Treatment Of Chronic Metabolic Diseases Research Articles

The Effects of Body Fat Reduction through the Metabolic Control of Steam-Processed Ginger Extract in High-Fat-Diet-Fed Mice.

The prevalence of metabolic syndrome is increasing globally due to behavioral and environmental changes. There are many therapeutic agents available for the treatment of chronic metabolic diseases, such as obesity and diabetes, but the data on their efficacy and safety are lacking. Through a pilot study by our group, Zingiber officinale rhizomes used as a spice and functional food were selected as an anti-obesity candidate. In this study, steam-processed ginger extract (GGE) was used and we compared its efficacy at alleviating metabolic syndrome-related symptoms with that of conventional ginger extract (GE). Compared with GE, GGE (25-100 μg/mL) had an increased antioxidant capacity and α-glucosidase inhibitory activity in vitro. GGE was better at suppressing the differentiation of 3T3-L1 adipocytes and lipid accumulation in HepG2 cells and promoting glucose utilization in C2C12 cells than GE. In 16-week high-fat-diet (HFD)-fed mice, GGE (100 and 200 mg/kg) improved biochemical profiles, including lipid status and liver function, to a greater extent than GE (200 mg/kg). The supplementation of HFD-fed mice with GGE (200 mg/kg) resulted in the downregulation of SREBP-1c and FAS gene expression in the liver. Collectively, our results indicate that GGE is a promising therapeutic for the treatment of obesity and metabolic syndrome.

The nutritional functions of dietary sphingomyelin and its applications in food.

Sphingolipids are common structural components of cell membranes and are crucial for cell functions in physiological and pathophysiological conditions. Sphingomyelin and its metabolites, such as sphingoid bases, ceramide, ceramide-1-phosphate, and sphingosine-1-phosphate, play signaling roles in the regulation of human health. The diverse structures of sphingolipids elicit various functions in cellular membranes and signal transduction, which may affect cell growth, differentiation, apoptosis, and maintain biological activities. As nutrients, dietary sphingomyelin and its metabolites have wide applications in the food and pharmaceutical industry. In this review, we summarized the distribution, classifications, structures, digestion, absorption and metabolic pathways of sphingolipids, and discussed the nutritional functioning of sphingomyelin in chronic metabolic diseases. The possible implications of dietary sphingomyelin in the modern food preparations including dairy products and infant formula, skin improvement, delivery system and oil organogels are also evaluated. The production of endogenous sphingomyelin is linked to pathological changes in obesity, diabetes, and atherosclerosis. However, dietary supplementations of sphingomyelin and its metabolites have been shown to maintain cholesterol homeostasis and lipid metabolism, and to prevent or treat these diseases. This seemly paradoxical phenomenon shows that dietary sphingomyelin and its metabolites are candidates for food additives and functional food development for the prevention and treatment of chronic metabolic diseases in humans.

Insights into Recent Studies on Biotransformation and Pharmacological Activities of Ginsenoside Rd.

It is well known that ginsenosides—major bioactive constituents of Panax ginseng—are attracting more attention due to their beneficial pharmacological activities. Ginsenoside Rd, belonging to protopanaxadiol (PPD)-type ginsenosides, exhibits diverse and powerful pharmacological activities. In recent decades, nearly 300 studies on the pharmacological activities of Rd—as a potential treatment for a variety of diseases—have been published. However, no specific, comprehensive reviews have been documented to date. The present review not only summarizes the in vitro and in vivo studies on the health benefits of Rd, including anti-cancer, anti-diabetic, anti-inflammatory, neuroprotective, cardioprotective, ischemic stroke, immunoregulation, and other pharmacological effects, it also delves into the inclusion of potential molecular mechanisms, providing an overview of future prospects for the use of Rd in the treatment of chronic metabolic diseases and neurodegenerative disorders. Although biotransformation, pharmacokinetics, and clinical studies of Rd have also been reviewed, clinical trial data of Rd are limited; the only data available are for its treatment of acute ischemic stroke. Therefore, clinical evidence of Rd should be considered in future studies.

Lactiplantibacillus plantarum Y15 alleviate type 2 diabetes in mice via modulating gut microbiota and regulating NF-κB and insulin signaling pathway.

Probiotics have been used for the treatment of chronic metabolic diseases, including type 2 diabetes (T2D). However, the mechanisms of antidiabetic effects are not well understood. The object of this study is to assess the antidiabetic effect of Lactiplantibacillus plantarum Y15 isolated from Chinese traditional dairy products in vivo. Results revealed that L. plantarum Y15 administration improved the biochemical indexes related to diabetes, reduced pro-inflammatory cytokines, L. plantarum Y15 administration reshaped the structure of gut microbiota, decreased the abundance of LPS-producing, and increased short-chain fatty acids (SCFAs)-producing bacteria, which subsequently reduce the levels of lipopolysaccharide (LPS) and pro-inflammatory cytokines. L. plantarum Y15 administration also regulated the expressions of the inflammation and insulin signaling pathway-related genes. These results suggest that L. plantarum Y15 may serve as a potential probiotic for developing food products to ameliorate T2D.Supplementary InformationThe online version contains supplementary material available at 10.1007/s42770-022-00686-5.

Inverse molecular docking reveals a novel function of thymol: Inhibition of fat deposition induced by high-dose glucose in Caenorhabditis elegans.

As a natural product isolated from thyme oil in thyme, thymol (2‐isopropyl‐5‐methylphenol) harbors antiviral, antioxidant, and other properties, and thus could be potentially used for the treatment of various diseases. However, the function of thymol has not been comprehensively studied. Here, we applied an inverse molecular docking approach to identify unappreciated functions of thymol. Potential targets of thymol in humans were identified by the server of DRAR‐CPI, and targets of interest were then assessed by GO and KEGG pathway analysis. Subsequently, homologous proteins of these targets in Caenorhabditis elegans were identified by Blast tool, and their three‐dimensional structures were achieved using Swiss‐Model workspace. Interaction between thymol and the targeted proteins in worms was verified using AutoDock 4.0. Analyses of the targets revealed that thymol could be potentially involved in the glycolysis/gluconeogenesis and fatty acid degradation pathways. To verify the activity of thymol on lipid deposition in vivo, the C. elegans model was established. The lipid content of nematodes induced by high‐dose glucose was determined by Oil Red O and Nile Red staining, and gene expression was assessed by qRT‐PCR. The results showed that thymol might lead to the acceleration of β‐oxidation by upregulating cpt‐1, aco, fabp, and tph‐1, causing the descent of lipid content in nematodes. Our findings indicated that thymol could be potentially used for the treatment of chronic metabolic diseases associated with increased fatty acid deposition.

Suppression of Hepatic Lipogenesis and Enhancement of β-oxidation in Skeletal Muscle by Betulinic Acid Lead to the Reduction of Body Adiposity and Dyslipidemia in Mice (P21-043-19)

Abstract Objectives Betulinic acid (BA) exists as a lipophilic conformation in nature, rich in fruits and vegetables, especially the bark of birch wood. Beneficial effects of BA on cancer, oxidative stress, and inflammation were previously reported. Studies of BA for anti-obesity and dyslipidemia have been recently emerged, however the outcomes are still not conclusive. We tested if BA improves obesity and/or dyslipidemia by incorporated mechanism of liver and skeletal muscle in vivo. Methods Five-week-old male C57BL/6 mice were fed Western type diet (45% kcal from fat with 1.25% cholesterol) ad libitum for 12 weeks. Mice were allocated into five groups: (−) control, BA 5 mg/kg, BA 15 mg/kg, BA 25 mg/kg, and fenofibrate as a (+) control. BA was orally administered every day. For proved phenotype alteration, we analyzed mRNA and protein expressions linked to lipogenesis and β-oxidation. Results Growth performance including final body weight, weight gain, and feed intake were not altered by BA. Body fat mass was decreased by all BA treated groups (P < 0.01) without changes of lean mass. Energy expenditure contributed by β-oxidation was increased by BA 25 (P < 0.001). Serum lipid profiles including triglyceride, free fatty acid, total cholesterol, and LDL cholesterol were significantly improved by all BA treated groups (P < 0.001). Lipid accumulation in the liver was reduced by BA 15 and 25 (all P < 0.001). The mRNA expressions of Acc1and Scd1were dose-dependently suppressed by betulinic acid in liver (P < 0.05). SREBP1 was diminished by BA treated groups (all P < 0.05). FAS showed reduced tendency by BA (P = 0.06). In protein levels, ACC1 and SCD1 were inhibited by BA treated groups (P < 0.001 and P < 0.05). FAS and SREBP1 tended to be reduced by BA (P = 0.40 and P = 0.70). LPL and CPT1, β-oxidation markers in skeletal muscle, were activated by BA 25 (P < 0.001 and P < 0.01). The activation of CPT1 was influenced by stimulating of AMPK-pT172 and ACC1-pS79 (all P < 0.05). Taken together, BA inhibitedde novolipogenesis in the liver and upregulated key proteins related to β-oxidation in skeletal muscle, contributing to the prevention of obesity and dyslipidemia. Conclusions We suggest that BA is a potent nutraceutical for prevention and treatment of chronic metabolic diseases including obesity and dyslipidemia. Funding Sources National Research Foundation of Korea.

Lifestyle Medicine: The Health Promoting Power of Daily Habits and Practices.

There is no longer any serious doubt that daily habits and actions profoundly affect both short-term and long-term health and quality of life. This concept is supported by literally thousands of research articles and incorporated in multiple evidence-based guidelines for the prevention and/or treatment of chronic metabolic diseases. The study of how habits and actions affect both prevention and treatment of diseases has coalesced around the concept of "lifestyle medicine." The purpose of this review is to provide an up-to-date summary of many of the modalities fundamental to lifestyle medicine, including physical activity, proper nutrition, weight management, and cigarette smoking cessation. This review will also focus specifically on how these modalities are employed both in the prevention and treatment of chronic diseases including coronary heart disease, diabetes, obesity, and cancer. The review concludes with a Call to Action challenging the medical community to embrace the modalities of lifestyle medicine in the daily practice of medicine.

The MXL-3/SBP-1 Axis Is Responsible for Glucose-Dependent Fat Accumulation in C. elegans.

Chronic exposure to elevated glucose levels leads to fatty acid accumulation, which promotes the development of metabolic diseases such as obesity and type 2 diabetes. MXL-3 is a conserved transcriptional factor that modulates the inhibition of lipolysis in Caenorhabditis elegans. However, the role of MXL-3 in lipid metabolism during nutrient excess remains unknown. We hypothesized that inhibition of MXL-3 prevents glucose-dependent fat accumulation. Nematodes from wild-type N2, MXL-3::GFP and sbp-1 or mxl-3 null strains were grown on standard, high glucose or high glucose plus metformin plates for 24 h. Using laser-scanning confocal microscopy, we monitored the glucose-induced activation of MXL-3 labeled with GFP (MXL-3::GFP). Lipid levels were determined by Oil Red O (ORO) staining and gas chromatography/mass spectrometry, and gene expression was assessed by qRT-PCR. We found that high glucose activated MXL-3 by increasing its rate of nuclear entry, which in turn increased lipid levels via sterol regulatory element-binding protein (SBP-1). This activated critical genes that synthesize long chain unsaturated fatty acids (MUFAs and PUFAs) and repress lipolytic genes. Interestingly, the anti-diabetic drug metformin inhibited MXL-3 activation and subsequently prevented glucose-dependent fat accumulation. These findings highlight the importance of the MXL-3/SBP-1 axis in the regulation of lipid metabolism during nutritional excess and provide new insight into the mechanism by which metformin prevents lipid accumulation. This study also suggests that inhibition of MXL-3 may serve as a potential target for the treatment of chronic metabolic diseases, including obesity, type 2 diabetes, and cardiovascular disease.

Physicochemical Characterization and Biological Activities of the Triterpenic Mixture α,β-Amyrenone.

α-Amyrenone and β-amyrenone are triterpenoid isomers that occur naturally in very low concentrations in several oleoresins from Brazilian Amazon species of Protium (Burseraceae). This mixture can also be synthesized by oxidation of α,β-amyrins, obtained as major compounds from the same oleoresins. Using a very simple, high yield procedure, and using a readily commercially available mixture of α,β-amyrins as substrate, the binary compound α,β-amyrenone was synthesized and submitted to physico-chemical characterization using different techniques such as high-performance liquid chromatography, nuclear magnetic resonance (1H and 13C), mass spectrometry, scanning electron microscopy, differential scanning calorimetry, thermogravimetry and derivative thermogravimetry, and Fourier transform infrared spectroscopy (FTIR). Biological effects were also evaluated by studying the inhibition of enzymes involved in the carbohydrate and lipid absorption process, such as α-amylase, α-glucosidase, lipase, and their inhibitory concentration values of 50% of activity (IC50) were also determined. α,β-Amyrenone significantly inhibited α-glucosidase (96.5% ± 0.52%) at a concentration of 1.6 g/mL. α,β-Amyrenone, at a concentration of 100 µg/mL, showed an inhibition rate on lipase with an IC50 value of 82.99% ± 1.51%. The substances have thus shown in vitro inhibitory effects on the enzymes lipase, α-glucosidase, and α-amylase. These findings demonstrate the potential of α,β-amyrenone for the development of drugs in the treatment of chronic metabolic diseases.

Clinical effect of using gut microbes enema combined with humanized nursing intervention on the treatment of pediatric chronic metabolic disease

Objective To observe the clinical effect of using gut microbes enema combined with humanized nursing intervention on the treatment of pediatric chronic metabolic disease. Methods A total of 90 children with chronic diarrhea from January 2012 to June 2013, were randomly divided into observation group and control group, and the patients of control group received routine and montmorillonite powder treatment while the patients of observation group received lactic acid bacteria tablet enema. In two groups, children were given humanized nursing intervention. We compared the curative effects and symptoms improving time between two groups. Results The effective rate of observation group was 95.56% and control group (66.67%), and the difference between the two groups has statistical significance (χ2=12.56, P<0.05); observed in normal defecation group, vomiting disappeared, the fever disappeared time were lower than those in the control group relationship (t=2.25, 2.14, 2.01; P<0.05). Conclusions The treatment of gut microbes enema method combined with humanized nursing is effective on chronic metabolic diseases and diarrhea, which is worthy of further popularization and application. Key words: Infantile diarrhea; Enema; Gut microbes; Children; Humanistic nursing

Regulation of skeletal muscle mitochondrial function by nuclear receptors: implications for health and disease.

Skeletal muscle metabolism is highly dependent on mitochondrial function, with impaired mitochondrial biogenesis associated with the development of metabolic diseases such as insulin resistance and type2 diabetes. Mitochondria display substantial plasticity in skeletal muscle, and are highly sensitive to levels of physical activity. It is thought that physical activity promotes mitochondrial biogenesis in skeletal muscle through increased expression of genes encoded in both the nuclear and the mitochondrial genome; however, how this process is co-ordinated at the cellular level is poorly understood. Nuclear receptors (NRs) are key signalling proteins capable of integrating environmental factors and mitochondrial function, thereby providing a potential link between exercise and mitochondrial biogenesis. The aim of this review is to highlight the function of NRs in skeletal muscle mitochondrial biogenesis and discuss the therapeutic potential of NRs for the management and treatment of chronic metabolic disease.

Comparative study of DHA‐enriched phospholipids and EPA‐enriched phospholipids on metabolic disorders in diet‐induced‐obese C57BL/6J mice

Recent reports have shown that n‐3 PUFA‐enriched phospholipids have various beneficial effects. The proportion of DHA and eicosapentaenoic acid (EPA) in the phospholipids might affect their biological functions. In the present study, marine DHA‐enriched phospholipids (DHA‐PL) and EPA‐enriched phospholipids (EPA‐PL) were administered to high fat (HF) diet‐induced obese C57BL/6J mice for 8 weeks to compare their effects on obesity‐related metabolic disorders. DHA‐PL and EPA‐PL significantly decreased epididymal and perirenal adipose tissue weights, reduced blood pressures and lowered serum and hepatic triacylglycerol levels in HF diet‐induced obese mice. Serum insulin, MCP‐1 and IL‐6 levels were also efficiently reduced by treatment with DHA‐PL and EPA‐PL. The anti‐obesity and lipid‐lowering effects of EPA‐PL were superior to DHA‐PL, while DHA‐PL exhibited better anti‐hypertension effects than EPA‐PL. The effects of DHA‐PL and EPA‐PL on glucose intolerance and inflammation were basically equivalent. DHA‐PL and EPA‐PL up‐regulated genes involved in insulin‐sensitizing actions in the adipose tissue and suppressed hepatic SREBP‐1c mediated lipogenesis. EPA‐PL also significantly activated PPARα mediated fatty acid β‐oxidation in the liver. These results indicate that DHA‐PL and EPA‐PL could efficaciously alleviate obesity‐related metabolic disorders but the ameliorative degree and regulatory mechanisms are not identical.Practical applications: This investigation would be useful in the selective development of functional foods containing DHA‐PL or EPA‐PL contributing to the prevention and treatment of chronic metabolic disease in humans. The study also showed the chemical compositions of phospholipids fractions of squid (Sthenoteuthis oualaniensis) egg and sea cucumber (Cucumaria frondosa) that may be useful for further studies.

Discovery and pharmacological characterization of SAR707 as novel and selective small molecule inhibitor of stearoyl-CoA desaturase (SCD1)

Stearoyl-CoA desaturase (SCD1) is linked to the pathogenesis of obesity, dyslipidemia and type 2 diabetes. It is the rate-limiting enzyme in the synthesis of monounsaturated 16:1 n-7 and 18:1 n-9 fatty acyl-CoAs and catalyzes an essential part of lipogenesis. Here, we describe the identification, in vitro properties and in vivo efficacy of a novel class of heterocyclic small molecule hexahydro-pyrrolopyrrole SCD1 inhibitors. SAR707, a compound representative for the series, was optimized to high in vitro potency, selectivity and favorable overall properties in enzymatic and cellular assays. In vivo, this compound reduced serum desaturation index, decreased body weight gain and improved lipid parameters and blood glucose levels of obese Zucker diabetic fatty rats treated for 4 weeks in a chronic study. In parallel, fissures of the eye lid, alopecia and inflammation of the skin were observed from day 11 on in all animals treated with the same metabolically active dose. In summary, we described in vitro and in vivo properties of a novel, potent and selective SCD1 inhibitor that improved body weight, blood glucose and triglycerides in an animal model of obesity, type 2 diabetes and dyslipidemia. However, the favorable in vivo properties of systemic SCD1 inhibition shown in our study were accompanied by dose-dependently occurring adverse target-related effects observed in skin. Thus, systemic SCD1 inhibition by small molecules might therefore not represent a feasible approach for the treatment of chronic metabolic diseases.