Insight into the mechanism and toxicology of nitrofurantoin: a metabolomics approach.

Safety and effectiveness are the two ends of the balance in drug development that needs to be evaluated. The biotransformation of drugs within a living organism could potentiate biochemical insults in the tissue and compromise the safety of drugs. Nitrofurantoin (NFT) is a cheap clinical antibiotic with a wide array of activities against gram-positive and gram-negative organisms. The NFT scaffold has been utilized to develop other derivates or analogues in the quest to repurpose drugs against other infectious diseases. Several techniques were developed over the years to study the mechanism of NFT metabolism and toxicity, such as voltammetry, chromatographic analysis, protein precipitation, liquid-liquid extraction, etc. Due to limitations in these methods, the mechanism of NFT biotransformation in the cell is poorly understood. Metabolomics has been adopted in drug metabolism to understand the mechanism of drug toxicity and could provide a solution to overcome the limitations of current techniques to determine mechanisms of toxicity. Unfortunately, little or no information regarding the metabolomics approach in NFT metabolism and toxicity is available. Hence, this review highlights the metabolomic techniques that can be adopted in NFT metabolism and toxicological studies to encourage the research community to widely adopt and utilize metabolomics in understanding NFT's metabolism and toxicity.

Gut microbiota crosstalk mechanisms are key in pulmonary hypertension: The involvement of melatonin is instrumental too.

The microbiota refers to a plethora of microorganisms with a gene pool of approximately three million, which inhabits the human gastrointestinal tract or gut. The latter, not only promotes the transport of nutrients, ions, and fluids from the lumen to the internal environment but is linked with the development of diseases including coronary artery disease, heart failure, and lung diseases. The exact mechanism of how the microbiota achieves crosstalk between itself and distant organs/tissues is not clear, but factors released to other organs may play a role, like inflammatory and genetic factors, and now we highlight melatonin as a novel mediator of the gut-lung crosstalk. Melatonin is present in high concentrations in the gut and the lung and has recently been linked to the pathogenesis of pulmonary hypertension (PH). In this comprehensive review of the literature, we suggest that melatonin is an important link between the gut microbiota and the development of PH (where suppressed melatonin-crosstalk between the gut and lungs could promote the development of PH). More studies are needed to investigate the link between the gut microbiota, melatonin and PH. Studies could also investigate whether microbiota genes play a role in the epigenetic aspects of PH. This is relevant because, for example, dysbiosis (caused by epigenetic factors) could reduce melatonin signaling between the gut and lungs, reduce subcellular melatonin concentrations in the gut/lungs, or reduce melatonin serum levels secondary to epigenetic factors. This area of research is largely unexplored and further studies are warranted.

Dual A1 and A2A adenosine receptor antagonists, methoxy substituted 2-benzylidene-1-indanone, suppresses intestinal postprandial glucose and attenuates hyperglycaemia in fructose-streptozotocin diabetic rats.

BACKGROUND/AIM: Recent research suggests that adenosine receptors (ARs) influence many of the metabolic abnormalities associated with diabetes. A non-xanthine benzylidene indanone derivative 2-(3,4-dihydroxybenzylidene)-4-methoxy-2,3-dihydro-1 H-inden-1-one (2-BI), has shown to exhibit higher affinity at A1/A2A ARs compared to caffeine. Due to its structural similarity to caffeine, and the established antidiabetic effects of caffeine, the current study was initiated to explore the possible antidiabetic effect of 2-BI. METHODS: The study was designed to assess the antidiabetic effects of several A1 and/or A2A AR antagonists, via intestinal glucose absorption and glucose-lowering effects in fructose-streptozotocin (STZ) induced diabetic rats. Six-week-old male Sprague-Dawley rats were induced with diabetes via fructose and streptozotocin. Rats were treated for 4 weeks with AR antagonists, metformin and pioglitazone, respectively. Non-fasting blood glucose (NFBG) was determined weekly and the oral glucose tolerance test (OGTT) was conducted at the end of the intervention period. RESULTS: Dual A1/A2A AR antagonists (caffeine and 2-BI) decreased glucose absorption in the intestinal membrane significantly (p < 0.01), while the selective A2A AR antagonist (Istradefylline), showed the highest significant (p < 0.001) reduction in intestinal glucose absorption. The selective A1 antagonist (DPCPX) had the least significant (p < 0.05) reduction in glucose absorption. Similarly, dual A1/A2A AR antagonists and selective A2A AR antagonists significantly reduced non-fast blood glucose and improved glucose tolerance in diabetic rats from the first week of the treatment. Conversely, the selective A1 AR antagonist did not reduce non-fast blood glucose significantly until the 4th week of treatment. 2-BI, caffeine and istradefylline compared well with standard antidiabetic treatments, metformin and pioglitazone, and in some cases performed even better. CONCLUSION: 2-BI exhibited good antidiabetic activity by reducing intestinal postprandial glucose absorption and improving glucose tolerance in a diabetic animal model. The dual antagonism of A1/A2A ARs presents a positive synergism that could provide a new possibility for the treatment of diabetes.

Butanol fraction of Alstonia boonei De Wild. leaves ameliorate oxidative stress and modulate key hypoglycaemic processes in diabetic rats.

OBJECTIVE: The effect of Alstonia boonei fractions on glucose homeostasis was investigated via in vitro enzyme inhibition activity, ex vivo glucose uptake assay, and in vivo methods in diabetic rats. METHODOLOGY: A. boonei fractions were subjected to in vitro α-glucosidase inhibitory assay and then ex vivo glucose uptake activity. The butanol fraction of the leaves (ABBF) was picked for the in vivo assay since it showed more activity in the initial tests conducted. ABBF was administrated via oral dosing to six-weeks old fructose-fed STZ-induced type 2 diabetic rats over a 5-week experimental period. RESULTS: ABBF treatment at a low dose of 150 mg/kg bw, significantly (p < .05) reduced blood glucose level, enhanced oral glucose tolerance ability, restored insulin secretion and hepatic glycogen synthesis as well as promoted islet regeneration than the high dose (300 mg/kg bw). CONCLUSION: These results suggest that ABBF could be exploited as a therapeutic potential for treating T2D.

Non-Genetic-Induced Zebrafish Model for Type 2 Diabetes with Emphasis on Tools in Model Validation.

The unrelenting increase in the incidence of type 2 diabetes (T2D) necessitates the urgent need for effective animal models to mimic its pathophysiology. Zebrafish possess human-like metabolic traits and share significant genetic similarities, making them valuable candidates for studying metabolic disorders, including T2D. This review emphasizes the critical role of animal models in diabetes research, especially focusing on zebrafish as an alternative model organism. Different approaches to a non-genetic model of T2D in zebrafish, such as the glucose solution, diet-induced, chemical-induced, and combined diet-induced and glucose solution methods, with an emphasis on model validation using indicators of T2D, were highlighted. However, a significant drawback lies in the validation of these models. Some of these models have not extensively demonstrated persistent hyperglycemia or response to insulin resistance and glucose tolerance tests, depicted the morphology of the pancreatic ß-cell, or showed their response to antidiabetic drugs. These tools are crucial in T2D pathology. Future research on non-genetic models of T2D in zebrafish must extensively focus on validating the metabolic deficits existing in the model with the same metabolic defects in humans and improve on the existing models for a better understanding of the molecular mechanisms underlying T2D and exploring potential therapeutic interventions.

Ethyl Acetate Fractions of Tectona Grandis Crude Extract Modulate Glucose Absorption and Uptake as Well as Antihyperglycemic Potential in Fructose-Streptozotocin-Induced Diabetic Rats.

Type 2 diabetes (T2D) is a global health challenge with increased morbidity and mortality rates yearly. Herbal medicine has provided an alternative approach to treating T2D with limited access to formal healthcare. Tectona grandis is being used traditionally in the treatment of diabetes. The present study investigated the antidiabetic potential of T. grandis leaves in different solvent extractions, and the crude extract that demonstrated the best activity was further fractionated through solvent-solvent partitioning. The ethyl acetate fraction of the ethanol crude extract showed the best antidiabetic activity in inhibiting α-glucosidase, delaying glucose absorption at the small intestine's lumen, and enhancing the muscle's postprandial glucose uptake. The ethyl acetate fraction was further elucidated for its ability to reduce hyperglycemia in diabetic rats. The ethyl acetate fraction significantly reduced high blood glucose levels in diabetic rats with concomitant modulation in stimulated insulin secretions through improved pancreatic ß-cell function, insulin sensitivity by increasing liver glycogen content, and reduced elevated levels of liver glucose-6-phosphatase activity. These activities could be attributed to the phytochemical constituents of the plant.

Crassocephalum rubens (Juss. Ex Jacq.) S. Moore improves pancreatic histology, insulin secretion, liver and kidney functions and ameliorates oxidative stress in fructose-streptozotocin induced type 2 diabetic rats.

Crassocephalum rubens (C. rubens) is a traditional leafy vegetables (TLV) eaten in parts of Africa for the management of symptoms of diabetes mellitus. This study was done to investigate the in vivo anti-diabetic activity of the aqueous extract of C. rubens aerial parts (CRAQ). Type 2 diabetes (T2D) was induced in male Sprague Dawley (SD) rats by feeding them with a 10% fructose solution for two weeks followed by single dose (40 mg/kg body weight) intraperitoneal injection of streptozotocin. After confirmation of T2D, animals were treated with a low and a high dose (150 and 300 mg/kg body weight) of extract for five weeks. Parameters used as markers of hyperglycemia were analyzed in the samples collected from rats. Hematoxylin-eosin staining was used in analyzing the morphological changes of the pancreas. Treatment with high dose of the extract significantly (p < 0.05) lowered blood glucose level, increased oral glucose tolerance level and pancreatic ß-cell function, while restoring the morphology of the pancreatic tissue damage. The high dose also increased insulin secretion, liver glycogen, antioxidant enzyme activities in serum and organs, and prevented liver and renal damages compared to the untreated diabetic animals. Data from this study suggest that C. rubens possesses impressive anti-diabetic activity and could be useful in ameliorating some complications associated with T2D therefore this plant can be exploited in finding new alternative therapies for the treatment of T2D.

Multicomponent reaction for the synthesis of new 1,3,4-thiadiazole-thiazolidine-4-one molecular hybrids as promising antidiabetic agents through α-glucosidase and α-amylase inhibition.

A simple and efficient protocol was developed to synthesize a new library of thiazolidine-4-one molecular hybrids (4a-n) via a one-pot multicomponent reaction involving 5-substituted phenyl-1,3,4-thiadiazol-2-amines, substituted benzaldehydes and 2-mercaptoacetic acid. The synthesized compounds were evaluated in vitro for their antidiabetic activities through α-glucosidase and α-amylase inhibition as well as their antioxidant and antimicrobial potentials. Compound 4e exhibited the most promising α-glucosidase and α-amylase inhibition with an IC50 value of 2.59 µM, which is ~1.5- and 14-fold superior as compared to the standard inhibitor acarbose. Structure-activity relationship (SAR) analysis revealed that the nature and position of substituents on the phenyl rings had a significant effect on the inhibitory potency.

Therapeutic potentials of agonist and antagonist of adenosine receptors in type 2 diabetes.

Type 2 diabetes has been a global health challenge over the decades and is among the leading causes of death. Several treatment approaches have been developed, but more effective and new therapies are still needed. The role of adenosine in glucose and lipid homeostasis has offered a different therapeutic approach. Adenosine mediates its physiological role through the activation of adenosine receptors. These adenosine receptors have been implicated in glucose and lipid homeostasis. The ability of agonists and antagonists of adenosine receptors to activate or inhibit the adenosine signalling cascade and thereby affecting the balance of glucose and lipid homeostasis has challenged the studies of agonists and antagonists of adenosine receptors, both preclinical and clinical, as potential anti-diabetic drugs. This review provides a background on different anti-diabetic therapeutic approaches, outlining the role of adenosine receptors in glucose and lipid homeostasis, and mechanisms underlying the action of agonists/antagonists of adenosine receptors as a therapeutic potential towards type 2 diabetes.

Aryl variation and anion effect on CT-DNA binding and in vitro biological studies of pyridinyl Ag(I) complexes.

Synthesis and spectroscopic characterization of five ligands ((E)-2-((pyridin-2-ylmethylene)amino)phenol L1, 2-(pyridin-2-yl)benzo[d]thiazole L2, (E)-N-(2-fluorophenyl)-1-(pyridin-2-yl)methanimine L3, (E)-1-(pyridin-2-yl)-N-(p-tolyl)methanimine L4 and (E)-1-(pyridin-2-yl)-N-(thiophen-2-ylmethyl)methanimine L5 along with fifteen silver(I) complexes of L1 - L5, with a general formula [AgL2]+X- (L = Schiff base and X = NO3-, ClO4- or CF3SO3-) is reported. The structures of complexes [Ag(L4)2]NO3, [Ag(L5)2]NO3, [Ag(L3)2]ClO4, [Ag(L4)2]ClO4 and [Ag(L5)2]CF3SO3 were determined unequivocally by single crystal X-ray diffraction analysis. Calf-thymus deoxyribonucleic acid (CT-DNA), bovine serum albumin (BSA) binding studies, antioxidant, and antibacterial studies were performed for all complexes. Complexes [Ag(L2)2]NO3, [Ag(L5)2]NO3, [Ag(L1)2]ClO4 and [Ag(L3)2]ClO4 whose ligands have an OH- and F- as substituents or with a thiophene or thiazole moiety showed better antibacterial activities with lower minimum inhibitory concentration (MIC) values compared to the standard ciprofloxacin, against most of the bacterial strains tested. Similarly, complexes [Ag(L1)2]NO3,[Ag(L2)2]NO3,[Ag(L3)2]NO3 and [Ag(L5)2]NO3 with the NO3- anion, [Ag(L1)2]ClO4 and [Ag(L2)2]ClO4 with ClO4- anion, and [Ag(L5)2]CF3SO3 with CF3SO3- anion showed higher activities for antioxidant studies. Complexes [Ag(L4)2]ClO4 and [Ag(L4)2]CF3SO3 with the Methyl substituent and CF3SO3- as the anion, displayed high antioxidant activities in FRAP (ferric reducing antioxidant power) than the standard ascorbic acid. Spectroscopic studies of all the complexes revealed their moderate to high interaction with calf thymus DNA via an intercalation mode. In addition, the relatively moderate interaction of most of the complexes with BSA was through a static quenching mechanism.

Cola Nitida (Kola Nuts) Attenuates Hepatic Injury in Type 2 Diabetes by Improving Antioxidant and Cholinergic Dysfunctions and Dysregulated Lipid Metabolism.

BACKGROUND: The therapeutic effect of Cola nitida hot infusion against diabetes hepatic injury was investigated in livers of diabetic rats. Cola nitida was infused in boiling water and concentrated. METHODS: The concentrated infusion was administered to T2D rats at low and high doses (150 and 300 mg/kg body weight (bw), respectively). The normal group (positive control) and another diabetic group (negative control) were administered distilled water, while metformin served as the standard drug. A toxic group that consists of normal rats administered a high dose of C. nitida. After 6 weeks, the rats were sacrificed, and their livers were collected. They were assayed for oxidative stress markers, myeloperoxidase, acetylcholinesterase and ATPase activities. Hepatic lipid metabolites were profiled with GC-MS and their metabolic pathways were analyzed using the MetaboAnalyst 4.0 online server. RESULTS: Treatment with C. nitida caused a significant elevation of glutathione level and SOD activity, while concomitantly inhibiting lipid peroxidation, myeloperoxidase, acetylcholinesterase and ATPase activities in hepatic tissues of the rats. Treatment with C. nitida also caused significant depletion of diabetes-generated lipid metabolites, with concomitant generation of fatty esters and steroids as well as inactivation of diabetes-activated pathways. CONCLUSION: These data demonstrate the therapeutic effect of C. nitida against diabetic hepatotoxicity in diabetic rats.

Phytochemical properties of black tea (Camellia sinensis) and rooibos tea (Aspalathus linearis); and their modulatory effects on key hyperglycaemic processes and oxidative stress.

The comparative phytochemicals, antioxidative and antidiabetic activities of Camellia sinensis (black tea) and Aspalathus linearis (rooibos tea) were studied in vitro and ex vivo. Concentrated infusions of the teas showed significant free radical scavenging activities in vitro. They significantly increased the glutathione level, superoxide dismutase and catalase enzyme activities in oxidative hepatic injury, while concomitantly depleting malondialdehyde level. The teas significantly inhibited intestinal glucose absorption and α-amylase activities, and elevated muscle glucose uptake. LCMS phytochemical profiling revealed the presence of hydroxycaffeic acid, l-threonate, caffeine, vanillic acid, n-acetylvaline, and spinacetin 3-glucoside in C. sinensis. While quinolinic acid, coumestrol, phloroglucinol, 8-hydroxyquercetagetin, umbelliferone, and ajoene were identified in A. linearis. These results portray the antioxidant and antidiabetic potencies of both teas, with A. linearis showed better activity compared to C. sinensis. These teas may thus be used as functional foods in the management of diabetes and other oxidative stress related metabolic disorders.

Fractions from Annona muricata attenuate oxidative stress in pancreatic tissues, inhibits key carbohydrate digesting enzymes and intestinal glucose absorption but enhances muscle glucose uptake.

The ameliorating effect of different fractions of Anonna muricata ethanol leaves extract in oxidative pancreatic injury as well as their antihyperglycemic effect were investigated in vitro and ex vivo. Oxidative pancreatic injury was induced by incubating pancreatic tissue with ferrous sulphate (FeSO4 ). The antioxidative potentials of the fractions together with its ability to inhibit carbohydrate digesting enzymes, intestinal glucose absorption, and its ability to modulate muscle glucose uptake were determined. All the fractions significantly scavenge free radicals in dose-dependent manner and increase significantly increase the catalase and superoxide dimutase level thereby ameliorating lipid peroxidation. All the fractions also inihibited glucose digesting enzymes and absorption in dose-dependent manner. Glucose uptake was enhanced by the fractions in isolated psoas muscle of rats. The ethyl acetate fraction showed more potent amelioration and anti-hyperglycemic potentials among all the fractions. This could be further exploited as therapeutic strategy for the management of postprandial hyperglycemia as well as T2D. PRACTICAL APPLICATIONS: Annona muricata is among the edible fruits in the world with reported nutritional as well as medicinal values. The anticancer activity of the leaves and the fruits have been reported. Its ability to inhibit carbohydrate digesting enzymes and absorption and enhancing muscle glucose uptake as well as protection of pancreatic ß-cell from oxidative damage further support its reported antidiabetic properties. A. muricata provided a cheap and alternative source of nutraceuticals, which could be further exploited as therapeutic strategy for the treatment of postprandial hyperglycemia in T2D.

Histochemistry, phenolic content, antioxidant, and anti-diabetic activities of Vernonia amygdalina leaf extract.

Vernonia amygdalina leaves were investigated for their histochemical properties and antidiabetic activities. Histochemical analysis of the leaf revealed distributions of acidic lipid, mucilage, and pectin, lipids, polyphenols, and alkaloids at the mid rib, glandular trichome, and epidermis. HPLC analysis of the leaves hot water infusion revealed the presence of quercetin and (-)-epi-catechin. The infusion had significant (p < 0.05) 2,2'-diphenyl-1-picrylhydrazyl scavenging activity and ferric reducing antioxidant power. Ex vivo antioxidative analysis revealed the ability of the infusion to increase glutathione level, superoxide dismutase, and catalase activities, while concomitantly depleting malondialdehyde level and DNA fragmentation in Fe2+ -induced hepatic injury. The infusion showed significant (p < 0.05) inhibitory activity against α-glucosidase and pancreatic lipase. It also inhibited intestinal glucose absorption and enhanced muscle glucose uptake, respectively. The ability of the infusion to abate oxidative stress, DNA fragmentation and stimulate muscle glucose uptake may suggest the antioxidative, anti-apoptotic, and insulin-sensitizing activity of V. amygdalina. PRACTICAL APPLICATIONS: Vernonia amygdalina (bitter leaf) is among the common leafy vegetables in West Africa reported for its various medicinal and nutritional properties. It is utilized as a food ingredient as well as supplement for the treatment and management of type 2 diabetes (T2D). Its ability to inhibit intestinal glucose absorption, enhance muscle glucose uptake, and protect against hepatic oxidative stress gives more credence to its reported antidiabetic properties. Being a common leafy vegetable, V. amygdalina can be a cheap source of nutraceutical for the treatment and management of T2D and its complications.

The antidiabetic properties of the hot water extract of kola nut (Cola nitida (Vent.) Schott & Endl.) in type 2 diabetic rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Cola nitida is amongst the evergreen plants native to West Africa used in the treatment of various ailments including diabetes. AIM OF THE STUDY: This study aims to investigate the antidiabetic effects of the hot water extract of C. nitida seeds in type 2 diabetic rats. METHODS: Type 2 diabetic rats were orally administered with low (150 mg/kg bw) and high (300 mg/kg bw) doses of the hot water extract for 6 wk and thereafter, blood glucose, insulin level, lipid profile, pancreatic ß-cell function, perfusion and morphology, redox imbalance, glycolytic and cholinergic enzymes, as well as of caspase-3 and Nrf2 expressions were measured. RESULTS: Treatment with the extract led to significant depletion of blood glucose, serum triglycerides, LDL-cholesterol, fructosamine, ALT, and uric acids, while elevating serum insulin and HDL-cholesterol levels. The infusion also significantly (p < 0.05) elevated GSH level, SOD, catalase, α-amylase, and ATPase activities, with concomitant depletion of myeloperoxidase enzyme activity, and NO and MDA levels in the serum and pancreas. Significantly (p < 0.05) improved pancreatic ß-cell function and morphology were observed in rats treated with C. nitida, with restored pancreatic capillary networks. C. nitida inhibited the activities of glycogen phosphorylase, fructose 1,6 biphosphatase, glucose 6 phosphatase, and acetylcholinesterase while downregulated the Nrf2 expression. NMR analysis of the extract revealed the presence of caffeine and theobromine. The molecular docking studies indicated that identified compounds displayed strong molecular interactions with caspase-3 and Nrf2. CONCLUSION: These results insinuate the antidiabetic activities of C. nitida hot water extract and may be attributed to the NMR-identified compounds.

Type 2 diabetes induced oxidative brain injury involves altered cerebellar neuronal integrity and elemental distribution, and exacerbated Nrf2 expression: therapeutic potential of raffia palm (Raphia hookeri) wine.

Neurodegenerative diseases, such as Alzheimer's disease have been recognized as one of the microvascular complications of type 2 diabetes (T2D). In this study, the effect of T2D on neuronal integrity and elemental distribution in the cerebellar cortex, as well as the therapeutic effect of Raffia Palm (Raphia hookeri) wine (RPW) were investigated in male albino rats. T2D was induced in 4 groups of rats using fructose and streptozotocin. One group served as negative control which was administered water, the second and third group were administered 150 and 300 mg/kg bodyweight of RPW, while the fourth was administered metformin (200 mg/kg bodyweight). Two other groups of normal rats were administered distilled water (control) and of RPW (300 mg/kg bodyweight). The rats were sacrificed after 5 weeks of treatment, and brains were collected. The cerebellum was removed, and several parts analyzed by immunochemistry, histology and scanning electron microscopy (SEM). Remaining brain tissues were used to analyze for the oxidative stress biomarkers and acetylcholinesterase activity. These analyses revealed oxidative damage with concomitantly increased acetylcholinesterase activity and upregulation of Nrf2 expression in the diabetic brain cerebellar cortexes. Histological and microscopic analysis also revealed altered distribution of neurons and axonal nodes with concomitant elevated levels of several heavy metals. Treatment with RPW significantly elevated glutathione (GSH) level, superoxide dismutase (SOD) and catalase activities, as well as depleted acetylcholinesterase and malondialdehyde (MDA) level and concomitantly inhibited Nrf2 expression. It also improved neuronal integrity and reduced the levels of heavy metals in brain. Taken together, the results of this study suggest that the RPW may afford a novel neuroprotective potential against diabetic neurodegeneration.

Anti-hyperglycemic and ameliorative effect of concentrated hot water-infusion of Phragmanthera incana leaves on type 2 diabetes and indices of complications in diabetic rats.

OBJECTIVES: This study investigated the anti-hyperglycemic effects of concentrated hot water infusion of Phragmanthra incana leaves as well as its ameliorative effect on indices related to diabetic complications in a type 2 diabetes model of rats. METHODS: Type 2 diabetes was induced by feeding 10% fructose solution ad libitum for two weeks followed by an intraperitoneal injection of streptozotocin (40 mg/kg body weight (b.w.)). Concentrated plant infusion was administered orally at a dose of 150 and 300 mg/kg b.w. to two type 2 diabetes rat groups. Diabetic rats without treatment served as a negative control while the group administered with metformin was served as a positive control. The intervention lasted for 4 weeks when a single oral dose was given daily for 5 days a week. Body weight and blood glucose were determined every week. An oral glucose tolerance test was performed in the last week of treatment. The rats were sacrificed after 4 weeks of intervention, and the blood and organs were harvested for further analysis. RESULTS: Both dosages of the plant infusion significantly improved body weight, pancreatic ß-cell function (HOMA-ß), insulin secretion and reduced blood glucose, insulin resistance (HOMA-IR) with concomitant reduction in the elevated level of serum α-amylase activity, fructosamine, uric acid, urea, and liver function enzymes. The liver glycogen content was significantly improved while the activity of liver glucose-6-phosphatase was significantly reduced. CONCLUSION: The results demonstrate the anti-hyperglycemic ability of P. incana and its ability to delay the onset of diabetic complications which can be exploited for the anti-diabetic drug discovery.

Azadirachta indica inhibits key enzyme linked to type 2 diabetes in vitro, abates oxidative hepatic injury and enhances muscle glucose uptake ex vivo.

The progression of secondary complications in type 2 diabetes (T2D) has been linked to oxidative stress caused by hyperglycemia. Therefore, the control of hyperglycemia is the main target in the treatment of diabetes. The present study investigated the scavenging and ameliorative potentials of different fractions of Azadirachta indica (A. indica) ethanol stem bark extract in Fe2+-induced oxidative injury in hepatic tissue as well as their ability to inhibit enzymes linked to diabetes and in enhancing muscle glucose uptake via some in vitro and ex vivo experimental models. The results revealed that the butanol fraction of the extract showed a significantly (p < 0.05) higher DPPH scavenging activity than the other fractions (IC50 0.0154 µg/mL), while the aqueous fraction showed the highest FRAP activity (IC50 25.32 µg/mL). Although all the fractions ameliorated Fe2+-induced oxidative injury in hepatic tissue by significantly reducing malondialdehyde (MDA) concentration in a dose dependent manner, the butanol fraction showed the highest activity in this regard. In addition, the activities of catalase and superoxide dismutase (SOD) were significantly improved by the butanol and dichloromethane fractions. Butanol and ethyl acetate fractions showed the highest inhibitory effect on α-glucosidase (IC50 0.23 µg/mL) and α-amylase (IC50 14.79 µg/mL) activities, respectively. Although all the fractions significantly improved glucose uptake in psoas muscle with or without insulin, the butanol fraction showed the highest activity (GU50 6.22 µg/mL) in this regard. Gas chromatography-mass spectroscopy (GC-MS) analysis of the fractions revealed the presence of sistosterol, stigmasterol, campestrol, squalene, nimbiol among others. Molecular docking of some of these compounds with AMP-activated protein kinase (α-AMPK), α-amylase and α-glucosidase showed a positive interaction. These results suggest that the butanol and ethyl acetate fractions of A. indica may have bioactive compounds with antidiabetic potentials.

Concentrated hot water-infusion of phragmanthera incana improves muscle glucose uptake, inhibits carbohydrate digesting enzymes and abates Fe2+-induced oxidative stress in hepatic tissues.

Chronic hyperglycemia has been implicated in the development of oxidative stress and as a major factor in etiology of secondary complication in diabetes. In the present study, the antidiabetic potential of Phragamenthra incana (P. incana) hot infusion and its possible inhibitory effects on carbohydrate digesting enzymes, promotion of muscle glucose uptake, and the antioxidative potentials in Fe2+-induced oxidative stress in hepatic tissue were investigated. The infusion significantly (p < 0.05) scavenged free radicals (DPPH) and displayed favourable ferric reducing antioxidant power (FRAP) with increasing concentrations. It also significantly ameliorated Fe2+-induced oxidative stress in hepatic tissues by increasing superoxide dismutase (SOD) and catalase activities and depleting malondialdehyde (MDA) level. The results further showed that the infusion significantly (p < 0.05) inhibited α-amylase and α-glucosidase activity, and enhanced muscle glucose uptake, with and without insulin. Liquid Chromatography-Mass Spectroscopy (LCMS) analysis of the infusion revealed the presence of 2-methoxythiazole; l-cysteine; nicotinic acid; S-methyl-l-cysteine; isoquinoline, 1-methyl-; and 1H-indole-2,3-dione,5-methyl. The results of this study suggest that the observed antidiabetic and antioxidative potentials of P. incana could be attributed to its identified phytochemical constituents, however, this supports folkloric medicinal use of this plant.