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Shaoyong Zhuang, Xiangwei Hua, Kang He, Tao Zhou, Jiang Zhang, Haoyu Wu, Xiong Ma, Qiang Xia, Jianjun Zhang
The contribution of glycogen synthase kinase-3β (GSK-3β) to cholestatic liver disease (CLD) remains unknown. We investigated the role and mechanism of GSK-3β in vivo in liver tissues of patients with CLD and the bile duct ligation (BDL) mouse model and in vitro using a hepatic progenitor cell (HPC) and hepatic stellate cell (HSC) coculture system. In liver tissues of patients with CLD, expression of the inactive form of GSK-3β, phospho-GSK-3β(Ser9), was increased in HPCs. GSK-3β inhibition by SB216763 treatment aggravated liver fibrosis and elevated the expression of osteopontin (OPN) in the BDL mouse model...
March 12, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Brittany A Potz, Laura A Scrimgeour, Sharif A Sabe, Richard T Clements, Neel R Sodha, Frank W Sellke
OBJECTIVES: Glycogen synthase kinase 3β (GSK-3β) inhibition has been reported to increase microvascular density and improve myocardial blood flow in a porcine model of chronic myocardial ischemia and metabolic syndrome. Inhibition of GSK-3β can also be cardioprotective by modulating fibrosis signaling and mitochondrial-induced apoptosis. We hypothesized GSK-3β inhibition would have a beneficial effect on myocardial fibrosis and oxidative stress in a porcine model of chronic myocardial ischemia and metabolic syndrome...
February 2, 2018: Journal of Thoracic and Cardiovascular Surgery
Harrison T Supnick, Rodica P Bunaciu, Andrew Yen
Differentiation therapy is used in cancer treatment. Epidemiologic studies showed that higher vitamin D levels are associated with reduced cancer risks. However, the therapeutic doses needed for differentiation are accompanied by hypercalcemia and intolerable pathological sequelae. In the present work we evaluated if RRD-251, a small-molecule, can enhance vitamin D3-induced differentiation of leukemic cells, in the hope of decreasing the needed vitamin D3-dose. We demonstrate that RRD-251 enhances vitamin D3-induced differentiation of leukemic cells, the enrichment of the c-Raf kinase in the nucleus, the binding of nuclear c-Raf to GSK-3, increased phosphorylation of GSK-3 ser 21/9 inhibitory sites, and the binding of GSK-3 to VDR, where GSK-3 inhibition is known to enhance transcriptional activation by VDR...
February 9, 2018: Oncotarget
Xiaoying He, Hongyu Guan, Weiwei Liang, Zhimin Huang, Lijuan Xu, Pengyuan Zhang, Fen Xu, Yanbing Li
BACKGROUND: Abdominal obesity is considered a major factor in the development of metabolic disorders. Glucagon-like peptide-1 (GLP-1) has been reported to have positive effects on improving body metabolism and to reducing insulin resistance. However, it remains less clear whether GLP-1 plays a role in the adipogenesis process of visceral fat. METHODS: Here, we analyzed the in vitro actions and probable mechanisms of Exendin-4, a GLP-1 receptor agonist, on human adipose-derived stromal cells (hADSCs) isolated from omentum...
February 8, 2018: International Journal of Obesity: Journal of the International Association for the Study of Obesity
Yassan Abdolazimi, Sooyeon Lee, Haixia Xu, Paul Allegretti, Timothy M Horton, Benjamin Yeh, Hannah P Moeller, Robert J Nichols, David McCutcheon, Aryaman Shalizi, Mark Smith, Neali A Armstrong, Justin P Annes
Pharmacologic expansion of endogenous β-cells is a promising therapeutic strategy for diabetes. To elucidate the molecular pathways that control β-cell growth we screened ∼2,400 bioactive compounds for rat β-cell replication-modulating activity. Numerous hit compounds impaired or promoted rat β-cell replication, including CC-401, an advanced clinical candidate previously characterized as a c-Jun N-terminal kinase (JNK) inhibitor. Surprisingly, CC-401 induced rodent (in vitro and in vivo) and human (in vitro) β-cell replication via dual specificity tyrosine-phosphorylation-regulated kinases (DYRK1A/B) inhibition...
March 5, 2018: Endocrinology
Hongjin Si, Yao Zhang, Yuqing Song, Lili Li
The poor survival rate of transplanted mesenchymal stem cells (MSCs) within the ischemic heart limits their therapeutic potential for cardiac repair. Adrenomedullin (ADM) has been identified as a potent apoptotic inhibitor. The present study aimed to investigate the protective effects of ADM on MSCs against hypoxia and serum deprivation (H/SD)‑induced apoptosis, and to determine the potential underlying mechanisms. In the present study, a recombinant adenovirus expressing the ADM gene was established and was infected into MSCs...
March 5, 2018: International Journal of Molecular Medicine
Wenji He, Xinyu Yan, Sanqiang Pan
Amphetamine (AMPH) abuse can influence neuropsychiatric disorders and cell apoptosis by interfering with the protein kinase B/ glycogen synthase kinase 3 beta (AKT/GSK3β) pathway. However, the mechanisms underlying this regulation are poorly understood. Using PC12 cells, we found that AMPH inhibited AKT and GSK-3β phosphorylation levels and increased total GSK-3β levels. Furthermore, AMPH caused an increase in the activity of protein phosphatase 2 (PP2A), a signaling protein upstream of AKT, which in turn inhibited phosphorylated AKT levels...
March 6, 2018: Neurotoxicity Research
Lin Ru Wang, Seung-Soo Baek
Social isolation is known to precipitate depression-like symptoms in rodents and has emerged as a dependable paradigm to screen the behavioral and neurobiological changes observed in humans. In the present study, the undying mechanisms of treadmill exercise on social isolation-induced depression was evaluated. The rat pups in the social isolation groups were housed individually. The social isolation procedures started on the postnatal day 14. The rat pups in the exercise groups were forced to run on treadmill for 30 min once a day from postnatal day 21 to postnatal day 34...
February 2018: Journal of Exercise Rehabilitation
Rui Yang, Ze-Zhang Tao, Mao-Ling Huang, Yong-Fa Zheng, Meng-Yuan Dai, You Zou, Shi-Ming Chen
The present study investigated the radiosensitizing effect of placenta specific 8 (PLAC8) in nasopharyngeal carcinoma (NPC) cells. A PLAC8-knockout CNE2 cell line was constructed using the CRISPR/Cas9 system. The CCK-8 assay demonstrated knockout of PLAC8 significantly reduced cell proliferation and cell survival after irradiation compared to both control cells and non-irradiated PLAC8-knockout cells. The clonogenic assay showed knockout of PLAC8 enhanced the radiosensitivity of NPC cells. Flow cytometry revealed knockout of PLAC8 increased apoptosis and G2/M phase arrest after irradiation...
2018: American Journal of Translational Research
Yingjuan Liu, Lihua Geng, Jingjing Zhang, Jing Wang, Qi Zhang, Delin Duan, Quanbin Zhang
Parkinson's disease (PD) is a neurodegenerative movement disorder that is caused by a selective loss of dopaminergic neurons. Current PD treatments provide symptomatic relief but do not prevent or decelerate disease progression. Previous studies have suggested that acetylated and phosphorylated porphyran, derived from Porphyra , produces a neuroprotective effect against 6-OHDA-induced damage. Due to its antioxidant and neuroprotective potential, this study evaluates whether oligo-porphyran (OP) could be beneficial in an experimental model of PD in mice...
March 6, 2018: Marine Drugs
Yingying Zhu, Everaert Nadia, Yang Yao, Zhenxing Shi, Guixing Ren
Lunasin is a novel promising health-beneficial peptide derived from soybean. However, the application of lunasin is limited by its high cost. In this study, we developed a successful protocol for expression of a dimer formation protein containing 4 tandem repeated lunasin analogs (lunasin-4) in Pichia pastoris. The expression level at the optimal condition (initial pH 7.0, 1.0% final methanol concentration and induction for 72 h at 26 °C) was 0.24 mg/mL cell-free broth. Lunasin analog, obtained from purified lunasin-4 protein through enterokinase digestion and ultrafiltration, significantly decreased (p < 0...
March 2, 2018: Journal of Bioscience and Bioengineering
Tao Xiong, Yi Qu, Huiqin Wang, Hongju Chen, Jianghu Zhu, Fengyan Zhao, Rong Zou, Li Zhang, Dezhi Mu
Glycogen synthase kinase 3 beta (GSK-3β) plays an important role in neurological outcomes after brain injury. However, its roles and mechanisms in hypoxia-ischemia (HI) are unclear. Activation of mTOR complex 1 (mTORC1) has been proven to induce the synthesis of proteins associated with regeneration. We hypothesized that GSK-3β inhibition could activate the mTORC1 signaling pathway, which may reduce axonal injury and induce synaptic protein synthesis and functional recovery of synapses after HI. By analyzing a P7 rat model of cerebral HI and an in vitro ischemic (oxygen glucose deprivation) model, we found that GSK-3β inhibitors (GSK-3β siRNA or lithium chloride) activated mTORC1 signaling, leading to increased expression of synaptic proteins, including synapsin 1, PSD95, and GluR1, and the microtubule-associated protein Tau and decreased expression of the axonal injury-associated protein amyloid precursor protein...
February 28, 2018: Journal of Neuropathology and Experimental Neurology
Arto A Palmu, Jukka Jokinen, Heta Nieminen, Hanna Rinta-Kokko, Esa Ruokokoski, Taneli Puumalainen, Marta Moreira, Lode Schuerman, Dorota Borys, Terhi M Kilpi
Estimation of the full disease burden caused by Streptococcus pneumoniae is challenging due to the difficulties in assigning the aetiology especially in lower and upper respiratory infections. We estimated the pneumococcal disease burden by using the vaccine-preventable disease incidence (VPDI) of PHiD-CV10 vaccine (GSK) in our clinical trial setting. Finnish Invasive Pneumococcal disease (FinIP) trial was a cluster-randomized, double-blind trial in children <19 months who received PHiD-CV10 in 52 clusters or hepatitis B/A vaccine as control in 26 clusters according to 3+1 or 2+1 schedules (infants < 7 months) or catch-up schedules (children 7-18 months)...
March 1, 2018: Vaccine
Chun Song, Han Yan, Han-Ming Wang, Yan Zhang, Huiqing Cao, Yiqi Wan, Lingbao Kong, Shenghan Chen, Hong Xu, Bing-Xing Pan, Jin Zhang, Guo-Huang Fan, Hong-Bo Xin, Zicai Liang, Weiping Jia, Xiao-Li Tian
Type 2 diabetes mellitus (T2DM) is a common metabolic disease influenced by both genetic and environmental factors. In this study, we performed an in-house genotyping and meta-analysis study using three independent GWAS datasets of T2DM and found that rs3743121, located 1 kb downstream of AQR, was a novel susceptibility SNP associated with T2DM. The risk allele C of rs3743121 was correlated with the increased expression of AQR in white blood cells, similar to that observed in T2DM models. The knockdown of AQR in HepG2 facilitated the glucose uptake, decreased the expression level of PCK2, increased the phosphorylation of GSK-3β, and restored the insulin sensitivity...
February 14, 2018: Journal of Genetics and Genomics, Yi Chuan Xue Bao
Xue Zhang, Wuping Bao, Xia Fei, Yingying Zhang, Guoqing Zhang, Xin Zhou, Min Zhang
Airway remodeling is a vital component of chronic obstructive pulmonary disease (COPD). Despite the broad anti-inflammation effects of glucocorticoids, they exhibit relatively little therapeutic benefit in COPD, indicating the accelerating demands of new agents for COPD. We aim to explore the effect of progesterone on airway remodeling in a murine modeling of exposing to ozone and to further examine the potential effect of progesterone on glucocorticoid insensitivity. C57/BL6 mice were exposed to ozone for 12 times over 6 weeks, and were administered with progesterone alone or combined with budesonide (BUD) after each exposure until the 10th week...
March 1, 2018: Molecular Immunology
Somrudee Reabroi, Arthit Chairoungdua, Rungnapha Saeeng, Teerapich Kasemsuk, Witchuda Saengsawang, Weiming Zhu, Pawinee Piyachaturawat
Hyperactivation of Wnt/β-catenin signaling implicated in oncogenesis of colorectal cancer (CRC) is a potential molecular target for chemotherapy. An andrographolide analogue, 3A.1 (19-tert-butyldiphenylsilyl-8, 17-epoxy andrographolide) has previously been reported to be potently cytotoxic toward cancer cells by unknown molecular mechanisms. The present study explored the anti-cancer activity of analogue 3A.1 on Wnt/β-catenin signaling in colon cancer cells (HT29 cells) which were more sensitive to the others (HCT116 and SW480 cells)...
March 1, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Haitao Sun, Guanxin Chen, Bin Wen, Jialing Sun, Haiyan An, Jie Pang, Wei Xu, Xuemei Yang, Songqi He
Oligo-peptide I-C-F-6 is a Carapax trionycis extract component that has an effect on hepatic fibrosis, however, its mechanism of action is still unclear. This study investigated whether oligo-peptide I-C-F-6 could inhibit liver fibrosis by suppressing NF-κB and Wnt/β-catenin signaling, which are important in liver fibrosis. HSC-T6 cells were treated with oligo-peptide I-C-F-6, and rats were divided randomly into five groups: control (saline), CCl4 , CCl4 plus oligo-peptide I-C-F-6 (0.12 and 0.24 mg/kg), and CCl4 plus colchicine (0...
February 2, 2018: Journal of Pharmacological Sciences
Qiang Wang, Yongjian Zhao, Nannan Sha, Yan Zhang, Chenguang Li, Hao Zhang, Dezhi Tang, Sheng Lu, Qi Shi, Yongjun Wang, Bing Shu, Dongfeng Zhao
Primary osteoporosis (POP), which is caused by unbalanced bone remodeling, leads to significant economic and societal burdens globally. Gushukang (GSK) granule serves as one commonly used prescription for POP in Traditional Chinese Medicine (TCM). The present study aimed to clarify the exact roles of GSK in bone remodeling with in vivo and in vitro assays. Here we showed that GSK prevented bone loss and the alternations of osteoporotic bone parameters as well as the decreased density of osteoclast in ovariectomized (OVX) mice...
February 10, 2018: Journal of Pharmacological Sciences
Kiran Kumar Alluri, Rudraraju Srilakshmi Reshma, Raghuram Suraparaju, Suryanarayana Gottapu, Dharmarajan Sriram
Need for new drugs to fight against tuberculosis (TB) is increasing day by day. In the present work we have taken a spiro compound (GSK 2200150A) reported by GSK as a lead and we modified the structure of the lead to study the antitubercular activity. For structure activity profiling twenty-one molecules have been synthesized, characterized and evaluated for their antimycobacterial potency against both active and dormant TB. Compound 06, 1-((4-methoxyphenyl)sulfonyl)-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran] was found to be the most potent compound (MIC: 8...
December 28, 2017: Bioorganic & Medicinal Chemistry
Nathan Saul, Kevin Wang, Shopna Bag, Heather Baldwin, Kate Alexander, Meena Chandra, Jane Thomas, Helen Quinn, Vicky Sheppeard, Stephen Conaty
BACKGROUND: Infants are at the highest risk of severe complications - including death - as a result of pertussis infection. Controlling pertussis in this group has been challenging, particularly in those too young to be vaccinated. Following revised national recommendations in March 2015, the state of New South Wales, Australia, introduced a funded maternal vaccination campaign at 28 - 32 weeks of gestation using a 3-component tetanus-diphtheria-acellular pertussis vaccine (dTpa; Boostrix, GSK)...
February 28, 2018: Vaccine
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