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
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
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
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
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
Histone deacetylases （HDACs） and histone acetyl transferases （HATs） are two counteracting enzyme families whose enzymatic activity controls the acetylation state of protein lysine residues, notably those contained...Histone deacetylases （HDACs） and histone acetyl transferases （HATs） are two counteracting enzyme families whose enzymatic activity controls the acetylation state of protein lysine residues, notably those contained in the N-terminal extensions of the core histones. Acetylation of histones affects gene expression through its influence on chromatin conformation. In addition, several non-histone proteins are regulated in their stability or biological function by the acetylation state of specific lysine residues. HDACs intervene in a multitude of biological processes and are part of a multiprotein family in which each member has its specialized functions. In addition, HDAC activity is tightly controlled through targeted recruitment, protein-protein interactions and post-translational modifications. Control of cell cycle progression, cell survival and differentiation are among the most important roles of these enzymes. Since these processes are affected by malignant transformation, HDAC inhibitors were developed as antineoplastic drugs and are showing encouraging efficacy in cancer patients.展开更多
Cell cycle progression is regulated by interactions between cyclins and cyclin-dependent kinases (CDKs). p21(WAF1) is one of the CIP/KIP family which inhibits CDKs activity. Increased expression of p21(WAF1) may play ...Cell cycle progression is regulated by interactions between cyclins and cyclin-dependent kinases (CDKs). p21(WAF1) is one of the CIP/KIP family which inhibits CDKs activity. Increased expression of p21(WAF1) may play an important role in the growth arrest induced in transformed cells. Although the stability of the p21( WAF1) mRNA could be altered by different signals, cell differentiation and numerous influencing factors. However, recent studies suggest that two known mechanisms of epigenesis, i.e.gene inactivation by methylation in promoter region and changes to an inactive chromatin by histone deacetylation, seem to be the best candidate mechanisms for inactivation of p21( WAF1). To date, almost no coding region p21(WAF1) mutations have been found in tumor cells, despite extensive screening of hundreds of various tumors. Hypermethylation of the p21(WAF1) promoter region may represent an alternative mechanism by which the p21(WAF1/CIP1) gene can be inactivated. The reduction of cellular DNMT protein levels also induces a corresponding rapid increase in the cell cycle regulator p21(WAF1) protein demonstrating a regulatory link between DNMT and p21(WAF1) which is independent of methylation of DNA. Both histone hyperacetylation and hypoacetylation appear to be important in the carcinoma process, and induction of the p21(WAF1) gene by histone hyperacetylation may be a mechanism by which dietary fiber prevents carcinogenesis. Here, we review the influence of histone acetylation and DNA methylation on p21(WAF1) transcription, and affection of pathways or factors associated such as p 53, E2A, Sp1 as well as several histone deacetylation inhibitors.展开更多
Although the clinical manifestations of alcoholic liver disease are well-described, little is known about the molecular basis of liver injury. Recent studies have indicated that ethanol exposure induces global protein...Although the clinical manifestations of alcoholic liver disease are well-described, little is known about the molecular basis of liver injury. Recent studies have indicated that ethanol exposure induces global protein hyperacetylationo This reversible, post- translational modification on the E-amino groups of lysine residues has been shown to modulate multiple, diverse cellular processes ranging from transcriptional activation to microtubule stability. Thus, alcohol- induced protein hyperacetylation likely leads to major physiological consequences that contribute to alcohol-induced hepatotoxicity. Lysine acetylation is controlled by the activities of two opposing enzymes, histone acetyltransferases and histone deacetylases. Currently, efforts are aimed at determining which enzymes are responsible for the increased acetylation of specific substrates. However, the greater challenge will be to determine the physiological ramifications of protein hyperacetylation and how they might contribute to the progression of liver disease. In this review, we will first list and discuss the proteins known to be hyperacetylated in the presence of ethanol. We will then describe what is known about the mechanisms leading to increased protein acetylation and how hyperacetylation may perturb hepatic function.展开更多
AIM: To determine if doxorubicin(Dox) alters hepatic proteome acetylation status and if acetylation status was associated with an apoptotic environment. METHODS: Doxorubicin(20 mg/kg; Sigma, Saint Louis, MO; n = 8) or...AIM: To determine if doxorubicin(Dox) alters hepatic proteome acetylation status and if acetylation status was associated with an apoptotic environment. METHODS: Doxorubicin(20 mg/kg; Sigma, Saint Louis, MO; n = 8) or NaCl(0.9%; n = 7) was administered as an intraperitoneal injection to male F344 rats, 6-wk of age. Once animals were treated with Dox or saline, all animals were fasted until sacrifice 24 h later. RESULTS: Dox treatment decreased proteome lysine acetylation likely due to a decrease in histone acetyltransferase activity. Proteome deacetylation may likely not be associated with a proapoptotic environment. Dox did not increase caspase-9,-8, or-3 activation nor poly(adenosine diphosphate-ribose) polymerase-1 cleavage. Dox did stimulate caspase-12 activation, however, it likely did not play a role in apoptosis induction. CONCLUSION: Early effects of Dox involve hepatic proteome lysine deacetylation and caspase-12 activa-tion under these experimental conditions.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
目的:探讨c-Myc、SIRT1及acetyl-p53蛋白在乳腺癌中的表达及其对预后的影响。方法:应用免疫组织化学方法检测90例乳腺癌和30例乳腺增生症中的c-Myc、SIRT1(Sirtuin type 1)、acetyl-p53蛋白表达,结合临床病理资料和随访资料,进行预后分...目的:探讨c-Myc、SIRT1及acetyl-p53蛋白在乳腺癌中的表达及其对预后的影响。方法:应用免疫组织化学方法检测90例乳腺癌和30例乳腺增生症中的c-Myc、SIRT1(Sirtuin type 1)、acetyl-p53蛋白表达,结合临床病理资料和随访资料,进行预后分析。结果:c-Myc阳性组乳腺癌患者的5年无瘤生存率和5年总生存率(分别为5 9.0%/6 7.2%)低于c-M y c阴性组(分别为8 6.2%/8 6.2%),S I RT 1阳性组乳腺癌患者的5年无瘤生存率和5年总生存率(分别为5 6.1%/6 4.9%)低于S I RT 1阴性组(87.9%/87.9%);acetyl-p53阳性组乳腺癌患者的5年无瘤生存率和5年总生存率(分别为86.7%/86.7%)高于acetyl-p53阴性组(分别为58.3%/66.7%),差异均有统计学意义(P<0.05)。结论:c-Myc及SIRT1蛋白高表达的乳腺癌患者预后差,而acetyl-p53蛋白高表达的乳腺癌患者预后好。展开更多
首次采用反相高效液相色谱法测定茜草根中1,3,6-trihydroxy-2-methylanthraquinone-3-O-[3-O-acetyl-α-L-rhamnopyranosyl-(1→2)-β-D-glucopyranoside]的含量。色谱柱为Purospher star RP C18色谱柱(250mm×4.6mm,5μm),流动相...首次采用反相高效液相色谱法测定茜草根中1,3,6-trihydroxy-2-methylanthraquinone-3-O-[3-O-acetyl-α-L-rhamnopyranosyl-(1→2)-β-D-glucopyranoside]的含量。色谱柱为Purospher star RP C18色谱柱(250mm×4.6mm,5μm),流动相为甲醇:水:四氢呋喃(65:34.7:0.3),流速为1.0mL/min,检测波长为276nm,柱温为25℃。该方法的线性范围为0.020~0.160μg,r=0.9998,平均回收率为101.5%,RSD为2.0%(n=6)。该方法测定1,3,6-trihydroxy-2-methylanthraquinone-3-O-[3-O-acetyl-α-L-rhamnopyranosyl-(1→2)-β-D-glucopyranoside]含量灵敏、准确、重现性好。展开更多
Among 39 species of microbial strains,Rhodococcus sp.AS 4.1147 possessed the ability to selectively acetylate puerarin（1） at C-6 position of the glucosyl moiety.The structure of the acetylated product,6’’-O-acetyl...Among 39 species of microbial strains,Rhodococcus sp.AS 4.1147 possessed the ability to selectively acetylate puerarin（1） at C-6 position of the glucosyl moiety.The structure of the acetylated product,6’’-O-acetylpuerarin（2） was determined by the analysis of MS,NMR spectroscopic data.The isolated yield of 2 was 22.2%.展开更多
MicroRNAs （miRNA） that guide sequence-specific posttranscriptional gene silencing play an important role in gene expression required for both developmental processes and responses to environmental conditions in plan...MicroRNAs （miRNA） that guide sequence-specific posttranscriptional gene silencing play an important role in gene expression required for both developmental processes and responses to environmental conditions in plants. However, little is known about the transcriptional and posttranscriptional regulation of miRNA expression. Histone acetylation plays an important role in chromatin remodeling and is required for gene activation. By analyzing the accumulation of subset of miRNAs and the corresponding primary miRNAs in mutants of Arabidopsis, we show that histone acetyltransferase GCN5 （General control non-repressed protein 5） has a general repressive effect on miRNA production, while it is required for the expression of a subset of （e.g. stress-inducible） MIRNA genes. The general negative function of GCN5 in miRNA production is likely achieved through an indirect repression of the miRNA machinery genes such as DICER LIKE1 （DCL1）, SERRATE （SE）, HYPONASTIC LEAVES1 （HYL1） and ARGONAUTE1 （AGO1）. Chromatin immunoprecipitation assays revealed that GCN5 targets to a subset of MIRNA genes and is required for acetylation of histone H3 lysine 14 at these loci. Moreover, inhibition of histone deacetylation by trichostatin A treatment or in histone deacetylase gene mutants impaired the accumulation of certain miRNAs. These data together suggest that Arabidopsis GCN5 interferes with the miRNA pathway at both the transcriptional and posttranscriptional levels and histone acetylation/deacetylation is an epigenetic mechanism involved in the regulation of miRNA production.展开更多
Previous reports showed that decreased histone deacetylase activity significantly potentiated the rewarding effects of psychostimulants, and that encoding of the 5-HT3 receptor by the htr3a gene was related to ethanol...Previous reports showed that decreased histone deacetylase activity significantly potentiated the rewarding effects of psychostimulants, and that encoding of the 5-HT3 receptor by the htr3a gene was related to ethanol-seeking behavior. However, the effects of a histone deacetylase inhibitor on ethanol-seeking behavior and epigenetic regulation of htr3a mRNA expression after chronic ethanol exposure are not fully understood. Using quantitative reverse transcription-polymerase chain reaction and chromatin immunoprecipitation analysis, we investigated the effects of chronic ethanol exposure and its interaction with a histone deacetylase inhibitor on histone-acetylation-mediated changes in htr3a mRNA expression in the htr3a promoter region. The conditioned place preference procedure was used to evaluate ethanol-seeking behavior. Chronic exposure to ethanol effectively elicited place conditioning. In the prefrontal cortex, the acetylation of H3K9 and htr3a mRNA expression in the htr3a promoter region were significantly higher in the ethanol group than in the saline group. The histone deacetylase inhibitor sodium butyrate potentiated the effects of ethanol on htr3a mRNA expression and enhanced ethanol-induced conditioned place preferences. These results suggest that ethanol upregulates htr3a levels through mechanisms involving H3K9 acetylation, and that histone acetylation may be a therapeutic target for treating ethanol abuse.展开更多
BACKGROUND The prognosis of gastric cancer continues to remain poor,and epigenetic drugs like histone deacetylase inhibitors(HDACi)have been envisaged as potential therapeutic agents.Nevertheless,clinical trials are f...BACKGROUND The prognosis of gastric cancer continues to remain poor,and epigenetic drugs like histone deacetylase inhibitors(HDACi)have been envisaged as potential therapeutic agents.Nevertheless,clinical trials are facing issues with toxicity and efficacy against solid tumors,which may be partly due to the lack of patient stratification for effective treatments.To study the need of patient stratification before HDACi treatment,and the efficacy of pre-treatment of HDACi as a chemotherapeutic drug sensitizer.METHODS The expression activity of class 1 HDACs and histone acetylation was examined in human gastric cancer cells and tissues.The potential combinatorial regime of HDACi and chemotherapy drugs was defined on the basis of observed drug binding assays,chromatin remodeling and cell death.RESULTS In the present study,the data suggest that the differential increase in HDAC activity and the expression of class 1 HDACs are associated with hypoacetylation of histone proteins in tumors compared to normal adjacent mucosa tissue samples of gastric cancer.The data highlights for the first time that pretreatment of HDACi results in an increased amount of DNA-bound drugs associated with enhanced histone acetylation,chromatin relaxation and cell cycle arrest.Fraction-affected plots and combination index-based analysis show that pre-HDACi chemo drug combinatorial regimes,including valproic acid with cisplatin or oxaliplatin and trichostatin A with epirubicin,exhibit synergism with maximum cytotoxic potential due to higher cell death at low combined doses in gastric cancer cell lines.CONCLUSION Expression or activity of class 1 HDACs among gastric cancer patients present an effective approach for patient stratification.Furthermore,HDACi therapy in pretreatment regimes is more effective with chemotherapy drugs,and may aid in predicting individual patient prognosis.展开更多
The immune system plays a vital role in maintaining the delicate balance between immune recognition and tumor development.Regardless,it is not uncommon that cancerous cells can intelligently acquire abilities to bypas...The immune system plays a vital role in maintaining the delicate balance between immune recognition and tumor development.Regardless,it is not uncommon that cancerous cells can intelligently acquire abilities to bypass the antitumor immune responses,thus allowing continuous tumor growth and development.Immune evasion has emerged as a significant factor contributing to the progression and immune resistance of pancreatic cancer.Compared with other cancers,pancreatic cancer has a tumor microenvironment that can resist most treatment modalities,including emerging immunotherapy.Sadly,the use of immunotherapy has yet to bring significant clinical breakthrough among pancreatic cancer patients,suggesting that pancreatic cancer has successfully evaded immunomodulation.In this review,we summarize the impact of genetic alteration and epigenetic modification(especially histone deacetylases,HDAC)on immune evasion in pancreatic cancer.HDAC overexpression significantly suppresses tumor suppressor genes,contributing to tumor growth and progression.We review the evidence on HDAC inhibitors in tumor eradication,improving T cells activation,restoring tumor immunogenicity,and modulating programmed death 1 interaction.We provide our perspective in targeting HDAC as a strategy to reverse immune evasion in pancreatic cancer.展开更多
The HIV-1 LTR controls the expression of HIV-1 viral genes and thus is critical for viral propagation and pathology. Numerous host factors have been shown to participate in the regulation of the LTR promoter. Among th...The HIV-1 LTR controls the expression of HIV-1 viral genes and thus is critical for viral propagation and pathology. Numerous host factors have been shown to participate in the regulation of the LTR promoter. Among them is the thyroid hormone (T3) receptor (TR). TR has been shown to bind to the critical region of the promoter that contain the NFbB and Sp1 binding sites. Interestingly, earlier transient transfection studies in tissue culture cells have yielded contradicting conclusions on the role of TR in LTR regulation, likely due to the use of different cell types and/or lack of proper chromatin organization. Here, using the frog oocyte as a model system that allows replication-coupled chromatin assembly, mimicking that in somatic cells, we demonstrate that unliganded heterodimers of TR and RXR (9-cis retinoic acid receptor) repress LTR while the addition of T3 relieves the repression and further activates the promoter. More importantly, we show that chromatin and unliganded TR/RXR synergize to repress the promoter in a histone deacetylase-dependent manner.展开更多
Two new acetyl cimicifugosides were isolated from the rhizomes of Cimicifuga racemosa. Their structures were elucidated as 2＇-O-acetyl cimicifugoside H-1 1 and 3＇-O-acetyl cimicifugoside H-1 2 by the spectroscopic e...Two new acetyl cimicifugosides were isolated from the rhizomes of Cimicifuga racemosa. Their structures were elucidated as 2＇-O-acetyl cimicifugoside H-1 1 and 3＇-O-acetyl cimicifugoside H-1 2 by the spectroscopic evidence and chemical methods.展开更多
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 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.
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 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Histone deacetylases （HDACs） and histone acetyl transferases （HATs） are two counteracting enzyme families whose enzymatic activity controls the acetylation state of protein lysine residues, notably those contained in the N-terminal extensions of the core histones. Acetylation of histones affects gene expression through its influence on chromatin conformation. In addition, several non-histone proteins are regulated in their stability or biological function by the acetylation state of specific lysine residues. HDACs intervene in a multitude of biological processes and are part of a multiprotein family in which each member has its specialized functions. In addition, HDAC activity is tightly controlled through targeted recruitment, protein-protein interactions and post-translational modifications. Control of cell cycle progression, cell survival and differentiation are among the most important roles of these enzymes. Since these processes are affected by malignant transformation, HDAC inhibitors were developed as antineoplastic drugs and are showing encouraging efficacy in cancer patients.
文摘Cell cycle progression is regulated by interactions between cyclins and cyclin-dependent kinases (CDKs). p21(WAF1) is one of the CIP/KIP family which inhibits CDKs activity. Increased expression of p21(WAF1) may play an important role in the growth arrest induced in transformed cells. Although the stability of the p21( WAF1) mRNA could be altered by different signals, cell differentiation and numerous influencing factors. However, recent studies suggest that two known mechanisms of epigenesis, i.e.gene inactivation by methylation in promoter region and changes to an inactive chromatin by histone deacetylation, seem to be the best candidate mechanisms for inactivation of p21( WAF1). To date, almost no coding region p21(WAF1) mutations have been found in tumor cells, despite extensive screening of hundreds of various tumors. Hypermethylation of the p21(WAF1) promoter region may represent an alternative mechanism by which the p21(WAF1/CIP1) gene can be inactivated. The reduction of cellular DNMT protein levels also induces a corresponding rapid increase in the cell cycle regulator p21(WAF1) protein demonstrating a regulatory link between DNMT and p21(WAF1) which is independent of methylation of DNA. Both histone hyperacetylation and hypoacetylation appear to be important in the carcinoma process, and induction of the p21(WAF1) gene by histone hyperacetylation may be a mechanism by which dietary fiber prevents carcinogenesis. Here, we review the influence of histone acetylation and DNA methylation on p21(WAF1) transcription, and affection of pathways or factors associated such as p 53, E2A, Sp1 as well as several histone deacetylation inhibitors.
基金Supported by The National Institute of Alcohol Abuse and Alcoholism (R21 AA015683) awarded to P.L.T.
文摘Although the clinical manifestations of alcoholic liver disease are well-described, little is known about the molecular basis of liver injury. Recent studies have indicated that ethanol exposure induces global protein hyperacetylationo This reversible, post- translational modification on the E-amino groups of lysine residues has been shown to modulate multiple, diverse cellular processes ranging from transcriptional activation to microtubule stability. Thus, alcohol- induced protein hyperacetylation likely leads to major physiological consequences that contribute to alcohol-induced hepatotoxicity. Lysine acetylation is controlled by the activities of two opposing enzymes, histone acetyltransferases and histone deacetylases. Currently, efforts are aimed at determining which enzymes are responsible for the increased acetylation of specific substrates. However, the greater challenge will be to determine the physiological ramifications of protein hyperacetylation and how they might contribute to the progression of liver disease. In this review, we will first list and discuss the proteins known to be hyperacetylated in the presence of ethanol. We will then describe what is known about the mechanisms leading to increased protein acetylation and how hyperacetylation may perturb hepatic function.
文摘AIM: To determine if doxorubicin(Dox) alters hepatic proteome acetylation status and if acetylation status was associated with an apoptotic environment. METHODS: Doxorubicin(20 mg/kg; Sigma, Saint Louis, MO; n = 8) or NaCl(0.9%; n = 7) was administered as an intraperitoneal injection to male F344 rats, 6-wk of age. Once animals were treated with Dox or saline, all animals were fasted until sacrifice 24 h later. RESULTS: Dox treatment decreased proteome lysine acetylation likely due to a decrease in histone acetyltransferase activity. Proteome deacetylation may likely not be associated with a proapoptotic environment. Dox did not increase caspase-9,-8, or-3 activation nor poly(adenosine diphosphate-ribose) polymerase-1 cleavage. Dox did stimulate caspase-12 activation, however, it likely did not play a role in apoptosis induction. CONCLUSION: Early effects of Dox involve hepatic proteome lysine deacetylation and caspase-12 activa-tion under these experimental conditions.
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.
文摘目的:探讨c-Myc、SIRT1及acetyl-p53蛋白在乳腺癌中的表达及其对预后的影响。方法:应用免疫组织化学方法检测90例乳腺癌和30例乳腺增生症中的c-Myc、SIRT1(Sirtuin type 1)、acetyl-p53蛋白表达,结合临床病理资料和随访资料,进行预后分析。结果:c-Myc阳性组乳腺癌患者的5年无瘤生存率和5年总生存率(分别为5 9.0%/6 7.2%)低于c-M y c阴性组(分别为8 6.2%/8 6.2%),S I RT 1阳性组乳腺癌患者的5年无瘤生存率和5年总生存率(分别为5 6.1%/6 4.9%)低于S I RT 1阴性组(87.9%/87.9%);acetyl-p53阳性组乳腺癌患者的5年无瘤生存率和5年总生存率(分别为86.7%/86.7%)高于acetyl-p53阴性组(分别为58.3%/66.7%),差异均有统计学意义(P<0.05)。结论:c-Myc及SIRT1蛋白高表达的乳腺癌患者预后差,而acetyl-p53蛋白高表达的乳腺癌患者预后好。
文摘首次采用反相高效液相色谱法测定茜草根中1,3,6-trihydroxy-2-methylanthraquinone-3-O-[3-O-acetyl-α-L-rhamnopyranosyl-(1→2)-β-D-glucopyranoside]的含量。色谱柱为Purospher star RP C18色谱柱(250mm×4.6mm,5μm),流动相为甲醇:水:四氢呋喃(65:34.7:0.3),流速为1.0mL/min,检测波长为276nm,柱温为25℃。该方法的线性范围为0.020~0.160μg,r=0.9998,平均回收率为101.5%,RSD为2.0%(n=6)。该方法测定1,3,6-trihydroxy-2-methylanthraquinone-3-O-[3-O-acetyl-α-L-rhamnopyranosyl-(1→2)-β-D-glucopyranoside]含量灵敏、准确、重现性好。
基金The Science & Technology Project of Guangdong Province (Grant No. 2011A080403020)the Program for New Century Excellent Talents in University (Grant No. NCET-06-0155)
文摘Among 39 species of microbial strains,Rhodococcus sp.AS 4.1147 possessed the ability to selectively acetylate puerarin（1） at C-6 position of the glucosyl moiety.The structure of the acetylated product,6’’-O-acetylpuerarin（2） was determined by the analysis of MS,NMR spectroscopic data.The isolated yield of 2 was 22.2%.
文摘MicroRNAs （miRNA） that guide sequence-specific posttranscriptional gene silencing play an important role in gene expression required for both developmental processes and responses to environmental conditions in plants. However, little is known about the transcriptional and posttranscriptional regulation of miRNA expression. Histone acetylation plays an important role in chromatin remodeling and is required for gene activation. By analyzing the accumulation of subset of miRNAs and the corresponding primary miRNAs in mutants of Arabidopsis, we show that histone acetyltransferase GCN5 （General control non-repressed protein 5） has a general repressive effect on miRNA production, while it is required for the expression of a subset of （e.g. stress-inducible） MIRNA genes. The general negative function of GCN5 in miRNA production is likely achieved through an indirect repression of the miRNA machinery genes such as DICER LIKE1 （DCL1）, SERRATE （SE）, HYPONASTIC LEAVES1 （HYL1） and ARGONAUTE1 （AGO1）. Chromatin immunoprecipitation assays revealed that GCN5 targets to a subset of MIRNA genes and is required for acetylation of histone H3 lysine 14 at these loci. Moreover, inhibition of histone deacetylation by trichostatin A treatment or in histone deacetylase gene mutants impaired the accumulation of certain miRNAs. These data together suggest that Arabidopsis GCN5 interferes with the miRNA pathway at both the transcriptional and posttranscriptional levels and histone acetylation/deacetylation is an epigenetic mechanism involved in the regulation of miRNA production.
基金supported by the National Key Basic Research and Development Program(NKBRDP)of China(No.2009CB522000)the National Natural Science Foundation of China(No.30971050)+1 种基金the State Key Program of the National Natural Science of China(No.81130020)the Key Program on Basic Science of Henan Science and Technology Department(No.094200510005)
文摘Previous reports showed that decreased histone deacetylase activity significantly potentiated the rewarding effects of psychostimulants, and that encoding of the 5-HT3 receptor by the htr3a gene was related to ethanol-seeking behavior. However, the effects of a histone deacetylase inhibitor on ethanol-seeking behavior and epigenetic regulation of htr3a mRNA expression after chronic ethanol exposure are not fully understood. Using quantitative reverse transcription-polymerase chain reaction and chromatin immunoprecipitation analysis, we investigated the effects of chronic ethanol exposure and its interaction with a histone deacetylase inhibitor on histone-acetylation-mediated changes in htr3a mRNA expression in the htr3a promoter region. The conditioned place preference procedure was used to evaluate ethanol-seeking behavior. Chronic exposure to ethanol effectively elicited place conditioning. In the prefrontal cortex, the acetylation of H3K9 and htr3a mRNA expression in the htr3a promoter region were significantly higher in the ethanol group than in the saline group. The histone deacetylase inhibitor sodium butyrate potentiated the effects of ethanol on htr3a mRNA expression and enhanced ethanol-induced conditioned place preferences. These results suggest that ethanol upregulates htr3a levels through mechanisms involving H3K9 acetylation, and that histone acetylation may be a therapeutic target for treating ethanol abuse.
基金Supported by TMH-IRG(account number-466/2012 and 164/2016)LTMT grant for project funding+1 种基金ACTREC-TMC for funding to Gupta labsupported by ACTREC fellowships
文摘BACKGROUND The prognosis of gastric cancer continues to remain poor,and epigenetic drugs like histone deacetylase inhibitors(HDACi)have been envisaged as potential therapeutic agents.Nevertheless,clinical trials are facing issues with toxicity and efficacy against solid tumors,which may be partly due to the lack of patient stratification for effective treatments.To study the need of patient stratification before HDACi treatment,and the efficacy of pre-treatment of HDACi as a chemotherapeutic drug sensitizer.METHODS The expression activity of class 1 HDACs and histone acetylation was examined in human gastric cancer cells and tissues.The potential combinatorial regime of HDACi and chemotherapy drugs was defined on the basis of observed drug binding assays,chromatin remodeling and cell death.RESULTS In the present study,the data suggest that the differential increase in HDAC activity and the expression of class 1 HDACs are associated with hypoacetylation of histone proteins in tumors compared to normal adjacent mucosa tissue samples of gastric cancer.The data highlights for the first time that pretreatment of HDACi results in an increased amount of DNA-bound drugs associated with enhanced histone acetylation,chromatin relaxation and cell cycle arrest.Fraction-affected plots and combination index-based analysis show that pre-HDACi chemo drug combinatorial regimes,including valproic acid with cisplatin or oxaliplatin and trichostatin A with epirubicin,exhibit synergism with maximum cytotoxic potential due to higher cell death at low combined doses in gastric cancer cell lines.CONCLUSION Expression or activity of class 1 HDACs among gastric cancer patients present an effective approach for patient stratification.Furthermore,HDACi therapy in pretreatment regimes is more effective with chemotherapy drugs,and may aid in predicting individual patient prognosis.
基金Supported by International Medical University to Sim W,Lim WM,and Leong CO,No.BMS I/2020(10)Shanghai Municipal Science and Technology Commission to Mai CW,No.20WZ250460.
文摘The immune system plays a vital role in maintaining the delicate balance between immune recognition and tumor development.Regardless,it is not uncommon that cancerous cells can intelligently acquire abilities to bypass the antitumor immune responses,thus allowing continuous tumor growth and development.Immune evasion has emerged as a significant factor contributing to the progression and immune resistance of pancreatic cancer.Compared with other cancers,pancreatic cancer has a tumor microenvironment that can resist most treatment modalities,including emerging immunotherapy.Sadly,the use of immunotherapy has yet to bring significant clinical breakthrough among pancreatic cancer patients,suggesting that pancreatic cancer has successfully evaded immunomodulation.In this review,we summarize the impact of genetic alteration and epigenetic modification(especially histone deacetylases,HDAC)on immune evasion in pancreatic cancer.HDAC overexpression significantly suppresses tumor suppressor genes,contributing to tumor growth and progression.We review the evidence on HDAC inhibitors in tumor eradication,improving T cells activation,restoring tumor immunogenicity,and modulating programmed death 1 interaction.We provide our perspective in targeting HDAC as a strategy to reverse immune evasion in pancreatic cancer.
文摘The HIV-1 LTR controls the expression of HIV-1 viral genes and thus is critical for viral propagation and pathology. Numerous host factors have been shown to participate in the regulation of the LTR promoter. Among them is the thyroid hormone (T3) receptor (TR). TR has been shown to bind to the critical region of the promoter that contain the NFbB and Sp1 binding sites. Interestingly, earlier transient transfection studies in tissue culture cells have yielded contradicting conclusions on the role of TR in LTR regulation, likely due to the use of different cell types and/or lack of proper chromatin organization. Here, using the frog oocyte as a model system that allows replication-coupled chromatin assembly, mimicking that in somatic cells, we demonstrate that unliganded heterodimers of TR and RXR (9-cis retinoic acid receptor) repress LTR while the addition of T3 relieves the repression and further activates the promoter. More importantly, we show that chromatin and unliganded TR/RXR synergize to repress the promoter in a histone deacetylase-dependent manner.
文摘Two new acetyl cimicifugosides were isolated from the rhizomes of Cimicifuga racemosa. Their structures were elucidated as 2＇-O-acetyl cimicifugoside H-1 1 and 3＇-O-acetyl cimicifugoside H-1 2 by the spectroscopic evidence and chemical methods.
