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Decline and fall of aging astrocytes:the human perspective

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Neural Regeneration Research 2025年第6期20卷 1713-1714页

作者： Alexei Verkhratsky Alexey Semyanov Faculty of Biology Medicine and HealthThe University of ManchesterManchesterUK Department of Neurosciences University of the Basque Country UPV/EHU and CIBERNEDLeioaSpain Department of Forensic Analytical toxicology School of Forensic MedicineChina Medical UniversityShenyangLiaoning ProvinceChina Department of Stem Cell Biology State Research Institute Centre for Innovative MedicineVilniusLithuania International Collaborative center on Big Science Plan for Purinergic Signalling Chengdu University of Traditional Chinese MedicineChengduSichuan ProvinceChina Department of Physiology Jiaxing University College of MedicineJiaxingZhejiang ProvinceChina

“Last scene of all that ends this strange,eventful history,is second childishness and mere oblivion.I am sans teeth,sans eyes,sans taste,sans everything.”William Shakespeare‘As You Like It'Act 2,Sc.7,l.139Aging of the human brain is characterized by a progressive decline of its functional capacity;this decline however varies widely,and cognitive longevity differs substantially between individuals.

关键词： aging teeth progressive

Role of farnesoid X receptor and bile acids in alcoholic liver disease

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Acta Pharmaceutica Sinica B 2015年第2期5卷 158-167页

作者： Sharon Manley Wenxing Ding Department of Pharmacology Toxicology and Therapeutics the University of Kansas Medical Center

Alcoholic liver disease(ALD) is one of the major causes of liver morbidity and mortality worldwide. Chronic alcohol consumption leads to development of liver pathogenesis encompassing steatosis, inflammation, fibrosis, cirrhosis, and in extreme cases, hepatocellular carcinoma. Moreover,ALD may also associate with cholestasis. Emerging evidence now suggests that farnesoid X receptor(FXR) and bile acids also play important roles in ALD. In this review, we discuss the effects of alcohol consumption on FXR, bile acids and gut microbiome as well as their impacts on ALD. Moreover, we summarize the findings on FXR, Fox O3a(forkhead box-containing protein class O3a) and PPARα(peroxisome proliferator-activated receptor alpha) in regulation of autophagy-related gene transcription program and liver injury in response to alcohol exposure.

关键词： Farnesoid X receptor Bile acids Autophagy Alcoholic liver disease FoxO3

Targeting an oncogenic kinase/phosphatase signaling network for cancer therapy

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Acta Pharmaceutica Sinica B 2018年第4期8卷 511-517页

作者： Xiao-Mei Qi Fang Wang Matthew Mortensen Ryan Wertz Guan Chen Department of Pharmacology and toxicology Medical College of Wisconsin Zablocki Veterans Affairs medical center Medical College of Wisconsin

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 PDZcoupled 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.

关键词： Kinase/phosphatase signaling network PDZ-coupled protein-protein complex Phosphorylation and dephosphorylation Cancer development and progression Targeted cancer therapy

T-2 toxin induces developmental toxicity and apoptosis in zebrafish embryos

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Journal of Environmental Sciences 2014年第4期26卷 917-925页

作者： Guogang Yuan Yimei Wang Xiaoyan Yuan Tingfen Zhang Jun Zhao Liuyu Huang Shuangqing Peng Evaluation and Research center for toxicology Institute of Disease Control and Prevention Academy of Military Medical Sciences

T-2 toxin is one of the most important trichothecene mycotoxins occurring in various agriculture products. The developmental toxicity of T-2 toxin and the exact mechanism of action at early life stages are not understood precisely. Zebrafish embryos were exposed to different concentrations of the toxin at 4-6 hours post fertilization （hpf） stage of development, and were observed for different developmental toxic effects at 24, 48, 72, and 144 hpf. Exposure to 0.20 Ixmol/L or higher concentrations of T-2 toxin significantly increased the mortality and malformation rate such as tail deformities, cardiovascular defects and behavioral changes in early developmental stages of zebrafish. T-2 toxin exposure resulted in significant increases in reactive oxygen species （ROS） production and cell apoptosis, mainly in the tall areas, as revealed by Acridine Orange staining at 24 hpf. In addition, T-2 toxin-induced severe tail deformities could be attenuated by co-exposure to reduced glutathione （GSH）. T-2 toxin and GSH co-exposure induced a significant decrease of ROS production in the embryos. The overall results demonstrate that T-2 toxin is able to produce oxidative stress and induce apoptosis, which are involved in the developmental toxicity of T-2 toxin in zebrafish embryos.

关键词： T-2 toxin developmental toxicity apoptosis zebrafish embryo oxidative stress

Developmental Lead Exposure Alters the Distribution of Protein Kinase C Activity in the Rat Hippocampus

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Biomedical and Environmental Sciences 1998年第1期11卷 61-69页

作者： HWEI-HSIEN CHEN TANGENG MA ARTHUR S. HUME AND ING K. HO(Deportment of Pharmacology and toxicology, University ofMississippi medical center, 2500 North State Street,Jackson, MS 39216, USA) Department of Pharmacology and toxicology University of Mississippi Medical Center Jackson 39216 USA.

Chronic low-level lead (Pb) exposure in children is known to cause a deficit in learning and memory. In vitro studies have demonstrated that Pb altered protein kinase C (PKC) activityt Especially, hippocampal PKC has been correlated with performance in several learning tasks. The effects of Pb exposure on hippocampal PKC were investigated during development at various postnatal ages: postnatal day (PN) 7, 14, 28, and 56. Two-tenth % Pb acetate was administered to pregnant and lactating dams and then administered to weanling rats in drinking water. PKC activity was measured in both membrane and cytosolic fractions from the hippocampi of the controls and Pb-exposed animals. Pb-induced increase in PKC activity in the cytosolic fraction was obsereved in the PN56 rats. In contrast, PKC activity was decreased by Pb at PN7 in the membrane fraction. Furthermore, a significant decrease in the ratio of membrane to cytosolic PKC activity which is representative of PKC distribution was observed in the PN28 and PN56 Pb-exposed rats relative to the same-age controls. This study indicates that chronic Pb exposure during development influences hippocampal PKC activity and distribution. These changes may be involved in the subclinical neurotoxicity of chronic Pb exposure in young children.

关键词： Activity Pb Developmental Lead Exposure Alters the Distribution of Protein Kinase C Activity in the Rat Hippocampus

Liuweiwuling tablets protect against acetaminophen hepatotoxicity: What is the protective mechanism?

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World Journal of Gastroenterology 2016年第11期22卷 3302-3304页

作者： Kuo Du Hartmut Jaeschke Department of Pharmacology Toxicology and TherapeuticsUniversity of Kansas Medical Center

Study of the effects of natural products, including traditional Chinese Medicines, on acetaminophen hepatotoxicity has gained considerable popularity in recent years, and some of them showed positive results and even promising therapeutic potentials. A recent report suggested that Liuweiwuling tablets protect against acetaminophen hepatotoxicity and promote liver regeneration in a rodent model through alleviating the inflammatory response. However, several concerns exist regarding the limitations of the experimental design and interpretation of the data presented in this manuscript.

关键词： Acetaminophen hepatotoxicity Liuweiwuling Sterile inflammation Natural products Liver regeneration

Mapping of liver-enriched transcription factors in the human intestine

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World Journal of Gastroenterology 2010年第31期16卷 3919-3927页

作者： Frank Lehner Ulf Kulik Juergen Klempnauer Juergen Borlak Department of General Visceral and Transplantation SurgeryHanover Medical School Molecular Medicine and medical Biotechnol-ogy Fraunhofer Institute of Toxicology and Experimental Medi-cine center of Pharmacology and toxicology Hanover Medical School

AIM: To investigate the gene expression pattern of hepatocyte nuclear factor 6 (HNF6) and other liverenriched transcription factors in various segments of the human intestine to better understand the differentiation of the gut epithelium. METHODS: Samples of healthy duodenum and jejunum were obtained from patients with pancreatic cancer whereas ileum and colon was obtained from patients undergoing right or left hemicolectomy or (recto)sigmoid or rectal resection. All surgical specimens were subjected to histopathology. Excised tissue was shock-frozen and analyzed for gene expression of liver-enriched transcription factors by semiquantitative reverse transcription polymerase chain and compared to the human colon carcinoma cell line Caco-2. Protein expression of major liver-enriched transcription factors was determined by Western blotting while the DNA binding of HNF6 was investigated by electromobility shift assays. RESULTS: The gene expression patterning of liverenriched transcription factors differed in the various segments of the human intestine with HNF6 gene expression being most abundant in the duodenum (P < 0.05) whereas expression of the zinc finger protein GATA4 and of the HNF6 target gene ALDH3A1 was most abundant in the jejunum (P < 0.05). Likewise, expression of FOXA2 and the splice variants 2 and 4 of HNF4α were most abundantly expressed in the jejunum (P < 0.05). Essentially, expression of transcription factors declined from the duodenum towards the colon with the most abundant expression in the jejunum and less in the ileum. The expression of HNF6 and of genes targeted by this factor, i.e. neurogenin 3 (NGN3) was most abundant in the jejunum followed by the ileum and the colon while DNA binding activity of HNF4α and of NGN3 was conf irmed by electromobility shift assays to an optimized probe. Furthermore, Western blotting provided evidence of the expression of several liver-enriched transcription factors in cultures of colon epithelial cells, albeit at

关键词： Liver-enriched transcription factors Human intestine Caco-2 Gene expression

New era of drug innovation in China

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Acta Pharmaceutica Sinica B 2019年第5期9卷 1084-1085页

作者： Xuan Ye Qingli Wang Haixue Wang Office of Pharmacology and toxicology center for Drug Evaluation National Medical Products Administration

In 2018, the China National medical Products Administration(NMPA) approved new drug applications (NDAs) of 48 new drugs, which was the highest annual approval rate by the Chinese regulatory agency in the past 20 years. Nine of the 48 new drugs,including fruquintinib, anlotinib, toripalimab and sintilimab, are global new molecular entities (NME) that were developed by Chinese pharmaceutical companies.

关键词： New era drug innovation China

Outcomes and toxicology of Herbal Drugs in Alcoholic Hepatitis-A Single center Experience from India

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Journal of Clinical and Translational Hepatology 2019年第4期7卷 329-340页

作者： Cyriac Abby Philips Sasidharan Rajesh Tom George Rizwan Ahamed Sandeep Kumbar Philip Augustine The Liver Unit and Monarch Liver Lab Cochin Gastroenterology GroupErnakulam Medical CenterKochiKeralaIndia Interventional Radiology Department of Gastroenterology and HepatologyCochin Gastroenterology GroupErnakulam Medical CenterKochiKeralaIndia Gastroenterology and Advanced G.I.Endoscopy Cochin Gastroenterology GroupErnakulam Medical CenterKochiKeralaIndia

Background and Aims:We aimed to study clinical out-comes and liver biopsy features of alcoholic hepatitis(AH)patients on complementary and alternative medicines(CAMs)and to analyze the retrieved drugs for chemical and toxic components linked to drug-induced liver ***:We retrospectively assessed clinical,biochemical and liver bi-opsy features of AH patients on CAM with drug-induced liver injury(AH-CAM,n=27)and compared them to a control group(classical AH,n=29)on standard of *** without liver biopsy evaluation and other causes for liver dis-ease were *** of the CAMs(n=42)from pa-tients were retrieved and assessed for chemical and ***:All were males,and significantly worse clinical pre-sentation,biochemical severity,and liver disease scores were notable in patients with *** Ayurve-dic-polyherbal formulations were the most commonly used *** liver histology,varying grades of severe-necrosis,severe hepatocellular,canalicular,cholangiolar cholestasis with predominant lymphocytic-portal-inflammation and varying grades of interface-hepatitis were noted in *** of CAMs revealed presence of heavy metals up to 100,000 times above detectable range and adulter-ants,such as antibiotics,chemotherapy agents,nonsteroi-dal anti-inflammatory drugs,alcohols,antidepressants,anxiolytics,and recreational *** follow up,a signifi-cantly higher number of patients with AH on CAM died at end of 1,3-and-6-months compared to controls(37%vs.83%,29%vs.62%,18%vs.52%respectively;p<0.001).Conclusions:Patients with AH and CAM-related drug-induced liver injury have extremely poor short-term survival in the absence of liver transplantation compared to those patients with AH on evidence-based *** transplant referral and educating on and curbing of CAM use in severe liver disease through strict monitoring of unregulated traditional health practices can help ease the burden of liver-related death.

关键词： Hepatitis Alcohol CAM DILI Ayurveda