Lactobacillus sakei WIKIM30 is a Gram-positive facultative anaerobic bacterium isolated from kimchi, a Korean fermented vegetable food. In this study, we found that WIKIM30 promoted regulatory T cell (Treg) differentiation by inducing dendritic cells with tolerogenic properties. The production of the T helper (Th) 2-associated cytokine interleukin (IL)-4 was decreased, but that of the Treg-associated cytokine IL-10 was increased in splenocytes from ovalbumin-sensitized mice treated with WIKIM30. We also investigated the inhibitory capacity of WIKIM30 on the development of 2,4-dinitrochlorobenzene-induced atopic dermatitis (AD), a Th2-dominant allergic disease in mice. Oral administration of L. sakei WIKIM30 significantly reduced AD-like skin lesions and serum immunoglobulin E and IL-4 levels while decreasing the number of CD4+ T cells and B cells and the levels of Th2 cytokines (IL-4, IL-5, and IL-13) in peripheral lymph nodes and enhancing Treg differentiation and IL-10 secretion in mesenteric lymph nodes. In addition, WIKIM30 modulated gut microbiome profiles that were altered in AD mice, which showed increases in Arthromitus and Ralstonia and a decrease in Ruminococcus abundance. These changes were reversed by WIKIM30 treatment. Notably, the increase in Ruminococcus was highly correlated with Treg-related responses and may contribute to the alleviation of AD responses. Together, these results suggest that oral administration of L. sakei WIKIM30 modulates allergic Th2 responses enhancing Treg generation and increases the relative abundance of intestinal bacteria that are positively related to Treg generation, and therefore has therapeutic potential for the treatment of AD.

The occurrence of atopic dermatitis (AD), a chronic inflammatory skin disease, has been increasing steadily in children and adults in recent decades. In this study, we evaluated the ability of the lactic acid bacterium Weissella cibaria WIKIM28 isolated from gatkimchi, a Korean fermented vegetable preparation made from mustard leaves, to suppress the development of AD induced by 2,4-dinitrochlorobenzene in a murine model. Oral administration of W. cibaria WIKIM28 reduced AD-like skin lesions, epidermal thickening, and serum immunoglobulin E levels. Furthermore, the production of type 2 helper T (Th2) cytokines such as interleukin (IL)-4, IL-5, and IL-13 decreased in peripheral lymph node cells. Moreover, the intake of W. cibaria WIKIM28 increased the proportion of CD4+CD25+Foxp3+ regulatory T (Treg) cells in mesenteric lymph nodes (MLNs) and IL-10 levels in polyclonally stimulated MLN cells. In conclusion, the oral administration of W. cibaria WIKIM28 isolated from gatkimchi ameliorated AD-like symptoms by suppressing allergic Th2 responses and inducing Treg responses. These results suggest that W. cibaria WIKIM28 may be applicable as a probiotic for the prevention and amelioration of AD.

The endocannabinoid system (ECS) is activated at the onset of obesity and diverse metabolic diseases. Endocannabinoids mediate their physiological and behavioral effects by activating specific cannabinoid receptors, mainly cannabinoid receptor 1 (CB(1)R). Diabetic nephropathy (DN) is induced by hyperlipidemia, and renal proximal tubule cells are an important site for the onset of DN. However, the pathophysiology of CB(1)R, especially in the hyperlipidemia of DN, has not been elucidated. Therefore, we examined the effect of palmitic acid (PA) on CB(1)R expression and its related signal pathways in human renal proximal tubular cells (HK-2 cells). PA significantly increased CB(1)R mRNA and protein levels and induced CB(1)R internalization. PA-induced activation of CB(1)R is prevented by the treatment of AACOCF(3) (a cPLA(2) inhibitor), indomethacin and NS398 (a COX 2 inhibitors). Indeed, PA increased cPLA(2), and COX-2 but not COX-1. We also investigated whether the PA-induced activation of CB(1)R is linked to apoptosis. As a result, AM251 (a CB(1)R antagonist) attenuated PA-mediated apoptosis in a concentration-dependent manner. Furthermore, PA decreased GRP78 expression and induced increases in the endoplasmic reticulum (ER) stress signaling pathways p-PERK, p-eIF2α, p-ATF4, and CHOP, which were blocked by AM251 treatment. Moreover, PA increased the Bax/Bcl-2 ratio, cleaved PARP, and caspase-3 levels. The PA-induced apoptotic effects were decreased with CB(1)R-specific antagonist (AM251) treatment and CB1 si-RNA transfection. In conclusion, PA induced apoptosis through ER stress via CB(1)R expression in human proximal tubule cells. Our results provide evidence that CB(1)R blockade may be a potential anti-diabetic therapy for the treatment of DN.

Arginine methylation is responsible for diverse biological functions and is mediated by protein arginine methyltransferases (PRMTs). Nonalcoholic fatty liver disease (NAFLD) is accompanied by excessive hepatic lipogenesis via liver X receptor α (LXRα). Thus we examined the pathophysiological role of PRMTs in NAFLD and their relationship with LXRα. In this study, palmitic acid (PA) treatment increased PRMT3, which is correlated with the elevation of hepatic lipogenic proteins. The expression of lipogenic proteins was increased by PRMT3 overexpression, but decreased by PRMT3 silencing and use of the PRMT3 knockout (KO) mouse embryonic fibroblast cell line. PRMT3 also increased the transcriptional activity of LXRα by directly binding with LXRα in a methylation-independent manner. In addition, PA treatment translocated PRMT3 to the nucleus. In animal models, a high-fat diet increased the LXRα and PRMT3 expressions and binding, which was not observed in LXRα KO mice. Furthermore, increased PRMT3 expression and its binding with LXRα were observed in NAFLD patients. Taken together, LXRα and PRMT3 expression was increased in cellular and mouse models of NAFLD and human patients, and PRMT3 translocated into the nucleus bound with LXRα as a transcriptional cofactor, which induced lipogenesis. In conclusion, PRMT3 translocation by PA is coupled to the binding of LXRα, which is responsible for the onset of fatty liver.

SH.Cannabinoid receptor 1 mediates high glucose-induced apoptosis via endoplasmic reticulum stress in primary cultured rat mesangial cells. Am J Physiol Renal Physiol 301: F179 -F188, 2011. First published February 16, 2011 doi:10.1152/ajprenal.00032.2010.-The endocannabinoid system in animals and humans is involved in the onset of diverse diseases, including obesity and diabetic nephropathy, which is a major end-stage renal disease characterized by high glucose (HG)-induced apoptosis of mesangial cells. Endocannabinoids induce physiological and behavioral effects by activating two specific receptors, cannabinoid receptor 1 (CB 1R) and cannabinoid receptor 2 (CB2R). However, the pathophysiology of CB 1R in diabetic nephropathy has not been elucidated. We investigated the effects of HG on CB 1R expression and its signaling pathways in primary cultured rat mesangial cells. HG significantly increased CB 1R mRNA and protein levels in a time-dependent manner and induced CB 1R internalization. NF-B and cPLA 2 were involved in the HG-induced increase in CB 1R levels. Using a CB1R antagonist (AM251) and CB1 siRNA transfection, we showed that HG-induced CB 1R is linked to apoptosis. Specifically, HG inhibited the expression of GRP78, but induced increases in endoplasmic reticulum (ER) stress proteins, including phosphorylated (p)-protein kinase-like ER-associated kinase, p-eukaryotic initiation factor 2␣, p-activating transcription factor-4, and C/EBP homologous protein. In addition, HG increased the Bax/Bcl-2 ratio and increased the amounts of cleaved poly(ADP-ribose) polymerase and caspase-3. These apoptotic effects were prevented by AM251 and by the downregulation of CB 1R expression by small interfering RNA. We propose a mechanism by which blockade of CB 1R attenuates HG-induced apoptosis in rat mesangial cells. Our findings suggest that blockade of CB 1R may be a potential therapy in diabetic nephropathy. endocannabinoid system DIABETIC NEPHROPATHY IS CHARACTERIZED by hyperglycemia-induced dysfunction of mesangial cells (21). In an environment of high glucose (HG), renal mesangial cells undergo cascades of deleterious reactions, including cell injury and extracellular matrix deposition, which lead to glomeruli dysfunction (1,25,49). Mesangial cell apoptosis promoted by HG contributes to the development of diabetic nephropathy (22,40).Endocannabinoids are endogenous lipid mediators with a wide range of biological effects, similar to those of marijuana. The endocannabinoid system (ECS) regulates synaptic plasticity, emotional responses, energy homeostasis, and glucose metabolism (44). Dysregulation of ECS is involved in the onset of obesity and diabetic nephropathy (12). Barutta et al. (5) have reported that cannabinoid receptor 1 (CB 1 R) was overexpressed within glomeruli in diabetic mice and CB 1 blockade prevented diabetes-induced albuminuria. It has been also reported that the condition of HG increased the endogenous ligands of the ECS, N-arachidonoyl ethanolamine (AEA) and 2-arachidonylglycerol ( 2-AG) in vivo...

Scope The gut microbiota has been linked to diet‐induced obesity, and microorganisms that influence obesity have important health implications. In this study, the anti‐obesity effects of two Lactobacillus plantarum strains (DSR M2 and DSR 920) isolated from kimchi are investigated. Methods and results Mice are fed a normal or high‐fat diet with or without DSR M2 and DSR 920 (DSR, 1 × 109 CFU d–1) for 12 weeks. DSR improves the obesity state, as evidenced by the i) suppressed obesity‐related markers, e.g., gains in body weight and fat mass, ii) reduced serum and liver triglyceride levels, iii) upregulated β‐oxidation and downregulated lipogenesis‐related genes in the liver, iv) reduced serum leptin levels, v) altered microbial communities, vi) increased regulatory T cell immunity, and vii) suppressed inflammatory response. In addition, correlation analysis shows that Akkermansia muciniphila and the genus Anaerostipes, which are increased in the DSR group, are negatively correlated with obesity‐related markers, but Mucispirillum schaedleri, which is increased in the high‐fat‐diet (HFD) group, is positively correlated with serum leptin level. Conclusion Lactobacillus plantarum DSR M2 and DSR 920 are candidate probiotics for the prevention and amelioration of obesity.

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