Mental disorders such as depression and anxiety inflict significant burdens on individuals and society.Commonly prescribed treatments often involve cognitive therapy and medications.However,for patients resistant to t...Mental disorders such as depression and anxiety inflict significant burdens on individuals and society.Commonly prescribed treatments often involve cognitive therapy and medications.However,for patients resistant to these conventional methods,alternative therapies like the Ketogenic Diet(KD)offer a promising avenue.KD and its key metabolite,β-hydroxybutyrate(BHB),have been hypothesized to alleviate mental disorders through antiinflammatory actions,a crucial pathway in the pathophysiology of depression.This mini-review examines 15 clinical trials exploring the influence of KD and BHB on inflammation and their potential roles in managing mental disorders.Both human and animal studies were scrutinized to elucidate possible cellular and molecular mechanisms.Out of the 15 trials,10 reported reduced levels of at least one inflammatory mediator or mRNA post KD or BHB treatment,while two observed an elevation in anti-inflammatory agents.These findings suggest that KD and BHB could modulate cellular inflammatory pathways,highlighting their potential for therapeutic application in mental disorders.展开更多
Lysine methylation is an important post-translational modification that regulates gene transcription,epigenetics,and cell proliferation.Dysregulation of lysine methylation is often observed in cancer cells.Therefore,i...Lysine methylation is an important post-translational modification that regulates gene transcription,epigenetics,and cell proliferation.Dysregulation of lysine methylation is often observed in cancer cells.Therefore,it is important to understand how cells regulate lysine methylation by lysine methyltransferases and lysine demethylases.However,there are still some biologically essential lysine methylation sites without known demethylases,such as H4K20me3 and H3K79me3.Jumonji-C domaincontaining lysine demethylases(JmjC KDMs),as non-heme iron oxygenases,erase methyl marks by hydroxylation of methyl groups,followed by the release of formaldehyde.Current KDM research focuses on the identification of substrates from specific KDMs,but there is a lack of good methods to identify KDM from specific lysine methylation sites.Here,we report a novel strategy to develop activity-based probes that selectively crosslink JmjC-demethylases,which was validated by crosslinking of KDM4A/4D and KDM5B in this study.Allyllysine-containing peptides,as methyllysine substrate mimics,that were prepared by simple cysteine alkylation,are converted to epoxide by demethylase catalysis.The electrophilic intermediate subsequently crosslinks residues inside the KDM catalytic pocket.Therefore,such probes that selectively conjugate KDMs could be applied to identify KDMs from specific methyllysine sites and uncover new biology of lysine methylation.展开更多
基金Department of Science and Technology of Jilin Province,No.20210402019GH,Fundamental Research Funds of Jilin University,Seed Fund,No.2021ZZ021Jilin Province Education Science Planning Project,No.GH21006 and the Fundamental Research Funds for the Central Universities,No.2022CXTD03.
文摘Mental disorders such as depression and anxiety inflict significant burdens on individuals and society.Commonly prescribed treatments often involve cognitive therapy and medications.However,for patients resistant to these conventional methods,alternative therapies like the Ketogenic Diet(KD)offer a promising avenue.KD and its key metabolite,β-hydroxybutyrate(BHB),have been hypothesized to alleviate mental disorders through antiinflammatory actions,a crucial pathway in the pathophysiology of depression.This mini-review examines 15 clinical trials exploring the influence of KD and BHB on inflammation and their potential roles in managing mental disorders.Both human and animal studies were scrutinized to elucidate possible cellular and molecular mechanisms.Out of the 15 trials,10 reported reduced levels of at least one inflammatory mediator or mRNA post KD or BHB treatment,while two observed an elevation in anti-inflammatory agents.These findings suggest that KD and BHB could modulate cellular inflammatory pathways,highlighting their potential for therapeutic application in mental disorders.
基金supported by the National Natural Science Foundation of China(22422703)the Zhejiang Provincial Natural Science Foundation of China(XHD23B0701)the Westlake University Startup。
文摘Lysine methylation is an important post-translational modification that regulates gene transcription,epigenetics,and cell proliferation.Dysregulation of lysine methylation is often observed in cancer cells.Therefore,it is important to understand how cells regulate lysine methylation by lysine methyltransferases and lysine demethylases.However,there are still some biologically essential lysine methylation sites without known demethylases,such as H4K20me3 and H3K79me3.Jumonji-C domaincontaining lysine demethylases(JmjC KDMs),as non-heme iron oxygenases,erase methyl marks by hydroxylation of methyl groups,followed by the release of formaldehyde.Current KDM research focuses on the identification of substrates from specific KDMs,but there is a lack of good methods to identify KDM from specific lysine methylation sites.Here,we report a novel strategy to develop activity-based probes that selectively crosslink JmjC-demethylases,which was validated by crosslinking of KDM4A/4D and KDM5B in this study.Allyllysine-containing peptides,as methyllysine substrate mimics,that were prepared by simple cysteine alkylation,are converted to epoxide by demethylase catalysis.The electrophilic intermediate subsequently crosslinks residues inside the KDM catalytic pocket.Therefore,such probes that selectively conjugate KDMs could be applied to identify KDMs from specific methyllysine sites and uncover new biology of lysine methylation.
