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The role of inflammasomes in human diseases and their potential as therapeutic targets

Signal Transduction and Targeted Therapy 2024年第2期9卷 479-508页

作者： jing Yao Keenan Sterling Zhe Wang yun Zhang Weihong Song The National Clinical Research Center for Geriatric Disease Xuanwu HospitalCapital Medical UniversityBeijing 100053China Townsend Family Laboratories Department of PsychiatryBrain Research CenterThe University of British Columbia2255 Wesbrook MallVancouverBC V6T 1Z3Canada Key Laboratory of Neurodegenerative Diseases Ministry of EducationBeijingP.R.China Zhejiang Clinical Research Center for Mental Disorders Key Laboratory of Alzheimer’s Disease of Zhejiang ProvinceSchool of Mental Health and The Affiliated Kangning HospitalInstitute of AgingWenzhou Medical UniversityWenzhouZhejiang 325000China Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine Vision and Brain Health)WenzhouZhejiang 325000China

Inflammasomes are large protein complexes that play a major role in sensing inflammatory signals and triggering the innate immune response.Each inflammasome complex has three major components:an upstream sensor molecule that is connected to a downstream effector protein such as caspase-1 through the adapter protein ASC.Inflammasome formation typically occurs in response to infectious agents or cellular damage.The active inflammasome then triggers caspase-1 activation,followed by the secretion of pro-inflammatory cytokines and pyroptotic cell death.Aberrant inflammasome activation and activity contribute to the development of diabetes,cancer,and several cardiovascular and neurodegenerative disorders.As a result,recent research has increasingly focused on investigating the mechanisms that regulate inflammasome assembly and activation,as well as the potential of targeting inflammasomes to treat various diseases.Multiple clinical trials are currently underway to evaluate the therapeutic potential of several distinct inflammasome-targeting therapies.Therefore,understanding how different inflammasomes contribute to disease pathology may have significant implications for developing novel therapeutic strategies.In this article,we provide a summary of the biological and pathological roles of inflammasomes in health and disease.We also highlight key evidence that suggests targeting inflammasomes could be a novel strategy for developing new disease-modifying therapies that may be effective in several conditions.

关键词： inflam therapeutic potential

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Assessment of the triglyceride glucose index in adult patients with chronic diarrhea and constipation

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World Journal of Clinical Cases 2024年第6期12卷 1094-1103页

作者： jing-Yi Zhu Mu-yun Liu Chang Sun Department of Gastroenterology The First Affiliated Hospital of Naval Medical UniversityShanghai 200433China Department of Gastroenterology Navy No.905 HospitalNaval Medical UniversityShanghai 200433China

BACKGROUND Accumulating evidence suggests that the gut microbiome is involved in the pathogenesis of insulin resistance(IR).However,the link between two of the most prevalent bowel disorders,chronic diarrhea and constipation,and the triglyceride glucose(TyG)index,a marker of IR,has not yet been investigated.AIM To investigate the potential association between TyG and the incidence of chronic diarrhea and constipation.METHODS This cross-sectional study enrolled 2400 participants from the National Health and Nutrition Examination Survey database from 2009-2010.TyG was used as an exposure variable,with chronic diarrhea and constipation as determined by the Bristol Stool Form Scale used as the outcome variables.A demographic investigation based on TyG quartile subgroups was performed.The application of multivariate logistic regression models and weighted generalized additive models revealed potential correlations between TyG,chronic diarrhea,and constipation.Subgroup analyses were performed to examine the stability of any potential associations.RESULTS In the chosen sample,chronic diarrhea had a prevalence of 8.00%,while chronic constipation had a prevalence of 8.04%.In multiple logistic regression,a more prominent positive association was found between TyG and chronic diarrhea,particularly in model 1(OR=1.45;95%CI:1.17-1.79,P=0.0007)and model 2(OR=1.40;95%CI:1.12-1.76,P=0.0033).No definite association was observed between the TyG levels and chronic constipation.The weighted generalized additive model findings suggested a more substantial positive association with chronic diarrhea when TyG was less than 9.63(OR=1.89;95%CI:1.05-3.41,P=0.0344),and another positive association with chronic constipation when it was greater than 8.2(OR=1.74;95%CI:1.02-2.95,P=0.0415).The results of the subgroup analyses further strengthen the extrapolation of these results to a wide range of populations.CONCLUSION Higher TyG levels were positively associated with abnormal bowel health.

关键词： Triglyceride glucose index National Health and Nutrition Examination Survey Chronic diarrhea Chronic constipation Cross-sectional study Bowel health

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Individualized intensive insulin therapy of diabetes: Not only thegoal, but also the time

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World Journal of Diabetes 2024年第1期15卷 11-14页

作者： yun Hu Hong-jing Chen Jian-Hua Ma Department of Endocrinology The Affiliated Wuxi People's Hospital of Nanjing Medical UniversityWuxi People's HospitalWuxi Medical CenterNanjing Medical UniversityWuxi 214023Jiangsu ProvinceChina Department of Endocrinology Nanjing First HospitalNanjing 210000Jiangsu ProvinceChina

Intensive insulin therapy has been extensively used to control blood glucose levels because of its ability to reduce the risk of chronic complications of diabetes.According to current guidelines,intensive glycemic control requires individu-alized glucose goals rather than as low as possible.During intensive therapy,rapid blood glucose reduction can aggravate microvascular and macrovascular complications,and prolonged overuse of insulin can lead to treatment-induced neuropathy and retinopathy,hypoglycemia,obesity,lipodystrophy,and insulin antibody syndrome.Therefore,we need to develop individualized hypoglycemic plans for patients with diabetes,including the time required for blood glucose normalization and the duration of intensive insulin therapy,which deserves further study.

关键词： Diabetes Intensive therapy Insulin Treatment-induced neuropathy

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Upadacitinib for refractory ulcerative colitis with primary nonresponse to infliximab and vedolizumab:A case report

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World Journal of Clinical Cases 2024年第9期12卷 1685-1690页

作者： Xuan Xu jing-Wen Jiang Bing-yun Lu Xia-Xi Li Department of Gastroenterology Shenzhen HospitalSouthern Medical UniversityShenzhen 518100Guangdong ProvinceChina The First Clinical Medical School Southern Medical UniversityGuangzhou 510515Guangdong ProvinceChina

BACKGROUND Many patients with ulcerative colitis(UC)do not respond well to,or tolerate conventional and biological therapies.There is currently no consensus on the treatment of refractory UC.Studies have demonstrated that the selective Janus kinase 1 inhibitor upadacitinib,a small-molecule drug,is effective and safe for treating UC.However,no studies have revealed that upadacitinib is effective in treating refractory UC with primary nonresponse to infliximab and vedolizumab.CASE SUMMARY We report the case of a 44-year-old male patient with a chief complaint of bloody diarrhoea with mucus and pus,in addition to dizziness.The patient had recurrent disease after receiving mesalazine,prednisone,azathioprine,infliximab and vedolizumab over four years.Based on the endoscopic findings and pathological biopsy,the patient was diagnosed with refractory UC.In particular,the patient showed primary nonresponse to infliximab and vedolizumab.Based on the patient’s history and recurrent disease,we decided to administer upadacitinib.During hospitalisation,the patient was received upadacitinib under our guidance.Eight weeks after the initiation of upadacitinib treatment,the patient’s symptoms and endoscopic findings improved significantly.No notable adverse reactions have been reported to date.CONCLUSION Our case report suggests that upadacitinib may represent a valuable strategy for treating refractory UC with primary nonresponse.

关键词： Upadacitinib Refractory ulcerative colitis Primary nonresponse Infliximab Vedolizumab Case report

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Scutellarein Ameliorated Chondrocyte Inflammation and Osteoarthritis in Rats

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Current Medical Science 2024年第2期44卷 355-368页

作者： Shao-ze jing Shu-han YANG yun-kun QU Hai-hu HAO Hua WU Department of Orthopedics Third Hospital of Shanxi Medical UniversityShanxi Bethune HospitalShanxi Academy of Medical SciencesTongji Shanxi HospitalTaiyuan 030032China Department of Orthopedics Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China

Objective:Osteoarthritis(OA)is a degenerative joint disorder characterized by the gradual degradation of joint cartilage and local inflammation.This study aimed to investigate the anti-OA effect of scutellarein(SCU),a single-unit flavonoid compound obtained from Scutellaria barbata D.Don,in rats.Methods:The extracted rat chondrocytes were treated with SCU and IL-1β.The chondrocytes were divided into control group,IL-1βgroup,IL-1β+SCU 50µmol/L group,and IL-1β+SCU 100µmol/L group.Morphology of rat chondrocytes was observed by toluidine blue and safranin O staining.CCK-8 method was used to detect the cytotoxicity of SCU.ELISA,qRT-PCR,Western blotting,immunofluorescence,SAβ-gal staining,flow cytometry,and bioinformatics analysis were applied to evaluate the effect of SCU on rat chondrocytes under IL-1βintervention.Additionally,anterior cruciate ligament transection(ACL-T)was used to establish a rat OA model.Histological changes were detected by safranin O/fast green,hematoxylin-eosin(HE)staining,and immunohistochemistry.Results:SCU protected cartilage and exhibited anti-inflammatory effects via multiple mechanisms.Specifically,it could enhance the synthesis of extracellular matrix in cartilage cells and inhibit its degradation.In addition,SCU partially inhibited the nuclear factor kappa-B/mitogen-activated protein kinase(NF-κB/MAPK)pathway,thereby reducing inflammatory cytokine production in the joint cartilage.Furthermore,SCU significantly reduced IL-1β-induced apoptosis and senescence in rat chondrocytes,further highlighting its potential role in OA treatment.In vivo experiments revealed that SCU(at a dose of 50 mg/kg)administered for 2 months could significantly delay the progression of cartilage damage,which was reflected in a lower Osteoarthritis Research Society International(OARSI)score,and reduced expression of matrix metalloproteinase 13(MMP13)in cartilage.Conclusion:SCU is effective in the therapeutic management of OA and could serve as a potential candidate for future clinical drug therapy for OA.

关键词： scutellarein osteoarthritis apoptosis mitogen-activated protein kinase(MAPK) nuclear factor kappa-B(NF-κB)

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Understanding livelihood vulnerability:a perspective from Western Sichuan’s ethnic rural settings

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Journal of Mountain Science 2024年第2期21卷 380-396页

作者： YU Yongqian jing Zheng WANG Yan QIU Xiaoping YANG Xueting XU yun School of Geography and Resource Science Sichuan Normal UniversityChengdu 610101China Key Laboratory of land Resources Evaluation and Monitoring in Southwest Ministry of EducationSichuan Normal UniversityChengdu 610101China Sichuan County Economic Development Research Center Mianyang Normal UniversityMianyang 621000China Institute of Mountain Hazards and Environment Chinese Academy of SciencesChengdu 610041China

To explore the livelihood status and key influencing factors of rural households in the minority areas,we collected flat data from 284 rural households in 32 villages across 12 counties of Western Sichuan from 2021 to 2022.We conducted participatory household survey on the livelihood status of the rural households and try to identify the key factors to influence their livelihood vulnerability using multiple linear regression.The results showed that:the livelihood situation of the rural households is relatively vulnerable.The vulnerability varies significantly with the income levels,education levels,and income sources.The vulnerability of farm households,categorized from low to high livelihood types,follows the sequence:non-agricultural dominant households,non-agricultural households,agricultural dominant households,and pure agricultural households.The degree of damage to the natural environment,education costs,loan opportunities,the proportion of agricultural income to annual household income,and the presence of sick people in the household have significant positive effects on the livelihood vulnerability index(LVI)of rural households;while help from relatives and friends,net income per capita,household size,household education,agricultural land area,participation in industrial organizations,number of livestock,purchase of commercial houses,drinking water source,and self-supply of food have significant negative effects.Based on the findings,we believe that local rural households operate in a complex livelihood system and recommend continuous interventions targeting key influences to provide empirical research support for areas facing similar situations.

关键词： Livelihood Vulnerability Rural households Ethnic areas

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An inulin-type fructan CP-A from Codonopsis pilosula attenuates experimental colitis in mice by promoting autophagy-mediated inactivation of NLRP3 inflammasome

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Chinese Journal of Natural Medicines 2024年第3期22卷 249-264页

作者： ZHOU Jiangtao WANG Jun WANG Jiajing LI Deyun HOU jing LI Jiankuan BAI yun’e GAO Jianping School of Pharmaceutical Science Shanxi Medical UniversityJinzhong 030600China

Inulin-type fructan CP-A,a predominant polysaccharide in Codonopsis pilosula,demonstrates regulatory effects on immune activity and anti-inflammation.The efficacy of CP-A in treating ulcerative colitis(UC)is,however,not well-established.This study employed an in vitro lipopolysaccharide(LPS)-induced colonic epithelial cell model(NCM460)and an in vivo dextran sulfate sodium(DSS)-induced colitis mouse model to explore CP-A’s protective effects against experimental colitis and its underlying mechanisms.We monitored the clinical symptoms in mice using various parameters:body weight,disease activity index(DAI),colon length,spleen weight,and histopathological scores.Additionally,molecular markers were assessed through enzyme-linked immunosorbent assay(ELISA),quantitative real-time polymerase chain reaction(qRT-PCR),immunofluorescence(IF),immunohistochemistry(IHC),and Western blotting assays.Results showed that CP-A significantly reduced reactive oxygen species(ROS),tumor necrosis factor-alpha(TNF-α),and interleukins(IL-6,IL-1β,IL-18)in LPS-induced cells while increasing IL-4 and IL-10 levels and enhancing the expression of Claudin-1,ZO-1,and occludin proteins in NCM460 cells.Correspondingly,in vivo findings revealed that CPA administration markedly improved DAI,reduced colon shortening,and decreased the production of myeloperoxidase(MPO),malondialdehyde(MDA),ROS,IL-1β,IL-18,and NOD-like receptor protein 3(NLRP3)inflammasome-associated genes/proteins in UC mice.CP-A treatment also elevated glutathione(GSH)and superoxide dismutase(SOD)levels,stimulated autophagy(LC3B,P62,Beclin-1,and ATG5),and reinforced Claudin-1 and ZO-1 expression,thereby aiding in intestinal epithelial barrier repair in colitis mice.Notably,the inhibition of autophagy via chloroquine(CQ)diminished CP-A’s protective impact against colitis in vivo.These findings elucidate that CP-A’s therapeutic effect on experimental colitis possibly involves mitigating intestinal inflammation through autophagymediated NLRP3 inflammasome inactivation.Consequently,inul

关键词： Inulin-type fructan CP-A Codonopsis pilosula Ulcerative colitis NLRP3 inflammasome Autophagy

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Application of exosomal miRNA mediated macrophage polarization in colorectal cancer:Current progress and challenges

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Oncology Research 2024年第1期32卷 61-71页

作者： yun ZHANG SHALING TANG YUBO GAO ZHONGTING LU YUAN YANG jing CHEN TAO LI Department of Oncology School of Clinical MedicineNingxia Medical UniversityYinchuanChina General Hospital of Ningxia Medical University YinchuanChina School of Basic Medical Sciences Ningxia Medical UniversityYinchuanChina Department of Surgical Oncology Tumor HospitalThe General Hospital of Ningxia Medical UniversityYinchuanChina

Colorectal cancer(CRC)is a major global health problem with high morbidity and mortality rates.Surgical resection is the main treatment for early-stage CRC,but detecting it early is challenging.Therefore,effective therapeutic targets for advanced patients are still lacking.Exosomes,tiny vesicles in body fluids,play a crucial role in tumor metastasis,immune regulation,and drug resistance.Interestingly,they can even serve as a biomarker for cancer diagnosis and prognosis.Studies have shown that exosomes can carry miRNA,mediate the polarization of M1/M2 macrophages,promote the proliferation and metastasis of cancer cells,and affect the prognosis of CRC.Since the gastrointestinal tract has many macrophages,understanding the mechanism behind exosomal miRNA-mediated macrophage polarization in CRC treatment is crucial.This article summarizes recent advancements in the study of exosomal miRNAs in CRC and their potential as diagnostic and prognostic markers.

关键词： Colorectal cancer Exosomes microRNA Macrophages Treatment

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Prediction of chemical short-range order in high-/medium-entropy alloys

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Journal of Materials Science & Technology 2024年第2期169卷 115-123页

作者： Pei-Yu Cao jing Wang Ping Jiang yun-Jiang Wang Fu-Ping Yuan Xiao-Lei Wu State Key Laboratory of Nonlinear Mechanics Institute of MechanicsChinese Academy of ScienceBeijing 100190China School of Engineering Science University of Chinese Academy of SciencesBeijing 100049China

Chemical short-range orders(CSROs),as the built-in sub-nanoscale entities in a high-/medium-entropy alloy(H/MEA),have aroused an ever-increasing interest.With multi-principal elements in an H/MEA to form a complex concentrated solution,a variety of sub-systems of species exist to induce the metastable ordered compounds as candidates for ultimate CSROs.The issues remain pending on the origin of CSROs as to how to judge if CSRO will form in an H/MEA and particularly,what kind of CSROs would be stably produced if there were multiple possibilities.Here,the first-principles method,along with the proposed local formation energy calculation in allusion to the atomic-scale chemical heterogeneities,is used to predict the CSRO formation based on the mechanical stability,thermodynamic formation energy,and electronic characteristics.The simulations are detailed in an equiatomic ternary VCoNi MEA with three kinds of potential compounds,i.e.,L1_(1),L1_(2),and B2,in the face-centered cubic matrix.It turns out that L1_(1)is stable but hard to grow up so as to become the final CSRO.L1_(1)is further predicted as CSROs in CrCoNi,but unable to form in FeCoNi and CrMnFeCoNi alloys.These predictions are consistent with the experimental observations.Our findings shed light on understanding the formation of CSROs.This method is applicable to other H/MEAs to design and tailor CSROs by tuning chemical species/contents and thermal processing for high performance.

关键词： Short-range order High-entropy alloy Microstructure First-principles calculation Gibbs free energy Local electronic density of states

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Universal paradigm of ternary metacomposites with tunable epsilon-negative and epsilon-near-zero response for perfect electromagnetic shielding

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Rare Metals 2024年第2期43卷 796-809页

作者： yun-Peng Qu yun-Lei Zhou Yang Luo Yao Liu Jun-Fei Ding Yan-Li Chen Xiu Gong jing-Liang Yang Qiong Peng Xiao-Si Qi College of Physics Guizhou UniversityGuiyang550025China Hangzhou Institute of Technology Xidian UniversityHangzhou311231China Department of Materials ETH Zurich8093ZurichSwitzerland Key Laboratory for Liquid-Solid Structural Evolution and Processing of Materials(Ministry of Education) Shandong UniversityJinan250061China

CaCu_(3)Ti_(4)O_(12)(CCTO)ceramic nanocomposites incorporating graphene–carbon black(GRCB)fillers were fabricated by spark plasma sintering process.The percolative effects of conductive GRCB fillers on dielectric response of GRCB/CCTO ternary metacomposites were systematically investigated.The weakly real permittivity(ε′)-negative response(ε′~−1×10^(2))was achieved which originated from weakly low-frequency plasmonic state of free carriers within constructed GRCB networks.With enhancing three-dimensional GRCB network,the plasma frequency of metacomposites increased while the damping factor decreased.Herein,theε′-negative values of metacomposites were tuned from−10^(2) to−10^(4) orders of magnitude andε′-near-zero(ENZ)frequencies from~142 to~340 MHz which substantially benefited from the moderate carrier concentration of GRCB dual fillers.The Drude model and equivalent circuit models were adopted to demonstrate dielectric and electrical characteristics.The obtained metacomposites show strong EM shielding effect along with enhanced plasmonic oscillation and even better achieving perfect EM shielding effect in ENZ media.This work achieves the tunableε′-negative andε′-near-zero response and more importantly clarifies its regulation mechanism in ceramic-based ternary metacomposites,which opens up the possibility of designing high-performance EM shielding materials based on metacomposites.

关键词： Metacomposites Ceramic matrix composites Negative permittivity Epsilon-near-zero Electromagnetic shielding

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