Novel reno-protective mechanism of Aspirin involves H2AK119 monoubiquitination and Set7 in preventing type 1 diabetic nephropathy

Background

Even after several novel therapeutic approaches, the number of people with diabetic nephropathy (DN) still continues to increase globally, this suggest to find novel therapeutic strategies to prevent it completely. Recent reports, are indicating the ubiquitin proteasome system alterations in DN. Recently, we also showed that, histone H2AK119 mono-ubiquitination (H2AK119-Ub) found to regulate Set7, a key epigenetic enzyme in the development of renal fibrosis under type 1 diabetic condition. Hence, we aimed to study the role of a known 20 s proteasome inhibitor Aspirin, on histone ubiquitination in the progression of DN.

丁酸钠联合电离辐射对肺癌A549细胞凋亡的影响及其机制

研究组蛋白去乙酰化酶抑制剂（HDACi）丁酸钠（NaBt）单独或联合X射线照射对人非小细胞肺癌（NSCLC）A549细胞凋亡的影响,并阐明其作用机制。     

Depressive disorder and antidepressants from an epigenetic point of view

Depressive disorder is a complex, heterogeneous disease that affects approximately 280 million people worldwide. Environmental, genetic, and neurobiological factors contribute to the depressive state. Since the nervous system is susceptible to shifts in activity of epigenetic modifiers, these allow for significant plasticity and response to rapid changes in the environment. Among the most studied epigenetic modifications in depressive disorder is DNA methylation, with findings centered on the brain-derived neurotrophic factor gene, the glucocorticoid receptor gene, and the serotonin transporter gene. In order to identify biomarkers that would be useful in clinical settings, for diagnosis and for treatment response, further research on antidepressants and alterations they cause in the epigenetic landscape throughout the genome is needed. Studies on cornerstone antidepressants, such as selective serotonin reuptake inhibitors, selective serotonin and norepinephrine reuptake inhibitors, norepinephrine, and dopamine reuptake inhibitors and their effects on depressive disorder are available, but systematic conclusions on their effects are still hard to draw due to the highly heterogeneous nature of the studies. In addition, two novel drugs, ketamine and esketamine, are being investigated particularly in association with treatment of resistant depression, which is one of the hot topics of contemporary research and the field of precision psychiatry.     

Discovery of Novel Multiacting Topoisomerase I/II and Histone Deacetylase Inhibitors

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丙戊酸钠对Kasumi-1细胞株细胞周期的影响

目的 观察丙戊酸钠(VPA)对急性髓性白血病(AML)Kasumi-1细胞周期的影响,并探讨其分子机制.方法 将对数生长期Kasumi-1细胞1×105/ml(观察组)分别经1、2、3 mmol/L VPA处理3 d;对照组不加药.RT-PCR法检测VPA不同浓度及不同作用时间(3 mmol/L作用0、1、2、3d)细胞周期调节因子cyclinE1、p21WAF1/CIP1、p27KIP1 mRNA及p21WAF1/CIP1蛋白变化.结果 观察组cyclinE1 mRNA表达明显降低(P<0.05),p21WAF1/CIP1 mRNA及其蛋白表达明显升高(P<0.05),且均呈剂量、时间依赖性;p27KIP1 mRNA表达水平无明显变化.结论 VPA可通过对Kasumi-1细胞周期蛋白及周期蛋白依赖性激酶抑制剂的影响调节细胞周期,使细胞阻滞于G0/G1期;本研究可为急性白血病的治疗提供理论依据.     

Selective inhibition of histone deacetylase 6 alters the composition of circulating blood cells in a lethal septic model

Background

Phagocytes, especially monocytes, macrophages, and dendritic cells, play a pivotal role in the innate and adaptive immune responses during sepsis. We have shown that inhibition of histone deacetylase 6 improves survival and increases bacterial clearance in a mouse model of cecal ligation and puncture (CLP). The aim of this study was to determine whether this effect was associated with changes in the number and composition of different blood cell types in the circulation.

Methods

C57BL/6J mice were subjected to CLP, and 1 h later given an intraperitoneal injection of either Tubastatin A dissolved in dimethyl sulfoxide, or dimethyl sulfoxide only. Sham-operated animals were treated in an identical fashion but not subjected to CLP. Forty-eight hours later, peripheral blood was obtained via cardiac puncture and analyzed using a HemaTrue veterinary hematology analyzer.

Results

Tubastatin A administration increased the number of circulating monocytes in the sham-operated and the CLP animals. In comparison with the sham, CLP animals displayed an increase in the granulocyte percentage in white blood cells and decrease in the lymphocyte number and percentage, with a resultant increase in the granulocyte-to-lymphocyte ratio. Treatment of CLP animals with Tubastatin A decreased the granulocyte percentage and restored the lymphocyte number and percentage, which decreased the granulocyte-to-lymphocyte ratio. In the sham animals, Tubastatin A increased red blood cell number, hematocrit, and hemoglobin. This effect was not seen in CLP animals.

Conclusions

Tubastatin A treatment has significant impact on the composition of circulating blood cells. It increases the number of circulating monocytes and the red blood cell mass in sham-operated animals. In the CLP animals, it increases the monocyte count, decreases the percentage of granulocytes, restores the lymphocyte population, and decreases the granulocyte-to-lymphocyte ratio. These results may explain why Tubastatin A treatment improves survival in the septic models.     

Valproic acid for the treatment of hemorrhagic shock: a dose-optimization study

Background

Valproic acid (VPA) has been shown to improve survival in animal models of hemorrhagic shock at a dose of 300 mg/kg. Our aim was to identify the ideal dose through dose-escalation, split-dosing, and dose de-escalation regimens.

Materials and methods

Rats were subjected to sublethal 40% hemorrhage and treated with vehicle or VPA (dose of 300, 400, or 450 mg/kg) after 30 min of shock. Acetylated histones and activated proteins from the PI3K–Akt–GSK-3β survival pathway at different time points were quantified by Western blot analysis. In a similar model, a VPA dose of 200 mg/kg followed 2 h later by another dose of 100 mg/kg was administered. Finally, animals were subjected to a lethal 50% hemorrhage and VPA was administered in a dose de-escalation manner (starting at dose of 300 mg/kg) until a significant drop in percent survival was observed.

Results

Larger doses of VPA resulted in greater acetylation of histone 3 and increased activation of PI3K pathway proteins. Dose-dependent differences were significant in histone acetylation but not in the activation of the survival pathway proteins. Split-dose administration of VPA resulted in similar results to a single full dose. Survival was as follows: 87.5% with 300 and 250 mg/kg of VPA, 50% with 200 mg/kg of VPA, and 14% with vehicle-treated animals.

Conclusions

Although higher doses of VPA result in greater histone acetylation and activation of prosurvival protein signaling, doses as low as 250 mg/kg of VPA confer the same survival advantage in lethal hemorrhagic shock. Also, VPA can be given in a split-dose fashion without a reduction in its cytoprotective effectiveness.