Drug Metformin Research Articles

Isoliquiritigenin Protects Against Diabetic Nephropathy in db/db Mice by Inhibiting Advanced Glycation End Product-Receptor for Advanced Glycation End Product Axis.

Diabetes nephropathy (DN) is a severe diabetic chronic microvascular complication and the major cause of end-stage renal disease (ESRD). Our study aimed to investigate the effects of isoliquiritigenin (ISL) a natural flavonoid compound on DN and to explore the underlying mechanisms. The db/db mice were received intragastric treatments of ISL (5, 10, or 20 mg/kg), vehicle or positive drug metformin (300 mg/kg) once a day for 12 weeks, and the db/m mice treated with vehicle were used as controls. ISL significantly ameliorated pathological changes and functional injury in the kidneys of db/db mice in a dose-dependent manner. The administration of 20 mg/kg ISL reduced the levels of serum creatinine (Scr; 49.0 ± 1.7 vs. 56.9 ± 2.9 μmol/L; p < 0.01), blood urine nitrogen (BUN; 9.6 ± 1.3 vs. 12.0 ± 1.1 mmol/L; p < 0.05), albumin to creatinine ratio (ACR; 1925.8 ± 798.1 vs. 4269.4 ± 925.6 μg/mg; p < 0.01) and urinary albumin (276.2 ± 39.9 vs. 576.9 ± 108.9 μg; p < 0.05). Further study identified advanced glycation end product (AGE)-receptor for AGE (RAGE) axis as a target of ISL. ISL (20 mg/kg) lowered renal AGE level (2.5 ± 0.5 vs. 3.8 ± 0.6 μg/mg; p < 0.01) and RAGE expression, leading to improvements in renal fibrosis, oxidative stress, and inflammation. To sum up, our study demonstrated that ISL displayed preventive effects on the experimental model of DN through suppressing AGE-RAGE pathway, and provided some insights into the application of ISL in DN treatment.

Effect of Metformin usage on Vitamin B12 deficiency in patients with Type 2 Diabetes Mellitus

Metformin is the most commonly used drug in antihyperglycemic treatment in patients with type 2 diabetes mellitus (T2 DM). In recent years, there have been many studies reporting B12 deficiency in diabetic individuals using metformin drug. This study evaluates B12 deficiency in individuals with T2 DM diagnosis using metformin in our hospital. This study is a cross-sectional and descriptive research. In this study, the data of 786 patients who applied to the Mugla Education and Research Hospital Internal Medicine outpatient clinic with T2DM diagnosis and used metformin between January 01, 2018 and March 01, 2019 were evaluated. Demographic data, vitamin B12, HbA1c levels of the patients were obtained retrospectively from the hospital information system records. Patients with missing data were excluded from the study.347 (44.1%) male and 439 (55.9%) female patients were included in the study. Metformin dose of 248 (31.6%) of the patients was 1000 mg or less, 123 (15.6%) was 1700 mg, 414 (52.8%) was 2000 mg or more. According to the distribution of medication use, 161 (20.5%) patients were receiving metformin only, 322 (41%) patients were receiving metformin + other oral antidiabetic agents (OAD), and 303 (38.5%) patients were receiving metformin + insulin treatment. Vitamin B12 deficiency (57.8%) was higher in patients aged 60 years old and was over who used metformin (p&lt;0.001). 347 (44.1%) of the patients included in the study received vitamin B12 replacement. We detected serious B12 deficiency in patients with T2DM who used metformin, especially in patients aged over 60 years old. Therefore, we emphasize the importance to monitor vitamin B12 levels in patients who are started on metformin and to perform B12 replacement in patients who are found to be deficient.

Repurposing of Metabolic Drugs Metformin and Simvastatin as an Emerging Class of Cancer Therapeutics.

Metabolic alterations are commonly associated with various cancers and are recognized as contributing factors to cancer progression, invasion, and metastasis. Drug repurposing, a strategy in drug discovery, utilizes existing knowledge to recommend established drugs for new indications based on clinical data or biological evidence. This approach is considered a less risky alternative to traditional drug development. Metformin, a biguanide, is a product of Galega officinalis (French lilac) primarily prescribed for managing type 2 diabetes, is recognized for its ability to reduce hepatic glucose production and enhance insulin sensitivity, particularly in peripheral tissues such as muscle. It also improves glucose uptake and utilization while decreasing intestinal glucose absorption. Statins, first isolated from the fungus Penicillium citrinum is another class of medication mainly used to lower cholesterol levels in individuals at risk for cardiovascular diseases, work by inhibiting the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which is essential for cholesterol biosynthesis in the liver. Metformin is frequently used in conjunction with statins to investigate their potential synergistic effects. Combination of metformin and simvastatin has gathered much attention in cancer research because of its potential advantages for cancer prevention and treatment. In this review, we analyze the effects of metformin and simvastatin, both individually and in combination, on key cancer hallmarks, and how this combination affects the expression of biomolecules and associated signaling pathways. We also summarize preclinical research, including clinical trials, on the efficacy, safety, and potential applications of repurposing metformin and simvastatin for cancer therapy.

Optimization of the extraction methods and evaluation of the hypoglycemic effect of Adhatoda Zeylanica extracts on artificially induced diabetic mice.

Synthetic antidiabetic drugs are often associated with various adverse side effects, including hypoglycemia, nausea, gastrointestinal disturbances, headaches, and even liver damage. In contrast, plant-derived natural antidiabetic bioactive compounds typically exhibit lower toxicity and fewer side effects and have been reported to aid effectively in diabetes management. These plant extracts regulate diabetes by restoring pancreatic function, enhancing insulin secretion, inhibiting intestinal glucose absorption, and facilitating insulin dependent metabolism. This study explored four extraction methods, including reflux distillation (RD), ultrasound assisted extraction (UAE), microwave assisted extraction (MAE), and enzyme assisted extraction (EAE) to optimize the yield of crude leaf extract and vasicine from Adhatoda zeylanica. RD produced the highest crude extract yield (98.29g/kg of dried leaf), while MAE was the most effective for vasicine extraction, yielding 2.44g vasicine per kg dried leaf. High Performance Liquid Chromatography (HPLC) with a diode array detector (DAD) was used to identify and quantify vasicine, a quinazoline alkaloid with known antidiabetic properties. The hypoglycemic effects of leaf extracts were evaluated in alloxan-induced diabetic mice, and the effect of A. zeylanica extract was compared to the extracts of Centella asiatica, Allamanda cathartica, and the standard drug metformin. At a dose of 400mg/kg body weight (BW), methanolic leaf extracts of A. zeylanica, C. asiatica, and A. cathartica reduced blood glucose level by 78.95%, 74.50%, and 70.19%, respectively, compared to the standard drug metformin, which reduced blood glucose levels by 85.84%. A. zeylanica at 400mg/kg BW dose and metformin demonstrated statistically similar and significant blood glucose level reduction (p<0.001). Additionally, therapeutic doses of A. zeylanica leaf extract exhibited low cytotoxicity (cell survival rate >89%), highlighting its potential as a safe and effective source of antidiabetic agent.

Picrotoxane-type sesquiterpenoids from Dendrobium improve insulin resistance and increase glucose-stimulated insulin secretion.

Twelve picrotoxane-type sesquiterpenoids were isolated from Dendrobium wardianum, of which dendrowardins K-N (1-4) are new compounds and dendrowardins O and P (9, 10) are new natural products. Notably, the structure of dendrowardin K contains the rarely observed 10,11-γ-lactone ring. The structural configurations of these compounds were determined through comprehensive 1D and 2D nuclear magnetic resonance (NMR), single-crystal X-ray diffraction, and other spectroscopic analyses. Additionally, the hypoglycaemic activities of the picrotoxane-type sesquiterpenes and their analogues were systematically evaluated by determining the antidiabetic activities of these compounds and six others (13-18) obtained from genus Dendrobium. Twelve compounds (1, 2, 4-6, 8, 12, 13- 15, 17, and 18) significantly improved insulin resistance. Further experiments revealed that compound 6 improved insulin resistance by increasing GLUT-4 expression. The possible mechanism is related to AKT-related pathways, and the effects of treatment with 50μM compound 6 were comparable to those of the positive control drug metformin. Compounds 4-6 and 13-15, 17 displayed great increases in the secretion of insulin from β-TC-6 cells. On the basis of these findings, the structure-activity relationships (SARs) of picrotoxane-type sesquiterpenoids were discussed for the first time.

Metformin-loaded nanoparticles reduce hyperglycemia-associated oxidative stress and induce eNOS phosphorylation in vascular endothelial cells

Diabetes mellitus is a chronic disease characterized by metabolic defects, including insulin deficiency and resistance. Individuals with diabetes are at increased risk of developing cardiovascular complications, such as atherosclerosis, coronary artery disease, and hypertension. Conventional treatment methods, though effective, are often challenging, costly, and may lead to systemic side effects. This study explores the potential of nanomedicine applications, specifically Metal–Organic Frameworks (MOFs), as drug carriers to overcome these limitations. The Materials Institute Lavoisier-89 nanoparticles (nanoMIL-89) have previously demonstrated promise as a drug delivery vehicle for chronic diseases due to their anti-oxidant and cardio-protective properties. In this investigation, nanoMIL-89 was loaded with the anti-diabetic drug metformin (MET), creating MET@nanoMIL-89 formulation. We examined the drug release kinetics of MET@nanoMIL-89 over 96 h and assessed its impact on the viability of various endothelial cells. Furthermore, we investigated the nanoformulation effect on the inflammatory marker CXCL8 in these cells and explored its influence on phosphorylated eNOS, total eNOS, and AKT levels. Our findings indicate that nanoMIL-89 effectively released metformin over 96 h and caused a concentration-dependent reduction in CXCL8 release from endothelial cells. Notably, MET@nanoMIL-89 reduced dihydroethidium levels and increased phosphorylated eNOS, total eNOS, and AKT levels. Our results underscore the potential of nanoMIL-89 as a versatile potential drug delivery platform for anti-diabetic drugs, offering a prospective therapeutic approach for diabetic patients with associated cardiovascular complications.

Antioxidant, Alpha-Amylase Inhibitory and Hypoglycemic Activity of Smallanthus sonchifolius Leaves from Nepal: An Integrated InVitro, InVivo, and In Silico Approach.

In 2019, diabetes mellitus affected 9.3% of the global population and accounted for one in nine adult deaths. Plant-based antioxidants neutralize harmful free radicals, mitigate oxidative stress, and significantly prevent diabetes and its complications. This study evaluated the invitro antioxidant, alpha-amylase inhibitory, invivo oral hypoglycemic, and in silico antidiabetic potential of Smallanthus sonchifolius (S. sonchifolius) leaf extract. Mice (n = 25) were divided into five groups after a 16-h fast with access to water. The groups received distilled water (normal control), metformin (100 mg/kg, standard), or S. sonchifolius ethanolic extract at 100, 250, or 500 mg/kg to compare the antidiabetic potential of the extract with that of the control. Fasting blood glucose levels were measured in tail vein blood before the experiment and at 30, 60, and 120 min post-administration to evaluate the hypoglycemic activity of the extract and standard drug. The ethanolic extract exhibited dose-dependent alpha-amylase inhibition (IC50 value 0.136 mg/mL) and significant hypoglycemic effects, reducing blood glucose levels similar to those of the standard drugs voglibose and metformin. The maximum blood glucose reduction was 17.99% and 15.74% in the normal and glucose-loaded mice, respectively, at 500 mg/kg within 120 min. In silico analysis shows, polymatin B and chlorogenic acid demonstrating the highest binding affinity of -8.2 and -7.2 kcal/mol, respectively, in PPAR-γ (3G9E). Polymatin B and chlorogenic acid showed strong binding affinities of -7.3 and -7.5 kcal/mol, respectively, in alpha-amylase (4W93). These findings indicate that S. sonchifolius possesses significant hypoglycemic and antioxidant properties, suggesting its potential as an antidiabetic agent, warranting further clinical research.

Metformin ameliorates diabetes-induced hepatic ultrastructural damage and the immune biomarker CD86 and inflammation in rats

ABSTRACT Diabetes is a known inducer of hepatic ultrastructural alterations, and the expression of the immune biomarker that involves in T-cell immunity, cluster of differentiation 86 (CD86) is increased in diabetic patients with liver cirrhosis. The antidiabetic drug metformin has not previously been used to protect against type 2 diabetes mellitus (T2DM)-induced alternations in hepatic ultrastructure and the induction of the hepatic CD86/inflammation axis in diabetic animal models induced by streptozotocin and a high fat diet. To test our hypotheses, T2DM was induced in rats (model group) and the protective animals were treated with the antidiabetic drug metformin (200 mg/kg) until being sacrificed at week 12. A profound ultrastructural damage to the hepatocytes and liver tissue injury was induced by T2DM as demonstrated by hepatocytes with dark shrunken irregular nuclei, rarefied cytoplasm with lipid droplets, mitochondria with disrupted cristae, as well as depletion of glycogen granules and damaged of liver architecture, which were effectively (p < .0001) protected with metformin. Metformin also suppressed diabetes-induced hepatic gene expression of CD86 and inflammation as well as glycemia and liver injury markers. Furthermore, a significant correlation between hepatocyte damage and CD86, inflammation, glycemia, and biomarkers of liver injury was observed. These findings demonstrate that diabetes is associated with the induction of the hepatic CD86/inflammation axis and hepatocyte ultrastructural alterations while being protected by metformin.

Network Pharmacology and Optimization of β-Sitosterol-Loaded Solid Lipid Nanoparticles Using Box-Behnken Design for Enhanced Solubility and Sustained Drug Release in Diabetes.

The pharmaceutical industry has paid a lot of attention to solid lipid nanoparticles (SLN) because they show promising drug delivery vehicles. This work aimed to design and optimize the SLN of β-sitosterol, a hydrophobic drug, to improve solubility and sustained action. An ultrasonication technique after melting was used to design SLN using a randomized response surface Box-Behnken design (BBD). Network pharmacology analysis was performed to explore the interactions between genes. According to the findings, Compritol ATO 888 was the most soluble at a drug: lipid ratio of 1:3. Particle size, PDI, zeta, and entrapment efficiency (EE) were observed as 168.83nm, 0.231 -28.9 Mv, and 68.29%, respectively. The optimized formulation did not undergo any chemical changes, as depicted through DSC. The in vitro drug release investigation showed that the SLN released the drug continuously for 28 hours. Scanning Electron Microscopy (SEM) revealed homogenous, spherical particles. The antidiabetic potential of the formulation was assessed through the potential of glucose uptake by yeast, and the α-amylase inhibitory assay revealed its significant antidiabetic potential when compared with that of the standard drug metformin. The network pharmacology of β-sitosterol demonstrated gene interaction with hexokinase, phosphoglucomutases, glucose-6-phosphate dehydrogenase, hexose-6-phosphate dehydrogenase, and glutathione disulfide reductase. The β-sitosterol-loaded SLN generated by BBD was found to be a potential method for improving drug solubility with sustained drug release and was found to be long-term storage stable.

Efficacy of red algae and artichoke extracts in disrupting antioxidant/PI3K/RBP-4 pathway in high-fat diet-induced metabolic disorders in rats

BackgroundInsulin resistance (IR) leads to various metabolic abnormalities, including diabetes mellitus, obesity, nonalcoholic steatohepatitis, and neurodegenerative disorders. Natural products rich in nontoxic phytochemicals are cost-effective and widely used to manage insulin resistance, reducing drug interactions. Artichoke stems and red algae contain several phytochemical compounds that exert antioxidant and anti-inflammatory effects.AimThis study aims to explore and compare the preventive and therapeutic effects of red algae and artichoke stem extracts against high-fat diet-induced insulin resistance and then compare their impacts with those of the reference drug metformin, which is commonly used for treating type 2 diabetes.MethodsThe animals were fed a high-fat diet for eight weeks to induce insulin resistance. The plants were then treated orally with 100 mg/kg body weight red algae, artichoke extracts, or metformin per day for 14 days. The protective rat groups received the extracts at the same dose for 14 days before being fed the high-fat diet for eight weeks. Commercial kits and standardized methods were used to measure blood diabetic profiles (glucose, insulin, lipid profile, fructosamine, and retinol-binding protein-4 (RBP-4)) and liver oxidative stress parameters, nuclear factor-κβ (NF-κβ), peroxisome proliferator-activated receptor gamma (PPAR-γ), phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K), retinol-binding protein-4 (RBP-4), and phosphatase and tensin homolog (PTEN).ResultsOur results showed that both extracts inhibited NF-κB and PTEN while enhancing PI3K, RPB-4, and PPAR-γ due to their potent antioxidant properties. They also increased insulin sensitivity, as reflected by reduced blood glucose and lipid profile levels and normalized fructosamine and RBP-4. Additionally, these extracts prevent oxidative stress-induced hepatic and nephric cell dysfunction, as confirmed by improved blood, liver, and kidney parameters.ConclusionTherefore, both extracts could be good antioxidant treatments for oxidative stress-related insulin resistance because they restore the balance of the PI3K/PPAR-γ/RBP-4 pathway. This pathway increases glucose uptake, stops gluconeogenesis, speeds up lipid metabolism, and stops the inflammation pathway.

Evaluation of the Hypoglycemic Activity of Methanolic Extract of Foeniculum vulgare in Streptozotocin-induced Diabetic Wistar Rats.

This study aimed to assess the hypoglycemic effects of methanolic extract of Foeniculum vulgare in male Wistar rats that were diabetic due to streptozotocin. Experimental diabetes was initially induced in male Wistar rats by intravenous injection of streptozotocin (55 mg/kg). Subsequently, the rats received daily oral administration of the methanolic extract of Foeniculum vulgare (250 mg/kg) and the standard drug metformin (300 mg/kg) for 28 days. Furthermore, a tolerance test was carried out. The study findings suggest that the diabetic rats in the untreated control group showed hyperglycemia and significant weight loss, as well as polydipsia, polyphagia, and polyuria. However, rats treated with methanolic extract of Foeniculum vulgare for 28 days showed a significant reduction in blood glucose levels and a marked improvement in body weight. Additionally, there was a notable decrease in the daily rate of food consumption and water intake and a significant reduction in serum glucose level, triglycerides, total cholesterol, creatinine, urea, AST, and ALT levels compared to the untreated diabetic control group. Histopathological examination revealed that after 28 days of treatment with 250 mg/kg of methanolic extract of the Foeniculum vulgare, the size of the islets of Langerhans in the pancreas tissue was decreased. Moreover, liver tissue demonstrated normalization with a normal central lobular structure, and kidney tissue showed normalization with a normal Bowman's capsule. These findings suggest that the methanolic extract of Foeniculum vulgare can potentially treat diabetes and should be evaluated further for drug development.

ASSESSMENT OF TOXICITY AND ANTI-DIABETIC POTENTIAL OF CHAYA (Cnidoscolus chayamansa) ETHANOLIC LEAF EXTRACT ON ALLOXAN INDUCED DIABETIC RATS

The need to scientifically prove the claim of traditional uses of plant materials in treating diseases has led to investigations into the medicinal potency of various plants. Cnidoscolus chayamansa (Euphorbiaceae) leaves have been traditionally used to treat diabetes and other ailments such as obesity and kidney stones. Toxicity test was conducted by administering different doses of extract to six (6) groups of rats which has six rats each. The first group was given distilled water. However, the second group onward received incremental doses of extract (1000 – 5000 mg/kg). Anti-diabetic activities of Chaya extract was investigated using thirty (30) rats weighing between 120 g – 180 g. Animals were distributed into control and five treatment groups of five rats each. Group one received standard diet and water ad libitum, while treated groups (2 – 6) were given 200 mg/kg and 400 mg/kg of Chaya extract, 150 mg/kg of alkaloid fraction and 150 mg/kg of standard drug (Metformin) respectively. After observation for 24 hours, no death of animals was recorded. Therefore, LD50 of the extract was determined to be greater than 5000 mg/kg. Results of treatment procedure showed that diabetic rats treated with two different doses of extract, alkaloid fraction and standard drug decreased blood glucose at day 7, 14 and a further decrease at day 21, which was significantly (p ≤ 0.05) different from the control group. Therefore, Cnidoscolus chayamansa leaf can be safely consumed and possesses anti-diabetic properties.

Diabetes mellitus therapy in the light of oxidative stress and cardiovascular complications.

Type 2 diabetes is a chronic disease requiring comprehensive pharmacological and non-pharmacological interventions to slow its progression and prevent or delay its micro- and macrovascular complications. Oxidative stress contributes to the development and progression of type 2 diabetes as well as to the development of its complications through several mechanisms. Therefore, therapeutic targeting of oxidative stress could aid in managing this disease and its complications. In our study, we have collected information on the most frequently used antidiabetic drugs (metformin, glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors) in the EU and the USA based on their antioxidant effects. Based on our results, we can conclude that the antioxidant effects of the investigated antidiabetics may contribute significantly to the management of the disease and its complications and may open new therapeutic perspectives in their prevention.

Community-level responses and environmental fate of metformin in freshwater mesocosms.

The type 2 diabetes drug metformin is among the most frequently prescribed, dispensed, and consumed pharmaceuticals worldwide; and its heavy use and poor breakdown means it is consequently detected in various wastewater treatment plant (WWTP) effluents and surface waters. The resulting environmental concentrations of metformin can have adverse impacts on aquatic ecosystems. An 8-week in-lake mesocosm experiment was conducted in a freshwater boreal lake at the IISD-Experimental Lakes Area (Ontario, Canada) to determine the environmental fate and effects of metformin. Mesocosms were assigned to nominal concentrations of 0, 5, or 50μgL-1 metformin, in replicates of four. Biotic communities (i.e. microbial, phytoplankton, zooplankton, benthic macroinvertebrate) were assessed and complementary Lemna gibba and Daphnia magna bioassays were conducted in the laboratory. Metformin was extremely stable during the 8-week experiment, with mean measured concentrations of 0.00, 5.42, and 42.79μgL-1 in mesocosm surface waters for the 0, 5, and 50μgL-1 treatments, respectively. While trace amounts of metformin were detected in mesocosm sediments, the compound was primarily found in the water column. After over 1year following metformin additions, the mean loss of metformin from surface water was 94.0% and 91.0% for the 5 and 50μgL-1 treatment groups, respectively. No adverse effects of metformin treatment on the diversity, abundance, or biomass of microbial, phytoplankton, zooplankton, or benthic macroinvertebrate communities were found. Additionally, no survival or reproductive effects were observed in the 21-d Daphnia magna bioassays and no significant effects were observed in the 7-d Lemna gibba growth assays. No substantial metformin transformation to guanylurea was observed in mesocosm surface waters or sediments, likely due to a lack of bacterial degradation occurring within mesocosms relative to WWTPs.

Preparation of Menthyl 3-amino-4-(2,4,5-trifluorophenyl) Butyrate and Investigation of its Hypoglycemic Activity.

3-Amino-4-(2,4,5-trifluorophenyl) butyric acid has potential pharmacological effects in promoting insulin secretion. Menthol promotes drug transdermal absorption and hypoglycemic effects. The objective of the study was to combine the 3-amino-4-(2,4,5- trifluorophenyl) butyric acid and menthol to develop a new candidate drug molecule that can be used as a hypoglycemic drug in type II diabetes. In this study, the molecular structure of 3-amino-4-(2,4,5-trifluorophenyl) butyric acid in sitagliptin was modified by replacing pyrazine imidazole with menthol. The structure of the target compound was characterized by nuclear magnetic resonance (NMR). The anti-diabetic activity of BHF in N000180 BKS.Cg-Dock7m+/ +Leprdb/Nju mice with spontaneous diabetes was preliminarily studied. A potential multi-target drug molecule, 3-amino-4-(2,4,5-trifluorophenyl) butyrate (BHF), was synthesized by combining 3-amino-4-(2,4,5-trifluorophenyl) butyric acid and menthol. BHF is suitable for hyperglycemic mice and has a significant hypoglycemic effect; the low dose of 10 mg/kg-1 started to be effective, and the high dose of 40 mg/kg-1 was more effective than the positive drug metformin. In this study, BHF has been synthesized and presented significant antidiabetic activities.

The Effect of Durio Zibethinus L. Seed Extract on Fasting Blood Glucose and Insulin Resistance in Metabolic Syndrome Model Rats

Metabolic syndrome is known as insulin resistance syndrome, characterized by chronic hyperglycemia. Management of metabolic syndrome involves several combinations, including lifestyle modifications and pharmacological interventions. Durian seeds are one source of antioxidants that have the potential to improve blood glucose homeostasis and insulin sensitivity. This study aims to analyze the effect of durian seed extract on changes in fasting blood glucose levels and insulin resistance. The extraction process utilized the maceration method with a 70% ethanol solution. This study consisted of 30 rats divided into six treatment groups: KN (normal group), K- (negative control), K+ (positive control metformin 9 mg/kgBW), P1, P2, and P3, which were given durian seed extract at doses of 100 mg/kgBW, 200 mg/kgBW, and 300 mg/kgBW, respectively. Metabolic syndrome rats were induced with a high-fat, high-fructose diet for 14 days, then induced with streptozocin (STZ) and nicotinamide (NA). Fasting blood glucose levels were determined using the GOD-PAP method. The HOMA-IR index was used to measure insulin resistance. The data results were evaluated using a paired T-test and one-way ANOVA. The analysis showed a significant variance in fasting blood glucose and HOMA-IR index following a 21-day treatment (p&lt;0.05). The highest decrease was found in the 300 mg/kgBW dose group with fasting blood glucose and HOMA-IR index of 90.00 ± 2.70 mg/dl and 3.55 ± 0.11. The P2 and P3 treatments did not show different results with metformin treatment (p&gt;0.05). The findings of this study suggest that consumption of durian seed extract for 21 days can effectively improve the condition of mice with metabolic syndrome. In addition, the drug metformin has the same effect as the intervention of durian seed extract doses of 200 and 300 mg/kgBW.

Diverse Applications of the Anti-Diabetic Drug Metformin in Treating Human Disease.

Metformin is a commonly used drug for treating type 2 diabetes. Metformin is an inexpensive drug with low/no side effects and is well tolerated in human patients of different ages. Recent therapeutic strategies for human disease have considered the benefits of drug repurposing. This includes the use of the anti-diabetic drug metformin. Accordingly, the anti-inflammatory, anti-cancer, anti-viral, neuroprotective, and cardioprotective potentials of metformin have deemed it a suitable candidate for treating a plethora of human diseases. As results from preclinical studies using cellular and animal model systems appear promising, clinical trials with metformin in the context of non-diabetes-related illnesses have been started. Here, we aim to provide a comprehensive overview of the therapeutic potential of metformin in different animal models of human disease and its suggested relationship to epigenetics and ailments with epigenetic components.

Targeting the menopause transition with metformin improves breast cancer outcomes, but discontinuation has deleterious effects on metabolic health: Findings from a preclinical model of postmenopausal breast cancer.

Women with obesity and/or type-II-diabetes have an increased breast cancer risk, increased metastasis, and poorer prognosis, especially after menopause. In a rat model of high-fat-diet and menopause-induced weight gain, we previously reported that treatment with the anti-diabetic drug metformin for 8-weeks after ovariectomy (OVX; modeling menopause) reduced growth of existing mammary tumors and inhibited new tumor formation. This identified the menopause transition as a potential window-of-opportunity for interventions to decrease obesity-associated breast cancer incidence and disease progression. Here, we extend these findings to determine if limiting metformin to the peak window of OVX-induced weight gain would have similar anti-cancer effects. Metformin during the first four weeks following OVX is critical to reducing tumor burden, as rats treated with metformin early (weeks0-4-postOVX) had reduced tumor burden. Conversely, initiating metformin later in the postOVX period (weeks 4-8postOVX) did not reduce cancer burden. Despite improved tumor outcomes, metformin withdrawal after the early postOVX time had detrimental metabolic effects, including weight gain and increased adiposity, insulin, IGF1, and HOMA-IR, which correlate with increased cancer risk. These data reveal early-postmenopause as a critical window when metformin decreases progression of existing disease and highlights the importance of maintaining treatment to prevent metabolic dysregulation, which could promote secondary tumors/metastasis. These findings also help explain the disconnect between epidemiological studies reporting anticancer benefits of metformin and more recent clinical trials that failed to see similar efficacy, potentially due to issues of timing and/or inclusion of women outside the early postmenopausal window and/or without underlying metabolic dysfunction.

NIR-II Fluorescence/Photoacoustic Dual Ratiometric Probes with Unique Recognition Site for Quantitatively Visualizing H2S2 in Vivo.

Hydrogen persulfide (H2S2) plays a significant role in redox biology and signal transduction; therefore, quantitative visualization of H2S2 in the deep tissue of living organisms is essential for obtaining reliable information about relevant pathophysiological processes directly. However, currently reported H2S2 probes are unsuitable for this purpose because of their poor selectivity for many polysulfide species or their short wavelength, which hinders precise imaging in deep tissues. Herein, for the first time, we report a unique H2S2-mediated dithiole formation reaction. Based on this reaction, we construct the first NIR-II fluorescence (FL) and photoacoustic (PA) dual-ratiometric probe (NIR-II-H2S2) for quantitatively visualizing H2S2 in vivo. This probe shows dual-ratiometric NIR-II fluorescence (I840/I1000, 107-fold) and photoacoustic (PA800/PA900, 6.5-fold) responses towards Na2S2 species with high specificity, excellent sensitivity (1.8 nM), improved water solubility, and deep-tissue penetration. More importantly, using NIR-II dual-ratiometric FL/PA imaging, we successfully demonstrated that the probe could be used to accurately quantify the fluctuating H2S2 levels in the liver-injury mouse models induced by lipopolysaccharides or metformin drugs. Overall, this study not only presents a promising tool for H2S2-related pathological research, but also provides a unique recognition site that may be generalized for designing more useful H2S2 imaging agents in the future.

NIR‐II Fluorescence/Photoacoustic Dual Ratiometric Probes with Unique Recognition Site for Quantitatively Visualizing H2S2in Vivo

AbstractHydrogen persulfide (H2S2) plays a significant role in redox biology and signal transduction; therefore, quantitative visualization of H2S2 in the deep tissue of living organisms is essential for obtaining reliable information about relevant pathophysiological processes directly. However, currently reported H2S2 probes are unsuitable for this purpose because of their poor selectivity for many polysulfide species or their short wavelength, which hinders precise imaging in deep tissues. Herein, for the first time, we report a unique H2S2‐mediated dithiole formation reaction. Based on this reaction, we construct the first NIR‐II fluorescence (FL) and photoacoustic (PA) dual‐ratiometric probe (NIR‐II‐H2S2) for quantitatively visualizing H2S2 in vivo. This probe shows dual‐ratiometric NIR‐II fluorescence (I840/I1000, 107‐fold) and photoacoustic (PA800/PA900, 6.5‐fold) responses towards Na2S2 species with high specificity, excellent sensitivity (1.8 nM), improved water solubility, and deep‐tissue penetration. More importantly, using NIR‐II dual‐ratiometric FL/PA imaging, we successfully demonstrated that the probe could be used to accurately quantify the fluctuating H2S2 levels in the liver‐injury mouse models induced by lipopolysaccharides or metformin drugs. Overall, this study not only presents a promising tool for H2S2‐related pathological research, but also provides a unique recognition site that may be generalized for designing more useful H2S2 imaging agents in the future.