Eight previously undescribed lanostane triterpenoids, including five nortriterpenoids with 26 carbons, ganothenoids A-E (1-5), and three lanostanoids, ganothenoids F-H (6-8), along with 24 known ones (9-32), were isolated from the fruiting bodies of Ganodrma theaecolum. The structures of the novel compounds were elucidated using comprehensive spectroscopic methods, including electronic circular dichroism (ECD) and nuclear magnetic resonance (NMR) calculations. Compounds 1-32 were assessed for their neuroprotective effects against H₂O₂-induced damage in human neuroblastoma SH-SY5Y cells, as well as their inhibitory activities against protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase. Compound 4 demonstrated the most potent neuroprotective activity against H₂O₂-induced oxidative stress by suppressing G₀/G₁ phase cell cycle arrest, reducing reactive oxygen species (ROS) levels, and inhibiting cell apoptosis through modulation of B-cell lymphoma 2 protein (Bcl-2) and Bcl-2 associated X-protein (Bax) protein expression. Compounds 26, 12, and 28 exhibited PTP1B inhibitory activities with IC₅₀ values ranging from 13.92 to 56.94 μmol·L^-1, while compound 12 alone displayed significant inhibitory effects on α-glucosidase with an IC₅₀ value of 43.56 μmol·L^-1. Additionally, enzyme kinetic analyses and molecular docking simulations were conducted for compounds 26 and 12 with PTP1B and α-glucosidase, respectively.
Humans ; Fruiting Bodies, Fungal/chemistry* ; Triterpenes/isolation & purification* ; Neuroprotective Agents/isolation & purification* ; Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism* ; Ganoderma/chemistry* ; Apoptosis/drug effects* ; Hypoglycemic Agents/isolation & purification* ; Molecular Structure ; alpha-Glucosidases/metabolism* ; Cell Line, Tumor ; Reactive Oxygen Species/metabolism* ; Oxidative Stress/drug effects* ; Hydrogen Peroxide/toxicity* ; Molecular Docking Simulation

In this study, araucarene diterpenes, characterized by a pimarene skeleton with a variably oxidized side chain at C-13, were investigated. A total of 16 araucarene diterpenoids and their derivatives were isolated from the woods of Agathis dammara, including 11 previously unreported compounds: dammaradione (1), dammarones D-G (2, 5, 14, 15), dammaric acids B-F (8-12), and dammarol (16). The structures of these new compounds were elucidated using high-resolution electrospray ionization mass spectroscopy (HR-ESI-MS) and one-dimensional/two-dimensional (1D/2D) nuclear magnetic resonance (NMR), while their absolute configurations were determined through the electronic circular dichroism (ECD) exciton chirality method and Snatzke's method. The hypoglycemic activity of all isolated compounds was evaluated using a transgenic zebrafish model, and a structure-activity relationship (SAR) analysis was conducted. Araucarone (3) and dammaric acid C (9), serving as representative compounds, demonstrated significant hypoglycemic effects on zebrafish. The primary mechanism involves the promotion of pancreatic β cell regeneration and glucose uptake. Specifically, these compounds enhance the differentiation of pancreatic endocrine precursor cells (PEP cells) into β cells in zebrafish.
Zebrafish ; Animals ; Diterpenes/isolation & purification* ; Insulin-Secreting Cells/cytology* ; Glucose/metabolism* ; Hypoglycemic Agents/isolation & purification* ; Molecular Structure ; Structure-Activity Relationship ; Plant Extracts/pharmacology* ; Regeneration/drug effects*

Aims: This study aimed to evaluate antidiabetic potential of indigenous Lactobacillus isolates by measuring the ability of α-glucosidase inhibitory (AGI) and antioxidant activity. The mechanism of probiotics as antidiabetic can occur through the AGI and antioxidant activity of LAB, which is able to suppress oxidative stress that causes chronic inflammation and pancreatic β cell apoptosis, and then through the ability to produce exopolysaccharide (EPS) and short chain fatty acids (SCFA). Methodology and results: MRS broth enriched with 10% glucose was selected as the growth medium for Lactobacillus. The growth medium was then centrifuged to obtain CFS and CFE was produced by extracting the medium with 96% ethanol as a solvent. The results showed that Lactobacillus pentosus MK42 had the highest AGI activity of 80.32 ± 2.20%. Antioxidant activity was not significantly different (P>0.05) among the tested Lactobacillus isolates. Lactobacillus paracasei RK41 produced the highest EPS (360.13 ± 50.01 mg/L), which was not significantly different (P>0.05) from Lactobacillus plantarum1 RB210. All Lactobacillus isolates were able to produce acetic acid, but not all were able to produce propionic and butyric acid. The highest propionic acid was produced by L. plantarum1 RB210 at 0.40 ± 0.31 mmol/L and the highest butyric acid was produced by L. plantarum1 MK2 at 0.22 ± 0.08 mmol/L. Conclusion, significance and impact of study The results show definitively that indigenous Lactobacillus isolates have considerable α-glucosidase inhibitor, antioxidant activity and the ability to produce of EPS and SCFA. This preliminary study suggests the use of indigenous Lactobacillus isolates which have the potential as antidiabetic agent, although the responsible compounds are unknown.
alpha-Glucosidases ; Antioxidants ; Lactobacillus--isolation & ; purification ; Hypoglycemic Agents

The present study aimed at exploring the therapeutic potential of standard extract of Bombax ceiba L. leaves (BCE) in type 2 diabetic mellitus (T2DM). Oral administration of BCE at doses of 70, 140, and 280 mg·kg, to the normal rats and the high-fat-diet- and streptozotocin-induced T2DM rats were carried out. Effects of BCE on blood glucose, body weight, and a range of serum biochemical parameters were tested, and histopathological observation of pancreatic tissues was also performed. HPLC-ESI-Q/TOF-MS/MS analysis indicated that the chemical composition of BCE mainly contained mangiferin, isoorientin, vitexin, isomangiferin, isovitexin, quercetin hexoside, 2'-trans-O-cumaroyl mangiferin, and nigricanside. BCE caused a significant decrease in the concentrations of fasting blood glucose, glycosylated hemoglobin, total cholesterol, triglyceride, low density lipoprotein-cholesterol, serum insulin, and malondialdehyde, and increases in oral glucose tolerance, high density lipoprotein-cholesterol, and superoxide dismutase in the T2DM model rats. Moreover, considerable pancreatic β-cells protection effect and stimulation of insulin secretion from the remaining pancreatic β-cells could be observed after BCE treatment. The results indicated that BCE exhibited an excellent hypoglycemic activity, and alleviated dyslipidemia which is associated with T2DM. Antioxidant activity and protecting pancreatic β-cells are the possible mechanisms involved in anti-diabetic activity of BCE.
Animals ; Antioxidants ; administration & dosage ; chemistry ; isolation & purification ; Blood Glucose ; metabolism ; Bombax ; chemistry ; Diabetes Mellitus, Type 2 ; drug therapy ; metabolism ; Humans ; Hypoglycemic Agents ; administration & dosage ; chemistry ; isolation & purification ; Hypolipidemic Agents ; administration & dosage ; chemistry ; isolation & purification ; Male ; Plant Extracts ; administration & dosage ; chemistry ; isolation & purification ; Plant Leaves ; chemistry ; Rats ; Rats, Sprague-Dawley

The present study aimed at identifying potential lead compounds for diabetes mellitus drug discovery. We developed a novel method involving centrifugal ultrafiltration separation subsequent liquid chromatography with quadrupole time of flight tandem mass spectrometry (LC-Q/TOF-MS/MS) determination to screen α-glucosidase inhibitors in complex Scutellaria baicalensis Georgi (SBG) extract. By adding a second filter to the screening process, the level of non-specific binding of Compounds 1, 3, 10 and 11 was significantly decreased, and the level of non-specific binding of Compounds 5 and 15 also was reduced. As a result, five flavonoids identified as baicalein, baicalein, wogonin, chrysin, and oroxylin A, were rapidly found to interact with α-glucosidase and possess potent anti-α-glucosidase activity in vitro. Specific binding of ligands to α-glucosidase was demonstrated though the proposed method and the ligands could be ranked in order of affinity for α-glucosidase, which were corresponded to the order of inhibitory activity in vitro. In conclusion, our results indicated that the developed method is a rapid and effective screening method for rat intestinal α-glucosidase inhibitors from complex herbal medicines such as SBG.
Animals ; Chromatography, Liquid ; methods ; Flavonoids ; immunology ; isolation & purification ; Glycoside Hydrolase Inhibitors ; immunology ; isolation & purification ; Hypoglycemic Agents ; immunology ; isolation & purification ; Plant Extracts ; chemistry ; Rats ; Tandem Mass Spectrometry ; methods ; Ultrafiltration ; methods

The effects of magnolol (Mag) on hyperglycemia and hyperlipemia, hepatic oxidative stress and cytochrome P4502E1 (CYP2E1) activity of diabetic rats induced by high-fat diet (HFD) and streptozotocin (STZ) were studied. After oral administration of Mag (25, 50 and 100 mg x kg(-1) x d(-1)) for continuous 10 weeks, the blood glucose and lipids (TC, TG and LDL-C) levels, as well as the hepatic CYP2E1 activity and MDA content of diabetic rats, decreased significantly (P < 0.05 or P < 0.01), whereas the oral glucose tolerance and hepatic antioxidant enzymatic activities (CAT and GSH-Px) of diabetic rats, increased significantly (P < 0.05 or P < 0.01). The results indicated that Mag was effective against the hepatic oxidative damage, hyperglycemia and hyperlipemia of diabetic rats induced by HFD and STZ, and the inhibition of Mag on hepatic CYP2E1 activity could be an important mechanism of Mag against hepatic insulin resistance and oxidative damage.
Animals ; Biphenyl Compounds ; isolation & purification ; pharmacology ; Blood Glucose ; metabolism ; Cholesterol ; blood ; Cholesterol, LDL ; blood ; Cytochrome P-450 CYP2E1 ; metabolism ; Diabetes Mellitus, Experimental ; blood ; drug therapy ; metabolism ; Diet, High-Fat ; Glucose Tolerance Test ; Hypoglycemic Agents ; isolation & purification ; pharmacology ; Lignans ; isolation & purification ; pharmacology ; Liver ; metabolism ; Magnolia ; chemistry ; Male ; Oxidative Stress ; drug effects ; Plants, Medicinal ; chemistry ; Protective Agents ; pharmacology ; Rats ; Rats, Wistar ; Streptozocin ; Triglycerides ; blood

Fibroblast growth factor -21 (FGF-21) is a recently discovered metabolic regulation factor, regulating glucose and lipid metabolism and increasing insulin sensitivity. FGF-21 is expected to be a potential anti-diabetic drug. Expression of FGF-21 as inclusion bodies has advantages for high yield and purity, but the bioactivity of the protein is almost totally lost after denature and renature. That is why FGF-21 is currently expressed in soluble form. As a result, the yield is considerably low. In this study, we used SUMO vector to express SUMO-human FGF-21 (SUMO-hFGF-21) in form of inclusion body. We optimized the culture conditions to increase the yield of the bioactive human fibroblast growth factor-21. We applied the hollow fiber membrane filtration column to enrich the bacteria, wash, denature and renature inclusion bodies. After affinity and gel filtration chromatography, we examined the hypoglycemic activity of FGF-21 by the glucose uptake assay in HepG2 cells. We also detected the blood glucose concentration of type 2 diabetic db/db model mice after short or long-term treatment. The results show that the yield of ihFGF-21 was 4 times higher than that of shFGF-21. The yield was 20 mg/L for ihFGF-21 vs. 6 mg/L for shFGF-21. The purity of ihFGF-21 was above 95%, while shFGF-21 was 90%. Compared with the traditional method of extracting inclusion bodies, the production cycle was about three times shortened by application of hollow fiber membrane filtration column technology, but the bioactivity did not significantly differ. This method provides an efficient and cost-effective strategy to the pilot and industrial production of hFGF-21.
Animals ; Bacteria ; metabolism ; Diabetes Mellitus, Experimental ; drug therapy ; Disease Models, Animal ; Fibroblast Growth Factors ; biosynthesis ; Genetic Vectors ; Glucose ; metabolism ; Hep G2 Cells ; Humans ; Hypoglycemic Agents ; isolation & purification ; Inclusion Bodies ; metabolism ; Mice ; Recombinant Fusion Proteins ; biosynthesis ; Small Ubiquitin-Related Modifier Proteins ; biosynthesis

The enzyme-inhibitor model and the sugar tolerance mouse model were used to evaluate the relationship between the inhibition rate of enzyme activity and concentration of Hippophae rhamnoides L. subsp. chinensis Rousi polysaccharide (HRP). The inhibitory patterns of enzyme and dose-dependent effects of HRP's effect on blood glucose using acarbose tablets as control were also examined. The mechanism underlying hypoglycemic effects of HRP was discussed. The results showed: in the enzyme-inhibitor model, the inhibitory activity of different concentrations of HRP (9.80, 19.60, 39.20, 78.40, 156.80 and 312.50 mg x L(-1)) on alpha-glucosaminidase (AG) inhibitory activity were 6.62%, 18.02%, 33.26%, 48.23%, 62.11%, 76.31%, 90.12%, IC50 was 31.59 mg x L(-1). The inhibitory rate of 25.00 x 10(3) mg x L(-1) acarbose tablets was only 64.87%, and IC50 was 10.75 x 10(3) mg x L(-1). In the sugar tolerance mouse model, different doses of HRP (240, 480, 960 mg x kg(-1)) tended to decrease levels of blood glucose compared with control group (acarbose tablets 375 mg x kg(-1)) at 15, 30, 60 and 120 min. It's further confirmed that HRP is a kind of competitive inhibitor of AG activity. Its inhibition rate increases with the increase of concentration in normal mice, and it subsequently improves the sugar tolerance showing the effect of reducing blood sugar.
Animals ; Blood Glucose ; metabolism ; Dose-Response Relationship, Drug ; Enzyme Inhibitors ; pharmacology ; Female ; Glucose Tolerance Test ; Glycoside Hydrolase Inhibitors ; Hippophae ; chemistry ; Hypoglycemic Agents ; administration & dosage ; isolation & purification ; pharmacology ; Inhibitory Concentration 50 ; Male ; Mice ; Plants, Medicinal ; chemistry ; Polysaccharides ; administration & dosage ; isolation & purification ; pharmacology ; Random Allocation ; alpha-Glucosidases ; metabolism

The objective of this study is to fully investigate the therapeutic effect and mechanisms of action of Gegen Qinlian decoction (GD) on type 2 diabetes mellitus (type 2 DM). A rat model of type 2 DM was established with the combination of high-fat diet and multiple low doses of streptozotocin (STZ). Biochemical indicators related to glucose metabolism disorders, insulin resistance, oxidative stress were observed. The type 2 DM rats were administrated with GD for 80 days, the above-mentioned indexes were detected. The results indicated that the hepatic glycogen synthesis level was promoted, fasting blood glucose level and fasting blood insulin level were significantly reduced, insulin sensitivity index was significantly improved; the level of superoxide dismutase (SOD) was increased and the level of malondialdehyde (MDA) was reduced; pathologic morphology of pancreas and kidney was ameliorated in the GD group. It was indicated that the therapeutic mechanisms of action of GD on type 2 DM might be related to its effect of ameliorating glucose metabolism disorders, relieving insulin resistance, increasing the tissues' sensitivity to insulin, improving the antioxidative ability of living system, GD has therapeutic effect on type 2 DM and protective effects against damaged pancreatic function.
Animals ; Blood Glucose ; metabolism ; Diabetes Mellitus, Type 2 ; drug therapy ; metabolism ; pathology ; Drugs, Chinese Herbal ; isolation & purification ; pharmacology ; therapeutic use ; Female ; Glycogen ; metabolism ; Hypoglycemic Agents ; isolation & purification ; pharmacology ; therapeutic use ; Insulin ; blood ; Insulin Resistance ; Kidney ; pathology ; Liver ; metabolism ; Male ; Malondialdehyde ; metabolism ; Pancreas ; pathology ; Phytotherapy ; Plants, Medicinal ; chemistry ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Streptozocin ; Superoxide Dismutase ; metabolism

The effect and mechanism of mulberry leaves extracts (MLE) on glucose uptake of insulin-resistant HepG2 cells in vitro was explored. The insulin resistant models of HepG2 were induced by high concentration of insulin for 24 h. The models were incubated in a buffer containing mulberry leaves extracts. The glucose consumption was detected by glucose assay kits and the AMP-activated protein kinase (AMPK), Akt activation was examined by Western blotting. Mulberry leaves polysaccharides, mulberry leaves flavonoids and mulberry leaves extracts advanced glucose uptake of insulin-resistant HepG2 cells; Mulberry leaves extracts enhance phosphorylation of AMPK. Mulberry leaves extracts do not change the phosphorylation status of Akt. The glucose consumptions of insulin resistant model of HepG2 were promoted by mulberry leaves extracts. MLE stimulates HepG2 cell AMPK activity acutely without changing the Akt activity.
AMP-Activated Protein Kinases ; metabolism ; Cell Proliferation ; drug effects ; Drugs, Chinese Herbal ; isolation & purification ; pharmacology ; Flavonoids ; isolation & purification ; pharmacology ; Glucose ; metabolism ; Hep G2 Cells ; Humans ; Hypoglycemic Agents ; isolation & purification ; pharmacology ; Insulin Resistance ; Morus ; chemistry ; Phosphorylation ; Plant Extracts ; pharmacology ; Plant Leaves ; chemistry ; Plants, Medicinal ; chemistry ; Polysaccharides ; isolation & purification ; pharmacology ; Proto-Oncogene Proteins c-akt ; metabolism