Research into lactylation modifications across various target organs in both health and disease has gained significant attention.Many essential life processes and the onset of diseases are not only related to protein ...Research into lactylation modifications across various target organs in both health and disease has gained significant attention.Many essential life processes and the onset of diseases are not only related to protein abundance but are also primarily regulated by various post-translational protein modifications.Lactate,once considered merely a byproduct of anaerobic metabolism,has emerged as a crucial energy substrate and signaling molecule involved in both physiological and pathological processes within the nervous system.Furthermore,recent studies have emphasized the significant role of lactate in numerous neurological diseases,including Alzheimer's disease,Parkinson's disease,acute cerebral ischemic stroke,multiple sclerosis,Huntington's disease,and myasthenia gravis.The purpose of this review is to synthesize the current research on lactate and lactylation modifications in neurological diseases,aiming to clarify their mechanisms of action and identify potential therapeutic targets.As such,this work provides an overview of the metabolic regulatory roles of lactate in various disorders,emphasizing its involvement in the regulation of brain function.Additionally,the specific mechanisms of brain lactate metabolism are discussed,suggesting the unique roles of lactate in modulating brain function.As a critical aspect of lactate function,lactylation modifications,including both histone and non-histone lactylation,are explored,with an emphasis on recent advancements in identifying the key regulatory enzymes of such modifications,such as lactylation writers and erasers.The effects and specific mechanisms of abnormal lactate metabolism in diverse neurological diseases are summarized,revealing that lactate acts as a signaling molecule in the regulation of brain functions and that abnormal lactate metabolism is implicated in the progression of various neurological disorders.Future research should focus on further elucidating the molecular mechanisms underlying lactate and lactylation modifications and exploring their potential as therapeutic targets for neurological diseases.展开更多
Background As a unique livestock adapted to the harsh environment,grazing yaks frequently suffer from malnutrition and even death because of the lower yield and quality of forage in the Qinghai-Tibet Plateau during th...Background As a unique livestock adapted to the harsh environment,grazing yaks frequently suffer from malnutrition and even death because of the lower yield and quality of forage in the Qinghai-Tibet Plateau during the cold season.Certain stress conditions,such as environmental changes,disease,and malnutrition,can lead to a decrease in glutamine(Gln)synthesis,which fails to cover the physiological needs of the organism.Supplementation with exogenous Gln can promote nutrient digestion and improve rumen fermentation in ruminant animals under malnutrition.However,whether Gln could alleviate the barrier function injury induced by malnutrition and its mechanism is still unclear.Methods In the in vivo experiments,24 healthy yaks(31 months,265.35±25.81 kg)were randomly divided into 3 groups,namely control group(Con,free access to the basal diet),feed restriction group(FR,50% level of ad libitum feed intake),and feed restriction+Gln group(FR+Gln,50% level of ad libitum feed intake from d 1 to 30,50% level of ad libitum feed intake+1%Gln from d 31 to 60).In the in vitro experiments,the yak rumen epithelial cells(YRECs)were divided into 4 groups:Con group(complete medium),Gln group(complete medium+10 mmol/L Gln),Gln deficiency group(Gln-D,Gln-free medium),and Gln deficiency+Gln group(Gln-D+Gln,Gln-free medium+10 mmol/L Gln).Results In the in vivo experiments,FR significantly decreased the ruminal concentrations of acetate,propionate,butyrate,iso-butyrate,and total volatile fatty acid(VFA)(P<0.05).FR also reduced the m RNA expression of NHE1,Na^(+)/K^(+)-ATPase,and Ca^(2+)/Mg^(2+)-ATPase,and the concentrations of lactate,histone acetyltransferase(p300),histone deacetylase(HDAC),as well as the histone lysine lactylation level compared to Con group,while Gln supplementation alleviated them(P<0.05).In the in vitro experiments,Gln alleviated the Gln-D-induced down-regulation of NHE1,Na^(+)/K^(+)-ATPase,and Ca^(2+)/Mg^(2+)-ATPase m RNA expressions and reduction of lactate,p300,HDAC concentrations,and histone lysine lactylation level(P<0.05).Besides,p300 inhibitor abrogated Gln repair of barrier function damage in YRECs(P<0.05).Conclusions Overall,our results revealed the potential mechanism of Gln supplementation to repair malnutritioninduced damage of rumen epithelial barrier function in yaks,which might be related to histone lysine lactylation.However,because we do not have a control group receiving glutamine alone,we cannot determine the impact of Gln on the rumen epithelial function of normal yaks.展开更多
Cholelithiasis has a complex pathogenesis,necessitating better therapeutic and preventive strategies.We recently read with interest Wang et al’s study on lysine acetyltransferase 2A(KAT2A)-mediated adenosine monophos...Cholelithiasis has a complex pathogenesis,necessitating better therapeutic and preventive strategies.We recently read with interest Wang et al’s study on lysine acetyltransferase 2A(KAT2A)-mediated adenosine monophosphate-activated protein kinase(AMPK)succinylation in cholelithiasis.Using mouse models and gallbladder mucosal epithelial cells,they found that KAT2A inhibits gallstones through AMPK K170 succinylation,thereby activating the AMPK/silent information regulator 1 pathway to reduce inflammation and pyroptosis.This study is the first to connect lysine succinylation with cholelithiasis,offering new insights and identifying succinylation as a potential therapeutic target.Future research should confirm these findings using patient samples,investigate other posttranslational modifications,and use structural biology to clarify succinylationinduced conformational changes,thereby bridging basic research to clinical applications.展开更多
Cognitive impairment is a complex neurodegenerative disorder,and increased homocysteine levels are recognized as a major risk factor for this condition.Epigenetic modifications,particularly histone acetylation,have be...Cognitive impairment is a complex neurodegenerative disorder,and increased homocysteine levels are recognized as a major risk factor for this condition.Epigenetic modifications,particularly histone acetylation,have been implicated in the progression of cognitive impairment;however,the mechanisms underlying hyperhomocysteinemia-induced cognitive impairment remain unclear.In this study,we developed an hyperhomocysteinemia-induced cognitive impairment model by feeding mice a high-methionine diet and conducted behavioral and molecular analyses to elucidate the mechanisms involved in cognitive impairment.Behavioral experiments revealed significant cognitive deficits and neuroinflammation accompanied by a marked decrease in histone H3 lysine 27 acetylation in the hippocampus and cortex.Furthermore,metabolomic profiling and chromatin immunoprecipitation sequencing demonstrated substantial shifts in the levels of homocysteine metabolites and identified histone H3 lysine 27 acetylation-targeted genes involved in synaptic long-term potentiation,including Gria1,Gria3,Grin2a,Grin2b,Slc1a1,Slc24a2,Ptk2b,and Src.RNA sequencing confirmed that hyperhomocysteinemia induced neurodegeneration.In vitro experiments confirmed that decreased histone H3 lysine 27 acetylation downregulates the expression of these target genes in homocysteine-treated HT-22 cells,thereby impairing synaptic plasticity.Collectively,these findings suggest that aberrant expression of long-term potentiation-related genes regulated by histone H3 lysine 27 acetylation is a key driver of hyperhomocysteinemia-induced cognitive impairment.Targeting histone H3 lysine 27 acetylation-mediated epigenetic dysregulation may be a promising therapeutic strategy,offering potential avenues for intervention in individuals with cognitive impairment and neurodegenerative disorders.展开更多
α-Synuclein accumulation and transmission are vital to the pathogenesis of Parkinson's disease,although the mechanisms underlying misfoldedα-synuclein accumulation and propagation have not been conclusively dete...α-Synuclein accumulation and transmission are vital to the pathogenesis of Parkinson's disease,although the mechanisms underlying misfoldedα-synuclein accumulation and propagation have not been conclusively determined.The expression of low-density lipoprotein receptor–related protein 1,which is abundantly expressed in neurons and considered to be a multifunctional endocytic receptor,is elevated in the neurons of patients with Parkinson's disease.However,whether there is a direct link between low-density lipoprotein receptor–related protein 1 andα-synuclein aggregation and propagation in Parkinson's disease remains unclear.Here,we established animal models of Parkinson's disease by inoculating monkeys and mice withα-synuclein pre-formed fibrils and observed elevated low-density lipoprotein receptor–related protein 1 levels in the striatum and substantia nigra,accompanied by dopaminergic neuron loss and increasedα-synuclein levels.However,low-density lipoprotein receptor–related protein 1 knockdown efficiently rescued dopaminergic neurodegeneration and inhibited the increase inα-synuclein levels in the nigrostriatal system.In HEK293A cells overexpressingα-synuclein fragments,low-density lipoprotein receptor–related protein 1 levels were upregulated only when the N-terminus ofα-synuclein was present,whereas anα-synuclein fragment lacking the N-terminus did not lead to low-density lipoprotein receptor–related protein 1 upregulation.Furthermore,the N-terminus ofα-synuclein was found to be rich in lysine residues,and blocking lysine residues in PC12 cells treated withα-synuclein pre-formed fibrils effectively reduced the elevated low-density lipoprotein receptor–related protein 1 andα-synuclein levels.These findings indicate that low-density lipoprotein receptor–related protein 1 regulates pathological transmission ofα-synuclein from the striatum to the substantia nigra in the nigrostriatal system via lysine residues in theα-synuclein N-terminus.展开更多
Reader proteins that bind specific methyllysine are important to biological functions of lysine methylation,but readers of many methyllysine sites are still unknown.Therefore,development of covalent probes is importan...Reader proteins that bind specific methyllysine are important to biological functions of lysine methylation,but readers of many methyllysine sites are still unknown.Therefore,development of covalent probes is important to identify readers from cell samples so as to understand biological roles of lysine methylation.Generally,readers bind methyllysine via aromatic cages that contain tryptophan,tyrosine and phenylalanine,that offer a unique motif for selective crosslinking.We recently reported a site-selective tryptophan crosslinking strategy based on dimethylsulfonium that mimics dimethyllysine to crosslink tryptophan in aromatic cages of readers.Since tyrosine is a key residue for binding affinity to methyllysine,especially some readers that do not contain tryptophan residues in the binding pocket.Here we developed strategies of site-selective crosslinking to tyrosine.Ultraviolet(UV)source was applied to excite tyrosine at neutral pH or phenoxide at basic p H,and subsequent single-electron transfer(SET)from Tyr*to sulfonium inside the binding pocket enables selective crosslinking.In consequence,methyllysine readers with tyrosine-containing aromatic cages could be selectively crosslinked by site-specific sulfonium peptide probes.In addition,we expanded substrates from aromatic cages to tyrosine residues of proximate contact with sulfonium probes.The pair of LgBiT and SmBiT exhibited orthogonal crosslinking in complicated cell samples.As a result,we may expand sulfonium tools to target local tyrosine in future investigations.展开更多
Chemical modification of native peptides and proteins is a versatile strategy to facilitate late-stage diversification for functional studies.Among the proteogenic amino acids,lysine is extensively involved in posttra...Chemical modification of native peptides and proteins is a versatile strategy to facilitate late-stage diversification for functional studies.Among the proteogenic amino acids,lysine is extensively involved in posttranslational modifications and the binding of ligands to target proteins,making its selective modification attractive.However,lysine’s high natural abundance and solvent accessibility,as well as its relatively low reactivity to cysteine,necessitate addressing chemoselectivity and regioselectivity for the Lys modification of native proteins.Although Lys chemoselective modification methods have been well developed,achieving site-selective modification of a specific Lys residue remains a great challenge.In this review,we discussed the challenges of Lys selective modification,presented recent examples of Lys chemoselective modification,and summarized the currently known methods and strategies for Lys site-selective modification.We also included an outlook on potential solutions for Lys site-selective labeling and its potential applications in chemical biology and drug development.展开更多
BACKGROUND Cholelithiasis is a prevalent biliary tract disorder primarily characterized by gallbladder or biliary stone formation.Although succinylation has been exten-sively studied as a protein post-translational mo...BACKGROUND Cholelithiasis is a prevalent biliary tract disorder primarily characterized by gallbladder or biliary stone formation.Although succinylation has been exten-sively studied as a protein post-translational modification,its role in cholelithiasis remains unexplored.AIM To investigate the functional role of succinylation in cholelithiasis and determine its underlying molecular mechanisms.METHODS A murine cholelithiasis model was established through high-fat diet feeding,followed by isolation of mouse gallbladder mucosal epithelial cells(GMECs)for in vitro analysis.Gallbladder tissues and serum samples were collected for subsequent analysis.Inflammatory cytokine production was quantified using enzyme-linked immunosorbent assay.Pyroptosis was analyzed by flow cytometry,while succinylation-and pyroptosis-related protein expression was detected via western blot.RESULTS Our findings demonstrated that lysine acetyltransferase 2A(KAT2A)-mediated succinylation regulated gallstone formation.KAT2A overexpression inhibited the pyroptosis,inflammatory responses,and promoted the activation of the adenosine monophosphate-activated protein kinase(AMPK)/silent information regulator 1(SIRT1)sig-naling pathway in GMECs.Mechanistically,AMPK exhibited succinylation at lysine 170(K170).Notably,AMPK inhibition significantly increased pyroptosis rates,inflammatory responses,and pyroptosis-related protein ex-pression in GMECs.Furthermore,in vivo experiments revealed that KAT2A overexpression suppressed both inflammation and gallstone formation.CONCLUSION KAT2A-mediated succinylation of AMPK inhibited cholelithiasis progression by modulating the AMPK/SIRT1 signaling pathway,offering potential therapeutic strategies for this condition.展开更多
Oral squamous cell carcinoma(OSCC)progresses from preneoplastic precursors via genetic and epigenetic alterations.Previous studies have focused on the treatment of terminally developed OSCC.However,the role of epigene...Oral squamous cell carcinoma(OSCC)progresses from preneoplastic precursors via genetic and epigenetic alterations.Previous studies have focused on the treatment of terminally developed OSCC.However,the role of epigenetic regulators as therapeutic targets during the transition from preneoplastic precursors to OSCC has not been well studied.Our study identified lysine-specific demethylase 1(LSD1)as a crucial promoter of OSCC,demonstrating that its knockout or pharmacological inhibition in mice reversed OSCC preneoplasia.LSD1 inhibition by SP2509 disrupted cell cycle,reduced immunosuppression,and enhanced CD4+and CD8+T-cell infiltration.In a feline model of spontaneous OSCC,a clinical LSD1 inhibitor(Seclidemstat or SP2577)was found to be safe and effectively inhibit the STAT3 network.Mechanistic studies revealed that LSD1 drives OSCC progression through STAT3 signaling,which is regulated by phosphorylation of the cell cycle mediator CDK7 and immunosuppressive CTLA4.Notably,LSD1 inhibition reduced the phosphorylation of CDK7 at Tyr170 and eIF4B at Ser422,offering insights into a novel mechanism by which LSD1 regulates the preneoplastic-to-OSCC transition.This study provides a deeper understanding of OSCC progression and highlights LSD1 as a potential therapeutic target for controlling OSCC progression from preneoplastic lesions.展开更多
Skin sensitization is a common adverse effect of a wide range of small reactive chemicals,leading to allergic contact dermatitis(ACD),the most frequent manifestation of immunotoxicity in humans.The prevalence of ACD i...Skin sensitization is a common adverse effect of a wide range of small reactive chemicals,leading to allergic contact dermatitis(ACD),the most frequent manifestation of immunotoxicity in humans.The prevalence of ACD is increasing,affecting up to 20%of the Western European population.This trend was particularly pronounced in high-risk occupational sectors,including healthcare,food services,metal and construction workers,and hairdressers[1].The skin sensitization adverse outcome pathway(AOP)comprises 11 elements,with four designated key events(KEs):formation of proteinhapten complexes(KE-1),inflammatory keratinocyte response(KE-2),dendritic cell(DC)activation(KE-3),and T-cell proliferation(KE-4)[2].As there is no cure for ACD,preventive strategies are of great relevance.In addition to avoiding exposure,preventive measures,such as the use of latex gloves,barrier creams,emollients,and moisturizers,often have limited effectiveness[3].展开更多
Lysine-rich protein gene (lys) was cloned from Psophocarpus tetragonolobus (L.) DC. A plant expression plasmid was constructed and lys gene was under the control of maize ubiquitin promoter which is the highest effici...Lysine-rich protein gene (lys) was cloned from Psophocarpus tetragonolobus (L.) DC. A plant expression plasmid was constructed and lys gene was under the control of maize ubiquitin promoter which is the highest efficient monocotyledon promoter. The plasmid was introduced into rice embryogenic calli by microprojectile bombardment. The regenerated fertile plants were obtained by effective selection for hygromycin B resistance. Genomic PCR and Southern blotting analyses showed that the lys gene has been integrated into rice genome. Simultaneously, the results of GUS histochemical assay demonstrated that gus report gene is also expressed in leaves, stems and roots of the transgenic rice plants. Data analysis showed that lysine content in most of the 11 transgenic plants is differently improved, and in one of them increased by 16.04%.展开更多
[Objective] This study aimed to provide a theoretical basis for the genetic improvement of maize quality in Shanxi Province. [Method] The variations in unit weight, crude starch content, crude protein content, crude f...[Objective] This study aimed to provide a theoretical basis for the genetic improvement of maize quality in Shanxi Province. [Method] The variations in unit weight, crude starch content, crude protein content, crude fat content and lysine content of maize cultivars approved by Shanxi Province during 2003-2012 were analyzed. [Result] In Shanxi Province, the average unit weight and crude starch content of maize cultivars approved during 2003-2012 were trended to be increased;the crude fat contents of maize cultivars approved during 2003-2012 showed no significant changes; the lysine contents of maize cultivars approved during 2003-2008 were essentially unchanged; the crude protein contents of maize cultivars approved during 2003-2012 declined slightly. [Conclusion] The crude starch content and unit weight of maize increased with the increased yield; the crude protein content, crude fat content and lysine content showed certain stability, and they were mainly controlled by genes. Therefore, the breeding of particular maize should be strengthened.展开更多
Establishing a method to detect the gluconate and lysine hydrochloride in calcium gluconate and zinc gluconate oral liquid by LC-MS.The mobile phase was acetonitrile and water (10:90),flow rate was 0.2 mL/min,and MS r...Establishing a method to detect the gluconate and lysine hydrochloride in calcium gluconate and zinc gluconate oral liquid by LC-MS.The mobile phase was acetonitrile and water (10:90),flow rate was 0.2 mL/min,and MS run in negative ion mode.The m/z of gluconic acid was 195,and m/z of lysine hydrochloride was 145.展开更多
In this study, nine high-lysine maize kernels and two kernels of common maize hybrid were used as experiment materials, and quantitative determination of lysine contents in high-lysine maize kernels and common maize k...In this study, nine high-lysine maize kernels and two kernels of common maize hybrid were used as experiment materials, and quantitative determination of lysine contents in high-lysine maize kernels and common maize kernels was carried out using Hitachi L-8900 Automatic Amino-acid Analyzer, to know the effect of the Analyzer in distinguishing the lysine contents between common maize kernels and high-lysine maize kernels. The results showed that the lysine contents of high-lysine maize kernels were among 0.34%-0.42%, while of common maize kernels were a- mong 0.24%-0.25%, and the difference was significant. Compared with other tradi- tional methods, this method is rapid, simple, sensitive, highly reproductive and needs fewer maize kernels, thus it is applicable in maize breeding.展开更多
Gastrointestinal(GI)cancers,including colorectal cancer,pancreatic cancer,liver cancer and gastric cancer,are severe social burdens due to high incidence and mortality rates.Bromodomain and extra-terminal(BET)proteins...Gastrointestinal(GI)cancers,including colorectal cancer,pancreatic cancer,liver cancer and gastric cancer,are severe social burdens due to high incidence and mortality rates.Bromodomain and extra-terminal(BET)proteins are epigenetic readers consisting of four conserved members(BRD2,BRD3,BRD4 and BRDT).BET family perform pivotal roles in tumorigenesis through transcriptional regulation,thereby emerging as potential therapeutic targets.BET inhibitors,disrupting the interaction between BET proteins and acetylated lysines,have been reported to suppress tumor initiation and progression in most of GI cancers.In this review,we will demonstrate how BET proteins participate in the GI cancers progression and highlight the therapeutic potential of targeting BET proteins for GI cancers treatment.展开更多
[Objective] This study aimed to investigate the action of mutant gene o2 and its effect on nutritional quality of different maize combinations. [Method] A total of 33 normal maize combinations from 18 inbred lines wer...[Objective] This study aimed to investigate the action of mutant gene o2 and its effect on nutritional quality of different maize combinations. [Method] A total of 33 normal maize combinations from 18 inbred lines were compared with 33 combinations including gene o2 from the corresponding o2 near-isogenic lines （o2-NILs）, to study the effect of o2 gene introduction on maize grain quality. [Result] The contents of lysine, protein and oil in o2-NILs were greatly more than that of normal maize combinations. Except for lysine, contents of other 14 amino acids changed when o2 gene was introduced. Contents of aspartic acid, threonine, glycine, isoleucine, histidine, arginine and proline were improved; while contents of serine, glutamic acid, alanine, valine, leucine, tyrosine and phenylalanine were decreased. Correlation analysis showed that contents of aspartic acid, arginine and threonine had the highest correlation with lysine content. Protein and oil contents had higher correlation with lysine content （0.48 and 0.38）. Analysis of 33 o2-NILs revealed that the o2 combinations CAL58×Ji477and CA156×196 showed high comprehensive quality and high yield with greater development potential. [Conclusion] This study will provide theoretical and material basis for improving the quality of temperate maize germplasm by introducing o2 gene.展开更多
Mesenchymal stem cells （MSCs） are characterized by their self-renewing capacity and differentiation potential into multiple tissues. Thus, management of the differentiation capacities of MSCs is important for MSC-ba...Mesenchymal stem cells （MSCs） are characterized by their self-renewing capacity and differentiation potential into multiple tissues. Thus, management of the differentiation capacities of MSCs is important for MSC-based regenerative medicine, such as craniofacial bone regeneration, and in new treatments for metabolic bone diseases, such as osteoporosis. In recent years, histone modification has been a growing topic in the field of MSC lineage specification, in which the Su（var）3-9, enhancer-of-zeste, trithorax （SET） domain-containing family and the Jumonji C （JmjC） domain-containing family represent the major histone lysine methyltransferases （KMTs） and histone lysine demethylases （KDMs）, respectively. In this review, we summarize the current understanding of the epigenetic mechanisms by which SET domain-containine KMTs and JmiC domain-containinlz KDMs balance the osteogenic and adipogenic differentiation of MSCs.展开更多
To formulate the optimal strategy of combatting bacterial biofilms,in this review we update current knowledge on the growing problem of biofilm formation and its resistance to antibiotics which has spurred the search ...To formulate the optimal strategy of combatting bacterial biofilms,in this review we update current knowledge on the growing problem of biofilm formation and its resistance to antibiotics which has spurred the search for new strategies to deal with this complication.Based on recent findings,the role of bacteriophages in the prevention and elimination of biofilm-related infections has been emphasized.In vitro,ex vivo and in vivo biofilm treatment models with single bacteriophages or phage cocktails have been compared.A combined use of bacteriophages with antibiotics in vitro or in vivo confirms earlier reports of the synergistic effect of these agents in improving biofilm removal.Furthermore,studies on the application of phage-derived lysins in vitro,ex vivo or in vivo against biofilm-related infections are encouraging.The strategy of combined use of phage and antibiotics seems to be different from using lysins and antibiotics.These findings suggest that phages and lysins alone or in combination with antibiotics may be an efficient weapon against biofilm formation in vivo and ex vivo,which could be useful in formulating novel strategies to combat bacterial infections.Those findings proved to be relevant in the prevention and destruction of biofilms occurring during urinary tract infections,orthopedic implant-related infections,periodontal and peri-implant infections.In conclusion,it appears that most efficient strategy of eliminating biofilms involves phages or lysins in combination with antibiotics,but the optimal scheme of their administration requires further studies.展开更多
基金supported by Applied Basic Research Joint Fund Project of Yunnan Province,No.202301AY070001-200Middle-aged Academic and Technical Training Project for High-Level Talents,No.202105AC160065+1 种基金Yunnan Clinical Medical Center for Neurological and Cardiovascular Diseases,No.YWLCYXZX2023300077Key Clinical Specialty of Neurology in Yunnan Province,No.300064(all to CL)。
文摘Research into lactylation modifications across various target organs in both health and disease has gained significant attention.Many essential life processes and the onset of diseases are not only related to protein abundance but are also primarily regulated by various post-translational protein modifications.Lactate,once considered merely a byproduct of anaerobic metabolism,has emerged as a crucial energy substrate and signaling molecule involved in both physiological and pathological processes within the nervous system.Furthermore,recent studies have emphasized the significant role of lactate in numerous neurological diseases,including Alzheimer's disease,Parkinson's disease,acute cerebral ischemic stroke,multiple sclerosis,Huntington's disease,and myasthenia gravis.The purpose of this review is to synthesize the current research on lactate and lactylation modifications in neurological diseases,aiming to clarify their mechanisms of action and identify potential therapeutic targets.As such,this work provides an overview of the metabolic regulatory roles of lactate in various disorders,emphasizing its involvement in the regulation of brain function.Additionally,the specific mechanisms of brain lactate metabolism are discussed,suggesting the unique roles of lactate in modulating brain function.As a critical aspect of lactate function,lactylation modifications,including both histone and non-histone lactylation,are explored,with an emphasis on recent advancements in identifying the key regulatory enzymes of such modifications,such as lactylation writers and erasers.The effects and specific mechanisms of abnormal lactate metabolism in diverse neurological diseases are summarized,revealing that lactate acts as a signaling molecule in the regulation of brain functions and that abnormal lactate metabolism is implicated in the progression of various neurological disorders.Future research should focus on further elucidating the molecular mechanisms underlying lactate and lactylation modifications and exploring their potential as therapeutic targets for neurological diseases.
基金the National Natural Science Foundation of China(NSFC),Grant/Award Number:32272909Discipline Construction Program in Sichuan Agricultural University(2221993012)China Agriculture(Beef Cattle/Yak)Research System of MOF and MARA(CARS-37)。
文摘Background As a unique livestock adapted to the harsh environment,grazing yaks frequently suffer from malnutrition and even death because of the lower yield and quality of forage in the Qinghai-Tibet Plateau during the cold season.Certain stress conditions,such as environmental changes,disease,and malnutrition,can lead to a decrease in glutamine(Gln)synthesis,which fails to cover the physiological needs of the organism.Supplementation with exogenous Gln can promote nutrient digestion and improve rumen fermentation in ruminant animals under malnutrition.However,whether Gln could alleviate the barrier function injury induced by malnutrition and its mechanism is still unclear.Methods In the in vivo experiments,24 healthy yaks(31 months,265.35±25.81 kg)were randomly divided into 3 groups,namely control group(Con,free access to the basal diet),feed restriction group(FR,50% level of ad libitum feed intake),and feed restriction+Gln group(FR+Gln,50% level of ad libitum feed intake from d 1 to 30,50% level of ad libitum feed intake+1%Gln from d 31 to 60).In the in vitro experiments,the yak rumen epithelial cells(YRECs)were divided into 4 groups:Con group(complete medium),Gln group(complete medium+10 mmol/L Gln),Gln deficiency group(Gln-D,Gln-free medium),and Gln deficiency+Gln group(Gln-D+Gln,Gln-free medium+10 mmol/L Gln).Results In the in vivo experiments,FR significantly decreased the ruminal concentrations of acetate,propionate,butyrate,iso-butyrate,and total volatile fatty acid(VFA)(P<0.05).FR also reduced the m RNA expression of NHE1,Na^(+)/K^(+)-ATPase,and Ca^(2+)/Mg^(2+)-ATPase,and the concentrations of lactate,histone acetyltransferase(p300),histone deacetylase(HDAC),as well as the histone lysine lactylation level compared to Con group,while Gln supplementation alleviated them(P<0.05).In the in vitro experiments,Gln alleviated the Gln-D-induced down-regulation of NHE1,Na^(+)/K^(+)-ATPase,and Ca^(2+)/Mg^(2+)-ATPase m RNA expressions and reduction of lactate,p300,HDAC concentrations,and histone lysine lactylation level(P<0.05).Besides,p300 inhibitor abrogated Gln repair of barrier function damage in YRECs(P<0.05).Conclusions Overall,our results revealed the potential mechanism of Gln supplementation to repair malnutritioninduced damage of rumen epithelial barrier function in yaks,which might be related to histone lysine lactylation.However,because we do not have a control group receiving glutamine alone,we cannot determine the impact of Gln on the rumen epithelial function of normal yaks.
基金Supported by Wenzhou Science and Technology Bureau,No.Y20240207.
文摘Cholelithiasis has a complex pathogenesis,necessitating better therapeutic and preventive strategies.We recently read with interest Wang et al’s study on lysine acetyltransferase 2A(KAT2A)-mediated adenosine monophosphate-activated protein kinase(AMPK)succinylation in cholelithiasis.Using mouse models and gallbladder mucosal epithelial cells,they found that KAT2A inhibits gallstones through AMPK K170 succinylation,thereby activating the AMPK/silent information regulator 1 pathway to reduce inflammation and pyroptosis.This study is the first to connect lysine succinylation with cholelithiasis,offering new insights and identifying succinylation as a potential therapeutic target.Future research should confirm these findings using patient samples,investigate other posttranslational modifications,and use structural biology to clarify succinylationinduced conformational changes,thereby bridging basic research to clinical applications.
基金supported by the Science Research Start-up Fund for Doctor of Shanxi Medical University,No.SD2114(to JL).
文摘Cognitive impairment is a complex neurodegenerative disorder,and increased homocysteine levels are recognized as a major risk factor for this condition.Epigenetic modifications,particularly histone acetylation,have been implicated in the progression of cognitive impairment;however,the mechanisms underlying hyperhomocysteinemia-induced cognitive impairment remain unclear.In this study,we developed an hyperhomocysteinemia-induced cognitive impairment model by feeding mice a high-methionine diet and conducted behavioral and molecular analyses to elucidate the mechanisms involved in cognitive impairment.Behavioral experiments revealed significant cognitive deficits and neuroinflammation accompanied by a marked decrease in histone H3 lysine 27 acetylation in the hippocampus and cortex.Furthermore,metabolomic profiling and chromatin immunoprecipitation sequencing demonstrated substantial shifts in the levels of homocysteine metabolites and identified histone H3 lysine 27 acetylation-targeted genes involved in synaptic long-term potentiation,including Gria1,Gria3,Grin2a,Grin2b,Slc1a1,Slc24a2,Ptk2b,and Src.RNA sequencing confirmed that hyperhomocysteinemia induced neurodegeneration.In vitro experiments confirmed that decreased histone H3 lysine 27 acetylation downregulates the expression of these target genes in homocysteine-treated HT-22 cells,thereby impairing synaptic plasticity.Collectively,these findings suggest that aberrant expression of long-term potentiation-related genes regulated by histone H3 lysine 27 acetylation is a key driver of hyperhomocysteinemia-induced cognitive impairment.Targeting histone H3 lysine 27 acetylation-mediated epigenetic dysregulation may be a promising therapeutic strategy,offering potential avenues for intervention in individuals with cognitive impairment and neurodegenerative disorders.
基金supported by the Natural Science Foundation of Guangxi Zhuang Automomous Region,Nos.2019GXNSFDA245015(to MC),2022GXNSFBA035654(to HL)the National Natural Science Foundation of China,Nos.82360241(to MC),82304876(to HL)+1 种基金Scientific Research and Technology Development Project of Guilin City,Nos.20220139-3(to MC),20210218-5(to HL)Guangxi Medical and Health Key Discipline Construction Project(to QL)。
文摘α-Synuclein accumulation and transmission are vital to the pathogenesis of Parkinson's disease,although the mechanisms underlying misfoldedα-synuclein accumulation and propagation have not been conclusively determined.The expression of low-density lipoprotein receptor–related protein 1,which is abundantly expressed in neurons and considered to be a multifunctional endocytic receptor,is elevated in the neurons of patients with Parkinson's disease.However,whether there is a direct link between low-density lipoprotein receptor–related protein 1 andα-synuclein aggregation and propagation in Parkinson's disease remains unclear.Here,we established animal models of Parkinson's disease by inoculating monkeys and mice withα-synuclein pre-formed fibrils and observed elevated low-density lipoprotein receptor–related protein 1 levels in the striatum and substantia nigra,accompanied by dopaminergic neuron loss and increasedα-synuclein levels.However,low-density lipoprotein receptor–related protein 1 knockdown efficiently rescued dopaminergic neurodegeneration and inhibited the increase inα-synuclein levels in the nigrostriatal system.In HEK293A cells overexpressingα-synuclein fragments,low-density lipoprotein receptor–related protein 1 levels were upregulated only when the N-terminus ofα-synuclein was present,whereas anα-synuclein fragment lacking the N-terminus did not lead to low-density lipoprotein receptor–related protein 1 upregulation.Furthermore,the N-terminus ofα-synuclein was found to be rich in lysine residues,and blocking lysine residues in PC12 cells treated withα-synuclein pre-formed fibrils effectively reduced the elevated low-density lipoprotein receptor–related protein 1 andα-synuclein levels.These findings indicate that low-density lipoprotein receptor–related protein 1 regulates pathological transmission ofα-synuclein from the striatum to the substantia nigra in the nigrostriatal system via lysine residues in theα-synuclein N-terminus.
基金the support from National Natural Science Foundation of China(No.22161132006)Key R&D Program of Zhejiang(No.2024SSYS0036)Westlake University Startup。
文摘Reader proteins that bind specific methyllysine are important to biological functions of lysine methylation,but readers of many methyllysine sites are still unknown.Therefore,development of covalent probes is important to identify readers from cell samples so as to understand biological roles of lysine methylation.Generally,readers bind methyllysine via aromatic cages that contain tryptophan,tyrosine and phenylalanine,that offer a unique motif for selective crosslinking.We recently reported a site-selective tryptophan crosslinking strategy based on dimethylsulfonium that mimics dimethyllysine to crosslink tryptophan in aromatic cages of readers.Since tyrosine is a key residue for binding affinity to methyllysine,especially some readers that do not contain tryptophan residues in the binding pocket.Here we developed strategies of site-selective crosslinking to tyrosine.Ultraviolet(UV)source was applied to excite tyrosine at neutral pH or phenoxide at basic p H,and subsequent single-electron transfer(SET)from Tyr*to sulfonium inside the binding pocket enables selective crosslinking.In consequence,methyllysine readers with tyrosine-containing aromatic cages could be selectively crosslinked by site-specific sulfonium peptide probes.In addition,we expanded substrates from aromatic cages to tyrosine residues of proximate contact with sulfonium probes.The pair of LgBiT and SmBiT exhibited orthogonal crosslinking in complicated cell samples.As a result,we may expand sulfonium tools to target local tyrosine in future investigations.
基金the National Natural Science Foundation of China(Nos.82373722,22077144)Hunan Provincial Natural Science Foundation of China(No.2023JJ30527)+2 种基金Guangdong Basic and Applied Basic Research Foundation(No.2023B1515040006)Guangdong Provincial Key Laboratory of Construction Foundation(No.2023B1212060022)Key Research and Development Program of Guangdong Province(No.2020B1111110003).
文摘Chemical modification of native peptides and proteins is a versatile strategy to facilitate late-stage diversification for functional studies.Among the proteogenic amino acids,lysine is extensively involved in posttranslational modifications and the binding of ligands to target proteins,making its selective modification attractive.However,lysine’s high natural abundance and solvent accessibility,as well as its relatively low reactivity to cysteine,necessitate addressing chemoselectivity and regioselectivity for the Lys modification of native proteins.Although Lys chemoselective modification methods have been well developed,achieving site-selective modification of a specific Lys residue remains a great challenge.In this review,we discussed the challenges of Lys selective modification,presented recent examples of Lys chemoselective modification,and summarized the currently known methods and strategies for Lys site-selective modification.We also included an outlook on potential solutions for Lys site-selective labeling and its potential applications in chemical biology and drug development.
基金Supported by National Natural Science Foundation of China,No.82000579 and No.81870205Natural Science Foundation of Shandong Province,No.ZR2021QH061 and No.ZR2021QH186.
文摘BACKGROUND Cholelithiasis is a prevalent biliary tract disorder primarily characterized by gallbladder or biliary stone formation.Although succinylation has been exten-sively studied as a protein post-translational modification,its role in cholelithiasis remains unexplored.AIM To investigate the functional role of succinylation in cholelithiasis and determine its underlying molecular mechanisms.METHODS A murine cholelithiasis model was established through high-fat diet feeding,followed by isolation of mouse gallbladder mucosal epithelial cells(GMECs)for in vitro analysis.Gallbladder tissues and serum samples were collected for subsequent analysis.Inflammatory cytokine production was quantified using enzyme-linked immunosorbent assay.Pyroptosis was analyzed by flow cytometry,while succinylation-and pyroptosis-related protein expression was detected via western blot.RESULTS Our findings demonstrated that lysine acetyltransferase 2A(KAT2A)-mediated succinylation regulated gallstone formation.KAT2A overexpression inhibited the pyroptosis,inflammatory responses,and promoted the activation of the adenosine monophosphate-activated protein kinase(AMPK)/silent information regulator 1(SIRT1)sig-naling pathway in GMECs.Mechanistically,AMPK exhibited succinylation at lysine 170(K170).Notably,AMPK inhibition significantly increased pyroptosis rates,inflammatory responses,and pyroptosis-related protein ex-pression in GMECs.Furthermore,in vivo experiments revealed that KAT2A overexpression suppressed both inflammation and gallstone formation.CONCLUSION KAT2A-mediated succinylation of AMPK inhibited cholelithiasis progression by modulating the AMPK/SIRT1 signaling pathway,offering potential therapeutic strategies for this condition.
基金NIH/NIDCR grant R01 DE031413 and CTSA pilot grant UL1TR001430 to Manish V.Bais.
文摘Oral squamous cell carcinoma(OSCC)progresses from preneoplastic precursors via genetic and epigenetic alterations.Previous studies have focused on the treatment of terminally developed OSCC.However,the role of epigenetic regulators as therapeutic targets during the transition from preneoplastic precursors to OSCC has not been well studied.Our study identified lysine-specific demethylase 1(LSD1)as a crucial promoter of OSCC,demonstrating that its knockout or pharmacological inhibition in mice reversed OSCC preneoplasia.LSD1 inhibition by SP2509 disrupted cell cycle,reduced immunosuppression,and enhanced CD4+and CD8+T-cell infiltration.In a feline model of spontaneous OSCC,a clinical LSD1 inhibitor(Seclidemstat or SP2577)was found to be safe and effectively inhibit the STAT3 network.Mechanistic studies revealed that LSD1 drives OSCC progression through STAT3 signaling,which is regulated by phosphorylation of the cell cycle mediator CDK7 and immunosuppressive CTLA4.Notably,LSD1 inhibition reduced the phosphorylation of CDK7 at Tyr170 and eIF4B at Ser422,offering insights into a novel mechanism by which LSD1 regulates the preneoplastic-to-OSCC transition.This study provides a deeper understanding of OSCC progression and highlights LSD1 as a potential therapeutic target for controlling OSCC progression from preneoplastic lesions.
基金support was provided by the European Regional Development Fund(ERDF),through the Centro 2020 Regional Operational Programme,Portugal(Project No.:CENTRO-01-0145-FEDER-000012(HealthyAging2020))through the COMPETE 2020-Operational Programme for Competitiveness and Internationalisation and Portuguese National Funds via Fundaçao para a Ciencia e a Tecnologia,Portugal(Project Nos.:POCI-01-0145-FEDER-029369 UIDB/04539/2020,iBiMED UIDB/04501/2020,DOI identifier https://doi.org/10.54499/UIDB/04501/2020 and project reference UIDP/04501/2020,DOI identifier https://doi.org/10.54499/UIDP/04501/2020,and LA/P/0058/2020)supported by Fundaçao para a Ciencia e a Tecnologia through the individual PhD fellowships,Portugal(Grant Nos.:PD/BDE/142926/2018 and SFRH/BD/110717/2015)。
文摘Skin sensitization is a common adverse effect of a wide range of small reactive chemicals,leading to allergic contact dermatitis(ACD),the most frequent manifestation of immunotoxicity in humans.The prevalence of ACD is increasing,affecting up to 20%of the Western European population.This trend was particularly pronounced in high-risk occupational sectors,including healthcare,food services,metal and construction workers,and hairdressers[1].The skin sensitization adverse outcome pathway(AOP)comprises 11 elements,with four designated key events(KEs):formation of proteinhapten complexes(KE-1),inflammatory keratinocyte response(KE-2),dendritic cell(DC)activation(KE-3),and T-cell proliferation(KE-4)[2].As there is no cure for ACD,preventive strategies are of great relevance.In addition to avoiding exposure,preventive measures,such as the use of latex gloves,barrier creams,emollients,and moisturizers,often have limited effectiveness[3].
文摘Lysine-rich protein gene (lys) was cloned from Psophocarpus tetragonolobus (L.) DC. A plant expression plasmid was constructed and lys gene was under the control of maize ubiquitin promoter which is the highest efficient monocotyledon promoter. The plasmid was introduced into rice embryogenic calli by microprojectile bombardment. The regenerated fertile plants were obtained by effective selection for hygromycin B resistance. Genomic PCR and Southern blotting analyses showed that the lys gene has been integrated into rice genome. Simultaneously, the results of GUS histochemical assay demonstrated that gus report gene is also expressed in leaves, stems and roots of the transgenic rice plants. Data analysis showed that lysine content in most of the 11 transgenic plants is differently improved, and in one of them increased by 16.04%.
基金Supported by Shanxi Provincial Fund for Development of Modern Crop Seed Industry(2014ZYFFZ-07)Twelfth Five-Year Plan of Shanxi Academy of Agricultural Sciences for Maize Breeding(11yzgc136)~~
文摘[Objective] This study aimed to provide a theoretical basis for the genetic improvement of maize quality in Shanxi Province. [Method] The variations in unit weight, crude starch content, crude protein content, crude fat content and lysine content of maize cultivars approved by Shanxi Province during 2003-2012 were analyzed. [Result] In Shanxi Province, the average unit weight and crude starch content of maize cultivars approved during 2003-2012 were trended to be increased;the crude fat contents of maize cultivars approved during 2003-2012 showed no significant changes; the lysine contents of maize cultivars approved during 2003-2008 were essentially unchanged; the crude protein contents of maize cultivars approved during 2003-2012 declined slightly. [Conclusion] The crude starch content and unit weight of maize increased with the increased yield; the crude protein content, crude fat content and lysine content showed certain stability, and they were mainly controlled by genes. Therefore, the breeding of particular maize should be strengthened.
文摘Establishing a method to detect the gluconate and lysine hydrochloride in calcium gluconate and zinc gluconate oral liquid by LC-MS.The mobile phase was acetonitrile and water (10:90),flow rate was 0.2 mL/min,and MS run in negative ion mode.The m/z of gluconic acid was 195,and m/z of lysine hydrochloride was 145.
基金Supported by Henan Major Scientific and Technological Project(121100110300)Outstanding Youth Project of Henan Academy of Agricultural Sciences(2013YQ006)~~
文摘In this study, nine high-lysine maize kernels and two kernels of common maize hybrid were used as experiment materials, and quantitative determination of lysine contents in high-lysine maize kernels and common maize kernels was carried out using Hitachi L-8900 Automatic Amino-acid Analyzer, to know the effect of the Analyzer in distinguishing the lysine contents between common maize kernels and high-lysine maize kernels. The results showed that the lysine contents of high-lysine maize kernels were among 0.34%-0.42%, while of common maize kernels were a- mong 0.24%-0.25%, and the difference was significant. Compared with other tradi- tional methods, this method is rapid, simple, sensitive, highly reproductive and needs fewer maize kernels, thus it is applicable in maize breeding.
基金Fellowship of the China Postdoctoral Science Foundation,No.2020M682594,and No.2021T140748.
文摘Gastrointestinal(GI)cancers,including colorectal cancer,pancreatic cancer,liver cancer and gastric cancer,are severe social burdens due to high incidence and mortality rates.Bromodomain and extra-terminal(BET)proteins are epigenetic readers consisting of four conserved members(BRD2,BRD3,BRD4 and BRDT).BET family perform pivotal roles in tumorigenesis through transcriptional regulation,thereby emerging as potential therapeutic targets.BET inhibitors,disrupting the interaction between BET proteins and acetylated lysines,have been reported to suppress tumor initiation and progression in most of GI cancers.In this review,we will demonstrate how BET proteins participate in the GI cancers progression and highlight the therapeutic potential of targeting BET proteins for GI cancers treatment.
基金Supported by Beijing Municipal Natural Science Foundation (6112003)~~
文摘[Objective] This study aimed to investigate the action of mutant gene o2 and its effect on nutritional quality of different maize combinations. [Method] A total of 33 normal maize combinations from 18 inbred lines were compared with 33 combinations including gene o2 from the corresponding o2 near-isogenic lines （o2-NILs）, to study the effect of o2 gene introduction on maize grain quality. [Result] The contents of lysine, protein and oil in o2-NILs were greatly more than that of normal maize combinations. Except for lysine, contents of other 14 amino acids changed when o2 gene was introduced. Contents of aspartic acid, threonine, glycine, isoleucine, histidine, arginine and proline were improved; while contents of serine, glutamic acid, alanine, valine, leucine, tyrosine and phenylalanine were decreased. Correlation analysis showed that contents of aspartic acid, arginine and threonine had the highest correlation with lysine content. Protein and oil contents had higher correlation with lysine content （0.48 and 0.38）. Analysis of 33 o2-NILs revealed that the o2 combinations CAL58×Ji477and CA156×196 showed high comprehensive quality and high yield with greater development potential. [Conclusion] This study will provide theoretical and material basis for improving the quality of temperate maize germplasm by introducing o2 gene.
基金supported by the National Institute of Dental and Craniofacial Research grants, K08DE024603-02, DE019412, and DE01651a grant from 111 Project of MOE, Chinasupported by Open Fund of State Key Laboratory of Oral Diseases, Sichuan University
文摘Mesenchymal stem cells （MSCs） are characterized by their self-renewing capacity and differentiation potential into multiple tissues. Thus, management of the differentiation capacities of MSCs is important for MSC-based regenerative medicine, such as craniofacial bone regeneration, and in new treatments for metabolic bone diseases, such as osteoporosis. In recent years, histone modification has been a growing topic in the field of MSC lineage specification, in which the Su（var）3-9, enhancer-of-zeste, trithorax （SET） domain-containing family and the Jumonji C （JmjC） domain-containing family represent the major histone lysine methyltransferases （KMTs） and histone lysine demethylases （KDMs）, respectively. In this review, we summarize the current understanding of the epigenetic mechanisms by which SET domain-containine KMTs and JmiC domain-containinlz KDMs balance the osteogenic and adipogenic differentiation of MSCs.
文摘To formulate the optimal strategy of combatting bacterial biofilms,in this review we update current knowledge on the growing problem of biofilm formation and its resistance to antibiotics which has spurred the search for new strategies to deal with this complication.Based on recent findings,the role of bacteriophages in the prevention and elimination of biofilm-related infections has been emphasized.In vitro,ex vivo and in vivo biofilm treatment models with single bacteriophages or phage cocktails have been compared.A combined use of bacteriophages with antibiotics in vitro or in vivo confirms earlier reports of the synergistic effect of these agents in improving biofilm removal.Furthermore,studies on the application of phage-derived lysins in vitro,ex vivo or in vivo against biofilm-related infections are encouraging.The strategy of combined use of phage and antibiotics seems to be different from using lysins and antibiotics.These findings suggest that phages and lysins alone or in combination with antibiotics may be an efficient weapon against biofilm formation in vivo and ex vivo,which could be useful in formulating novel strategies to combat bacterial infections.Those findings proved to be relevant in the prevention and destruction of biofilms occurring during urinary tract infections,orthopedic implant-related infections,periodontal and peri-implant infections.In conclusion,it appears that most efficient strategy of eliminating biofilms involves phages or lysins in combination with antibiotics,but the optimal scheme of their administration requires further studies.
