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Inhibiting SHP2 reduces glycolysis, promotes microglial M1 polarization, and alleviates secondary inflammation following spinal cord injury in a mouse model

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Neural Regeneration Research 2025年第3期20卷 858-872页

作者： Xintian Ding Chun Chen Heng Zhao Bin Dai Lei Ye Tao Song Shuai Huang Jia Wang Tao You Department of Orthopedics The First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhui ProvinceChina Department of Orthopedics Provincial Hospital Affiliated to Anhui Medical UniversityHefeiAnhui ProvinceChina

Reducing the secondary inflammatory response, which is partly mediated by microglia, is a key focus in the treatment of spinal cord injury. Src homology 2-containing protein tyrosine phosphatase 2(SHP2), encoded by PTPN11, is widely expressed in the human body and plays a role in inflammation through various mechanisms. Therefore, SHP2 is considered a potential target for the treatment of inflammation-related diseases. However, its role in secondary inflammation after spinal cord injury remains unclear. In this study, SHP2 was found to be abundantly expressed in microglia at the site of spinal cord injury. Inhibition of SHP2 expression using siRNA and SHP2 inhibitors attenuated the microglial inflammatory response in an in vitro lipopolysaccharide-induced model of inflammation. Notably, after treatment with SHP2 inhibitors, mice with spinal cord injury exhibited significantly improved hind limb locomotor function and reduced residual urine volume in the bladder. Subsequent in vitro experiments showed that, in microglia stimulated with lipopolysaccharide, inhibiting SHP2 expression promoted M2 polarization and inhibited M1 polarization. Finally, a co-culture experiment was conducted to assess the effect of microglia treated with SHP2 inhibitors on neuronal cells. The results demonstrated that inflammatory factors produced by microglia promoted neuronal apoptosis, while inhibiting SHP2 expression mitigated these effects. Collectively, our findings suggest that SHP2 enhances secondary inflammation and neuronal damage subsequent to spinal cord injury by modulating microglial phenotype. Therefore, inhibiting SHP2 alleviates the inflammatory response in mice with spinal cord injury and promotes functional recovery postinjury.

关键词： apoptosis glycolysis inflammatory response microglia neurons polarization spinal cord injury Src homology 2-containing protein tyrosine phosphatase 2

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Ascyrones A-E, type B bicyclic ployprenylated acylphloroglucinol derivatives from Hypericum ascyron

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Chinese Journal of Natural Medicines 2022年第6期20卷 473-480页

作者： DENG Xin XIA Jing QIAN Meng-Yu WANG Xiu-Rong HU Bo LIU Xue-Song WU Lin School of Pharmacy Anhui Medical UniversityInflammation and Immune Mediated Disease Laboratory of Anhui ProvinceHefei 230032China

Five new polycyclic polyprenylated acylphloroglucinols(1-5),ascyrones A-E,and four known compounds(6-9)were isolated from the aerial parts of Hypericum *** of the isolates containing a bicyclo[3.3.1]nonane-2,4,9-trione core and a benzoyl group,belonged to type B bicyclic polyprenylated acylphloroglucinols(BPAPs).Their structures and absolute configurations were established based on spectroscopic analyses and calculated electronic circular dichroism(ECD)*** anti-inflammatory,neuroprotective and cytotoxicity activities of compounds 1-4 and 6-9 were *** 6 exhibited obvious anti-inflammatory activity in lipopolysaccharide(LPS)-induced RAW264.7 *** 1 and 9 exhibited slight cytotoxicity against Hep3B ***,compound 1 showed mild neuroprotective activity against corticosterone(CORT)-induced PC 12 cell damage at 10 μmol-L^(-1).

关键词： Hypericum ascyron Acylphloroglucinol Anti-inflammatory activity Neuroprotective activity

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FUBP3 mediates the amyloid-β-induced neuronal NLRP3 expression

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Neural Regeneration Research 2025年第7期20卷 2068-2083页

作者： Jing Yao Yuan Li Xi Liu Wenping Liang Yu Li Liyong Wu Zhe Wang Weihong Song The National Clinical Research Center for Geriatric Disease Xuanwu HospitalCapital Medical UniversityBeijingChina Department of Neurology The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina Department of Neurosurgery Xuanwu HospitalCapital Medical UniversityBeijingChina Department of Pediatrics The Second Affiliated Hospital and Yuying Children’s HospitalKey Laboratory of Alzheimer’s Disease of Zhejiang ProvinceInstitute of AgingWenzhou Medical UniversityWenzhouZhejiang ProvinceChina Oujiang laboratory(Zhejiang laboratory for Regenerative Medicine Visionand Brain Health)WenzhouZhejiang ProvinceChina

Alzheimer's disease is characterized by deposition of amyloid-β,which forms extracellular neuritic plaques,and accumulation of hyperphosphorylated tau,which aggregates to form intraneuronal neurofibrillary tangles,in the *** NLRP3 inflammasome may play a role in the transition from amyloid-βdeposition to tau phosphorylation and *** NLRP3 is primarily found in brain microglia,and tau is predominantly located in neurons,it has been suggested that NLRP3 expressed by microglia indirectly triggers tau phosphorylation by upregulating the expression of pro-inflammatory ***,we found that neurons also express NLRP3 in vitro and in vivo,and that neuronal NLRP3 regulates tau *** biochemical methods,we mapped the minimal NLRP3 promoter and identified FUBP3 as a transcription factor regulating NLRP3 expression in *** primary neurons and the neuroblastoma cell line Neuro2A,FUBP3 is required for endogenous NLRP3 expression and tau phosphorylation only when amyloid-βis *** the brains of aged wild-type mice and a mouse model of Alzheimer's disease,FUBP3 expression was markedly increased in cortical *** analysis suggested that FUBP3 plays a role in neuron-mediated immune *** also found that FUBP3 trimmed the 5′end of DNA fragments that it bound,implying that FUBP3 functions in stress-induced *** findings suggest that neuronal NLRP3 may be more directly involved in the amyloid-β-to–phospho-tau transition than microglial NLRP3,and that amyloid-βfundamentally alters the regulatory mechanism of NLRP3 expression in *** that FUBP3 was only expressed at low levels in young wild-type mice and was strongly upregulated in the brains of aged mice and Alzheimer's disease mice,FUBP3 could be a safe therapeutic target for preventing Alzheimer's disease progression.

关键词： 5′end trimming Alzheimer's disease amyloid-beta amyloid-β-dependent transcription FUBP3 inflammasome inflammation neuron NLRP3 tau transcription factor

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Genome-wide meta-analysis identifies ten new psoriasis susceptibility loci in the Chinese population

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Journal of Genetics and Genomics 2022年第2期49卷 177-180页

作者： Weiwei Chen Wenjun Wang Liang Yong Qi Zhen Yafen Yu Huiyao Ge Yiwen Mao Lu Cao Ruixue Zhang Xia Hu Zhuo Li Yirui Wang Wencheng Fan Qiongqiong Xu Hui Zhang Shirui Chen Jing Wu Liangdan Sun Department of Dermatology The First Affiliated Hospital of Anhui Medical UniversityHefeiAnhui 230031China Key laboratory of Dermatology(anhui Medical University) Ministry of EducationHefei 230031China anhui province laboratory of inflammation and immune mediated diseases 230031 China anhui Provincial Institute of Translational Medicine 230031 China Department of Dermatology Huangshi Central HospitalAffiliated Hospital of Hubei Polytechnic UniversityHuangGang 438000China

Psoriasis is caused by many factors and is characterized by excessive proliferation of the epidermis and erythema with silver scales on the surface of the skin and concomitant with a variety of diseases(Griffiths et al., 2021). Despite the unclear aetiology,increasing evidence has demonstrated that genetic factors play key roles in the pathogenesis of psoriasis.

关键词： psoriasis diseases

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P2X7 Receptor in Alcoholic Steatohepatitis and Alcoholic Liver Fibrosis

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Journal of Clinical and Translational Hepatology 2022年第6期10卷 1205-1212页

作者： Guo-Qing Xia Qian Fang Jun-Nan Cai Zi-Xuan Li Feng-Zhi Zhang Xiong-Wen Lv Institute for Liver diseases of anhui Medical University HefeiAnhuiChina The Key laboratory of Anti-inflammatory and immune Medicines Ministry of EducationHefeiAnhuiChina inflammation and immune-mediated diseases laboratory of anhui province Anhui Institute of Innovative DrugsSchool of PharmacyAnhui Medical UniversityHefeiAnhuiChina Wannan Medical College Yijishan HospitalAffiliated Hospital 1WuhuAnhuiChina

Alcoholic liver disease is one of the most common chronic liver diseases in the *** is a liver disease caused by prolonged heavy drinking and its main clinical features are nausea,vomiting,enlargement of the liver,and *** studies suggest that Kupffer cell-mediated inflam-matory response is a core driver in the development of alco-holic steatohepatitis and alcoholic liver *** a danger signal,extracellular ATP activates the assembly of NLPR3 inflammasome by acting on purine P2X7 receptor,the ac-tivated NLRP3 inflammasome prompts ASC to cleave pro-cCaspase-1 into active caspase-1in *** caspase-1 promotes the conversion of pro-IL-1βto IL-1β,which fur-ther enhances the inflammatory ***,we briefly review the role of the P2X7R-NLRP3 inflammasome axis in the pathogenesis of alcoholic liver disease and the evolution of alcoholic steatohepatitis and alcoholic liver ***-ulation of the inflammasome axis of P2X7R-NLRP3 may be a new approach for the treatment of alcoholic liver disease.

关键词： ATP P2X7 receptor Kupffer cells NLRP3 inflammasome Alcoholic steatohepatitis Alcoholic liver fibrosis

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Puerarin inhibits inflammation and lipid accumulation in alcoholic liver disease through regulating MMP8

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Chinese Journal of Natural Medicines 2023年第9期21卷 670-681页

作者： HU Ying WANG Shuxian WU Lan YANG Kai YANG Fan YANG Junfa HU Shuang YAO Yan XIA Xun LIU Yixin PENG Li WAN Jihong SHEN Chuanpu XU Tao inflammation and immune mediated diseases laboratory of anhui province School of PharmacyAnhui Medical UniversityHefei 230032China Institute for Liver diseases of anhui Medical University Hefei 230032China Medical Device Production Supervision Office Anhui Provincial Drug AdministrationHefei 230051China Department of Ophthalmology the First Affiliated Hospital of Anhui Medical UniversityHefei 230022China

Alcoholic liver disease(ALD)is a growing global health concern,and its early pathogenesis includes steatosis and *** lipid accumulation and inflammation is a crucial step in relieving *** shows that puerarin(Pue),an isoflavone isolated from Pueraria lobata,exerts cardio-protective,neuroprotective,anti-inflammatory,antioxidant ***,the therapeutic potential of Pue on ALD remains *** the study,both the NIAAA model and ethanol(EtOH)-induced AML-12 cell were used to explore the protective effect of Pue on alcoholic liver injury in vivo and in vitro and related *** results showed that Pue(100 mg·kg^(−1))attenuated EtOH-induced liver injury and inhibited the levels of SREBP-1c,TNF-α,IL-6 and IL-1β,compared with silymarin(Sil,100 mg·kg^(−1)).In vitro results were consistent with in vivo ***,Pue might suppress liver lipid accumulation and inflammation by regulating *** conclusion,Pue might be a promising clinical candidate for ALD treatment.

关键词： Puerarin MMP8 Alcoholic liver disease Inflammatory Lipid accumulation

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immune cells in alcohol-related liver disease

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Liver Research 2022年第1期6卷 1-9页

作者： Honghai Xu Hua Wang Department of Pathology the First Affiliated Hospital of Anhui Medical UniversityHefeiAnhuiChina Department of Oncology the First Affiliated Hospital of Anhui Medical UniversityHefeiAnhuiChina inflammation and immune mediated diseases laboratory of anhui province Anhui Medical UniversityHefeiAnhuiChina

Alcohol-related liver disease(ALD),which is caused by excessive alcohol consumption,is one of the most common types of liver disease and a primary cause of hepatic injury,with a disease spectrum that in-cludes steatosis,steatohepatitis,fibrosis,cirrhosis,and hepatocellular *** lines of evi-dence have indicated that immune cells play a significant role in the inflammatory processes of *** the one hand,the liver contains various resident immune cells that have been proven to perform different functions in *** example,in the progression of the disease,Kupffer cells(KCs)are activated by lipopolysaccharide-Toll-like receptor 4 signaling and release various proinflammatory ***,alcohol intake has been shown to depress the function of natural killer ***,two types of unconventional T cells(natural killer T cells and mucosal-associated invariant T cells)are involved in the development of *** the other hand,alcohol and many different cytokines stimulate the recruitment and infiltration of circulating immune cells(neutrophils,T cells,macrophages,and mast cells)into the *** neutrophils can produce proinflammatory mediators and cause the dysfunction of anti-infection ***,alcohol intake can change the phenotype of T cells,resulting in their increased production of *** from KCs,infiltrating macrophages have also been observed in patients with ALD,but the roles of all of these cells in the progression of the disease have shown both similarities and ***,the activated mast cells are also associated with the development of ***,we review the diverse roles of the various immune cells in the progression of ALD.

关键词： Alcohol-related liver disease(ALD) Resident immune cells Circulating immune cells Infiltrating immune cells inflammation Cytokines

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Decoding m^(6)A mRNA methylation by reader proteins in liver diseases

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Genes & diseases 2024年第2期11卷 711-726页

作者： Lijiao Sun Xin Chen Sai Zhu Jianan Wang Shaoxi Diao Jinyu Liu Jinjin Xu Xiaofeng Li Yingyin Sun Cheng Huang Xiaoming Meng Xiongwen Lv Jun Li inflammation and immune mediated diseases laboratory of anhui province Anhui Institute of Innovative DrugsSchool of PharmacyAnhui Medical UniversityHefeiAnhui 230032China The Key laboratory of Anti-inflammatory and immune Medicines Anhui Medical UniversityMinistry of EducationHefeiAnhui 230032China Institute for Liver diseases of anhui Medical University ILD-AMUAnhui Medical UniversityHefeiAnhui 230032China Department of Nephropathy The First Affiliated Hospital of Anhui Medical UniversityHefeiAnhui 230022China Department of Oncology The First Affiliated Hospital of Anhui Medical UniversityHefeiAnhui 230032China

N6-methyladenosine(m^(6)A)is a dynamic and reversible epigenetic *** the most prevalent internal post-transcriptional modification in eukaryotic RNA,it participates in the regulation of gene expression through various mechanisms,such as mRNA splicing,nuclear export,localization,translation efficiency,mRNA stability,and structural *** involvement of m^(6)A in the regulation of gene expression depends on the specific recognition of m^(6)A-modified RNA by reader *** the pathogenesis and treatment of liver disease,studies have found that the expression levels of key genes that promote or inhibit the development of liver disease are regulated by m^(6)A modification,in which abnormal expression of reader proteins determines the fate of these gene *** this review,we introduce m^(6)A readers,summarize the recognition and regulatory mechanisms of m^(6)A readers on mRNA,and focus on the biological functions and mechanisms of m^(6)A readers in liver cancer,viral hepatitis,non-alcoholic fatty liver disease(NAFLD),hepatic fibrosis(HF),acute liver injury(ALI),and other liver *** information is expected to be of high value to researchers deciphering the links between m^(6)A readers and human liver diseases.

关键词： IGF2BPs Liver diseases m^(6)A modification m^(6)A reader mRNA metabolism YTH domain protein

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G protein-coupled receptor 35 attenuates nonalcoholic steatohepatitis by reprogramming cholesterol homeostasis in hepatocytes

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Acta Pharmaceutica Sinica B 2023年第3期13卷 1128-1144页

作者： Xiaoli Wei Fan Yin Miaomiao Wu Qianqian Xie Xueqin Zhao Cheng Zhu Ruiqian Xie Chongqing Chen Menghua Liu Xueying Wang Ruixue Ren Guijie Kang Chenwen Zhu Jingjing Cong Hua Wang Xuefu Wang Department of Oncology the First Affiliated Hospital of Anhui Medical UniversityHefei 230036China Department of Pharmacy Huainan First People's Hospitalthe First Affiliated Hospital of Anhui University of Science and TechnologyHuainan 232001China School of Pharmacy Anhui Medical UniversityHefei 230032China inflammation and immune mediated diseases laboratory of anhui province Anhui Medical UniversityHefei 230032China

Nonalcoholic fatty liver disease(NAFLD)is the most common chronic liver disease *** accumulation“sensitizes”the liver to insult and leads to nonalcoholic steatohepatitis(NASH).G protein-coupled receptor 35(GPR35)is involved in metabolic stresses,but its role in NAFLD is *** report that hepatocyte GPR35 mitigates NASH by regulating hepatic cholesterol ***,we found that GPR35 overexpression in hepatocytes protected against high-fat/cholesterol/fructose(HFCF)diet-induced steatohepatitis,whereas loss of GPR35 had the opposite *** of the GPR35 agonist kynurenic acid(Kyna)suppressed HFCF diet-induced steatohepatitis in ***/GPR35 induced expression of StAR-related lipid transfer protein 4(STARD4)through the ERK1/2 signaling pathway,ultimately resulting in hepatic cholesterol esterification and bile acid synthesis(BAS).The overexpression of STARD4 increased the expression of the BAS rate-limiting enzymes cytochrome P450 family 7 subfamily A member 1(CYP7A1)and CYP8B1,promoting the conversion of cholesterol to bile *** protective effect induced by GPR35 overexpression in hepatocytes disappeared in hepatocyte STARD4-knockdown ***4 overexpression in hepatocytes reversed the aggravation of HFCF diet-induced steatohepatitis caused by the loss of GPR35 expression in hepatocytes in *** findings indicate that the GPR35–STARD4 axis is a promising therapeutic target for NAFLD.

关键词： G protein-coupled receptor 35 Kynurenic acid Steatohepatitis Cholesterol Bile acid STARD4 ACAT2 CYP7A1

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Application and progress of the detection technologies in hepatocellular carcinoma

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Genes & diseases 2023年第5期10卷 1857-1869页

作者： Qi Yan Yuan-song Sun Ran An Fang Liu Qi Fang Zhen Wang Tao Xu Lijian Chen Jian Du School of Basic Medical Sciences Anhui Medical UniversityHefeiAnhui 230032China Department of Emergency Surgery The Second Hospital of Anhui Medical UniversityHefeiAnhui 230032China Department of Anesthesiology The First Affiliated Hospital of Anhui Medical UniversityHefeiAnhui 230032China inflammation and immune mediated diseases laboratory of anhui province Anhui Institute of Innovative DrugsSchool of PharmacyHefeiAnhui 230032China Institute for Liver diseases of anhui Medical University Anhui Medical UniversityHefeiAnhui 230032China

Hepatocellular carcinoma(HCC)has a very high incidence and fatality rate,and in most cases,it is already at an advanced stage when ***,early prevention and detection of HCC are two of the most effective ***,the methods recommended in the practice guidelines for the detection of HCC cannot guarantee high sensitivity and specificity except for the liver biopsy,which is known as the“gold standard”.In this review,we divided the detection of HCC into pre-treatment diagnosis and post-treatment monitoring,and found that in addition to the traditional imaging detection and liver biopsy,alpha fetoprotein(AFP),lens culinaris-agglutinin-reactive fraction of AFP(AFP-L3),protein induced by vitamin K absence or antagonist-II(PIVKA-II)and other biomarkers are excellent biomarkers for HCC,especially when they are combined *** notably,the emerging liquid biopsy shows great promise in detecting *** addition,lactic dehydrogenase(LDH),suppressor of cytokine signaling(SOCS)and other relevant biomarkers may become promising biomarkers for HCC post-treatment *** the detailed introduction of the diagnostic technology of HCC,we can have a detailed understanding of its development process and then obtain some enlightenment from the diagnosis,to improve the diagnostic rate of HCC and reduce its mortality.

关键词： HCC Invasive diagnosis Minimally invasive diagnosis Noninvasive diagnosis Prognostic monitoring

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