المؤلفون: Qian Li, Yiting Zhang, Bingshun Wang, Zonghai Li, Jin Ren, Yongzhen Liu, Hua Jiang, Hualiang Jiang, Henglei Lu, Likun Gong, Huamao Wang, Wei Wan, Jianhua Sun, Minjia Tan

المصدر: Molecular Therapy. 26:1457-1470

مصطلحات موضوعية: Male, 0301 basic medicine, genetic structures, medicine.drug_class, Protein subunit, Integrin, Integrin alpha2, Pharmacology, Monoclonal antibody, 03 medical and health sciences, Drug Discovery, Genetics, medicine, Animals, Humans, Platelet, Epidermal growth factor receptor, Molecular Biology, biology, business.industry, Integrin beta3, Antibodies, Monoclonal, Thrombocytopenia, Rats, Macaca fascicularis, 030104 developmental biology, Drug development, Monoclonal antibody CH12, Toxicity, biology.protein, Molecular Medicine, Original Article, Female, business

الوصف: CH12 is a novel humanized monoclonal antibody against epidermal growth factor receptor variant III (EGFRvIII) for cancer treatment. Unfortunately, in pre-clinical safety evaluation studies, acute thrombocytopenia was observed after administration of CH12 in cynomolgus monkeys, but not rats. More importantly, in vitro experiments found that CH12 can bind and activate platelets in cynomolgus monkey, but not human peripheral blood samples. Cynomolgus monkey-specific thrombocytopenia has been reported previously; however, the underlying mechanism remains unclear. Here, we first showed that CH12 induced thrombocytopenia in cynomolgus monkeys through off-target platelet binding and activation, resulting in platelet destruction. We subsequently found that integrin αIIbβ3 (which is expressed on platelets) contributed to this off-target toxicity. Furthermore, three-dimensional structural modeling of the αIIbβ3 molecules in cynomolgus monkeys, humans, and rats suggested that an additional unique loop exists in the ligand-binding pocket of the αIIb subunit in cynomolgus monkeys, which may explain why CH12 binds to platelets only in cynomolgus monkeys. Moreover, this study supported the hypothesis that the minor differences between cynomolgus monkeys and humans can confuse human risk assessments and suggests that species differences can help the prediction of human risks and avoid losses in drug development.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4b6e6706940dabe05c0ac22e20630b2cTest
https://doi.org/10.1016/j.ymthe.2018.04.005Test

المؤلفون: Luyang Yuan, Xinming Qi, Jin Ren, Yusi Tai, Zhouteng Tao, Jing Chen, Henglei Lu, Mei Pu, Guanghui Wang, Junwen Qiao, Huijie Guo

المصدر: Life Sciences. 276:119415

مصطلحات موضوعية: Male, Aging, Ubiquitin-Protein Ligases, PINK1, Mitochondrion, General Biochemistry, Genetics and Molecular Biology, Parkin, Mice, Ubiquitin, Downregulation and upregulation, microRNA, Mitophagy, Animals, Humans, Phosphorylation, General Pharmacology, Toxicology and Pharmaceutics, biology, HEK 293 cells, General Medicine, Mitochondria, Cell biology, Mice, Inbred C57BL, MicroRNAs, HEK293 Cells, biology.protein, Protein Processing, Post-Translational

الوصف: Aims PTEN induced putative kinase 1 (PINK1)-mediated mitophagy process is tightly associated with various age-dependent diseases in mammals. The roles of miRNAs (miRNAs) in the PINK1-mediated mitophagy process are not fully understood. Here we discovered that miR-34a-5p suppresses PINK1 expression directly though two post-transcriptional non-classical binding modes, resulting in inhibition of PINK1-mediated mitophagy process. Main methods For in vivo experiments, brains were dissected from 8 weeks old and 40 weeks old C57BL/6 male mice to measure miR-34a-5p expression and PINK1 expression. For in vitro experiments, overexpression of miR-34a-5p mimics in HEK293 cells was performed to investigate the effect of miR-34a-5p on PINK1 expression and its regulatory mechanism, parkin recruitment and mitophagy process. Key findings The level of miR-34a-5p was upregulated and the level of PINK1 mRNA was downregulated in brains of aged mice. Both the 3′-untranslated region (3’UTR) and the Coding DNA sequence (CDS) of PINK1 mRNA were bound to the non-seed region of miR-34a-5p, rather than the seed region, resulting in a decrease in PINK1 expression. Endogenous miR-34a-5p knockout increased PINK1 expression. Further results indicated that miR-34a-5p inhibits mitophagy process by reduction of PINK1. miR-34a-5p hinders phosphorylated Ser65-ubiquitin (pS65-Ub) accumulation, prevents the mitochondrial recruitment of Parkin, attenuates ubiquitination and delays the clearance of damaged mitochondria. Significance We firstly found that miR-34a-5p suppresses PINK1 directly and further regulates mitophagy through non-canonical modes. This finding hints at a crucial role of miR-34a-5p implicated in accelerating the pathogenesis of age-related neurological diseases.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::21945f2241032602fecbb1470b84b479Test
https://doi.org/10.1016/j.lfs.2021.119415Test

المؤلفون: Jin Ren, Yuan Zhang, Fangfang Yang, Xiang He, Xinming Qi, Zhaochu Wang, Yuli Wang, Jianyun Ma, Likun Gong, Yifu Yang, Houzu Zhou, Henglei Lu, Zhongping Deng, Yongzhen Liu

المصدر: Toxicology Research. 10:959-959

مصطلحات موضوعية: Health, Toxicology and Mutagenesis, Aristolochic acid I, Pharmacology, Stem cell, Biology, Toxicology

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::325f1e1efb7076f9798827c3f4252f18Test
https://doi.org/10.1093/toxres/tfab061Test

المؤلفون: Yongzhen Liu, Xiang He, Yuli Wang, Houzu Zhou, Yuan Zhang, Jianyun Ma, Zhaochu Wang, Fangfang Yang, Henglei Lu, Yifu Yang, Zhongping Deng, Xinming Qi, Likun Gong, Jin Ren

المصدر: Toxicology Research; May2021, Vol. 10 Issue 3, p1-10, 10p

مصطلحات موضوعية: ARISTOLOCHIC acid, STEM cells, BIOACTIVE compounds, SPERMATOGENESIS, LABORATORY rodents

مستخلص: Aristolochic acid I (AAI) is a natural bioactive substance found in plants from the Aristolochiaceae family and impairs spermatogenesis. However, whether AAI-induced spermatogenesis impairment starts at the early stages of spermatogenesis has not yet been determined. Spermatogonial stem cells (SSCs) are undifferentiated spermatogonia that balance self-renewing and differentiating divisions to maintain spermatogenesis throughout adult life and are the only adult stem cells capable of passing genes onto the next generation. The objective of this study was to investigate whether AAI impairs SSCs during the early stages of spermatogenesis. After AAI treatment, we observed looser, smaller and fewer colonies, decreased cell viability, a decreased relative cell proliferation index, and increased apoptosis in SSCs in a concentrationand/or time-dependent manner. Additionally, AAI promoted apoptosis in SSCs, which was accompanied by upregulation of caspase 3, P53 and BAX expression and downregulation of Bcl-2 expression, and suppressed autophagy, which was accompanied by upregulation of P62 expression and downregulation of ATG5 and LC3B expression, in a concentration-dependent manner. Then we found that AAI impaired spermatogenesis in rats, as identified by degeneration of the seminiferous epithelium, and increased apoptosis of testicular cells. Taken together, our findings demonstrate that AAI causes damage to SSCs and implicate apoptosis and autophagy in this process. The impairment of SSCs may contribute to AAI-induced testicular impairment. Our findings provide crucial information for the human application of botanical products containing trace amounts of AAI. [ABSTRACT FROM AUTHOR]

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المؤلفون: Henglei Lu, Jin Ren, Jing Chen, Ze-an Zhang, Qiang Li, Xinming Qi, Yunxia Dong, Li Yuanchao

المصدر: Life Sciences. 232:116644

مصطلحات موضوعية: Male, 0301 basic medicine, medicine.medical_specialty, Aspartate transaminase, Fructose, Diet, High-Fat, 030226 pharmacology & pharmacy, General Biochemistry, Genetics and Molecular Biology, Mice, 03 medical and health sciences, 0302 clinical medicine, Lipid oxidation, Non-alcoholic Fatty Liver Disease, Internal medicine, medicine, Animals, Lipolysis, PPAR alpha, Aspartate Aminotransferases, General Pharmacology, Toxicology and Pharmaceutics, Triglycerides, ACADM, biology, Chemistry, Lipogenesis, Fatty liver, Alanine Transaminase, Lipid metabolism, General Medicine, Peroxisome, Lipid Metabolism, medicine.disease, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Endocrinology, Liver, biology.protein, ACOX1, lipids (amino acids, peptides, and proteins), Diterpenes, Oxidation-Reduction

الوصف: Aims (5R)-5-hydroxytriptolide (LLDT-8) is a triptolide analog with excellent capability against cancers, cerebral ischemic injury and rheumatoid arthritis. Here, we discovered its hepatoprotective effects in a mouse model of non-alcoholic fatty liver disease (NAFLD) by ameliorating liver lipid accumulation. Main methods Male C57BL/6J mice were fed with a high-fat/high-fructose (HFHFr) diet for 29 weeks to induce the pathological phenomena of NAFLD. Then the mice were treated with LLDT-8 (0.5mg/kg and 1mg/kg) or Vehicle for 8 weeks. Finally, the serum biochemical indexes, liver histological features, fatty acids (FAs) profile and related gene expression in liver were detected to investigate the effect of LLDT-8 on lipid accumulation and its possible mechanism. Key findings LLDT-8 treatment significantly inhibited hepatic injury featured by the decrease of serum alanine aminotransferase (ALT) and aspartate transaminase (AST), the lessening of hepatic ballooning and macrovesicular steatosis. Moreover, LLDT-8 could downregulate the expression of stearoyl-CoA desaturase 1 (SCD1), which further led to the lower ratios of C16:1/C16:0 and C18:1/C18:0 and thus inhibited lipid synthesis. LLDT-8 treatment also could upregulate liver peroxisome proliferator-activated receptor α (PPARα), carnitine palmitoyltransferase 1a (Cpt1a), peroxisomal acyl-CoA oxidase 1 (Acox1), long-chain acyl-CoA dehydrogenase (Acadl) and medium-chain acyl-CoA dehydrogenase (Acadm) expression levels involved in fatty acids oxidation (FAO) and markedly promoted lipolysis. Significance Our results provide a novel application of LLDT-8 in improving NAFLD.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::aa96990ccb45de115bf1571d2a527afaTest
https://doi.org/10.1016/j.lfs.2019.116644Test

المؤلفون: Bingru Ren, H.Y. Kang, N. De Kimpe, Henglei Lu, Ji-Jun Chen, Wen-Yong Li, An Adams, Haotian Zhang, J.L. Wu

المصدر: Journal of Ethnopharmacology. 122:486-491

مصطلحات موضوعية: Blood Glucose, Male, medicine.medical_treatment, Pharmacology, Diabetes Mellitus, Experimental, law.invention, Mice, chemistry.chemical_compound, law, Alloxan, Diabetes mellitus, Glycated Serum Proteins, Drug Discovery, medicine, Animals, Hypoglycemic Agents, Insulin, Triglycerides, Glycoproteins, Hypolipidemic Agents, Dose-Response Relationship, Drug, Triglyceride, Plant Extracts, Superoxide Dismutase, Cholesterol, Blood Proteins, medicine.disease, Blood proteins, Effective dose (pharmacology), Triterpenes, Plant Leaves, Eriobotrya, chemistry, Biochemistry, Phytotherapy

الوصف: For seeking the good natural material to develop new agent to treat diabetes, the total triterpene acid (TTA) fraction extracted from Folium Eriobotryae [leaves of Eriobotrya japonica (Thunb.) Lindl.] was evaluated for its hypoglycemic and hypolipidemic potential through normal, alloxan and streptozotocin-induced diabetic mice administered with graded oral doses (100, 200, 300 mg/(kg day)) for 7 or 14 days. The results showed that a dose of 300 mg/kg of TTA is the most effective dose to cause significant (p

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e212053811a03fe6ebae1e26f337e652Test
https://doi.org/10.1016/j.jep.2009.01.030Test

المؤلفون: Henglei Lu, Likun Gong, Liang Zhu, Junwen Qiao, Yumei Cheng, Hao Wang, Yongzhen Liu, Jin Ren, Jingjun Sun

المصدر: Drug and chemical toxicology. 36(4)

مصطلحات موضوعية: Male, medicine.medical_specialty, No-observed-adverse-effect level, Erythrocytes, medicine.drug_class, Health, Toxicology and Mutagenesis, Administration, Oral, Hematocrit, Toxicology, Kidney, Rats, Sprague-Dawley, Eating, Internal medicine, Toxicity Tests, medicine, Animals, Antihypertensive drug, Antihypertensive Agents, Pharmacology, Chemical Health and Safety, medicine.diagnostic_test, Dose-Response Relationship, Drug, business.industry, Biphenyl Compounds, Body Weight, Public Health, Environmental and Occupational Health, Imidazoles, Heart, General Medicine, Angiotensin II, Rats, Dose–response relationship, Endocrinology, medicine.anatomical_structure, Toxicity, Female, Hemoglobin, Blood Coagulation Tests, business, Angiotensin II Type 1 Receptor Blockers, Blood Chemical Analysis

الوصف: Allisartan isoproxil (ALS-3) is a selective, nonpeptide blocker of the angiotensin II type 1 receptor. It is a new antihypertensive drug under development with a novel chemical structure. The aim of this study was to evaluate the potential toxicity of ALS-3 in Sprague-Dawley rats. Animals were orally administered either vehicle or ALS-3 at doses of 20, 80 and 320 mg/kg once-daily for 26 weeks, followed by a 6-week recovery period. Toxicity was assessed by mortality, clinical signs, body weight, food consumption, hematology, coagulation, serum chemistry, gross necropsy, organ weights and microscopic examination. Decreased body-weight gain was noted at 320 mg/kg/day in both sexes as well as at the 80-mg/kg/day dose in females. Food consumption was decreased at all doses in males and at 80- and 320-mg/kg/day doses in females. Decreased erythrocyte parameters (erythrocyte count, hemoglobin and hematocrit) were observed in males receiving 320 mg/kg/day. Elevated urea nitrogen (BUN), increased kidney weight, decreased heart weight and exacerbation of chronic progressive nephropathy (CPN) severity were all observed in males at 80 and 320 mg/kg/day. However, only an exacerbated incidence of CPN was observed in females at 320 mg/kg/day. All changes were reversed after the 6-week recovery period, except BUN and CPN. Based on these results, we concluded that a dose of 20 mg/kg/day was the no observed adverse effect level. The toxicity target organ was the kidney. Males were more affected than females.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::10133486e72b54e44dba7e45f8d75382Test
https://pubmed.ncbi.nlm.nih.gov/23534454Test

المؤلفون: Ying Xiao, Xiang Xue, Likun Gong, Yan Li, Shuhong Guan, Xiongfei Wu, Xinming Qi, Jin Ren, Henglei Lu, Yongzhen Liu, Yunhai Zhang

المصدر: Journal of ethnopharmacology. 119(1)

مصطلحات موضوعية: Male, No-observed-adverse-effect level, Renal glomerulus, Kidney Glomerulus, Administration, Oral, Pharmacognosy, Aristolochia, Akebia quinata, Mice, Drug Discovery, Medicine, Animals, Oral toxicity, Pharmacology, No-Observed-Adverse-Effect Level, Traditional medicine, biology, Dose-Response Relationship, Drug, business.industry, Body Weight, Akebia, Endothelial Cells, biology.organism_classification, Mice, Inbred C57BL, Toxicity, Kidney Diseases, business, Drugs, Chinese Herbal

الوصف: Ethnopharmacological relevance Longdan Xieganwan, which contains Aristolochia species, is a traditional Chinese prescription. It has been used for thousands of years to “enhance liver”. However, many cases of Longdan Xieganwan induced nephropathy were reported recently. Aim of the study This study was designed to compare the possible toxic effects of Longdan Xieganwan and three different Aristolochia species, i.e. Akebia trifoliate (Thunb.) koid (Akebia trifoliate), Akebia quinata (Thunb.) Decne. (Akebia quinata) and Caulis aristolochiae manshuriensis (Aristolochia manshuriensis). Materials and methods Mice were orally administered these drugs for 28 days. Clinical signs, body weights, serum biochemistry, organ weights and histopathology were examined. Results Significantly decreased body weights and obvious nephropathy were noticed in the Aristolochia manshuriensis groups at doses higher than 0.24 g/kg/d. A few endothelial cell degenerations in renal glomerulus were observed in the Akebia trifoliate group at a high-dose of 2.00 g/kg/d. No significant changes were observed in the other groups. Conclusions The no-observed-adverse-effect levels (NOAELs) for Aristolochia manshuriensis, Akebia trifoliate, Akebia quinata and Longdan Xieganwan in this study for mice were 0.06 g/kg/d, 0.40 g/kg/d, higher than 3.00 g/kg/d and higher than 10.00 g/kg/d, which were equivalent to 0.25 times, 5 times, 25 times and 10 times of normal human dose in clinical prescription, respectively.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cf7dde37313fb00be29e8366d21c5b80Test
https://pubmed.ncbi.nlm.nih.gov/18582552Test