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Ischemic stroke is an acute cerebrovascular disease due to poor blood flow to the brain. Nevertheless, there is still no effective therapy for it and the pathology contributing to ischemic stroke is not fully understood. Histone Deacetylase 9 (HDAC9) is a class IIa chromatin-modifying enzyme. HDAC9 gene region is a leading risk locus for large artery atherosclerotic stroke. However, the mechanisms linking HDAC9 to ischemic remain elusive. In the study, we attempted to explore HDAC9-associated inflammatory response using the wild type (WT) and HDAC9-knockout (KO) mice with brain ischemic injury. The results indicated that WT mice with ischemia brain exhibited higher expression levels of HDAC9. HDAC9 depletion resulted in a decreased infarct volume and an improved neurological function in mice after ischemic reperfusion (I/R) injury. I/R injury markedly enhanced GFAP and Iba-1 expressions in cortex and HDAC9 knockout significantly reversed this up-regulation. Loss of HDAC9 inhibited the release of inducible NO-synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin 1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), and IL-18 in cortex, hippocampus and hypothalamus of mice with I/R injury, which occurred at the transcription levels. Furthermore, the inhibitory actions of HDAC9 deficiency were associated with the down-regulation of phosphorylated-IκBα, phosphorylated-nuclear factor-kappa B (NF-κB), and p-mitogen-activated protein kinases (MAPKs), including phosphorylated-p38, phosphorylated-extracellular signal-regulated kinase 1/2 (ERK1/2), and phosphorylated- c -Jun N-terminal kinase (JNK). Importantly, the in vitro study indicated that HDAC9 inhibition-reduced inflammation and activation of IκBα/NF-κB were restored by promoting MAPKs activity in LPS-stimulated cells. Our findings suggest that HDAC9 inhibition showed neuroprotective effects on ischemic stroke by restraining inflammation, which might help develop new and effective strategies for the therapeutic interventions in ischemic stroke. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is a risk factor for abnormal heart development, but the molecular mechanism remains obscure. Histone deacetylase 11 (HDAC11), the most recently identified histone deacetylase, is the sole member of class IV HDACs. However, its role in diabetic cardiac injury is still poorly understood. In the present study, we attempted to explore the effects of HDAC11 on fructose (Fru)-induced cardiac injury using the wild type (HDAC11 +/+ ) and knockout (HDAC11 −/− ) mice. The results indicated that HDAC11 was significantly expressed in human and mouse diabetic heart failure (DHF) hearts. HDAC11 −/− reduced the body weight, inguinal fat-pad mass, and elevated blood pressure in Fru-fed mice. Compared to HDAC11 +/+ /Fru group, cardiac function was significantly improved in HDAC11 −/− /Fru mice. HDAC11 −/− /Fru mice exhibited reduced cardiac triacylglycerol (TG), total cholesterol (TC) and free fatty acid (FFA) levels, along with decreased mRNA levels of lipid synthesis-, lipid storage- and lipid oxidation-associated genes. In addition, HDAC11 −/− attenuated apoptosis, oxidative stress and inflammation in the heart of Fru-fed mice, as evidenced by the reduced cleavage of Caspase-3, nicotinamide adenine dinucleotide phosphate (NADPH), and xanthine oxidase (XOD) activity, enhanced superoxide dismutase (SOD) activity, as well as the decreased interleukin 1β (IL-1β) and tumor necrosis factor-α (TNF-α) levels, which was accompanied with down-regulated p-NF-κB. The results above were verified in Fru-treated primary cardiomyocytes isolated from HDAC11 +/+ or HDAC11 −/− mice. Intriguingly, suppressing the expressions of anti-oxidants using zinc protoporphyrin (ZnPP) or siNrf-2 siRNA markedly abolished the results that HDAC11 suppression-induced reduction of apoptosis, reactive oxygen species (ROS) production, inflammation, as well as the improvement of dyslipidemia in Fru-incubated primary cardiomyocytes. Thus, ROS production was responsible for HDAC11-modulated diabetic heart injury. These findings suggested that suppressing HDAC11 has therapeutic potential for treating diabetes mellitus-associated cardiac injury. [ABSTRACT FROM AUTHOR]

Ischemia/reperfusion (IR) injury causes damage in aerobically metabolizing organs or tissues, which is an essential injury mechanism in various clinical settings. SRY-related high mobility group-Box gene 9 (SOX9) is a transcription factor of the SRY family, modulating various cellular processes, including fibrosis formation and tumor growth. However, the effects of SOX9 on hepatic IR injury have not been explored. In the present study, a hepatic IR injury model was established, supported by a significant histological alteration with high Suzuki scores, and a remarkable up-regulation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Importantly, we found that SOX9 was over-expressed in liver of mice after IR operation. Suppressing SOX9 markedly reduced inflammatory response, as evidenced by the reduced mRNA expressions of tumor necrosis factor α (TNF-α), interleukin (IL)-6 and IL-1β and inactivation of inhibitor of κBα (IκBα)/nuclear factor (NF)-κB pathway. In addition, SOX9 suppression alleviated apoptosis in liver of mice after IR injury, as supported by the reduced number of terminal deoxyribonucleotidyl transferse (TdT)-mediated biotin-16-dUTP nick-end labelling (TUNEL)-staining cells and decreased expression of Caspase-3 in liver tissue sections. The role of SOX9 in accelerating hepatic IR injury was further confirmed in primary hepatocytes under hypoxiaand reoxygenation (HR) treatment by enhancing inflammatory response and apoptosis. Of note, we found that transforming growth factor (TGF)-β1 was highly induced in liver of mice after IR injury. HR treatment also stimulated TGF-β1 expressions in vitro. Significantly, SOX9 over-expression-induced inflammation and apoptosis were obviously reduced by pirfenidone (Pirf), TGF-β1 inhibitor. In contrast, TGF-β1 exposure to cells further enhanced inflammation and apoptosis in HR-operated cells either with SOX9 knockdown or over-expression. Therefore, we identified a novel SOX9-dependent pathway that contributed to hepatic IR injury through enhancing inflammation and apoptosis by activating TGF-β1. [ABSTRACT FROM AUTHOR]