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Ghrelin O-acyltransferase(GOAT) and energy metabolism

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Science China(Life Sciences) 2016年第3期59卷 281-291页

作者： Ziru Li Michael Mulholland Weizhen Zhang Department of Surgery University of Michigan Medical Center Department of Physiology and pathophysiology Peking University Health Science Center

Ghrelin O-acyltransferase(GOAT), a member of MBOATs family, is essential for octanoylation of ghrelin, which is required for active ghrelin to bind with and activate its receptor. GOAT is expressed mainly in the stomach, pancreas and hypothalamus. Levels of GOAT are altered by energy status. GOAT contains 11 transmembrane helices and one reentrant loop. Its invariant residue His-338 and conserved Asn-307 are located in the endoplasmic reticulum lumen and cytosol respectively. GOAT contributes to the regulation of food intake and energy expenditure, as well as glucose and lipids homeostasis. Deletion of GOAT blocks the acylation of ghrelin leading to subsequent impairment in energy homeostasis and survival when mice are challenged with high energy diet or severe caloric restriction. GO-Co A-Tat, a peptide GOAT inhibitor, attenuates acyl-ghrelin production and prevents weight gain induced by a medium-chain triglycerides-rich high fat diet. Further, GO-Co A-Tat increases glucose-induced insulin secretion. Overall, inhibition of GOAT is a novel strategy for treatment of obesity and related metabolic disorders.

关键词： ghrelin 酰基转移酶能量代谢山羊 Ghrelin 中链甘油三酯高能量饲料胰岛素分泌

Role of chondroitin sulfate proteoglycan signaling in regulating neuroinflammation following spinal cord injury

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Neural Regeneration Research 2018年第12期13卷 2080-2082页

作者： Scott M.Dyck Soheila Karimi-Abdolrezaee Department of Physiology and pathophysiology the Regenerative Medicine Program the Spinal Cord Research Center University of Manitoba

Spinal cord injury （SCI） elicits a robust inflammatory response that is a hallmark of the secondary injury mechanisms. Neuroinflammation is orchestrated initially by the response of resident astrocytes and microglia to injury, which subsequently facilitates the recruitment of peripheral immune cells into the SCI lesion （Orr and Gensel, 2018）. This inflammatory response contributes to cell death and tissue degeneration through the production of pro-inflammatory cytokines and chemokines, free radicals and proteolytic enzymes. However, neuroinflammatory cells also play beneficial regulatory role in repair mechanisms after SCI by adopting a reparative and wound healing phenotype （Orr and Gensel, 2018; Tran et al., 2018）. Hence, understanding the underlying mechanisms by which immune cells are reg- ulated within the microenvironment of injury would aid in harnessing the reparative potential of inflammation following SCI.

关键词： Role of chondroitin sulfate proteoglycan signaling in regulating neuroinflammation following spinal cord injury PTP SCI

Qualitative Analysis of Xinyue Capsules(心悦胶囊)by High-Performance Liquid Chromatography:Preliminary Evaluation of Drug Quality in A Sino-Austrian Joint Study

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Chinese Journal of Integrative Medicine 2015年第10期21卷 772-777页

作者：薛梅杨琳史大卓 Christian Radauer Heimo Breiteneder 马燕 center of Cardiology Xiyuan HospitalChina Academy of Chinese Medical Sciences Molecular Research in Traditional Chinese Medicine Group Department of Pathophysiology and Allergy ResearchCenter of PathophysiologyInfectiology & ImmunologyMedical University of Vienna

ABSTRACT Objective： To develop a reliable method to assess the stability of Xinyue Capsules （心悦胶囊） containing Panax quinquefolius saponins according to European quality standards. Methods： An efficient high-performance liquid chromatography ultraviolet （HPLC-UV） method was established to analyse six main ginsenosides （Rb1, Rb2, Rc, Rd, Re and Rg1） in six different batches （120 capsules/batch） from the same lot of Xinyue Capsules and in one batch measured six times within one day. The six ginsenosides were separated on a Hypersil BDS-C18 column （3 μm, 100 mm × 3 mm） at a flow rate of 0.5 mL/min. Gradient elution was performed using a mobile phase gradient of acetonitrile-water modified with 0.01% formic acid. The HPLC chromatograms were analyzed with ＂LC data comparison＂ using Lab Solutions software. Results： The HPLC peaks were identified by comparing their retention times （Rg1： 23.44 min, Re： 23.77 rain, Rb1： 35.24 min, Rc： 36.18 min, Rb2：38.55 min and Rd： 40.88 min） with those of the standards under the same chromatographic conditions, which showed similar results among the samples of six different batches and among the samples from one batch detected six times within one day. Conclusions： Xinyue Capsules have good drug intra-day consistency at room temperature and exhibit a consistent quality between different batches. This study established a reliable method to assess the stability of Xinyue Capsules, which is suitable for further qualitative analysis and may assist in promoting the safe and effective use of Chinese herbal medicine.

关键词： Panax quinquefo/ius saponins ginsenosides high-performance liquid chromatography,ultraviolet stability Chinese medicine

Dachaihu decoction ameliorates pancreatic fibrosis by inhibiting macrophage infiltration in chronic pancreatitis

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World Journal of Gastroenterology 2017年第40期23卷 7242-7252页

作者： Li-Fang Duan Xiao-Fan Xu Lin-Jia Zhu Fang Liu Xiao-Qin Zhang Nan Wu Jian-Wei Fan Jia-Qi Xin Hong Zhang Department of pathophysiology Shaanxi University of Chinese Medicine Medical Experiment center Shaanxi University of Chinese Medicine

AIM To explore the role of macrophages in chronic pancreatitis(CP) and the effect of Dachaihu decoction(DCHD) on pancreatic fibrosis in mice.METHODS Kun Ming mice were randomly divided into a control group, CP group, and DCHD group. In the CP and DCHD groups, mice were intraperitoneally injected with 20% L-arginine(3 g/kg twice 1 d/wk for 6 wk). Mice in the DCHD group were administered DCHD intragastrically at a dose of 14 g/kg/d 1 wk after CP induction. At 2 wk, 4 wk and 6 wk post-modeling, the morphology of the pancreas was observed using hematoxylin and eosin, and Masson staining. Interleukin-6(IL-6) serum levels were assayed using an enzyme-linked immunosorbent assay. Double immunofluorescence staining was performed to observe the co-expression of F4/80 and IL-6 in the pancreas. Inflammatory factors including monocyte chemoattractant protein-1(MCP-1), macrophage inflammatory protein-1α(MIP-1α) and IL-6 were determined using real time-polymerase chain reaction. Western blot analysis was used to detect fibronectin levels in the pancreas. RESULTS Compared with the control group, mice with 20% L-arginine-induced CP had obvious macrophage infiltration and a higher level of fibrosis. IL-6 serum concentrations were significantly increased. Double immunofluorescence staining showed that IL-6 and F4/80 were co-expressed in the pancreas. With the administration of DCHD, the infiltration of macrophages and degree of fibrosis in the pancreas were significantly attenuated; IL-6, MCP-1 and MIP-1α m RNA, and fibronectin levels were reduced. CONCLUSION The dominant role of macrophages in the development of CP was mainly related to IL-6 production. DCHD was effective in ameliorating pancreatic fibrosis by inhibiting macrophage infiltration and inflammatory factor secretion in the pancreas.

关键词： Dachaihu decoction Pancreatic fibrosis Macrophages Interleukin-6

The mechanisms linking adiposopathy to type 2 diabetes

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Frontiers of Medicine 2013年第4期7卷 433-444页

作者： Jichun Yang Jihong Kang Youfei Guan Department of Physiology and pathophysiology Peking University Diabetes CenterPeking University Health Science CenterBeijing 100191China

Obesity is defined as excessive accumulation of body fat in proportion to body size.When obesity occurs,the functions of adipose tissue may be deregulated,which is termed as adiposopathy.Adiposopathy is an independent risk factor for many diseases,including diabetes and cardiovascular diseases.In overweight or obese subjects with adiposopathy,hyperlipidemia exerts lipotoxicity in pancreatic islet and liver and induces pancreaticβcell dysfunction and liver insulin resistance,which are the decisive factors causing type 2 diabetes.Moreover,adipokines have been shown to play important roles in the regulation of glucose homeostasis.When adiposopathy occurs,abnormal changes in the serum adipokine profile correlate with the development and progression of pancreaticβcell dysfunction and insulin resistance in peripheral tissue.The current paper briefly discusses the latest findings regarding the effects of adiposopathy-related lipotoxicity and cytokine toxicity on the development of type 2 diabetes.

关键词： obesity adiposopathy lipotoxicity adipokines diabetes

Effects of Ganfukang(肝复康) on Expression of Connective Tissue Growth Factor and Focal Adhesion Kinase/Protein Kinase B Signal Pathway in Hepatic Fibrosis Rats

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Chinese Journal of Integrative Medicine 2014年第6期20卷 438-444页

作者：张坤姜妙娜张彩华李骢贾玉杰 Department of pathophysiology Dalian Medical University Department of pathophysiology Baotou Medical College

Objective： To investigate the effect of Ganfukang （肝复康, GFK） on connective tissue growth factor （CTGF） and focal adhesion kinase （FAK）/protein kinase B （PKB or Akt） signal pathway in a hepatic fibrosis rat model and to explore the underlying therapeutic molecular mechanisms of GFK. Methods： Fifty SD rats were randomly divided into five groups as follows： the control group, the model group （repeated subcutaneous injection of CCl4）, and the three GFK treatment groups （31.25, 312.5, and 3125 mg/kg, intragastric administration）. Reverse transcriptase-polymerase chain reaction （RT-PCR）, Western blotting, and immunohistochemistry were used to examine the expression of CTGF, integrin α 5, integrin β 1, FAK/Akt signal pathway, cyclinD1, and collagen in the different-treated rats. Results： GFK attenuated the up-regulation of CTGF, integrin α 5, and integrin β 1 in hepatic fibrosis rats and suppressed both the phosphorylation of FAK and the phosphorylation of Akt simultaneously （P〈0.01）. At the same time, the expression of cyclinD1, collagen Ⅰ, and collagen Ⅲ was decreased by GFK significantly （P〈0.01）. Conclusions： CTGF and FAK/Akt signal pathway were activated in the CCl4-induced hepatic fibrosis rats, which contribute to increased expression of cyclinD1 and collagen genes. The mechanisms of the anti-fibrosis activity of GFK may be due to its effects against CTGF and FAk/Akt signal pathway.

关键词： connective tissue growth factor Ganfukang hepatic fibrosis FAK/Akt signal pathway

Spreading depression and focal venous cerebral ischemia enhance cortical neurogenesis

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Neural Regeneration Research 2017年第8期12卷 1278-1286页

作者： Ryo Tamaki Samuel Ige Orie Beat Alessandri Oliver Kempski Axel Heimann Department of Neurosurgery Nara Medical University University Medical center of the Johannes Gutenberg-University of Mainz Institute for Neurosurgical Pathophysiology

Endogenous neurogenesis can arise from a variety of physiological stimuli including exercise, learning, or ＂enriched environment＂ as well as pathological conditions such as ischemia, epilepsy or cortical spreading depression. Whether all these conditions use a common trigger to set off endogenous neurogenesis is yet unclear. We hypothesized that cortical spreading depression（CSD） induces neurogenesis in the cerebral cortex and dentate gyrus after cerebral venous ischemia. Forty-two Wistar rats alternatively underwent sham operation（Sham）, induction of ten CSDs or venous ischemia provoked via occlusion of two adjacent superficial cortical vein followed by ten induced CSDs（CSD ＋ 2-VO）. As an additional control, 15 na？ve rats received no intervention except 5-bromo-2′-deoxyuridine（Brd U） treatment for 7 days. Sagittal brain slices（40 μm thick） were co-stained for Brd U and doublecortin（DCX; new immature neuronal cells） on day 9 or Neu N（new mature neuronal cells） on day 28. On day 9 after sham operation, cell proliferation and neurogenesis occurred in the cortex in rats. The sole induction of CSD had no effect. But on days 9 and 28, more proliferating cells and newly formed neurons in the ipsilateral cortex were observed in rats subjected to CSD ＋ 2VO than in rats subjected to sham operation. On days 9 and 28, cell proliferation and neurogenesis in the ipsilateral dentate gyrus was increased in sham-operated rats than in na？ve rats. Our data supports the hypothesis that induced cortical neurogenesis after CSD ＋ 2-VO is a direct effect of ischemia, rather than of CSD alone.

关键词： nerve regeneration cortical spreading depression two-vein occlusion adult neurogenesis stem cells cerebral cortex neural precursor cells neuron penumbra neural regeneration

Emerging role of neuregulin-1beta1 in pathogenesis and progression of multiple sclerosis

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中国神经再生研究：英文版 2023年第1期18卷 133-134页

作者： Seyyed Mohyeddin Ziaee Soheila Karimi-Abdolrezaee Department of Physiology and pathophysiology Spinal Cord Research CenterRady Faculty of Health SciencesUniversity of ManitobaChildren Hospital Research Institute of ManitobaWinnipegMBCanada

Multiple sclerosis(MS)is a chronic immune-mediated disorder of the central nervous system(CNS)that causes focal demyelinating lesions,followed by axonal and neuronal degeneration.Several genetic and environmental factors are found to be associated with MS incidence.While MS etiology seems to be multifactorial and needs further elucidation,it is understood that the response of an immune system to specific myelin antigens triggers the onset of MS(Dendrou et al.,2015).However,how the autoimmune response initiates against myelin,and the cellular and molecular mechanisms underpinning the development and progression of MS are not fully understood.Thus,deconstructing MS pathogenesis is of paramount importance for identifying novel diagnostic and therapeutic targets for this complex disease.

关键词： pathogenesis sclerosis degeneration

Angiotensin Type 1 Receptors and Superoxide Anion Production in Hypothalamic Paraventricular Nucleus Contribute to Capsaicin-Induced Excitatory Renal Reflex and Sympathetic Activation

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Neuroscience Bulletin 2020年第5期36卷 463-474页

作者： Yun Qiu Fen Zheng Chao Ye Ai-Dong Chen Jue-Jin Wang Qi Chen Yue-Hua Li Yu-Ming Kang Guo-Qing Zhu Key Laboratory of Targeted Intervention of Cardiovascular Disease Collaborative Innovation Center of Translational Medicine for Cardiovascular Diseaseand Department of PhysiologyNanjing Medical UniversityNanjing 211166China Department of pathophysiology Nanjing Medical UniversityNanjing 211166China Department of Physiology and pathophysiology Cardiovascular Research CenterXi'an Jiaotong University School of MedicineXi'an 710061China

Chemical stimulation of the kidney increases sympathetic activity and blood pressure in rats.The hypothalamic paraventricular nucleus(PVN)is important in mediating the excitatory renal reflex(ERR).In this study,we examined the role of molecular signaling in the PVN in mediating the capsaicin-induced ERR and sympathetic activation.Bilateral PVN microinjections were performed in rats under anesthesia.The ERR was elicited by infusion of capsaicin into the cortico-medullary border of the right kidney.The reflex was evaluated as the capsaicin-induced changes in left renal sympathetic nerve activity and mean arterial pressure.Blockade of angiotensin type 1 receptors with losartan or inhibition of angiotensin-converting enzyme with captopril in the PVN abolished the capsaicin-induced ERR.Renal infusion of capsaicin significantly increased NAD(P)H oxidase activity and superoxide anion production in the PVN,which were prevented by ipsilateral renal denervation or microinjection of losartan into the PVN.Furthermore,either scavenging of superoxide anions or inhibition of NAD(P)H oxidase in the PVN abolished the capsaicin-induced ERR.We conclude that the ERR induced by renal infusion of capsaicin is mediated by angiotensin type 1 receptor-related NAD(P)H oxidase activation and superoxide anion production within the PVN.

关键词： Renal reflex Sympathetic activity Blood pressure Paraventricular nucleus Angiotensin Reactive oxygen species