Methylsulfonylmethane ameliorates metabolic-associated fatty liver disease by restoring autophagy flux via AMPK/mTOR/ULK1 signaling pathway

Introduction: Metabolism-associated fatty liver disease (MAFLD) is a global health concern because of its association with obesity, insulin resistance, and other metabolic abnormalities. Methylsulfonylmethane (MSM), an organic sulfur compound found in various plants and animals, exerts antioxidant and anti-inflammatory effects. Here, we aimed to assess the anti-obesity activity and autophagy-related mechanisms of Methylsulfonylmethane.Method: Human hepatoma (HepG2) cells treated with palmitic acid (PA) were used to examine the effects of MSM on autophagic clearance. To evaluate the anti-obesity effect of MSM, male C57/BL6 mice were fed a high-fat diet (HFD; 60% calories) and administered an oral dose of MSM (200 or 400 mg/kg/day). Moreover, we investigated the AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin complex 1 (mTORC1)/UNC-51-like autophagy-activating kinase 1 (ULK1) signaling pathway to further determine the underlying action mechanism of MSM.Results: Methylsulfonylmethane treatment significantly mitigated PA-induced protein aggregation in human hepatoma HepG2 cells. Additionally, Methylsulfonylmethane treatment reversed the PA-induced impairment of autophagic flux. Methylsulfonylmethane also enhanced the insulin sensitivity and significantly suppressed the HFD-induced obesity and hepatic steatosis in mice. Western blotting revealed that Methylsulfonylmethane improved ubiquitinated protein clearance in HFD-induced fatty liver. Remarkably, Methylsulfonylmethane promoted the activation of AMPK and ULK1 and inhibited mTOR activity.Conclusion: Our study suggests that MSM ameliorates hepatic steatosis by enhancing the autophagic flux via an AMPK/mTOR/ULK1-dependent signaling pathway. These findings highlight the therapeutic potential of MSM for obesity-related MAFLD treatment

Practical Synthesis of (±)-Nyasol

<div><p></p><p>A practical total synthesis of racemic nyasol (<b>7</b>) was explored. The α-hydroxyketo compound <b>3</b> was prepared from commercially available starting materials in two steps. Chelation-controlled reduction of the α-hydroxyketo compound <b>3</b> with Zn(BH₄)₂ gave the anti-1,2-diol compound <b>4</b> as the major product (<i>anti/syn</i> = 11.5:1). Stereospecific elimination reaction of a 1,3-cyclic thionocarbonate intermediate (<b>5</b>) exclusively yielded the Z-alkene compound <b>6</b>. Our total synthesis is very concise (seven steps), uses commercially available starting materials, and offers good overall yield (40%).</p> </div

Multivariate Analysis of Anthropometric Traits Using Summary Statistics of Genome-Wide Association Studies from GIANT Consortium.

Meta-analysis of single trait for multiple cohorts has been used for increasing statistical power in genome-wide association studies (GWASs). Although hundreds of variants have been identified by GWAS, these variants only explain a small fraction of phenotypic variation. Cross-phenotype association analysis (CPASSOC) can further improve statistical power by searching for variants that contribute to multiple traits, which is often relevant to pleiotropy. In this study, we performed CPASSOC analysis on the summary statistics from the Genetic Investigation of ANthropometric Traits (GIANT) consortium using a novel method recently developed by our group. Sex-specific meta-analysis data for height, body mass index (BMI), and waist-to-hip ratio adjusted for BMI (WHRadjBMI) from discovery phase of the GIANT consortium study were combined using CPASSOC for each trait as well as 3 traits together. The conventional meta-analysis results from the discovery phase data of GIANT consortium studies were used to compare with that from CPASSOC analysis. The CPASSOC analysis was able to identify 17 loci associated with anthropometric traits that were missed by conventional meta-analysis. Among these loci, 16 have been reported in literature by including additional samples and 1 is novel. We also demonstrated that CPASSOC is able to detect pleiotropic effects when analyzing multiple traits

Straightforward and Facile Synthesis of a Bioactive Component from <i>Zingiber cassumunar</i> Roxb.

<div><p></p><p>Straightforward and facile synthesis of a bioactive component A from <i>Zingiber cassumunar</i>Roxb. is described. The phenylbutenoid dimer A was reported to possess anti-inflammatory and cytotoxic activities. The optically active cyclohexene ring fragment was obtained via the highly diastereo- and enantioselective Diels–Alder reaction of chiral acryloyloxazolidinones (<b>1a</b> and <b>1b</b>) and 1-(4-hydroxy-3-methoxyphenyl)butadiene (<b>2</b>). The enantiomeric excess of Diels–Alder adducts <b>3a</b> and <b>3b</b>were determined via high-performance liquid chromatotography of the corresponding bis-acetate (<b>6</b>). The greatest enantiomeric excess (99.9% ee) was obtained when the 4-phenyloxazolidin-2-one (<b>1a</b>) chiral auxiliary was used in combination with TiCl4. The optically pure bioactive compound A was prepared from the optically active Diels–Alder adduct (<b>3a</b>) in two additional steps.</p> </div

Neural correlates of anxiety under interrogation in guilt or innocence contexts.

Interrogation elicits anxiety in individuals under scrutiny regardless of their innocence, and thus, anxious responses to interrogation should be differentiated from deceptive behavior in practical lie detection settings. Despite its importance, not many empirical studies have yet been done to separate the effects of interrogation from the acts of lying or guilt state. The present fMRI study attempted to identify neural substrates of anxious responses under interrogation in either innocent or guilt contexts by developing a modified "Doubt" game. Participants in the guilt condition showed higher brain activations in the right central-executive network and bilateral basal ganglia. Regardless of the person's innocence, we observed higher activation of the salience, theory of mind and sensory-motor networks-areas associated with anxiety-related responses in the interrogative condition, compared to the waived conditions. We further explored two different types of anxious responses under interrogation-true detection anxiety in the guilty (true positive) and false detection anxiety in the innocent (false positive). Differential neural responses across these two conditions were captured at the caudate, thalamus, ventral anterior cingulate and ventromedial prefrontal cortex. We conclude that anxiety is a common neural response to interrogation, regardless of an individual's innocence, and that there are detectable differences in neural responses for true positive and false positive anxious responses under interrogation. The results of our study highlight a need to isolate complex cognitive processes involved in the deceptive acts from the emotional and regulatory responses to interrogation in lie detection schemes

Genome-wide significant loci that were only detected by CPASSOC when combining 3 traits but not by conventional meta-analysis of GIANT consortium from discovery phase.

<p>Genome-wide significant loci that were only detected by CPASSOC when combining 3 traits but not by conventional meta-analysis of GIANT consortium from discovery phase.</p

Regional plots of the novel locus rs7842858 identified by <i>S</i>_<i>Het</i>.

<p>Regional plots of the novel locus rs7842858 identified by <i>S</i>_<i>Het</i>.</p