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Lipid droplet (LD) accumulation in hepatocytes is one of the major symptoms associated with fatty liver disease. Mitochondria play a key role in catabolizing fatty acids for energy production through β-oxidation. The interplay between mitochondria and LD assumes a crucial role in lipid metabolism, while it is obscure how mitochondrial morphology affects systemic lipid metabolism in the liver. We previously reported that cilnidipine, an already existing anti-hypertensive drug, can prevent pathological mitochondrial fission by inhibiting protein–protein interaction between dynamin-related protein 1 (Drp1) and filamin, an actin-binding protein. Here, we found that cilnidipine and its new dihydropyridine (DHP) derivative, 1,4-DHP, which lacks Ca2+ channel-blocking action of cilnidipine, prevent the palmitic acid-induced Drp1–filamin interaction, LD accumulation and cytotoxicity of human hepatic HepG2 cells. Cilnidipine and 1,4-DHP also suppressed the LD accumulation accompanied by reducing mitochondrial contact with LD in obese model and high-fat diet-fed mouse livers. These results propose that targeting the Drp1–filamin interaction become a new strategy for the prevention or treatment of fatty liver disease. [ABSTRACT FROM AUTHOR]

We recently reported that transient receptor potential canonical (TRPC) 6 channel activity contributes to intracellular Zn2+ homeostasis in the heart. Zn2+ has also been implicated in the regulation of intestinal redox and microbial homeostasis. This study aims to investigate the role of TRPC6-mediated Zn2+ influx in the stress resistance of the intestine. The expression profile of TRPC1-C7 mRNAs in the actively inflamed mucosa from inflammatory bowel disease (IBD) patients was analyzed using the GEO database. Systemic TRPC3 knockout (KO) and TRPC6 KO mice were treated with dextran sulfate sodium (DSS) to induce colitis. The Zn2+ concentration and the mRNA expression levels of oxidative/inflammatory markers in colon tissues were quantitatively analyzed, and gut microbiota profiles were compared. TRPC6 mRNA expression level was increased in IBD patients and DSS-treated mouse colon tissues. DSS-treated TRPC6 KO mice, but not TRPC3 KO mice, showed severe weight loss and increased disease activity index compared with DSS-treated WT mice. The mRNA abundances of antioxidant proteins were basically increased in the TRPC6 KO colon, with changes in gut microbiota profiles. Treatment with TRPC6 activator prevented the DSS-induced colitis progression accompanied by increasing Zn2+ concentration. We suggest that TRPC6-mediated Zn2+ influx activity plays a key role in stress resistance against IBD, providing a new strategy for treating colitis. [ABSTRACT FROM AUTHOR]

The involvement of muscarinic receptors in neurogenic responses of the ileum was studied in wild-type and muscarinic-receptor (M-receptor) knockout (KO) mice. Electrical field stimulation to the wild-type mouse ileum induced a biphasic response, a phasic and sustained contraction that was abolished by tetrodotoxin. The sustained contraction was prolonged for an extended period after the termination of electrical field stimulation. The phasic contraction was completely inhibited by atropine. In contrast, the sustained contraction was enhanced by atropine. Ileal strips prepared from [M.sub.2]-receptor KO mice exhibited a phasic contraction similar to that seen in wild-type mice and a sustained contraction that was larger than that in wild-type mice. In [M.sub.3]-receptor KO mice, the phasic contraction was smaller than that observed in wild-type mice. Acetylcholine exogenously administrated induced concentration-dependent contractions in strips isolated from wild-type, [M.sub.2]- and [M.sub.3]-receptor KO mice. However, contractions in [M.sub.3]-receptor KO mice shifted to the right. The sustained contraction was inhibited by capsaicin and neurokinin N[K.sub.2] receptor antagonist, suggesting that it is mediated by substance P (SP). SP-induced contraction of [M.sub.2]-receptor KO mice did not differ from that of wild-type mice. SP immunoreactivity was located in enteric neurons, colocalized with [M.sub.2] receptor immunoreactivity. These results suggest that atropine-sensitive phasic contraction is mainly mediated via the [M.sub.3] receptor, and SP-mediated sustained contraction is negatively regulated by the [M.sub.2] receptor at a presynaptic level. [M.sub.2]- and [M.sub.3]-receptor knockout mouse; neurogenic response; acetylcholine-mediated phasic contraction; substance P-mediated tonic contraction

Internalization of G protein-coupled receptors (GPCRs) is a fundamental mechanism to maintain cellular homeostasis by switching off receptor-mediated signaling and controlling protein quality of these receptors ([1], [2]). In addition, two ITC groups were necessary to exert an inhibitory effect on P2Y SB 6 sb R. MRS2578 oligomerized P2Y SB 6 sb R, but other compounds with one ITC failed to oligomerize P2Y SB 6 sb R (fig. Dimethyl itaconate (DI), a cell-permeable itaconate analog, also caused P2Y SB 6 sb R degradation in HEK293 cells and decreased UDP-induced CCL2 release in RAW264.7 cells (fig. Because a MRS2578 derivative that lacks ITC residues loses the inhibitory action on P2Y SB 6 sb R ([9]), we investigated whether other ITC-containing compounds also inhibited P2Y SB 6 sb R-stimulated C-C motif chemokine 2 (CCL2) release in RAW264.7 cells. [Extracted from the article]