Regulatory T(Treg)cells are pivotal for maintaining immune homeostasis and play essential roles in various diseases,such as autoimmune diseases,graft-versus-host disease(GVHD),tumors,and infectious diseases.Treg cells...Regulatory T(Treg)cells are pivotal for maintaining immune homeostasis and play essential roles in various diseases,such as autoimmune diseases,graft-versus-host disease(GVHD),tumors,and infectious diseases.Treg cells exert suppressive function via distinct mechanisms,including inhibitory cytokines,granzyme or perforin-mediated cytolysis,metabolic disruption,and suppression of dendritic cells.Forkhead Box P3(FOXP3),the characteristic transcription factor,is essential for Treg cell function and plasticity.Cumulative evidence has demonstrated that FOXP3 activity and Treg cell function are modulated by a variety of post-translational modifications(PTMs),including ubiquitination,acetylation,phosphorylation,methylation,glycosylation,poly(ADP-ribosyl)ation,and uncharacterized modifications.This review describes Treg cell suppressive mechanisms and summarizes the current evidence on PTM regulation of FOXP3 and Treg cell function.Understanding the regulatory role of PTMs in Treg cell plasticity and function will be helpful in designing therapeutic strategies for autoimmune diseases,GVHD,tumors,and infectious diseases.展开更多
Developing favorable bio-based polymers that replace petroleum-based plastics is an essential environmental demand.Lignin is a by-product of the chemical pulping industry.It is a natural UV protection ingredient in br...Developing favorable bio-based polymers that replace petroleum-based plastics is an essential environmental demand.Lignin is a by-product of the chemical pulping industry.It is a natural UV protection ingredient in broad-spectrum(UVA and UVB)sunscreens.It could be partially and selectively acetylated in a simple,fast,and more reliable process.In this work,a composite film was prepared with UV-resistant properties through a casting method.Bio-based cellulose acetate(CA)was employed as a major matrix while nano-acetylated kraft lignin(AL-NPs)was used as filler during synthesizing UV-shielding films loaded with various amounts(1–5 wt.%)of AL-NPs.Kraft lignin was acetylated through a simple and fast microwave-assisted process using acetic acid as a solvent and acetylating agent.The physicochemical and morphological characteristics of the prepared films were evaluated using different methods,including scanning electron microscopy(SEM),Fourier Transform Infrared Spectroscopy(FTIR),X-ray diffraction analysis(XRD),mechanical testing and contact angle measurement.The UV-Vis spectroscopy optical investigation of the prepared films revealed that AL-NPs in the CA matrix showed strong UV absorption.This feature demonstrated the effectiveness of our research in developing UV-resistant bio-based polymer films.Hence,the prepared films can be considered as successful candidates to be applied in packaging applications.展开更多
Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal funct...Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's disease.Microtubule acetylation/deacetylation plays a central role in lysosomal acidification.Here,we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's disease.Fu rthermore,we found that treatment with valproic acid markedly enhanced autophagy.promoted clearance of amyloid-βaggregates,and ameliorated cognitive deficits in a mouse model of Alzheimer's disease.Our findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease,in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification.展开更多
Background:Accumulating studies have shown the important role of circular RNAs(circRNAs)in the oncogenesis and metastasis of various cancers.We previously reported that circACTN4 could bind with FUBP1 to promote tumor...Background:Accumulating studies have shown the important role of circular RNAs(circRNAs)in the oncogenesis and metastasis of various cancers.We previously reported that circACTN4 could bind with FUBP1 to promote tumorigenesis and the development of breast cancer(BC)by increasing the expression of MYC.However,its exact molecular mechanism and biological function have not been fully elucidated.Methods:Here,Circular RNA microarray analysis was conducted in 3 pairs of BC and paracancerous tissues.The expression of circACTN4 in BC cells and tissues was detected via reverse transcription‒quantitative PCR(RT‒qPCR).Cell Counting Kit-8(CCK-8),5-ethynyl-2-deoxyuridine(EdU),transwell migration,and invasion assays were performed to further detect the biological functions of circACTN4 in BC cells.Xenograft models were used to investigate the in vivo role of circACTN4.Fluorescence in situ hybridization,Chromatin immunoprecipitation(ChIP)‒qPCR,coimmunoprecipitation,fluorometric,western blot,and rescue experiments were performed to explore the mechanism of circACTN4.Results:Our results revealed that circACTN4 was highly expressed in BC cells and tissues.The upregulated expression of circACTN4 was significantly related to the T stage and TNM stage and poor prognosis of patients with BC.circACTN4 was located primarily in the nucleus of BC cells.Upregulation of circACTN4 significantly increased the proliferation,invasion,and growth of BC cells,whereas the downregulation of circACTN4 exerted the opposite effects and induced G1/S cell cycle arrest.Mechanistically,we showed that circACTN4 could upregulate the expression of MYC and that MYC might interact with TIP60 histone acetyltransferase to increase the recruitment of TIP60 to MYC target genes and histone H4 acetylation(AcH4),thus promoting the progression of the breast cancer cell cycle and tumorigenesis.Conclusion:Taken together,our findings reveal for the first time a new mechanism by which circACTN4 could promote oncogenesis and the development of BC by increasing the AcH4 of MYC target genes via TIP60.Therefore,circACTN4 could be a novel target for BC diagnosis and remedy.展开更多
Melanoma is an aggressive type of skin cancer notorious for its resistance to chemotherapy,radiotherapy and immunotherapy,which greatly impacts its lethality.The hedgehog(HH)signaling cascade,originally known for its ...Melanoma is an aggressive type of skin cancer notorious for its resistance to chemotherapy,radiotherapy and immunotherapy,which greatly impacts its lethality.The hedgehog(HH)signaling cascade,originally known for its roles in embryonic development,regulates growth,proliferation and cancer stem cell(CSC)self-renewal.The glioma-associated oncogene homolog(GLI)transcription factors play crucial roles in melanoma.However,oncogenic B-Raf proto-oncogene,serine/threonine kinase(BRAF)steals the spotlight by driving the aberrant activation of HH-GLI1/2 signaling.Oncogenic BRAF-driven HH-GLI1/2 signaling imparts invasive phenotype to melanoma cells and sustains CSC self-renewal.Interestingly,the transcriptional activities of GLI1 and GLI2 are suppressed by acetylation,a process that is counteracted by the deacetylating actions of histone deacetylase(HDAC)1/2.Therefore,inhibiting HDAC1/2 might keep GLI proteins in inactive acetylated form,thus representing an attractive druggable target.Notably,both HDAC1 and HDAC2 are induced by HH signaling,creating a positive feedback loop where HH signaling upregulates the expression of both HDAC1 and HDAC2.Selective inhibition of BRAF/HH/HDAC/GLI signaling axis is likely to unravel new therapeutic opportunities in melanoma.However,the precise contribution of oncogenic BRAF-driven HH signaling to therapy resistance and CSC renewal remains unclear and requires thorough investigation.In this article,we endeavored to explore the crosstalk between oncogenic BRAF and HH signaling,and the pivotal role this interaction plays in the self-renewal of melanoma stem cells.A better understanding of the molecular mechanisms governing these interactions is essential for improving melanoma treatment strategies and identifying new therapeutic targets.展开更多
Bromodomain(BRD)-containing proteins are central mediators of gene regulation,serving as key components of chromatin remodeling complexes and histone recognition scaffolds.By specifically recognizing acetylated lysine...Bromodomain(BRD)-containing proteins are central mediators of gene regulation,serving as key components of chromatin remodeling complexes and histone recognition scaffolds.By specifically recognizing acetylated lysine residues on histones(Kac)via their conserved BRD,these proteins influence chromatin structure and gene expression.Although their overarching role is well-established,the precise molecular functions and mechanisms of individual BRD proteins remain incompletely characterized.The ciliate Tetrahymena thermophila,a unicellular eukaryote with a transcriptionally active macronucleus enriched in histone acetylation,is an excellent model for exploring the significance of BRD-containing proteins.In this comprehensive review,all BRD-containing proteins encoded in the T.thermophila genome are systematically examined,including their expression profiles,histone acetylation targets,interacting proteins,and potential roles.This review lays the groundwork for future investigations into the complex roles of BRD proteins in chromatin remodeling and transcription regulation,offering insights into basic eukaryotic biology and the molecular mechanisms underlying BRD-linked diseases.展开更多
It has been reported that sea cucumber intestine hydrolysates(SCIH)could promote glutamine metabolism in mice,while there is a close connection between glutamine metabolism and insulin sensitivity.However,the effect o...It has been reported that sea cucumber intestine hydrolysates(SCIH)could promote glutamine metabolism in mice,while there is a close connection between glutamine metabolism and insulin sensitivity.However,the effect of SCIH on insulin resistance is still unclear.The results showed that SCIH hydrolyzed by flavor protease had significant activity using the insulin-induced Hep G2 cell model.Animal experiments exhibited that SCIH supplementation significantly improved the high-fat and high-sucrose diet-induced impaired glucose tolerance,reduced fasting serum glucose and glycosylated serum protein.Besides,SCIH ameliorated islet vacuolization and decreased the pancreas TNF-αand IL-6 by 32.1%and 36.2%,respectively.Immunofluorescence staining results showed that SCIH promoted insulin secretion.Interestingly,SCIH significantly increased the liver glutamine levels and upregulated the expression of glutaminase1(GLS1)and glutamate dehydrogenase 1(GLUD1).Furthermore,SCIH increased liver acetyl-Co A levels to enhance histone acetylation and activate the gene transcription and translation on glucose metabolism-related IRS/PI3K/AKT signaling pathway,thereby attenuating insulin resistance.The present findings proposed the potential value for developing functional foods in SCIH utilization.展开更多
The Rpd3 histone deacetylase complex is a multiple-subunit complex that mediates the regulation of chromatin accessibility and gene expression.Sin3,the largest subunit of Rpd3 complex,is conserved in a broad range of ...The Rpd3 histone deacetylase complex is a multiple-subunit complex that mediates the regulation of chromatin accessibility and gene expression.Sin3,the largest subunit of Rpd3 complex,is conserved in a broad range of eukaryotes.Despite being a molecular scaffold for complex assembly,the functional sites and mechanism of action of Sin3 remain unexplored.In this study,we functionally characterized a glutamate residue(E810)in Fg Sin3,the ortholog of yeast Sin3 in Fusarium graminearum(known as wheat scab fungus).Our findings indicate that E810 was important for the functions of Fg Sin3 in regulating vegetative growth,sexual reproduction,wheat infection,and DON biosynthesis.Furthermore,the E810K missense mutation restored the reduced H4 acetylation caused by the deletion of FNG1,the ortholog of the human inhibitor of growth(ING1)gene in F.graminearum.Correspondingly,the defects of the fng1 mutant were also partially rescued by the E810K mutation in Fg Sin3.Sequence alignment and evolutionary analysis revealed that E810 residue is well-conserved in fungi,animals,and plants.Based on Alphafold2 structure modeling,E810 localized on the Fg Rpd3–Fg Sin3 interface for the formation of a hydrogen bond with Fg Rpd3.Mutation of E810 disrupts the hydrogen bond and likely affects the Fg Rpd3–Fg Sin3 interaction.Taken together,E810 of Fg Sin3 is functionally associated with Fng1 in the regulation of H4 acetylation and related biological processes,probably by affecting the assembly of the Rpd3 complex.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
The persistence of covalently closed circular DNA(cccDNA)in hepatitis B virus(HBV)-infected hepatocytes remains a major obstacle to effective antiviral treatment.Understanding the molecular mechanisms regulating HBV c...The persistence of covalently closed circular DNA(cccDNA)in hepatitis B virus(HBV)-infected hepatocytes remains a major obstacle to effective antiviral treatment.Understanding the molecular mechanisms regulating HBV cccDNA transcription is essential for developing novel therapeutic strategies.In this study,we investigated the role of RNA binding motif protein 25(RBM25)in HBV replication,focusing on its interaction with cccDNA and its regulation of host transcription factors.The results demonstrated that RBM25 knockdown markedly inhibited HBV replication,reducing levels of HBV DNA,hepatitis B e antigen(HBeAg),hepatitis B surface antigen(HBsAg),HBV RNA,and L-HBs in HBV-replicating and infected cell models.Consistent results were observed in a mouse model hydrodynamically injected with 1.2HBV plasmid.Conversely,RBM25 overexpression significantly enhanced HBV replication.Mechanistically,RBM25 promoted HBV promoter activities by binding to cccDNA through its RE/RD and PWI domains.This effect was mediated by increased Yin Yang 1(YY1)expression,which enhanced acetylation of cccDNA-bound histones,promoting HBV transcription.Furthermore,RBM25 expression was upregulated and translocated to the nucleus following core protein expression and accumulation,while overexpression of RBM25 promoted core protein degradation.In conclusion,this study demonstrates that RBM25 is a novel host factor that enhances HBV replication by upregulating YY1-dependent transcriptional activation of cccDNA.It also reveales a reciprocal regulatory mechanism between the HBV core protein and RBM25,which helps sustain HBV replication.展开更多
Alzheimer’s disease is the most prevalent neurodegenerative disease affecting older adults.Primary features of Alzheimer’s disease include extra cellular aggregation of amyloid-βplaques and the accumulation of neur...Alzheimer’s disease is the most prevalent neurodegenerative disease affecting older adults.Primary features of Alzheimer’s disease include extra cellular aggregation of amyloid-βplaques and the accumulation of neurofibrillary tangles,fo rmed by tau protein,in the cells.While there are amyloid-β-ta rgeting therapies for the treatment of Alzheimer’s disease,these therapies are costly and exhibit potential negative side effects.Mounting evidence suggests significant involvement of tau protein in Alzheimer’s disease-related neurodegeneration.As an important microtubule-associated protein,tau plays an important role in maintaining the stability of neuronal microtubules and promoting axonal growth.In fact,clinical studies have shown that abnormal phosphorylation of tau protein occurs before accumulation of amyloid-βin the brain.Various therapeutic strategies targeting tau protein have begun to emerge,and are considered possible methods to prevent and treat Alzheimer’s disease.Specifically,abnormalities in post-translational modifications of the tau protein,including aberrant phosphorylation,ubiquitination,small ubiquitin-like modifier(SUMO)ylation,acetylation,and truncation,contribute to its microtubule dissociation,misfolding,and subcellular missorting.This causes mitochondrial damage,synaptic impairments,gliosis,and neuroinflammation,eventually leading to neurodegeneration and cognitive deficits.This review summarizes the recent findings on the underlying mechanisms of tau protein in the onset and progression of Alzheimer’s disease and discusses tau-targeted treatment of Alzheimer’s disease.展开更多
The gut microbiome interacts with the host to maintain body homeostasis,with gut microbial dysbiosis implicated in many diseases.However,the underlying mechanisms of gut microbe regulation of host behavior and brain f...The gut microbiome interacts with the host to maintain body homeostasis,with gut microbial dysbiosis implicated in many diseases.However,the underlying mechanisms of gut microbe regulation of host behavior and brain functions remain unclear.This study aimed to elucidate the influence of gut microbiota on brain functions via post-translational modification mechanisms in the presence or absence of bacteria without any stimulation.We conducted succinylome analysis of hippocampal proteins in germ-free(GF)and specific pathogen-free(SPF)mice and metagenomic analysis of feces from SPF mice.These results were integrated with previously reported hippocampal acetylome and phosphorylome data from the same batch of mice.Subsequent bioinformatics analyses revealed 584 succinylation sites on 455 proteins,including 54 up-regulated succinylation sites on 91 proteins and 99 down-regulated sites on 51 proteins in the GF mice compared to the SPF mice.We constructed a panoramic map of gut microbiota-regulated succinylation,acetylation,and phosphorylation,and identified cross-talk and relative independence between the different types of post-translational modifications in modulating complicated intracellular pathways.Pearson correlation analysis indicated that 13 taxa,predominantly belonging to the Bacteroidetes phylum,were correlated with the biological functions of post-translational modifications.Positive correlations between these taxa and succinylation and negative correlations between these taxa and acetylation were identified in the modulation of intracellular pathways.This study highlights the hippocampal physiological changes induced by the absence of gut microbiota,and proteomic quantification of succinylation,phosphorylation,and acetylation,contributing to our understanding of the role of the gut microbiome in brain function and behavioral phenotypes.展开更多
The cancer cell metastasis is a major death reason for patients with non-small cell lung cancer(NSCLC).Although researchers have disclosed that interleukin 17(IL-17)can increase matrix metalloproteinases(MMPs)inductio...The cancer cell metastasis is a major death reason for patients with non-small cell lung cancer(NSCLC).Although researchers have disclosed that interleukin 17(IL-17)can increase matrix metalloproteinases(MMPs)induction causing NSCLC cell metastasis,the underlying mechanism remains unclear.In the study,we found that IL-17 receptor A(IL-17RA),p300,p-STAT3,Ack-STAT3,and MMP19 were up-regulated both in NSCLC tissues and NSCLC cells stimulated with IL-17.p300,STAT3 and MMP19 overexpression or knockdown could raise or reduce IL-17-induced p-STAT3,Ack-STAT3 and MMP19 level as well as the cell migration and invasion.Mechanism investigation revealed that STAT3 and p300 bound to the same region(−544 to−389 nt)of MMP19 promoter,and p300 could acetylate STAT3-K631 elevating STAT3 transcriptional activity,p-STAT3 or MMP19 expression and the cell mobility exposed to IL-17.Meanwhile,p300-mediated STAT3-K631 acetylation and its Y705-phosphorylation could interact,synergistically facilitating MMP19 gene transcription and enhancing cell migration and invasion.Besides,the animal experiments exhibited that the nude mice inoculated with NSCLC cells by silencing p300,STAT3 or MMP19 gene plus IL-17 treatment,the nodule number,and MMP19,Ack-STAT3,or p-STAT3 production in the lung metastatic nodules were all alleviated.Collectively,these outcomes uncover that IL-17-triggered NSCLC metastasis involves up-regulating MMP19 expression via the interaction of STAT3-K631 acetylation by p300 and its Y705-phosphorylation,which provides a new mechanistic insight and potential strategy for NSCLC metastasis and therapy.展开更多
OBJECTIVE:To explore whether the regulation of matrix metalloproteinase 9(MMP-9)/tissue inhibitors of MMPs(TIMPs)gene expression through histone acetylation is a possible mechanism by which electroacupuncture(EA)prote...OBJECTIVE:To explore whether the regulation of matrix metalloproteinase 9(MMP-9)/tissue inhibitors of MMPs(TIMPs)gene expression through histone acetylation is a possible mechanism by which electroacupuncture(EA)protects blood-brain barrier(BBB)integrity in a middle cerebral artery occlusion(MCAO)rat model.METHODS:Male Sprague-Dawley rats were divided into four groups:the sham group,the MCAO group,the MCAO+EA(MEA)group,and the MCAO+EA+HAT inhibitor(HATi)group.The MCAO model was generated by blocking the middle cerebral artery.EA was applied to Baihui(GV20).Samples were collected 1 or 3 d after reperfusion.Neurological function scores and Evans blue extravasation were employed to evaluate the poststroke injury.The effect of EA on MMP-9/TIMPs gene expression was assessed by real-time fluorescence quantitative polymerase chain reaction(RT-qPCR)and chromatin immunoprecipitation(ChIP).RESULTS:Our results showed that EA treatment prominently improved neurological function and ameliorated BBB disruption.The RT-qPCR assay showed that EA reduced the expression of MMP-9 and promoted TIMP-2 mRNA expression,but HATi reversed these effects of EA.In addition,ChIP results revealed that EA decreased the enrichment of H3K9ace/H3K27ace at MMP-9 promoters and notably stimulated the recruitment of H3K9ace/H3K27ace at TIMP-2 promoter.CONCLUSION:EA treatment at Baihui(GV20)regulates the transcription of MMP-9 and TIMP-2 through histone acetylation modification in the acute stage of stroke,which preserves the structural integrity of the BBB in MCAO rats.These findings suggested that the histone acetylation-mediated transcriptional activity of target genes may be a crucial mechanism of EA treatment in stroke.展开更多
Influenza A virus(IAV)continues to pose a pandemic threat to public health,resulting a high mortality rate annually and during pandemic years.Posttranslational modification of viral protein plays a substantial role in...Influenza A virus(IAV)continues to pose a pandemic threat to public health,resulting a high mortality rate annually and during pandemic years.Posttranslational modification of viral protein plays a substantial role in regulating IAV infection.Here,based on immunoprecipitation(IP)-based mass spectrometry(MS)and purified virus-coupled MS,a total of 89 phosphorylation sites distributed among 10 encoded viral proteins of IAV were identified,including 60 novel phosphorylation sites.Additionally,for the first time,we provide evidence that PB2 can also be acetylated at site K187.Notably,the PB2 S181 phosphorylation site was consistently identified in both IP-based MS and purified virus-based MS.Both S181 and K187 are exposed on the surface of the PB2 protein and are highly conserved in various IAV strains,suggesting their fundamental importance in the IAV life cycle.Bioinformatic analysis results demonstrated that S181E/A and K187Q/R mimic mutations do not significantly alter the PB2 protein structure.While continuous phosphorylation mimicked by the PB2 S181E mutation substantially decreases viral fitness in mice,PB2 K187Q mimetic acetylation slightly enhances viral virulence in mice.Mechanistically,PB2 S181E substantially impairs viral polymerase activity and viral replication,remarkably dampens protein stability and nuclear accumulation of PB2,and significantly weakens IAV-induced inflammatory responses.Therefore,our study further enriches the database of phosphorylation and acetylation sites of influenza viral proteins,laying a foundation for subsequent mechanistic studies.Meanwhile,the unraveled antiviral effect of PB2 S181E mimetic phosphorylation may provide a new target for the subsequent study of antiviral drugs.展开更多
MIcroglia/macrophage-mediated erythrophagocytosis plays a crucial role in hematoma clearance after intracerebral hemorrhage.Dynamic cytoskeletal changes accompany phagocytosis.However,whether and how these changes are...MIcroglia/macrophage-mediated erythrophagocytosis plays a crucial role in hematoma clearance after intracerebral hemorrhage.Dynamic cytoskeletal changes accompany phagocytosis.However,whether and how these changes are associated with microglia/macrophage-mediated erythrophagocytosis remain unclear.In this study,we investigated the function of acetylatedα-tubulin,a stabilized microtubule form,in microglia/macrophage erythrophagocytosis after intracerebral hemorrhage both in vitro and in vivo.We first assessed the function of acetylatedα-tubulin in erythrophagocytosis using primary DiO GFP-labeled red blood cells co-cultured with the BV2 microglia or RAW264.7 macrophage cell lines.Acetylatedα-tubulin expression was significantly decreased in BV2 and RAW264.7 cells during erythrophagocytosis.Moreover,silencingα-tubulin acetyltransferase 1(ATAT1),a newly discoveredα-tubulin acetyltransferase,decreased Ac-α-tub levels and enhanced the erythrophagocytosis by BV2 and RAW264.7 cells.Consistent with these findings,in ATAT1-/-mice,we observed increased ionized calcium binding adapter molecule 1(Iba1)and Perls-positive microglia/macrophage phagocytes of red blood cells in peri-hematoma and reduced hematoma volume in mice with intracerebral hemorrhage.Additionally,knocking out ATAT1 alleviated neuronal apoptosis and pro-inflammatory cytokines and increased anti-inflammatory cytokines around the hematoma,ultimately improving neurological recovery of mice after intracerebral hemorrhage.These findings suggest that ATAT1 deficiency accelerates erythrophagocytosis by microglia/macrophages and hematoma absorption after intracerebral hemorrhage.These results provide novel insights into the mechanisms of hematoma clearance and suggest ATAT1 as a potential target for the treatment of intracerebral hemorrhage.展开更多
Background Hepatic steatosis is a prevalent manifestation of fatty liver, that has detrimental effect on the health and productivity of laying hens, resulting in economic losses to the poultry industry. Here, we aimed...Background Hepatic steatosis is a prevalent manifestation of fatty liver, that has detrimental effect on the health and productivity of laying hens, resulting in economic losses to the poultry industry. Here, we aimed to systematically investigate the genetic regulatory mechanisms of hepatic steatosis in laying hens.Methods Ninety individuals with the most prominent characteristics were selected from 686 laying hens according to the accumulation of lipid droplets in the liver, and were graded into three groups, including the control, mild hepatic steatosis and severe hepatic steatosis groups. A combination of transcriptome, proteome, acetylome and lipidome analyses, along with bioinformatics analysis were used to screen the key biological processes, modifications and lipids associated with hepatic steatosis.Results The rationality of the hepatic steatosis grouping was verified through liver biochemical assays and RNA-seq. Hepatic steatosis was characterized by increased lipid deposition and multiple metabolic abnormalities. Integration of proteome and acetylome revealed that differentially expressed proteins(DEPs) interacted with differentially acetylated proteins(DAPs) and were involved in maintaining the metabolic balance in the liver. Acetylation alterations mainly occurred in the progression from mild to severe hepatic steatosis, i.e., the enzymes in the fatty acid oxidation and bile acid synthesis pathways were significantly less acetylated in severe hepatic steatosis group than that in mild group(P < 0.05). Lipidomics detected a variety of sphingolipids(SPs) and glycerophospholipids(GPs) were negatively correlated with hepatic steatosis(r ≤-0.5, P < 0.05). Furthermore, the severity of hepatic steatosis was associated with a decrease in cholesterol and bile acid synthesis and an increase in exogenous cholesterol transport.Conclusions In addition to acquiring a global and thorough picture of hepatic steatosis in laying hens, we were able to reveal the role of acetylation in hepatic steatosis and depict the changes in hepatic cholesterol metabolism. The findings provides a wealth of information to facilitate a deeper understanding of the pathophysiology of fatty liver and contributes to the development of therapeutic strategies.展开更多
Starting from sissotrin (1), a natural isoflavonoid isolated from Trifolium baccarinii (Fabaceae), one new semisynthetic derivative, 6-nitrobiochanin A (1b) and two known derivatives, 8-nitrobiochanin A (1a) and 2&quo...Starting from sissotrin (1), a natural isoflavonoid isolated from Trifolium baccarinii (Fabaceae), one new semisynthetic derivative, 6-nitrobiochanin A (1b) and two known derivatives, 8-nitrobiochanin A (1a) and 2",3",4",6"-tetraacetylsissotrin (1c) have been obtained after performing nitration and acetylation reactions. Their structures were assigned after interpretation of their spectrometric (HR-ESI-MS) and spectroscopic (NMR 1D and 2D) data and by comparison with those reported in the literature. The substrate as well as the semisynthetic derivatives were evaluated for their antibacterial activities against six strains. The results reveal that they are inactive or weakly active on the strains tested with the exception of 8-nitrobiochanin A (1a) which showed moderate activity (MIC = 62.5 μg∙mL<sup>−1</sup>) on Staphylococcus aureus ATCC 43300.展开更多
Chinese bamboo flour was chemically modified by acetylation with acetic anhydride by using trichloroacetic acid as an activation agent and the optimized condition for acetylation of bamboo flour was determined as the ...Chinese bamboo flour was chemically modified by acetylation with acetic anhydride by using trichloroacetic acid as an activation agent and the optimized condition for acetylation of bamboo flour was determined as the trichloroacetic acid amount 6.0 g per 1.5-g bamboo flour, ultrasosonication duration 40 min and the reaction time 1 h at 65℃. The composition, microstructure and thermal behavior of acetylated bamboo flour were preliminarily characterized by FT-IR, DSC and SEM etc. The acetylated bamboo flour can be molded into sheets at 130℃ and 10 MPa, indicating the modified bamboo flour possesses thermalplastic performance.展开更多
基金supported by grants from the National Key R&D Program of China(2022YFC2403000 and 2021YFC2400500)the National Natural Science Foundation of China(32200728 and 32170925)+3 种基金the Clinical Research Project of Shenzhen Medical Academy of Research and Translation(C2301008)Shenzhen Science and Technology Program(JCYJ20220531100406014,JCYJ2022081800807016,RCBS20221008093336088,KQTD20210811090115019)Guangdong Basic and Applied Basic Research Foundation(2021A1515110375)the Innovative Research Team of High-level Local Universities in Shanghai(SHSMU-ZDCX20210601).
文摘Regulatory T(Treg)cells are pivotal for maintaining immune homeostasis and play essential roles in various diseases,such as autoimmune diseases,graft-versus-host disease(GVHD),tumors,and infectious diseases.Treg cells exert suppressive function via distinct mechanisms,including inhibitory cytokines,granzyme or perforin-mediated cytolysis,metabolic disruption,and suppression of dendritic cells.Forkhead Box P3(FOXP3),the characteristic transcription factor,is essential for Treg cell function and plasticity.Cumulative evidence has demonstrated that FOXP3 activity and Treg cell function are modulated by a variety of post-translational modifications(PTMs),including ubiquitination,acetylation,phosphorylation,methylation,glycosylation,poly(ADP-ribosyl)ation,and uncharacterized modifications.This review describes Treg cell suppressive mechanisms and summarizes the current evidence on PTM regulation of FOXP3 and Treg cell function.Understanding the regulatory role of PTMs in Treg cell plasticity and function will be helpful in designing therapeutic strategies for autoimmune diseases,GVHD,tumors,and infectious diseases.
文摘Developing favorable bio-based polymers that replace petroleum-based plastics is an essential environmental demand.Lignin is a by-product of the chemical pulping industry.It is a natural UV protection ingredient in broad-spectrum(UVA and UVB)sunscreens.It could be partially and selectively acetylated in a simple,fast,and more reliable process.In this work,a composite film was prepared with UV-resistant properties through a casting method.Bio-based cellulose acetate(CA)was employed as a major matrix while nano-acetylated kraft lignin(AL-NPs)was used as filler during synthesizing UV-shielding films loaded with various amounts(1–5 wt.%)of AL-NPs.Kraft lignin was acetylated through a simple and fast microwave-assisted process using acetic acid as a solvent and acetylating agent.The physicochemical and morphological characteristics of the prepared films were evaluated using different methods,including scanning electron microscopy(SEM),Fourier Transform Infrared Spectroscopy(FTIR),X-ray diffraction analysis(XRD),mechanical testing and contact angle measurement.The UV-Vis spectroscopy optical investigation of the prepared films revealed that AL-NPs in the CA matrix showed strong UV absorption.This feature demonstrated the effectiveness of our research in developing UV-resistant bio-based polymer films.Hence,the prepared films can be considered as successful candidates to be applied in packaging applications.
基金supported by the National Natural Science Foundation of China,No.82201582(to QT)Scientific and Technological Research Program of Chongqing Municipal Education Commission,No.KJQN202200457(to QT)+3 种基金General Project of Changqing Natural Science Foundation,No.cstc2021jcyjmsxmX0442(to ZL)CQMU Program for Youth Innovation in Future Medicine,No.W0044(to ZD and GH)Direct Research Project for PhD of Chongqing,No.CSTB2022BSXM-JCX0051(to ZL)the Project of the Top-Notch Talent Cultivation Program For the Graduate Students of Chongqing Medical University,No.BJRC202310(to CG)。
文摘Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's disease.Microtubule acetylation/deacetylation plays a central role in lysosomal acidification.Here,we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's disease.Fu rthermore,we found that treatment with valproic acid markedly enhanced autophagy.promoted clearance of amyloid-βaggregates,and ameliorated cognitive deficits in a mouse model of Alzheimer's disease.Our findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease,in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification.
基金supported by National Natural Science Foundation of China(No.82173170,Junxia ChenNo.82103089,Lei Xing)Natural Science Foundation of Chongqing,China(No.CSTB2022BSXMJCX0057,Lei Xing).
文摘Background:Accumulating studies have shown the important role of circular RNAs(circRNAs)in the oncogenesis and metastasis of various cancers.We previously reported that circACTN4 could bind with FUBP1 to promote tumorigenesis and the development of breast cancer(BC)by increasing the expression of MYC.However,its exact molecular mechanism and biological function have not been fully elucidated.Methods:Here,Circular RNA microarray analysis was conducted in 3 pairs of BC and paracancerous tissues.The expression of circACTN4 in BC cells and tissues was detected via reverse transcription‒quantitative PCR(RT‒qPCR).Cell Counting Kit-8(CCK-8),5-ethynyl-2-deoxyuridine(EdU),transwell migration,and invasion assays were performed to further detect the biological functions of circACTN4 in BC cells.Xenograft models were used to investigate the in vivo role of circACTN4.Fluorescence in situ hybridization,Chromatin immunoprecipitation(ChIP)‒qPCR,coimmunoprecipitation,fluorometric,western blot,and rescue experiments were performed to explore the mechanism of circACTN4.Results:Our results revealed that circACTN4 was highly expressed in BC cells and tissues.The upregulated expression of circACTN4 was significantly related to the T stage and TNM stage and poor prognosis of patients with BC.circACTN4 was located primarily in the nucleus of BC cells.Upregulation of circACTN4 significantly increased the proliferation,invasion,and growth of BC cells,whereas the downregulation of circACTN4 exerted the opposite effects and induced G1/S cell cycle arrest.Mechanistically,we showed that circACTN4 could upregulate the expression of MYC and that MYC might interact with TIP60 histone acetyltransferase to increase the recruitment of TIP60 to MYC target genes and histone H4 acetylation(AcH4),thus promoting the progression of the breast cancer cell cycle and tumorigenesis.Conclusion:Taken together,our findings reveal for the first time a new mechanism by which circACTN4 could promote oncogenesis and the development of BC by increasing the AcH4 of MYC target genes via TIP60.Therefore,circACTN4 could be a novel target for BC diagnosis and remedy.
基金Supported by the Science and Engineering Research Board,No.PDF/2016/002730.
文摘Melanoma is an aggressive type of skin cancer notorious for its resistance to chemotherapy,radiotherapy and immunotherapy,which greatly impacts its lethality.The hedgehog(HH)signaling cascade,originally known for its roles in embryonic development,regulates growth,proliferation and cancer stem cell(CSC)self-renewal.The glioma-associated oncogene homolog(GLI)transcription factors play crucial roles in melanoma.However,oncogenic B-Raf proto-oncogene,serine/threonine kinase(BRAF)steals the spotlight by driving the aberrant activation of HH-GLI1/2 signaling.Oncogenic BRAF-driven HH-GLI1/2 signaling imparts invasive phenotype to melanoma cells and sustains CSC self-renewal.Interestingly,the transcriptional activities of GLI1 and GLI2 are suppressed by acetylation,a process that is counteracted by the deacetylating actions of histone deacetylase(HDAC)1/2.Therefore,inhibiting HDAC1/2 might keep GLI proteins in inactive acetylated form,thus representing an attractive druggable target.Notably,both HDAC1 and HDAC2 are induced by HH signaling,creating a positive feedback loop where HH signaling upregulates the expression of both HDAC1 and HDAC2.Selective inhibition of BRAF/HH/HDAC/GLI signaling axis is likely to unravel new therapeutic opportunities in melanoma.However,the precise contribution of oncogenic BRAF-driven HH signaling to therapy resistance and CSC renewal remains unclear and requires thorough investigation.In this article,we endeavored to explore the crosstalk between oncogenic BRAF and HH signaling,and the pivotal role this interaction plays in the self-renewal of melanoma stem cells.A better understanding of the molecular mechanisms governing these interactions is essential for improving melanoma treatment strategies and identifying new therapeutic targets.
基金supported by the National Natural Science Foundation of China(32200399 to Y.W.,32125006 to S.G.)Natural Science Foundation of Shandong Province(ZR2024ZD40 to S.G.,ZR2024MC112 to Y.W.)+4 种基金Young Talent of Lifting Engineering for Science and Technology in Shandong,China(SDAST2024QTA008 to Y.W.)Fundamental Research Funds for the Central Universities(202441014 to Y.W.)Postdoctoral Fellowship Program of the China Postdoctoral Science Foundation(CPSF)(GZC20232503 to Y.L.)China Postdoctoral Science Foundation(2024M753050 to Y.L.)Laoshan Laboratory(LSKJ202203203 to S.G.)。
文摘Bromodomain(BRD)-containing proteins are central mediators of gene regulation,serving as key components of chromatin remodeling complexes and histone recognition scaffolds.By specifically recognizing acetylated lysine residues on histones(Kac)via their conserved BRD,these proteins influence chromatin structure and gene expression.Although their overarching role is well-established,the precise molecular functions and mechanisms of individual BRD proteins remain incompletely characterized.The ciliate Tetrahymena thermophila,a unicellular eukaryote with a transcriptionally active macronucleus enriched in histone acetylation,is an excellent model for exploring the significance of BRD-containing proteins.In this comprehensive review,all BRD-containing proteins encoded in the T.thermophila genome are systematically examined,including their expression profiles,histone acetylation targets,interacting proteins,and potential roles.This review lays the groundwork for future investigations into the complex roles of BRD proteins in chromatin remodeling and transcription regulation,offering insights into basic eukaryotic biology and the molecular mechanisms underlying BRD-linked diseases.
基金supported by National Key Research and Development Program of China(2023YFF1103901)the Taishan Scholars Program(tstp20240812)+2 种基金China Postdoctoral Science Foundation(2024M763107)Postdoctoral Fellowship Program of CPSF(GZC20241617)Youth Innovation Team Program of Universities in Shandong Province(2023KJ040)。
文摘It has been reported that sea cucumber intestine hydrolysates(SCIH)could promote glutamine metabolism in mice,while there is a close connection between glutamine metabolism and insulin sensitivity.However,the effect of SCIH on insulin resistance is still unclear.The results showed that SCIH hydrolyzed by flavor protease had significant activity using the insulin-induced Hep G2 cell model.Animal experiments exhibited that SCIH supplementation significantly improved the high-fat and high-sucrose diet-induced impaired glucose tolerance,reduced fasting serum glucose and glycosylated serum protein.Besides,SCIH ameliorated islet vacuolization and decreased the pancreas TNF-αand IL-6 by 32.1%and 36.2%,respectively.Immunofluorescence staining results showed that SCIH promoted insulin secretion.Interestingly,SCIH significantly increased the liver glutamine levels and upregulated the expression of glutaminase1(GLS1)and glutamate dehydrogenase 1(GLUD1).Furthermore,SCIH increased liver acetyl-Co A levels to enhance histone acetylation and activate the gene transcription and translation on glucose metabolism-related IRS/PI3K/AKT signaling pathway,thereby attenuating insulin resistance.The present findings proposed the potential value for developing functional foods in SCIH utilization.
基金supported by the grants from the National Natural Science Foundation of China(32102181)the Shaanxi Science Fund for Distinguished Young Scholars,China(2022JC-14)。
文摘The Rpd3 histone deacetylase complex is a multiple-subunit complex that mediates the regulation of chromatin accessibility and gene expression.Sin3,the largest subunit of Rpd3 complex,is conserved in a broad range of eukaryotes.Despite being a molecular scaffold for complex assembly,the functional sites and mechanism of action of Sin3 remain unexplored.In this study,we functionally characterized a glutamate residue(E810)in Fg Sin3,the ortholog of yeast Sin3 in Fusarium graminearum(known as wheat scab fungus).Our findings indicate that E810 was important for the functions of Fg Sin3 in regulating vegetative growth,sexual reproduction,wheat infection,and DON biosynthesis.Furthermore,the E810K missense mutation restored the reduced H4 acetylation caused by the deletion of FNG1,the ortholog of the human inhibitor of growth(ING1)gene in F.graminearum.Correspondingly,the defects of the fng1 mutant were also partially rescued by the E810K mutation in Fg Sin3.Sequence alignment and evolutionary analysis revealed that E810 residue is well-conserved in fungi,animals,and plants.Based on Alphafold2 structure modeling,E810 localized on the Fg Rpd3–Fg Sin3 interface for the formation of a hydrogen bond with Fg Rpd3.Mutation of E810 disrupts the hydrogen bond and likely affects the Fg Rpd3–Fg Sin3 interaction.Taken together,E810 of Fg Sin3 is functionally associated with Fng1 in the regulation of H4 acetylation and related biological processes,probably by affecting the assembly of the Rpd3 complex.
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].
基金supported by the National Key R&D Program of China(No.2022YFA1303600 and No.2023YFC2306800)the National Natural Science Foundation of China(No.82372235 and No.82272315)the Sanming Project of Medicine in Shenzhen(No.SZSM202311032).
文摘The persistence of covalently closed circular DNA(cccDNA)in hepatitis B virus(HBV)-infected hepatocytes remains a major obstacle to effective antiviral treatment.Understanding the molecular mechanisms regulating HBV cccDNA transcription is essential for developing novel therapeutic strategies.In this study,we investigated the role of RNA binding motif protein 25(RBM25)in HBV replication,focusing on its interaction with cccDNA and its regulation of host transcription factors.The results demonstrated that RBM25 knockdown markedly inhibited HBV replication,reducing levels of HBV DNA,hepatitis B e antigen(HBeAg),hepatitis B surface antigen(HBsAg),HBV RNA,and L-HBs in HBV-replicating and infected cell models.Consistent results were observed in a mouse model hydrodynamically injected with 1.2HBV plasmid.Conversely,RBM25 overexpression significantly enhanced HBV replication.Mechanistically,RBM25 promoted HBV promoter activities by binding to cccDNA through its RE/RD and PWI domains.This effect was mediated by increased Yin Yang 1(YY1)expression,which enhanced acetylation of cccDNA-bound histones,promoting HBV transcription.Furthermore,RBM25 expression was upregulated and translocated to the nucleus following core protein expression and accumulation,while overexpression of RBM25 promoted core protein degradation.In conclusion,this study demonstrates that RBM25 is a novel host factor that enhances HBV replication by upregulating YY1-dependent transcriptional activation of cccDNA.It also reveales a reciprocal regulatory mechanism between the HBV core protein and RBM25,which helps sustain HBV replication.
基金supported by the National Natural Science Foundation of China,No.82101493(to JY)。
文摘Alzheimer’s disease is the most prevalent neurodegenerative disease affecting older adults.Primary features of Alzheimer’s disease include extra cellular aggregation of amyloid-βplaques and the accumulation of neurofibrillary tangles,fo rmed by tau protein,in the cells.While there are amyloid-β-ta rgeting therapies for the treatment of Alzheimer’s disease,these therapies are costly and exhibit potential negative side effects.Mounting evidence suggests significant involvement of tau protein in Alzheimer’s disease-related neurodegeneration.As an important microtubule-associated protein,tau plays an important role in maintaining the stability of neuronal microtubules and promoting axonal growth.In fact,clinical studies have shown that abnormal phosphorylation of tau protein occurs before accumulation of amyloid-βin the brain.Various therapeutic strategies targeting tau protein have begun to emerge,and are considered possible methods to prevent and treat Alzheimer’s disease.Specifically,abnormalities in post-translational modifications of the tau protein,including aberrant phosphorylation,ubiquitination,small ubiquitin-like modifier(SUMO)ylation,acetylation,and truncation,contribute to its microtubule dissociation,misfolding,and subcellular missorting.This causes mitochondrial damage,synaptic impairments,gliosis,and neuroinflammation,eventually leading to neurodegeneration and cognitive deficits.This review summarizes the recent findings on the underlying mechanisms of tau protein in the onset and progression of Alzheimer’s disease and discusses tau-targeted treatment of Alzheimer’s disease.
基金supported by the Natural Science Foundation Project of China(81820108015,82201683)China Postdoctoral Science Foundation(2021M693926,2020TQ0393,2020M683634XB)+1 种基金Chongqing Science&Technology Commission(cstc2021jcyj-bshX0150,cstc2021jcyj-bshX0201)Special Funding for Chongqing Postdoctoral Research Projects(2021XMT001)。
文摘The gut microbiome interacts with the host to maintain body homeostasis,with gut microbial dysbiosis implicated in many diseases.However,the underlying mechanisms of gut microbe regulation of host behavior and brain functions remain unclear.This study aimed to elucidate the influence of gut microbiota on brain functions via post-translational modification mechanisms in the presence or absence of bacteria without any stimulation.We conducted succinylome analysis of hippocampal proteins in germ-free(GF)and specific pathogen-free(SPF)mice and metagenomic analysis of feces from SPF mice.These results were integrated with previously reported hippocampal acetylome and phosphorylome data from the same batch of mice.Subsequent bioinformatics analyses revealed 584 succinylation sites on 455 proteins,including 54 up-regulated succinylation sites on 91 proteins and 99 down-regulated sites on 51 proteins in the GF mice compared to the SPF mice.We constructed a panoramic map of gut microbiota-regulated succinylation,acetylation,and phosphorylation,and identified cross-talk and relative independence between the different types of post-translational modifications in modulating complicated intracellular pathways.Pearson correlation analysis indicated that 13 taxa,predominantly belonging to the Bacteroidetes phylum,were correlated with the biological functions of post-translational modifications.Positive correlations between these taxa and succinylation and negative correlations between these taxa and acetylation were identified in the modulation of intracellular pathways.This study highlights the hippocampal physiological changes induced by the absence of gut microbiota,and proteomic quantification of succinylation,phosphorylation,and acetylation,contributing to our understanding of the role of the gut microbiome in brain function and behavioral phenotypes.
基金National Natural Science Foundation of China(Grants Numbers 81902878 and 81971468).
文摘The cancer cell metastasis is a major death reason for patients with non-small cell lung cancer(NSCLC).Although researchers have disclosed that interleukin 17(IL-17)can increase matrix metalloproteinases(MMPs)induction causing NSCLC cell metastasis,the underlying mechanism remains unclear.In the study,we found that IL-17 receptor A(IL-17RA),p300,p-STAT3,Ack-STAT3,and MMP19 were up-regulated both in NSCLC tissues and NSCLC cells stimulated with IL-17.p300,STAT3 and MMP19 overexpression or knockdown could raise or reduce IL-17-induced p-STAT3,Ack-STAT3 and MMP19 level as well as the cell migration and invasion.Mechanism investigation revealed that STAT3 and p300 bound to the same region(−544 to−389 nt)of MMP19 promoter,and p300 could acetylate STAT3-K631 elevating STAT3 transcriptional activity,p-STAT3 or MMP19 expression and the cell mobility exposed to IL-17.Meanwhile,p300-mediated STAT3-K631 acetylation and its Y705-phosphorylation could interact,synergistically facilitating MMP19 gene transcription and enhancing cell migration and invasion.Besides,the animal experiments exhibited that the nude mice inoculated with NSCLC cells by silencing p300,STAT3 or MMP19 gene plus IL-17 treatment,the nodule number,and MMP19,Ack-STAT3,or p-STAT3 production in the lung metastatic nodules were all alleviated.Collectively,these outcomes uncover that IL-17-triggered NSCLC metastasis involves up-regulating MMP19 expression via the interaction of STAT3-K631 acetylation by p300 and its Y705-phosphorylation,which provides a new mechanistic insight and potential strategy for NSCLC metastasis and therapy.
基金the National Natural Science Foundation of China:the Role of Intestinal Flora-Treg/γδT Cell-IL-17 Signaling in the Neuroprotective Effect of Electroacupuncture on Ischemic Brain Injury(No.81774403)the Natural Science Foundation of the Jiangsu Province of China:Study on the Mechanism of Acupuncture Antistroke Immune Inflammatory Response Based on Intestinal Treg/γδT Cell-IL-17 Signaling Pathway(No.BK20171492)+2 种基金the Postgraduate Scientific Research Innovation Practice Project of the Jiangsu Province of China:a Study based on the Butyric Acid-HDAC-Foxp3 Pathway to Explore the Regulatory Effect of Acupuncture on Intestinal Treg in Rats with Stroke(No.KYCX21_1715)a Study on the Anti-brain Injury of Electroacupuncture Based on Intestinal Microbiota-Treg/γδT Cell-IL-17 Pathway(No.KYCX21_1716)the Key University Science Research Project of Jiangsu Province:the Role of Preactivation of the Treg Immune Response in the Mechanism of Anti-stroke Neuroinflammatory Response in Acupuncture Pretreatment(No.22KJA360003)。
文摘OBJECTIVE:To explore whether the regulation of matrix metalloproteinase 9(MMP-9)/tissue inhibitors of MMPs(TIMPs)gene expression through histone acetylation is a possible mechanism by which electroacupuncture(EA)protects blood-brain barrier(BBB)integrity in a middle cerebral artery occlusion(MCAO)rat model.METHODS:Male Sprague-Dawley rats were divided into four groups:the sham group,the MCAO group,the MCAO+EA(MEA)group,and the MCAO+EA+HAT inhibitor(HATi)group.The MCAO model was generated by blocking the middle cerebral artery.EA was applied to Baihui(GV20).Samples were collected 1 or 3 d after reperfusion.Neurological function scores and Evans blue extravasation were employed to evaluate the poststroke injury.The effect of EA on MMP-9/TIMPs gene expression was assessed by real-time fluorescence quantitative polymerase chain reaction(RT-qPCR)and chromatin immunoprecipitation(ChIP).RESULTS:Our results showed that EA treatment prominently improved neurological function and ameliorated BBB disruption.The RT-qPCR assay showed that EA reduced the expression of MMP-9 and promoted TIMP-2 mRNA expression,but HATi reversed these effects of EA.In addition,ChIP results revealed that EA decreased the enrichment of H3K9ace/H3K27ace at MMP-9 promoters and notably stimulated the recruitment of H3K9ace/H3K27ace at TIMP-2 promoter.CONCLUSION:EA treatment at Baihui(GV20)regulates the transcription of MMP-9 and TIMP-2 through histone acetylation modification in the acute stage of stroke,which preserves the structural integrity of the BBB in MCAO rats.These findings suggested that the histone acetylation-mediated transcriptional activity of target genes may be a crucial mechanism of EA treatment in stroke.
基金supported by the National Natural Science Foundation of China(32072832,32372976)by the National Key Research and Development Project of China(2021YFD1800202)+3 种基金by Jiangsu Province Agricultural Science&Technology Independent Innovation Funds[CX(21)3141]by the Postgraduate Research&Practice Innovation Program of Jiangsu Province(KYCX22_3553 and KYCX21_3277)by the Earmarked Fund for China Agriculture Research System(CARS-40)a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.
文摘Influenza A virus(IAV)continues to pose a pandemic threat to public health,resulting a high mortality rate annually and during pandemic years.Posttranslational modification of viral protein plays a substantial role in regulating IAV infection.Here,based on immunoprecipitation(IP)-based mass spectrometry(MS)and purified virus-coupled MS,a total of 89 phosphorylation sites distributed among 10 encoded viral proteins of IAV were identified,including 60 novel phosphorylation sites.Additionally,for the first time,we provide evidence that PB2 can also be acetylated at site K187.Notably,the PB2 S181 phosphorylation site was consistently identified in both IP-based MS and purified virus-based MS.Both S181 and K187 are exposed on the surface of the PB2 protein and are highly conserved in various IAV strains,suggesting their fundamental importance in the IAV life cycle.Bioinformatic analysis results demonstrated that S181E/A and K187Q/R mimic mutations do not significantly alter the PB2 protein structure.While continuous phosphorylation mimicked by the PB2 S181E mutation substantially decreases viral fitness in mice,PB2 K187Q mimetic acetylation slightly enhances viral virulence in mice.Mechanistically,PB2 S181E substantially impairs viral polymerase activity and viral replication,remarkably dampens protein stability and nuclear accumulation of PB2,and significantly weakens IAV-induced inflammatory responses.Therefore,our study further enriches the database of phosphorylation and acetylation sites of influenza viral proteins,laying a foundation for subsequent mechanistic studies.Meanwhile,the unraveled antiviral effect of PB2 S181E mimetic phosphorylation may provide a new target for the subsequent study of antiviral drugs.
基金supported by Science and Technology Innovation Enhancement Project of Army Medical University(to LX).
文摘MIcroglia/macrophage-mediated erythrophagocytosis plays a crucial role in hematoma clearance after intracerebral hemorrhage.Dynamic cytoskeletal changes accompany phagocytosis.However,whether and how these changes are associated with microglia/macrophage-mediated erythrophagocytosis remain unclear.In this study,we investigated the function of acetylatedα-tubulin,a stabilized microtubule form,in microglia/macrophage erythrophagocytosis after intracerebral hemorrhage both in vitro and in vivo.We first assessed the function of acetylatedα-tubulin in erythrophagocytosis using primary DiO GFP-labeled red blood cells co-cultured with the BV2 microglia or RAW264.7 macrophage cell lines.Acetylatedα-tubulin expression was significantly decreased in BV2 and RAW264.7 cells during erythrophagocytosis.Moreover,silencingα-tubulin acetyltransferase 1(ATAT1),a newly discoveredα-tubulin acetyltransferase,decreased Ac-α-tub levels and enhanced the erythrophagocytosis by BV2 and RAW264.7 cells.Consistent with these findings,in ATAT1-/-mice,we observed increased ionized calcium binding adapter molecule 1(Iba1)and Perls-positive microglia/macrophage phagocytes of red blood cells in peri-hematoma and reduced hematoma volume in mice with intracerebral hemorrhage.Additionally,knocking out ATAT1 alleviated neuronal apoptosis and pro-inflammatory cytokines and increased anti-inflammatory cytokines around the hematoma,ultimately improving neurological recovery of mice after intracerebral hemorrhage.These findings suggest that ATAT1 deficiency accelerates erythrophagocytosis by microglia/macrophages and hematoma absorption after intracerebral hemorrhage.These results provide novel insights into the mechanisms of hematoma clearance and suggest ATAT1 as a potential target for the treatment of intracerebral hemorrhage.
基金funded in part by grants from the National Natural Science Foundation of China (No.31930105)National Key Research and Development Program of China (2022YFF1000204)China Agriculture Research Systems (CARS-40)。
文摘Background Hepatic steatosis is a prevalent manifestation of fatty liver, that has detrimental effect on the health and productivity of laying hens, resulting in economic losses to the poultry industry. Here, we aimed to systematically investigate the genetic regulatory mechanisms of hepatic steatosis in laying hens.Methods Ninety individuals with the most prominent characteristics were selected from 686 laying hens according to the accumulation of lipid droplets in the liver, and were graded into three groups, including the control, mild hepatic steatosis and severe hepatic steatosis groups. A combination of transcriptome, proteome, acetylome and lipidome analyses, along with bioinformatics analysis were used to screen the key biological processes, modifications and lipids associated with hepatic steatosis.Results The rationality of the hepatic steatosis grouping was verified through liver biochemical assays and RNA-seq. Hepatic steatosis was characterized by increased lipid deposition and multiple metabolic abnormalities. Integration of proteome and acetylome revealed that differentially expressed proteins(DEPs) interacted with differentially acetylated proteins(DAPs) and were involved in maintaining the metabolic balance in the liver. Acetylation alterations mainly occurred in the progression from mild to severe hepatic steatosis, i.e., the enzymes in the fatty acid oxidation and bile acid synthesis pathways were significantly less acetylated in severe hepatic steatosis group than that in mild group(P < 0.05). Lipidomics detected a variety of sphingolipids(SPs) and glycerophospholipids(GPs) were negatively correlated with hepatic steatosis(r ≤-0.5, P < 0.05). Furthermore, the severity of hepatic steatosis was associated with a decrease in cholesterol and bile acid synthesis and an increase in exogenous cholesterol transport.Conclusions In addition to acquiring a global and thorough picture of hepatic steatosis in laying hens, we were able to reveal the role of acetylation in hepatic steatosis and depict the changes in hepatic cholesterol metabolism. The findings provides a wealth of information to facilitate a deeper understanding of the pathophysiology of fatty liver and contributes to the development of therapeutic strategies.
文摘Starting from sissotrin (1), a natural isoflavonoid isolated from Trifolium baccarinii (Fabaceae), one new semisynthetic derivative, 6-nitrobiochanin A (1b) and two known derivatives, 8-nitrobiochanin A (1a) and 2",3",4",6"-tetraacetylsissotrin (1c) have been obtained after performing nitration and acetylation reactions. Their structures were assigned after interpretation of their spectrometric (HR-ESI-MS) and spectroscopic (NMR 1D and 2D) data and by comparison with those reported in the literature. The substrate as well as the semisynthetic derivatives were evaluated for their antibacterial activities against six strains. The results reveal that they are inactive or weakly active on the strains tested with the exception of 8-nitrobiochanin A (1a) which showed moderate activity (MIC = 62.5 μg∙mL<sup>−1</sup>) on Staphylococcus aureus ATCC 43300.
基金Fujian Province science and technology office (2007F5030)(in part) National Natural Scince Foundation of China (grant 50473063)
文摘Chinese bamboo flour was chemically modified by acetylation with acetic anhydride by using trichloroacetic acid as an activation agent and the optimized condition for acetylation of bamboo flour was determined as the trichloroacetic acid amount 6.0 g per 1.5-g bamboo flour, ultrasosonication duration 40 min and the reaction time 1 h at 65℃. The composition, microstructure and thermal behavior of acetylated bamboo flour were preliminarily characterized by FT-IR, DSC and SEM etc. The acetylated bamboo flour can be molded into sheets at 130℃ and 10 MPa, indicating the modified bamboo flour possesses thermalplastic performance.
