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Fantastic voyage: The journey of NLRP3 inflammasome activation

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Genes & Diseases 2024年第2期11卷 819-829页

作者： Xiangyong Que Sihao Zheng Qibin Song Huadong Pei Pingfeng Zhang cancer Center Renmin Hospital of Wuhan UniversityWuhanHubei 430060China department of Oncology Georgetown Lombardi Comprehensive Cancer CenterGeorgetown University Medical CenterWashingtonDC 20057USA

NLRP3 inflammasome,an intracellular multiprotein complex,can be activated by a range of pathogenic microbes or endogenous hazardous chemicals.Its activation results in the release of cytokines such as IL-1β and IL-18,as well as Gasdermin D which eventually causes pyroptosis.The activation of NLRP3 inflammasome is under strict control and regulation by numerous pathways and mechanisms.Its excessive activation can lead to a persistent inflammatory response,which is linked to the onset and progression of severe illnesses.Recent studies have revealed that the subcellular localization of NLRP3 changes significantly during the activation process.In this review,we review the current understanding of the molecular mechanism of NLRP3 inflammasome activation,focusing on the subcellular localization of NLRP3 and the associated regulatory mechanisms.We aim to provide a comprehensive understanding of the dynamic transportation,activation,and degradation processes of NLRP3.

关键词： Inflammasome activation Innate immunity NLRP3 NLRP3 inflammasome Subcellular localization

Prioritization of risk genes in colorectal cancer by integrative analysis of multi-omics data and gene networks

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Science China(Life Sciences) 2024年第1期67卷 132-148页

作者： Ming Zhang Xiaoyang Wang Nan Yang Xu Zhu Zequn Lu Yimin Cai Bin Li Ying Zhu Xiangpan Li Yongchang Wei Shaokai Zhang Jianbo Tian Xiaoping Miao department of Epidemiology and Biostatistics School of Public HealthDepartment of Gastrointestinal OncologyZhongnan Hospital of Wuhan UniversityDepartment of Radiation OncologyRenmin Hospital of Wuhan UniversityTaiKang Center for Life and Medical SciencesWuhan UniversityWuhan 430071China Research Center of Public Health Renmin hospital of Wuhan UniversityWuhan UniversityWuhan 430060China department of cancer Epidemiology The Affiliated Cancer Hospital of Zhengzhou University&Henan Cancer HospitalHenan Engineering Research Center of Cancer Prevention and ControlHenan International Joint Laboratory of Cancer PreventionZhengzhou 450008China department of Gastrointestinal Surgery Renmin Hospital of Wuhan UniversityWuhan 430060China department of Radiation Oncology Renmin Hospital of Wuhan UniversityWuhan 430060China department of Gastrointestinal Oncology Hubei Cancer Clinical Study CenterZhongnan Hospital of Wuhan UniversityWuhan 430062China department of Epidemiology and Biostatistics School of Public HealthTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430073China Jiangsu Collaborative Innovation Center for cancer Personalized Medicine Nanjing Medical UniversityNanjing 211166China

Genome-wide association studies(GWASs)have identified over 140 colorectal cancer(CRC)-associated loci;however,target genes at the majority of loci and underlying molecular mechanisms are poorly understood.Here,we utilized a Bayesian approach,integrative risk gene selector(iRIGS),to prioritize risk genes at CRC GWAS loci by integrating multi-omics data.As a result,a total of 105 high-confidence risk genes(HRGs)were identified,which exhibited strong gene dependencies for CRC and enrichment in the biological processes implicated in CRC.Among the 105 HRGs,CEBPB,located at the 20q13.13 locus,acted as a transcription factor playing critical roles in cancer.Our subsequent assays indicated the tumor promoter function of CEBPB that facilitated CRC cell proliferation by regulating multiple oncogenic pathways such as MAPK,PI3K-Akt,and Ras signaling.Next,by integrating a fine-mapping analysis and three independent case-control studies in Chinese populations consisting of 8,039 cases and 12,775 controls,we elucidated that rs1810503,a putative functional variant regulating CEBPB,was associated with CRC risk(OR=0.90,95%CI=0.86–0.93,P=1.07×10^(−7)).The association between rs1810503 and CRC risk was further validated in three additional multi-ancestry populations consisting of 24,254 cases and 58,741 controls.Mechanistically,the rs1810503 A to T allele change weakened the enhancer activity in an allele-specific manner to decrease CEBPB expression via longrange promoter-enhancer interactions,mediated by the transcription factor,REST,and thus decreased CRC risk.In summary,our study provides a genetic resource and a generalizable strategy for CRC etiology investigation,and highlights the biological implications of CEBPB in CRC tumorigenesis,shedding new light on the etiology of CRC.

关键词： susceptibility genes gene screening models multi-omics GWAS CEBPB long-range promoter-enhancer interactions

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Comprehensive genomic analysis of early and late-onset hepatocellular carcinoma

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Genes & Diseases 2024年第4期11卷 77-81页

作者： Jialin Yang Chao Chen Song Wang Yaru Zhang Jiaohui Pang Yajun Wang Qiuxiang Ou Hao Jiang Juying Liu department of Radiation Oncology Sichuan Cancer Hospital&InstituteSichuan Cancer CenterSchool of MedicineUniversity of Electronic Science and Technology of ChinaChengduSichuan 610041China Jinling Hospital Department of OncologyNanjing Medical UniversityNanjingJiangsu 210002China Geneseeq Research Institute Nanjing Geneseeq Technology Inc.NanjingJiangsu 210000China department of Oncology Haian Hospital of Traditional Chinese MedicineHaianJiangsu 226600China Interventional Therapy department Jiangsu Cancer Hospital&Jiangsu Institute of Cancer Research&The Affiliated Cancer Hospital of Nanjing Medical UniversityNanjingJiangsu 210009China

Hepatocellular carcinoma(HCC)is the major histologic type of primary liver cancer,accounting for approximately 75%of liver cancer cases.'Despite many advancements in its treatment,the prognosis and drug response of HCC patients are dismal.Therefore,there is an unmet clinical need to explore genomic aberrations underlying early-and lateonset HcC,which might facilitate drug discovery and provide personalized biomarker-driven treatment options for these patients.

关键词： patients prognosis cancer

Preoperative prognostic nutritional index predicts long-term outcomes of patients with ampullary adenocarcinoma after curative pancreatoduodenectomy

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World Journal of Gastrointestinal Surgery 2024年第5期16卷 1291-1300页

作者： Chong-Yuan Sun Xiao-Jie Zhang Zheng Li He Fei Ze-Feng Li Dong-Bing Zhao department of Pancreatic and Gastric Surgical Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China

BACKGROUND The prognostic nutritional index(PNI),a marker of immune-nutrition balance,has predictive value for the survival and prognosis of patients with various cancers.AIM To explore the clinical significance of the preoperative PNI on the prognosis of ampullary adenocarcinoma(AC)patients who underwent curative pancreaticoduodenectomy.METHODS The data concerning 233 patients diagnosed with ACs were extracted and analyzed at our institution from January 1998 to December 2020.All patients were categorized into low and high PNI groups based on the cutoff value determined by receiver operating characteristic curve analysis.We compared disease-free survival(DFS)and overall survival(OS)between these groups and assessed prognostic factors through univariate and multivariate analyses.RESULTS The optimal cutoff value for the PNI was established at 45.3.Patients with a PNI≥45.3 were categorized into the PNI-high group,while those with a PNI<45.3 were assigned to the PNI-low group.Patients within the PNI-low group tended to be of advanced age and exhibited higher levels of aspartate transaminase and total bilirubin and a lower creatinine level than were those in the PNI-high group.The 5-year OS rates for patients with a PNI≥45.3 and a PNI<45.3 were 61.8%and 43.4%,respectively,while the 5-year DFS rates were 53.5%and 38.3%,respectively.Patients in the PNI-low group had shorter OS(P=0.006)and DFS(P=0.012).In addition,multivariate analysis revealed that the PNI,pathological T stage and pathological N stage were found to be independent prognostic factors for both OS and DFS.CONCLUSION The PNI is a straightforward and valuable marker for predicting long-term survival after pancreatoduodenectomy.The PNI should be incorporated into the standard assessment of patients with AC.

关键词： Ampullary carcinoma Prognostic nutritional index Prognosis Pancreaticoduodenectomy

DNA-delivered monoclonal antibodies targeting the p53 R175H mutant epitope inhibit tumor development in mice

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Genes & Diseases 2024年第4期11卷 368-380页

作者： Dafei Chai Xu Wang Praveen Neeli Shan Zhou Xingfang Yu Kanaga Sabapathy Yong Li department of Medicine Section of Epidemiology and Population SciencesDan L Duncan Comprehensive Cancer CenterBaylor College of MedicineHoustonTX 77030USA Division of Cellular&Molecular Research Humphrey Oei Institute of Cancer ResearchNational Cancer Centre SingaporeSingapore 168583Singapore

tThe tumor suppressor p53 is the most common mutated gene in cancer,with the R175H as the most frequent p53 missense mutant.However,there are currently no approved targeted therapies or immunotherapies against mutant p53.Here,we characterized and inves-tigated a monoclonal antibody(mAb)that recognizes the mutant p53-R175H for its affinity,specificity,and activity against tumor cells in vitro.We then delivered DNA plasmids expres-sing the anti-R175H mAb or a bispecific antibody(BsAb)into mice to evaluate their therapeutic effects.Our results showed that the anti-R175H mAb specifically bound to the p53-R175H an-tigen with a high affinity and recognized the human mutant p53-R175H antigen expressed on HEK293T or MC38 cells,with no cross-reactivity with wild-type p53.In cultured cells,the anti-R175H mAb showed higher cytotoxicity than the control but did not induce antibody-dependent cellular cytotoxicity.We made a recombinant MC38 mouse cell line(MC38-p53-R175H)that overexpressed the human p53-R175H after knocking out the endogenous mutant p53 alleles.In vivo,administration of the anti-R175H mAb plasmid elicited a robust anti-tumor effect against MC38-p53-R175H in mice.The administration of the anti-R175H BsAb plasmid showed no therapeutic effects,yet potent anti-tumor activity was observed in combination with the anti-PD-1 antibody.These results indicate that targeting specific mutant epitopes using DNA-delivered mAbs or BsAbs presents a form of improved natural immunity derived from tumor-infiltrating B cells and plasma cells against intracellular tumor antigens.

关键词： BsAb Cytotoxicity mAb Mutant p53 PD-1 R175H

miR-30a-5p/PHTF2 axis regulates the tumorigenesis and metastasis of lung adenocarcinoma

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BIOCELL 2024年第4期48卷 581-590页

作者： LIJUAN ZHANG QINGYIN MENG LI ZHUANG QUAN GONG XIANDA HUANG XUEQIN LI SHIJUAN LI GUOQIN WANG XICAI WANG department of Rehabilitation and Palliative Medicine The Third Affiliated Hospital of Kunming Medical UniversityYunnan Cancer HospitalKunmingChina department of Pathology The Third Affiliated Hospital of Kunming Medical UniversityYunnan Cancer HospitalKunmingChina Emergency department(Outpatient Chemotherapy Center) The Third Affiliated Hospital of Kunming Medical UniversityYunnan Cancer HospitalKunmingChina department of cancer BioTreatment Center The Third Affiliated Hospital of Kunming Medical UniversityYunnan Cancer HospitalKunmingChina department of cancer Institute The Third Affiliated Hospital of Kunming Medical UniversityYunnan Cancer HospitalKunmingChina

Background:Lung adenocarcinoma is a very pervasive histological form of lung cancers,and inhibiting metastasis is crucial for effective treatment.In this investigation,we explored the functional interaction of miR-30a-5p and the putative transcription factor 2 of the homeodomain(PHTF2)in dictating the aggressiveness and metastasis of lung adenocarcinoma.Method:We collected clinical samples to evaluate the expression patterns of miR-30a-5p and PHTF2 in lung adenocarcinoma along with normal tissues.Cellular experiments including cell count kit(CCK)-8 growth assay,apoptosis analysis,migration and invasion examinations were performed to assess the aggressiveness of lung adenocarcinoma cells.Furthermore,we examined tumorigenesis and metastasis in a nude mouse model.Results:MiR-30a-5p exhibited downregulation pattern in lung adenocarcinoma samples.Transfection of miR-30a-5p mimic in lung adenocarcinoma cells resulted in the suppression of malignant characteristics.Notably,the administration of miR-30a-5p mimic also curbed tumorigenesis and metastasis of lung adenocarcinoma cells in animal model.Moreover,PHTF2 was found to be a molecular target of miR-30a-5p.Upregulating PHTF2 counteracted the tumor-suppressive effect of the miR-30a-5p mimic.Conclusion:miR-30a-5p functions as a tumor-suppressive molecule while PHTF2 acts as an oncogenic factor in the development and metastasis of lung adenocarcinoma.Therefore,targeting miR-30a-5p and PHTF2 could be developed into a promising therapeutic approach for inhibiting metastasis in lung adenocarcinoma.

关键词： Lung cancer Malignant phenotype Tumor formation Tumor suppressor Oncogene

Curcumin Interferes with TGF-β1-Induced Fibrosis in NRK-49F Cells by Reversing ADAMTS18 Gene Methylation

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Chinese Journal of Integrative Medicine 2024年第7期30卷 600-607页

作者： XU Ben ZHANG Jia-en YE Lin YUAN Chang-wei department of Urology Peking University First Hospital and Institute of Urology Peking UniversityNational Urological Cancer Center

Objective: To explore the molecular mechanism by which curcumin affects renal interstitial fibrosis（RIF） progression by regulating ADAM metallopeptidase with thrombospondin type 1 motif 18（ADAMTS18） methylation. Methods: NRK-49F cells RIF model were induced with transforming growth factor β1（TGF-β1）. Effects of different concentrations of curcumin（0, 10, 20, and 30 μmol/L） on cell proliferation, cell cycle, cell apoptosis as well as cyclin D1 expression were analyzed by cell counting kit-8, flow cytometry and Western blot, respectively. ADAMTS18 methylation levels were determined by methylation-specific polymerase chain reaction. ADAMTS18, fibronectin（FN）, type Ⅰ collagen（Col-Ⅰ） and alpha-smooth muscle actin（α-SMA） mRNA and protein expressions were analyzed by real-time PCR（RT-PCR） and Western blot, respectively. Meanwhile, cells were treated with 50 mmol/L 5-aza-2'-deoxycytidine（5-aza-dC, demethylation agent） for 72 h. Effect of curcumin on extracellular matrix（ECM） deposition was evaluated by immunochemical staining and Western blot. NRK-49F cells were transfected with ADAMTS18 small interfering RNA and grouped into a normal control, ADAMTS18-knock-out（KO）, and ADAMTS18-KO+ 30 μmol/L curcumin groups, and whether curcumin can reverse the effect of ADAMTS18 knockdown on RIF was evaluated. Results: Compared with the control group, TGF-β1 significantly inhibited the proliferation of NRK-49F cells, blocked the G1/G0phase, promoted cell apoptosis and inhibited cyclin D1 expression（P<0.01）. Among the different concentrations of curcumin, 30 μmol/L curcumin significantly reversed these processes（P<0.01）. Immunochemical staining and Western blot results showed that curcumin significantly inhibited the deposition of FN, Col-Ⅰ and α-SMA（P<0.01）. Curcumin and 5-zaz-dC had synergistic effects, promoting ADAMTS18 expression, removing ADAMTS18 methylation, and reducing ECM deposition. ADAMTS18 knockdown promoted ECM accumulation, and curcumin reversed this process（P<0.01）. Conclusion: TGF-β1 induced fibrosis in NRK-49F cells.

关键词： renal fibrosis curcumin Chinese medicine ADAMTS18 methylation modification

A test of the species confidence hypothesis in dusky damselfish

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Current Zoology 2024年第1期70卷 79-86页

作者： Elle Overs Sydney Stump Isabel Severino Daniel T.Blumstein department of Ecology and Evolutionary biology University of CaliforniaLos AngelesCA 90095-1606USA

Visual cues are important in both interspecific and intraspecific communication.The species confidence hypothesis proposes that animals are more attracted to conspecific colors and repelled by colors,not on their bodies.Studies on terrestrial lizards and birds have tested the species confidence hypothesis and shown that conspecific colors elicit reduced antipredator behavior.To date,the species confidence hypothesis has not been tested in the marine environment,specifically on coral reefs where color communication is of vital importance.We addressed this knowledge gap by measuring flight initiation distance(the distance an individual moves away from an approaching threat)in dusky damselfish(Stegastes nigricans)in response to an approaching disc of 1 of 4 different color treatments:conspecific,blue,yellow,and black.If the species confidence hypothesis explained variation in damselfish flight initiation distance,then we expected individuals to tolerate closer approaches when approached by a conspecific color.In addition,we calculated the color difference between each stimulus and its corresponding back-ground as a potential alternative explanation for flight responses.Damselfish tolerated the closest approach from the conspecific color stimulus;there were no significant differences between other colors and there was no support for the alternative color difference hypothesis.As with similar terrestrial studies,these results are relevant to ecotourists'choice of swimsuit and wetsuit colors because color choice may modify naturalantipredatorbehavior.

关键词： antipredator behavior flight initiation distance risk assessment species confidence hypothesis Stegastes nigricans

Could mammalian inorganic polyphosphate be a crucial signaling molecule in neurological disorders?

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Neural Regeneration Research 2024年第4期19卷 701-702页

作者： Renata Torres Da Costa Maria E.Solesio Rutgers University Department of BiologyCamdenNJUSA

Since the early stages of life on earth,cellular metabolism has evolved to adapt to fluctuations in nutrient and oxygen availability.In this context,mammals,which are probably the organisms that show one of the highest levels of metabolic complexity,have developed an elegant system that uses constant and rechargeable energy sources of modulate their metabolism.This homeostasis is especially important in the central nervous system,as neurons and other cells in the brain are highly susceptible to fluctuations in nutrients and oxygen availability.

关键词： metabolism homeostasis neurological

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