The lysine methyltransferase SMYD2 facilitates neointimal hyperplasia by regulating the HDAC3-SRF axis

Coronary restenosis is an important cause of poor long-term prognosis in patients with coronary heart disease. Here, we show that lysine methyltransferase SMYD2 expression in the nucleus is significantly elevated in serum- and PDGF-BB-induced vascular smooth muscle cells (VSMCs), and in tissues of carotid artery injury-induced neointimal hyperplasia. Smyd2 overexpression in VSMCs (Smyd2-vTg) facilitates, but treatment with its specific inhibitor LLY-507 or SMYD2 knockdown significantly inhibits VSMC phenotypic switching and carotid artery injury-induced neointima formation in mice. Transcriptome sequencing revealed that SMYD2 knockdown represses the expression of serum response factor (SRF) target genes and that SRF overexpression largely reverses the inhibitory effect of SMYD2 knockdown on VSMC proliferation. HDAC3 directly interacts with and deacetylates SRF, which enhances SRF transcriptional activity in VSMCs. Moreover, SMYD2 promotes HDAC3 expression via tri-methylation of H3K36 at its promoter. RGFP966, a specific inhibitor of HDAC3, not only counteracts the pro-proliferation effect of SMYD2 overexpression on VSMCs, but also inhibits carotid artery injury-induced neointima formation in mice. HDAC3 partially abolishes the inhibitory effect of SMYD2 knockdown on VSMC proliferation in a deacetylase activity-dependent manner. Our results reveal that the SMYD2-HDAC3-SRF axis constitutes a novel and critical epigenetic mechanism that regulates VSMC phenotypic switching and neointimal hyperplasia.

Role of Histone Methyltransferase in Fibrosis and Traditional Chinese Medicine Treatment： A Review / 中国实验方剂学杂志

Fibrosis， a tumor-like lesion between benign tissue and malignant tumor， mostly occurs in the liver， kidney， heart， lung， bone marrow and other organs and tissues. It can affect almost every organ and eventually induce multiple organ failure and cancers， seriously endangering human life. It will be of great importance to prevent cancer if the disease can be opportunely blocked in the fibrotic stage. The pathogenesis of fibrosis is still not completely clear. It is of great clinical significance to study the occurrence， development， and mechanism of fibrosis as well as to screen new therapeutic targets. Enhancer of zeste homolog 2 （EZH2） is mainly located in the nucleus and involved in the formation of the polycomb repressive complex 2. EZH2 is a methyltransferase which makes the lysine on position 27 of histone H3 （H3K27me3） undergo trimethyl modification induces gene silencing through classical or nonclassical actions， so as to inhibit or activate transcription. EZH2 plays a critical role in cell growth， proliferation， differentiation， and apoptosis， which is regulated by different targets and signaling pathways. EZH2 regulates the transformation of myofibroblasts and participates in the fibrosis of multiple organs. Recent studies have shown that EZH2 plays a role in fibrosis-related pathophysiological processes such as epithelial-mesenchymal transition， oxidative stress， and inflammation. EZH2 as the target of fibrosis， EZH2 inhibitors， and EZH2-related traditional Chinese medicine （TCM） formula and active compounds have gradually become hot research directions. EZH2 may be a powerful target for organ fibrosis. Exploring the structure， function， and distribution of EZH2， the role of EZH2 in fibrosis， the EZH2 inhibitors， and TCM formulas and active components targeting EZH2 has great meanings. This paper reviews the research progress in EZH2 and fibrosis， providing new ideas for the diagnosis， treatment， and drug development of fibrosis.

Alterações epigenéticas associadas a agenesia dentária não sindrômica: uma revisão sistemática / Epigenetic alterations associated with non-syndromic tooth agenesis: a systematic review

Objetivo: Avaliar se alterações epigenéticas estão associadas à ocorrência da agenesia dentária não sindrômica. Métodos: Buscas computadorizadas foram conduzidas no PubMed, Web of Science, Ovid, Embase e Scopus. Consultas na literatura cinzenta (Open Grey), no Google Scholar e pesquisas manuais nas listas de referências dos artigos incluídos também foram realizadas. Apenas estudos caso-controle avaliando indivíduos com e sem agenesia dentária não sindrômica eram elegíveis. A seleção dos estudos, a extração de dados e a avaliação do risco de viés (ferramenta da Universidade da Adelaide) foram realizadas por dois autores de forma independente. Devido à diferença metodológica dos artigos incluídos, uma meta-análise não foi possível. Resultados: 206 artigos foram identificados nas bases de dados. Após a remoção de 128 duplicatas e a análise de 78 referências, oito artigos preencheram os critérios de elegibilidade e foram incluídos. Os estudos incluídos foram realizados na China, Turquia, Tunísia, Romênia e República Tcheca. As datas de publicação ocorreram entre 2015 e 2023. Os estudos com as menores amostras avaliaram cinco indivíduos com agenesia e cinco sem agenesia e o estudo com a maior amostra avaliou 625 indivíduos com agenesia e 1144 indivíduos sem agenesia. No total, essa revisão analisou 1325 indivíduos com agenesia e 1867 sem agenesia. Dos 33 polimorfismos de nucleotídeo único avaliados, 19 deles estavam potencialmente associados a uma maior suscetibilidade à agenesia dentária não sindrômica, sendo eles identificados nos genes PAX9, AXIN2, WNT10A, MDM2, MSX1 e BMP2. Foram identificadas 29 novas mutações. No geral, os artigos incluídos apresentaram baixo risco de viés. Conclusão: Existe a associação de algumas alterações epigenéticas com a ocorrência de agenesia dentária não sindrômica.

Aim: To assess whether epigenetic alterations are associated with the occurrence of non-syndromic tooth agenesis. Methods: Computerized searches were conducted in PubMed, Web of Science, Ovid, Embase, and Scopus databases. Grey literature searches (Open Grey), Google Scholar, and manual searches in the reference lists of included articles were also performed. Only case-control studies evaluating individuals with and without non-syndromic tooth agenesis were eligible. Study selection, data extraction, and bias assessment (University of Adelaide tool) were independently conducted by two authors. Due to methodological differences in the included articles, a meta-analysis was not feasible. Results: This study identified 206 articles in the databases. After removing 128 duplicates and reviewing 78 references, eight articles met the eligibility criteria and were included. The included studies were conducted in China, Turkey, Tunisia, Romania, and the Czech Republic. Publication dates ranged from 2015 to 2023. Studies with the smallest sample assessed five individuals with agenesis and five without agenesis, and the study with the largest sample assessed 625 individuals with agenesis and 1,144 without agenesis. In total, this review analyzed 1,325 individuals with agenesis and 1,867 without agenesis. Of the 33 single nucleotide polymorphisms evaluated, 19 were potentially associated with an increased susceptibility to non-syndromic tooth agenesis, and these were identified in the PAX9, AXIN2, WNT10A, MDM2, MSX1, and BMP2 genes. Twenty-nine new mutations were identified. Overall, the included articles demonstrated a low risk of bias. Conclusion: There is an association between certain epigenetic alterations and the occurrence of non-syndromic tooth agenesis.

5HT2A modulation attenuates pancreatic cancer induced pain mouse model by inhibiting HDAC

Purpose Patients have been severely suffered from cancer associated pain, and pancreatic cancer is the most severe form of cancer associated with pain. There are very few options available to manage it. The present report evaluated the effect of 5HT2A on pancreatic cancer associated pain. Methods Pancreatic cancer was induced by injecting SW 1,990 cells (~3×106 in a 20 µL suspension) into the pancreas and formed a 2­3-mm vesicle using an inoculator fitted with a 26-gauge needle in BALB/c-nu mice. Survival rate and body weight of the mice were observed. Pain behaviour testing was performed at the end of each week (third and fourth week) after surgery. Inflammatory mediators and HDAC 2 proteins were determined in the spinal tissue using quantitative real-time polymerase chain reaction. Results There was improvement in the survival rate and body weight in 5HT2A antagonist treated group than pancreatic cancer group of mice. Moreover, 5HT2A antagonist ameliorated the alteration in pain behaviour of pancreatic cancer mice. mRNA expression of HDAC2 and level of inflammatory cytokines were reduced in the spinal tissue of 5HT 2A antagonist treated group than pancreatic cancer group of mice. Conclusions Data revealed that 5HT2A antagonist ameliorates pain associated with pancreatic cancer mice by HDAC inhibition and inflammatory cytokines. The result of investigation supports that modulation of 5HT2A receptor could be used clinically to protects neuropathic pain in pancreatic cancer.

Trichostatin C attenuates TNFα-induced inflammation in endothelial cells by up-regulating Krüppel-like factor 2 / 药学学报

Krüppel-like transcription factor 2 (KLF2) plays a key regulatory role in endothelial inflammation, thrombosis, angiogenesis and macrophage inflammation and polarization, and up-regulation of KLF2 expression has the potential to prevent and treatment atherosclerosis. In this study, trichostatin C (TSC) was obtained from the secondary metabolites of rice fermentation of Streptomyces sp. CPCC 203909 as a KLF2 up-regulator by using a high throughput screening model based on a KLF2 promoter luciferase reporter assay. TSC significantly inhibited the adhesion of tumor necrosis factor-α (TNFα) induced monocytes (THP-1) to human umbilical vein endothelial cells (HUVECs). Western blot results showed that TSC decreased TNFα induced the protein expression increase of vascular cell adhesion molecule-1 (VCAM-1), and thereby inhibited endothelial inflammation. The results of histone deacetylase (HDAC) overexpression and molecular docking experiments showed that TSC upregulated the expression of KLF2 by inhibiting subtypes of HDAC 4/5/7. In conclusion, this study suggests that TSC up-regulates the expression of KLF2 through inhibiting HDAC 4/5/7 and thus inhibits TNFα induced endothelial inflammation, and it has the potential to prevent and treat atherosclerosis.

Advances in histone epigenetic enzyme inhibitors based on proteomics / 药学学报

As an important component of nucleosomes on the chromatin of eukaryotic cells, histones play an important role in the development and progression of tumour diseases by regulating epigenetic post-translational modifications such as acetylation and methylation. In addition, development of inhibitors targeting methyltransferase and deacetylase provides novel therapeutic strategies for cancer treatment. Mass spectrometry-based proteomics can reveal the global changes of histone modifications under the action of drugs during disease progression, which in turn provides important support for revealing drug action mechanism, drug resistance mechanism, and investigating novel drug combination strategies. This article focuses on the progress and status of proteomic research on a variety of histone modifying enzyme inhibitors, including methyltransferase inhibitors and histone deacetylase inhibitors, which will help to understand the current and further utilization of proteomics in studying histone modifications.

Effects and mechanism of ginsenoside Rh2 on the proliferation and apoptosis of human glioma cells / 中国药房

ABSTRACT OBJECTIVE To investigate the effects and mechanism of ginsenoside Rh2 on the proliferation and apoptosis in human glioma U87 and U251 cells. METHODS Using human glioma U87 and U251 cells as subjects， the proliferation and apoptosis， as well as the expression of histone deacetylase 1（HDAC1） protein and apoptosis-related proteins [B cell lymphoma-2（Bcl-2）， Bcl-2-associated X protein （Bax） and cleaved caspase-3] were detected after being treated with different concentrations of ginsenoside Rh2. RESULTS The concentrations of 10，20，30，40，50，60，70，80 μmol/L ginsenoside Rh2 could generally significantly increase the proliferation inhibition rate of U87 and U251 cells （P＜0.05 or P＜0.01）， and the half inhibitory concentrations of this component after 48 hours of action were 51.34 and 55.84 μmol/L， respectively；30，50 μmol/L ginsenoside Rh2 could increase the total apoptotic rate of both types of cells， reduced the protein expressions of HDAC1 and Bcl-2， and increased the protein expressions of Bax and cleaved caspase-3 significantly （P＜0.05 or P＜0.01）. CONCLUSIONS Ginsenoside Rh2 has a significant inhibitory effect on the proliferation of glioma cells and promotes the apoptosis of cells， which may be through reducing the expression of HDAC1 protein and activating the Bcl-2 family protein-mediated apoptosis pathway.

Effect of surgery under propofol anesthesia during mid-pregnancy on cognitive function and hippocampal HDAC2-CREB-NR2B signaling pathway in offspring rats / 中华麻醉学杂志

Objective:To evaluate the effect of surgery under propofol anesthesia during mid-pregnancy on the cognitive function and hippocampal histone deacetylase 2 (HDAC2)-cAMP response element-binding protein (CREB)-N-methyl-D-aspartate (NMDA) receptor 2B subunit (NR2B)-containing NMDA receptor (NR2B) signaling pathway in the offspring rats.Methods:Thirty healthy Sprague-Dawley rats at 14 days of gestation were divided into 3 groups ( n=10 each) using a random number table method: propofol anesthesia group (P group), surgery under propofol anesthesia group (S group) and control group (C group). In S group, propofol 20 mg/kg was injected via the caudal vein, and then propofol was continuously infused at a rate of 20 mg·kg -1·h -1 to maintain anesthesia for 4 h, and exploratory laparotomy was performed. Group P received no exploratory laparotomy and the other treatments were similar to those previously described in group S. The equal volume of normal saline was given instead in group C. The learning and memory of the offspring rats was assessed using Morris water maze test on postnatal day 30. The expression of HDAC2, phosphorylated CREB (p-CREB), NR2B, brain-derived neurotriphic factor (BDNF) and phosphorylated tyrosine kinase B (p-TrkB) in offspring′s hippocampi was evaluated by Western blot. Apoptosis in hippocampal neurons was detected by TUNEL staining. Results:Compared with group C, the escape latency was significantly prolonged, the frequency of crossing the original platform was decreased, the time spent in the second quadrant was shortened, the expression of HDAC2 was up-regulated, the expression of p-CREB, NR2B, BDNF and p-TrkB was down-regulated, and the apoptosis rate of the hippocampal neurons was increased in P and S groups ( P<0.05). Compared with P group, the escape latency was significantly prolonged, the frequency of crossing the original platform was decreased, the time spent in the second quadrant was shortened, the expression of HDAC2 was up-regulated, the expression of p-CREB, NR2B, BDNF and p-TrkB was down-regulated, and the apoptosis rate of the hippocampal neurons was increased in S group ( P<0.05). Conclusions:Surgery under propofol anesthesia during mid-pregnancy can decrease the cognitive function of offspring rats, and the mechanism is related to the regulation of HDAC2-CREB-NR2B signaling pathway and the promotion of apoptosis in hippocampal neurons.

Research progress of histone lactylation in immunomodulation after traumatic brain injury / 中华创伤杂志

Traumatic brain injury (TBI) is a major reason for temporary or permanent dyskinesia and cognitive impairment of the organism. Generally, TBI induces subsequent neuroinflammation to assist cell debris removal and tissue repair and regeneration after injury. However, overactivation or long-term activation of immune cells will exacerbate nerve damage or death, cause cognitive dysfunction, and ultimately lead to neurodegenerative diseases. Therefore, secondary damage caused by persistent inflammation is a key component of TBI pathological process. As the main metabolite of anaerobic glycolysis, lactate is increased after TBI and participates in brain inflammation as an important immune regulatory molecule rather than a metabolic waste. Importantly, histone lysine lactylation as a novel type of histone post-translational modifications (HPTM) derived from lactate allows lactate to participate in the regulation of complex immunopathophysiological processes of the central nervous system after TBI. Further study on the process of histone lactylation and its immune regulation mechanism during TBI may provide new insights for early intervention and improvement of TBI prognosis. Thus, the authors reviewed the role of histone lactylation in the immune regulation of TBI, so as to further elucidate the mechanism of TBI and the explore new warning and prevention measures from the perspective of HPTM.

Relationship between histone deacetylase gene polymorphism and type 2 diabetes mellitus in Bai and Han populations in Dali of Yunnan Province / 中国基层医药

Objective:To investigate the relationship between histone deacetylase (HDAC) gene polymorphism and type 2 diabetes mellitus (T2DM) in Bai and Han populations in Dali of Yunnan province.Methods:A total of 148 patients with T2DM of Bai and Han nationalities who received treatment in Dali Bai Autonomous Prefecture People's Hospital from May 2019 to March 2021 were included in the T2DM group. An additional 100 healthy controls of Bai and Han nationalities who concurrently received physical examination in the same hospital from May 2019 to December 2020 were included in the normal control group. The susceptibility genes of T2DM were detected using the Taqman MGB probe method. The susceptibility gene loci were amplified using polymerase chain reaction. The whole sequence of susceptibility gene was sequenced.Results:There were no significant differences in the distribution frequencies of rs2530223 genotype, rs11741808 genotype, rs2547547 genotype, and rs1741981 genotype between Bai and Han populations (all P > 0.05). There was a significant difference in blood lipid level between four loci ( t = -1.06, -0.19, 0.39, -2.12, -2.04, 0.16, 1.47, < 0.01, -0.16, -3.17, -2.93, 0.69, -2.58, -2.33, all P < 0.05). There was a significant difference in homeostasis model assessment of insulin resistance between different states (all P < 0.05). The frequency distributions of each genotype and each allele did not differ significantly between healthy control people of Bai nationality and T2DM patients of Bai nationality and between healthy control people of Han nationality and T2DM patients of Han nationality (all P > 0.05). Logistic regression analysis showed that the polymorphism was not an independent risk factor for T2DM. Conclusion:The relationships between HDAC gene polymorphism and T2DM, obesity and dyslipidemia differ between Bai and Han populations.

Novel insights into histone lysine methyltransferases in cancer therapy:From epigenetic regulation to selective drugs / 药物分析学报

The reversible and precise temporal and spatial regulation of histone lysine methyltransferases(KMTs)is essential for epigenome homeostasis.The dysregulation of KMTs is associated with tumor initiation,metastasis,chemoresistance,invasiveness,and the immune microenvironment.Therapeutically,their promising effects are being evaluated in diversified preclinical and clinical trials,demonstrating encouraging outcomes in multiple malignancies.In this review,we have updated recent understandings of KMTs'functions and the development of their targeted inhibitors.First,we provide an updated overview of the regulatory roles of several KMT activities in oncogenesis,tumor suppression,and im-mune regulation.In addition,we summarize the current targeting strategies in different cancer types and multiple ongoing clinical trials of combination therapies with KMT inhibitors.In summary,we endeavor to depict the regulation of KMT-mediated epigenetic landscape and provide potential epigenetic targets in the treatment of cancers.

Epigenetic drug library screening reveals targeting DOT1L abrogates NAD+synthesis by reprogramming H3K79 methylation in uveal melanoma / 药物分析学报

Uveal melanoma(UM)is the most frequent and life-threatening ocular malignancy in adults.Aberrant histone methylation contributes to the abnormal transcriptome during oncogenesis.However,a comprehensive understanding of histone methylation patterns and their therapeutic potential in UM remains enigmatic.Herein,using a systematic epi-drug screening and a high-throughput transcriptome profiling of histone methylation modifiers,we observed that disruptor of telomeric silencing-1-like(DOT1L),a methyltransferase of histone H3 lysine 79(H3K79),was activated in UM,especially in the high-risk group.Concordantly,a systematic epi-drug library screening revealed that DOT1 L inhibitors exhibited salient tumor-selective inhibitory effects on UM cells,both in vitro and in vivo.Combining Cleavage Under Targets and Tagmentation(CUT&Tag),RNA sequencing(RNA-seq),and bioinformatics analysis,we identified that DOT1 L facilitated H3K79 methylation of nicotinate phosphoribosyltransferase(NAPRT)and epigenetically activated its expression.Importantly,NAPRT served as an oncogenic accel-erator by enhancing nicotinamide adenine dinucleotide(NAD+)synthesis.Therapeutically,DOT1L inhi-bition epigenetically silenced NAPRT expression through the diminishment of dimethylation of H3K79(H3K79me2)in the NAPRT promoter,thereby inhibiting the malignant behaviors of UM.Conclusively,our findings delineated an integrated picture of the histone methylation landscape in UM and unveiled a novel DOT1L/NAPRT oncogenic mechanism that bridges transcriptional addiction and metabolic reprogramming.

Epigenetic mechanism of myopia / 中华实验眼科杂志

Myopia has become a serious public health problem, but its pathogenesis is still unclear, and effective interventions are relatively scarce.It is recognized that myopia is influenced by both genetic and environmental factors, in which epigenetics may play a key role.Epigenetics refers to the changes in gene expression and function that do not involve DNA sequence variation.Mainly including DNA methylation, non-coding RNA (microRNA, long non-coding RNA and circular RNA, etc.), histone modification and mRNA modification, epigenetic modifications interact to form a complex regulatory network in the pathophysiological process of myopia.By controlling the process of scleral matrix remodeling, eye cell proliferation and retinal development, the morphological characteristics of the eye are jointly regulated, ultimately affecting the onset and development of myopia.Epigenetics has provided new targets of myopia intervention and has become a hotspot in the field.In this paper, we reviewed the current findings of myopia epigenetics to provide a reference for related research.

Effect of trichostatin A on lipopolysaccharide-induced injury and apoptosis of human microvascular endothelial cell / 中国小儿急救医学

Objective:To investigate the effect of histone deacetylase inhibitor trichostatin A(TSA) on the lipopolysaccharide(LPS)-induced injury and apoptosis of human microvascular endothelial cell(HMEC).Methods:HMECs were used as research cells to establish LPS-induced septic cell model, which were divided into three groups according to different treatments: control group (150 μL of phosphate buffer), LPS group (150 μL of 5 μg/mL LPS), LPS+ TSA group (150 μL of 5 μg/mL LPS and 500 μg/L TSA). After cells of each group were cultured for 24 h and 48 h, the concentration of lactate dehydrogenase(LDH)in the culture supernatant was detected by enzyme-linked immunosorbent assay and the apoptosis rate of HMECs was detected by Annexin V-FTTC/PI staining, then comparison between different groups were made.Results:Compared with the control group, LDH concentration in LPS group increased significantly at 24 h[(4.67±1.27) ng/L vs. (11.57±0.83) ng/L ] and 48 h[(7.93±0.80) ng/L vs. (12.72±0.89) ng/L ]; Compared with LPS group, LDH concentration in LPS + TSA group decreased significantly at 24 h[(6.01±0.29) ng/L ] and 48 h[(5.96±0.27) ng/L ], and the differences were statistically significant ( P<0.05). Compared with the control group, the apoptosis rates of HMEC cells in LPS group were significantly higher at 24 h[(0.92±0.89)% vs. (1.66±0.09)% ] and 48 h[(1.09±0.14)% vs. (5.01±0.16)%]; Compared with LPS group, the apoptosis rate of HMEC cells in LPS + TSA group significantly decreased at 24 h[(1.36±0.01)% ] and 48 h[(4.19±0.23)% ], the differences were statistically significant ( P<0.05). Conclusion:TSA has the protective effect of reducing cell injury and apoptosis in sepsis.

Progress of enhancer of zeste homolog 2 in hematological tumors / 白血病·淋巴瘤

The enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase, which is widely studied in histone methylation modification. It can promote epigenetic gene silencing and mediate the occurrence of tumors through a variety of regulatory mechanisms. The gain-of-function and loss-of-function mutations of EZH2 have been confirmed in many cancers. At present, with the extensive attention paid to the regulatory role of EZH2 in epigenetic mechanism, the exact way in which EZH2 imbalance affects the pathogenesis of hematologic malignancies remains to be clarified. This article reviews the pathogenetic role of EZH2 in hematological tumors, and hope to find new targets for the prevention and treatment of hematological tumors.

Research progress on the mechanism of valproic acid against glioma / 中国药房

Gliomas are commonly central nervous system tumors. The conventional treatment is surgical resection combined with chemoradiotherapy， but glioma patients often have a poor prognosis. Therefore， there is an urgent need to identify new potential targets in gliomas and develop more effective treatments. Valproic acid has the properties of histone deacetylase inhibitor， which has been proven to have inhibitory effects on various tumors. It is confirmed that valproic acid could promote apoptosis and cell arrest of glioma cells， inhibit cell invasion and glioma stem cells， increase the sensitivity of glioma cells to radiotherapy and chemotherapy by regulating ERK/Akt signaling pathway， Akt/mTOR signaling pathway， and regulating expression levels of RECK， MGMT， Nrf2， PON2， Smad4， GSK3β and other proteins. In addition， valproic acid can also enhance the effectiveness of anticancer drugs by inhibiting the growth of glioma stem cells and inducing their differentiation. In conclusion， valproic acid can inhibit glioma through multiple targeted actions， and may become a new targeted drug for the treatment of glioma.

Role of Histone Modifications and 12/15-lipoxygenase Metabolic Pathway in the Development of Diabetic Kidney Disease / 中山大学学报(医学科学版)

Diabetic kidney disease （DKD） is one of the most common microvascular complications in patients with diabetes. DKD is also the main cause of end-stage renal failure， with very complex pathogenesis. A large number of experiments have confirmed that epigenetic mechanisms， including histone chemical modifications and lipid metabolites 12/15-lipoxygenase （12/15-LO）， are involved in regulating the characteristic pathophysiological process of DKD， based on which， this review further explores the pathogenesis of DKD and provides the new research direction for DKD treatment.

Effect of histone H4 on polarization of alveolar macrophages in mice with acute respiratory distress syndrome / 中国职业医学

Objective To investigate the role of histone H4 in the polarization of alveolar macrophages (AM) in lipopolysaccharide (LPS)-induced acute respiratory distress syndrome (ARDS) in mice. Methods i) The specific pathogen free male C57BL/6 mice were randomly divided into control group and 2, 4, 6 and 8 mg/kg LPS groups, with six mice in each group. The mice in the LPS groups were intratracheally administered LPS according to their respective doses, while the mice in the control group received an equivalent volume of 0.9% saline. After 12 hours, the arterial blood gas was analyzed, and the pulmonary edema and histopathological changes in lung tissues of mice in each group were observed. The level of histone H4 in bronchoalveolar lavage fluid (BALF) of mice was detected using enzyme-linked immunosorbent assay , and mice AMs of the five group were isolated using adherent method. ii) AMs from normal mice were isolated using adherent method and randomly divided into control group, histone H4 injury group, BALF injury group and anti-histone H4 antibody (anti-H4) intervention group. In the histone H4 injury group, AMs were treated with histone H4 at a final concentration of 20 mg/L. In the BALF injury group and anti-H4 intervention group, AMs were treated with 200 μL BALF supernatant from mice intratracheally administered 6 mg/kg body weight LPS, with the latter group treated with 25 mg/L anti-H4 antibody. The control group AMs were treated with phosphate-buffered saline. iii) After 12 hours of stimulation, the cells were collected, and the relative expression of tumor necrosis factor-α (Tnfa), interleukin-1β (Il1b), differentiation antigen 206 (Cd206) and arginase 1 (Arg1) in AMs was detected using real-time quantitative polymerase chain reaction. Results i) Compared with the control group, mice in all four LPS groups exhibited rapid breathing, inflammatory reaction and lung edema in lung tissues, which were aggravated in a dose-dependent manner. The ratio of partial pressure of arterial oxygen to fraction of inspired oxygen in mice decreased with the increase of LPS dose (P<0.05). The wet/dry weight ratio of lung, the level of histone H4 in BALF and the relative expression of Tnfa and Il1b mRNA in AMs increased with the increase of LPS dose (all P<0.05). The mice in the 6 and 8 mg/kg LPS groups developed ARDS. The level of histone H4 in BALF and the relative expression of Tnfa and Il1b mRNA in AMs of mice in 6 and 8 mg/kg LPS groups were higher than those in the other three groups (all P<0.05). ii) The relative expression of Tnfa and Il1b mRNA increased (both P<0.05), and the relative expression of Cd206 and Arg1 mRNA decreased (both P<0.05) in AMs of histone H4 injury group and BALF injury group compared with the control group. Compared with BALF injury group, the relative mRNA expression of Tnfa and Il1b in AMs of anti-H4 intervention group decreased (both P<0.05), while the relative expression of Arg1 mRNA increased (P<0.05). Conclusion LPS can induce a dose-dependent increase in histone H4 levels in BALF in mice. Histone H4 drives the development of ARDS by activating AMs to M1 polarization. Antagonizing histone H4 to interfere with AM polarization to M1 could be a target for the treatment of ARDS.

HDAC3-a key target for preventing organ ischemia-reperfusion injury / 中国药理学通报

Histone deacetylase 3 (HDAC3) plays an important role in chromatin remodeling, which in turn regulates gene transcription, so HDAC3 is involved in the pathophysiology of various diseases through epigenetic regulation. Organ ischemia-reperfusion injury (I R I) is a pathophysiological process that leads to the development of a variety of diseases such as delayed neuronal necrosis, irreversible shock, myocardial infarction, acute organ failure and organ transplant rejection. In this paper we review the pathophysiological function of HDAC3 and its role in the development of IRI in human parenchymal organs, and also explore the therapeutic value of HDAC3 in IRI.

Role of epigenetic regulation of biological clock genes in tumors / 中国药理学通报

The circadian clock is regulated at the molecular level by transcriptional-translational feedback loop of clock genes, which ensures that a variety of physiological processes have a-round 24 h circadian rhythms, including cell metabolism, cell proliferation, cell apoptosis and tumorigenesis, to maintain the homeostasis. Thus, the disturbance of circadian clock will disrupt homeostasis, causing various diseases, including neoplasm, metabolic syndrome, Parkinson's disease, COPD and cardiovascular diseases. Disturbance of circadian clock is closely related with tumorigenesis, and acts on various molecules and pathways leading to tumorigenesis, including oncogene and tumor suppressor gene, cell cycle, metabolic reprogramming, immune escape, endocrine disruption, alteration of gastrointestinal microbiome. This review focuses on changes in clock genes expression which disrupt cell cycle and may play a role in tumorigenesis, and epi-geneties, an important way to regulate gene expression, which can alter clock gene expression, thus playing an important role in the process of " the alternation of clock gene expression-disruption of cell cycle-tumorigenesis".