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Morphine is routinely used for pain management in heart failure patients. However, extended morphine exposure associates with major adverse cardiovascular events. Reports link the dopamine receptor D2-family with morphine-induced nociception modulation. This study first assessed whether morphine induces cardiac remodeling in healthy mice, then whether DRD3 agonist (DRD3ag, D2-family member) adjunct therapy prevents morphine-induced cardiac remodeling. Mice received morphine (2 mg/kg/day i. p.) for 7 days (D7) and were either euthanized at D7 or kept 7 more days without morphine (i.e. withdrawal period, D8-D14) G1, morphine; G2, morphine/DRD3ag; G3, morphine + withdrawal; G4, morphine/DRD3ag + withdrawal; G5, morphine + withdrawal/DRD3ag. A separate cohort of animals were used as naïve tissues. We evaluated functional and molecular parameters of cardiac remodeling. Although we did not observe significant differences in systolic function, morphine induced both interstitial fibrosis and cardiomyocyte hypertrophy. Interestingly, DRD3ag abolished these effects. Compared to naïve tissues, collagen 1 increased after withdrawal in G3 and G4 and collagen 3 increased in G1-G4 but at higher levels in G1 and G2. Only G5 did not show collagen differences compared to naïve, suggesting DRD3ag treatment during withdrawal may be beneficial and prevent morphine-induced fibrosis. CX-5461 Smad2/3 phosphorylation increased during withdrawal, indicating a likely upstream pathway for the observed morphine-induced fibrosis. Overall, our data suggest that DRD3ag adjunct therapy decreases morphine-induced adverse cardiac remodeling.DNA methylation is an epigenetic modification that regulates gene transcription. DNA methyltransferase 1 (DNMT1) plays an important role in DNA methylation. However, the involvement of DNMT1 and DNA methylation in the pathogenesis of atopic dermatitis (AD) remains unclear. In this study, microarray analysis revealed that peripheral blood mononuclear cells of AD patients with low DNMT1 expression (DNMT1-low) highly expressed dendritic cell (DC) activation-related genes. Also, DNMT1-low AD patients exhibited a higher itch score compared to AD patients with high DNMT1 expression (DNMT1-high). By using an AD-like mouse model induced by the application of Dermatophagoides farinae body ointment, we found that Dnmt1 expression was decreased, while the expression of C-C chemokine receptor type 7 (Ccr7) was upregulated in mouse skin DCs. Furthermore, mice exposed to social defeat stress exhibited Dnmt1 downregulation and Ccr7 upregulation in skin DCs. Additionally, dermatitis and itch-related scratching behavior were exacerbated in AD mice exposed to stress. The relationship between low DNMT1 and itch induction was found in both human AD patients and AD mice. In mouse bone marrow-derived DCs, Ccr7 expression was inhibited by 5-aza-2-deoxycytidine, a methylation inhibitor. Furthermore, in mouse skin DCs, methylation of CpG sites in Ccr7 was modified by either AD induction or social defeat stress. Collectively, these findings suggest that social defeat stress exacerbates AD pathology through Dnmt1 downregulation and Ccr7 upregulation in mouse skin DCs. The data also suggest a role of DNMT1 downregulation in the exacerbation of AD pathology.Obesity has become a worldwide pandemic and is associated with various metabolic diseases such as type 2 diabetes mellitus and non-alcoholic fatty liver disease. Fas-activated serine/threonine kinase (Fastk) is a multifunctional protein localized in the mitochondrion; however, the role of Fastk in obesity-related metabolic disorders remains unexplored. Here we found that Fastk expression was specifically induced in livers of high fat (HF) diet-fed mice and in saturated fatty acid (such as palmitate)-loaded hepatocytes. Genetic ablation of Fastk ameliorated HF diet-induced insulin resistance, glucose intolerance, and hepatic steatosis. Further studies confirmed that Fastk knockout suppressed hepatic gluconeogenesis and lipogenesis in HF diet-stressed livers and in palmitate-loaded hepatocytes. Mechanistically, Fastk ablation significantly preserved sirtuin-1 (SIRT1) expression and activity in livers of HF diet-fed mice and in palmitate-loaded hepatocytes. Inhibition of SIRT1 activity by EX-527 (a specific inhibitor of SIRT1) totally abolished the suppressive effects of Fastk knockout on gluconeogenesis and lipogenesis in cultured hepatocytes. In conclusion, these data for the first time demonstrate that Fastk critically controls hepatic gluconeogenesis and lipogenesis mainly through modulating SIRT1 signaling. Intervening Fastk expression or activity might be a promising therapeutic strategy for the treatment of obesity-associated metabolic diseases.Human monocarboxylate transporters (hMCTs) 1-4 transport monocarboxylates, such as l-lactate and pyruvate, as well as H+ across the plasma membrane. hMCT1, 2, and 4 play important roles in energy balance, pH homeostasis. However, the molecular mechanism of these transporters, especially their pH dependency, remains unknown. The aim of this study was to identify the residues involved in the pH dependence of hMCT1, 2, and 4. Firstly, we focused on the effects of extracellular acids of hMCT1. l-Lactate uptake assay and site-directed mutagenesis revealed that the aspartic acid of hMCT1 (hMCT1 D414) was an important residue conserved in MCT1, 2, and 4 (hMCT2 D398 and hMCT4 D379). Because the functional characteristic of hMCT2-mediated l-lactate transport has not been reported, we built a hMCT2-expressing system using Xenopus laevis oocytes. The transport activity of hMCT2 was enhanced by co-expression with embigin, an ancillary protein, and kinetic analysis of hMCT2-mediated l-lactate uptake revealed that the apparent Km value (0.32 ± 0.02 mM) was lower than that mediated by hMCT1 and 4. Finally, we investigated the conserved aspartic acids of hMCT2 and 4, and revealed that these residues were essential for l-lactate transport. These findings suggested that the extracellular aspartic acids conserved in hMCT1, 2, and 4 played important roles in transport activity and pH dependency, and can function as a first step of substrate and H+ recognition and transport from the extracellular to the intracellular region. These findings contributed to enhance our understanding of the transport process of hMCT1, 2, and 4.
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