. In this study, we selected one of the CendR peptides (sequence RGERPPR) as the parent L-peptide and substituted D-amino acids for the L-amino acids to synthesize its inverso peptide D(RGERPPR). We investigated the NRP-1 binding activity and tumor-penetrating ability of D(RGERPPR). We found that the binding affinity of D(RGERPPR) with NRP-1 and the cellular uptake was significantly higher than that of RGERPPR. Evans Blue tests revealed that D(RGERPPR) exhibited improved tumor-penetrating ability in C6, U87 and A549 tumor-bearing nude mice. Using nude mice bearing A549 xenograft tumors as a model, we found that the rate of tumor growth in the group co-administered with D(RGERPPR) and gemcitabine (Gem) was significantly lower than the gemcitabine-treated group with a tumor suppression rate (TSR%) of 55.4%. Together, our results demonstrate that D(RGERPPR) is a potential tumor-penetrating peptide.Graphical abstractC-end rule (CendR) peptides enhance the permeability of tumor blood vessels and tumor tissues via binding to neuropilin-1 (NRP-1), thus aiding in drug delivery. In this study, we selected one of the CendR peptides (sequence RGERPPR) as the parent L-peptide and substituted D-amino acids for the L-amino acids to synthesize its inverso peptide D(RGERPPR). The binding affinity of D(RGERPPR) with NRP-1 and the cellular uptake was significantly higher than that of RGERPPR.Graphical abstract for this article
       
  • Human carboxylesterases: a comprehensive review

    • Abstract: Publication date: Available online 25 June 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Dandan Wang, Liwei Zou, Qiang Jin, Jie Hou, Guangbo Ge, Ling Yang Mammalian carboxylesterases (CEs) are key enzymes from the serine hydrolase superfamily. In the human body, two predominant carboxylesterases (CES1 and CES2) have been identified and extensively studied over the past decade. These two enzymes play crucial roles in the metabolism of a wide variety of endogenous esters, ester-containing drugs and environmental toxicants. The key roles of CES in both human health and xenobiotic metabolism arouse great interest in the discovery of potent CES modulators to regulate endobiotic metabolism or to improve the efficacy of ester drugs. This review covers the structural and catalytic features of CES, tissue distributions, biological functions, genetic polymorphisms, substrate specificities and inhibitor properties of CES1 and CES2, as well as the significance and recent progress on the discovery of CES modulators. The information presented here will help pharmacologists explore the relevance of CES to human diseases or to assign the contribution of certain CES in xenobiotic metabolism. It will also facilitate medicinal chemistry efforts to design prodrugs activated by a given CES isoform, or to develop potent and selective modulators of CES for potential biomedical applications.Graphical abstractHuman carboxylesterases (CES) play crucial roles in both endo- and xenobiotic metabolism, which arouse great interest in the discovery of potent CES modulators to regulate endobiotic metabolism or to improve the outcomes of ester drugs. This review covers the structural and catalytic features of human CES, tissue distributions, biological functions and substrate specificities of two predominant human CES, as well as the significance and recent progress on the discovery of human CES modulators.fx1
       
  • Adapting liposomes for oral drug delivery

    • Abstract: Publication date: Available online 20 June 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Haisheng He, Yi Lu, Jianping Qi, Quangang Zhu, Zhongjian Chen, Wei Wu Liposomes 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
       
  • Cembrane-type diterpenoids from the South China Sea soft coral
           Sarcophyton mililatensis

    • Abstract: Publication date: Available online 19 June 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Songwei Li, Fei Ye, Zhengdan Zhu, Hui Huang, Shuichun Mao, Yuewei Guo Eight cembrane-type diterpenoids, namely, (+)-(6R)-6-hydroxyisosarcophytoxide (1), (+)-(6R)-6-acetoxyisosarcophytoxide (2), (+)-17-hydroxyisosarcophytoxide (3), sarcomililatins A–D (4–7), and sarcomililatol (8), were isolated from the soft coral Sarcophyton mililatensis collected from Weizhou Island, Guangxi Autonomous Region, together with 2 known related analogues, (+)-isosarcophytoxide (9) and (+)-isosarcophine (10). The structures of these compounds were elucidated by a combination of detailed spectroscopic analyses, chemical methods, and comparison with reported data. The absolute configuration of compound 1 was established by the modified Mosher׳s method, while the absolute configurations of compounds 4 and 5 were assigned by electronic circular dichroism (ECD) spectroscopy and that of compound 8 was established by time-dependent density functional theory electronic circular dichroism (TD-DFT ECD) calculation. In in vitro bioassays, compound 9 displayed significant cytotoxicity against the human cancer cell lines human promyelocytic leukemia cells (HL-60) and human lung adenocarcinoma cells (A-549) with IC50 values of 0.78±0.21 and 1.26±0.80 μmol/L, respectively. Compounds 4 and 9 also showed moderate inhibitory effects on the TNFα-induced Nuclear factor kappa B (NF-κB, a therapeutical target in cancer) activation, showing IC50 values of 35.23±12.42 and 22.52±4.44 μmol/L, respectively.Graphical abstractEight new cembrane-type diterpenoids (1–8) were isolated from the soft coral Sarcophyton mililatensis. Compound 9 displayed significant cytotoxicity, and compounds 4 and 9 showed inhibitory effects on the TNFα-induced NF-κB.fx1
       
  • Development of carrier-free nanocrystals of poorly water-soluble drugs by
           exploring metastable zone of nucleation

    • Abstract: Publication date: Available online 19 June 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Xiaoting Ren, Jianping Qi, Wei Wu, Zongning Yin, Tonglei Li, Yi Lu There 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
       
  • Olmutinib (HM61713) reversed multidrug resistance by inhibiting the
           activity of ATP-binding cassette subfamily G member 2 in vitro and in vivo
           

    • Abstract: Publication date: Available online 15 June 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Zhiqiang Zhang, Xiaoran Guo, Kenneth K.W. To, Zhen Chen, Xiaona Fang, Min Luo, Chunling Ma, Jianhua Xu, Shirong Yan, Liwu Fu Overexpressing of ATP-binding cassette (ABC) transporters is the essential cause of multidrug resistance (MDR), which is a significant hurdle to the success of chemotherapy in many cancers. Therefore, inhibiting the activity of ABC transporters may be a logical approach to circumvent MDR. Olmutinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), which has been approved in South Korea for advanced EGFR T790M-positive non-small cell lung cancer (NSCLC). Here, we found that olmutinib significantly increased the sensitivity of chemotherapy drug in ABCG2-overexpressing cells. Furthermore, olmutinib could also increase the retention of doxorubicin (DOX) and rhodamine 123 (Rho 123) in ABC transporter subfamily G member 2 (ABCG2)-overexpressing cells. In addition, olmutinib was found to stimulate ATPase activity and inhibit photolabeling of ABCG2 with [125I]-iodoarylazidoprazosin (IAAP). However, olmutinib neither altered ABCG2 expression at protein and mRNA levels nor blocked EGFR, Her-2 downstream signaling of AKT and ERK. Importantly, olmutinib enhanced the efficacy of topotecan on the inhibition of S1-MI-80 cell xenograft growth. All the results suggest that olmutinib reverses ABCG2-mediated MDR by binding to ATP bind site of ABCG2 and increasing intracellular chemotherapeutic drug accumulation. Our findings encouraged to further clinical investigation on combination therapy of olmutinib with conventional chemotherapeutic drugs in ABCG2-overexpressing cancer patients.Graphical abstractOlmutinib could bind to ATP-binding cassette transporter subfamily G member 2 (ABCG2) ATP binding site, inhibit its drug efflux function, increase intracellular chemotherapeutic drug accumulation, and then restore sensitivity of multidrug resistance cells to ABCG2 substrate drug.fx1
       
  • Hypoxia-stressed cardiomyocytes promote early cardiac differentiation of
           cardiac stem cells through HIF-1α/Jagged1/Notch1 signaling

    • Abstract: Publication date: Available online 12 June 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Keke Wang, Ranran Ding, Yanping Ha, Yanan Jia, Xiaomin Liao, Sisi Wang, Rujia Li, Zhihua Shen, Hui Xiong, Junli Guo, Wei Jie Hypoxia is beneficial for the differentiation of stem cells transplanted for myocardial injury, but mechanisms underlying this benefit remain unsolved. Here, we report the impact of hypoxia-induced Jagged1 expression in cardiomyocytes (CMs) for driving the differentiation of cardiac stem cells (CSCs). Forced hypoxia-inducible factor 1α (HIF-1α) expression and physical hypoxia (5% O2) treatment could induce Jagged1 expression in neonatal rat CMs. Pharmacological inhibition of HIF-1α by YC-1 attenuated hypoxia-promoted Jagged1 expression in CMs. An ERK inhibitor (PD98059), but not inhibitors of JNK (SP600125), Notch (DAPT), NF-κB (PTDC), JAK (AG490), or STAT3 (Stattic) suppressed hypoxia-induced Jagged1 protein expression in CMs. c-Kit+ CSCs isolated from neonatal rat hearts using a magnetic-activated cell sorting method expressed GATA4, SM22α or vWF, but not Nkx2.5 and cTnI. Moreover, 87.3% of freshly isolated CSCs displayed Notch1 receptor expression. Direct co-culture of CMs with BrdU-labeled CSCs enhanced CSCs differentiation, as evidenced by an increased number of BrdU+/Nkx2.5+ cells, while intermittent hypoxia for 21 days promoted co-culture-triggered differentiation of CSCs into CM-like cells. Notably, YC-1 and DAPT attenuated hypoxia-induced differentiation. Our results suggest that hypoxia induces Jagged1 expression in CMs primarily through ERK signaling, and facilitates early cardiac lineage differentiation of CSCs in CM/CSC co-cultures via HIF-1α/Jagged1/Notch signaling.Graphical abstractHypoxia stress provokes Jagged1 expression in cardiomyocytes mainly through ERK signaling, subsequently leads to activation of Notch1 signaling in c-Kit+ cardiac stem cells (CSCs) via direct cell contact, which in turn favors cardiogenic lineage differentiation in CSCs.fx1
       
  • N6-methyladenosine modification: a novel pharmacological target for
           anti-cancer drug development

    • Abstract: Publication date: Available online 6 June 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Yi Niu, Arabella Wan, Ziyou Lin, Xiongbin Lu, Guohui Wan N6-methyladenosine (m6A) modification is the most pervasive modification of human mRNA molecules. It is reversible via regulation of m6A modification methyltransferase, demethylase and proteins that preferentially recognize m6A modification as “writers”, “erasers” and “readers”, respectively. Altered expression levels of the m6A modification key regulators substantially affect their function, leading to significant phenotype changes in the cell and organism. Recent studies have proved that the m6A modification plays significant roles in regulation of metabolism, stem cell self-renewal, and metastasis in a variety of human cancers. In this review, we describe the potential roles of m6A modification in human cancers and summarize their underlying molecular mechanisms. Moreover, we will highlight potential therapeutic approaches by targeting the key m6A modification regulators for cancer drug development.Graphical abstractN6-methyladenosine (m6A) modification is the most pervasive internal modification in mRNA and plays an important role in cancers via affecting proliferation, invasion, drug resistance and immunosuppression. This review summarizes the pathogenesis and development of cancer that are mainly affected by m6A modification, and demonstrates the mechanisms of m6A modification inhibitors in various cancers. The key regulators for m6A modification may act as potential therapeutic targets for anti-cancer drug development.fx1
       
  • Gold nanorods together with HSP inhibitor-VER-155008 micelles for colon
           cancer mild-temperature photothermal therapy

    • Abstract: Publication date: Available online 5 June 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Xichuan Tang, Liwei Tan, Kun Shi, Jinrong Peng, Yao Xiao, Wenting Li, Lijuan Chen, Qian Yang, Zhiyong Qian Enhancing the heat-sensitivity of tumor cells provides an alternative solution to maintaining the therapeutic outcome of photothermal therapy (PTT). In this study, we constructed a therapeutic system, which was composed of methoxy-polyethylene-glycol-coated-gold-nanorods (MPEG-AuNR) and VER-155008-micelles, to evaluate the effect of VER-155008 on the sensitivity of tumor cells to heat, and further investigate the therapeutic outcome of MPEG-AuNR mediated PTT combined with VER-155008- micelles. VER-155008- micelles down-regulate the expression of heat shock proteins and attenuate the heat-resistance of tumor cell. The survival of HCT116 cells treated with VER-155008- micelles under 45 °C is equal to that treated with high temperature hyperthermia (55 °C) in vitro. Furthermore, we proved either the MPEG-AuNR or VER-155008- micelles can be accumulate in the tumor site by photoacoustic imaging and fluorescent imaging. In vivo anti-cancer evaluation showed that tumor size remarkably decreased (smaller than 100 mm3 or vanished) when treated with combing 45 °C mild PTT system, which contrasted to the tumor size when treated with individual 45 °C mild PTT (around 500 nm3) or normal saline as control (larger than 2000 nm3). These results proved that the VER-155008- micelles can attenuate the heat-resistance of tumor cells and enhance the therapeutic outcome of mild-temperature photothermal therapy.Graphical abstractSpecifically HSP suppression with the increasing temperature, the combined system MPEG-AuNR@VER-M improved the thermal sensitivity of tumor cells and, in consequences, achieved marked anti-tumor effect through mild-temperature photothermal therapy. This system pioneered a mild-temperature photothermal therapeutic regimen of cancer.fx1
       
  • Understanding the biology of HER3 receptor as a therapeutic target in
           human cancer

    • Abstract: Publication date: Available online 2 June 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Hui Lyu, Amy Han, Erik Polsdofer, Shuang Liu, Bolin Liu HER3 belongs to the human epidermal growth factor receptor (HER) family which also includes HER1/EGFR/erbB1, HER2/erbB2, and HER4/erbB4. As a unique member of the HER family, HER3 lacks or has little intrinsic tyrosine kinase activity. It frequently co-expresses and forms heterodimers with other receptor tyrosine kinases (RTKs) in cancer cells to activate oncogenic signaling, especially the PI-3K/Akt pathway and Src kinase. Elevated expression of HER3 has been observed in a wide variety of human cancers and associates with a worse survival in cancer patients with solid tumors. Studies on the underlying mechanism implicate HER3 expression as a major cause of treatment failure in cancer therapy. Activation of HER3 signaling has also been shown to promote cancer metastasis. These data strongly support the notion that therapeutic inactivation of HER3 and/or its downstream signaling is required to overcome treatment resistance and improve the outcomes of cancer patients.Graphical abstractHER3 belongs to the human epidermal growth factor receptor (HER) family. HER3 lacks or has little intrinsic tyrosine kinase activity, but it frequently co-expresses and forms heterodimers with other receptor tyrosine kinases (RTKs) to activate oncogenic signaling in cancer cells. Therapeutic inactivation of HER3 and/or its downstream signaling is required to overcome treatment resistance and improve the outcomes of cancer patients.fx1
       
  • Accurate authentication of Dendrobium officinale and its closely related
           species by comparative analysis of complete plastomes

    • Abstract: Publication date: Available online 1 June 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Shuying Zhu, Zhitao Niu, Qingyun Xue, Hui Wang, Xuezhu Xie, Xiaoyu Ding Owing to its great medicinal and ornamental values, Dendrobium officinale is frequently adulterated with other Dendrobium species on the market. Unfortunately, the utilization of the common DNA markers ITS, ITS2, and matK+rbcL is unable to distinguish D. officinale from 5 closely related species of it (D. tosaense, D. shixingense, D. flexicaule, D. scoriarum and D. aduncum). Here, we compared 63 Dendrobium plastomes comprising 40 newly sequenced plastomes of the 6 species and 23 previously published plastomes. The plastomes of D. officinale and its closely related species were shown to have conserved genome structure and gene content. Comparative analyses revealed that small single copy region contained higher variation than large single copy and inverted repeat regions, which was mainly attributed to the loss/retention of ndh genes. Furthermore, the intraspecific sequence variability among different Dendrobium species was shown to be diversified, which necessitates a cautious evaluation of genetic markers specific for different Dendrobium species. By evaluating the maximum likelihood trees inferred from different datasets, we found that the complete plastome sequence dataset had the highest discriminatory power for D. officinale and its closely related species, indicating that complete plastome sequences can be used to accurately authenticate Dendrobium species.Graphical abstractIn this study, the authors compared 63 Dendrobium plastomes comprising 40 newly sequenced plastomes of this group and 23 previously published plastomes. By evaluating the maximum likelihood (ML) trees inferred from different sequence datasets, we found that D. officinale and its closely related species could be accurately authenticated by using the complete plastome sequences.fx1
       
  • In situ monitoring of the structural change of microemulsions in simulated
           gastrointestinal conditions by SAXS and FRET

    • Abstract: Publication date: Available online 23 May 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Xia Lv, Shuguang Zhang, Huipeng Ma, Peipei Dong, Xiaodong Ma, Ming Xu, Yan Tian, Zeyao Tang, Jinyong Peng, Haibo Chen, Jianbin Zhang Microemulsions are promising drug delivery systems for the oral administration of poorly water-soluble drugs. However, the evolution of microemulsions in the gastrointestinal tract is still poorly characterized, especially the structural change of microemulsions under the effect of lipase and mucus. To better understand the fate of microemulsions in the gastrointestinal tract, we applied small-angle X-ray scattering (SAXS) and fluorescence resonance energy transfer (FRET) to monitor the structural change of microemulsions under the effect of lipolysis and mucus. First, the effect of lipolysis on microemulsions was studied by SAXS, which found the generation of liquid crystalline phases. Meanwhile, FRET spectra indicated micelles with smaller particle sizes were generated during lipolysis, which could be affected by CaCl2, bile salts and lecithin. Then, the effect of mucus on the structural change of lipolysed microemulsions was studied. The results of SAXS and FRET indicated that the liquid crystalline phases disappeared, and more micelles were generated. In summary, we studied the structural change of microemulsions in simulated gastrointestinal conditions by SAXS and FRET, and successfully monitored the appearance and disappearance of the liquid crystalline phases and micelles.Graphical abstractSmall-angle X-ray scattering (SAXS) and fluorescence resonance energy transfer (FRET) methods were applied to monitor the structural change of microemulsions under the effect of lipolysis and mucus in this work. We found that liquid crystalline phases and micelles were appeared under lipolysis, and liquid crystalline phases were disappeared in mucus.fx1
       
  • Targeting an oncogenic kinase/phosphatase signaling network for cancer
           therapy

    • Abstract: Publication date: Available online 22 May 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Xiao-Mei Qi, Fang Wang, Matthew Mortensen, Ryan Wertz, Guan Chen Protein kinases and phosphatases signal by phosphorylation and dephosphorylation to precisely control the activities of their individual and common substrates for a coordinated cellular outcome. In many situations, a kinase/phosphatase complex signals dynamically in time and space through their reciprocal regulations and their cooperative actions on a substrate. This complex may be essential for malignant transformation and progression and can therefore be considered as a target for therapeutic intervention. p38γ is a unique MAPK family member that contains a PDZ motif at its C-terminus and interacts with a PDZ domain-containing protein tyrosine phosphatase PTPH1. This PDZ-coupled binding is required for both PTPH1 dephosphorylation and inactivation of p38γ and for p38γ phosphorylation and activation of PTPH1. Moreover, the p38γ/PTPH1 complex can further regulate their substrates phosphorylation and dephosphorylation, which impacts Ras transformation, malignant growth and progression, and therapeutic response. This review will use the p38γ/PTPH1 signaling network as an example to discuss the potential of targeting the kinase/phosphatase signaling complex for development of novel targeted cancer therapy.Graphical abstractOncogene may activate kinase/phosphatase crosstalk dynamics and further their substrates leading to malignant transformation, growth and progression. Targeting this signaling dynamic may be a novel cancer therapy.fx1
       
  • Mitochondria-targeting drug conjugates for cytotoxic, anti-oxidizing and
           sensing purposes: current strategies and future perspectives

    • Abstract: Publication date: Available online 18 May 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Gantumur Battogtokh, Yeon Su Choi, Dong Seop Kang, Sang Jun Park, Min Suk Shim, Kang Moo Huh, Yong-Yeon Cho, Joo Young Lee, Hye Suk Lee, Han Chang Kang Mitochondrial targeting is a promising approach for solving current issues in clinical application of chemotherapy and diagnosis of several disorders. Here, we discuss direct conjugation of mitochondrial-targeting moieties to anticancer drugs, antioxidants and sensor molecules. Among them, the most widely applied mitochondrial targeting moiety is triphenylphosphonium (TPP), which is a delocalized cationic lipid that readily accumulates and penetrates through the mitochondrial membrane due to the highly negative mitochondrial membrane potential. Other moieties, including short peptides, dequalinium, guanidine, rhodamine, and F16, are also known to be promising mitochondrial targeting agents. Direct conjugation of mitochondrial targeting moieties to anticancer drugs, antioxidants and sensors results in increased cytotoxicity, anti-oxidizing activity and sensing activity, respectively, compared with their non-targeting counterparts, especially in drug-resistant cells. Although many mitochondria-targeted anticancer drug conjugates have been investigated in vitro and in vivo, further clinical studies are still needed. On the other hand, several mitochondria-targeting antioxidants have been analyzed in clinical phases I, II and III trials, and one conjugate has been approved for treating eye disease in Russia. There are numerous ongoing studies of mitochondria-targeted sensors.Graphical abstractMitochondria-targeted anticancer, antioxidant, and sensing agents can selectively accumulate in the mitochondria, where their modes of action occur. In most cases, lipophilic molecules intercalate into the mitochondrial membrane through lipophilic affinity and further move through the matrix owing to the membrane potential difference.fx1
       
  • Novel benzamido derivatives as PTP1B inhibitors with anti-hyperglycemic
           and lipid-lowering efficacy

    • Abstract: Publication date: Available online 8 May 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Yanbo Tang, Xiaolin Zhang, Zheng Chen, Wenwen Yin, Guanglei Nan, Jinying Tian, Fei Ye, Zhiyan Xiao Based on a non-competitive and selective PTP1B inhibitor reported by us previously, thirty-nine benzamido derivatives were designed and synthesized as novel PTP1B inhibitors. Among them, twelve compounds exhibited IC50 values at micromolar level against human recombinant PTP1B, and most of them exhibited significant selectivity to PTP1B over TC-PTP and CD45. Further evaluation of the most potent compound 27 on high-fat diet (HFD)-induced insulin-resistant (IR) obese mice indicated that 27 could modulate glucose metabolism and ameliorate dyslipidemia simultaneously.Graphical abstractThirty-nine benzamido derivatives were designed and synthesized as PTP1B inhibitors. In vivo examination of compound 27 with HFD-induced insulin-resistant (IR) obese mice identified 27 as a new and orally active inhibitor with both anti-hyperglycemic and lipid-lowering effects.fx1
       
  • Editorial for Molecular Imaging and Theranostics

    • Abstract: Publication date: May 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 3Author(s): Wei Lu
       
  • Editor Profile: Guest Editor of Special Column on Molecular Imaging and
           Theranostics

    • Abstract: Publication date: May 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 3Author(s):
       
  • Activation of an unconventional meroterpenoid gene cluster in Neosartorya
           glabra leads to the production of new berkeleyacetals

    • Abstract: Publication date: May 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 3Author(s): Tao Zhang, Jun Wan, Zhajun Zhan, Jian Bai, Bingyu Liu, Youcai Hu Fungal genomes carry many gene clusters seemingly capable of natural products biosynthesis, yet most clusters remain cryptic or down-regulated. Genome mining revealed an unconventional paraherquonin-like meroterpenoid biosynthetic gene cluster in the chromosome of Neosartorya glabra. The cryptic or down-regulated pathway was activated by constitutive expression of pathway-specific regulator gene berA encoded within ber biosynthetic gene cluster. Chemical analysis of mutant Ng-OE: berA extracts enabled the isolation of four berkeleyacetal congeners, in which two of them are new. On the basis of careful bioinformatic analysis of the coding enzymes in the ber gene cluster, the biosynthetic pathway of berkeleyacetals was proposed. These results indicate that this approach would be valuable for discovery of novel natural products and will accelerate the exploitation of prodigious natural products in filamentous fungi.Graphical abstractGenome mining revealed an unconventional paraherquonin-like meroterpenoid biosynthetic gene cluster in the chromosome of Neosartorya glabra. Overexpression of the pathway specific transcriptional regulator (BerA) led to the production of two new compounds berkeleyacetal D (1) and 11-epi-berkeleyacetal C (2). The biosynthetic pathway of berkeleyacetals was proposed by a combined approach, comprising molecular biology, bioinformatics and chemical analysis.fx1
       
  • Biomonitoring for traditional herbal medicinal products using DNA
           metabarcoding and single molecule, real-time sequencing

    • Abstract: Publication date: May 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 3Author(s): Tianyi Xin, Zhichao Xu, Jing Jia, Christine Leon, Songnian Hu, Yulin Lin, Subramanyam Ragupathy, Jingyuan Song, Steven G. Newmaster Global concerns have been paid to the potential hazard of traditional herbal medicinal products (THMPs). Substandard and counterfeit THMPs, including traditional Chinese patent medicine, health foods, dietary supplements, etc. are potential threats to public health. Recent marketplace studies using DNA barcoding have determined that the current quality control methods are not sufficient for ensuring the presence of authentic herbal ingredients and detection of contaminants/adulterants. An efficient biomonitoring method for THMPs is of great needed. Herein, metabarcoding and single-molecule, real-time (SMRT) sequencing were used to detect the multiple ingredients in Jiuwei Qianghuo Wan (JWQHW), a classical herbal prescription widely used in China for the last 800 years. Reference experimental mixtures and commercial JWQHW products from the marketplace were used to confirm the method. Successful SMRT sequencing results recovered 5416 and 4342 circular-consensus sequencing (CCS) reads belonging to the ITS2 and psbA-trnH regions. The results suggest that with the combination of metabarcoding and SMRT sequencing, it is repeatable, reliable, and sensitive enough to detect species in the THMPs, and the error in SMRT sequencing did not affect the ability to identify multiple prescribed species and several adulterants/contaminants. It has the potential for becoming a valuable tool for the biomonitoring of multi-ingredient THMPs.Graphical abstractIn this paper, metabarcoding and single-molecule, real-time (SMRT) sequencing were used to detect the multiple ingredients in Jiuwei Qianghuo Wan (JWQHW), a classical herbal prescription widely used in China for the last 800 years. Successful SMRT sequencing results recovered 5416 and 4342 circular-consensus sequencing (CCS) reads belonging to the ITS2 and psbA-trnH regions, suggesting the combination of metabarcoding and SMRT sequencing is a valuable tool for the biomonitoring of multi-ingredient THMPs.fx1
       
  • Integrated metabolomic and transcriptomic analyses revealed the
           distribution of saponins in Panax notoginseng

    • Abstract: Publication date: May 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 3Author(s): Guangfei Wei, Linlin Dong, Juan Yang, Lianjuan Zhang, Jiang Xu, Feng Yang, Ruiyang Cheng, Ran Xu, Shilin Chen Panax notoginseng is famous for its important therapeutic effects. Saponins are bioactive compounds found in different parts and developmental stages of P. notoginseng plants. Thus, it is urgently to study saponins distribution in different parts and growth ages of P. notoginseng plants. In this study, potential biomarkers were found, and their chemical characteristic differences were revealed through metabolomic analysis. High-performance liquid chromatography data indicated the higher content of saponins (i.e., Rg1, Re, Rd, and Rb1) in the underground parts than that in the aerial parts. 20(S)-Protopanaxadiol saponins were mainly distributed in the aerial parts. Additionally, the total saponin content in the 3-year-old P. notoginseng plant (188.0 mg/g) was 1.4-fold higher than that in 2-year-old plant (130.5 mg/g). The transcriptomic analysis indicated the tissue-specific transcription expression of genes, namely, PnFPS, PnSS, PnSE1, PnSE2, and PnDS, which encoded critical synthases in saponin biosyntheses. These genes showed similar expression patterns among the parts of P. notoginseng plants. The expression levels of these genes in the flowers and leaves were 5.2fold higher than that in the roots and fibrils. These results suggested that saponins might be actively synthesized in the aerial parts and transformed to the underground parts. This study provides insights into the chemical and genetic characteristics of P. notoginseng to facilitate the synthesis of its secondary metabolites and a scientific basis for appropriate collection and rational use of this plant.Graphical abstractThis study elaborates the distribution of saponins and the expression patterns of related genes in different parts and developmental stages of P. notoginseng plants.fx1
       
  • Synergistic immunoreaction of acupuncture-like dissolving microneedles
           containing thymopentin at acupoints in immune-suppressed rats

    • Abstract: Publication date: May 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 3Author(s): Qian Zhang, Chuncao Xu, Shiqi Lin, Huanbin Zhou, Gangtao Yao, Hu Liu, Lili Wang, Xin Pan, Guilan Quan, Chuanbin Wu Dissolving microneedles carried drug molecules can effectively penetrate the stratum corneum of skin to improve the transdermal drug delivery. The traditional Chinese medicine acupuncture is based on the needle stimulation at a specific location (acupoint) to generate and transmit biochemical and physiological signals which alter the pathophysiological state of patients. However, the pain associated with conventional acupuncture needles and the requirement of highly trained professionals limit the development of acupuncture in non-Asian countries. The purpose of this study is to investigate whether the dissolving microneedles can be utilized as a self-administered painless replacement for acupuncture and locally released drug molecules can achieve expected therapeutic outcomes. Immunosuppressive rats were treated with acupuncture at Zusanli (ST36) acupoint using microneedles containing thymopentin. The immune functions and psychological mood of the immunosuppressed animals were examined. The proliferation of splenocytes was examined by CCK-8 assay. CD4 and CD8 expression patterns in spleen cells were detected by flow cytometry. The current study showed that use of either microneedles containing thymopentin or conventional acupuncture both resulted in immune cell proliferation, which was confirmed by flow cytometry. Furthermore, either conventional acupuncture or microneedles were able to effectively mitigate the anxiety caused by immune-suppression when applied on the ST36.Graphical abstractAcupuncture-like dissolving microneedles containing TP5 exhibited synergistic immunoreaction in immune-suppressed rats, which resulted in immune cell proliferation and anxiety mitigation.fx1
       
  • Inhalation treatment of primary lung cancer using liposomal curcumin dry
           powder inhalers

    • Abstract: Publication date: May 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 3Author(s): Tongtong Zhang, Yanming Chen, Yuanyuan Ge, Yuzhen Hu, Miao Li, Yiguang Jin Lung cancer is the leading cause of cancer-related deaths. Traditional chemotherapy causes serious toxicity due to the wide bodily distribution of these drugs. Curcumin is a potential anticancer agent but its low water solubility, poor bioavailability and rapid metabolism significantly limits clinical applications. Here we developed a liposomal curcumin dry powder inhaler (LCD) for inhalation treatment of primary lung cancer. LCDs were obtained from curcumin liposomes after freeze-drying. The LCDs had a mass mean aerodynamic diameter of 5.81 μm and a fine particle fraction of 46.71%, suitable for pulmonary delivery. The uptake of curcumin liposomes by human lung cancer A549 cells was markedly greater and faster than that of free curcumin. The high cytotoxicity on A549 cells and the low cytotoxicity of curcumin liposomes on normal human bronchial BEAS-2B epithelial cells yielded a high selection index partly due to increased cell apoptosis. Curcumin powders, LCDs and gemcitabine were directly sprayed into the lungs of rats with lung cancer through the trachea. LCDs showed higher anticancer effects than the other two medications with regard to pathology and the expression of many cancer-related markers including VEGF, malondialdehyde, TNF-α, caspase-3 and BCL-2. LCDs are a promising medication for inhalation treatment of lung cancer with high therapeutic efficiency.Graphical abstractA liposomal curcumin dry powder inhaler (LCD) was developed for inhalation treatment of primary lung cancer. LCDs are a promising medication for inhalation treatment of lung cancer with high therapeutic efficiency.fx1
       
  • Plastome-wide comparison reveals new SNV resources for the authentication
           of Dendrobium huoshanense and its corresponding medicinal slice (Huoshan
           Fengdou)

    • Abstract: Publication date: May 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 3Author(s): Zhitao Niu, Jiajia Pan, Qingyun Xue, Shuying Zhu, Wei Liu, Xiaoyu Ding Dendrobium species and their corresponding medicinal slices have been extensively used as traditional Chinese medicine (TCM) in many Asian countries. However, it is extremely difficult to identify Dendrobium species based on their morphological and chemical features. In this study, the plastomes of D. huoshanense were used as a model system to investigate the hypothesis that plastomic mutational hotspot regions could provide a useful single nucleotide variants (SNVs) resource for authentication studies. We surveyed the plastomes of 17 Dendrobium species, including the newly sequenced plastome of D. huoshanense. A total of 19 SNVs that could be used for the authentication of D. huoshanense were detected. On the basis of this comprehensive comparison, we identified the four most informative hotspot regions in the Dendrobium plastome that encompass ccsA to ndhF, matK to 3′trnG, rpoB to psbD, and trnT to rbcL. Furthermore, to established a simple and accurate method for the authentication of D. huoshanense and its medicinal slices, a total of 127 samples from 20 Dendrobium species including their corresponding medicinal slices (Fengdous) were used in this study. Our results suggest that D. huoshanense and its medicinal slices can be rapidly and unequivocally identified using this method that combines real-time PCR with the amplification refractory mutation system (ARMS).Graphical abstractThe plastome sequence of Dendrobium huoshanense were sequenced and compared with other 16 Dendrobium species. Our plastome-wide comparison revealed a total of 19 SNVs that could be used for the authentication of D. huoshanense. On the base of the explored SNVs, D. huoshanense and its medicinal slices were quickly distinguished from its adulterants using the RT-ARMS method.fx1
       
  • Implantable sandwich PHBHHx film for burst-free controlled delivery of
           thymopentin peptide

    • Abstract: Publication date: May 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 3Author(s): Ke Peng, Chengyu Wu, Guoxu Wei, Jinghui Jiang, Zhirong Zhang, Xun Sun Sustained release and non-parental formulations of peptides and protein drugs are highly desirable because of enhanced therapeutic effects as well as improved patient compliance. This is especially true for small peptides such as thymopentin (TP5). To this end, implantable sandwich poly (hydroxybutyrate-co-hydroxyhexanoate) (PHBHHx) films were designed to prolong release time and to inhibit burst release phenomenon of TP5 by a simple volatilization method. In vitro release studies revealed that sandwich films had nearly no burst release. In vivo release time of sandwich films was prolonged to 42 days. Pharmacodynamic evaluation demonstrated that TP5 sandwich films significantly increased survival rates in a rat immunosuppressive model and normalized CD4+/CD8+ values. These results suggest that TP5 released from sandwich films can attenuate cyclophosphamide's immunosuppressive activity, and possibly achieve results comparable to daily TP5 injection therapy. Thus, sandwich PHBHHx films show excellent potential as a sustained, burst-free release system for small molecular weight, hydrophilic peptide drugs.Graphical abstractSubcutaneously implanted sandwich poly(hydroxybutyrate-co-hydroxyhexanoate) (PHBHHx) films were proven to prolong release time and to inhibit burst release phenomenon of thymopentin (TP5). Pharmacodynamics analysis revealed that implantable sandwich films could achieve comparative or even superior therapeutic outcomes to TP5 everyday injection therapy.fx1
       
  • Nanoparticles with high payloads of pipemidic acid, a poorly soluble
           crystalline drug: drug-initiated polymerization and self-assembly approach
           

    • Abstract: Publication date: May 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 3Author(s): Elisabetta Pancani, Mario Menendez-Miranda, Alexandra Pastor, François Brisset, Marie-Françoise Bernet-Camard, Didier Desmaële, Ruxandra Gref Nowadays, biodegradable polymers such as poly(lactic acid) (PLA), poly(D,L-lactic-co-glycolic acid) (PLGA) and poly(ε-caprolactone) (PCL) remain the most common biomaterials to produce drug-loaded nanoparticles (NPs). Pipemidic acid (PIP) is a poorly soluble antibiotic with a strong tendency to crystallize. PIP incorporation in PLA/PLGA NPs was challenging because of PIP crystals formation and burst release. As PIP had a poor affinity for the NPs, an alternative approach to encapsulation was used, consisting in coupling PIP to PCL. Thus, a PCL–PIP conjugate was successfully synthesized by an original drug-initiated polymerization in a single step without the need of catalyst. PCL–PIP was characterized by NMR, IR, SEC and mass spectrometry. PCL–PIP was used to prepare self-assembled NPs with PIP contents as high as 27% (w/w). The NPs were characterized by microscopy, DLS, NTA and TRPS. This study paves the way towards the production of NPs with high antibiotic payloads by drug-initiated polymerization. Further studies will deal with the synthesis of novel polymer–PIP conjugates with ester bonds between the drug and PCL. PIP can be considered as a model drug and the strategy developed here could be extended to other challenging antibiotics or anticancer drugs and employed to efficiently incorporate them in NPs.Graphical abstractDrug-initiated ring-opening polymerization of ε-caprolactone leads to the formation of a polymer which self-assembles under the form of nanoparticles. Drug content reaches 27% (w/w).fx1
       
  • C19-Diterpenoid alkaloid arabinosides from an aqueous extract of the
           lateral root of Aconitum carmichaelii and their analgesic activities

    • Abstract: Publication date: May 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 3Author(s): Qinglan Guo, Huan Xia, Xianhua Meng, Gaona Shi, Chengbo Xu, Chenggen Zhu, Tiantai Zhang, Jiangong Shi Eight new C19-diterpenoid alkaloid arabinosides, named aconicarmichosides E–L (1–8), were isolated from an aqueous extract of the lateral roots of Aconitum carmichaelii (Fu Zi). Their structures were determined by spectroscopic and chemical methods including 2D NMR experiments and acid hydrolysis. Compounds 1–8, together with the previously reported four neoline 14-O-arabinosides from the same plant, represent the only examples of glycosidic diterpenoid alkaloids so far. At a dose of 1.0 mg/kg (i.p.), as compared with the black control, compounds 1, 2, and 4–6 exhibited analgesic effects with>65.6% inhibitions against acetic acid-induced writhing of mice. Structure–activity relationship was also discussed.Graphical abstractEight new C19-diterpenoid alkaloid arabinosides, named aconicarmichosides E−L (1−8), were isolated and characterized from an aqueous extract of the lateral roots of Aconitum carmichaelii (Fu Zi). These compounds, together with the previously reported four neoline 14-O-arabinosides from the same extract, represent the only examples of glycosidic diterpenoid alkaloids from nature. At a dose of 1.0 mg/kg (i.p.), compounds 1, 2, and 4–6 exhibited analgesic effects against acetic acid-induced writhing of mice.fx1
       
  • A novel nitroreductase-enhanced MRI contrast agent and its potential
           application in bacterial imaging

    • Abstract: Publication date: May 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 3Author(s): Yun Liu, Leilei Zhang, Marc Nazare, Qingqiang Yao, Hai-Yu Hu Nitroreductases (NTRs) are known to be able to metabolize nitro-substituted compounds in the presence of reduced nicotinamide adenine dinucleotide (NADH) as an electron donor. NTRs are present in a wide range of bacterial genera and, to a lesser extent, in eukaryotes hypoxic tumour cells and tumorous tissues, which makes it an appropriate biomarker for an imaging target to detect the hypoxic status of cancer cells and potential bacterial infections. To evaluate the specific activation level of NTR, great efforts have been devoted to the development of fluorescent probes to detect NTR activities using fluorogenic methods to probe its behaviour in a cellular context; however, NTR-responsive MRI contrast agents are still by far underexplored. In this study, para-nitrobenzyl substituted T1-weighted magnetic resonance imaging (MRI) contrast agent Gd-DOTA-PNB (probe 1) has been designed and explored for the possible detection of NTR. Our experimental results show that probe 1 could serve as an MRI-enhanced contrast agent for monitoring NTR activity. The in vitro response and mechanism of the NTR catalysed reduction of probe 1 have been investigated through LC–MS and MRI. Para-nitrobenzyl substituted probe 1 was catalytically reduced by NTR to the intermediate para-aminobenzyl substituted probe which then underwent a rearrangement elimination reaction to Gd-DOTA, generating the enhanced T1-weighted MR imaging. Further, LC–MS and MRI studies of living Escherichia coli have confirmed the NTR activity detection ability of probe 1 at a cellular level. This method may potentially be used for the diagnosis of bacterial infections.Graphical abstractA novel smart magnetic resonance imaging (MRI) contrast agent for selective sensing nitroreductase (NTR) activity and its initial applications in real time NTR activity detection in living Escherichia coli have been reported.fx1
       
  • 131I-Evans blue: evaluation of necrosis targeting property and preliminary
           assessment of the mechanism in animal models

    • Abstract: Publication date: May 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 3Author(s): Qiaomei Jin, Xin Shan, Qi Luo, Dongjian Zhang, Yuanyu Zhao, Nan Yao, Fei Peng, Dejian Huang, Zhiqi Yin, Wei Liu, Jian Zhang Necrosis is a form of cell death, which is related to various serious diseases such as cardiovascular disease, cancer, and neurodegeneration. Necrosis-avid agents (NAAs) selectively accumulated in the necrotic tissues can be used for imaging and/or therapy of related diseases. The aim of this study was to preliminarily investigate necrosis avidity of 131I-evans blue (131I-EB) and its mechanism. The biodistribution of 131I-EB at 24 h after intravenous administration showed that the radioactivity ratio of necrotic to viable tissue was 3.41 in the liver and 11.82 in the muscle as determined by γ counting in model rats. Autoradiography and histological staining displayed preferential uptake of 131I-EB in necrotic tissues. In vitro nuclear extracts from necrotic cells exhibited 82.3% of the uptake in nuclei at 15 min, as well as 79.2% of the uptake at 2 h after 131I-EB incubation. The DNA binding study demonstrated that evans blue (EB) has strong binding affinity with calf-thymus DNA (CT-DNA) (Ksv=5.08×105 L/(mol/L)). Furthermore, the accumulation of 131I-EB in necrotic muscle was efficiently blocked by an excess amount of unlabeled EB. In conclusion, 131I-EB can not only detect necrosis by binding the DNA released from necrotic cells, but also image necrotic tissues generated from the disease clinically.Graphical abstractIn the present study, we demonstrated that 131I-evens blue (EB) could specifically bind to necrotic tissues image necrosis in living animals. Furthermore, the necrosis targeting mechanism of EB might be attributed to its binding to exposed DNA in necrotic areas.fx1
       
  • Design of SERS nanoprobes for Raman imaging: materials, critical factors
           and architectures

    • Abstract: Publication date: May 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 3Author(s): Mingwang Li, Yuanyuan Qiu, Chenchen Fan, Kai Cui, Yongming Zhang, Zeyu Xiao Raman imaging yields high specificity and sensitivity when compared to other imaging modalities, mainly due to its fingerprint signature. However, intrinsic Raman signals are weak, thus limiting medical applications of Raman imaging. By adsorbing Raman molecules onto specific nanostructures such as noble metals, Raman signals can be significantly enhanced, termed surface-enhanced Raman scattering (SERS). Recent years have witnessed great interest in the development of SERS nanoprobes for Raman imaging. Rationally designed SERS nanoprobes have greatly enhanced Raman signals by several orders of magnitude, thus showing great potential for biomedical applications. In this review we elaborate on recent progress in design strategies with emphasis on material properties, modifying factors, and structural parameters.Graphical abstractRational design of surface-enhanced Raman scattering (SERS) nanoprobes is important for maximizing their biomedical applications. This review gives a brief introduction on the development of SERS-active materials, explores the factors that affect SERS enhancement, and illustrates the strategies used to fabricate SERS-active nanostructures for a wide range of applications.Graphical abstract for this article
       
  • The combined therapeutic effects of 131iodine-labeled multifunctional
           copper sulfide-loaded microspheres in treating breast cancer

    • Abstract: Publication date: May 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 3Author(s): Qiufang Liu, Yuyi Qian, Panli Li, Sihang Zhang, Zerong Wang, Jianjun Liu, Xiaoguang Sun, Michael Fulham, Dagan Feng, Zhigang Chen, Shaoli Song, Wei Lu, Gang Huang Compared to conventional cancer treatment, combination therapy based on well-designed nanoscale platforms may offer an opportunity to eliminate tumors and reduce recurrence and metastasis. In this study, we prepared multifunctional microspheres loading 131I-labeled hollow copper sulfide nanoparticles and paclitaxel (131I-HCuSNPs-MS-PTX) for imaging and therapeutics of W256/B breast tumors in rats. 18F-fluordeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) imaging detected that the expansion of the tumor volume was delayed (P
       
  • Radiopaque nano and polymeric materials for atherosclerosis imaging,
           embolization and other catheterization procedures

    • Abstract: Publication date: May 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 3Author(s): Li Tian, Linfeng Lu, James Feng, Marites P. Melancon A review of radiopaque nano and polymeric materials for atherosclerosis imaging and catheterization procedures is presented in this paper. Cardiovascular diseases (CVDs) are the leading cause of death in the US with atherosclerosis as a significant contributor for mortality and morbidity. In this review paper, we discussed the physics of radiopacity and X-ray/CT, clinically used contrast agents, and the recent progress in the development of radiopaque imaging agents and devices for the diagnosis and treatment of CVDs. We focused on radiopaque imaging agents for atherosclerosis, radiopaque embolic agents and drug eluting beads, and other radiopaque medical devices related to catheterization procedures to treat CVDs. Common strategies of introducing radiopacity in the polymers, together with examples of their applications in imaging and medical devices, are also presented.Graphical abstractIn this review paper, we discussed the physics of radiopacity and X-ray/ CT, clinically used contrast agents, and the recent progress in the development of radiopaque imaging agents and devices for the diagnosis and treatment of cardiovascular diseases (CVDs). We focused on radiopaque imaging agents for atherosclerosis, radiopaque embolic agents, drug eluting beads, and other radiopaque medical devices related to catheterization procedures to treat CVDs. Common strategies of introducing radiopacity in the polymers, together with examples of their applications in imaging and medical devices, are also presented.fx1
       
  • Surface-enhanced Raman nanoparticles for tumor theranostics applications

    • Abstract: Publication date: May 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 3Author(s): Yangyang Li, Qiaolin Wei, Fei Ma, Xin Li, Fengyong Liu, Min Zhou Raman spectroscopy, amplified by surface-enhanced Raman scattering (SERS) nanoparticles, can provide an in vivo imaging modality due to its high molecular specificity, high sensitivity, and negligible autofluorescence. The basis, composition, and methodologies developed for SERS nanoparticles are herein described. The research hotspots that are the focus in this paper are tumor imaging-guided theranostics and biosensing. The next breakthrough may be the development of biocompatible SERS nanoparticles and spectroscopic devices for clinical applications.Graphical abstractSurface-enhanced Raman scattering (SERS) nanoparticles have been widely used for biomedical applications including image-directed theranostics and biomarker detection. The basis, composition and methodologies developed for SERS nanoparticles are discussed. Development of biocompatible SERS nanoparticles has promising prospects for clinic applications.fx1
       
  • Fluorogen-activating proteins: beyond classical fluorescent proteins

    • Abstract: Publication date: May 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 3Author(s): Shengnan Xu, Hai-Yu Hu Fluorescence imaging is a powerful technique for the real-time noninvasive monitoring of protein dynamics. Recently, fluorogen activating proteins (FAPs)/fluorogen probes for protein imaging were developed. Unlike the traditional fluorescent proteins (FPs), FAPs do not fluoresce unless bound to their specific small-molecule fluorogens. When using FAPs/fluorogen probes, a washing step is not required for the removal of free probes from the cells, thus allowing rapid and specific detection of proteins in living cells with high signal-to-noise ratio. Furthermore, with different fluorogens, living cell multi-color proteins labeling system was developed. In this review, we describe about the discovery of FAPs, the design strategy of FAP fluorogens, the application of the FAP technology and the advances of FAP technology in protein labeling systems.Graphical abstractFluorescence imaging is a powerful technique for the real-time noninvasive monitoring of protein dynamics. Recently, fluorogen activating proteins (FAPs)/fluorogen probes for protein imaging were developed. In this review, we describe about the discovery of FAPs, the design strategy of FAP fluorogens, the application of the FAP technology and the advances of FAP technology in protein labeling systems.fx1
       
  • Recent developments in multimodality fluorescence imaging probes

    • Abstract: Publication date: May 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 3Author(s): Jianhong Zhao, Junwei Chen, Shengnan Ma, Qianqian Liu, Lixian Huang, Xiani Chen, Kaiyan Lou, Wei Wang Multimodality optical imaging probes have emerged as powerful tools that improve detection sensitivity and accuracy, important in disease diagnosis and treatment. In this review, we focus on recent developments of optical fluorescence imaging (OFI) probe integration with other imaging modalities such as X-ray computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT), and photoacoustic imaging (PAI). The imaging technologies are briefly described in order to introduce the strengths and limitations of each techniques and the need for further multimodality optical imaging probe development. The emphasis of this account is placed on how design strategies are currently implemented to afford physicochemically and biologically compatible multimodality optical fluorescence imaging probes. We also present studies that overcame intrinsic disadvantages of each imaging technique by multimodality approach with improved detection sensitivity and accuracy.Graphical abstractThis review is focused on the recent development of optical fluorescence imaging (OFI) probe integrating with imaging contrast agents. The multimodality fluorescence imaging probes are aimed to overcome intrinsic drawbacks of each imaging modality with complementary information from different modalities for improved sensitivity and accuracy, which are important in disease diagnosis and treatment.fx1
       
  • The enzymatic biosynthesis of acylated steroidal glycosides and their
           cytotoxic activity

    • Abstract: Publication date: Available online 1 May 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Ming Liu, Jian-Qiang Kong Herein we describe the discovery and functional characterization of a steroidal glycosyltransferase (SGT) from Ornithogalum saundersiae and a steroidal glycoside acyltransferase (SGA) from Escherichia coli and their application in the biosynthesis of acylated steroidal glycosides (ASGs). Initially, an SGT gene, designated as OsSGT1, was isolated from O. saundersiae. OsSGT1-containing cell free extract was then used as the biocatalyst to react with 49 structurally diverse drug-like compounds. The recombinant OsSGT1 was shown to be active against both 3β- and 17β-hydroxyl steroids. Unexpectedly, in an effort to identify OsSGT1, we found the bacteria lacA gene in lac operon actually encoded an SGA, specifically catalyzing the acetylations of sugar moieties of steroid 17β-glucosides. Finally, a novel enzymatic two-step synthesis of two ASGs, acetylated testosterone-17-O-β-glucosides (AT-17β-Gs) and acetylated estradiol-17-O-β-glucosides (AE-17β-Gs), from the abundantly available free steroids using OsSGT1 and EcSGA1 as the biocatalysts was developed. The two-step process is characterized by EcSGA1-catalyzed regioselective acylations of all hydroxyl groups on the sugar unit of unprotected steroidal glycosides (SGs) in the late stage, thereby significantly streamlining the synthetic route towards ASGs and thus forming four monoacylates. The improved cytotoxic activities of 3′-acetylated testosterone17-O-β-glucoside towards seven human tumor cell lines were thus observable.Graphical abstractA steroidal glycosyltransferase OsSGT1 from Ornithogalum saundersiae and a bacterial steroidal glycoside acyltransferase EcSGT1 were functionally characterized, respectively. Under the synergistic actions of OsSGT1 and EsSGA1, an enzymatic biosynthesis of four acetylated testosterone17-O-β-glucosides was thus achieved for the first time.fx1
       
  • Personalized medicine in non-small cell lung cancer: A review from a
           pharmacogenomics perspective

    • Abstract: Publication date: Available online 30 April 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Wenxiao Jiang, Guiqing Cai, Peter C. Hu, Yue Wang Non-small cell lung cancer is a prevalent and rapidly-expanding challenge to modern medicine. While generalized medicine with traditional chemotherapy yielded comparatively poor response rates and treatment results, the cornerstone of personalized medicine using genetic profiling to direct treatment has exalted the successes seen in the field and raised the standard for patient treatment in lung and other cancers. Here, we discuss the current state and advances in the field of personalized medicine for lung cancer, reviewing several of the mutation-targeting strategies that are approved for clinical use and how they are guided by patient genetic information. These classes include inhibitors of tyrosine kinase (TKI), anaplastic lymphoma kinase (ALK), and monoclonal antibodies. Selecting from these treatment plans and determining the optimal dosage requires in-depth genetic guidance with consideration towards not only the underlying target genes but also other factors such as individual metabolic capability and presence of resistance-conferring mutations both directly on the target gene and along its cascade(s). Finally, we provide our viewpoints on the future of personalized medicine in lung cancer, including target-based drug combination, mutation-guided drug design and the necessity for data of population genetics, to provide rough guidance on treating patients who are unable to get genetic testing.Graphical abstractThis review discusses the current state and advances in the field of personalized medicine for lung cancer, reviewing several of the mutation-targeting strategies that are approved for clinical use and how they are guided by patient genetic information, and finally provide the viewpoints on the future of personalized medicine in lung cancer.fx1
       
  • Taxane resistance in castration-resistant prostate cancer: mechanisms and
           therapeutic strategies

    • Abstract: Publication date: Available online 30 April 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Brandon Bumbaca, Wei Li Despite its good initial response and significant survival benefit in patients with castration-resistant prostate cancer (CRPC), taxane therapy inevitably encounters drug resistance in all patients. Deep understandings of taxane resistant mechanisms can significantly facilitate the development of new therapeutic strategies to overcome taxane resistance and improve CRPC patient survival. Multiple pathways of resistance have been identified as potentially crucial areas of intervention. First, taxane resistant tumor cells typically have mutated microtubule binding sites, varying tubulin isotype expression, and upregulation of efflux transporters. These mechanisms contribute to reducing binding affinity and availability of taxanes. Second, taxane resistant tumors have increased stem cell like characteristics, indicating higher potential for further mutation in response to therapy. Third, the androgen receptor pathway is instrumental in the proliferation of CRPC and multiple hypotheses leading to this pathway reactivation have been reported. The connection of this pathway to the AKT pathway has received significant attention due to the upregulation of phosphorylated AKT in CRPC. This review highlights recent advances in elucidating taxane resistant mechanisms and summarizes potential therapeutic strategies for improved treatment of CRPC.
       
  • Genome-wide characterization and analysis of bHLH transcription factors in
           Panax ginseng

    • Abstract: Publication date: Available online 12 April 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Yang Chu, Shuiming Xiao, He Su, Baosheng Liao, Jingjing Zhang, Jiang Xu, Shilin Chen Ginseng (Panax ginseng C.A. Meyer) is one of the best-selling herbal medicines, with ginsenosides as its main pharmacologically active constituents. Although extensive chemical and pharmaceutical studies of these compounds have been performed, genome-wide studies of the basic helix-loop-helix (bHLH) transcription factors of ginseng are still limited. The bHLH transcription factor family is one of the largest transcription factor families found in eukaryotic organisms, and these proteins are involved in a myriad of regulatory processes. In our study, 169 bHLH transcription factor genes were identified in the genome of P. ginseng, and phylogenetic analysis indicated that these PGbHLHs could be classified into 24 subfamilies. A total of 21 RNA-seq data sets, including two sequencing libraries for jasmonate (JA)-responsive and 19 reported libraries for organ-specific expression analyses were constructed. Through a combination of gene-specific expression patterns and chemical contents, 6 PGbHLH genes from 4 subfamilies were revealed to be potentially involved in the regulation of ginsenoside biosynthesis. These 6 PGbHLHs, which had distinct target genes, were further divided into two groups depending on the absence of MYC-N structure. Our results would provide a foundation for understanding the molecular basis and regulatory mechanisms of bHLH transcription factor action in P. ginseng.Graphical abstractAltogether 169 basic helix-loop-helix type transcription factor genes were identified in the genome of P. ginseng, and phylogenetic analysis indicated that these PGbHLHs could be classified into 24 subfamilies. Six PGbHLH genes from 4 subfamilies were revealed to be potentially involved in the regulation of ginsenoside biosynthesis. These 6 PGbHLHs, which had distinct target genes, were further divided into two groups depending on the absence of MYC-N structure.fx1
       
  • Drug metabolism in drug discovery and development

    • Abstract: Publication date: Available online 12 April 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Zhoupeng Zhang, Wei Tang Drug metabolism as a discipline plays an important role in drug discovery and development and the effects of drug metabolism on pharmacokinetics (PK), pharmacodynamics (PD), and safety should be carefully considered. This communication provides an overview of common strategies in the area of drug metabolism for improving PK/PD and safety profiles of drug candidates; these include, but are not limited to, collaboration with medicinal chemists on structure–activity relationships (SAR) to overcome high clearance, using deuterium replacement to further optimize a lead, prodrug approaches to circumvent formulation and delivery difficulties, and addressing issues such as species differences in metabolism, drug–drug interactions (DDI) and formation of reactive metabolites.Graphical abstractDrug metabolism plays important roles in optimizing pharmacokinetics (PK), pharmacodynamics (PD), and safety profiles of drug candidates in drug discovery and development.fx1
       
  • Bioactive thionic compounds and aromatic glycosides from Ligusticum
           chuanxiong

    • Abstract: Publication date: Available online 11 April 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Xu Zhang, Bing Han, Ziming Feng, Jianshuang Jiang, Yanan Yang, Peicheng Zhang Three new thionic compounds, (S)-2-(2-carboxyl-2-hydroxyethylthio)-ferulic acid (1), (E)-2-methoxy-4-(3-(methylsulfonyl)prop-1-en-1-yl)phenol (2), and thiosenkyunolide C (3), together with two new aromatic glycosides (4 and 5) were isolated from the rhizome of Ligusticum chuanxiong Hort. Two known compounds (6 and 7) were also obtained. Their structures were elucidated based on extensive spectroscopic data (UV, IR, 1D and 2D NMR, and HR-ESI-MS). Furthermore the absolute configurations were established by comparison of their calculated and experimental circular dichroism spectra and by a dimolybdenum tetraacetate [Mo2(AcO)4]-induced circular dichroism procedure. All compounds were evaluated against lipopolysaccharide (LPS)-induced NO production in BV2 cells, and compounds 4 and 5 showed strong inhibitory activities with IC50 values of 2.03 and 3.09 µmol/L, respectively (positive control curcumin, IC50 = 6.17 µmol/L). In addition, compound 1 showed weak proteintyrosine phosphatase-1B (PTP1B) inhibitory activity.Graphical abstractGraphical abstract for this article
       
  • The application of CAR-T cell therapy in hematological malignancies:
           Advantages and challenges

    • Abstract: Publication date: Available online 5 April 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Zijun Zhao, Yu Chen, Ngiambudulu M. Francisco, Yuanqing Zhang, Minhao Wu Chimeric antigen receptor T cell (CAR-T cell) therapy is a novel adoptive immunotherapy where T lymphocytes are engineered with synthetic receptors known as chimeric antigen receptors (CAR). The CAR-T cell is an effector T cell that recognizes and eliminates specific cancer cells, independent of major histocompatibility complex molecules. The whole procedure of CAR-T cell production is not well understood. The CAR-T cell has been used predominantly in the treatment of hematological malignancies, including acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphoma, and multiple myeloma. Solid tumors including melanoma, breast cancer and sarcoma offer great promise in CAR-T cell research and development. CD19 CAR-T cell is most commonly used, and other targets, including CD20, CD30, CD38 and CD138 are being studied. Although this novel therapy is promising, there are several disadvantages. In this review we discuss the applications of CAR-T cells in different hematological malignancies, and pave a way for future improvement on the effectiveness and persistence of these adoptive cell therapies.Graphical abstractChimeric antigen receptor T cells (CAR-T cells) are effector T cells processed from natural T cells by replacing the T cell receptor (TCR) part to CAR part which can recognize and eliminate tumor cells specifically. Their application has been made great progress in hematological malignancies, whereas various difficulties should be overcame in treating solid tumors. This review mainly focuses on the applications of CAR-T cells in different hematological malignancies.fx1
       
  • Helioscopianoids A–Q, bioactive jatrophane diterpenoid esters from
           Euphorbia helioscopia

    • Abstract: Publication date: Available online 1 April 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Zhenpeng Mai, Gang Ni, Yanfei Liu, Zhao Zhang, Li Li, Naihong Chen, Dequan Yu The EtOH extracts of the whole plants of Euphorbia helioscopia afforded 17 new jatrophane diterpenoid esters, helioscopianoids A–Q (117), along with eight known compounds (18–25). Their structures were elucidated by extensive spectroscopic methods and Mo2(OAc)4-induced ECD analysis, and the structures of compounds 1, 2, and 7 were confirmed by X-ray crystallography. Compounds 1–17 were evaluated for inhibitory effects on P-glycoprotein (P-gp) in an adriamycin (ADM)-resistant human breast adenocarcinoma cell line (MCF-7/ADR) and neuroprotective effects against serum deprivation-induced and rotenone-induced PC12 cell damage. Compounds 8 and 16 increased the accumulation of ADM in MCF-7/ADR cells by approximately 3-fold at a concentration of 20 μmol/L. Compound 8 could attenuate rotenone-induced PC12 cell damage, and compounds 2, 8, and 12 showed neuroprotective activities against serum deprivation-induced PC12 cell damage.Graphical abstractSeventeen new jatrophane diterpenoid esters, helioscopianoids A–Q (117), were isolated from the whole plants of Euphorbia helioscopia. Compounds 8 and 16 showed P-glycoprotein inhibitory activities, and compounds 2, 8, and 12 showed neuroprotective activities.fx1
       
  • Preparation and characterization of multimodal hybrid organic and
           inorganic nanocrystals of camptothecin and gold

    • Abstract: Publication date: Available online 22 March 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Christin P. Hollis, Alan K. Dozier, Barbara L. Knutson, Tonglei Li We 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
       
  • 3D tissue engineering, an emerging technique for pharmaceutical research

    • Abstract: Publication date: Available online 21 March 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Gregory Jensen, Christian Morrill, Yu Huang Tissue engineering and the tissue engineering model have shown promise in improving methods of drug delivery, drug action, and drug discovery in pharmaceutical research for the attenuation of the central nervous system inflammatory response. Such inflammation contributes to the lack of regenerative ability of neural cells, as well as the temporary and permanent loss of function associated with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and traumatic brain injury. This review is focused specifically on the recent advances in the tissue engineering model made by altering scaffold biophysical and biochemical properties for use in the treatment of neurodegenerative diseases. A portion of this article will also be spent on the review of recent progress made in extracellular matrix decellularization as a new and innovative scaffold for disease treatment.Graphical abstractTissue engineering and the tissue engineering model have shown promise in improving methods of drug delivery, drug action, and drug discovery in pharmaceutical research for the attenuation of the central nervous system inflammatory response. The recent advances reviewed here focus on three major types of tissue engineering models used in pharmaceutical research, especially for the treatment of neurodegenerative diseases.fx1
       
  • Structure-based design, synthesis, and biological evaluation of novel
           pyrimidinone derivatives as PDE9 inhibitors

    • Abstract: Publication date: Available online 12 March 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Xu-Nian Wu, Ya-Dan Huang, Jin-Xuan Li, Yan-Fa Yu, Zhou Qian, Chen Zhang, Yinuo Wu, Hai-Bin Luo The pathological processes of Alzheimer's disease and type 2 diabetes mellitus have been demonstrated to be linked together. Both PDE9 inhibitors and PPARγ agonists such as rosiglitazone exhibited remarkable preclinical and clinical treatment effects for these two diseases. In this study, a series of PDE9 inhibitors combining the pharmacophore of rosiglitazone were discovered. All the compounds possessed remarkable affinities towards PDE9 and four of them have the IC50 values
       
  • Biocatalytic access to diverse prenylflavonoids by combining a
           

    • Abstract: Publication date: Available online 5 March 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Jianhua Li, Ridao Chen, Ruishan Wang, Xiao Liu, Kebo Xie, Dawei Chen, Jungui Dai Prenylflavonoids are valuable natural products that have diverse biological properties, and are usually generated biologically by multiple metabolic enzymes in nature. In this study, structurally diverse prenylflavonoids were conveniently synthesized by enzymatic catalysis by combining GuILDT, a regiospecific chalcone prenyltransferase, and GuCHI, a stereospecific chalcone isomerase that has promiscuous activity for both chalcones and prenylchalcones as substrates. Our findings provided a new approach for the synthesis of natural/unnatural bioactive prenylflavonoids, including prenylchalcones and optical prenylflavanones with chalcone origins.Graphical abstractThis study demonstrates that structurally diverse prenylflavonoids were conveniently synthesized through promiscuously enzymatic catalysis by combining a regiospecific chalcone prenyltransferase and a stereospecific chalcone isomerase.fx1
       
  • Beneficial effects of Houttuynia cordata polysaccharides on “two-hit”
           acute lung injury and endotoxic fever in rats associated with
           anti-complementary activities

    • Abstract: Publication date: March 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 2Author(s): Yan Lu, Yun Jiang, Lijun Ling, Yunyi Zhang, Hong Li, Daofeng Chen Houttuynia cordata Thunb. is a traditional herb used for clearing heat and eliminating toxins, and has also been used for the treatment of severe acute respiratory syndrome (SARS). In vitro, the crude H. cordata polysaccharides (CHCP) exhibited potent anti-complementary activity through both the classical and alternative pathways by acting on components C3 and C4 of the complement system without interfering with the coagulation system. This study was to investigate the preventive effects of CHCP on acute lung injury (ALI) induced by hemorrhagic shock plus lipopolysaccharide (LPS) instillation (two-hit) and LPS-induced fever in rats. CHCP significantly attenuated pulmonary injury in the “two-hit” ALI model by reducing pulmonary edema and protein exudation in bronchoalveolar lavage fluid (BALF). In addition, it reduced the deposit of complement activation products in the lung and improved oxidant-antioxidant imbalance. Moreover, CHCP administration inhibited fever in rats, reduced the number of leukocytes and restored serum complement levels. The inhibition on the inappropriate activation of complement system by CHCP may play an important role in its beneficial effects on inflammatory diseases. The anti-complementary polysaccharides are likely to be among the key substances for the heat-clearing function of H. cordata.Graphical abstractCrude extracts of Houttuynia cordata polysaccharides (CHCP) significantly attenuated pulmonary injury in rats in the ‘two-hit’ acute lung injury induced by hemorrhagic shock plus lipopolysaccharide (LPS) instillation, and inhibited LPS-induced fever in rats. The anti-complementary activity of CHCP plays an important role in its beneficial effects on the inflammatory diseases.fx1
       
  • A novel quantified bitterness evaluation model for traditional Chinese
           herbs based on an animal ethology principle

    • Abstract: Publication date: March 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 2Author(s): Xue Han, Hong Jiang, Li Han, Xi Xiong, Yanan He, Chaomei Fu, Runchun Xu, Dingkun Zhang, Junzhi Lin, Ming Yang Traditional Chinese herbs (TCH) are currently gaining attention in disease prevention and health care plans. However, their general bitter taste hinders their use. Despite the development of a variety of taste evaluation methods, it is still a major challenge to establish a quantitative detection technique that is objective, authentic and sensitive. Based on the two-bottle preference test (TBP), we proposed a novel quantitative strategy using a standardized animal test and a unified quantitative benchmark. To reduce the difference of results, the methodology of TBP was optimized. The relationship between the concentration of quinine and animal preference index (PI) was obtained. Then the PI of TCH was measured through TBP, and bitterness results were converted into a unified numerical system using the relationship of concentration and PI. To verify the authenticity and sensitivity of quantified results, human sensory testing and electronic tongue testing were applied. The quantified results showed a good discrimination ability. For example, the bitterness of Coptidis Rhizoma was equal to 0.0579 mg/mL quinine, and Nelumbinis Folium was equal to 0.0001 mg/mL. The validation results proved that the new assessment method for TCH was objective and reliable. In conclusion, this study provides an option for the quantification of bitterness and the evaluation of taste masking effects.Graphical abstractA quantitative strategy for bitterness of traditional Chinese herbs was developed using a standardized animal test and a unified quantitative benchmark in this study. It provides an option for the quantification of bitterness and the evaluation of taste masking effects.fx1
       
  • A pilot study of the modulation of sirtuins on arylamine
           N-acetyltransferase 1 and 2 enzymatic activity

    • Abstract: Publication date: March 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 2Author(s): Eneida Turiján-Espinoza, Rául Alejandro Salazar-González, Edith Elena Uresti-Rivera, Gloria Estela Hernández-Hernández, Montserrat Ortega-Juárez, Rosa Milán, Diana Portales-Pérez Arylamine N-acetyltransferase (NAT; E.C. 2.3.1.5) enzymes are responsible for the biotransformation of several arylamine and hydrazine drugs by acetylation. In this process, the acetyl group transferred to the acceptor substrate produces NAT deacetylation and, in consequence, it is susceptible of degradation. Sirtuins are protein deacetylases, dependent on nicotine adenine dinucleotide, which perform post-translational modifications on cytosolic proteins. To explore possible sirtuin participation in the enzymatic activity of arylamine NATs, the expression levels of NAT1, NAT2, SIRT1 and SIRT6 in peripheral blood mononuclear cells (PBMC) from healthy subjects were examined by flow cytometry and Western blot. The in situ activity of the sirtuins on NAT enzymatic activity was analyzed by HPLC, in the presence or absence of an agonist (resveratrol) and inhibitor (nicotinamide) of sirtuins. We detected a higher percentage of positive cells for NAT2 in comparison with NAT1, and higher numbers of SIRT1+ cells compared to SIRT6 in lymphocytes. In situ NAT2 activity in the presence of NAM inhibitors was higher than in the presence of its substrate, but not in the presence of resveratrol. In contrast, the activity of NAT1 was not affected by sirtuins. These results showed that NAT2 activity might be modified by sirtuins.Graphical abstractThe present study exhibited a highly significant effect (P
       
  • 1,25-Dihydroxyvitamin D3 protects obese rats from metabolic syndrome via
           promoting regulatory T cell-mediated resolution of inflammation

    • Abstract: Publication date: March 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 2Author(s): Wen Jin, Bing Cui, Pingping Li, Fang Hua, Xiaoxi Lv, Jichao Zhou, Zhuowei Hu, Xiaowei Zhang Vitamin D3 has been found to produce therapeutic effects on obesity-associated insulin resistance and dyslipidemia through its potent anti-inflammatory activity, but the precise immunomodulatory mechanism remains poorly understood. In the present study we found that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the biologically active form of vitamin D3, significantly attenuated monosodium glutamate (MSG)-induced obesity and insulin resistance as indicated by body weight reduction, oral glucose tolerance improvement, and a glucose infusion rate increase as detected with hyperinsulinemic-euglycemic clamp. Moreover, 1,25(OH)2D3 not only restored pancreatic islet functions but also improved lipid metabolism in insulin-targeted tissues. The protective effects of 1,25(OH)2D3 on glycolipid metabolism were attributed to its ability to inhibit an obesity-activated inflammatory response in insulin secretory and targeted tissues, as indicated by reduced infiltration of macrophages in pancreas islets and adipose tissue while enhancing the expression of Tgf-β1 in liver tissue, which was accompanied by increased infiltration of Treg cells in immune organs such as spleen and lymph node as well as in insulin-targeted tissues such as liver, adipose, and muscle. Together, our findings suggest that 1,25(OH)2D3 serves as a beneficial immunomodulator for the prevention and treatment of obesity or metabolic syndrome through its anti-inflammatory effects.Graphical abstractObesity is associated with multiple adverse health outcomes collectively summarized as the “metabolic syndrome”, consisting of insulin resistance and dyslipidemia. Administration of 1,25(OH)2D3 protects MSG obese rats from the development of obesity and its related metabolic risks via increasing the infiltration of CD4+CD25+ regulatory T-cells in primary insulin targeted-tissues.fx1
       
  • Mesoporous silica nanoparticles for drug and gene delivery

    • Abstract: Publication date: March 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 2Author(s): Yixian Zhou, Guilan Quan, Qiaoli Wu, Xiaoxu Zhang, Boyi Niu, Biyuan Wu, Ying Huang, Xin Pan, Chuanbin Wu Mesoporous silica nanoparticles (MSNs) are attracting increasing interest for potential biomedical applications. With tailored mesoporous structure, huge surface area and pore volume, selective surface functionality, as well as morphology control, MSNs exhibit high loading capacity for therapeutic agents and controlled release properties if modified with stimuli-responsive groups, polymers or proteins. In this review article, the applications of MSNs in pharmaceutics to improve drug bioavailability, reduce drug toxicity, and deliver with cellular targetability are summarized. Particularly, the exciting progress in the development of MSNs-based effective delivery systems for poorly soluble drugs, anticancer agents, and therapeutic genes are highlighted.Graphical abstractMesoporous silica nanoparticles (MSNs) with unique properties have attracted increasing interest for biomedical applications. Particularly, MSNs have shown great potential to deliver poorly soluble drugs, anticancer agents, and therapeutic genes.fx1
       
  • Designing the new generation of intelligent biocompatible carriers for
           protein and peptide delivery

    • Abstract: Publication date: March 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 2Author(s): Angela M. Wagner, Margaret P. Gran, Nicholas A. Peppas Therapeutic proteins and peptides have revolutionized treatment for a number of diseases, and the expected increase in macromolecule-based therapies brings a new set of challenges for the pharmaceutics field. Due to their poor stability, large molecular weight, and poor transport properties, therapeutic proteins and peptides are predominantly limited to parenteral administration. The short serum half-lives typically require frequent injections to maintain an effective dose, and patient compliance is a growing issue as therapeutic protein treatments become more widely available. A number of studies have underscored the relationship of subcutaneous injections with patient non-adherence, estimating that over half of insulin-dependent adults intentionally skip injections. The development of oral formulations has the potential to address some issues associated with non-adherence including the interference with daily activities, embarrassment, and injection pain. Oral delivery can also help to eliminate the adverse effects and scar tissue buildup associated with repeated injections. However, there are several major challenges associated with oral delivery of proteins and peptides, such as the instability in the gastrointestinal (GI) tract, low permeability, and a narrow absorption window in the intestine. This review provides a detailed overview of the oral delivery route and associated challenges. Recent advances in formulation and drug delivery technologies to enhance bioavailability are discussed, including the co-administration of compounds to alter conditions in the GI tract, the modification of the macromolecule physicochemical properties, and the use of improved targeted and controlled release carriers.Graphical abstractTherapeutic proteins and peptides have revolutionized treatment for a number of diseases, and the expected increase in macromolecule-based therapies brings a new set of challenges for the pharmaceutics field. In order to fully realize the ‘holy grail’ and enable oral delivery, there are several major challenges associated that must be overcome. These include therapeutic instability in the gastrointestinal (GI) tract, low permeability, and a narrow absorption window in the intestine. This review provides a detailed discussion of the oral delivery route, associated advantages and challenges, and recent advances in delivery technology.fx1
       
  • An updated overview on the development of new photosensitizers for
           anticancer photodynamic therapy

    • Abstract: Publication date: March 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 2Author(s): Juan Zhang, Chengshi Jiang, João Paulo Figueiró Longo, Ricardo Bentes Azevedo, Hua Zhang, Luis Alexandre Muehlmann Photodynamic therapy (PDT), based on the photoactivation of photosensitizers (PSs), has become a well-studied therapy for cancer. Photofrin®, belonging to the first generation of PS, is still widely used for the treatment of different kinds of cancers; however, it has several drawbacks that significantly limit its general clinical use. Consequently, there has been extensive research on the design of PS molecules with optimized pharmaceutical properties, with aiming of overcoming the disadvantages of traditional PS, such as poor chemical purity, long half-life, excessive accumulation into the skin, and low attenuation coefficients. The rational design of novel PS with desirable properties has attracted considerable research in the pharmaceutical field. This review presents an overview on the classical photosensitizers and the most significant recent advances in the development of PS with regard to their potential application in oncology.Graphical abstractPhotodynamic therapy, based on the photoactivation of photosensitizers (PS), has become a well-studied therapy for cancer. This review presents an overview on the classical photosensitizers and the most significant recent advances in the development of PS with regard to their potential application in oncology.fx1
       
  • Anti-retroviral drugs: current state and development in the next decade

    • Abstract: Publication date: March 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 2Author(s): Xingquan Zhang The pace of discovery of new antiretroviral (ARV) drugs has slowed, although the efficacy and safety of once-daily fixed dose combinations have been extensively investigated. Several traditional ARV drugs remain in phase III clinical trials. This review summarizes current information on ARV drugs in phase III clinical trials and focuses on the development of ARV drugs in the next decade.Graphical abstractThis review summarizes current information on antiretroviral (ARV) drugs in phase III clinical trials and focuses on the development of ARV drugs in the next decade.fx1
       
  • Antihyperuricemic effect of mangiferin aglycon derivative J99745 by
           inhibiting xanthine oxidase activity and urate transporter 1 expression in
           mice

    • Abstract: Publication date: March 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 2Author(s): Zhizhen Qin, Shoubao Wang, Yihuang Lin, Ying Zhao, Shengqian Yang, Junke Song, Tao Xie, Jinlong Tian, Song Wu, Guanhua Du A mangiferin aglycon derivative J99745 has been identified as a potent xanthine oxidase (XOD) inhibitor by previous in vitro study. This study aimed to evaluate the hypouricemic effects of J99745 in experimental hyperuricemia mice, and explore the underlying mechanisms. Mice were orally administered 600 mg/kg xanthine once daily for 7 days and intraperitoneally injected 250 mg/kg oxonic acid on the 7th day to induce hyperuricemia. Meanwhile, J99745 (3, 10, and 30 mg/kg), allopurinol (20 mg/kg) or benzbromarone (20 mg/kg) were orally administered to mice for 7 days. On the 7th day, uric acid and creatinine in serum and urine, blood urea nitrogen (BUN), malondialdehyde (MDA) content and XOD activities in serum and liver were determined. Morphological changes in kidney were observed using hematoxylin and eosin (H&E) staining. Hepatic XOD, renal urate transporter 1 (URAT1), glucose transporter type 9 (GLUT9), organic anion transporter 1 (OAT1) and ATP-binding cassette transporter G2 (ABCG2) were detected by Western blot and real time polymerase chain reaction (PCR). The results showed that J99745 at doses of 10 and 30 mg/kg significantly reduced serum urate, and enhanced fractional excretion of uric acid (FEUA). H&E staining confirmed that J99745 provided greater nephroprotective effects than allopurinol and benzbromarone. Moreover, serum and hepatic XOD activities and renal URAT1 expression declined in J99745-treated hyperuricemia mice. In consistence with the ability to inhibit XOD, J99745 lowered serum MDA content in hyperuricemia mice. Our results suggest that J99745 exerts urate-lowering effect by inhibiting XOD activity and URAT1 expression, thus representing a promising candidate as an anti-hyperuricemia agent.Graphical abstractMangiferin aglycon derivative J99745 possessed potent xanthine oxidase (XOD) inhibition in vitro. In hyperuricemic mice, J99745 reduced serum urate and MDA content, enhanced fractional excretion of uric acid, and attenuated kidney damage. J99745 might represent a promising antihyperuricemia agent by inhibiting XOD activity and urate transporter 1 expression.fx1
       
  • Genomic survey of bZIP transcription factor genes related to tanshinone
           biosynthesis in Salvia miltiorrhiza

    • Abstract: Publication date: March 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 2Author(s): Yu Zhang, Zhichao Xu, Aijia Ji, Hongmei Luo, Jingyuan Song Tanshinones are a class of bioactive components in the traditional Chinese medicine Salvia miltiorrhiza, and their biosynthesis and regulation have been widely studied. Current studies show that basic leucine zipper (bZIP) proteins regulate plant secondary metabolism, growth and developmental processes. However, the bZIP transcription factors involved in tanshinone biosynthesis are unknown. Here, we conducted the first genome-wide survey of the bZIP gene family and analyzed the phylogeny, gene structure, additional conserved motifs and alternative splicing events in S. miltiorrhiza. A total of 70 SmbZIP transcription factors were identified and categorized into 11 subgroups based on their phylogenetic relationships with those in Arabidopsis. Moreover, seventeen SmbZIP genes underwent alternative splicing events. According to the transcriptomic data, the SmbZIP genes that were highly expressed in the Danshen root and periderm were selected. Based on the prediction of bZIP binding sites in the promoters and the co-expression analysis and co-induction patterns in response to Ag+ treatment via quantitative real-time polymerase chain reaction (qRT-PCR), we concluded that SmbZIP7 and SmbZIP20 potentially participate in the regulation of tanshinone biosynthesis. These results provide a foundation for further functional characterization of the candidate SmbZIP genes, which have the potential to increase tanshinone production.Graphical abstractThis paper provided a first overview of the SmbZIP TF family in S. miltiorrhiza. SmbZIP gene expression profiles under Ag+ treatment and in different organs and root tissues of S. miltiorrhiza was also investigated. SmbZIP7 and SmbZIP20 are predicted to be potential regulatory factors related to tanshinone biosynthesis in S. miltiorrhiza. These findings provide a foundation for further studies of the function of these genes via genetic engineering combined with metabolite profiling in S. miltiorrhiza.fx1
       
  • Biosynthesis of antibiotic chuangxinmycin from Actinoplanes
           tsinanensis

    • Abstract: Publication date: March 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 2Author(s): Yuanyuan Shi, Zhibo Jiang, Xingxing Li, Lijie Zuo, Xuan Lei, Liyan Yu, Linzhuan Wu, Jiandong Jiang, Bin Hong Chuangxinmycin is an antibiotic isolated from Actinoplanes tsinanensis CPCC 200056 in the 1970s with a novel indole-dihydrothiopyran heterocyclic skeleton. Chuangxinmycin showed in vitro antibacterial activity and in vivo efficacy in mouse infection models as well as preliminary clinical trials. But the biosynthetic pathway of chuangxinmycin has been obscure since its discovery. Herein, we report the identification of a stretch of DNA from the genome of A. tsinanensis CPCC 200056 that encodes genes for biosynthesis of chuangxinmycin by bioinformatics analysis. The designated cxn cluster was then confirmed to be responsible for chuangxinmycin biosynthesis by direct cloning and heterologous expressing in Streptomyces coelicolor M1146. The cytochrome P450 CxnD was verified to be involved in the dihydrothiopyran ring closure reaction by the identification of seco-chuangxinmycin in S. coelicolor M1146 harboring the cxn gene cluster with an inactivated cxnD. Based on these results, a plausible biosynthetic pathway for chuangxinmycin biosynthesis was proposed, by hijacking the primary sulfur transfer system for sulfur incorporation. The identification of the biosynthetic gene cluster of chuangxinmycin paves the way for elucidating the detail biochemical machinery for chuangxinmycin biosynthesis, and provides the basis for the generation of novel chuangxinmycin derivatives by means of combinatorial biosynthesis and synthetic biology.Graphical abstractIn this study, the biosynthetic gene cluster of chuangxinmycin (1) was firstly identified, cloned and heterologously expressed and a plausible pathway for its biosynthesis was proposed: L-tryptophan was converted to seco-chuangxinmycin (3) through a series of biochemical reaction processes and by hijacking the sulfur transfer system from primary metabolism using the cluster-situated sulfur carrier protein CxnE. Then the second C–S bond formation was achieved by the cytochrome P450 CxnD.fx1
       
  • Rhizospheric microbial communities are driven by Panax ginseng at
           different growth stages and biocontrol bacteria alleviates replanting
           mortality

    • Abstract: Publication date: March 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 2Author(s): Linlin Dong, Jiang Xu, Lianjuan Zhang, Ruiyang Cheng, Guangfei Wei, He Su, Juan Yang, Jun Qian, Ran Xu, Shilin Chen The cultivation of Panax plants is hindered by replanting problems, which may be caused by plant-driven changes in the soil microbial community. Inoculation with microbial antagonists may efficiently alleviate replanting issues. Through high-throughput sequencing, this study revealed that bacterial diversity decreased, whereas fungal diversity increased, in the rhizosphere soils of adult ginseng plants at the root growth stage under different ages. Few microbial community, such as Luteolibacter, Cytophagaceae, Luteibacter, Sphingomonas, Sphingomonadaceae, and Zygomycota, were observed; the relative abundance of microorganisms, namely, Brevundimonas, Enterobacteriaceae, Pandoraea, Cantharellales, Dendryphion, Fusarium, and Chytridiomycota, increased in the soils of adult ginseng plants compared with those in the soils of 2-year-old seedlings. Bacillus subtilis 50-1, a microbial antagonist against the pathogenic Fusarium oxysporum, was isolated through a dual culture technique. These bacteria acted with a biocontrol efficacy of 67.8%. The ginseng death rate and Fusarium abundance decreased by 63.3% and 46.1%, respectively, after inoculation with B. subtilis 50-1. Data revealed that microecological degradation could result from ginseng-driven changes in rhizospheric microbial communities; these changes are associated with the different ages and developmental stages of ginseng plants. Biocontrol using microbial antagonists alleviated the replanting problem.Graphical abstractGinseng cropping induced changes in rhizospheric microbial communities and decreased bacterial diversity. These effects could collectively cause microecological degradation, which consequently results in replanting problems. However, inoculation with a biocontrol bacterial strain alleviated the replanting problem and improved the growth of ginseng. These results provide insight into the reasons that underlie the replanting issues caused by rhizospheric microbial communities.fx1
       
  • Liposomes and lipid disks traverse the BBB and BBTB as intact forms as
           revealed by two-step Förster resonance energy transfer imaging

    • Abstract: Publication date: March 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 2Author(s): Tongcheng Dai, Kuan Jiang, Weiyue Lu The blood–brain barrier (BBB) and the blood–brain tumor barrier (BBTB) prevent drug and nano-drug delivery systems from entering the brain. However, ligand-mediated nano-drug delivery systems have significantly enhanced the therapeutic treatment of glioma. In this study we investigated the mechanism especially the integrity of liposomes and lipid disks while traversing the BBB and BBTB both in vitro and in vivo. Fluorophores (DiO, DiI and DiD) were loaded into liposomes and lipid disks to form Förster resonance energy transfer (FRET) nano-drug delivery systems. Using brain capillary endothelial cells as a BBB model, we show that liposomes and disks are present in the cytoplasm as their intact forms and traverse the BBB with a ratio of 0.68‰ and 1.67‰, respectively. Using human umbilical vein endothelial cells as BBTB model, liposomes and disks remained intact and traversed the BBTB with a ratio of 2.31‰ and 8.32‰ at 3 h. Ex vivo imaging and immunohistochemical results revealed that liposomes and disks could traverse the BBB and BBTB in vivo as intact forms. In conclusion, these observations explain in part the mechanism by which nano-drug delivery systems increase the therapeutic treatment of glioma.Graphical abstractFluorophores (DiO, DiI and DiD) were loaded into liposomes and disks to form Förster resonance energy transfer (FRET) nano-drug delivery systems. Using this method, we investigated the integrity of liposomes and disks traversing BBB and BBTB both in vitro and in vivo.fx1
       
  • Comparative untargeted proteomic analysis of ADME proteins and tumor
           antigens for tumor cell lines

    • Abstract: Publication date: March 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 2Author(s): Xiaomei Gu, Qing Xiao, Qian Ruan, Yuezhong Shu, Ashok Dongre, Ramaswamy Iyer, W. Griffith Humphreys, Yurong Lai In the present study, total membrane proteins from tumor cell lines including HepG2, Hep3B2, H226, Ovcar3 and N87 were extracted and digested with γLysC and trypsin. The resulting peptide lysate were pre-fractionated and subjected to untargeted quantitative proteomics analysis using a high resolution mass spectrometer. The mass spectra were processed by the MaxQuant and the protein abundances were estimated using total peak area (TPA) method. A total of 6037 proteins were identified, and the analysis resulted in the identification of 2647 membrane proteins. Of those, tumor antigens and absorption, metabolism, disposition and elimination (ADME) proteins including UDP-glucuronosyltransferase, cytochrome P450, solute carriers and ATP-binding cassette transporters were detected and disclosed significant variations among the cell lines. The principal component analysis was performed for the cluster of cell lines. The results demonstrated that H226 is closely related with N87, while Hep3B2 aligned with HepG2. The protein cluster of Ovcar3 was apart from that of other cell lines investigated. By providing for the first time quantitative untargeted proteomics analysis, the results delineated the expression profiles of membrane proteins. These findings provided a useful resource for selecting targets of choice for anticancer therapy through advancing data obtained from preclinical tumor cell line models to clinical outcomes.Graphical abstractComparative untargeted proteomics analysis was conducted to identify and quantify membrane proteins in tumor cell lines through database searching with MaxQuant software. The identified proteins were annotated by gene ontology (GO) and assigned into four distinct subcellular categories. The proteomics analysis demonstrated significant variations among the tumor cell lines and lead to a greater appreciation for the role of membrane proteins in tumor development and drug resistance, and present targets of choice as tumor marker proteins.fx1
       
  • Correlation analysis between the chemical contents and bioactivity for the
           quality control of Alismatis Rhizoma

    • Abstract: Publication date: March 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 2Author(s): Xiaoxv Gao, Chengpeng Sun, Zhenglong Yu, Jian Cang, Xiangge Tian, Xiaokui Huo, Lei Feng, Xinguang Liu, Chao Wang, Baojing Zhang, Xiaochi Ma In order to clarify regions of production and to discriminate processing methods, quantitative and qualitative analyses for saccharides and terpenes in 35 batches of Alismatis Rhizoma were performed. Methodologies included HPLCPDA, HPLCVWD and UHPLCMSn, combined with principal component analysis (PCA) and partial least squares regression techniques (PLSR). The inhibitory effects of triterpenes and Alismatis Rhizoma extracts on lipase activity were evaluated in vitro. PLSR analysis revealed significant positive correlations (R2 = 0.5795) between the contents of triterpenes 10, 14, 15, 18 and 22 and the inhibitory effects of Alismatis Rhizoma. The present study establishes an effective method for simultaneous determination of multiple components, and identifies key bioactive triterpenes. These results can be used for systematic and novel analytical strategies for the quality control of Alismatis Rhizoma production.Graphical abstractWith the application of 1H-NMR-based metabolomics, a new processing method was proposed for medicinal slices of Cistanche deserticola. Different parts of C. deserticola were also differentiated, indicating that 1H-NMR-based metabolomics was a versatile analytical platform.fx1
       
  • Rapid and sensitive liquid chromatography–tandem mass spectrometric
           method for the quantitative determination of potentially harmful substance
           5,5′-oxydimethylenebis (2-furfural) in traditional Chinese medicine
           injections

    • Abstract: Publication date: March 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 2Author(s): Qingce Zang, Yang Gao, Luojiao Huang, Jiuming He, Sheng Lin, Hongtao Jin, Ruiping Zhang, Zeper Abliz With the rapid development and wide application of traditional Chinese medicine injection (TCMI), a number of adverse events of some TCMIs have incessantly been reported and have drawn broad attention in recent years. Establishing effective and practical analytical methods for safety evaluation and quality control of TCMI can help to improve the safety of TCMIs in clinical applications. In this study, a sensitive and rapid high-performance liquid chromatography–tandem mass spectrometry (HPLC–MS/MS) method has been developed and validated for the quantitative determination of potentially harmful substance 5,5′-oxydimethylenebis (2-furfural, OMBF) in TCMI samples. Chromatographic separation was performed on a C18 reversed-phase column (150 mm × 2.1 mm, 5 µm) by gradient elution, using methanol–water containing 0.1% formic acid as mobile phase at the flow rate of 0.3 mL/min. MS/MS detection was performed on a triple quadrupole mass spectrometer with positive electrospray ionization in the multiple reaction-monitoring mode. The method was sensitive with a limit of quantification of 0.3 ng/mL and linear over the range of 0.3–30 ng/mL (r=0.9998). Intra- and inter-day precision for analyte was
       
  • Separation and simultaneous quantitation of PGF2α and its epimer
           8-iso-PGF2α using modifier-assisted differential mobility spectrometry
           tandem mass spectrometry

    • Abstract: Publication date: March 2018Source: Acta Pharmaceutica Sinica B, Volume 8, Issue 2Author(s): Chunsu Liang, Hui Sun, Xiangjun Meng, Lei Yin, J. Paul Fawcett, Huaidong Yu, Ting Liu, Jingkai Gu Because many therapeutic agents are contaminated by epimeric impurities or form epimers as a result of metabolism, analytical tools capable of determining epimers are increasingly in demand. This article is a proof-of-principle report of a novel DMS–MS/MS method to separate and simultaneously quantify epimers, taking PGF2α and its 8-epimer, 8-iso-PGF2α, as an example. Good accuracy and precision were achieved in the range of 10–500 ng/mL with a run time of only 1.5 min. Isopropanol as organic modifier facilitated a good combination of sensitivity and separation. The method is the first example of the quantitation of epimers without chromatographic separation.Graphical abstractThis article is a proof-of-principle report of a novel DMS–MS/MS method to separate and simultaneously quantify epimers, taking PGF2α and its 8-epimer, 8-iso-PGF2α, as an example. Good accuracy and precision were achieved in the range of 10–500 ng/mL with a run time of only 1.5 min. The method is the first example of the quantitation of epimers without chromatographic separation.fx1
       
  • Epigenetic modification in histone deacetylase deletion strain of
           Calcarisporium arbuscula leads to diverse diterpenoids

    • Abstract: Publication date: Available online 21 February 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Jian Bai, Rong Mu, Man Dou, Daojiang Yan, Bingyu Liu, Qian Wei, Jun Wan, Yi Tang, Youcai Hu Epigenetic modifications have been proved to be a powerful way to activate silent gene clusters and lead to diverse secondary metabolites in fungi. Previously, inactivation of a histone H3 deacetylase in Calcarisporium arbuscula had led to pleiotropic activation and overexpression of more than 75% of the biosynthetic genes and isolation of ten compounds. Further investigation of the crude extract of C. arbuscula ΔhdaA strain resulted in the isolation of twelve new diterpenoids including three cassanes (1−3), one cleistanthane (4), six pimaranes (5−10), and two isopimaranes (11 and 12) along with two know cleistanthane analogues. Their structures were elucidated by extensive NMR spectroscopic data analysis. Compounds 2 and 4 showed potent inhibitory effects on the expression of MMP1 and MMP2 (matrix metalloproteinases family) in human breast cancer (MCF-7) cells.Graphical abstractEpigenetic modifications have been proved to be a powerful technique to activate silent gene clusters and had led to diverse secondary metabolites in fungi. Investigation of the crude extract of Calcarisporium arbuscula ΔhdaA strain, in which a histone H3 deacetylase was deleted, resulted in the isolation of twelve new diterpenoids including three cassanes (1−3), one cleistanthane (4), six pimaranes (5−10), and two isopimaranes (11−12). Compounds 2 and 4 showed potent inhibitory effects on the expression of MMP1 and MMP2 (matrix metalloproteinases family) in human breast cancer cells.fx1
       
  • Authentic compound-free strategy for simultaneous determination of primary
           coumarins in Peucedani Radix using offline high performance liquid
           chromatography–nuclear magnetic resonance spectroscopy–tandem mass
           spectrometry

    • Abstract: Publication date: Available online 21 February 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Yao Liu, Qingqing Song, Wenjing Liu, Peng Li, Jun Li, Yunfang Zhao, Liang Zhang, Pengfei Tu, Yitao Wang, Yuelin Song Herein, a strategy is proposed for the simultaneous determination of primary coumarins in Peucedani Radix (Chinese name: Qianhu). The methodology consists of three consecutive steps: 1) Semi-preparative LC in combination with a home-made automated fraction collection module to fragment the universal metabolome standard into ten fractions (Frs. I–X); 2) LC–accurate MS/MS and quantitative 1H NMR spectroscopy conducted in parallel to acquire the qualitative and quantitative data of each fraction; 3) Robust identification and quantification of components by use of LC coupled to multiple reaction monitoring. In this final step, the most significant fractions (Frs. III–X) were pooled to serve as the pseudo-mixed standard solution. Meticulous online parameter optimization was performed to obtain the optimal parameters, including ion transitions and collision energies. Concerns were particularly paid onto pursuing the parameters being capable of monitoring regio-specific isomers, notably praeruptorin E vs. 3′-isovaleryl-4′-angeloylkhellactone. The quantitative performance of the method was validated according to diverse assays. Eleven primary coumarins (1–11) were unambiguously identified and absolutely quantified, even though no external reference compound was used. Above all, the integrated strategy not only provides a feasible pipeline for the quality assessment of Peucedani Radix, but more importantly, shows the potential for authentic compound-free quantitative evaluation of traditional Chinese medicines.Graphical abstractAn authentic compound-free strategy was proposed by offline LC–NMR–MS/MS. The quantitative performance of the method was validated according to diverse assays. Eleven primary coumarins were unambiguously identified and absolutely quantified, even though no external reference compound was used.fx1
       
  • Synthesis and biological evaluation of novel tricyclic matrinic
           derivatives as potential anti-filovirus agents

    • Abstract: Publication date: Available online 21 February 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Xin Zhang, Qiang Liu, Qianqian Li, Yinghong Li, Zhandong Liu, Hongbin Deng, Sheng Tang, Yanxiang Wang, Youchun Wang, Danqing Song Twenty-six novel tricyclic sophoridinic and matrinic derivatives containing a common chlorinated benzene fragment were designed, synthesized and evaluated for their anti-ebolavirus (EBOV) activities. Structureactivity relationship analysis indicated: (i) 12N-dichlorobenzyl motif was beneficial for the activity; (ii) the chiral configuration at C5 atom might not affect the activity much. Among the target compounds, compound 7d exhibited the most potent potency against EBOV with an IC50 value of 5.29 μmol/L and an SI value of over 37.8. Further in vivo anti-EBOV assay of 7d identified its high effectiveness, and in vivo anti-MARV assay of 7d suggested its inspiring broad-spectrum anti-filovirus activity. The results provided powerful information on further strategic optimization and development of this kind of compounds against filoviruses.Graphical abstractTwenty-six new tricyclic matrinic derivatives were designed, synthesized and evaluated for their activities against Ebola virus in vitro using a pHIV-EBOVGP-Fluc model. Compound 7d exhibited better in vivo anti-EBOV and anti-MARV effects than the positive control sertraline. The results suggested its inspiring broad-spectrum anti-filovirus activity.fx1
       
  • Targeting ERK, an Achilles' Heel of the MAPK pathway, in cancer therapy

    • Abstract: Publication date: Available online 16 February 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Feifei Liu, Xiaotong Yang, Meiyu Geng, Min Huang The mitogen-activated protein kinases (MAPK) pathway, often known as the RAS-RAF-MEK-ERK signal cascade, functions to transmit upstream signals to its downstream effectors to regulate physiological process such as cell proliferation, differentiation, survival and death. As the most frequently mutated signaling pathway in human cancer, targeting the MAPK pathway has long been considered a promising strategy for cancer therapy. Substantial efforts in the past decades have led to the clinical success of BRAF and MEK inhibitors. However, the clinical benefits of these inhibitors are compromised by the frequently occurring acquired resistance due to cancer heterogeneity and genomic instability. This review briefly introduces the key protein kinases involved in this pathway as well as their activation mechanisms. We also generalize the correlations between mutations of MAPK members and human cancers, followed by a summarization of progress made on the development of small molecule MAPK kinases inhibitors. In particular, this review highlights the potential advantages of ERK inhibitors in overcoming resistance to upstream targets and proposes that targeting ERK kinase may hold a promising prospect for cancer therapy.Graphical abstractDownstream ERK kinase appears to be the Achilles' Heel of the MAPK pathway. Targeting ERK kinase provides potential therapeutic opportunities for a broad spectrum of cancers bearing RAS, RAF and MEK mutations as well as those with acquired resistance to BRAF and MEK inhibitors (RAFi and MEKi).fx1
       
  • Limonoids from seeds of Azadirachta indica A. Juss. and their
           cytotoxic activity

    • Abstract: Publication date: Available online 1 February 2018Source: Acta Pharmaceutica Sinica BAuthor(s): Jian Chen, Xiaona Fan, Jianhua Zhu, Liyan Song, Zhiwei Li, Fei Lin, Rongmin Yu, Hanhong Xu, Jiachen Zi Four new limonoid-type nortriterpenoids, 1-detigloyl-1-O-methacryloylsalannin (1), 28-deoxo-2,3-dihydronimbolide (2), 12-acetoxy-3-O-acetyl-7-O-tigloylvilasinin (3) and 12-acetoxy-3-O-acetyl-7-O-methacryloylvilasinin (4), along with five known ones, were isolated from seeds of Azadirachta indica A. Juss. Their structures were elucidated by various spectroscopic methods, including UV, IR, MS, NMR, X-ray crystallography, quantum chemical calculation, as well as by comparison of their spectroscopic data with those reported. In the in vitro cytotoxic assay, 2 showed inhibitory activity against human breast cancer MDA-MB-231 cell line with IC50 value of 7.68±1.74 μmol/L, and 5 inhibited growth of human cervical cancer Hela cell line, melanoma A375 cell line and promyelocytic leukemia HL-60 cell line, with IC50 12.00±2.08 17.44±2.11 13.95±5.74 μmol/L, respectively.Graphical abstractFour new limonoids, together with five known ones, were isolated from dry seeds of neem (Azadirachta indica A. Juss). Their structures were elucidated by spectroscopic methods and quantum chemical calculation. Compounds 2 and 5 selectively inhibited growth of human cancer cells.fx1
       
 
 
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