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Activation of cerebral Ras-related C3 botulinum toxin substrate(Rac) 1 promotes post-ischemic stroke functional recovery in aged mice

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Neural Regeneration Research 2024年第4期19卷 881-886页

作者： Fan Bu Jia-Wei Min Md Abdur Razzaque Ahmad El Hamamy Anthony Patrizz Li Qi Akihiko Urayama Jun Li department of Neurology University of Texas Health Science Center department of Neurology&Psychology The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine

Brain functional impairment after stroke is common;however,the molecular mechanisms of post-stroke recovery remain *** is well-recognized that age is the most important independent predictor of poor outcomes after stroke as older patients show poorer functional outcomes following *** evidence suggests that axonal regeneration and angiogenesis,the major forms of brain plasticity responsible for post-stroke recovery,diminished with advanced *** studies suggest that Ras-related C3 botulinum toxin substrate(Rac)1 enhances stroke recovery as activation of Rac1 improved behavior recovery in a young mice stroke ***,we investigated the role of Rac1 signaling in long-term functional recovery and brain plasticity in an aged(male,18 to 22 months old C57BL/6J)brain after ischemic *** found that as mice aged,Rac1 expression declined in the *** overexpression of Rac1,using lentivirus encoding Rac1 injected day 1 after ischemic stroke,promoted cognitive(assessed using novel object recognition test)and sensorimotor(assessed using adhesive removal tests)recovery on days 14–*** was accompanied by the increase of neurite and proliferative endothelial cells in the periinfarct zone assessed by *** a reverse approach,pharmacological inhibition of Rac1 by intraperitoneal injection of Rac1 inhibitor NSC23766 for 14 successive days after ischemic stroke worsened the outcome with the reduction of neurite and proliferative endothelial ***,Rac1 inhibition reduced the activation of p21-activated kinase 1,the protein level of brain-derived neurotrophic factor,and increased the protein level of glial fibrillary acidic protein in the ischemic brain on day 28 after *** work provided insight into the mechanisms behind the diminished plasticity after cerebral ischemia in aged brains and identified Rac1 as a potential therapeutic target for improving functional recovery in the older adults after stroke.

关键词： aging angiogenesis brain-derived neurotrophic factor(BDNF) cerebral ischemia cognitive recovery neurite Pak1 Rac1 sensorimotor recovery

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Accurate prediction of biliary atresia with an integrated model using MMP-7 levels and bile acids

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World Journal of Pediatrics 2024年第8期20卷 822-833页

作者： Yi-Jiang Han Shu-Qi Hu Jin-Hang Zhu Xiao Cai Deng-Ming Lai Bao-Hai Chen Kun Zhu Qiao Tong Xin-Rui Zhou Jia-Le Deng Jin-Fa Tou Zhuo Fang Li-Zhong Du department of Neonatal Surgery Children’s HospitalZhejiang University School of MedicineNational Clinical Research Center for Child HealthHangzhouChina department of Data and Analytics WuXi Diagnostics Innovation Research InstituteShanghaiChina department of Information Center Children’s HospitalZhejiang University School of MedicineNational Clinical Research Center for Child HealthHangzhouChina department of Pathology Children’s HospitalZhejiang University School of MedicineNational Clinical Research Center for Child HealthHangzhouChina department of Neonatology Children’s HospitalZhejiang University School of MedicineNational Clinical Research Center for Child HealthHangzhouChina

Background Biliary atresia(BA)is a rare fatal liver disease in children,and the aim of this study was to develop a method to diagnose BA *** We determined serum levels of matrix metalloproteinase-7(MMP-7),the results of 13 liver tests,and the levels of 20 bile acids,and integrated computational models were constructed to diagnose *** Our findings demonstrated that MMP-7 expression levels,as well as the results of four liver tests and levels of ten bile acids,were significantly different between 86 BA and 59 non-BA patients(P<0.05).The computational prediction model revealed that MMP-7 levels alone had a higher predictive accuracy[area under the receiver operating characteristic curve(AUC)=0.966,95%confidence interval(CI):0.942,0.989]than liver test results and bile acid *** AUC was 0.890(95%CI 0.837,0.943)for liver test results and 0.825(95%CI 0.758,0.892)for bile acid ***,bile levels had a higher contribution to enhancing the predictive accuracy of MMP-7 levels(AUC=0.976,95%CI 0.953,1.000)than liver test *** AUC was 0.983(95%CI 0.962,1.000)for MMP-7 levels combined with liver test results and bile acid *** addition,we found that MMP-7 levels were highly correlated with gamma-glutamyl transferase levels and the liver fibrosis *** The innovative integrated models based on a large number of indicators provide a noninvasive and cost-effective approach for accurately diagnosing BA in children.

关键词： Bile aid.Biliary atresia Diagnosis Liver fibrosis Liver test MMP-7

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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

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No Incidence of Liver Cancer Was Observed in A Retrospective Studyof Patients with Aristolochic Acid Nephropathy

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Chinese Journal of Integrative medicine 2024年第2期30卷 99-106页

作者： SU Tao FANG Zhi-e GUO Yu-ming WANG Chun-yu WANG Jia-bo JI Dong BAI Zhao-fang YANG Li XiAO Xiao-he Renal Division Department of MedicinePeking University First HospitalBeijing(100034)China department of Pharmacy Chongqing Hospital of Traditional Chinese MedicineChongqing(400021)China department of Hepatology Fifth Medical Center of Chinese PLA General HospitalBeijing(100039)China China Military Institute of Chinese Materia Fifth Medical Center of Chinese PLA General HospitalBeijing(100039)China Phase I clinical Trials Unit Department of Medicine for Infectious DiseasesFifth Medical Center of Chinese PLA General HospitalBeijing(100039)China department of Pharmacy Affiliated Hospital of Shandong University of Traditional Chinese MedicineJinan(250000)China National Key Laboratory of Kidney diseases Beijing(100039)China

Objective:To assess the risk of aristolochic acid(AA)-associated cancer in patients with AA nephropathy(AAN).Methods:A retrospective study was conducted on patients diagnosed with AAN at Peking University First Hospital from January 1997 to December ***-term surveillance and follow-up data were analyzed to investigate the influence of different factors on the prevalence of *** primary endpoint was the incidence of liver cancer,and the secondary endpoint was the incidence of urinary cancer during 1 year after taking AA-containing medication to ***:A total of 337 patients diagnosed with AAN were included in this *** the initiation of taking AA to the termination of follow-up,39 patients were diagnosed with *** cases of liver cancer were observed throughout the entire follow-up period,with urinary cancer being the predominant type(34/39,87.17%).Logistic regression analysis showed that age,follow-up period,and diabetes were potential risk factors,however,the dosage of the drug was not significantly associated with urinary ***:No cases of liver cancer were observed at the end of ***,a high prevalence of urinary cancer was observed in AAN *** a direct causality between AA and HCC is challenging.

关键词： aristolochic acid hepatocellular carcinoma urinary cancer drug safety retrospective study

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Progress on immuno-microenvironment and immune-related therapies in patients with pseudomyxoma peritonei

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Cancer Biology & medicine 2024年第7期21卷 586-605页

作者： Qidi Zhao Tian Wei Ru Ma Yubin Fu Rui Yang Yandong Su Yang Yu Bing Li Yan Li School of clinical medicine Tsinghua UniversityBeijing 100084China department of Surgical Oncology Beijing Tsinghua Changgung HospitalSchool of Clinical MedicineTsinghua UniversityBeijing 102218China department of Peritoneal Cancer Surgery Bejing Shijitan HospitalCapital Medical UniversityBejing 100038China

Pseudomyxoma peritonei(PMP) is an indolent malignant syndrome. The standard treatment for PMP is cytoreductive surgery combined with intraperitoneal hyperthermic chemotherapy(CRS + HIPEC). However, the high recurrence rate and latent clinical symptoms and signs are major obstacles to further improving clinical outcomes. Moreover, patients in advanced stages receive little benefit from CRS + HIPEC due to widespread intraperitoneal metastases. Another challenge in PMP treatment involves the progressive sclerosis of PMP cell-secreted mucus, which is often increased due to activating mutations in the gene coding for guanine nucleotide-binding protein alpha subunit(GNAS). Consequently, the development of other PMP therapies is urgently needed. Several immune-related therapies have shown promise, including the use of bacterium-derived non-specific immunogenic agents, radioimmunotherapeutic agents, and tumor cell-derived neoantigens, but a well-recognized immunotherapy has not been established. In this review the roles of GNAS mutations in the promotion of mucin secretion and disease development are discussed. In addition, the immunologic features of the PMP microenvironment and immune-associated treatments are discussed to summarize the current understanding of key features of the disease and to facilitate the development of immunotherapies.

关键词： Pseudomyxoma peritonei tumor immuno-microenvironment immune-related therapy mucin 2 GNAS mutation

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Tenecteplase versus alteplase for acute ischaemic stroke:a meta-analysis of phaseⅢrandomised trials

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Stroke & Vascular Neurology 2024年第4期9卷 360-366,I0001-I0021页

作者： Yunyun Xiong Liyuan Wang Guangshuo Li Kai-Xuan Yang Manjun Hao Shuya Li Yuesong Pan Yongjun Wang department of Neurology Beijing Tiantan HospitalCapital Medical UniversityBeijingChina China National clinical Research Center for Neurological diseases BeijingChina Chinese Institute for Brain Research BeijingChina Beijing Key Laboratory of Translational medicine for Cerebrovascular Disease BeijingChina

Background Tenecteplase(TNK)was found non-inferior to alteplase in recent clinical *** aimed to elucidate the efficacy and safety of TNK versus alteplase for acute ischaemic stroke(AIS).Methods Systematic literature search and a meta-analysis of phaseⅢclinical trials in ischaemic stroke patients with TNK use were *** primary outcome was excellent functional outcome which was defined as modified Rankin Scale score of 0–1 at 90 days and safety outcomes included symptomatic intracerebral haemorrhage and death at 90 *** used random-effects model to estimate the pooled risk difference and 95%CI in R package‘Meta’.The included trials were adapted to the non-inferiority analysis with a margin of-4%.Results Three trials enrolling 4094 patients were identified by systematic *** trials included AIS patients within 4.5hours time ***-analysis indicated that 1089(53.0%)of 2056 patients in the TNK arm and 1016(50.5%)of 2012 in the alteplase arm had excellent functional outcome at 90 days(0.03(95%CI-0.00 to 0.06);I^(2)=0%),meeting the prespecified non-inferiority *** TNK thrombolysis was not correlated with increased risk of symptomatic intracerebral haemorrhage(0.00(95%CI-0.01 to 0.01);I^(2)=0%)or death(0.01(95%CI-0.01 to 0.02);I^(2)=0%)at 90 *** sensitivity analysis with the 0.25mg/kg trials exclusively showed similar results to the main *** TNK was non-inferior to alteplase for achieving excellent functional outcome at 90 days without increasing the safety concern in treating patients with *** findings suggest that TNK can be an alternative to alteplase.

关键词： analysis random phase

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Beta-alanine promotes angiogenesis in laser-induced choroidal neovascularization mice models

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International Journal of Ophthalmology(English edition) 2024年第9期17卷 1592-1598页

作者： Jia-Li Wu Min Zhang Xiao-Dong Sun department of Ophthalmology Shanghai General Hospital(Shanghai First People’s Hospital)Shanghai Jiao Tong UniversitySchool of MedicineShanghai 200080China National clinical Research Center for Ophthalmic diseases Shanghai 200080China National clinical Research Center for Eye diseases Shanghai 200080China Shanghai Key Laboratory of Fundus diseases Shanghai 200080China Shanghai Engineering Center for Visual Science and Photomedicine Shanghai 200080China

AIM:To investigate the effect ofβ-alanine(BA)on laserinduced choroidal neovascularization(CNV)mice ***:Laser-induced CNV mice models were established,and BA was administrated for one week and two weeks in advance,***,retinal pigment epithelium(RPE)-choroid flat mounts were separated,and immunohistochemical staining was *** laser-induced CNV lesion areas were measured and *** addition,liver and kidney morphologies were observed to identify potential hepatorenal ***:Enlarged CNV lesion areas were observed in the BA treated *** significant differences were observed in the liver and kidney sections between ***:BA treatment increase CNV lesion areas,suggesting the detrimental effects of BA as a nutritional supplement in age-related macular degeneration(AMD)population.

关键词： age-related macular degeneration choroidal neovascularization β-alanine angiogenesis

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FUT8-mediated aberrant N-glycosylation of SEMA7A promotes head and neck squamous cell carcinoma progression

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International Journal of Oral Science 2024年第2期16卷 333-348页

作者： Zhonglong Liu Xiaoyan Meng Yuxin Zhang Jingjing Sun Xiao Tang Zhiyuan Zhang Liu Liu Yue He department of Oral Maxillofacial&Head and Neck Oncology Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineNational Clinical Research Center for Oral DiseaseShanghaiChina department of Oral Surgery Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineCollege of StomatologyShanghai Jiao Tong UniversityNational Center for StomatologyNational Clinical Research Center for Oral DiseasesShanghaiChina department of Oral Pathology Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineNational Clinical Research Center for Oral Disease ShanghaiShanghaiChina

SEMA7A belongs to the Semaphorin family and is involved in the oncogenesis and tumor *** glycosylation has been intricately linked with immune escape and tumor ***7A is a highly glycosylated protein with five glycosylated *** underlying mechanisms of SEMA7A glycosylation and its contribution to immunosuppression and tumorigenesis are ***,we identify overexpression and aberrant N-glycosylation of SEMA7A in head and neck squamous cell carcinoma,and elucidate fucosyltransferase FUT8 catalyzes aberrant core fucosylation in SEMA7A at N-linked oligosaccharides(Asn 105,157,258,330,and 602)via a direct protein‒protein interaction.A glycosylated statue of SEMA7A is necessary for its intra-cellular trafficking from the cytoplasm to the *** EGF triggers SEMA7A N-glycosylation through increasing the binding affinity of SEMA7A toward FUT8,whereas TGF-β1 promotes abnormal glycosylation of SEMA7A via induction of epithelial–mesenchymal *** N-glycosylation of SEMA7A leads to the differentiation of CD8^(+)T cells along a trajectory toward an exhausted state,thus shaping an immunosuppressive microenvironment and being resistant immunogenic cell *** of SEMA7A significantly improves the clinical outcome of EGFR-targeted and anti-PD-L1-based ***,we also define RBM4,a splice regulator,as a downstream effector of glycosylated SEMA7A and a pivotal mediator of PD-L1 alternative *** findings suggest that targeting FUT8-SEMA7A axis might be a promising strategy for improving antitumor responses in head and neck squamous cell carcinoma patients.

关键词： aberrant squamous SEMA

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Id2 epigenetically controls CD8^(+)T-cell exhaustion by disrupting the assembly of the Tcf3-LSD1 complex

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Cellular & Molecular Immunology 2024年第3期21卷 292-308页

作者： Yiming Li Mingwei Han Haolin Wei Wan Huang Zhinan Chen Tianjiao Zhang Meirui Qian Lin Jing Gang Nan Xiuxuan Sun Shuhui Dai Kun Wang Jianli Jiang Ping Zhu Liang Chen department of Cell Biology of National Translational Science Center for Molecular medicine and department of clinical Immunology of Xijing Hospital Fourth Military Medical UniversityXi’anShaanxi 710032China State Key Laboratory of New Targets Discovery and Drug Development for Major diseases GanzhouJiangxi341000Xi’anShaanxi 710032China School of medicine Shanghai UniversityShanghai 200444China

CD8^(+)T-cell exhaustion is a state of dysfunction that promotes tumor progression and is marked by the generation of Slamf6^(+)progenitor exhausted(Tex^(prog))and Tim-^(3+)terminally exhausted(Tex^(term))*** of DNA binding protein 2(Id2)has been shown to play important roles in T-cell development and CD8^(+)T-cell ***,the role of Id2 in CD8^(+)T-cell exhaustion is ***,we found that Id2 transcriptionally and epigenetically regulates the generation of Texprog cells and their conversion to Texterm *** deletion of Id2 dampens CD8^(+)T-cell-mediated immune responses and the maintenance of stem-like CD8^(+)T-cell subpopulations,suppresses PD-1 blockade and increases tumor ***,through its HLH domain,Id2 binds and disrupts the assembly of the Tcf3-Tal1 transcriptional regulatory complex,and thus modulates chromatin accessibility at the Slamf6 promoter by preventing the interaction of Tcf3 with the histone lysine demethylase ***,Id2 increases the abundance of the permissive H3K4me2 mark on the Tcf3-occupied E-boxes in the Slamf6 promoter,modulates chromatin accessibility at the Slamf6 promoter and epigenetically regulates the generation of Slamf6+Texprog *** LSD1 inhibitor GSK2879552 can rescue the Id2 knockout phenotype in tumor-bearing *** of LSD1 increases the abundance of Slamf6^(+)Tim-3^(−)Tex^(prog) cells in tumors and the expression level of Tcf1 in Id2-deleted CD8+T *** study demonstrates that Id2-mediated transcriptional and epigenetic modification drives hierarchical CD8^(+)T-cell exhaustion,and the mechanistic insights gained may have implications for therapeutic intervention with tumor immune evasion.

关键词： Id2 T-cell exhaustion Epigenetic modification Immune evasion

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SOX11 as a potential prognostic biomarker in hepatocellular carcinoma linked to immune infiltration and ferroptosis

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Chinese Journal of Cancer Research 2024年第4期36卷 378-397页

作者： Hongyu Chen Qiangguo Ao Yueling Wang Yue Qian Qingli Cheng Wei Zhang department of Nephrology the Second Medical Center of PLA General HospitalNational Clinical Research Center for Geriatric DiseasesBeijing 100853China clinical Laboratory the First Affiliated Hospital of Henan UniversityKaifeng 475000China Cell Biology department Wuxi School of MedicineJiangnan UniversityWuxi 214122China department of Pathogen Biology Guizhou Nursing Vocational CollegeGuiyang 550000China

Objective:SOX11 is expressed in numerous malignancies,including hepatocellular carcinomas(HCC),but its oncogenic function has not been ***,we performed a comprehensive bioinformatics analysis of the Liver Hepatocellular Carcinoma(LIHC)dataset to investigate the function of SOX11 in ***:SOX11 expression data from The Cancer Genome Atlas(TCGA)and Gene Expression Omnibus(GEO)were validated by immunohistochemistry(IHC).Co-expression,differential expression,and functional analyses utilized TCGA-LIHC,Timer 2.0,Metascape,GTEx,and LinkedOmics *** with immune infiltration,ferroptosis,and immune checkpoint genes were *** changes were explored via *** regression,receiver operating characteristic curve(ROC),Kaplan-Meier analysis,and nomogram modeling evaluated associations with HCC clinicopathological ***11’s impact on proliferation and migration was studied in HepG2 and HuH7 cell ***:SOX11 was significantly elevated in HCC tumors compared to ***11-associated genes exhibited differential expression in pathways involving extracellular membrane ion *** associations were found between SOX11 levels,immune infiltration,ferroptosis,and immune checkpoint genes in HCC ***11 levels correlated with HCC stage,histologic grade,and tumor status,and independently predicted overall and disease-specific ***11 expression effectively distinguished between tumor and normal liver *** correlations highlighted a significant relationship between SOX11 and ferroptosis-associated *** SOX11 levels in HepG2 and HuH7 cells resulted in reduced proliferation and ***:SOX11 was found to represent a promising biomarker within HCC diagnosis and prognosis together with being a possible drug-target.

关键词： SOX11 biomarker HCC prognosis genetic alterations tumor-immune infiltration ferroptosis

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