Sustainable production of natural products using synthetic biology: Ginsenosides.

Synthetic biology approaches offer potential for large-scale and sustainable production of natural products with bioactive potency, including ginsenosides, providing a means to produce novel compounds with enhanced therapeutic properties. Ginseng, known for its non-toxic and potent qualities in traditional medicine, has been used for various medical needs. Ginseng has shown promise for its antioxidant and neuroprotective properties, and it has been used as a potential agent to boost immunity against various infections when used together with other drugs and vaccines. Given the increasing demand for ginsenosides and the challenges associated with traditional extraction methods, synthetic biology holds promise in the development of therapeutics. In this review, we discuss recent developments in microorganism producer engineering and ginsenoside production in microorganisms using synthetic biology approaches.

Fenofibrate Regulates Visceral Obesity and Nonalcoholic Steatohepatitis in Obese Female Ovariectomized C57BL/6J Mice.

Fibrates, including fenofibrate, are a class of hypolipidemic drugs that activate peroxisome proliferator-activated receptor α (PPARα), which in-turn regulates the expression of lipid and lipoprotein metabolism genes. We investigated whether fenofibrate can reduce visceral obesity and nonalcoholic fatty liver disease via adipose tissue PPARα activation in female ovariectomized (OVX) C57BL/6J mice fed a high-fat diet (HFD), a mouse model of obese postmenopausal women. Fenofibrate reduced body weight gain (-38%, p < 0.05), visceral adipose tissue mass (-46%, p < 0.05), and visceral adipocyte size (-20%, p < 0.05) in HFD-fed obese OVX mice. In addition, plasma levels of alanine aminotransferase and aspartate aminotransferase, as well as free fatty acids, triglycerides, and total cholesterol, were decreased. Fenofibrate also inhibited hepatic lipid accumulation (-69%, p < 0.05) and infiltration of macrophages (-72%, p < 0.05), while concomitantly upregulating the expression of fatty acid ß-oxidation genes targeted by PPARα and decreasing macrophage infiltration and mRNA expression of inflammatory factors in visceral adipose tissue. These results suggest that fenofibrate inhibits visceral obesity, as well as hepatic steatosis and inflammation, in part through visceral adipose tissue PPARα activation in obese female OVX mice.

The herbal extract ALS-L1023 from Melissa officinalis reduces weight gain, elevated glucose levels and ß-cell loss in Otsuka Long-Evans Tokushima fatty rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Melissa officinalis L. (Labiatae; lemon balm) is a traditional medicinal plant with hypoglycemic and hypolipidemic effects; however, how it imparts its beneficial effects remains unclear. We thus hypothesized that the herbal extract ALS-L1023, isolated from Melissa officinalis, inhibits obesity and diabetes, and tested our hypothesis using Otsuka Long-Evans Tokushima fatty (OLETF) rats, which are an established animal model of type 2 diabetes. MATERIALS AND METHODS: In this study, 28-week-old OLETF rats were fed a high-fat diet for 4 weeks to induce a marked impairment of the insulin response and were treated with or without ALS-L1023. Subsequently, the variables and determinants of glucose metabolism and pancreatic function were assessed via blood analysis, histology, immunohistochemistry, and real-time polymerase chain reaction. RESULTS: The administration of ALS-L1023 resulted in a weight reduction without changes in food intake. It also markedly inhibited hyperglycemia and hypoinsulinemia, and restored ß-cell mass that was severely impaired in OLETF rats. There was a decrease in lipid accumulation in the liver and skeletal muscle of the obese rats after treatment with ALS-L1023. Concomitantly, there was an increase in the expression levels of fatty acid-oxidizing enzymes (AMPKα2, ACOX, MCAD, and VLCAD) in the liver and skeletal muscle after ALS-L1023 treatment. Furthermore, ALS-L1023 attenuated the pancreatic inflammation including the infiltration of CD68-positive macrophages and mast cells, in addition to attenuating the expression of inflammatory factors (IL-6 and CD68). CONCLUSIONS: These results suggest that treatment with ALS-L1023 may reduce weight gain, elevated glucose levels, and ß-cell loss, by changing the expression of fatty acid-oxidizing enzymes in the liver and skeletal muscle, including inflammatory factors in the pancreas. These findings indicate that ALS-L1023 may be an effective therapeutic strategy to treat human obesity and type 2 diabetes.

Lemon Balm Extract ALS-L1023 Regulates Obesity and Improves Insulin Sensitivity via Activation of Hepatic PPARα in High-Fat Diet-Fed Obese C57BL/6J Mice.

Our previous studies demonstrated that peroxisome proliferator-activated receptor α (PPARα) activation reduces weight gain and improves insulin sensitivity in obese mice. Since excess lipid accumulation in non-adipose tissues is suggested to be responsible for the development of insulin resistance, this study was undertaken to examine whether the lemon balm extract ALS-L1023 regulates hepatic lipid accumulation, obesity, and insulin resistance and to determine whether its mechanism of action involves PPARα. Administration of ALS-L1023 to high-fat-diet-induced obese mice caused reductions in body weight gain, visceral fat mass, and visceral adipocyte size without changes of food consumption profiles. ALS-L1023 improved hyperglycemia, hyperinsulinemia, glucose and insulin tolerance, and normalized insulin-positive ß-cell area in obese mice. ALS-L1023 decreased hepatic lipid accumulation and concomitantly increased the expression of PPARα target genes responsible for fatty acid ß-oxidation in livers. In accordance with the in vivo data, ALS-L1023 reduced lipid accumulation and stimulated PPARα reporter gene expression in HepG2 cells. These effects of ALS-L1023 were comparable to those of the PPARα ligand fenofibrate, while the PPARα antagonist GW6471 inhibited the actions of ALS-L1023 on lipid accumulation and PPARα luciferase activity in HepG2 cells. Higher phosphorylated protein kinase B (pAkt)/Akt ratios and lower expression of gluconeogenesis genes were observed in the livers of ALS-L1023-treated mice. These results indicate that ALS-L1023 may inhibit obesity and improve insulin sensitivity in part through inhibition of hepatic lipid accumulation via hepatic PPARα activation.

The herbal extract ALS-L1023 from Melissa officinalis alleviates visceral obesity and insulin resistance in obese female C57BL/6J mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Melissa officinalis L. (Labiatae; lemon balm) has traditionally been used as a medicinal herb to treat stress, anxiety, and insomnia. Current reports suggest that not only chronic stress stimulates angiogenesis, but angiogenesis also regulates adipogenesis and obesity. Because the herbal extract ALS-L1023 from Melissa officinalis inhibits angiogenesis, we hypothesized that ALS-L1023 could suppress visceral obesity and insulin resistance in obese female C57BL/6J mice, a mouse model of obese premenopausal women. MATERIALS AND METHODS: The mice were grouped and fed for 16 weeks as follows: 1) low-fat diet (LFD), 2) high-fat diet (HFD), or 3) HFD supplemented with 0.4 or 0.8% ALS-L1023. Variables and determinants of visceral obesity, insulin resistance, and pancreatic dysfunction were then assessed via blood analysis, histology, immunohistochemistry, and real-time polymerase chain reaction. RESULTS: ALS-L1023 decreased weight gain, visceral adipocyte size, and serum lipid levels in HFD-fed obese mice. ALS-L1023 also normalized hyperglycemia and hyperinsulinemia and concomitantly reduced blood glucose levels during oral glucose tolerance tests. The pancreatic islet size and insulin-positive ß-cell area were significantly reduced in ALS-L1023-treated mice compared with untreated obese controls, reaching a level similar to that of LFD-fed lean mice. ALS-L1023 suppressed pancreatic lipid accumulation, infiltration of inflammatory cells, and collagen levels. ALS-L1023 treatment altered the pancreatic expression of genes involved in steatosis, inflammation, and fibrosis. CONCLUSIONS: Our findings indicate that the herbal extract ALS-L1023 from Melissa officinalis not only inhibits visceral obesity, but also attenuates the increased fasting blood glucose, impaired glucose tolerance, and pancreatic dysfunction seen in female obese mice. These results suggest that ALS-L1023 may be effective in the prevention of visceral obesity and insulin resistance in obese premenopausal women.