Kaempferol Improves Exercise Performance by Regulating Glucose Uptake, Mitochondrial Biogenesis, and Protein Synthesis via PI3K/AKT and MAPK Signaling Pathways.

Kaempferol is a natural flavonoid with reported bioactivities found in many fruits, vegetables, and medicinal herbs. However, its effects on exercise performance and muscle metabolism remain inconclusive. The present study investigated kaempferol's effects on improving exercise performance and potential mechanisms in vivo and in vitro. The grip strength, exhaustive running time, and distance of mice were increased in the high-dose kaempferol group (p < 0.01). Also, kaempferol reduced fatigue-related biochemical markers and increased the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) related to antioxidant capacity. Kaempferol also increased the glycogen and adenosine triphosphate (ATP) content in the liver and skeletal muscle, as well as glucose in the blood. In vitro, kaempferol promoted glucose uptake, protein synthesis, and mitochondrial function and decreased oxidative stress in both 2D and 3D C2C12 myotube cultures. Moreover, kaempferol activated the PI3K/AKT and MAPK signaling pathways in the C2C12 cells. It also upregulated the key targets of glucose uptake, mitochondrial function, and protein synthesis. These findings suggest that kaempferol improves exercise performance and alleviates physical fatigue by increasing glucose uptake, mitochondrial biogenesis, and protein synthesis and by decreasing ROS. Kaempferol's molecular mechanism may be related to the regulation of the PI3K/AKT and MAPK signaling pathways.

The Lipophilic Extract from Ginkgo biloba L. Leaves Promotes Glucose Uptake and Alleviates Palmitate-Induced Insulin Resistance in C2C12 Myotubes.

Ginkgo biloba L. (ginkgo) is a widely used medicinal plant around the world. Its leaves, which have been used as a traditional Chinese medicine, are rich in various bioactive components. However, most of the research and applications of ginkgo leaves have focused on terpene trilactones and flavonol glycosides, thereby overlooking the other active components. In this study, a lipophilic extract (GL) was isolated from ginkgo leaves. This extract is abundant in lipids and lipid-like molecules. Then, its effect and potential mechanism on glucose uptake and insulin resistance in C2C12 myotubes were investigated. The results showed that GL significantly enhanced the translocation of GLUT4 to the plasma membrane, which subsequently promoted glucose uptake. Meanwhile, it increased the phosphorylation of AMP-activated protein kinase (AMPK) and its downstream targets. Both knockdown of AMPK with siRNA and inhibition with AMPK inhibitor compound C reversed these effects. Additionally, GL ameliorated palmitate-induced insulin resistance by enhancing insulin-stimulated glucose uptake, increasing the phosphorylation of protein kinase B (PKB/AKT), and restoring the translocation of GLUT4 from the cytoplasm to the membrane. However, pretreatment with compound C abolished these beneficial effects of GL. In conclusion, GL enhances basal glucose uptake in C2C12 myotubes and improves insulin sensitivity in palmitate-induced insulin resistant myotubes through the AMPK pathway.

Anti-diabetic compounds from Uvaria dulcis Dunal.

Medicinal plants have long been a source of lead compounds for drug discovery. Among these, the Annonaceae family has gained recognition for its potential to yield novel compounds, particularly those that can be used in the development of drugs targeting chronic diseases like diabetes mellitus (DM). We employed various chromatographic methods to isolate bioactive compounds from the roots, leaves, and twigs of Uvaria dulcis Dunal. We used spectroscopic methods to determine the chemical structures of these compounds. We successfully identified twelve known compounds from various parts of U. dulcis: patchoulenon, polygochalcone, 2'3'-dihydroxy-4',6'-dimethoxydihydrochalcone, 2',3'-dihydroxy-4',6'-dimethoxychalcone, chrysin, techochrysin, 8-hydroxy-5,7-dimethoxyflavanone, pinocembrin, 3-farnesylindole, onysilin, cinchonain la, and cinchonain lb. Interestingly, cinchonain la and cinchonain lb exhibited more potent anti-α-glucosidase activity than acarbose (standard drug), with IC50 values of 11.88 ± 1.41 µg/mL and 15.18 ± 1.19 µg/mL, respectively. Cinchonain la inhibited the DPP-IV enzyme, with IC50 value lower than the standard compound (diprotin A) at 81.78 ± 1.42 µg/mL. While 2',3'-dihydroxy-4',6'-dimethoxychalcone show more potent inhibitory effect than standard drug with IC50 value of 8.62 ± 1.19 µg/mL. Additionally, at a concentration of 10 µg/mL, cinchonain lb and 2',3'-dihydroxy-4',6'-dimethoxychalcone promoted glucose uptake in L6 myotubes cells to the same extent as 100 nM insulin. These findings suggest that cinchonain la, cinchonain lb, and 2',3'-dihydroxy-4',6'-dimethoxychalcone are the U. dulcis-derived bioactive compounds that hold promise as potential structures to use in the development of anti-diabetic drugs.

Glycolipids Derived from the Korean Endemic Plant Aruncus aethusifolius Inducing Glucose Uptake in Mouse Skeletal Muscle C2C12 Cells.

Aruncus spp. has been used as a traditional folk medicine worldwide for its anti-inflammatory, hemostatic, and detoxifying properties. The well-known species A. dioicus var. kamtschaticus has long been used for multifunctional purposes in Eastern Asia. Recently, it was reported that its extract has antioxidant and anti-diabetic effects. In this respect, it is likely that other Aruncus spp. possess various biological activities; however, little research has been conducted thus far. The present study aims to biologically identify active compounds against diabetes in the Korean endemic plant A. aethusifolius and evaluate the underlying mechanisms. A. aethusifolius extract enhanced glucose uptake without toxicity to C2C12 cells. A bioassay-guided isolation of A. aethusifolius yielded two pure compounds, and their structures were characterized as glycolipid derivatives, gingerglycolipid A, and (2S)-3-linolenoylglycerol-O-ß-d-galactopyranoside by an interpretation of nuclear magnetic resonance and high-resolution mass spectrometric data. Both compounds showed glucose uptake activity, and both compounds increased the phosphorylation levels of insulin receptor substrate 1 (IRS-1) and 5'-AMP-activated protein kinase (AMPK) and protein expression of peroxisome proliferator-activated receptor γ (PPARγ). Gingerglycolipid A docked computationally into the active site of IRS-1, AMPK1, AMPK2, and PPARγ (-5.8, -6.9, -6.8, and -6.8 kcal/mol).

Arginine and Lysine Supplementation Potentiates the Beneficial ß-Hydroxy ß-Methyl Butyrate (HMB) Effects on Skeletal Muscle in a Rat Model of Diabetes.

Skeletal muscle is the key tissue for maintaining protein and glucose homeostasis, having a profound impact on the development of diabetes. Diabetes causes deleterious changes in terms of loss of muscle mass, which will contribute to reduced glucose uptake and therefore progression of the disease. Nutritional approaches in diabetes have been directed to increase muscle glucose uptake, and improving protein turnover has been at least partially an oversight. In muscle, ß-hydroxy ß-methyl butyrate (HMB) promotes net protein synthesis, while arginine and lysine increase glucose uptake, albeit their effects on promoting protein synthesis are limited. This study evaluates if the combination of HMB, lysine, and arginine could prevent the loss of muscle mass and function, reducing the progression of diabetes. Therefore, the combination of these ingredients was tested in vitro and in vivo. In muscle cell cultures, the supplementation enhances glucose uptake and net protein synthesis due to an increase in the amount of GLUT4 transporter and stimulation of the insulin-dependent signaling pathway involving IRS-1 and Akt. In vivo, using a rat model of diabetes, the supplementation increases lean body mass and insulin sensitivity and decreases blood glucose and serum glycosylated hemoglobin. In treated animals, an increase in GLUT4, creatine kinase, and Akt phosphorylation was detected, demonstrating the synergic effects of the three ingredients. Our findings showed that nutritional formulations based on the combination of HMB, lysine, and arginine are effective, not only to control blood glucose levels but also to prevent skeletal muscle atrophy associated with the progression of diabetes.

Oral Glucose Tolerance Test (OGTT) Evidence for the Postprandial Anti-Hyperglycemic Property of Salacca zalacca (Gaertn.) Voss Seed Extract.

Salak seed extract (Salacca zalacca) is known for its high antioxidant content and low caffeine levels, making it a promising candidate for the development of value-added health products. However, there is a lack of scientific evidence for its anti-hyperglycemic effects. To address this, we investigated the in vitro and in vivo anti-hyperglycemic and antioxidant effects of salak seed extract. The HPLC chromatogram of salak seed extract shows a prominent peak that corresponds to chlorogenic acid. In vitro studies revealed that salak seeds inhibited α-glucosidase activity and glucose uptake in Caco-2 cells in a concentration-dependent manner, while also exhibiting antioxidant properties. The extract exhibits a non-competitive inhibition on α-glucosidase activity, with an IC50 and Ki of 16.28 ± 7.22 and 24.81 µg/mL, respectively. In vivo studies utilizing streptozotocin-nicotinamide-induced diabetic mice showed that the extract significantly reduced fasting blood glucose (FBG) levels in the oral glucose tolerance test. Continuous administration of the salak seed extract resulted in lower FBG levels by 13.8% as compared with untreated diabetic mice, although this change was not statistically significant. The estimated LD50 value of salak seed extract exceeds 2000 mg/kg, and no toxicity symptoms have been detected. Our research supports that salak seed extract has the potential to serve as a functional food or supplement that may be beneficial in reducing postprandial hyperglycemia among people with type 2 diabetes. This effect was explained by the salak's inhibitory mechanisms of glucose absorption due to inhibition of both α-glucosidase activity and intestinal glucose uptake, coupled with its antioxidant effects.

Unlocking the Therapeutic Potential of Stevia rebaudiana Bertoni: A Natural Antiglycating Agent and Non-Toxic Support for HDF Cell Health.

Sugar carbonyl groups interact with protein amino groups, forming toxic components referred to as advanced glycation end products (AGEs). The glycation system (BSA, a model protein, and fructose) was incubated for five weeks at 37 °C in the presence and absence of Stevia leaf extract. The results indicated that the leaf extract (0.5 mg/mL) decreased the incidence of browning (70.84 ± 0.08%), fructosamine (67.27 ± 0.08%), and carbonyl content (64.04 ± 0.09%). Moreover, we observed an 81 ± 8.49% reduction in total AGEs. The inhibition of individual AGE (argpyrimidine, vesper lysine, and pentosidine) was ~80%. The decrease in the protein aggregation was observed with Congo red (46.88 ± 0.078%) and the Thioflavin T (31.25 ± 1.18%) methods in the presence of Stevia leaf extract. The repercussion of Stevia leaf extract on DNA glycation was examined using agarose gel electrophoresis, wherein the DNA damage was reversed in the presence of 1 mg/mL of leaf extract. When the HDF cell line was treated with 0.5 mg/mL of extract, the viability of cells decreased by only ~20% along with the same cytokine IL-10 production, and glucose uptake decreased by 28 ± 1.90% compared to the control. In conclusion, Stevia extract emerges as a promising natural agent for mitigating glycation-associated challenges, holding potential for novel therapeutic interventions and enhanced management of its related conditions.

The Effect of Lower Limb Combined Neuromuscular Electrical Stimulation on Skeletal Muscle Signaling for Glucose Utilization, Myofiber Distribution, and Metabolic Function after Spinal Cord Injury.

Maintaining healthy myofiber type and metabolic function early after spinal cord injury (SCI) may prevent chronic metabolic disorders. This study compares the effects of a 2-5 week combined (aerobic + resistance) neuromuscular electrical stimulation (Comb-NMES) regimen versus a sham control treatment on muscle protein signaling for glucose uptake, myofiber type distribution, and metabolic function. Twenty participants (31 ± 9 years of age) with an SCI (C4-L1, AIS level A-C) within 14 days of the SCI were randomly assigned to control (N = 8) or Comb-NMES (N = 12). Sessions were given three times per week. Fasting blood samples and vastus lateralis muscle biopsies were collected 24-48 h before or after the last session. Western blots were performed to quantify proteins, immunohistochemical analyses determined muscle myofiber distribution, and enzymatic assays were performed to measure serum glucose, insulin, and lipids. Our main findings include a decrease in fasting glucose (p < 0.05) and LDL-C (p < 0.05) levels, an upregulation of CamKII and Hexokinase (p < 0.05), and an increase in type I (+9%) and a decrease in type IIx (-36%) myofiber distribution in response to Comb-NMES. Our findings suggest that maintaining healthy myofiber type and metabolic function may be achieved via early utilization of Comb-NMES.

Selenium nanoparticles improve fish sperm quality by enhancing glucose uptake capacity via AMPK activation.

Appropriate additives can provide a suitable physiological environment for storage of fish sperm and facilitate the large-scale breeding of endangered species and commercial fish. Suitable additives for fish sperm storage in vitro are required for artificial insemination. This study evaluate the effects of 0.1, 0.5, 1.5, and 4.5 mg/L selenium nanoparticles (SeNPs) on the quality of Schizothorax prenanti and Onychostoma macrolepis sperm storage in vitro at 4 °C for 72 h. We found that 0.5 mg/L SeNPs was a suitable concentration for maintaining the normal physiological state of O. macrolepis sperm during storage at 4 °C (p < 0.05). Higher adenosine triphosphate (ATP) content of O. macrolepis sperm before and after activation was present at that concentration. To further explore the potential mechanism of action of SeNPs on O. macrolepis sperm, western blotting and glucose uptake analyses were performed. The results implied that after 24 h of in vitro preservation, 0.5 mg/L SeNPs significantly improved p-AMPK levels and glucose uptake capacity of O. macrolepis sperm, while compound C (CC), the inhibitor of activated AMP-activated protein kinase (p-AMPK), significantly restricted the function of SeNPs on stored sperm. Similar effects of 0.5 mg/L SeNPs were found on Schizothorax prenanti sperm. Our study demonstrates that SeNPs maintained ATP content and O. macrolepis and Schizothorax prenanti sperm function during storage in vitro for 72 h, possibly because SeNPs enhanced the glucose uptake capacity of sperm by maintaining the level of p-AMPK.

Antihyperglycemic Properties of Extracts and Isolated Compounds from Australian Acacia saligna on 3T3-L1 Adipocytes.

Our early work indicated that methanolic extracts from the flowers, leaves, bark, and isolated compounds of Acacia saligna exhibited significant antioxidant activities in vitro. The overproduction of reactive oxygen species (ROS) in the mitochondria (mt-ROS) interfered with glucose uptake, metabolism, and its AMPK-dependent pathway, contributing to hyperglycemia and diabetes. This study aimed to screen the ability of these extracts and isolated compounds to attenuate the production of ROS and maintain mitochondrial function via the restoration of mitochondrial membrane potential (MMP) in 3T3-L1 adipocytes. Downstream effects were investigated via an immunoblot analysis of the AMPK signalling pathway and glucose uptake assays. All methanolic extracts effectively reduced cellular ROS and mt-ROS levels, restored the MMP, activated AMPK-α, and enhanced cellular glucose uptake. At 10 µM, (-)-epicatechin-6 (from methanolic leaf and bark extracts) markedly reduced ROS and mt-ROS levels by almost 30% and 50%, respectively, with an MMP potential ratio 2.2-fold higher compared to the vehicle control. (-)-Epicatechin 6 increased the phosphorylation of AMPK-α by 43%, with an 88% higher glucose uptake than the control. Other isolated compounds include naringenin 1, naringenin-7-O-α-L-arabinopyranoside 2, isosalipurposide 3, D-(+)-pinitol 5a, and (-)-pinitol 5b, which also performed relatively well across all assays. Australian A. saligna active extracts and compounds can reduce ROS oxidative stress, improve mitochondrial function, and enhance glucose uptake through AMPK-α activation in adipocytes, supporting its potential antidiabetic application.

Juniper Berries Regulate Diabetes and Obesity Markers Through Modulating PPARα, PPARγ, and LXR: In Vitro and In Vivo Effects.

The berries of Juniperus communis have been traditionally used for therapeutic purposes. They have been reported to possess various pharmacological effects such as anti-inflammatory, hypoglycemic and hypolipidemic activities. In this study, a methanolic extract of J. communis berries (JB) was evaluated for its effects on peroxisome proliferator-activated receptors alpha and gamma (PPARα and PPARγ), liver X receptor (LXR), glucose uptake and lipid accumulation using various cellular systems. At a concentration of 25 µg/mL, JB caused 3.77-fold activation of PPARα, 10.90-fold activation of PPARγ, and 4.43-fold activation of LXR in hepatic cells. JB inhibited (11%) the adipogenic effect induced by rosiglitazone in adipocytes and increased glucose uptake (90%) in muscle cells. In high-fat diet (HFD) fed mice, JB at a dose of 25 mg/kg body weight exhibited a 21% decrease in body weight. Fasting glucose levels in mice treated with 12.5 mg/kg of JB were significantly decreased (39%) indicating its efficacy in regulating hyperglycemia and obesity induced by HFD thus ameliorating the symptoms of type 2 diabetes. A series of energy metabolic genes, including Sirt1 (2.00-fold) and RAF1 (2.04-fold), were upregulated by JB, while rosiglitazone regulated the hepatic PPARγ only. Phytochemical analysis of JB indicated presence of a number of flavonoids and biflavonoids which seem to be responsible for the observed activity. It was concluded that JB acted as a multiple agonist of PPARα, PPARγ and LXR without the undesired effect of adipogenesis and exhibited the property of enhancing glucose uptake. The regulation of PPARα, PPARγ and LXR seems to be through Sirt1 and RAF1. In vivo results confirmed the antidiabetic and antiobesity potential of JB and indicated its utility in metabolic disorder and type 2 diabetes.

Polyphenolic compounds of Phyllanthus amarus Schum & Thonn. (1827) and diabetes-related activity of an aqueous extract as affected by in vitro gastrointestinal digestion.

ETHNOPHARMACOLOGICAL RELEVANCE: Extracts of the aerial part of Phyllanthus amarus have been extensively used in several countries to cure diabetes. No data is available on the impact of gastrointestinal digestion of such crude extracts on their antidiabetic activity. AIM OF THE STUDY: The aim of this study was to identify active fractions and compounds of fresh aerial parts of P. amarus extracted by an infusion method that are responsible for antidiabetic effects occurring at the level of glucose homeostasis. MATERIALS AND METHODS: An aqueous extract was obtained by an infusion method and its polyphenolic composition was analysed by reverse phase UPLC-DAD-MS. The influence of in vitro gastrointestinal digestion was evaluated both on the chemical composition and on the antidiabetic effect of P. amarus infusion extract using glucose-6-phosphatase enzyme inhibition and stimulation of glucose uptake. RESULTS: Analysis of the chemical composition of the crude extract revealed the presence of polysaccharides and various families of polyphenols such as phenolic acids, tannins, flavonoids and lignans. After simulated digestion, the total content of polyphenols decreased by about 95%. Caffeoylglucaric acid derivates and lignans exhibited strong stimulation of glucose uptake similar to metformin with an increase of 35.62 ± 6.14% and 34.74 ± 5.33% respectively. Moreover, corilagin, geraniin, the enriched polysaccharides fraction and the bioaccessible fraction showed strong anti-hyperglycemic activity with about 39-62% of glucose-6-phosphatase inhibition. CONCLUSION: Caffeoylglucaric acid isomers, tannin acalyphidin M1 and lignan demethyleneniranthin were reported for the first time in the species. After in vitro gastroinstestinal digestion, the composition of the extract changed. The dialyzed fraction showed strong glucose-6-phosphatase inhibition.

HM-chromanone from Portulaca oleracea L. inhibits protein tyrosine phosphatase 1B and mitigates glucose production in insulin-resistant HepG2 cells.

This study aimed to identify the effect of (E)-5-hydroxy-7-methoxy-3-(2'-hydroxybenzyl)-4-chromanone (HM-chromanone), isolated from Portulaca oleracea L., on tyrosine phosphatase 1B (PTP1B) and glucose production in insulin-resistant HepG2 cells. The results revealed that HM-chromanone significantly decreases PTP1B expression and glucose production in insulin-resistant HepG2 cells. Furthermore, a molecular docking stimulation showed HM-chromanone inhibits PTP1B by binding to its active site. Additionally, HM-chromanone was found to significantly modulate insulin receptor substrate-1 (IRS1) by decreasing phosphorylated serine 307 and increasing phosphorylated tyrosine 612 and activating phosphatidylinositol 3-kinase (PI3K) in insulin-resistant HepG2 cells. Furthermore, HM-chromanone augmented the phosphorylation of Akt and forkhead box protein O1 in insulin-resistant HepG2 cells in a dose-dependent manner at the concentrations of 15-60 µM. Additionally, it significantly reduced the expression of glucose 6-phosphatase and phosphoenolpyruvate carboxykinase, which are main enzymes included in hepatic gluconeogenesis. Consequently, HM-chromanone was confirmed to significantly decrease glucose production and increase glucose uptake in insulin-resistant HepG2 cells.

Uses of Papaya Leaf and Seaweed Supplementations for Controlling Glucose Homeostasis in Diabetes.

Studies from laboratory animal models and complementary medical practices have implied that nutrients from special plants or herbs contain antidiabetic, antioxidant, anti-obese, anti-hypertensive, and anti-inflammatory properties. Seaweed and tropical papaya, which are widely available in Asian and Pacific countries, have been used as home remedies for centuries. The bioactive extracts from these plants contain vitamins A, C, B and E complexes, as well as polysaccharides, phenolic compounds, essential fatty acids, flavonoids, saponins, fucoidan, and phlorotannin. In this review, the authors examine the pathogenesis of diabetes characterized by hyperglycemia due to the dysregulation of glucose homeostasis, antidiabetic/antihyperglycemic seaweed or/and papaya derived bioactive phytochemicals and their proposed mechanisms of action in the management of Type 2 Diabetes Mellitus (T2DM). The authors also propose combining papaya and seaweed to enhance their antidiabetic effects, leveraging the advantages of herb-to-herb combination. Papaya and seaweed have demonstrated antidiabetic effects through in vitro assays, cellular models, and animal studies despite the limited clinical trials. Nutraceuticals with antidiabetic effects, such as secondary metabolites isolated from seaweed and papaya, could be combined for a synergistic effect on T2DM management. However, the application of these compounds in their purified or mixed forms require further scientific studies to evaluate their efficacy against diabetes-related complications, such as hyperlipidemia, elevated free radicals, pro-inflammatory molecules, insulin insensitivity, and the degeneration of pancreatic beta cells.

Characterization of Green and Yellow Papaya (Carica papaya) for Anti-Diabetic Activity in Liver and Myoblast Cells and Wound-Healing Activity in Fibroblast Cells.

Obesity and diabetes, often characterized as "metabolic syndrome", have been recognized as two of the most important public health issues worldwide. The objective of the present research was to evaluate green and yellow papaya for anti-oxidation and anti-diabetic properties. Leaves, skin, pulp, and seed samples from papayas were freeze-dried and then extracted in water or 80% methanol. The extracts were used to determine total polyphenolic content and anti-oxidation activities, and to determine biological activities, including glucose uptake, Glut-2 expression, triglyceride reduction, and wound-healing activity. Our data demonstrated that methanol and water extracts of green and yellow papaya have similar concentrations of polyphenols in skin (10-20 mg/g dry powder), leaf (25-30 mg/g dry powder), and pulp (1-3 mg/g dry powder) fractions. However, both methanol and water extracts of seeds from yellow papaya have substantially higher concentrations of polyphenols compared to green papaya. Both water and methanol extracts of yellow papaya exhibited higher anti-oxidation activity compared to green papaya in skin (50-60%), pulp (200-300%), and seeds (10-800%). Old leaves also showed greater anti-oxidation activity (30-40%) compared to new leaves. Pulp extracts from both yellow and green papaya stimulated greater glucose uptake, but only pulp from green papaya stimulated glucose uptake in muscle cells. Similarly, pulp extract stimulated glucose transporter Glut-2 expression in liver cells. The skin, pulp, and seeds of green or yellow papaya showed triglyceride-lowering activity in liver cells by 60-80%, but samples taken from yellow papaya had a more potent effect. Seeds from both green and yellow papaya significantly stimulated the migration of fibroblasts in the wounded area by 2-2.5-fold compared to the untreated control. Consistent with these data, seeds from both green and yellow papaya also significantly stimulated collagen synthesis in fibroblast cells by almost 3-fold. In conclusion, our data indicate that different parts of papaya produce stimulatory effects on glucose uptake, Glut-2 expression, TG reduction, and wound-healing activities. This study concludes that different parts of the papaya can be beneficial for preventing diabetes and diabetes-related wound healing.

Polyacetylenes from the adventitious roots of Centella asiatica with glucose uptake stimulatory activity.

Centella asiatica (L.) Urban is an herbaceous perennial plant of the Apiaceae family that has diverse medicinal uses. Its active components are saponin, phenolics, and polyacetylenes. Plant cell cultures have been exploited for the efficient production of metabolites with pharmacological activity. In this work, we prepared adventitious root cultures of C. asiatica and analyzed their content and biological activity. Adventitious root extracts were found to increase glucose uptake by differentiated L6 skeletal muscle cells and to be more efficient than the extract of whole plants. Chromatographic fractionation of the extracts from adventitious roots of C. asiatica led to the isolation of two known polyacetylenes, araliadiol (1) and 8-acetoxy-1,9-pentadecadiene-4,6-diyn-3-ol (2), in addition to a new polyacetylene, which we have named centellidiol (3). All the three polyacetylenes stimulated glucose uptake in a dose-dependent manner. The methanol extract of adventitious roots contained 0.53% and 0.82% of compounds 1 and 2, respectively, which are values that were 15 and 21 times higher that are found in mother plants. We therefore suggest that the high content of these polyacetylenes contributes to the high efficacy of C. asiatica adventitious root cultures. Overall, adventitious root cultures of C. asiatica can be part of a secure supply of effective ingredients including polyacetylenes.

The potential antidiabetic properties of green and purple tea [Camellia sinensis (L.) O Kuntze], purple tea ellagitannins, and urolithins.

ETHNOPHARMACOLOGICAL RELEVANCE: Tea (Camellia sinensis) has been consumed for centuries as traditional medicine for various diseases, including diabetes. The mechanism of action of many traditional medicines, including tea, often requires elucidation. Purple tea is a natural mutant of Camellia sinensis, grown in China and Kenya, and is rich in anthocyanins and ellagitannins. AIM OF THE STUDY: Here we aimed to determine whether commercial green and purple teas are a source of ellagitannins and whether green and purple teas, purple tea ellagitannins and their metabolites urolithins have antidiabetic activity. MATERIALS AND METHODS: Targeted UPLC-MS/MS was employed to quantify the ellagitannins corilagin, strictinin and tellimagrandin I, in commercial teas. The inhibitory effect of commercial green and purple teas and purple tea ellagitannins was evaluated on α-glucosidase and α-amylase. The bioavailable urolithins were then investigated for additional antidiabetic effects, by evaluating their effect on cellular glucose uptake and lipid accumulation. RESULTS: Corilagin, strictinin and tellimagrandin I (ellagitannins) were identified as potent inhibitors of α-amylase and α-glucosidase, with Ki values significantly lower (p < 0.05) than acarbose. Commercial green-purple teas were identified as ellagitannin sources, with especially high concentrations of corilagin. These commercial purple teas, containing ellagitannins, were identified as potent α-glucosidase inhibitors with IC50 values significantly lower (p < 0.05) than green teas and acarbose. Urolithin A and urolithin B were as effective (p> 0.05) as metformin in increasing glucose uptake in adipocytes, muscle cells and hepatocytes. In addition, similar (p > 0.05) to metformin, both urolithin A and urolithin B reduced lipid accumulation in adipocytes and hepatocytes. CONCLUSIONS: This study identified green-purple teas as an affordable widely available natural source with antidiabetic properties. Furthermore, additional antidiabetic effects of purple tea ellagitannins (corilagin, strictinin and tellimagrandin I) and urolithins were identified.

The standardized Jamu pahitan, an Indonesian antidiabetic formulation, stimulating the glucose uptake and insulin secretion in the in-vitro models.

Jamu pahitan is a polyherbal formulation commonly used for the traditional management of diabetes in Indonesia and is mainly prepared from Andrographis paniculata (Burm.f.) Nees. It is widely varied in herbal composition for every region has their own plant component addition to the formulation. A version of the formulation used in the greater Surakarta area contained five plant constituents. This study evaluated the in-vitro glucose uptake and insulin secretion stimulatory activities of Jamu pahitan to provide scientific evidence on its efficacy and safety of use. The water and ethanol extracts of three Jamu pahitan formulations were prepared. The total phenolic content (TPC) of the extracts was evaluated by the standard Folin-Ciocalteau method. Their effects on the viability of L6 skeletal muscle and RIN-m5F pancreatic cells were evaluated by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The glucose utilized by L6 myotubes treated with Jamu pahitan was assessed indirectly by the glucose oxidase method. The insulin secreted by RIN-m5F treated with the formulation extracts was analyzed by the enzyme-linked immunosorbent assay (ELISA). The correlation between TPC and the profile of safety and efficacy of the formulation was statistically evaluated. The water extracts of Jamu pahitan were safe and exerted significant glucose uptake and insulin secretion stimulatory activity in L6 and RIN-m5F, respectively. The ethanol extracts showed more potent effects than their water counterpart, albeit they exerted cytotoxic effects on the cells at the higher tested concentrations. The formulations at lower concentrations stimulated the proliferation of RIN-m5F. In addition, the TPC was strongly correlated with the glucose uptake and insulin secretion stimulatory activities and also the IC50 of the cells in positive manner. The present study supported the use of Jamu pahitan for the traditional management of diabetes in Indonesia by stimulating glucose uptake in the muscle cells and improving insulin secretion in ß-cells.

Long-term dietary folic acid supplementation attenuated aging-induced hippocampus atrophy and promoted glucose uptake in 25-month-old rats with cognitive decline.

The brain has high energy demand making it sensitive to changes in energy fuel supply. Aging shrinks brain volume, decreases glucose uptake availability of the brain, and finally, causes cognitive dysfunction. Folic acid supplementation delayed cognitive decline and neurodegeneration. However, whether folic acid affects brain energy metabolism and structural changes is unclear. The study aimed to determine if long-term dietary folic acid supplementation could alleviate age-related cognitive decline by attenuating hippocampus atrophy and promoting brain glucose uptake in Sprague-Dawley (SD) rats. According to folic acid levels in diet, 3-months old male SD rats were randomly divided into four intervention groups for 22 months in equal numbers: folic acid-deficient diet (FA-D) group, folic acid-normal diet (FA-N) group, low folic acid-supplemented diet (FA-L) group, and high folic acid-supplemented diet (FA-H) group. The results showed that serum folate concentrations decreased and serum homocysteine (Hcy) concentrations increased with age, and dietary folic acid supplementation increased serum folate concentrations and decreased Hcy concentrations at 11, 18, and 22 months of intervention. Dietary folic acid supplementation attenuated aging-induced hippocampus atrophy, which was showed by higher fractional anisotropy and lower mean diffusivity in the hippocampus, increased brain 18F-Fluorodeoxyglucose (18F-FDG) uptake, then stimulated neuronal survival, and alleviated age-related cognitive decline in SD rats. In conclusion, long-term dietary folic acid supplementation alleviated age-related cognitive decline by attenuating hippocampus atrophy and promoting brain glucose uptake in SD rats.

Antioxidant, Anti-Inflammatory and Anti-Diabetic Activities of Tectona grandis Methanolic Extracts, Fractions, and Isolated Compounds.

Tectona grandis is a traditional Dai medicine plant belonging to the Lamiaceae family, which can be used to treat malaria, inflammation, diabetes, liver disease, bronchitis, tumors, cholelithiasis, jaundice, skin disease and as an anti-helminthic. To find more novel therapeutic agents contained in this medicinal plant, the antioxidant, anti-inflammatory and anti-diabetic activities of T. grandis methanolic extract, fractions and compounds were evaluated. In this study, 26 compounds were isolated from the leaves and branches of T. grandis. Their structures were identified based on extensive spectral experiments, including NMR, ESI-MS and comparison with published spectral data. Among them, compounds 1-2, 4-6, 9-14 and 16-22 were reported for the first time for this plant. The antioxidant activity screening results showed that compounds 5, 15 and 23 had potent antioxidant capacities, with SC50 values from 0.32 to 9.92 µmol/L, 0.92 to 1.10 mmol Trolox/L and 1.02 to 1.22 mmol Trolox/L for DPPH, ABTS and FRAP, respectively. In addition, their anti-inflammatory effects were investigated by releasing TNF-α, IL-1ß and IL-6 through the use of mouse monocytic macrophages (RAW 264.7). Compounds 1, 13, 18 and 23 had the effects of reducing the expression of inflammatory factors. Compounds 13 and 18 were reported for the first time for their anti-inflammatory activities. Furthermore, the methanolic extract (ME), petroleum ether extract (PEE) and EtOAc extract (EAE) of T. grandis showed significant glucose uptake activities; compounds 21 and 23 significantly promoted glucose uptake of 3T3-L1 adipocytes at 40 µM. Meanwhile, compounds 4, 5 and 7 showed significant inhibitory activities against α-glucosidase, with IC50 values of 14.16 ± 0.34 µmol/L, 19.29 ± 0.26 µmol/L and 3.04 ± 0.08 µmol/L, respectively. Compounds 4 and 5 were reported for the first time for their α-glucosidase inhibitory activities. Our investigation explored the possible therapeutic material basis of T. grandis to prevent oxidative stress and related diseases, especially inflammation and diabetes.