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Histone deacetylases 6 (HDAC6) has been reported to be involved in the pathogenesis of rhabdomyolysis-induced acute kidney injury (AKI). Selective inhibition of HDAC6 activity might be a potential treatment for AKI. In our lab, N-hydroxy-6-(4-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)nicotinamide (F7) has been synthesized and inhibited HDAC6 activity with the IC50 of 5.8 nM. However, whether F7 possessed favorable renoprotection against rhabdomyolysis-induced AKI and the involved mechanisms remained unclear. In the study, glycerol-injected mice developed severe AKI symptoms as indicated by acute renal dysfunction and pathological changes, accompanied by the overexpression of HDAC6 in tubular epithelial cells. Pretreatment with F7 at a dose of 40 mg/kg/d for 3 days significantly attenuated serum creatinine, serum urea, renal tubular damage and suppressed renal inflammatory responses. Mechanistically, F7 enhanced the acetylation of histone H3 and α-tubulin to reduce HDAC6 activity. Glycerol-induced AKI triggered multiple signal mediators of NF-κB pathway as well as the elevation of ERK1/2 protein and p38 phosphorylation. Glycerol also induced the high expression of proinflammatory cytokine IL-1β and IL-6 in kidney and human renal proximal tubule HK-2 cells. Treatment of F7 notably improved above-mentioned inflammatory responses in the injured kidney tissue and HK-2 cell. Overall, these data highlighted that 2-methylquinazoline derivative F7 inhibited renal HDAC6 activity and inflammatory responses to protect against rhabdomyolysis-induced AKI. [ABSTRACT FROM AUTHOR]

Medicine-food homology is a long-standing concept in traditional Chinese medicine. YiNianKangBao (YNKB) tea is a medicine-food formulation based on Sichuan dark tea (Ya’an Tibetan tea), which is traditionally used for its lipid-lowering properties. In this study, we evaluated the effects of YNKB on dyslipidemia and investigated the mechanism underlying its correlation with gut microbiota and serum metabolite regulation. Wild-type mice were fed a normal diet as a control. Male ApoE-/- mice were randomly divided into three high-fat diet (HFD) groups, a model group, and two treated groups (100, 400 mg/kg/d for low, high-dose), and fed by gavage for 12 weeks. Serum lipid levels, composition of gut microbiota, and serum metabolites were then analyzed before treatment with YNKB. We extracted the ingredients of YNKB in boiled water for one hour. YNKB supplementation at a high dose of 400 mg/kg/day reduced bodyweight gains (relative epididymal fat pad and liver weight), and markedly attenuated serum lipid profiles and atherosclerosis index, with no significant differences present between the low-dose treatment and HFD groups. Gut microbiota and serum metabolic analysis indicated that significant differences were observed between normal, HFD, and YNKB treatment groups. These differences in gut microbiota exhibited strong correlations with dyslipidemia-related indexes and serum metabolite levels. Oral administration of high-dose YNKB also showed significant lipid-lowering activity against hyperlipidemia in apoE-deficient mice, which might be associated with composition alterations of the gut microbiota and changes in serum metabolite abundances. These findings highlight that YNKB as a medicine-food formulation derived from Sichuan dark tea could prevent dyslipidemia and improve the understanding of its mechanisms and the pharmacological rationale for preventive use. [ABSTRACT FROM AUTHOR]

Regulation of DNMT1 is critical for epigenetic control of many genes and for genome stability. Using phylogenetic analysis we characterized a block of 27 nucleotides in the 3′UTR of Dnmt1 mRNA identical between humans and Xenopus and investigated the role of the individual elements contained within it. This region contains a cytoplasmic polyadenylation element (CPE) and a Musashi binding element (MBE), with CPE binding protein 1 (CPEB1) known to bind to the former in mouse oocytes. The presence of these elements usually indicates translational control by elongation and shortening of the poly(A) tail in the cytoplasm of the oocyte and in some somatic cell types. We demonstrate for the first time cytoplasmic polyadenylation of Dnmt1 during periods of oocyte growth in mouse and during oocyte activation in Xenopus. Furthermore we show by RNA immunoprecipitation that Musashi1 (MSI1) binds to the MBE and that this element is required for polyadenylation in oocytes. As well as a role in oocytes, site-directed mutagenesis and reporter assays confirm that mutation of either the MBE or CPE reduce DNMT1 translation in somatic cells, but likely act in the same pathway: deletion of the whole conserved region has more severe effects on translation in both ES and differentiated cells. In adult cells lacking MSI1 there is a greater dependency on the CPE, with depletion of CPEB1 or CPEB4 by RNAi resulting in substantially reduced levels of endogenous DNMT1 protein and concurrent upregulation of the well characterised CPEB target mRNA cyclin B1. Our findings demonstrate that CPE- and MBE-mediated translation regulate DNMT1 expression, representing a novel mechanism of post-transcriptional control for this gene. [ABSTRACT FROM AUTHOR]

Methyl-CpG binding domain protein 5 (MBD5) belongs to the MBD family proteins, which play central roles in transcriptional regulation and development. The significance of MBD5 function is highlighted by recent studies implicating it as a candidate gene involved in human 2q23.1 microdeletion syndrome. To investigate the physiological role of Mbd5, we generated knockout mice. The Mbd5-deficient mice showed growth retardation, wasting and pre-weaning lethality. The observed growth retardation was associated with the impairment of GH/IGF-1 axis in Mbd5-null pups. Conditional knockout of Mbd5 in the brain resulted in the similar phenotypes as whole body deletion, indicating that Mbd5 functions in the nervous system to regulate postnatal growth. Moreover, the mutant mice also displayed enhanced glucose tolerance and elevated insulin sensitivity as a result of increased insulin signaling, ultimately resulting in disturbed glucose homeostasis and hypoglycemia. These results indicate Mbd5 as an essential factor for mouse postnatal growth and maintenance of glucose homeostasis.