Euphorstranoids A and B, Two Highly Rearranged Ingenane Diterpenoids from Euphorbia stracheyi: Structural Elucidation, Chemical Transformation, and Lipid-Lowering Activity

Euphorstranoids A (1) and B (2), two highly rearranged ingenane diterpenoids with an unusual 5/6/7/3 carbon ring system, were isolated from Euphorbia stracheyi. Their structures were determined by a combination...

Extraction optimisation and lipid-lowering activity of Auricularia heimuer polysaccharides

Assessments of molecular weight distribution and activity/efficacy of Auricularia heimuer polysaccharides (AAP) are of substantial significance for its extraction process optimisation. In the present study, single-factor orthogonal test and response surface methodology were employed to optimise extraction conditions of AAP. Furthermore, a rat hyperlipidaemia model was established to compare the lipid-lowering activity of polysaccharides obtained by three extraction methods. Conditions for enzymatic hydrolysis were optimised as pH 5.0, 1% cellulase, 2.5% substrate concentration and enzymolysis time of 1.5 h, leading to an up to 31.8% polysaccharide yield and 89.13% of polysaccharides within the molecular weight range of 5 000 Da to 10 000 Da. The results of animal experiments showed that the lipid-lowering activity of enzymolysis-extracted polysaccharides was significantly higher than that of water- and ultrasonic-extracted ones (P < 0.01). So the present study revealed that enzymatic hydrolysis-extracted polysaccharides showed the strongest hypolipidaemia activity, providing a basis for the development of A. heimuer-based functional foods and drugs.

Paracrine FGFs target skeletal muscle to exert potent anti-hyperglycemic effects

Several members of the FGF family have been identified as potential regulators of glucose homeostasis. We previously reported that a low threshold of FGF-induced FGF receptor 1c (FGFR1c) dimerization and activity is sufficient to evoke a glucose lowering activity. We therefore reasoned that ligand identity may not matter, and that besides paracrine FGF1 and endocrine FGF21, other cognate paracrine FGFs of FGFR1c might possess such activity. Indeed, via a side-by-side testing of multiple cognate FGFs of FGFR1c in diabetic mice we identified the paracrine FGF4 as a potent anti-hyperglycemic FGF. Importantly, we found that like FGF1, the paracrine FGF4 is also more efficacious than endocrine FGF21 in lowering blood glucose. We show that paracrine FGF4 and FGF1 exert their superior glycemic control by targeting skeletal muscle, which expresses copious FGFR1c but lacks β-klotho (KLB), an obligatory FGF21 co-receptor. Mechanistically, both FGF4 and FGF1 upregulate GLUT4 cell surface abundance in skeletal muscle in an AMPKα-dependent but insulin-independent manner. Chronic treatment with rFGF4 improves insulin resistance and suppresses adipose macrophage infiltration and inflammation. Notably, unlike FGF1 (a pan-FGFR ligand), FGF4, which has more restricted FGFR1c binding specificity, has no apparent effect on food intake. The potent anti-hyperglycemic and anti-inflammatory properties of FGF4 testify to its promising potential for use in the treatment of T2D and related metabolic disorders.

IAF, QGF, and QDF Peptides Exhibit Cholesterol-Lowering Activity through a Statin-like HMG-CoA Reductase Regulation Mechanism: In Silico and In Vitro Approach

In this study, in silico approaches are employed to investigate the binding mechanism of peptides derived from cowpea β-vignin and HMG-CoA reductase. With the obtained information, we designed synthetic peptides to evaluate their in vitro enzyme inhibitory activity. In vitro, the total protein extract and <3 kDa fraction, at 5000 µg, support this hypothesis (95% and 90% inhibition of HMG-CoA reductase, respectively). Ile-Ala-Phe, Gln-Gly-Phe, and Gln-Asp-Phe peptides were predicted to bind to the substrate binding site of HMGCR via HMG-CoAR. In silico, it was established that the mechanism of HMG-CoA reductase inhibition largely entailed mimicking the interactions of the decalin ring of simvastatin and via H-bonding; in vitro studies corroborated the predictions, whereby the HMG-CoA reductase activity was decreased by 69%, 77%, and 78%, respectively. Our results suggest that Ile-Ala-Phe, Gln-Gly-Phe, and Gln-Asp-Phe peptides derived from cowpea β-vignin have the potential to lower cholesterol synthesis through a statin-like regulation mechanism.

Defining the Cholesterol Lowering Mechanism of Bergamot (Citrus bergamia) Extract in HepG2 and Caco-2 Cells

Bergamot, a Mediterranean citrus fruit native to southern Italy, has been reported to have cholesterol-lowering properties; however, the mechanism of action is not well understood. Due to structural similarities with 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitors, it has been proposed that the phenolic compounds in bergamot may also inhibit HMGCR. Statins are widely used for their cholesterol-lowering properties; however, they are not universally well tolerated, suggesting there is a need to identify novel cholesterol-lowering strategies. In the present study, we investigated bergamot fruit extract (BFE) and its principal components (neoeriocitrin, naringin, neohesperidin, melitidin, and brutieridin) for their ability to regulate cholesterol levels in HepG2 and Caco-2 cells. BFE at increasing concentrations decreased the levels of total and free cholesterol in HepG2 cells. BFE and its constituents did not directly inhibit HMGCR activity. However, BFE and neohesperidin decreased HMGCR levels in HepG2 cells, suggesting that neohesperidin and BFE may downregulate HMGCR expression. An increase in AMP-kinase phosphorylation was observed in BFE and neohesperidin-treated cells. In Caco-2 cells, brutieridin exhibited a significant reduction in cholesterol uptake and decreased the level of Niemann-Pick C1 Like 1, an important cholesterol transporter. Taken together, our data suggest that the cholesterol-lowering activity of bergamot is distinct from statins. We hypothesize that BFE and its principal constituents lower cholesterol by inhibiting cholesterol synthesis and absorption.

Formulation & Evaluation of Naringin Nanoethosome by Cold Method

Naringin is a flavonoid which shows various pharmacological effects, such as, anti-inflammatory and antioxidant,cholesterol lowering activity, free radical scavenging activity. Although naringin is easily found in citrus fruits but has lower bioavailability, biodistribution and undergoes biotransformation to naringenin. To overcome this, the main objective of this work is to formulate nanoethosome formulation containing naringin. The use of nanoethosomes as vesicle drug carrier having ability to increase solubility, improve biodistribution, slows the biotransformation which improves the activity of naringin for treating neurological disorder. The ethosomes were formulated by varying the variables such as concentrations of soya lecithine, polyethylene glycol, and ethanol. The formulations were evaluated with entrapment efficiency, and particle size. Results specify that prepared nanoethosomes of naringin shows decreased particle size, better entrapment efficiency as compared to rigid ethosomes. The F4 was selected as optimized formulation which was further characterized for vesicle size determination. The F4 shows vesicles size of 145.9 nm having 83.9% entrapment efficiency. The nanoethosomes were proved to be significantly superior in terms of amount of drug permeated into the skin, with an enhancement ratio of 3.77 when compared to rigid ethosomes. Our results suggests that nanoethosomes are an efficient carrier for improved naringin permeation & stability.