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
Activation of nuclear factor erythroid 2-related factor 2(Nrf2)by Kelch-like ECH-associated protein 1(Keap1)alkylation plays a central role in anti-inflammatory therapy.However,activators of Nrf2 through alkylation of...Activation of nuclear factor erythroid 2-related factor 2(Nrf2)by Kelch-like ECH-associated protein 1(Keap1)alkylation plays a central role in anti-inflammatory therapy.However,activators of Nrf2 through alkylation of Keap1-Kelch domain have not been identified.Deoxynyboquinone(DNQ)is a natural small molecule discovered from marine actinomycetes.The current study was designed to investigate the anti-inflammatory effects and molecular mechanisms of DNQ via alkylation of Keap1.DNQ exhibited significant anti-inflammatory properties both in vitro and in vivo.The pharmacophore responsible for the anti-inflammatory properties of DNQ was determined to be theα,β-unsaturated amides moieties by a chemical reaction between DNQ and N-acetylcysteine.DNQ exerted anti-inflammatory effects through activation of Nrf2/ARE pathway.Keap1 was demonstrated to be the direct target of DNQ and bound with DNQ through conjugate addition reaction involving alkylation.The specific alkylation site of DNQ on Keap1 for Nrf2 activation was elucidated with a synthesized probe in conjunction with liquid chromatography-tandem mass spectrometry.DNQ triggered the ubiquitination and subsequent degradation of Keap1 by alkylation of the cysteine residue 489(Cys489)on Keap1-Kelch domain,ultimately enabling the activation of Nrf2.Our findings revealed that DNQ exhibited potent anti-inflammatory capacity throughα,β-unsaturated amides moieties active group which specifically activated Nrf2 signal pathway via alkylation/ubiquitination of Keap1-Kelch domain,suggesting the potential values of targeting Cys489 on Keap1-Kelch domain by DNQ-like small molecules in inflammatory therapies.展开更多
Objective In this study,the role and potential mechanism of transformer 2β(Tra2β)in cervical cancer were explored.Methods The transcriptional data of Tra2βin patients with cervical cancer from Gene Expression Profi...Objective In this study,the role and potential mechanism of transformer 2β(Tra2β)in cervical cancer were explored.Methods The transcriptional data of Tra2βin patients with cervical cancer from Gene Expression Profiling Interactive Analysis(GEPIA)and cBioPortal databases were investigated.The functions of Tra2βwere evaluated by using Western blot,MTT,colony formation,Transwell assays,and nude mouse tumor formation experiments.Target genes regulated by Tra2βwere studied by RNA-seq.Subsequently,representative genes were selected for RT-qPCR,confocal immunofluorescence,Western blot,and rescue experiments to verify their regulatory relationship.Results The dysregulation of Tra2βin cervical cancer samples was observed.Tra2βoverexpression in Siha and Hela cells enhanced cell viability and proliferation,whereas Tra2βknockdown showed the opposite effect.Alteration of Tra2βexpression did not affect cell migration and invasion.Furthermore,tumor xenograft models verified that Tra2βpromoted cervical cancer growth.Mechanically,Tra2βpositively regulated the mRNA and protein level of SP1,which was critical for the proliferative capability of Tra2β.Conclusion This study demonstrated the important role of the Tra2β/SP1 axis in the progression of cervical cancer in vitro and in vivo,which provides a comprehensive understanding of the pathogenesis of cervical cancer.展开更多
BACKGROUND 3,6-dichlorobenzo[b]thiophene-2-carboxylic acid(BT2)is a benzothiophene carboxylate derivative that can suppress the catabolism of branched-chain amino acid(BCAA)-associated mammalian target of rapamycin co...BACKGROUND 3,6-dichlorobenzo[b]thiophene-2-carboxylic acid(BT2)is a benzothiophene carboxylate derivative that can suppress the catabolism of branched-chain amino acid(BCAA)-associated mammalian target of rapamycin complex 1(mTORC1)activation.Previous studies have demonstrated the therapeutic effects of BT2 on arthritis,liver cancer,and kidney injury.However,the effects of BT2 on ulcerative colitis(UC)are unknown.AIM To investigate the anti-UC effects of BT2 and the underlying mechanism.METHODS Mouse UC models were created through the administration of 3.5%dextran sodium sulfate(DSS)for 7 d.The mice in the treated groups were administered salazosulfapyridine(300 mg/kg)or BT2(20 mg/kg)orally from day 1 to day 7.At the end of the study,all of the mice were sacrificed,and colon tissues were removed for hematoxylin and eosin staining,immunoblot analyses,and immunohistochemical assays.Cytokine levels were measured by flow cytometry.The contents of BCAAs including valine,leucine,and isoleucine,in mouse serum were detected by liquid chromatography-tandem mass spectrometry,and the abundance of intestinal flora was analyzed by 16S ribosomal DNA sequencing.RESULTS Our results revealed that BT2 significantly ameliorated the inflammatory symptoms and pathological damage induced by DSS in mice.BT2 also reduced the production of the proinflammatory cytokines interleukin 6(IL-6),IL-9,and IL-2 and increased the anti-inflammatory cytokine IL-10 level.In addition,BT2 notably improved BCAA catabolism and suppressed mTORC1 activation and cyclooxygenase-2 expression in the colon tissues of UC mice.Furthermore,highthroughput sequencing revealed that BT2 restored the gut microbial abundance and diversity in mice with colitis.Compared with the DSS group,BT2 treatment increased the ratio of Firmicutes to Bacteroidetes and decreased the abundance of Enterobacteriaceae and Escherichia-Shigella.CONCLUSION Our results indicated that BT2 significantly ameliorated DSS-induced UC and that the latent mechanism involved the suppression of BCAA-associated mTORC1 activation and modulation of the intestinal flora.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the Science and Technology Development Fund,Macao SAR(Grant Nos.:No.0159/2020/A3,No.0058/2020/AMJ,No.0096/2019/A2 and SKL-QRCM(UM)-2023-2025)the Research Committee of the University of Macao(Grant No.:MYRG2022-00189-ICMS)+2 种基金the Guangdong Provincial Special Fund for Marine Economic Development Project(Project No.:GDNRC[2021]48)National Natural Science Foundation of China(Grant No.:82260801)K.C.Wong Education Foundation(Grant No.:GJTD-2020-12).
文摘Activation of nuclear factor erythroid 2-related factor 2(Nrf2)by Kelch-like ECH-associated protein 1(Keap1)alkylation plays a central role in anti-inflammatory therapy.However,activators of Nrf2 through alkylation of Keap1-Kelch domain have not been identified.Deoxynyboquinone(DNQ)is a natural small molecule discovered from marine actinomycetes.The current study was designed to investigate the anti-inflammatory effects and molecular mechanisms of DNQ via alkylation of Keap1.DNQ exhibited significant anti-inflammatory properties both in vitro and in vivo.The pharmacophore responsible for the anti-inflammatory properties of DNQ was determined to be theα,β-unsaturated amides moieties by a chemical reaction between DNQ and N-acetylcysteine.DNQ exerted anti-inflammatory effects through activation of Nrf2/ARE pathway.Keap1 was demonstrated to be the direct target of DNQ and bound with DNQ through conjugate addition reaction involving alkylation.The specific alkylation site of DNQ on Keap1 for Nrf2 activation was elucidated with a synthesized probe in conjunction with liquid chromatography-tandem mass spectrometry.DNQ triggered the ubiquitination and subsequent degradation of Keap1 by alkylation of the cysteine residue 489(Cys489)on Keap1-Kelch domain,ultimately enabling the activation of Nrf2.Our findings revealed that DNQ exhibited potent anti-inflammatory capacity throughα,β-unsaturated amides moieties active group which specifically activated Nrf2 signal pathway via alkylation/ubiquitination of Keap1-Kelch domain,suggesting the potential values of targeting Cys489 on Keap1-Kelch domain by DNQ-like small molecules in inflammatory therapies.
基金supported by grants from Foshan Science and Technology Innovation Project(Medical Science and Technology Innovation Platform Construction Project)Guangdong,China[grant number FS0AA-KJ218-1301-0037]Medical Science and Technology Research Fund project of Guangdong Province,Guangdong,China[grant number A2021111].
文摘Objective In this study,the role and potential mechanism of transformer 2β(Tra2β)in cervical cancer were explored.Methods The transcriptional data of Tra2βin patients with cervical cancer from Gene Expression Profiling Interactive Analysis(GEPIA)and cBioPortal databases were investigated.The functions of Tra2βwere evaluated by using Western blot,MTT,colony formation,Transwell assays,and nude mouse tumor formation experiments.Target genes regulated by Tra2βwere studied by RNA-seq.Subsequently,representative genes were selected for RT-qPCR,confocal immunofluorescence,Western blot,and rescue experiments to verify their regulatory relationship.Results The dysregulation of Tra2βin cervical cancer samples was observed.Tra2βoverexpression in Siha and Hela cells enhanced cell viability and proliferation,whereas Tra2βknockdown showed the opposite effect.Alteration of Tra2βexpression did not affect cell migration and invasion.Furthermore,tumor xenograft models verified that Tra2βpromoted cervical cancer growth.Mechanically,Tra2βpositively regulated the mRNA and protein level of SP1,which was critical for the proliferative capability of Tra2β.Conclusion This study demonstrated the important role of the Tra2β/SP1 axis in the progression of cervical cancer in vitro and in vivo,which provides a comprehensive understanding of the pathogenesis of cervical cancer.
基金Supported by National Natural Science Foundation of ChinaNo. 82074241+1 种基金Project of Jiangsu Province Hospital of Traditional Chinese Medicine Peak TalentNo. y2021rc36
文摘BACKGROUND 3,6-dichlorobenzo[b]thiophene-2-carboxylic acid(BT2)is a benzothiophene carboxylate derivative that can suppress the catabolism of branched-chain amino acid(BCAA)-associated mammalian target of rapamycin complex 1(mTORC1)activation.Previous studies have demonstrated the therapeutic effects of BT2 on arthritis,liver cancer,and kidney injury.However,the effects of BT2 on ulcerative colitis(UC)are unknown.AIM To investigate the anti-UC effects of BT2 and the underlying mechanism.METHODS Mouse UC models were created through the administration of 3.5%dextran sodium sulfate(DSS)for 7 d.The mice in the treated groups were administered salazosulfapyridine(300 mg/kg)or BT2(20 mg/kg)orally from day 1 to day 7.At the end of the study,all of the mice were sacrificed,and colon tissues were removed for hematoxylin and eosin staining,immunoblot analyses,and immunohistochemical assays.Cytokine levels were measured by flow cytometry.The contents of BCAAs including valine,leucine,and isoleucine,in mouse serum were detected by liquid chromatography-tandem mass spectrometry,and the abundance of intestinal flora was analyzed by 16S ribosomal DNA sequencing.RESULTS Our results revealed that BT2 significantly ameliorated the inflammatory symptoms and pathological damage induced by DSS in mice.BT2 also reduced the production of the proinflammatory cytokines interleukin 6(IL-6),IL-9,and IL-2 and increased the anti-inflammatory cytokine IL-10 level.In addition,BT2 notably improved BCAA catabolism and suppressed mTORC1 activation and cyclooxygenase-2 expression in the colon tissues of UC mice.Furthermore,highthroughput sequencing revealed that BT2 restored the gut microbial abundance and diversity in mice with colitis.Compared with the DSS group,BT2 treatment increased the ratio of Firmicutes to Bacteroidetes and decreased the abundance of Enterobacteriaceae and Escherichia-Shigella.CONCLUSION Our results indicated that BT2 significantly ameliorated DSS-induced UC and that the latent mechanism involved the suppression of BCAA-associated mTORC1 activation and modulation of the intestinal flora.
