This editorial summarizes the latest literature on the roles of neuronal PAS domain protein 2 and KN motif/ankyrin repeat domain 1 in type 2 diabetes(T2D).We highlight their involvement inβ-cell dysfunction,explore t...This editorial summarizes the latest literature on the roles of neuronal PAS domain protein 2 and KN motif/ankyrin repeat domain 1 in type 2 diabetes(T2D).We highlight their involvement inβ-cell dysfunction,explore their potential as therapeutic targets,and discuss the implications for new treatment strategies.We offer valuable insights into relevant gene regulation and cellular mechanisms relevant for the targeted management of T2D.展开更多
Leucine-rich repeat kinase 1 （LRRK1） plays a critical role in regulating cytoskeletal organization, osteoclast activity, and bone resorption with little effect on bone formation parameters. Deficiency of Lrrkl in mi...Leucine-rich repeat kinase 1 （LRRK1） plays a critical role in regulating cytoskeletal organization, osteoclast activity, and bone resorption with little effect on bone formation parameters. Deficiency of Lrrkl in mice causes a severe osteopetrosis in the metaphysis of the long bones and vertebrae bones, which makes LRRK1 an attractive alternative drug target for the treatment of osteoporosis and other high-turnover bone diseases. This review recent advances on the functions of the Lrrkl-related family members, Lrrkl deficiency-induced skeletal phenotypes, LRRK1 structure-function, potential biological substrates and interacting proteins, and the mechanisms of LRRK1 action in osteoclasts.展开更多
Leucine-rich repeats and immunoglobulin-like domains 1 （LRIG1） is an anti-oncogene. LRIG1 is correlated with Bcl-2 in ependymomas. Decreased Bcl-2 and manganese superoxide dismutase expression can improve the chemos...Leucine-rich repeats and immunoglobulin-like domains 1 （LRIG1） is an anti-oncogene. LRIG1 is correlated with Bcl-2 in ependymomas. Decreased Bcl-2 and manganese superoxide dismutase expression can improve the chemosensitivity of glioma. In the present study, a tissue microarray of human brain astrocytomas was constructed. To investigate the relationship of LRIG1 with Bcl-2 and manganese superoxide dismutase, LRIG1, Bcl-2 and manganese superoxide dismutase expression in our tissue microarray was determined using immunohistochemistry. In addition, we constructed the LRIG1-U251 cell line, and its responses to doxorubicin and temozolomide were detected using the MTT assay. Results showed that LRIG1 expression was significantly negatively correlated with Bcl-2 and manganese superoxide dismutase expression in glioma. Also, proliferation of LRIG1-U251 cells exposed to doxorubicin or temozolomide was significantly inhibited, i.e. in the LRIG1-U251 cell line, the chemosensitivity to doxorubicin and temozolomide was increased. This indicates that increased LRIG1 expression produces a chemosensitivity in glioma.展开更多
Interferon-induced protein with tetratricopeptide repeats 1(IFIT1), also known as interferon-induced protein 56(IFI56) or Interferon-stimulated protein 56(ISG56), was originally identified as a protein induced upon tr...Interferon-induced protein with tetratricopeptide repeats 1(IFIT1), also known as interferon-induced protein 56(IFI56) or Interferon-stimulated protein 56(ISG56), was originally identified as a protein induced upon treatment with interferon and inhibited by viral replication and translational initiation. In this study, Epinephelus lanceolatus IFIT1(ELIFIT1) gene was cloned for the first time. The complete cDNA of El IFIT1 gene includes 2921 nucleotides, and encodes a 437-amino acid(AA) protein. The putative ELIFIT1 protein has 9 TRP domains and is highly similar with IFIT1 proteins in other teleosts. In healthy fish, ELIFIT1 gene was highly expressed in the blood, which indicate its specific function in the peripheral immune system. Its expression was also observed in various immunity-related tissues including spleen, intestine, and kidney, Inducted with spotted knifejaw iridovirus(SKIV), ELIFIT1 gene expression was upregulated in the spleen, kidney, and liver 24 h after induction and reached its peak at 72 h, indicating that ELIFIT1 may play an important role in antivirus. These findings contribute to the understanding of the antiviral regulation of ELIFIT1 gene in teleost.展开更多
Objective:To know whether the effect of interferon-induced protein with tetratricopeptide repeats(IFIT)1 polymorphism influences the susceptibility of cerebral malaria outcome.Methods:Case-control association study wa...Objective:To know whether the effect of interferon-induced protein with tetratricopeptide repeats(IFIT)1 polymorphism influences the susceptibility of cerebral malaria outcome.Methods:Case-control association study was performed among 314 Thai patients(110 with cerebral malaria and 204 with uncomplicated malaria)infected with Plasmodium falciparum.Genotyping for five tag-single nucleotide polymorphisms of IFIT1 was performed by endpoint genotyping.Results:Genotype frequencies of all tag-SNPs(single nucleotide polymorphisms)showed no association with malaria outcome.However,C allele of rs11203109 was associated with the protection from cerebral malaria(OR=0.62,95%CI=0.38-0.99,P=0.048).Two single nucleotide polymorphisms(rs5786868 and rs57941432)were in linkage disequilibrium with rs11203109.Conclusions:This suggests that our associated single nucleotide polymorphism(rs11203109)might be a genetic marker of cerebral malaria progression in the Thai population.展开更多
Objective： To study the expression level of TRF1 （telomeric repeat binding factor 1） protein in human acute leukemia and relationship between expression level of TRF1 protein and telomerase, Methods： A quantitativ...Objective： To study the expression level of TRF1 （telomeric repeat binding factor 1） protein in human acute leukemia and relationship between expression level of TRF1 protein and telomerase, Methods： A quantitative Western±Blot technique was developed using anti±TRF1^33±277 monoclonal antibody and GST±TRFI purity protein as a standard to further determine the expression level of TRF1 protein in total proteins extracted from clinical specimens. Results： Bone marrow tissues of 20 acute leukemia patients were studied, 11 healthy donors＇ bone marrows were taken as a control. The expression level of TRF1 protein was significantly higher （P〈0.01） in normal bone marrow （（2.2174±0.462） μg/μl） than that of acute leukemia patients （（0.7544±0.343） μg/μl）, But there was no remarkable difference between ALL and ANLL patients （（0.6184±0.285） μg/μl vs （0.8454±0.359） μg/μl, P〉0.05）. After chemotherapy, TRFI expression level of patients with complete remission elevated （（0.7724±0.307）/μg/μl vs （1.6834±0,344）μg/μl, P〈0.01 ）, but lower than that of normal （（2.2174±0.462）/μg/μl, P〈0.01）. There was no significantly difference after chemotherapy （（0.7264±0.411） μg/μl vs （0.895±0.339） μg/μl,p〉0.05）. TRF1 expression level of patients with complete remission is higher than that of patients without complete remission （（1,683±0.344）μg/μl vs （0.895±0.339）μg/μl P〈0.01）. All samples were determined for telomerase activity. It was confirmed that the activity of telomerase in normal bone marrow was lower than that of acute leukemia patients （（0.125±0.078） μg/μl vs （0.765±0.284）μg/μl, P〈0.01）. There was no significant difference of expression level ofTRF I protein between ALL and ANLL patients （（0.897±0.290） μg/μl vs （0.677±0.268） μg/μl, P〉0.05）. After chemotherapy, telomerase activity of patients with complete remission decreased （（0.393±0.125） μg/μl）, but was still higher than that of normal （（0.125±0.078） μg/μl, P〈0.01）. Conclusion： The expression level of TRF1 protein has correlativity to the activity of telomerase （P〈0.001）.展开更多
The current study investigated correlations between the expression of leucine-rich repeats and immunoglobulin-like domain 1 （LRIG1） and antioxidant enzymes and related proteins, including manganese superoxide dismut...The current study investigated correlations between the expression of leucine-rich repeats and immunoglobulin-like domain 1 （LRIG1） and antioxidant enzymes and related proteins, including manganese superoxide dismutase, glutamate cysteine ligase catalytic or regulatory subunit, thioredoxin and thioredoxin reductase, in both human ependymoma and oligodendroglioma. Results revealed that the cytoplasmic expression of LRIG1 was associated with expression of glutamate cysteine ligase catalytic subunit in the human ependymoma, while the nuclear expression of LRIG1 was associated with expression of thioredoxin reductase. In human oligodendroglioma, the cytoplasmic expression of LRIG1 was associated with expression of the glutamate cysteine ligase catalytic subunit. Both the nuclear and perinuclear expressions of LRIG1 were associated with expression of glutamate cysteine ligase regulatory subunit. These results indicated that several antioxidant enzymes and related proteins contributed to LRIG1 expression, and that these may participate in the antioxidation of the cells.展开更多
Hepatocyte nuclear factor 1 alpha(HNF1A),hepatocyte nuclear factor 4 alpha(HNF4A),and forkhead box protein A2(FOXA2)are key transcription factors that regulate a complex gene network in the liver,cre-ating a regulator...Hepatocyte nuclear factor 1 alpha(HNF1A),hepatocyte nuclear factor 4 alpha(HNF4A),and forkhead box protein A2(FOXA2)are key transcription factors that regulate a complex gene network in the liver,cre-ating a regulatory transcriptional loop.The Encode and ChIP-Atlas databases identify the recognition sites of these transcription factors in many glycosyltransferase genes.Our in silico analysis of HNF1A,HNF4A.and FOXA2 binding to the ten candidate glyco-genes studied in this work confirms a significant enrich-ment of these transcription factors specifically in the liver.Our previous studies identified HNF1A as a master regulator of fucosylation,glycan branching,and galactosylation of plasma glycoproteins.Here,we aimed to functionally validate the role of the three transcription factors on downstream glyco-gene transcriptional expression and the possible effect on glycan phenotype.We used the state-of-the-art clus-tered regularly interspaced short palindromic repeats/dead Cas9(CRISPR/dCas9)molecular tool for the downregulation of the HNF1A,HNF4A,and FOXA2 genes in HepG2 cells-a human liver cancer cell line.The results show that the downregulation of all three genes individually and in pairs affects the transcrip-tional activity of many glyco-genes,although downregulation of glyco-genes was not always followed by an unambiguous change in the corresponding glycan structures.The effect is better seen as an overall change in the total HepG2 N-glycome,primarily due to the extension of biantennary glycans.We propose an alternative way to evaluate the N-glycome composition via estimating the overall complexity of the glycome by quantifying the number of monomers in each glycan structure.We also propose a model showing feedback loops with the mutual activation of HNF1A-FOXA2 and HNF4A-FOXA2 affecting glyco-genes and protein glycosylation in HepG2 cells.展开更多
The nucleotide-binding domain,leucine-rich repeat,and pyrin domain-containing protein 3(NLRP3)inflammasome is a critical modulator in inflammatory disease.Activation and mutation of NLRP3 can cause severe inflammation...The nucleotide-binding domain,leucine-rich repeat,and pyrin domain-containing protein 3(NLRP3)inflammasome is a critical modulator in inflammatory disease.Activation and mutation of NLRP3 can cause severe inflammation in diseases such as chronic infantile neurologic cutaneous and articular syndrome,Muckle-Wells syndrome,and familial cold autoinflammatory syndrome 1.To date,a great effort has been made to decode the underlying mechanisms of NLRP3 activation.The priming and activation of NLRP3 drive the maturation and release of active interleukin(IL)-18 and IL-1βto cause inflammation and pyroptosis,which can significantly trigger many diseases including inflammatory diseases,immune disorders,metabolic diseases,and neurodegenerative diseases.The investigation of NLRP3 as a therapeutic target for disease treatment is a hot topic in both preclinical studies and clinical trials.Developing potent NLRP3 inhibitors and downstream IL-1 inhibitors attracts wide-spectrum attention in both research and pharmaceutical fields.In this minireview,we first updated the molecular mechanisms involved in NLRP3 inflammasome activation and the associated downstream signaling pathways.We then reviewed the molecular and cellular pathways of NLRP3 in many diseases,including obesity,diabetes,and other metabolic diseases.In addition,we briefly reviewed the roles of NLRP3 in cancer growth and relative immune checkpoint therapy.Finally,clinical trials with treatments targeting NLRP3 and its downstream signaling pathways were summarized.展开更多
目的:探讨严重烧伤急性应激期干扰素诱导含TPR基序的蛋白1(interferon-induced protein with tetratricopetide repeats 1,IFIT1)表达与肝细胞凋亡的关系。方法:健康C57/129小鼠25只,随机分成5组,每组5只:正常对照(0 h)组、烧伤后1,6,12...目的:探讨严重烧伤急性应激期干扰素诱导含TPR基序的蛋白1(interferon-induced protein with tetratricopetide repeats 1,IFIT1)表达与肝细胞凋亡的关系。方法:健康C57/129小鼠25只,随机分成5组,每组5只:正常对照(0 h)组、烧伤后1,6,12和24 h组。制作烧伤组大鼠20%总体表面积(total body surface area,TBSA)III度烧伤模型。取肝组织,Western印迹观察IFIT1表达;免疫组织化学检测caspase-3和caspase-8表达;脱氧核糖核苷酸末端转移酶介导的缺口末端标记法(terminal deoxynucleotidyl transferase mediated nick end labeling,TUNEL)检测肝细胞凋亡。结果:IFIT1烧伤后1 h开始增高,6 h最高,12 h开始降低,24 h降至最低,组间比较差异有统计学意义(P<0.01);caspase-3和caspase-8烧伤后随时间逐渐增高,组间比较差异有统计学意义(P<0.01);TUNEL法显示烧伤后肝细胞凋亡1 h与0 h比较差异无统计学意义(P>0.05),6 h至24 h呈逐渐增高,组间比较差异有统计学意义(P<0.01)。结论:严重烧伤后IFIT1表达增高可促使肝细胞凋亡的增强。展开更多
文摘This editorial summarizes the latest literature on the roles of neuronal PAS domain protein 2 and KN motif/ankyrin repeat domain 1 in type 2 diabetes(T2D).We highlight their involvement inβ-cell dysfunction,explore their potential as therapeutic targets,and discuss the implications for new treatment strategies.We offer valuable insights into relevant gene regulation and cellular mechanisms relevant for the targeted management of T2D.
基金supported by National Institutes of Health grant AR066831-01ASBMR GAP grant to Weirong R Xingsupported by a senior research career scientist award from the Department of Veteran’s Affairs
文摘Leucine-rich repeat kinase 1 （LRRK1） plays a critical role in regulating cytoskeletal organization, osteoclast activity, and bone resorption with little effect on bone formation parameters. Deficiency of Lrrkl in mice causes a severe osteopetrosis in the metaphysis of the long bones and vertebrae bones, which makes LRRK1 an attractive alternative drug target for the treatment of osteoporosis and other high-turnover bone diseases. This review recent advances on the functions of the Lrrkl-related family members, Lrrkl deficiency-induced skeletal phenotypes, LRRK1 structure-function, potential biological substrates and interacting proteins, and the mechanisms of LRRK1 action in osteoclasts.
基金the National Natural Science Foundation of China, No. 30973072Independent Research Project of Wuhan University for Graduate Students, No. 201130202020001Fundamental Research Funds for the Central Universities
文摘Leucine-rich repeats and immunoglobulin-like domains 1 （LRIG1） is an anti-oncogene. LRIG1 is correlated with Bcl-2 in ependymomas. Decreased Bcl-2 and manganese superoxide dismutase expression can improve the chemosensitivity of glioma. In the present study, a tissue microarray of human brain astrocytomas was constructed. To investigate the relationship of LRIG1 with Bcl-2 and manganese superoxide dismutase, LRIG1, Bcl-2 and manganese superoxide dismutase expression in our tissue microarray was determined using immunohistochemistry. In addition, we constructed the LRIG1-U251 cell line, and its responses to doxorubicin and temozolomide were detected using the MTT assay. Results showed that LRIG1 expression was significantly negatively correlated with Bcl-2 and manganese superoxide dismutase expression in glioma. Also, proliferation of LRIG1-U251 cells exposed to doxorubicin or temozolomide was significantly inhibited, i.e. in the LRIG1-U251 cell line, the chemosensitivity to doxorubicin and temozolomide was increased. This indicates that increased LRIG1 expression produces a chemosensitivity in glioma.
基金supported by the Shandong Breeding Project (No. 2016LZGC009)the Projects from Laboratory for Marine Fisheries Science and Food Production Processes+2 种基金Pilot National Laboratory for Marine Science and Technology (Qingdao)(Nos. 2018-MFS-T08, 2017A STCP-OS15)the Central Public-interest Scientific Institution Basal Research Fund,CAFS (No. 2020TD20)the Central Public-Interest Scientific Institution Basal Re-search Fund,YSFRI,CAFS (No. 20603022018026)。
文摘Interferon-induced protein with tetratricopeptide repeats 1(IFIT1), also known as interferon-induced protein 56(IFI56) or Interferon-stimulated protein 56(ISG56), was originally identified as a protein induced upon treatment with interferon and inhibited by viral replication and translational initiation. In this study, Epinephelus lanceolatus IFIT1(ELIFIT1) gene was cloned for the first time. The complete cDNA of El IFIT1 gene includes 2921 nucleotides, and encodes a 437-amino acid(AA) protein. The putative ELIFIT1 protein has 9 TRP domains and is highly similar with IFIT1 proteins in other teleosts. In healthy fish, ELIFIT1 gene was highly expressed in the blood, which indicate its specific function in the peripheral immune system. Its expression was also observed in various immunity-related tissues including spleen, intestine, and kidney, Inducted with spotted knifejaw iridovirus(SKIV), ELIFIT1 gene expression was upregulated in the spleen, kidney, and liver 24 h after induction and reached its peak at 72 h, indicating that ELIFIT1 may play an important role in antivirus. These findings contribute to the understanding of the antiviral regulation of ELIFIT1 gene in teleost.
基金financially supported by the Thailand Research Fund(TRF)Office of the Higher Education Commission,the Faculty of Medical Technology to PN(MRG5480062)
文摘Objective:To know whether the effect of interferon-induced protein with tetratricopeptide repeats(IFIT)1 polymorphism influences the susceptibility of cerebral malaria outcome.Methods:Case-control association study was performed among 314 Thai patients(110 with cerebral malaria and 204 with uncomplicated malaria)infected with Plasmodium falciparum.Genotyping for five tag-single nucleotide polymorphisms of IFIT1 was performed by endpoint genotyping.Results:Genotype frequencies of all tag-SNPs(single nucleotide polymorphisms)showed no association with malaria outcome.However,C allele of rs11203109 was associated with the protection from cerebral malaria(OR=0.62,95%CI=0.38-0.99,P=0.048).Two single nucleotide polymorphisms(rs5786868 and rs57941432)were in linkage disequilibrium with rs11203109.Conclusions:This suggests that our associated single nucleotide polymorphism(rs11203109)might be a genetic marker of cerebral malaria progression in the Thai population.
文摘Objective： To study the expression level of TRF1 （telomeric repeat binding factor 1） protein in human acute leukemia and relationship between expression level of TRF1 protein and telomerase, Methods： A quantitative Western±Blot technique was developed using anti±TRF1^33±277 monoclonal antibody and GST±TRFI purity protein as a standard to further determine the expression level of TRF1 protein in total proteins extracted from clinical specimens. Results： Bone marrow tissues of 20 acute leukemia patients were studied, 11 healthy donors＇ bone marrows were taken as a control. The expression level of TRF1 protein was significantly higher （P〈0.01） in normal bone marrow （（2.2174±0.462） μg/μl） than that of acute leukemia patients （（0.7544±0.343） μg/μl）, But there was no remarkable difference between ALL and ANLL patients （（0.6184±0.285） μg/μl vs （0.8454±0.359） μg/μl, P〉0.05）. After chemotherapy, TRFI expression level of patients with complete remission elevated （（0.7724±0.307）/μg/μl vs （1.6834±0,344）μg/μl, P〈0.01 ）, but lower than that of normal （（2.2174±0.462）/μg/μl, P〈0.01）. There was no significantly difference after chemotherapy （（0.7264±0.411） μg/μl vs （0.895±0.339） μg/μl,p〉0.05）. TRF1 expression level of patients with complete remission is higher than that of patients without complete remission （（1,683±0.344）μg/μl vs （0.895±0.339）μg/μl P〈0.01）. All samples were determined for telomerase activity. It was confirmed that the activity of telomerase in normal bone marrow was lower than that of acute leukemia patients （（0.125±0.078） μg/μl vs （0.765±0.284）μg/μl, P〈0.01）. There was no significant difference of expression level ofTRF I protein between ALL and ANLL patients （（0.897±0.290） μg/μl vs （0.677±0.268） μg/μl, P〉0.05）. After chemotherapy, telomerase activity of patients with complete remission decreased （（0.393±0.125） μg/μl）, but was still higher than that of normal （（0.125±0.078） μg/μl, P〈0.01）. Conclusion： The expression level of TRF1 protein has correlativity to the activity of telomerase （P〈0.001）.
基金the Swedish Institute, No. 00287/2006210the North Sweden Cancer Foundation, Specialized Research Fund for the Doctoral Program New Teacher of Higher Education by the Chinese Ministry of Education, No. 200804861039the National Natural Science Foundation of China, No. 30973073, 30973072
文摘The current study investigated correlations between the expression of leucine-rich repeats and immunoglobulin-like domain 1 （LRIG1） and antioxidant enzymes and related proteins, including manganese superoxide dismutase, glutamate cysteine ligase catalytic or regulatory subunit, thioredoxin and thioredoxin reductase, in both human ependymoma and oligodendroglioma. Results revealed that the cytoplasmic expression of LRIG1 was associated with expression of glutamate cysteine ligase catalytic subunit in the human ependymoma, while the nuclear expression of LRIG1 was associated with expression of thioredoxin reductase. In human oligodendroglioma, the cytoplasmic expression of LRIG1 was associated with expression of the glutamate cysteine ligase catalytic subunit. Both the nuclear and perinuclear expressions of LRIG1 were associated with expression of glutamate cysteine ligase regulatory subunit. These results indicated that several antioxidant enzymes and related proteins contributed to LRIG1 expression, and that these may participate in the antioxidation of the cells.
基金the European Structural and Investment Funded Grant"Cardio Metabolic"(#KK.01.2.1.02.0321)the Croatian National Centre of Research Excellence in Personalized Healthcare Grant(#KK.01.1.1.01.0010)+2 种基金the European Regional Development Fund Grant,project"CRISPR/Cas9-CasMouse"(#KK.01.1.1.04.0085)the European Structural and Investment Funded Project of Centre of Competence in Molecular Diagnostics(#KK.01.2.2.03.0006)the Croatian National Centre of Research Excellence in Personalized Healthcare Grant(#KK.01.1.1.01.0010).
文摘Hepatocyte nuclear factor 1 alpha(HNF1A),hepatocyte nuclear factor 4 alpha(HNF4A),and forkhead box protein A2(FOXA2)are key transcription factors that regulate a complex gene network in the liver,cre-ating a regulatory transcriptional loop.The Encode and ChIP-Atlas databases identify the recognition sites of these transcription factors in many glycosyltransferase genes.Our in silico analysis of HNF1A,HNF4A.and FOXA2 binding to the ten candidate glyco-genes studied in this work confirms a significant enrich-ment of these transcription factors specifically in the liver.Our previous studies identified HNF1A as a master regulator of fucosylation,glycan branching,and galactosylation of plasma glycoproteins.Here,we aimed to functionally validate the role of the three transcription factors on downstream glyco-gene transcriptional expression and the possible effect on glycan phenotype.We used the state-of-the-art clus-tered regularly interspaced short palindromic repeats/dead Cas9(CRISPR/dCas9)molecular tool for the downregulation of the HNF1A,HNF4A,and FOXA2 genes in HepG2 cells-a human liver cancer cell line.The results show that the downregulation of all three genes individually and in pairs affects the transcrip-tional activity of many glyco-genes,although downregulation of glyco-genes was not always followed by an unambiguous change in the corresponding glycan structures.The effect is better seen as an overall change in the total HepG2 N-glycome,primarily due to the extension of biantennary glycans.We propose an alternative way to evaluate the N-glycome composition via estimating the overall complexity of the glycome by quantifying the number of monomers in each glycan structure.We also propose a model showing feedback loops with the mutual activation of HNF1A-FOXA2 and HNF4A-FOXA2 affecting glyco-genes and protein glycosylation in HepG2 cells.
文摘The nucleotide-binding domain,leucine-rich repeat,and pyrin domain-containing protein 3(NLRP3)inflammasome is a critical modulator in inflammatory disease.Activation and mutation of NLRP3 can cause severe inflammation in diseases such as chronic infantile neurologic cutaneous and articular syndrome,Muckle-Wells syndrome,and familial cold autoinflammatory syndrome 1.To date,a great effort has been made to decode the underlying mechanisms of NLRP3 activation.The priming and activation of NLRP3 drive the maturation and release of active interleukin(IL)-18 and IL-1βto cause inflammation and pyroptosis,which can significantly trigger many diseases including inflammatory diseases,immune disorders,metabolic diseases,and neurodegenerative diseases.The investigation of NLRP3 as a therapeutic target for disease treatment is a hot topic in both preclinical studies and clinical trials.Developing potent NLRP3 inhibitors and downstream IL-1 inhibitors attracts wide-spectrum attention in both research and pharmaceutical fields.In this minireview,we first updated the molecular mechanisms involved in NLRP3 inflammasome activation and the associated downstream signaling pathways.We then reviewed the molecular and cellular pathways of NLRP3 in many diseases,including obesity,diabetes,and other metabolic diseases.In addition,we briefly reviewed the roles of NLRP3 in cancer growth and relative immune checkpoint therapy.Finally,clinical trials with treatments targeting NLRP3 and its downstream signaling pathways were summarized.
文摘目的:探讨严重烧伤急性应激期干扰素诱导含TPR基序的蛋白1(interferon-induced protein with tetratricopetide repeats 1,IFIT1)表达与肝细胞凋亡的关系。方法:健康C57/129小鼠25只,随机分成5组,每组5只:正常对照(0 h)组、烧伤后1,6,12和24 h组。制作烧伤组大鼠20%总体表面积(total body surface area,TBSA)III度烧伤模型。取肝组织,Western印迹观察IFIT1表达;免疫组织化学检测caspase-3和caspase-8表达;脱氧核糖核苷酸末端转移酶介导的缺口末端标记法(terminal deoxynucleotidyl transferase mediated nick end labeling,TUNEL)检测肝细胞凋亡。结果:IFIT1烧伤后1 h开始增高,6 h最高,12 h开始降低,24 h降至最低,组间比较差异有统计学意义(P<0.01);caspase-3和caspase-8烧伤后随时间逐渐增高,组间比较差异有统计学意义(P<0.01);TUNEL法显示烧伤后肝细胞凋亡1 h与0 h比较差异无统计学意义(P>0.05),6 h至24 h呈逐渐增高,组间比较差异有统计学意义(P<0.01)。结论:严重烧伤后IFIT1表达增高可促使肝细胞凋亡的增强。
