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Journal of Molecular Medicine
Journal Prestige (SJR): 2.177
Citation Impact (citeScore): 5
Number of Followers: 11  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 1432-1440 - ISSN (Online) 0946-2716
Published by Springer-Verlag Homepage  [2349 journals]
  • Trichostatin A, a histone deacetylase inhibitor, induces synergistic
           cytotoxicity with chemotherapy via suppression of Raf/MEK/ERK pathway in
           urothelial carcinoma
    • Authors: Wei-Chou Lin; Fu-Shun Hsu; Kuan-Lin Kuo; Shing-Hwa Liu; Chia-Tung Shun; Chung-Sheng Shi; Hong-Chiang Chang; Yu-Chieh Tsai; Ming-Chieh Lin; June-Tai Wu; Yu Kuo; Po-Ming Chow; Shih-Ming Liao; Shao-Ping Yang; Jo-Yu Hong; Kuo-How Huang
      Pages: 1307 - 1318
      Abstract: In this study, we aimed to investigate the antitumor effects of trichostatin A (TSA), an antifungal antibiotic that inhibits histone deacetylase (HDAC) family of enzymes, alone or in combination with anyone of the three chemotherapeutic agents (cisplatin, gemcitabine, and doxorubicin) for the treatment of human urothelial carcinoma (UC). Two high-grade human UC cell lines (T24 and NTUB1) were used. Cytotoxicity and apoptosis were assessed by MTT assay and flow cytometry, respectively. The expression of phospho-c-Raf, phospho-MEK1/2, and phospho-ERK1/2 was measured by western blotting. ERK siRNA knockdown and the specific MEK inhibitor U0126 were used to examine the role of Raf/MEK/ERK signaling pathway in combined cytotoxicity of TSA and chemotherapy. TSA co-treatment with any one of the three chemotherapeutic agents induced synergistic cytotoxicity (combination index < 1) and concomitantly suppressed chemotherapeutic drug-induced activation of Raf-MEK-ERK pathway. Combination of ERK siRNA knockdown and treatment with the specific MEK inhibitor (U0126) enhanced the cytotoxic effects of the chemotherapy on UC cells. These observations were confirmed in a xenograft nude mouse model. Moreover, activated Raf/MEK/ERK pathway was observed in human bladder UC specimens from patients with chemoresistant status. In conclusion, TSA elicits a synergistic cytotoxic response in combination with chemotherapy via targeting the Raf/MEK/ERK pathway. TSA elicits synergistic cytotoxic response in combination with three DNA-damaging drugs (cisplatin, gemcitabine, and doxorubicin). Activated Raf/MEK/ERK pathway is involved in chemoresistant mechanism of UC. Combining chemotherapeutic agents with HDAC inhibitor (TSA) or with targeting Raf/MEK/ERK pathway is promising to circumvent chemoresistance in UCs.
      PubDate: 2018-12-01
      DOI: 10.1007/s00109-018-1697-7
      Issue No: Vol. 96, No. 12 (2018)
       
  • Pentraxin 3 promotes long-term cerebral blood flow recovery, angiogenesis,
           and neuronal survival after stroke
    • Authors: Ivana Rajkovic; Raymond Wong; Eloise Lemarchand; Jack Rivers-Auty; Olivera Rajkovic; Cecilia Garlanda; Stuart M. Allan; Emmanuel Pinteaux
      Pages: 1319 - 1332
      Abstract: Restoration of cerebral blood flow (CBF) and upregulation of angiogenesis are crucial for brain repair and functional recovery after cerebral ischaemia. Pentraxin 3 (PTX3) is a key regulator of angiogenesis and is emerging as a promising target for cerebrovascular repair after stroke. Here, we investigated for the first time the role of PTX3 in long-term CBF, angiogenesis, and neuronal viability after ischaemic stroke induced by transient middle cerebral artery occlusion (MCAo). Lack of PTX3 had no effect on early brain damage, but significantly impaired restoration of CBF, 14 and 28 days after MCAo, compared to wild-type (WT) mice. Immunohistochemical analysis revealed that PTX3 KO mice have significantly greater neuronal loss, significantly decreased vessel diameter, vessel proliferation, vascular density, and reactive astrocytes and decreased expression of vascular endothelial growth factor receptor 2 (VEGR2), vascular extracellular matrix (ECM)-proteins (collagen IV, laminin), and integrin-β, in the ipsilateral (stroke) hemisphere compared to WT mice, 28 days after MCAo. Therefore, PTX3 promotes sustained long-term recovery of CBF, angiogenesis, and neuronal viability after cerebral ischaemia. Collectively, these findings demonstrate the potential and clinical relevance of PTX3 as a promising therapeutic target, providing sustained long-term post-stroke neurovascular repair and reducing the loss of neurons. Key messages Pentraxin 3 (PTX3) is a key regulator of angiogenesis and is emerging as a promising target for cerebrovascular repair after stroke. Restoration of cerebral blood flow (CBF) and angiogenesis are crucial for brain repair and functional recovery after cerebral ischaemia. PTX3 promotes sustained long-term recovery of CBF, angiogenesis, and neuronal viability after cerebral ischaemia.
      PubDate: 2018-12-01
      DOI: 10.1007/s00109-018-1698-6
      Issue No: Vol. 96, No. 12 (2018)
       
  • Plasminogen/thrombomodulin signaling enhances VEGF expression to promote
           cutaneous wound healing
    • Authors: Tsung-Lin Cheng; Po-Ku Chen; Wei-Kai Huang; Cheng-Hsiang Kuo; Chia-Fong Cho; Kuan-Chieh Wang; Guey-Yueh Shi; Hua-Lin Wu; Chao-Han Lai
      Pages: 1333 - 1344
      Abstract: Plasminogen (Plg) and thrombomodulin (TM) are glycoproteins well known for fibrinolytic and anticoagulant functions, respectively. Both Plg and TM are essential for wound healing. However, their significance during the reparative process was separately demonstrated in previous studies. Here, we investigate the interaction between Plg and epithelial TM and its effect on wound healing. Characterization of the wound margin revealed that Plg and TM were simultaneously upregulated at the early stage of wound healing and the two molecules were bound together. In vitro, TM silencing or knockout in keratinocytes inhibited Plg activation. Plg treatment enhanced keratinocyte proliferation and migration, and these actions were abolished by TM antibody. Keratinocyte-expressed vascular endothelial growth factor (VEGF), which presented a dose-response relationship with Plg treatment, can be suppressed by TM silencing. Moreover, treatment with VEGF antibody inhibited Plg-enhanced keratinocyte proliferation and wound recovery. In vivo, TM antibody treatment and keratinocyte-specific TM knockout can impede Plg-enhanced wound healing in mice. In high-glucose environments, Plg-enhanced VEGF expression and wound healing were suppressed due at least in part to downregulation of keratinocyte-expressed TM. Taken together, our findings suggest that activation of Plg/TM signaling may hold therapeutic potential for chronic wounds in diabetic or non-diabetic individuals. Key messages Plg binds to TM in cutaneous wound healing. TM facilitates the activation of Plg to Plm in keratinocytes. Epithelial TM regulates Plg-enhanced wound healing through VEGF expression.
      PubDate: 2018-12-01
      DOI: 10.1007/s00109-018-1702-1
      Issue No: Vol. 96, No. 12 (2018)
       
  • AdipoRon, an adiponectin receptor agonist, attenuates cardiac remodeling
           induced by pressure overload
    • Authors: Ning Zhang; Wen-Ying Wei; Hai-Han Liao; Zheng Yang; Can Hu; Sha-sha Wang; Wei Deng; Qi-Zhu Tang
      Pages: 1345 - 1357
      Abstract: AdipoRon, a small-molecule adiponectin receptor (AdipoR) agonist, has been reported to be implicated in cardiovascular diseases. However, its role in pressure-overload-induced cardiac remodeling is still elusive. To elucidate the role of AdipoRon in the pathogenesis of cardiac remodeling in vivo and vitro, in the left ventricle of human end-stage heart failure, the expression of AdipoR2 is upregulated. Meanwhile, increased expression of AdipoR2 was also observed in mice failing hearts. Oral administration of AdipoRon alleviated cardiac hypertrophy and fibrosis induced by pressure overload, as evidenced by the beneficial change of cross-sectional area of cardiomyocytes, heart weight-to-body weight ratio, gene expression of hypertrophic markers, ventricle collagen ratio, and cardiac function. The AMPKα activation mediated by AdipoRon significantly inhibited AngII-induced TGF-β1 expression and cardiac fibroblast differentiation, and these inhibitory effects were abrogated by treatment with the AMPK inhibitor Compound C. Consistent with the above results, AdipoRon abolished the ability to retard AngII-induced TGF-β1 expression in AMPKα2−/− cardiac fibroblasts. In AMPKα2−/− mice subjected to aortic banding, AdipoRon abolished the protective effect, as indicated by increased cross-sectional area, cardiac collagen ratio, and cardiac dysfunction. Our results demonstrated that AdipoR2 expression was markedly increased in the failing hearts. AdipoRon inhibited TGF-β1 expression and myofibroblast differentiation in AMPKα-dependent manner in vitro. In line with the vitro results, AMPKα2−/− mice markedly abrogated the inhibitory effects of AdipoRon in cardiac remodeling. These results indicated AdipoRon may hold promise of an effective therapy against pressure-overload-induced cardiac remodeling. Key messages • The increased expression of AdipoR2 is observed in human and mice failing hearts, the changeable expression of AdipoR suggests the possible role of AdipoR in cardiac remodeling. • Oral administration of AdipoRon alleviates cardiac hypertrophy and fibrosis induced by pressure overload, and AMPKα activation mediated by AdipoRon significantly inhibited AngII-induced TGF-β1 expression and cardiac fibroblast differentiation. • These findings provide new mechanistic insight and open new therapeutic pathways for heart failure.
      PubDate: 2018-12-01
      DOI: 10.1007/s00109-018-1696-8
      Issue No: Vol. 96, No. 12 (2018)
       
  • Progranulin associates with hexosaminidase A and ameliorates GM2
           ganglioside accumulation and lysosomal storage in Tay-Sachs disease
    • Authors: Yuehong Chen; Jinlong Jian; Aubryanna Hettinghouse; Xueheng Zhao; Kenneth D. R. Setchell; Ying Sun; Chuan-ju Liu
      Pages: 1359 - 1373
      Abstract: Tay-Sachs disease (TSD) is a lethal lysosomal storage disease (LSD) caused by mutations in the HexA gene, which can lead to deficiency of β-hexosaminidase A (HexA) activity and consequent accumulation of its substrate, GM2 ganglioside. Recent reports that progranulin (PGRN) functions as a chaperone of lysosomal enzymes and its deficiency is associated with LSDs, including Gaucher disease and neuronal ceroid lipofuscinosis, prompted us to screen the effects of recombinant PGRN on lysosomal storage in fibroblasts from 11 patients affected by various LSDs, which led to the isolation of TSD in which PGRN demonstrated the best effects in reducing lysosomal storage. Subsequent in vivo studies revealed significant GM2 accumulation and the existence of typical TSD cells containing zebra bodies in both aged and ovalbumin-challenged adult PGRN-deficient mice. In addition, HexA, but not HexB, was aggregated in PGRN-deficient cells. Furthermore, recombinant PGRN significantly reduced GM2 accumulation and lysosomal storage in these animal models. Mechanistic studies indicated that PGRN bound to HexA through granulins G and E domain and increased the enzymatic activity and lysosomal delivery of HexA. More importantly, Pcgin, an engineered PGRN derivative bearing the granulin E domain, also effectively bound to HexA and reduced the GM2 accumulation. Collectively, these studies not only provide new insights into the pathogenesis of TSD but may also have implications for developing PGRN-based therapy for this life-threatening disorder. Key messages GM2 accumulation and the existence of typical TSD cells containing zebra bodies are detected in both aged and ovalbumin-challenged adult PGRN deficient mice. Recombinant PGRN significantly reduces GM2 accumulation and lysosomal storage both in vivo and in vitro, which works through increasing the expression and lysosomal delivery of HexA. Pcgin, an engineered PGRN derivative bearing the granulin E domain, also effectively binds to to HexA and reduces GM2 accumulation.
      PubDate: 2018-12-01
      DOI: 10.1007/s00109-018-1703-0
      Issue No: Vol. 96, No. 12 (2018)
       
  • Genomics and response to long-term oxygen therapy in chronic obstructive
           pulmonary disease
    • Authors: Minseok Seo; Weiliang Qiu; William Bailey; Gerard J. Criner; Mark T. Dransfield; Anne L. Fuhlbrigge; John J. Reilly; Mary Beth Scholand; Peter Castaldi; Robert Chase; Margaret Parker; Aabida Saferali; Jeong H. Yun; James D. Crapo; Michael H. Cho; Terri H. Beaty; Edwin K. Silverman; Craig P. Hersh
      Pages: 1375 - 1385
      Abstract: Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide, and long-term oxygen therapy has been shown to reduce mortality in COPD patients with severe hypoxemia. However, the Long-term Oxygen Treatment Trial (LOTT), a large randomized trial, found no benefit of oxygen therapy in COPD patients with moderate hypoxemia. We hypothesized that there may be differences in response to oxygen which depend on genotype or gene expression. In a genome-wide time-to-event analysis of the primary outcome of death or hospitalization in 331 subjects, 97 single nucleotide polymorphisms (SNPs) showed evidence of interaction with oxygen therapy at P < 1e−5, including 7 SNPs near arylsulfatase B (ARSB; P = 6e−6). In microarray expression profiling on 51 whole blood samples from 37 individuals, at screening and/or at 12-month follow-up, ARSB expression was associated with the primary outcome depending on oxygen treatment. The significant SNPs were conditional expression quantitative trait loci for ARSB expression. In a network analysis of genes affected by long-term oxygen, two observed clusters including 26 co-expressed genes were enriched in mitochondrial function. Using data from the observational COPDGene Study, we validated the expression of 25 of these 26 genes, plus ARSB. The effect of long-term oxygen therapy in COPD varied based on ARSB expression and genotype. ARSB has previously been shown to be associated with hypoxemia in human bronchial and colonic epithelial cells and in a mouse model. In peripheral blood, long-term oxygen treatment affected expression of mitochondrial-related genes, a biologically relevant pathway in COPD. SNPs and expression of ARSB are associated with response to long-term oxygen in COPD. The ARSB SNPs were expression quantitative trait loci depending on oxygen therapy. Genes differentially expressed by long-term oxygen were enriched in mitochondrial functions. This suggests a potential biomarker to personalize use of long-term oxygen in COPD.
      PubDate: 2018-12-01
      DOI: 10.1007/s00109-018-1708-8
      Issue No: Vol. 96, No. 12 (2018)
       
  • Zika virus infection and implications for kidney disease
    • Authors: Donald J. Alcendor
      Pages: 1145 - 1151
      Abstract: High-level and persistent viruria observed in patients infected by Zika virus (ZIKV) has been well documented. However, renal pathology in acutely infected, immunocompetent patients remains subclinical. Moreover, the long-term impact of ZIKV infection, replication, and persistence in the renal compartment of adults and infants as well as immunosuppressed patients and solid organ transplant (SOT) recipients is unknown. Mechanisms involving host and viral factors that limit or control ZIKV pathogenesis in the renal compartment are important yet unexplored. The observation that long-term viral shedding occurs in the renal compartment in the absence of clinical disease requires further investigation. In this review, I explore Zika virus-induced renal pathology in animal models, the dynamics of virus shedding in urine, virus replication in glomerular cells, ZIKV infection in human renal transplantation, and the potential impact of long-term persistent ZIKV infection in the renal compartment.
      PubDate: 2018-11-01
      DOI: 10.1007/s00109-018-1692-z
      Issue No: Vol. 96, No. 11 (2018)
       
  • Stimulation of angiogenesis using single-pulse low-pressure shock wave
           treatment
    • Authors: Susinder Sundaram; Karthi Sellamuthu; Krishnaveni Nagavelu; Harikumar R Suma; Arpan Das; Raghu Narayan; Dipshikha Chakravortty; Jagadeesh Gopalan; Sandeep M Eswarappa
      Pages: 1177 - 1187
      Abstract: Endothelial cells respond to mechanical stimuli such as stretch. This property can be exploited with caution to induce angiogenesis which will have immense potential to treat pathological conditions associated with insufficient angiogenesis. The primary aim of this study is to test if low-pressure shock waves can be used to induce angiogenesis. Using a simple diaphragm-based shock tube, we demonstrate that a single pulse of low pressure (0.4 bar) shock wave is enough to induce proliferation in bovine aortic endothelial cells and human pulmonary microvascular endothelial cells. We show that this is associated with enhanced Ca++ influx and phosphorylation of phosphatidylinositol-3-kinase (PI3K) which is normally observed when endothelial cells are exposed to stretch. We also demonstrate the pro-angiogenic effect of shock waves of single pulse (per dose) using murine back punch wound model. Shock wave treated mice showed enhanced wound-induced angiogenesis as reflected by increased vascular area and vessel length. They also showed accelerated wound closure compared to control mice. Overall, our study shows that just a single pulse/shot (per dose) of shock waves can be used to induce angiogenesis. Importantly, we demonstrate this effect using a pulse of low-pressure shock waves (0.4 bar, in vitro and 0.15 bar, in vivo). Key messages Low-pressure single-pulse shock waves can induce endothelial cell migration and proliferation. This effect is endothelial cell specific. These shock waves enhance wound-induced angiogenesis in vivo. These shock waves can also accelerate wound healing in vivo.
      PubDate: 2018-11-01
      DOI: 10.1007/s00109-018-1690-1
      Issue No: Vol. 96, No. 11 (2018)
       
  • High-fat diet consumption reduces hepatic folate transporter expression
           via nuclear respiratory factor-1
    • Authors: Victoria Sid; Yaw L. Siow; Yue Shang; Connie W. Woo; Karmin O
      Pages: 1203 - 1213
      Abstract: Folate is an essential micronutrient for biological function. The liver, a primary organ for folate metabolism and storage, plays an important role in folate homeostasis. Proton-coupled folate transporter (PCFT) and reduced folate carrier (RFC) are the major folate transporters responsible for folate uptake at basolateral membrane of hepatocytes. Low serum folate levels are frequently associated with obesity. We investigated the mechanism that regulated folate status in a mouse model with diet-induced obesity. Mice (C57BL/6J) were fed a high-fat diet (60% kcal fat) for 8 weeks. Mice displayed increased hepatic lipid accumulation and decreased folate levels in the liver and serum compared to mice fed a normal chow diet (10% kcal fat). High-fat diet-fed mice had low expression of PCFT and RFC and decreased nuclear respiratory factor-1 (NRF-1)/DNA-binding activity. Treatment with NRF-1 siRNA or palmitic acid reduced folate transporter expression in hepatocytes. Inhibition of NRF-1 mediated folate transporter expression significantly reduced intracellular folate levels. These results suggest that chronic consumption of high-fat diets impairs folate transporter expression via NRF-1-dependent mechanism, leading to reduced hepatic folate storage. Understanding the regulation of folate homeostasis in obesity may have an important implication in current guideline of folate intake. Key messages Serum and liver folate levels are decreased in diet-induced obese mice. Chronic high-fat diet consumption impairs expression of hepatic PCFT and RFC. NRF-1 regulates hepatic folate transporters expression and folate levels.
      PubDate: 2018-11-01
      DOI: 10.1007/s00109-018-1688-8
      Issue No: Vol. 96, No. 11 (2018)
       
  • Emerging role of circadian rhythm in bone remodeling
    • Authors: Qian-Yuan Wu; Jian Wang; Xiao Tong; Jie Chen; Bei Wang; Zong-Ning Miao; Xia Li; Jun-Xing Ye; Feng-Lai Yuan
      Abstract: The 24-h rhythm of behavioral and physiological processes is a typical biological phenomenon regulated by a group of circadian rhythm genes. Dysfunction of the circadian rhythm can cause a wide range of problems, such as cancer and metabolic diseases. In recent decades, increased understanding of the roles of circadian rhythm genes in the bone remodeling process have been documented, including osteoblastic bone formation, osteoclastic bone resorption, and osteoblast/osteoclast communication. A timely review of the current findings may help to facilitate the new field of circadian rhythmic bone remodeling research. Targeted pharmacological modulation of circadian rhythm genes is a possible therapeutic approach through which to overcome bone remodeling problems in the future.
      PubDate: 2018-11-16
      DOI: 10.1007/s00109-018-1723-9
       
  • Macrophage-derived CCL18 promotes osteosarcoma proliferation and migration
           by upregulating the expression of UCA1
    • Authors: Yang Su; Yan Zhou; Yuan-jue Sun; Ya-Ling Wang; Jun-yi Yin; Yu-jing Huang; Jian-jun Zhang; Ai-na He; Kun Han; Hui-zhen Zhang; Yang Yao; Xiao-Bin Lv; Hai-yan Hu
      Abstract: Osteosarcoma (OS), which is the most common primary malignant bone tumor, has a high incidence of pulmonary metastasis. CCL18 (C-C motif chemokine ligand 18), which is secreted by tumor-associated macrophages (TAMs), has been found to be increased in various tumors and is associated with tumor metastasis. However, the role of CCL18 in OS remains unclear. Here, we evaluated the effect of CCL18 on the OS cell lines MG63 and 143B and explored its potential mechanisms. We found that CCL18 enhanced the proliferation and migration of OS cells and upregulated UCA1 through transcription factor EP300. Subsequently, we further revealed that the downstream Wnt/β-catenin signaling pathway participated in this process. In addition, the high expression of CCL18 in both tissue and serum from patients was closely related to pulmonary metastasis and poor survival in OS patients. The tumor xenograft models also showed that CCL18 promoted the metastasis of OS cells. Collectively, our study indicated that macrophage-derived CCL18 promotes OS proliferation and metastasis via the EP300/UCA1/Wnt/β-catenin pathway and that CCL18 may be used as a prognostic marker and therapeutic target of OS. Key messages CCL18 promotes proliferation and migration of osteosarcoma cells by EP300/ UCA1/ Wnt/β-catenin pathway. CCL18+ TAMs are significantly correlated with pulmonary metastasis and poor survival in osteosarcoma patients. CCL18 may be used as a prognostic marker and therapeutic target for osteosarcoma.
      PubDate: 2018-11-13
      DOI: 10.1007/s00109-018-1711-0
       
  • ALMS1 and Alström syndrome: a recessive form of metabolic,
           neurosensory and cardiac deficits
    • Authors: Tom Hearn
      Abstract: Alström syndrome (AS) is characterised by metabolic deficits, retinal dystrophy, sensorineural hearing loss, dilated cardiomyopathy and multi-organ fibrosis. Elucidating the function of the mutated gene, ALMS1, is critical for the development of specific treatments and may uncover pathways relevant to a range of other disorders including common forms of obesity and type 2 diabetes. Interest in ALMS1 is heightened by the recent discovery of its involvement in neonatal cardiomyocyte cell cycle arrest, a process with potential relevance to regenerative medicine. ALMS1 encodes a ~ 0.5 megadalton protein that localises to the base of centrioles. Some studies have suggested a role for this protein in maintaining centriole-nucleated sensory organelles termed primary cilia, and AS is now considered to belong to the growing class of human genetic disorders linked to ciliary dysfunction (ciliopathies). However, mechanistic details are lacking, and recent studies have implicated ALMS1 in several processes including endosomal trafficking, actin organisation, maintenance of centrosome cohesion and transcription. In line with a more complex picture, multiple isoforms of the protein likely exist and non-centrosomal sites of localisation have been reported. This review outlines the evidence for both ciliary and extra-ciliary functions of ALMS1.
      PubDate: 2018-11-12
      DOI: 10.1007/s00109-018-1714-x
       
  • Identification of molecular signatures involved in radiation-induced lung
           fibrosis
    • Authors: Hee Jin; Ga-Young Kang; Seulgi Jeon; Jin-Mo Kim; You Na Park; Jaeho Cho; Yun-Sil Lee
      Abstract: In radiotherapy, radiation (IR)-induced lung fibrosis has severe and dose-limiting side effects. To elucidate the molecular effects of IR fibrosis, we examined the fibrosis process in irradiated mouse lung tissues. High focal IR (90 Gy) was exposed to a 3-mm volume of the left lung in C57BL6 mice. In the diffused irradiation, 20 Gy dose delivered with a 7-mm collimator almost covered the entire left lung. Histological examination for lung tissues of both irradiated and neighboring regions was done for 4 weeks after irradiation. Long-term effects (12 months) of 20Gy IR were compared on a diffuse region of the left lung and non-irradiated right lung. Fibrosis was initiated as early as 2 weeks after IR in the irradiated lung region and neighboring region. Upregulation of gtse1 in both 90Gy-irradiated and neighboring regions was observed. Upregulation of fgl1 in both 20Gy diffused irradiated and non-irradiated lungs was identified. When gtse1 or flg1 was knock-downed, TGFβ or IR-induced epithelial-mesenchymal transition was inhibited, accompanied with the inhibition of cellular migration, suggesting fibrosis responsible genes. Immunofluorescence analysis using mouse fibrotic lung tissues suggested that fibrotic regions showed increased expressions of Gtse1 and Fgl1, indicating novel molecular signatures of gtse1and fgl1 for IR-induced lung fibrosis. Even though their molecular mechanisms and IR doses or irradiated volumes for lung fibrosis may be different, these genes may be novel targets for understanding IR-induced lung fibrosis and in treatment strategies. Key messages Upregulation of gtse1 by 90Gy focal irradiation and upregulation of fgl1 by 20Gy diffused irradiation are identified in mouse lung fibrosis model. Gtse1 and Fgl1 are involved in radiation or TGFβ-induced epithelial-mesenchymal transition. Radiation-induced fibrotic regions of mouse lungs showed increased expressions of Gtse1 and Fgl1. Gtse1 and Fgl1 are suggested to be novel targets for radiation-induced lung fibrosis.
      PubDate: 2018-11-07
      DOI: 10.1007/s00109-018-1715-9
       
  • Propionibacterium acnes induces discogenic low back pain via stimulating
           nucleus pulposus cells to secrete pro-algesic factor of IL-8/CINC-1
           through TLR2–NF-κB p65 pathway
    • Authors: Yucheng Jiao; Ye Yuan; Yazhou Lin; Zezhu Zhou; Yuehuan Zheng; Wenjian Wu; Guoqing Tang; Yong Chen; Jiaqi Xiao; Changwei Li; Zhe Chen; Peng Cao
      Abstract: Latent infection of Propionibacterium acnes was considered as a new pathogeny for low back pain (LBP); however, there is no credible animal evidence or mechanism hypothesis. This study proved that P. acnes is a causative pathogen of bacteria-induced LBP and investigated its underlying mechanism. For this, P. acnes was firstly identified in patients’ degenerated intervertebral disc (IVDs) samples. The results of patients’ Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ), Japanese Orthopaedic Association (JOA), and Oswestry Disability Index (ODI) scores indicated that P. acnes-positive patients showed more severe LBP and physical disability. Then, a P. acnes-inoculated lumbar IVDs model was established in rats. The results of paw/foot withdrawal threshold and qRT-PCR indicated that P. acnes-inoculated rats had obvious LBP in behavioral evaluation and over-expression of substance P (SP) and calcitonin gene-related peptide (CGRP) in IVDs. Subsequently, enzyme-linked immunosorbent assay (ELISA) results demonstrated that increased expression of IL-8 or CINC-1 (the homolog of IL-8 in rats) in the P. acnes-positive IVDs of human and rats. The CINC-1 injected animal model proved that the cytokines were able to induce LBP. Finally, the co-culture experiments showed that nucleus pulposus cells (NPCs) were able to respond to P. acnes and secreted IL-8/CINC-1 via TLR-2/NF-κB p65 pathway. In conclusion, P. acnes had strong association with LBP by stimulating NPCs to secrete pro-algesic factor of IL-8/CINC-1 via TLR2/NF-κBp65 pathway. The finding may provide a promising alternative therapy strategy for LBP in clinical. Key messages Patients with P. acnes-positive IVDs tended to have more severe LBP, physical disability, and increased IL-8 expressions. P. acnes can induce LBP via IL-8/CINC-1 in IVDs. P. acnes stimulate the NPCs to secrete pro-algesic factor of IL-8/CINC-1 via TLR2/NF-κBp65 pathway.
      PubDate: 2018-11-06
      DOI: 10.1007/s00109-018-1712-z
       
  • Antigen-presenting cell diversity for T cell reactivation in central
           nervous system autoimmunity
    • Authors: Ari Waisman; Lisa Johann
      Abstract: Autoreactive T cells are considered the major culprits in the pathogenesis of many autoimmune diseases like multiple sclerosis (MS). Upon activation in the lymphoid organs, autoreactive T cells migrate towards the central nervous system (CNS) and target the myelin sheath-forming oligodendrocytes, resulting in detrimental neurological symptoms. Despite the availability of extensively studied systems like the experimental autoimmune encephalomyelitis (EAE) model, our understanding of this disease and the underlying pathogenesis is still elusive. One vividly discussed subject represents the T cell reactivation in the CNS. In order to exert their effector functions in the CNS, autoreactive T cells must encounter antigen-presenting cells (APCs). This interaction provides an antigen-restricted stimulus in the context of major histocompatibility complex class II (MHC-II) and other co-stimulatory molecules. Peripherally derived dendritic cells (DCs), B cells, border-associated macrophages (BAM), CNS-resident microglia, and astrocytes have the capacity to express molecules required for antigen presentation under inflammatory conditions. Also, endothelial cells can fulfill these prerequisites in certain situations. Which of these cells in fact act as APCs for T cell reactivation and to which extent they can exert this function has been studied intensively, but unfortunately with no firm conclusion. In this review, we will summarize the findings that support or question the antigen presenting capacities of the mentioned cell types of CNS-localized T cell reactivation.
      PubDate: 2018-11-01
      DOI: 10.1007/s00109-018-1709-7
       
  • Hypoxia-inducible factor-1α regulation of myeloid cells
    • Authors: C. L. Stothers; L. Luan; B. A. Fensterheim; J. K. Bohannon
      Abstract: Hematopoietic myeloblasts give rise to macrophages, dendritic cells, and neutrophils. Circulating myeloid cells detect invading microbes using pattern recognition receptors and subsequently orchestrate an innate immune response to contain and kill the pathogens. This innate immune response establishes an inflammatory niche characterized by hypoxia due to host and pathogen factors. Hypoxia-inducible factor (HIF) transcription factors are the primary regulators of the myeloid response to hypoxia. In particular, HIF-1α is a critical hub that integrates hypoxic and immunogenic signals during infection or inflammation. Hypoxia induces HIF-1α stabilization, which drives metabolic and phenotypic reprogramming of myeloid cells to maximize antimicrobial potential. HIF-1α activity in myeloid-derived cells enhances the host response to infection, but may also play a role in pathogenic inflammatory processes, such as atherosclerosis. In this review, we summarize recent advances that have elucidated the mechanism by which myeloid cells regulate HIF-1α activity and, in turn, how HIF-1α shapes myeloid cell function.
      PubDate: 2018-11-01
      DOI: 10.1007/s00109-018-1710-1
       
  • Pre-treatment with angiotensin-(1–7) inhibits tumor growth via autophagy
           by downregulating PI3K/Akt/mTOR signaling in human nasopharyngeal
           carcinoma xenografts
    • Authors: Yu-Tsai Lin; Hung-Chen Wang; Hui-Ching Chuang; Yi-Chiang Hsu; Ming-Yu Yang; Chih-Yen Chien
      Abstract: The highest incidence of nasopharyngeal carcinoma (NPC) is in southeast China, including Taiwan. Many side effects have been observed following radiation therapy with chemotherapy; hence, exploring new treatment modalities for NPC is an important future direction. Angiotensin-(1–7) [Ang-(1–7)] is an endogenous heptapeptide hormone and important component of the renin–angiotensin system that acts through both the Mas receptor and AT2 receptor, exhibiting anti-proliferative and anti-angiogenic properties in cancer cells. However, the anti-cancer activity of Ang-(1–7) related to autophagy in NPC remains largely debated. The effects and signaling pathway(s) involved in the Ang-(1–7)/Mas receptor axis in NPC were investigated both in vitro and in vivo. Ang-(1–7) inhibited cell proliferation, migration, and invasion in NPC-TW01 cells. Ang-(1–7) induced autophagy by increasing the levels of the autophagy marker LC3-II and by enhancing p62 degradation via activation of the Beclin-1/Bcl-2 signaling pathway with involvement of the PI3K/Akt/mTOR and p38 pathways in vitro study. In addition, pre-treatment with Ang-(1–7) inhibited tumor growth in NPC xenografts by inducing autophagy, suggesting a correlation between PI3K/Akt/mTOR pathway inhibition and the abovementioned anti-cancer activities. However, no autophagy was observed following Ang-(1–7) post-treatment. Taken together, these data indicate that Ang-(1–7) plays a novel role in autophagy downstream signaling pathways in NPC, supporting its potential as a therapeutic agent for alleviation the incidence of NPC and preventive treatment of recurrent NPC. Key messages Ang-(1–7) inhibits cell proliferation, migration, and invasion by activating autophagy Ang-(1–7)pre-treatment inhibits tumor growth via autophagy by suppressing PI3K/Akt/mTOR pathway. Ang-(1–7) may provide a novel preventative treatment for NPC and recurrent NPC
      PubDate: 2018-10-29
      DOI: 10.1007/s00109-018-1704-z
       
  • Hypoxia-inducible factor 1α protects peripheral sensory neurons from
           diabetic peripheral neuropathy by suppressing accumulation of reactive
           oxygen species.
    • Authors: Daniel Rangel Rojas; Irmgard Tegeder; Rohini Kuner; Nitin Agarwal
      Abstract: Diabetic peripheral neuropathy (DPN) is one of the most common diabetic complications. Mechanisms underlying nerve damage and sensory loss following metabolic dysfunction remain largely unclear. Recently, hyperglycemia-induced mitochondrial dysfunction and the generation of reactive oxygen species (ROS) have gained attention as possible mechanisms of organ damage in diabetes. Hypoxia-inducible factor 1 (HIF1α) is a key transcription factor activated by hypoxia, hyperglycemia, nitric oxide as well as ROS, suggesting a fundamental role in DPN susceptibility. We analyzed regulation of HIF1α in response to prolonged hyperglycemia. Genetically modified mutant mice, which conditionally lack HIF1α in peripheral sensory neurons (SNS-HIF1α−/−), were analyzed longitudinally up to 6 months in the streptozotocin (STZ) model of type1 diabetes. Behavioral measurements of sensitivity to thermal and mechanical stimuli, quantitative morphological analyses of intraepidermal nerve fiber density, measurements of ROS, ROS-induced cyclic GMP-dependent protein kinase 1α (PKG1α), and levels of vascular endothelial growth factor (VEGF) in sensory neurons in vivo were undertaken over several months post-STZ injections to delineate the role of HIF1α in DPN. Longitudinal behavioral and morphological analyses at 5, 13, and 24 weeks post-STZ treatment revealed that SNS-HIF1α−/− developed stronger hyperglycemia-evoked losses of peripheral nociceptive sensory axons associated with stronger losses of mechano- and heat sensation with a faster onset than HIF1αfl/fl mice. Mechanistically, these histomorphologic, behavioral, and biochemical differences were associated with a significantly higher level of STZ-induced production of ROS and ROS-induced PKG1α dimerization in sensory neurons of SNS-HIF1α−/− mice as compared with HIF1αfl/fl. We found that prolonged hyperglycemia induced VEGF expression in the sciatic nerve which is impaired in SNS-HIF1α mice. Our results indicate that HIF1α is as an upstream modulator of ROS in peripheral sensory neurons and exerts a protective function in suppressing hyperglycemia-induced nerve damage by limiting ROS levels and by inducing expression of VEGF which may promote peripheral nerve survival. Our data suggested that HIF1α stabilization may be thus a new strategy target for limiting sensory loss, a debilitating late complication of diabetes. Key messages • Impaired hypoxia-inducible factor 1α (HIF1α) signaling leads to early onset of STZ-induced loss of sensation in mice. • STZ-induced loss of sensation in HIF1α mutant mice is associated with loss of sensory nerve fiber in skin. • Activation of HIF1α signaling in diabetic mice protects the sensory neurons by limiting ROS formation generated due to mitochondrial dysfunction and by inducing VEGF expression.
      PubDate: 2018-10-25
      DOI: 10.1007/s00109-018-1707-9
       
  • Thymus-derived Foxp3 + regulatory T cells upregulate RORγt expression
           under inflammatory conditions
    • Authors: Juhao Yang; Mangge Zou; Joern Pezoldt; Xuyu Zhou; Jochen Huehn
      Abstract: Foxp3+ regulatory T cells (Tregs) co-expressing the Th17-lineage specification factor RORγt represent a unique Treg subpopulation that has been reported to be induced upon response to gut microbiota within the intestinal immune system. Hence, RORγt+ Tregs are considered to solely consist of peripherally induced Foxp3+ Tregs (pTregs), and the possibility that also thymus-derived Treg (tTregs) can upregulate RORγt expression and contribute to the pool of RORγt+ Tregs was largely ignored. Here, we expand our knowledge on the origin of RORγt+ Tregs by demonstrating that also tTregs can attain RORγt expression. In transgenic Foxp3∆CNS1-Cre reporter mice, a substantial fraction of CNS1-independent Tregs, predominantly consisting of tTregs, was found to co-express RORγt. In addition, genuine tTregs isolated from thymi of Foxp3hCD2RAGGFP reporter mice initiated RORγt expression both in vitro and in vivo, particularly under inflammatory conditions. In conclusion, our data demonstrate that tTregs can upregulate RORγt expression under inflammatory conditions and that hence RORγt+ Tregs can be regarded as a heterogeneous population consisting of both pTregs and tTregs. Key messages RORγt cannot be considered as a marker for pTregs. CNS1-independent tTregs within the colon display RORγt expression. RORγt can be induced in genuine tTregs, particularly under inflammatory conditions. RORγt+ Tregs are a heterogeneous population consisting of both pTregs and tTregs.
      PubDate: 2018-10-24
      DOI: 10.1007/s00109-018-1706-x
       
  • TRIB2 regulates the differentiation of MLL – TET1 transduced myeloid
           progenitor cells
    • Authors: Hyeng-Soo Kim; Seung Hwan Oh; Ju-Heon Kim; Wern-Joo Sohn; Jae-Young Kim; Do-Hyung Kim; Sang-Un Choi; Kwon Moo Park; Zae Young Ryoo; Tae Sung Park; Sanggyu Lee
      Abstract: The function and mechanism of action of MLL–TET1 (MT1) fusion protein in hematological cells are unclear and require further investigation. In the present study, we found that the MT1 fusion protein attenuated the expression of Cebpa, Csf1r, and Cd11b and inhibited the differentiation of myeloid progenitor cells. Increased binding of the MT1 fusion protein to the Trib2 promoter upregulated Trib2 mRNA and protein expression and downregulated Cebpa expression. Trib2 knockdown relieved the inhibition of myeloid cell differentiation induced by the MT1 fusion protein. Thus, TRIB2 is important for the survival of leukemia cells during MT1-related leukemogenesis and is important in maintaining differentiation blockade of leukemic cells. Key messages • MLL–TET1 fusion decreases the 5-hmC levels in the myeloid progenitor cells. • MLL–TET1 fusion inhibits myeloid differentiation through decreased expression of Cebpa. • MLL–TET1 fusion blocks the differentiation of the myeloid progenitor cells by overexpressing Trib2. • Knockdown of Trib2 in MLL–TET1 transduced cells induces myeloid differentiation.
      PubDate: 2018-10-15
      DOI: 10.1007/s00109-018-1700-3
       
 
 
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