The ubiquitous transient receptor potential canonical (TRPC) channels function as non-selective, Ca(2+)-permeable channels and mediate numerous cellular functions. It is commonly assumed that TRPC channels are activated by stimulation of Gα(q)-PLC-coupled receptors. However, whether the Gα(q)-PLC pathway is the main regulator of TRPC4/5 channels and how other Gα proteins may regulate these channels are poorly understood. We previously reported that TRPC4/TRPC5 can be activated by Gα(i). In the current work, we found that Gα(i) subunits, rather than Gα(q), are the primary and direct activators of TRPC4 and TRPC5. We report a novel molecular mechanism in which TRPC4 is activated by several Gα(i) subunits, most prominently by Gα(i2), and TRPC5 is activated primarily by Gα(i3). Activation of Gα(i) by the muscarinic M2 receptors or expression of the constitutively active Gα(i) mutants equally and fully activates the channels. Moreover, both TRPC4 and TRPC5 are activated by direct interaction of their conserved C-terminal SESTD (SEC14-like and spectrin-type domains) with the Gα(i) subunits. Two amino acids (lysine 715 and arginine 716) of the TRPC4 C terminus were identified by structural modeling as mediating the interaction with Gα(i2). These findings indicate an essential role of Gα(i) proteins as novel activators for TRPC4/5 and reveal the molecular mechanism by which G-proteins activate the channels.

Emerging evidence suggests that probiotics are beneficial in non-alcoholic fatty liver disease (NAFLD). This study aimed to explore the effects of two Lactobacillus plantarum strains, ATG-K2 and ATG-K6 (isolated from Korean fermented cabbage), in a rat model of high fat/high fructose (HF/HF) diet-induced NAFLD. Rats with NAFLD were randomized into four groups (HF/HF diet control, (HC); HF/HF diet with silymarin, (PC); HF/HF diet with ATG-K2, (K2); and HF/HF diet with ATG-K6, (K6)) with healthy rats on a normal diet serving as the negative control. After treatment, histopathological and biochemical analyses of the blood and liver tissue were conducted. In addition, fecal microbiota was analyzed using the MiSeq platform. Compared with HC rats, K2 and K6 rats experienced significantly lower body weight gain, displayed decreased hepatic lipid accumulation, had lower serum levels of aspartate aminotransferase and alanine aminotransferase, and showed increased antioxidant enzyme activities. Moreover, de novo lipogenesis-related genes were downregulated following K2 and K6 administration. The fecal microbiota of K2 and K6 rats contained a higher proportion of Bacteriodetes and a lower proportion of Fimicutes than that of HC rats. Taken together, our results suggest that L. plantarum strains ATG-K2 and ATG-K6 are potential therapeutic agents for NAFLD.

Geraniol, an acyclic dietary monoterpene, has been found to suppress cancer survival and growth. However, the molecular mechanism underlying the antitumor action of geraniol has not been investigated at the genome‐wide level. In this study, we analyzed the microarray data obtained from geraniol‐treated prostate cancer cells. Geraniol potently altered a gene expression profile and primarily down‐regulated cell cycle‐related gene signatures, compared to linalool, another structurally similar monoterpene that induces no apparent phenotypic changes. Master regulator analysis using the prostate cancer‐specific regulatory interactome identified that the transcription factor E2F8 as a specific target molecule regulates geraniol‐specific cell cycle signatures. Subsequent experiments confirmed that geraniol down‐regulated E2F8 expression and the knockdown of E2F8 was sufficient to suppress cell growth by inducing G₂/M arrest. Epidemiological analysis showed that E2F8 is up‐regulated in metastatic prostate cancer and associated with poor prognosis. These results indicate that E2F8 is a crucial transcription regulator controlling cell cycle and survival in prostate cancer cells. Therefore, our study provides insight into the role of E2F8 in prostate cancer biology and therapeutics.