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Role of mitochondrial dysfunction in kidney disease:Insights from the cGAS-STING signaling pathway

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Chinese Medical Journal 2024年第9期137卷 1044-1053页

作者： Lu Li Fei Liu Chunyue Feng Zhenjie Chen Nan Zhang Jianhua Mao Department of Nephrology Children’s HospitalZhejiang University School of MedicineNational Clinical Research Center for Child HealthHangzhouZhejiang 310052China Department of Pediatric Intensive Care unit Children’s HospitalZhejiang University School of MedicineNational Clinical Research Center for Child HealthHangzhouZhejiang 310052China

Over the past decade,mitochondrial dysfunction has been investigated as a key contributor to acute and chronic kidney ***,the precise molecular mechanisms linking mitochondrial damage to kidney disease remain *** recent insights into the cyclic guanosine monophosphate-adenosine monophosphate(GMP-AMP)synthetase(cGAS)-stimulator of interferon gene(STING)signaling pathway have revealed its involvement in many renal *** of these findings is that mitochondrial DNA(mtDNA)induces inflammatory responses via the cGAS-STING ***,we provide an overview of the mechanisms underlying mtDNA release following mitochondrial damage,focusing specifically on the association between mtDNA release-activated cGAS-STING signaling and the development of kidney ***,we summarize the latest findings of cGAS-STING signaling pathway in cell,with a particular emphasis on its downstream signaling related to kidney *** review intends to enhance our understanding of the intricate relationship among the cGAS-STING pathway,kidney diseases,and mitochondrial dysfunction.

关键词： Mitochondrial dysfunction Mitochondrial DNA cGAS-STING pathway Kidney diseases Chronic kidney disease

Molecular mechanisms underlying microglial sensing and phagocytosis in synaptic pruning

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Neural Regeneration research 2024年第6期19卷 1284-1290页

作者： Anran Huo Jiali Wang Qi Li Mengqi Li Yuwan Qi Qiao Yin Weifeng Luo Jijun Shi Qifei Cong clinical research Center of Neurological Disease The Second Affiliated Hospital of Soochow UniversityInstitute of Neuroscience and Jiangsu Key Laboratory of Neuropsychiatric Diseases Soochow University Department of Neurology and clinical research Center of Neurological Disease The Second Affiliated Hospital of Soochow University

Microglia are the main non-neuronal cells in the central nervous system that have important roles in brain development and functional connectivity of neural circuits. In brain physiology, highly dynamic microglial processes are facilitated to sense the surrounding environment and stimuli. Once the brain switches its functional states, microglia are recruited to specific sites to exert their immune functions, including the release of cytokines and phagocytosis of cellular debris. The crosstalk of microglia between neurons, neural stem cells, endothelial cells, oligodendrocytes, and astrocytes contributes to their functions in synapse pruning, neurogenesis, vascularization, myelination, and blood-brain barrier permeability. In this review, we highlight the neuron-derived “find-me,” “eat-me,” and “don’t eat-me” molecular signals that drive microglia in response to changes in neuronal activity for synapse refinement during brain development. This review reveals the molecular mechanism of neuron-microglia interaction in synaptic pruning and presents novel ideas for the synaptic pruning of microglia in disease, thereby providing important clues for discovery of target drugs and development of nervous system disease treatment methods targeting synaptic dysfunction.

关键词： complement immune signals microglia molecular signal synapse elimination synapse formation synapse refinement synaptic pruning

Targeting ASIC1a Promotes Neural Progenitor Cell Migration and Neurogenesis in Ischemic Stroke

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research 2024年第1期2023卷 369-387页

作者： Hongfei Ge Tengyuan Zhou Chao Zhang Yupeng Cun Weixiang Chen Yang Yang Qian Zhang Huanhuan Li Jun Zhong Xuyang Zhang Hua Feng Rong Hu Department of Neurosurgery and Key Laboratory of Neurotrauma Southwest HospitalThird Military Medical University(Army Medical University)400038 ChongqingChina Medical research Center Southwest HospitalThird Military Medical University(Army Medical University)400038 ChongqingChina Pediatric research Institute Ministry of Education Key Laboratory of Child Development and DisordersNational Clinical Research Center for Child Health and DisordersChildren’s Hospital of Chongqing Medical University400014 ChongqingChina

Cell replacement therapy using neural progenitor cells(NPCs)has been shown to be an effective treatment for ischemic ***,the therapeutic effect is unsatisfactory due to the imbalanced homeostasis of the local microenvironment after *** acidosis is a common imbalanced homeostasis in the penumbra and could activate acid-sensing ion channels 1a(ASIC1a),a subunit of proton-gated cation channels following ischemic ***,the role of ASIC1a in NPCs post-ischemia remains ***,our results indicated that ASIC1a was expressed in NPCs with channel functionality,which could be activated by extracellular *** evidence revealed that ASIC1a activation inhibited NPC migration and neurogenesis through RhoA signaling-mediated reorganization of filopodia formation,which could be primarily reversed by pharmacological or genetic disruption of *** vivo data showed that the knockout of the ASIC1a gene facilitated NPC migration and neurogenesis in the penumbra to improve behavioral recovery after stroke.

关键词： ASIC1a homeostasis inhibited

Postoperativeinte rictalepil eptiform discharges predict seizure recurrence after antiepileptic drug withdrawal regardless of concordance with surgical site

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World Journal of Pediatric Surgery 2024年第1期7卷 33-41页

作者： Yuxin Wu ZaiYu Zhang Ping Liang Lusheng Li Bin Zou Difei Wang Xinyu Dong Haotian Tang Hanli Qiu Xuan Zhai Department of Neurosurgery Children's Hospital of Chongqing Medical UniversityNational Clinical Research Center for Child Health and DisordersMinistry of Education Key Laboratory of Child Development and DisordersChongqingChina

Objective The study aimed to explore the association between the site of interictal epileptic discharges(IEDs)on postoperative electroencephalogram(EEG)and seizure recurrence after antiepileptic drug(AED)*** study hypothesizes that the concordance of IED sites with surgical sites indicates incomplete resection of epileptic focus,while non-concordance of IED sites with surgical sites indicates postoperative changes or cortical *** former has a higher risk of seizure *** We retrospectively analyzed the postoperative EEG pattern of 182 consecutive children who underwent resection *** identify the risk factors for seizure recurrence,we compared the attributes of seizure recurred and seizure-free groups by univariate and multivariate *** tapering was standardized,involving a 25% reduction in the dose of a single type of AED every 2 weeks,independent of the presurgical AED *** We attempted AED withdrawal in 116(63.7%)***-eight(24.1%)children experienced seizure recurrence during or after AED withdrawal.A greater number of AEDs used at the time of surgery(p=0.005),incomplete resection(p=0.001),and presence of IED on postoperative EEG(p=0.011)are predictors of *** resectionand seizure recurrence after AED withdrawal were related to the presence of IED on the EEG,but not to the concordance of IED with surgical *** For children with abnormal EEG,the decision to discontinue AED should be made more cautiously,regardless of the relative location of the discharge site and the surgical site.

关键词： surgical seizure epileptic

Bispecific antibody drug conjugates:Making 1+1>2

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Acta Pharmaceutica Sinica B 2024年第5期14卷 1965-1986页

作者： Yilin Gu Zhijia Wang Yuxi Wang Targeted Tracer research and development Laboratory Institute of Respiratory HealthFrontiers Science Center for Disease-Related Molecular NetworkNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengdu 610041China Frontiers Medical Center Tianfu Jincheng LaboratoryChengdu 610212China

Bispecific antibody‒drug conjugates(BsADCs)represent an innovative therapeutic category amalgamating the merits of antibody‒drug conjugates(ADCs)and bispecific antibodies(BsAbs).Positioned as the next-generation ADC approach,BsADCs hold promise for ameliorating extant clinical challenges associated with ADCs,particularly pertaining to issues such as poor internalization,off-target toxicity,and drug ***,ten BsADCs are undergoing clinical trials,and initial findings underscore the imperative for ongoing *** review initially delves into specific design considerations for BsADCs,encompassing target selection,antibody formats,and the linker–payload *** sections delineate the extant progress and challenges encountered by BsADCs,illustrated through pertinent case *** amalgamation of BsAbs with ADCs offers a prospective solution to prevailing clinical limitations of ***,the symbiotic interplay among BsAb,linker,and payload necessitates further optimizations and coordination beyond a simplistic“1+1”to effectively surmount the extant challenges facing the BsADC domain.

关键词： Bispecific antibody drug conjugates Antibody drug conjugates Bispecific antibody Targeted therapy Safety HER2 EGFR

NLRP3 activation in macrophages promotes acute intestinal injury in neonatal necrotizing enterocolitis

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World Journal of Pediatrics 2024年第2期20卷 153-164页

作者： Bo Shi Cheng-Jie Lyu Zhen-Kai Le Hao-Sen Ji Yi Xiao Yuan-Yuan Zhang Shou-Jiang Huang Lin-Jun Yu Qiang Shu Jin-Fa Tou Deng-Ming Lai Department of Neonatal Surgery Children’s HospitalZhejiang University School of MedicineNational Clinical Research Center for Child HealthHangzhou 310052China Department of Pulmonology Children’s HospitalZhejiang University School of MedicineNational Clinical Research Center for Child HealthHangzhou 310052China Department of Thoracic and Cardiovascular Surgery Children’s HospitalZhejiang University School of MedicineNational Clinical Research Center for Child HealthHangzhou 310052China

Background Macrophages are involved in various immune inflammatory disease *** study aimed to investigate the role and mechanism of macrophages in regulating acute intestinal injury in neonatal necrotizing enterocolitis(NEC).Methods CD68,nucleotide-binding oligomerization domain,leucine-rich repeat,and pyrin domain-containing 3(NLRP3),cysteine aspartate-specific protease-1(caspase-1),and interleukin-1β(IL-1β)in paraffin sections of intestinal tissues from NEC and control patients were detected with immunohistochemistry,immunofluorescence,and western *** pet milk,hypoxia and cold stimulation were used to establish a mouse(wild type and Nlrp3^(-/-))model of *** mouse macrophage(RAW 264.7)and rat intestinal epithelial cell-6 lines were also cultured followed by various ***,intestinal epithelial cell injuries,and IL-1β release were *** Compared to the gut“healthy”patients,the intestinal lamina propria of NEC patients had high macrophage infiltration and high NLRP3,caspase-1,and IL-1β ***,in vivo,the survival rate of Nlrp3^(-/-)NEC mice was dramatically improved,the proportion of intestinal macrophages was reduced,and intestinal injury was decreased compared to those of wild-type NEC ***3,caspase-1,and IL-1β derived from macrophages or supernatant from cocultures of macrophages and intestinal epithelial cells also caused intestinal epithelial cell *** Macrophage activation may be essential for NEC ***3/caspase-1/IL-1β cellular signals derived from macrophages may be the underlying mechanism of NEC development,and all these may be therapeutic targets for developing treatments for NEC.

关键词： Caspase-1 Interleukin-1β Macrophage Necrotizing enterocolitis NLRP3

Vitamin A deficiency suppresses CEACAM1 to impair colonic epithelial barrier function via downregulating microbial-derived short-chain fatty acids

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Genes & Diseases 2024年第2期11卷 1066-1081页

作者： Junyan Yan Lu Xiao Di Feng Baolin Chen Ting Yang Bei Tong Ruifang Luo Yuting Wang Jie Chen Children Nutrition research Center Children's Hospital of Chongqing Medical UniversityChongqing Key Laboratory of Child Nutrition and HealthMinistry of Education Key Laboratory of Child Development and DisordersNational Clinical Research Center for Child Health and DisordersChongqing 401122China Department of Gastroenterology Children's Hospital of Chongqing Medical UniversityChongqing 401122China

Vitamin A (VA) plays an essential role in modulating both the gut microbiota and gut barrier ***-chain fatty acids (SCFAs),as metabolites of the gut microbiota,protect the physiological intestinal barrier;however,they are compromised when VA is ***,there is an urgent need to understand how and which SCFAs modulate colonic epithelial barrier integrity in VA deficiency (VAD).Herein,compared with normal VA rats (VAN),at the beginning of pregnancy,we confirmed that the colonic desmosome junction was impaired in the VAD group,and the amounts of acetate,propionate,and butyrate declined because of the decreased abundance of SCFA-producing bacteria (Romboutsia ,Collinsella ,and Allobaculum ).The differentially expressed genes correlated with the gut barrier and the histone deacetylase complex between the VAD and VAN groups were enriched by RNA *** the VAD group,the expression levels of colonic CEA cell adhesion molecule 1 (CEACAM1) were down-regulated,and the levels of histone deacetylase 1 (HDAC1) and HDAC3 were ***,the above changes in the VAD groups were rescued by VA supplementation in the early postnatal *** study indicated that in Caco-2 cells,butyrate treatment significantly repressed the enrichment of HDAC3 on the promoter of the CEACAM1 gene to induce its *** findings support that butyrate intervention can alleviate the impairment of colonic barrier function caused by VAD,and timely postnatal VA intervention may reverse the damage caused by VAD on gut barrier integrity during pregnancy.

关键词： CEACAM1 Colonic epithelial barrier HDAC3 Short-chain fatty acids Vitamin A deficiency

Early-onset and later-onset cancer: trends, risk factors, and prevention in Northern China

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Science China Life Sciences 2024年第9期67卷 1928-1940页

作者： Tong Liu Chen-An Liu Qing-Song Zhang Qi Zhang Yi-Ming Wang Meng-Meng Song Shi-Qi Lin Li Deng Shou-Ling Wu Han-Ping Shi Department of Gastrointestinal Surgery Department of Clinical Nutrition Beijing Shijitan Hospital Capital Medical University National clinical research Center for Geriatric Diseases Xuanwu Hospital Capital Medical University Key Laboratory of Cancer FSMP for State Market Regulation Laboratory for clinical Medicine Capital Medical University Department of General Surgery Kailuan General Hospital Department of Genetics Yale School of Medicine Department of Hepatobiliary Surgery Kailuan General Hospital Cardiovascular research Institute University of California Department of Cardiology Kailuan General Hospital

The characteristics of early-onset(onset age <50 years) and later-onset(onset age ≥50 years) cancers differ significantly. Identifying novel risk factors for both types of cancer is crucial for increasing awareness of cancer prevention and for reducing its burden. This study aimed to analyze the trends in incidence and risk factors for early-onset and late-onset cancers. We conducted a prospective study by drawing data from the Kailuan Study. This study included 6,741 participants with cancer(624 with early-onset cancer and 6,117 with later-onset cancer)and 6,780 matched controls among the 186,249 participants who underwent Kailuan health examinations from 2006 to 2019. The primary outcomes were cancer incidence rates, and associated risk factors for early-and later-onset cancer. Weighted Cox regression was used to calculate hazard ratios and 95% confidence intervals of each exposure factor for early-and later-onset cancer by cancer type. Populationattributable risk proportions were used to estimate the number of cases that could be prevented by eliminating a risk factor from the population. Except for liver cancer, incidence rates for nearly all types of cancer increased during the study period. Smoking, alcohol consumption, lipid metabolism disorders, hypertension, diabetes mellitus, fatty liver, and inflammation were associated with a significantly increased risk of cancer at multiple sites, but risk factors for cancer incidence differed by site. Smoking, alcohol consumption, inflammation,and hypertension were the major contributors to preventable cancer. The incidence of several different types of cancer, including earlyonset cancer, is increasing in northeastern China. Differences in risk factors between early-onset and later-onset malignancies may contribute to the divergence in the observed changes in incidence trends between these two specific types of cancer.

关键词： cancer early-onset later-onset trend risk factor prevention

RNA modifications in cellular metabolism:implications for metabolism-targeted therapy and immunotherapy

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1565-1594页

作者： Wei-Wei Liu Si-Qing Zheng Tian Li Yun-Fei Fei Chen Wang Shuang Zhang Fei Wang Guan-Min Jiang Hao Wang Department of Laboratory Medicine The First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiChina School of clinical Medicine Shandong UniversityJinanChina Core unit of National clinical research Center for Laboratory Medicine HefeiChina Neurosurgical Department The First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiChina Department of clinical Laboratory The Fifth Affiliated HospitalSun Yat-sen UniversityZhuhaiChina

Cellular metabolism is an intricate network satisfying bioenergetic and biosynthesis requirements of *** studies have been constantly making inroads in our understanding of pathophysiology,and inspiring development of *** a crucial component of epigenetics at post-transcription level,RNA modification significantly determines RNA fates,further affecting various biological processes and cellular *** be noted,immunometabolism defines the metabolic alterations occur on immune cells in different stages and immunological *** this review,we characterize the distribution features,modifying mechanisms and biological functions of 8 RNA modifications,including N6-methyladenosine(m6A),N6,2'-O-dimethyladenosine(m6Am),N1-methyladenosine(m1A),5-methylcytosine(m5C),N4-acetylcytosine(ac4C),N7-methylguanosine(m7G),Pseudouridine(V),adenosine-to-inosine(A-to-l)editing,which are relatively the most studied *** regulatory roles of these RNA modification on metabolism in diverse health and disease contexts are comprehensively described,categorized as glucose,lipid,amino acid,and mitochondrial *** we highlight the regulation of RNA modifications on immunometabolism,further influencing immune *** all,we provide a thorough discussion about clinical implications of RNA modification in metabolism-targeted therapy and immunotherapy,progression of RNA modification-targeted agents,and its potential in RNAtargeted ***,we give legitimate perspectives for future researches in this field from methodological requirements,mechanistic insights,to therapeutic applications.

关键词： metabolism targeted alterations