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Hepatic Zbtb18 (Zinc Finger and BTB Domain Containing 18) alleviates hepatic steatohepatitis via FXR (Farnesoid X Receptor)

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Signal Transduction and Targeted Therapy 2024年第2期9卷 766-781页

作者： Lei Zhang Jiabing Chen Xiaoying Yang Chuangpeng Shen Jiawen Huang Dong Zhang Naihua Liu Chaonan Liu Yadi Zhong Yingjian Chen Kaijia Tang Jingyi Guo Tianqi Cui Siwei Duan Jiayu Li Shangyi Huang Huafeng Pan Huabing Zhang Xiaoqiang Tang Yongsheng Chang Yong Gao State Key Laboratory of Traditional Chinese Medicine Syndrome Science and Technology Innovation CenterGuangzhou University of Chinese MedicineGuangzhouChina Key Laboratory of Immune Microenvironment and Disease(Ministry of Education) Tianjin Key Laboratory of Cellular Homeostasis and DiseaseDepartment of Physiology and PathophysiologyTianjin Medical UniversityTianjinChina Jiangsu Key Laboratory of Immunity and Metabolism Department of Pathogen Biology and ImmunologyJiangsu International Laboratory of Immunity and MetabolismXuzhou Medical UniversityXuzhouChina Department of Endocrinology The First Clinical CollegeGuangzhou University of Chinese MedicineGuangdongChina The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine ShenzhenChina Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor Nanjing University of Chinese MedicineNanjingChina Department of Biochemistry and molecular Biology Metabolic Disease Research CenterSchool of Basic MedicineAnhui Medical UniversityHefeiChina Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE State Key Laboratory of BiotherapyWest China Second University HospitalSichuan UniversityChengduChina

A lasting imbalance between fatty acid synthesis and consumption leads to non-alcoholic fatty liver disease(NAFLD),coupled with hepatitis and insulin resistance.Yet the details of the underlying mechanisms are not fully understood.Here,we unraveled that the expression of the transcription factor Zbtb18 is markedly decreased in the livers of both patients and murine models of NAFLD.Hepatic Zbtb18 knockout promoted NAFLD features like impaired energy expenditure and fatty acid oxidation(FAO),and induced insulin resistance.Conversely,hepatic Zbtb18 overexpression alleviated hepato-steatosis,insulin resistance,and hyperglycemia in mice fed on a high-fat diet(HFD)or in diabetic mice.Notably,in vitro and in vivo mechanistic studies revealed that Zbtb18 transcriptional activation of Farnesoid X receptor(FXR)mediated FAO and Clathrin Heavy Chain(CLTC)protein hinders NLRP3 inflammasome activity.This key mechanism by which hepatocyte’s Zbtb18 expression alleviates NAFLD and consequent liver fibrosis was further verified by FXR’s deletion and forced expression in mice and cultured mouse primary hepatocytes(MPHs).Moreover,CLTC deletion significantly abrogated the hepatic Zbtb18 overexpression-driven inhibition of NLRP3 inflammasome activity in macrophages.Altogether,Zbtb18 transcriptionally activates the FXR-mediated FAO and CLTC expression,which inhibits NLRP3 inflammasome’s activity alleviating inflammatory stress and insulin resistance,representing an attractive remedy for hepatic steatosis and fibrosis.

关键词： hepatic Hepatic impaired

Does time to theater matter in simple gastroschisis?

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World Journal of Pediatric Surgery 2023年第4期6卷 238-243页

作者： Kathryn O'Shea Rachel Harwood Sean O’Donnell Colin Baillie Paediatric Surgery Alder Hey Children's NHS Foundation TrustLiverpoolUK cellular and molecular physiology University of LiverpoolLiverpoolUK

Objective A recent publication has suggested that expedited time to theater in gastroschisis results in higher rates of primary closure and decreases the length of stay(LOS).This study primarily aims to assess the impact of time to first management of neonates with gastroschisis on the LOS.Methods Neonates admitted between August 2013 and August 2020 with gastroschisis were included.Data were collected retrospectively,and neonates with complex gastroschisis were excluded.Variables including gestation,birth weight,time of first management,primary/delayed closure and use of patch were evaluated as possible confounding variables.The outcome measures were time to full feeds,time on parenteral nutrition(PN)and LOS.Univariate and multivariate linear regression analyses were performed.P<0.05 was regarded as significant.Results Eighty-six neonates were identified,and 16 were then excluded(eight patients with complex gastroschisis,eight patients with time to first management not documented).The median LOS for those who underwent primary closure was 21 days(interquartile range(IQR)=16-29)and for those who underwent silo placement and delayed closure was 59 days(IQR=44-130).The mean time to first management was 473 min(standard deviation(SD)=146 min),with only 20% of these infants being operated on at less than 6 hours of age.Univariate and multivariate analyses demonstrated no relationship between time to first management and LOS(r^(2)=0.00,p=0.82)but did demonstrate a consistent positive association between time to first feed and LOS and delayed closure,resulting in a longer time to full feeds and a longer time on PN.Conclusions The time to first management was not associated with a change in LOS in these data.Further prospective evaluation of the impact of reducing the time to first feed on the LOS is recommended.

关键词： gastro admitted closure

RIPK1 plays a crucial role in maintaining regulatory T-Cell homeostasis by inhibiting both RIPK3-and FADD-mediated cell death

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cellular & molecular Immunology 2024年第1期21卷 80-90页

作者： Xiaoxue Deng Lingxia Wang Yunze Zhai Qiuyue Liu Fengxue Du Yu Zhang Wenxing Zhao Tingtao Wu Yiwen Tao Jie Deng Yongbing Cao Pei Hao Jiazi Ren Yunli Shen Zuoren Yu Yuejuan Zheng Haibing Zhang Haikun Wang State Key Laboratory of cardiology Shanghai East HospitalTongji University School of MedicineShanghai200120China CAS Key Laboratory of molecular Virology and Immunology Shanghai Institute of Immunity and InfectionChinese Academy of SciencesUniversity of Chinese Academy of SciencesShanghai200031China CAS Key Laboratory of Nutrition Metabolism and Food SafetyShanghai Institute of Nutrition and HealthShanghai Institutes for Biological SciencesUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai200031China The Research Center for Traditional Chinese Medicine Shanghai Institute of Infectious Diseases and BiosecurityShanghai University of Traditional Chinese MedicineShanghai201203China Institute of Vascular Disease Shanghai TCM-Integrated HospitalShanghai University of Traditional Chinese MedicineShanghai200433China

Regulatory T(T_(reg))cells play an essential role in maintaining immune balance across various physiological and pathological conditions.However,the mechanisms underlying T_(reg)homeostasis remain incompletely understood.Here,we report that RIPK1 is crucial for T_(reg) cell survival and homeostasis.We generated mice with T_(reg) cell-specific ablation of Ripk1 and found that these mice developed fatal systemic autoimmunity due to a dramatic reduction in the Treg cell compartment caused by excessive cell death.Unlike conventional T cells,Treg cells with Ripk1 deficiency were only partially rescued from cell death by blocking FADD-dependent apoptosis.However,simultaneous removal of both Fadd and Ripk3 completely restored the homeostasis of Ripk1-deficient Treg cells by blocking two cell death pathways.Thus,our study highlights the critical role of RIPK1 in regulating Treg cell homeostasis by controlling both apoptosis and necroptosis,thereby providing novel insights into the mechanisms of Treg cell homeostasis.

关键词： Treg cell Homeostasis Apoptosis Necroptosis

β-cryptoxanthin and fatty liver disease:new insights

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Hepatobiliary Surgery and Nutrition 2023年第3期12卷 450-452页

作者： Robin D.Clugston Department of physiology University of AlbertaEdmontonABCanada The Group on molecular and cellular Biology of Lipids University of AlbertaEdmontonABCanada

β-cryptoxanthin is a nutritionally important xanthophyll found in orange-fleshed tropical and citrus fruits,including papaya,oranges,and tangerines(1).It is also one of the most commonly detected carotenoids in human tissues(1).Uniquely,β-cryptoxanthin is the only regularly consumed dietary xanthophyll to have an intactβ-ionone ring,thus in addition to functioning as an antioxidant it can also be metabolized to vitamin A.A limited number of past studies have shown a beneficial effect ofβ-cryptoxanthin supplementation in animal models of hepatic steatosis(2).As discussed below,the recent publication by Liu et al.from the group led by Dr.Xiang-Dong Wang has provided new insight into the benefits ofβ-cryptoxanthin supplementation in the context of fatty liver disease(3).

关键词： Liver non-alcoholic fatty liver disease β-cryptoxanthin

Cerebral organoids exhibit mature neurons and astrocytes and recapitulate electrophysiological activity of the human brain

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Neural Regeneration Research 2019年第5期14卷 757-761页

作者： Abraam M.Yakoub Department of molecular and cellular physiology Stanford University

Multiple protocols have been devised to generate cerebral organoids that recapitulate features of the developing human brain, including the presence of a large, multi-layered, cortical-like neuronal zone. However, the central question is whether these organoids truly present mature, functional neurons and astrocytes, which may qualify the system for in-depth molecular neuroscience studies focused at neuronal and synaptic functions. Here, we demonstrate that cerebral organoids derived under optimal differentiation conditions exhibit mature, fully functional neurons and astrocytes, as validated by immunohistological, gene expression, and electrophysiological, analyses. Neurons in cerebral organoids showed gene expression profiles and electrophysiological properties similar to those reported for fetal human brain. These important findings indicate that cerebral organoids recapitulate the developing human brain and may enhance use of cerebral organoids in modeling human brain development or investigating neural deficits that underlie neurodevelopmental and neuropsychiatric conditions, such as autism or intellectual disorders.

关键词： cerebral organoids human brain stem cells neurons astrocytes neurodevelopmental disorders neuropsychiatric disorders autism

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Seasonal variations in gonad morphology and hypothalamic GnRH-I and GnIH in Eurasian Tree Sparrow,a multi-brooded passerine

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Avian Research 2022年第3期13卷 369-378页

作者： Limin Wang Ghulam Nabi Li Zhang Dan Liu Mo Li Juyong Li Kaixin Shi Ibrahim M.Ahmad Yuefeng Wu John C.Wingfield Dongming Li Ministry of Education Key Laboratory of molecular and cellular Biology Key Laboratory of Animal PhysiologyBiochemistry and Molecular Biology of Hebei ProvinceCollege of Life SciencesHebei Normal UniversityShijiazhuang050024China Department of Neurobiology Physiology and BehaviorUniversity of Californi1DavisCAUSA

The hypothalamic-pituitary-gonadal(HPG)axis ubiquitously regulates seasonal reproduction,following the rhythmicity of a suite of environmental cues.Birds display prominent seasonal variations in gonad size regulated by two hypothalamic peptides,gonadotropin-releasing hormone-1(GnRH-I)and gonadotropin-inhibiting hormone(GnIH).How multi-brooded avian species adjust GnRH-I and GnIH to regulate gonadal morphology seasonally remains largely unknown.Here,we studied the variations in the hypothalamic immunoreactivity(ir)of GnRH-I and GnIH,gonadal proliferation,and apoptosis in a typical multi-brooded species,the Eurasian Tree Sparrow(Passer montanus),across the pre-breeding(PB),first breeding(FB),second breeding(SB),pre-basic molt(PM),and wintering stages(WS).Our results showed that both sexes had higher preoptic area(POA)-GnRH-I-ir but lower paraventricular nucleus(PVN)-GnIH-ir neurons during the breeding stages(FB and SB)relative to other life-history stages,with no significant differences between two broods.The testes and ovaries were significantly larger during the breeding stages.Testicular volume increased during the two broods due to anincreased diameter of seminiferous tubules.Furthermore,there were more testicular apoptotic cells in PB and WS stages than in breeding stages,and in PB stage than in PM stage.Males had higher POA-GnRH-I expression than females during the breeding stages,but both sexes had comparable PVN-GnIH expression throughout the annual cycle.Both sexes of the sparrows may undergo a similar pattern of life-history stage-dependent variation in the hypothalamic GnRH-I,GnIH,and gonadal morphology,except that during breeding stages,males may display higher expression of POA-GnRH-I relative to females.The higher expression of POA-GnRH-I-ir in breeding male sparrows may be critical for male-dependent parental care.

关键词： Eurasian Tree Sparrow Gonads Hypothalamus Reproduction Seasonality

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cellular senescence-driven transcriptional reprogramming of the MAFB/NOTCH3 axis activates the PI3K/AKT pathway and promotes osteosarcoma progression

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Genes & Diseases 2024年第2期11卷 952-963页

作者： Zhenhao Zhang Doudou Jing Baijun Xuan Zhicai Zhang Wei Wu Zengwu Shao Department of Orthopedics Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei 430022China Department of Orthopedics The Second Hospital of Shanxi Medical UniversityTaiyuanShanxi 030001China Department of cardiology Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei 430022China

Osteosarcoma is the most common primary malignancy of bones and primarily occurs in adolescents and young adults.However,a second smaller peak of osteosarcoma incidence was reported in the elderly aged more than 60.Elderly patients with osteosarcoma exhibit different characteristics compared to young patients,which usually results in a poor prognosis.The mechanism underlying osteosarcoma development in elderly patients is intriguing and of significant value in clinical applications.Senescent cells can accelerate tumor progression by metabolic reprogramming.Recent research has shown that methylmalonic acid(MMA)was significantly up-regulated in the serum of older individuals and played a central role in the development of aggressive characteristics.We found that the significant accumulation of MMA in elderly patients imparted proliferative potential to osteosarcoma cells.The expression of MAFB was excessively up-regulated in osteosarcoma specimens and was further enhanced in response to MMA accumulation as the patient aged.Specifically,we first confirmed a novel molecular mechanism between cellular senescence and cancer,in which the MMA-driven transcriptional reprogramming of the MAFB-NOTCH3 axis accelerated osteosarcoma progression via the activation of PI3K-AKT pathways.Moreover,the down-regulation of the MAFB-NOTCH3 axis increased the sensitivity and effect of AKT inhibitors in osteosarcoma through significant inhibition of AKT phosphorylation.In conclusion,we confirmed that MAFB is a novel age-dependent biomarker for osteosarcoma,and targeting the MAFB-NOTCH3 axis in combination with AKT inhibition can serve as a novel therapeutic strategy for elderly patients with osteosarcoma in experimental and clinical trials.

关键词： cellular senescence Elderly patients MAFB-NOTCH3axis Methylmalonic acid Osteosarcoma PI3K-AKTpathway

A remembrance of Professor TP FENG

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生理学报 2007年第6期59卷 713-715页

作者： Richard W.Tsien Department of molecular and cellular physiology Stanford University

It is both an honor and pleasure to be given this opportunity to remember Professor TP FENG and his many contributions.He made many important scientific discoveries,labored mightily to establish firmly physiology and Neuroscience in China,and was a major force in setting a high standard for scientific inquiry.It is safe to say that the past and future of Neuroscience in China would be very different had Professor FENG not provided leadership,by dint of organization,persuasion and strong personal example.

关键词：神经系统科学中国冯德培生理学院士科研教学

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LonP1 Links Mitochondria–ER Interaction to Regulate Heart Function

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Research 2024年第1期2023卷 595-609页

作者： Yujie Li Dawei Huang Lianqun Jia Fugen Shangguan Shiwei Gong Linhua Lan Zhiyin Song Juan Xu Chaojun Yan Tongke Chen Yin Tan Yongzhang Liu Xingxu Huang Carolyn K.Suzuki Zhongzhou Yang Guanlin Yang Bin Lu The Affiliated Nanhua Hospital and School of Basic Medical Sciences Hengyang Medical SchoolUniversity of South ChinaHengyangHunan 421001China School of Laboratory Medicine and Life Sciences Wenzhou Medical UniversityWenzhouZhejiang 325035China National Health Commission Key Laboratory of Birth Defect Research and Prevention Hunan Provincial Maternal and Child Health Care HospitalChangshaHunan 410008China Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications Ministry of Education of ChinaLiaoning University of Traditional Chinese MedicineShenyangLiaoning 110847China Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province The First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiangChina Hubei Key Laboratory of Cell Homeostasis College of Life SciencesWuhan UniversityWuhanHubei 430072China Nanjing Maternity and Child Health Care Hospital Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical UniversityNanjing 210004China Animal Center Wenzhou Medical UniversityWenzhouZhejiang 325035China Department of cardiology The First Affiliated Hospital of University of South ChinaHengyangHunanChina School of Life Science and Technology Shanghai Tech UniversityShanghai 201210China Department of Microbiology Biochemistry and Molecular GeneticsNew Jersey Medical School-RutgersThe State University of New JerseyNewarkNJUSA State Key Laboratory of Pharmaceutical Biotechnology Department of CardiologyNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical School and MOE Key Laboratory of Model Animal for Disease StudyModel Animal Research CenterNanjing UniversityNanjing 210061China

Interorganelle contacts and communications are increasingly recognized to play a vital role in cellular function and homeostasis.In particular,the mitochondria–endoplasmic reticulum(ER)membrane contact site(MAM)is known to regulate ion and lipid transfer,as well as signaling and organelle dynamics.However,the regulatory mechanisms of MAM formation and their function are still elusive.Here,we identify mitochondrial Lon protease(LonP1),a highly conserved mitochondrial matrix protease,as a new MAM tethering protein.The removal of LonP1 substantially reduces MAM formation and causes mitochondrial fragmentation.Furthermore,deletion of LonP1 in the cardiomyocytes of mouse heart impairs MAM integrity and mitochondrial fusion and activates the unfolded protein response within the ER(UPR^(ER)).Consequently,cardiac-specific LonP1 deficiency causes aberrant metabolic reprogramming and pathological heart remodeling.These findings demonstrate that LonP1 is a novel MAM-localized protein orchestrating MAM integrity,mitochondrial dynamics,and UPR^(ER),offering exciting new insights into the potential therapeutic strategy for heart failure.

关键词： offering programming insight