Anti-obesity effect of butyrate links to modulation of gut microbiome and epigenetic regulation of muscular circadian clock.

The role of the muscle circadian clock in regulating oxidative metabolism exerts a significant influence on whole-body energy metabolism; however, research on the connection between the muscle circadian clock and obesity is limited. Moreover, there is a lack of studies demonstrating the regulatory effects of dietary butyrate on muscle circadian clock and the resulting antiobesity effects. This study aimed to investigate the impacts of dietary butyrate on metabolic and microbiome alterations and muscle circadian clock in a diet-induced obesity model. Male Sprague-Dawley rats were fed a high-fat diet with or without butyrate. Gut microbiota and serum metabolome were analyzed, and molecular changes were examined using tissues and a cell line. Further correlation analysis was performed on butyrate-induced results. Butyrate supplementation reduced weight gain, even with increased food intake. Gut microbiome analysis revealed an increased abundance of Firmicutes in butyrate group. Serum metabolite profile in butyrate group exhibited reduced amino acid and increased fatty acid content. Muscle circadian clock genes were upregulated, resulting in increased transcription of fatty acid oxidation-related genes. In myoblast cells, butyrate also enhanced pan-histone acetylation via histone deacetylase inhibition, particularly modulating acetylation at the promoter of circadian clock genes. Correlation analysis revealed potential links between Firmicutes phylum, including certain genera within it, and butyrate-induced molecular changes in muscle as well as phenotypic alterations. The butyrate-driven effects on diet-induced obesity were associated with alterations in gut microbiota and a muscle-specific increase in histone acetylation, leading to the transcriptional activation of circadian clock genes and their controlled genes.

Association between use of vitamin and mineral supplement and non-alcoholic fatty liver disease in hypertensive adults.

Non-alcoholic fatty liver disease (NAFLD) is the most common hepatic metabolic disorder in hypertensive adults. Impaired metabolism of micronutrients may increase NAFLD risk by exacerbating oxidative stress, insulin resistance, and inflammation among hypertensive adults. In this first cross-sectional analysis of 7,376 hypertensive adults with 2,015 NAFLD cases in the Korea National Health and Nutrition Examination Survey, vitamin and mineral supplements (VMS) use was identified via questionnaire. NAFLD was defined by a hepatic steatosis index > 36. Multivariable-adjusted odds ratios (MVOR) and 95% confidence intervals (CIs) were calculated using logistic regression models. In our study, 18.6% were current users of VMS; of these, 76.7% used multi-vitamin/mineral supplements. Current VMS users had significantly lower odds of NAFLD, compared with non-users (MVOR [95% CI]: 0.73 [0.58-0.92]). The inverse association became attenuated and non-significant among those consuming VMS at higher frequency (≥ 2 times/day), for longer duration (> 16 months), and taking ≥ 2 VMS products. The inverse association with current use of VMS was only evident in those aged < 56 years (MVOR [95% CI]: 0.54 [0.40-0.72]) and men (MVOR [95% CI]: 0.56 [0.40-0.80])(Pinteraction ≤ 0.04). Our results suggest that VMS use may lower NAFLD risk, particularly among younger or male hypertensive adults, if taken in moderation.

Meal-Based Intervention on Health Promotion in Middle-Aged Women: A Pilot Study.

Middle-aged women belong to a risk group for metabolic dysregulation and menopausal symptoms, mainly due to a dramatic hormonal shift. Supplementation with functional compounds or a single nutrient has been dominantly explored as a nutritional approach for improving aging-related health parameters. However, a meal-based approach might be another strategy for promoting the overall health of the target population. This pilot study aimed to develop a meal-based intervention for middle-aged women and to evaluate its potential health benefits. Considering the nutrient intake status of Korean middle-aged women, diets enriched with four major nutrients (isoflavone, omega-3, fiber, and calcium) were designed and provided to forty-nine women aged 50 to 65 with mild levels of menopausal symptoms for 8 weeks. In the post-intervention phase, they showed reduced body weight and body fat, and improved biochemical metabolic parameters with decreased levels of cholesterol, low-density lipoprotein-cholesterol, ApoB, and fasting insulin. Moreover, bone resorption markers and menopause symptoms were lower in the post-intervention phase. In conclusion, the meal-based intervention might be a prominent strategy for overall health promotion in relatively healthy middle-aged women and further investigation is needed to test its efficacy with a randomized controlled study.

The Anticancer Effect of Natural Plant Alkaloid Isoquinolines.

Isoquinoline alkaloids-enriched herbal plants have been used as traditional folk medicine for their anti-inflammatory, antimicrobial, and analgesic effects. They induce cell cycle arrest, apoptosis, and autophagy, leading to cell death. While the molecular mechanisms of these effects are not fully understood, it has been suggested that binding to nucleic acids or proteins, enzyme inhibition, and epigenetic modulation by isoquinoline alkaloids may play a role in the effects. This review discusses recent evidence on the molecular mechanisms by which the isoquinoline alkaloids can be a therapeutic target of cancer treatment.

Effects of Coffee Intake on Dyslipidemia Risk According to Genetic Variants in the ADORA Gene Family among Korean Adults.

Current evidence on the effects of coffee intake on cardiovascular diseases is not consistent, in part contributed by the genetic variability of the study subjects. While adenosine receptors (ADORAs) are involved in caffeine signaling, it remains unknown how genetic variations at the ADORA loci correlate the coffee intake with cardiovascular diseases. The present study examined the associations of coffee intake with dyslipidemia risk depending on genetic variants in the ADORA gene family. The study involved a population-based cohort of 4898 Korean subjects. Consumption of more than or equal to a cup of coffee per day was associated with lower dyslipidemia risk in females carrying the ADORA2B minor allele rs2779212 (OR: 0.645, 95% CI: 0.506-0.823), but not in those with the major allele. At the ADORA2A locus, male subjects with the minor allele of rs5760423 showed instead an increased risk of dyslipidemia when consuming more than or equal to a cup of coffee per day (OR: 1.352, 95% CI: 1.014-1.802). The effect of coffee intake on dyslipidemia risk differs depending on genetic variants at the ADORA loci in a sex-specific manner. Our study suggests that a dietary guideline for coffee intake in the prevention and management of dyslipidemia ought to consider ADORA-related biomarkers carefully.

Promotion of Cell Death in Cisplatin-Resistant Ovarian Cancer Cells through KDM1B-DCLRE1B Modulation.

Ovarian cancer is the gynecological malignancy with the poorest prognosis, in part due to its high incidence of recurrence. Platinum agents are widely used as a first-line treatment against ovarian cancer. Recurrent tumors, however, frequently demonstrate acquired chemo-resistance to platinum agent toxicity. To improve chemo-sensitivity, combination chemotherapy regimens have been investigated. This study examined anti-tumor effects and molecular mechanisms of cytotoxicity of Oldenlandia diffusa (OD) extracts on ovarian cancer cells, in particular, cells resistant to cisplatin. Six ovarian cancer cells including A2780 and cisplatin-resistant A2780 (A2780cis) as representative cell models were used. OD was extracted with water (WOD) or 50% methanol (MOD). MOD significantly induced cell death in both cisplatin-sensitive cells and cisplatin-resistant cells. The combination treatment of MOD with cisplatin reduced viability in A2780cis cells more effectively than treatment with cisplatin alone. MOD in A2780cis cells resulted in downregulation of the epigenetic modulator KDM1B and the DNA repair gene DCLRE1B. Transcriptional suppression of KDM1B and DCLRE1B induced cisplatin sensitivity. Knockdown of KDM1B led to downregulation of DCLRE1B expression, suggesting that DCLRE1B was a KDM1B downstream target. Taken together, OD extract effectively promoted cell death in cisplatin-resistant ovarian cancer cells under cisplatin treatment through modulating KDM1B and DCLRE1B.

Altered expression of inflammation-associated genes in the hypothalamus of obesity mouse models.

Metabolic inflammation is a distinct feature of obesity. Increased inflammation in the adipose tissue and the liver has been so far implicated to affect metabolic homeostasis, mainly insulin resistance. In addition to the peripherals, the inflammation in the hypothalamus which governs systemic metabolism by linking neuronal and endocrine signals has been suggested to be linked to the metabolic disease. However, the underlying molecular mechanisms are poorly understood. We hypothesized that a high-fat diet (HFD) led to central metabolic inflammation via transcriptional changes in the hypothalamus. To address the hypothesis, we characterized obesity-related hypothalamic, transcriptional alterations, and their effects on functional networks. Male C57BL/6J mice were fed with either a control diet (CD) or an HFD for 20 weeks. Microarray and gene ontology analyses of the hypothalamus demonstrated that immune-related pathways, including inflammatory and cytokine signaling, were overrepresented in the hypothalamus of HFD-fed mice compared to that of CD mice. In addition, through secondary analysis of leptin-deficient obese (ob/ob) mouse hypothalamus, we found that enriched gene sets for tumor necrosis factor-α signaling pathways and cancer pathways were common in both the obese mouse models. The results suggest that inflammatory pathway is transcriptionally enriched in the hypothalamus in obesity models and is related with hyperadiposity rather than the primary causes of obesity including the dietary fat and the genetic mutation.

Anti-cancer effect of Scutellaria baicalensis in combination with cisplatin in human ovarian cancer cell.

BACKGROUND: Ovarian cancer is one of the major causes of death among females in worldwide. Cisplatin is a primary anti-cancer drug against ovarian cancer, but the recurrent tumors after treatment frequently show acquired chemoresistance. Extract of Scutellaria baicalensis (SbE) has been reported to have functional compounds including baicalin, which has anti-cancer effects. However, the anti-cancer effects of SbE in ovarian cancer and its underlying mechanisms are elusive. METHODS: We investigated that the effects of SbE and/or cisplatin on cell death in the cisplatin sensitive ovarian cancer cell line A2780 (CSC) and the counterpart cell line that has cisplatin resistance (CRC). Molecular mechanisms of the effects, focusing on apoptosis and autophagy, were examined. RESULTS: Treatment of cisplatin or SbE reduced cell viability significantly in CSC and too much lesser extent in CRC. Cisplatin-induced cell death in CSC was mediated by p53-induced apoptosis acompanied by expresson of damage-regulated autophagy modulator (DRAM). In CRC, decreased DRAM expression (p < 0.01) hindered p21-mediated cell death and contributed to cisplatin resistance. Treatment of SbE also induced cell death in CSC by p53-dependent apoptosis, not in CRC. Autophagy was not induced by neither cisplatin nor SbE. Intriguingly, the combinational treatment of SbE and cisplatin significantly decreased cell viability in CRC. The cell death was mediated by autophagy with increased expression of Atg5 and Atg12 (p < 0.05), rather than p53-dependent pathway with repressed expression of p21 (p < 0.001) through HDAC1 activation. CONCLUSIONS: The combined treatment of SbE with cisplatin was effective in CRC, leading to cell death via Beclin1-independent autophagy, suggesting that SbE treatment in combination with cisplatin has a potential as a chemotherapeutic agent in cisplatin-resistant ovarian cancer.

Neuroprotective effects of Paeonia Lactiflora extract against cell death of dopaminergic SH-SY5Y cells is mediated by epigenetic modulation.

BACKGROUND: The Paeonia lactiflora extract (PLE) has been reported to have neuroprotective effect against neurodegeneration that are induced by cellular stress such as oxidative stress. Its underlying mechanisms, however, remain unclear. In latest decades, emerging evidence has suggested that epigenetic mechanisms play a key role in gene regulation in response to the cellular stress. We investigated whether epigenetic modulation was involved in neuronal cell death by the neurotoxicant, 1-Methyl-4-phenylpyridinium (MPP(+)), and the neuroprotective effect of PLE. METHODS: Differentiated SH-SY5Y, which is a well-established dopaminergic cell line model, was treated with 0 ~ 200 µg/ml PLE for 4 h prior to MPP(+) treatment. The effect of PLE on cell viability was determined by MTT assays. Gene expression levels of oxidative stress responsive genes, such as Heme oxygenase 1 (HMOX1), and histone modifiers, such as histone acetyltransferases (HATs) and deacetylases (HDACs) were measured by quantitative RT PCR. In order to investigate the changes in epigenetic modifications, the acetylated lysine 9 (H3K9ac) and lysine 27 (H3K27ac) of Histone H3 were measured by western blot using histones extracted from the cells. RESULTS: MPP(+)-induced cell death in SH-SY5Y cells was significantly reduced by PLE pretreatment in a dose-dependent manner, indicating the potent neuroprotective effects of PLE. It was accompanied by induced expression of HMOX1. MPP(+) treatment increased the expression of HATs and consistently increased H3K9ac and H3K27ac of Histone H3. PLE pretreatment impeded the changes in H3K9ac and H3K27ac, coincided with increased expression of HDAC5 without changes in HAT expression. CONCLUSIONS: The results suggested that MPP(+)-induced cell death in the dopaminergic SH-SY5Y cells was related with transcriptional induction of HATs and increased histone H3 acetylation and that PLE might prevent the cells from MPP(+)-induced cell death via tempering histone H3 acetylation.