Clinacanthus nutans leaf extract reduces pancreatic ß-cell apoptosis by inhibiting JNK activation and modulating oxidative stress and inflammation in streptozotocin-induced diabetic rats.

Background: Controlling apoptosis induced by oxidative stress in pancreatic ß-cells provides promising strategies for preventing and treating diabetes. Clinacanthus nutans leaves possess bioactive constituents with potential antioxidant and anti-diabetic properties. Aim: This study aimed to investigate the molecular mechanisms by which C. nutans extract protects pancreatic ß-cells from apoptotic damage in streptozotocin (STZ)-induced diabetic rats. Methods: Diabetes was induced in male Wistar rats by intraperitoneal injection of 45 mg/kg STZ, followed by 28 days of treatment with C. nutans leaf extract and Glibenclamide as the standard drug. At the end of the study, blood samples were collected to measure glucose levels, oxidative stress markers, and inflammation. Pancreatic tissue was stained immunohistochemically to detect c-Jun N-terminal kinase (JNK) and Caspase-3 expression. Results: The administration of C. nutans leaf extract to diabetic rats significantly reduced fasting blood glucose, malondialdehyde, and tumor necrosis factor-α levels, while concurrently enhancing the activity of superoxide dismutase. The immunohistochemical studies revealed a decrease in the expression of JNK and caspase-3 in the pancreatic islets of diabetic rats. Conclusion: Clinacanthus nutans exhibits the potential to protect pancreatic ß-cells from apoptosis by suppressing oxidative stress and inflammation.

Ameliorative effects of Scutellaria Pinnatifida subsp. pichleri (Stapf) Rech.f. Extract in streptozotocin-induced diabetic rats: chemical composition, biochemical and histopathological evaluation.

BACKGROUNDS: Scutellaria Pinnatifida subsp. pichleri (Stapf) Rech.f. (SP) is used in folk medicine for the treatment of diabetes. The aim of the study was to determine the phenolic profile of SP extract (SPE) by LC-MS/MS and to investigate the antidiabetic, hepatoprotective and nephroprotective effects of SPE in streptozotosin (STZ)-induced diabetic rat model. METHODS: Forty-two rats were randomly divided into six groups (n = 7): Control (nondiabetic), diabetes mellitus (DM), DM + SP-100 (diabetic rats treated with SPE, 100 mg/kg/day), DM + SP-200 (diabetic rats treated with SPE, 200 mg/kg/day), DM + SP-400 (diabetic rats treated with SPE, 400 mg/kg/day) and DM + Gly-3 (diabetic rats treated with glibenclamide, 3 mg/kg/day). Live body weight, fasting blood glucose (FBG) level, antidiabetic, serum biochemical and lipid profile parameters, antioxidant defense system, malondyaldehyde (MDA) and histopathological examinations in liver, kidney and pancreas were evaluated. RESULTS: Apigenin, luteolin, quinic acid, cosmosiin and epigallocatechin were determined to be the major phenolic compounds in the SPE. Administration of the highest dose of SP extract (400 mg/kg) resulted in a significant reduction in FBG levels and glycosylated hemoglobin levels in STZ-induced diabetic rats, indicating an antihyperglycemic effect. SPE (200 and 400 mg/kg) and glibenclamide significantly improved MDA in liver and kidney tissues. In addition, SPE contributed to the struggle against STZ-induced oxidative stress by stimulating antioxidant defense systems. STZ induction negatively affected liver, kidney and pancreas tissues according to histopathological findings. Treatment with 400 mg/kg and glibenclamide attenuated these negative effects. CONCLUSIONS: In conclusion, the extract of the aerial part of Scutellaria pinnatifida subsp. pichleri has hepatoprotective, nephroprotective and insulin secretion stimulating effects against STZ-induced diabetes and its complications due to its antidiabetic and antioxidant phytochemicals such as apigenin, luteolin, quinic acid, cosmosiin and epigallocatechin.

Impacts of trelagliptin and remogliflozin alone and in combination with Alpha Lipoic Acid on cardiac function in streptozotocin-induced diabetes mellitus in rats.

This study investigated the effects of trelagliptin and remogliflozin, alone and in combination with alpha lipoic acid (ALA), on cardiac biomarkers in diabetic cardiomyopathy (DCM). We aimed to assess the management of glucotoxicity consequences in streptozotocin-induced diabetic rats by measuring serum levels of pharmacologically active endogenous ligands. Forty-eight male rats were divided into different treatment groups, including negative control, positive control, and four experimental groups. After inducing diabetes, the rats were treated for 28 days, and serum levels of biomarkers associated with oxidative stress (malondialdehyde and thioredoxin-interacting protein), inflammation (nuclear factor NF-kappa-B p105 and lipoprotein-associated phospholipase A2), and myopathy (neprilysin and high selective cardiac troponin T) were measured. Immunohistochemical analysis of heart cells was also performed. The results showed that inducing hyperglycemia increased serum glucose levels and biomarkers associated with DCM. However, all treatment groups exhibited a significant decrease in these biomarkers and an increase in insulin levels compared to the diabetic control group. The groups receiving combination therapy with ALA showed greater improvements in cardiac biomarkers compared to the individual treatments. The immunohistochemical analysis supported these findings by demonstrating a reduction in the percentage area of cathepsin B, a protein involved in DCM pathophysiology. In conclusion, supplementing the base treatments with ALA showed promise in enhancing cardiac biomarkers associated with DCM. The combination of trelagliptin, remogliflozin, and ALA may have additional clinical value in managing DCM by targeting oxidative stress, inflammation, and glucotoxicity. However, further research is needed to validate these findings and explore their potential clinical applications.

Comparing the Effect of Moringa Aqueous Extract and Selenium Nanoparticles Against Complications of Type 2 Diabetes Mellitus.

<b>Background and Objective:</b> Plant extracts were widely used to maintain postprandial levels and minimize diabetes complications. The main goal of this study was to evaluate the therapeutic effect of selenium nanoparticles and aqueous extract of the <i>Moringa</i> plant against diabetes mellitus complications and compare their therapeutic effects. <b>Materials and Methods:</b> Fifty six Wistar male rats were divided randomly into 8 groups (7 rats each): (i) Control, (ii): Received corn oil, (iii): Treated with Se-NPs, (iv): Injected orally with <i>Moringa</i> aqueous extract (MAE), (v): Treated with a single i.p., dose of streptozotocin (STZ), (vi): Single i.p., dose of STZ followed by Se-NPs, (vii): Treated with a single i.p., dose of STZ then MAE orally and (viii): Injected with STZ and then received Se-NPs. After 4 weeks the blood sera were isolated and stored at -20°C for investigation of values of insulin, GSH, MDA, SOD, GSH-PX, triglycerides, T-cholesterol, HDL-cholesterol and LDL-cholesterol. <b>Results:</b> The STZ treatment decreased insulin, HDL cholesterol and body weight values while increasing glucose, total cholesterol, LDL cholesterol and triglycerides and mild degeneration of islets of Langerhans. The single treatment of diabetic rats with either MAE or Se-NPs exhibited a decline in the levels of serum glucose, LDL-cholesterol, triglycerides, MDA and GSH, improving the HDL-cholesterol, insulin level and body weight. <b>Conclusion:</b> The co-administration of diabetic rats with MAE and Se-NPs resulted in a prominent improvement that was revealed by restoring beta-cell function, reducing blood glucose levels and stimulating insulin production rather than their single therapeutic use.

Oxidative stress in liver of streptozotocin-induced diabetic mice fed a high-fat diet: A treatment role of Artemisia annua L.

Objective. The aim of this study was the investigation of a treatment role of Artemisia annua L. (AA) on liver dysfunction and oxidative stress in high-fat diet/streptozotocin-induced diabetic (HFD/STZ) mice. Methods. Sixty mice were divided into 12 groups including control, untreated diabetic, and treated diabetic ones with metformin (250 mg/kg), and doses of 100, 200, and 400 mg/kg of water (hot and cold) and alcoholic (methanol) extracts of AA. Type 2 diabetes mellitus (T2DM) was induced in mice by high-fat diet for 8 weeks and STZ injection in experimental animals. After treatment with doses of 100, 200 or 400 mg/kg of AA extracts in HFD/STZ diabetic mice for 4 weeks, oxidative stress markers such as malondialdehyde (MDA), glutathione (GSH), and free radicals (ROS) were determined in the liver tissue in all groups. Results. Diabetic mice treated with metformin and AA extracts showed a significant decrease in ROS and MDA concentrations and a notable increase in GSH level in the liver. Effectiveness of higher doses of AA extracts (200 and 400 mg/kg), especially in hot-water and alcoholic ones, were similar to and/or even more effective than metformin. Conclusion. Therapeutic effects of AA on liver dysfunction showed that antioxidant activity of hot-water and alcoholic AA extracts were similar or higher than of metformin.

Anti-amyloidogenic amphipathic arginine-dehydrophenylalanine spheres capped selenium nanoparticles as potent therapeutic moieties for Alzheimer's disease.

Aggregation of both amyloid beta (Aß) peptide and hyperphosphorylated tau proteins is the major pathological hallmark of Alzheimer's disease (AD). Moieties that carry anti-amyloidogenic potency against both of the aggregating entities are considered to be promising drug candidatures for the disease. In the current work, we have synthesized amphipathic dipeptide vesicle-templated selenium nanoparticles (RΔF-SeNPs) as potential entities to combat AD. We have investigated and established their anti-amyloidogenic activity against different peptide-based amyloid models, such as the reductionist model based on the dipeptide phenylalanine-phenylalanine (FF) derived from Aß; a model based on the hexapeptide Ac-PHF6 (306VQIVYK311) derived from tau protein; and the full-length Aß42 polypeptide-based model. We also evaluated the neuroprotective characteristics of RΔF-SeNPs against FF, Ac-PHF6, and Aß42 fibril-induced toxicity in neuroblastoma, SH-SY5Y cells. RΔF-SeNPs further exhibited neuroprotective effects in streptozotocin (STZ) treated neuronal (N2a) cells carrying AD-like features. In addition, studies conducted in an intra-cerebroventricular STZ-instigated rat model of dementia revealed that RΔF-SeNP-treated animals showed improved cognitive activity and reduced Aß42 aggregate burden in brain tissues as compared with the STZ-treated group. Moreover, in vivo brain distribution studies conducted in animal models additionally demonstrated the brain-homing ability of RΔF-SeNPs. All together, these studies supported the potency of RΔF-SeNPs as efficient and propitious disease-modifying therapeutic agents for combating AD.

The Hypoglycemic and Hypolipidemic Effects of Polyphenol-Rich Strawberry Juice on Diabetic Rats.

Obesity and diabetes are some of the most important modern health problems requiring simple preventative or palliative measures using dietary means. This study investigated the impact of strawberry juice on diabetic rats. Diabetes was induced in rats using a single intraperitoneal injection of 50 mg/kg streptozotocin (STZ). Fifty male rats were divided into five groups: normal control (NC), strawberry juice only (S), diabetic control (DC), and two diabetic groups treated with strawberry juice (DC + S) or metformin (DC + met). Rats were administered a single dose of both strawberry juice and oral metformin, and biochemical and histological analyses were conducted. The experiment was conducted in compliance with the Ethics Committee's regulations for the care and utilization of animals, microorganisms, and living cell cultures in education and scientific research at the Faculty of Agriculture, Minia University (MU/FA/006/12/22). Treatment of diabetic rats with strawberry juice led to a significant decrease in blood glucose. Insulin levels were also significantly increased, while lipid profiles were lowered in the diabetic rats treated with strawberry juice. Carbohydrate metabolism enzymes and antioxidant enzyme activities in the treated rats were restored to normal levels, and the levels of lipid peroxidation and proinflammatory cytokines were notably reduced. The microstructure of pancreatic and liver cells in diabetic rats was also improved with strawberry juice treatment. In addition, HPLC analysis revealed that strawberry juice was rich in flavonoids and phenolic compounds and exhibited potent antioxidant activity. These findings suggest that strawberry juice has considerable hypoglycemic and hypolipidemic effects on rats with diabetes which may be used in human after further investigations.

Evaluation of Pleurotus Mushroom Effects on Histopathological Changes in Organs of Diabetic Rats.

Diabetes mellitus (DM) is a metabolic disorder that can be categorized mainly into type 1 and type 2. Diabetes type 1 is caused due to ß-cell destruction, whereas type 2 is caused by the resistance of cell receptors. Many therapies are available for the management of diabetes, but they have some side effects, and as a result of this, people are attracted to natural treatments. Pleurotus mushrooms are well documented for their medicinal attributes and their role in the treatment of diseases like cancer, infectious disease, neurodiseases, and inflammatory disease. The protective mechanism of the Pleurotus fossulatus (P. fossulatus) mushroom and its detailed histological study on kidneys and the liver in diabetic conditions were unexplored. The present study evaluated the effects of P. fossulatus aqueous extract on histological changes in the diabetic rat model. Male Wistar albino rats were used to create the diabetic model by using streptozotocin (STZ) intraperitoneal (IP) injection. The animals were separated into five different groups, with six animals in each. Only group I, animals that did not receive STZ, was considered a normal control. Group II was a diabetic control and received normal saline, and group III was a drug control and received metformin as a standard drug. Groups IV and V were dosing groups, which received the aqueous extract of P. fossulatus in 250 mg/kg and 500 mg/kg of body weight concentrations, labeled as T1 and T2 groups, respectively. The T1 and T2 groups clearly showed their potential to reverse the histopathological changes in the kidney and liver. However, the T2 group was more effective than the T1 group, as results indicate that functions of the glomerulus and its structural deformity were restored to their near-natural form in the T2 group. In the case of the liver, the histological changes like the dilatation of sinusoids, more numbers of the Kupffer cell formation, and necrosis were restored in the T2 group. All these results proved the potential of P. fossulatus against the side effects of diabetes. It could protect the organs from developing diabetic nephropathy (DN) and liver-related diseases like cirrhosis and nonalcoholic fatty liver disease (NAFLD).

Antioxidant effects of silver nanoparticles obtained by green synthesis from the aqueous extract of Eryngium carlinae on the brain mitochondria of streptozotocin-induced diabetic rats.

Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycemia that affects practically all tissues and organs, being the brain one of most susceptible, due to overproduction of reactive oxygen species induced by diabetes. Eryngium carlinae is a plant used in traditional Mexican medicine to treat diabetes, which has already been experimentally shown have hypoglycemic, antioxidant and hypolipidemic properties. The green synthesis of nanoparticles is a technique that combines plant extracts with metallic nanoparticles, so that the nanoparticles reduce the absorption and distribution time of drugs or compounds, increasing their effectiveness. In this work, the antioxidant effects and mitochondrial function in the brain were evaluated, as well as the hypoglycemic and hypolipidemic effect in serum of both the aqueous extract of the aerial part of E. carlinae, as well as its combination with silver nanoparticles of green synthesis. Administration with both, extract and the combination significantly decreased the production of reactive oxygen species, lipid peroxidation, and restored the activity of superoxide dismutase 2, glutathione peroxidase, and electron transport chain complexes in brain, while that the extract-nanoparticle combination decreased blood glucose and triglyceride levels. The results obtained suggest that both treatments have oxidative activity and restore mitochondrial function in the brain of diabetic rats.

Evaluation of Sida cordifolia and Sida rhombifolia extracts in a rat model of streptozotocin-induced diabetic nephropathy.

BACKGROUND: Sida cordifolia and Sida rhombifolia are regarded as useful herbs as they have been shown to be effective, inexpensive and harmless in the prevention of diabetes, and are recognized as valuable therapeutic substances. OBJECTIVES: The purpose of this study was to assess the effect of S. cordifolia and S. rhombifolia in the treatment of diabetic nephropathy using a rat model. MATERIAL AND METHODS: Extracts of S. cordifolia and S. rhombifolia were obtained using the Soxhlet method. The hydroalcoholic extract solvent was used in the following proportions: 70:30, 50:50 and 80:20. The 80:20 hydroalcoholic extract was observed to be the most potent. The inhibitory effects of the extract were determined using the α-amylase assay. The most potent extract also underwent total flavonoid, phenolic and free radical scavenging tests, and was incorporated into an animal study. Diabetes was induced in rats by administering nicotinamide (NAD; 230 mg/kg) and streptozotocin (STZ; 65 mg/kg) intraperitoneally. In addition to a standard control of pioglitazone, the rats received extract dosages of 100 mg/kg/day or 200 mg/kg/day. Body weight, blood glucose, glycated hemoglobin (HbA1c), blood urea nitrogen (BUN), serum albumin, serum creatinine, homeostatic model assessment of insulin resistance (HOMA-IR), and oral glucose tolerance were assessed at various time points. The animals also underwent histopathological examination to observe alterations induced by the treatment. RESULTS: Sida cordifolia was the most successful in lowering blood glucose and HbA1c levels. Renal function indices and antioxidant enzyme levels were regained in a dose-dependent manner. Furthermore, S. cordifolia (200 mg/kg/day) extract, similar to pioglitazone, inhibited the production of advanced glycation byproducts by the kidney. CONCLUSIONS: The effects of various S. cordifolia and S. rhombifolia extracts on rats with diabetic nephropathy were observed. Sida cordifolia may be further explored for the treatment of diabetic nephropathy and, due to its diverse nature, may be utilized for the treatment of a wide range of diseases, as it provided more significant findings.

Apigetrin-enriched Pulmeria alba extract prevents assault of STZ on pancreatic ß-cells and neuronal oxidative stress with concomitant attenuation of tissue damage and suppression of inflammation in the brain of diabetic rats.

In the present study, in vitro, in vivo, and in silico models were used to evaluate the therapeutic potential of Pulmeria alba methanolic (PAm) extract, and we identified the major phytocompound, apigetrin. Our in vitro studies revealed dose-dependent increased glucose uptake and inhibition of α-amylase (50% inhibitory concentration (IC50)= 217.19 µg/mL), antioxidant (DPPH, ferric-reducing activity of plasma (FRAP), and lipid peroxidation (LPO) [IC50 = 103.23, 58.72, and 114.16 µg/mL respectively]), and anti-inflammatory potential (stabilizes human red blood cell (HRBC) membranes, and inhibits proteinase and protein denaturation [IC50 = 143.73, 131.63, and 198.57 µg/mL]) by the PAm extract. In an in vivo model, PAm treatment reversed hyperglycemia and attenuated insulin deficiency in rats with streptozotocin (STZ)-induced diabetes. A post-treatment tissue analysis revealed that PAm attenuated neuronal oxidative stress, neuronal inflammation, and neuro-cognitive deficiencies. This was evidenced by increased levels of antioxidants enzymes (superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH)), and decreased malondialdehyde (MDA), proinflammatory markers (cyclooxygenase 2 (COX2), nuclear factor (NF)-κB and nitric oxide (NOx)), and acetylcholinesterase (AChE) activities in the brain of PAm-treated rats compared to the STZ-induced diabetic controls. However, no treatment-related changes were observed in levels of neurotransmitters, including serotonin and dopamine. Furthermore, STZ-induced dyslipidemia and alterations in serum biochemical markers of hepatorenal dysfunction were also reversed by PAm treatment. Extract characterization identified apigetrin (retention time: 21,227 s, 30.48%, m/z: 433.15) as the major bioactive compound in the PAm extract. Consequently, we provide in silico insights into the potential of apigetrin to target AChE/COX-2/NOX/NF-κB Altogether the present study provides preclinical evidence of the therapeutic potential of the apigetrin-enriched PAm extract for treating oxidative stress and neuro-inflammation associated with diabetes.

Metabolic Alterations in Streptozotocin-nicotinamide-induced Diabetic Rats Treated with Muntingia calabura Extract via 1H-NMR-based Metabolomics.

Diabetes mellitus (DM) is a metabolic endocrine disorder caused by decreased insulin concentration or poor insulin response. Muntingia calabura (MC) has been used traditionally to reduce blood glucose levels. This study aims to support the traditional claim of MC as a functional food and blood-glucose-lowering regimen. The antidiabetic potential of MC is tested on a streptozotocin-nicotinamide (STZ-NA)-induced diabetic rat model by using the 1H-NMR-based metabolomic approach. Serum biochemical analyses reveal that treatment with 250 mg/kg body weight (bw) standardized freeze-dried (FD) 50% ethanolic MC extract (MCE 250) shows favorable serum creatinine (37.77 ± 3.53 µM), urea (5.98 ± 0.84 mM) and glucose (7.36 ± 0.57 mM) lowering capacity, which was comparable to the standard drug, metformin. The clear separation between diabetic control (DC) and normal group in principal component analysis indicates the successful induction of diabetes in the STZ-NA-induced type 2 diabetic rat model. A total of nine biomarkers, including allantoin, glucose, methylnicotinamide, lactate, hippurate, creatine, dimethylamine, citrate and pyruvate are identified in rats' urinary profile, discriminating DC and normal groups through orthogonal partial least squares-discriminant analysis. Induction of diabetes by STZ-NA is due to alteration in the tricarboxylic acid (TCA) cycle, gluconeogenesis pathway, pyruvate metabolism and nicotinate and nicotinamide metabolism. Oral treatment with MCE 250 in STZ-NA-induced diabetic rats shows improvement in the altered carbohydrate metabolism, cofactor and vitamin metabolic pathway, as well as purine and homocysteine metabolism.

The recovery effect of Vitamin C on structural alterations due to Streptozotocin-Induced diabetes in rat testicular tissues.

Type I Diabetes is a multisystem disease that causes alterations in carbohydrate, protein, and fat metabolisms due to hyperglycemia. It has an extensive pathology, especially the mechanism involving oxidative stress is still complex. Type I diabetes is correlated with increased formation of free radicals and decreased levels of antioxidant potential. Vitamin C (Vit C) is a powerful antioxidant that participates in antioxidant defense, protecting lipid membranes and proteins from oxidative damage by donating electrons to free radicals. The effect of type I diabetes and the recovery role of Vit C on the structure and composition of the biomolecular content of testicular tissue is still unknown. Therefore, the current study aimed to investigate the alterations in the biomolecules of rat testes due to Streptozotocin (STZ)-induced type I diabetes using Attenuated Total Reflectance (ATR)-Fourier Transform Infrared (FTIR) spectroscopy and histological staining. The results revealed that the biomolecular structure and composition of testicular tissue are highly affected due to the development of diabetes. We obtained decreased saturation levels and increased unsaturation index in the lipids indicating the presence of lipid peroxidation in the diabetic state. The elevated lipid peroxidation levels have been implicated in the pathogenesis of naturally occurring and chemically induced diabetes. On the other hand, the protein content of diabetic rat testicular tissue was shown to decrease considerably, indicating an increase in proteolysis processes. Supporting the ratio of protein structural and conformational change, protein secondary structural components were also found to alter substantially in the diabetic state. Diabetes was also shown to lead to a decrease in the content of nucleic acids compared to proteins. These diabetes-induced alterations were found to be substantially recovered with the administration of Vit C. Although different doses and administration types of Vit C have been reported in the literature, there is no consensus yet. Therefore, we used three different doses of Vit C in our study as high (100 mg/kg/day), medium (50 mg/kg/day) and low (15 mg/kg/day) doses intraperitoneally in the present study, and the medium dose was found to be the most effective in the recovery from the diabetes-induced structural damages on rat testicular tissue. Vit C may have a therapeutic effect to be used as a complementary therapy in the treatment of diabetes.

Oxygen scavenging, anti-inflammatory, and antiglycation activity of pomegranate flavonoids (Punica granum) against streptozotocin toxicity induced diabetic nephropathy in rats.

Bioactive natural products are essential components for drug development. Protein glycation in diabetic subjects leads to diabetic complications as nephropathy and neuropathy. We investigated the impact of pomegranate hexane extract (PHE) as antioxidant, anti-inflammatory, and antiglycation in diabetic rats. Gas chromatography/mass spectrum (GC/MS) analysis of PHE revealed presence of resorcinol, catechol, tau-cadinol, metacetamol, scopoletin, phytol, and phenol, 3-pentadecyl as the most active ingredients that related to biological activity. Results obtained showed that, PHE increased serum aldose reductase and total antioxidant activity compared with untreated diabetic rats (p < 0.001). In addition, PHE exert antioxidant by enhancing, catalase and SOD (p < 0.001) and decreased MDA (p < 0.001), anti-inflammatory by inhibition production of 1 ß (IL-1ß), tumor necrosis factor (TNF-α) (p < 0.001), and AGEs (p < 0.001) against nephropathy in diabetic rats compared with untreated group. It was concluded that, pomegranate is promising in development a functional biomolecule in treatment and protection against diabetic complications as nephropathy. More study required to investigate the molecular action of these molecules.

Ameliorative effect of selenium yeast in combination with pioglitazone on diabetes outcomes in streptozotocin-induced.

Anti-diabetic therapies possess many side effects; thus, searching for alternative strategies with low cost, minimal side effects, and high therapeutic value is very important. The present study aimed to explore the combined use of selenium yeast (SY) and standard anti-diabetic drug pioglitazone (PGZ) for diabetes mellitus (DM) treatment in streptozotocin (STZ)-induced DM. STZ was injected daily intraperitoneally with a low dose (40 mg/kg) into Sprague-Dawley rats to induce DM. The synergistic effect of the SY (0.2 mg/kg) and PGZ (0.65 mg/kg) on DM complications was evaluated after 88 weeks of treatment. The impact of our medication on glucose levels, insulin sensitivity, lipid abnormalities, oxidative mediators, and inflammatory markers was assessed by biochemical techniques. STZ-induced diabetes has toxic effects, including toxic hepatic tissues, lipid disturbances, massive oxidative damage, and hyperinflammation. Experimental rats either treated with monotherapy alone or combined therapy resulted in a significant anti-diabetic effect. The PGZ+ SY combination has the best effect, as illustrated by significant (P < 0.05) decreases in fasting blood glucose, (FBG) insulin, HbA1c, and HOMA-IR levels. This combination attenuated (P < 0.05) lipid disturbances and their associated elevated atherogenicity biomarkers. At the same time, treatments with PGZ+ SY exhibited an anti-inflammatory effect as they ameliorated the increase in inflammatory parameters (CRP, TNF-α, IL-6). Also, it restored the total antioxidant capacity and peroxisome proliferator-activated receptor (PPARƔ) levels that were decreased by STZ-DM induction. In conclusion, this study finds PGZ+ SY as a promising DM therapeutic alternative. This synergistic combination alleviates most DM-related complications and insulin resistance.

Antioxidant and anti-inflammatory activities of Centratherum anthelminticum (L.) Kuntze seed oil in diabetic nephropathy via modulation of Nrf-2/HO-1 and NF-κB pathway.

BACKGROUND: Type 2 diabetes mellitus (T2DM) approximately constitutes 90% of the reported cases. 30-40% of diabetics eventually develop diabetic nephropathy (DN); accounting for one of the major causes of morbidity and mortality. Increased glucose autoxidation and non-enzymatic glycation of proteins in diabetic kidneys lead to the excessive generation of reactive oxygen species (ROS) that results in lipid peroxidation and activation of inflammatory mediators which overwhelms the scavenging capacity of the antioxidant defense system (Nrf2/Keap1/HO-1). Centratherum anthelminticum commonly called as kali zeeri (bitter cumin) and its seeds are well known for culinary purposes in Asia (Pakistan). It has reported anti-inflammatory, antioxidant, and anti-diabetic activities. The present study has attempted to explore the in-vivo anti-inflammatory, antioxidant and antihyperglycemic potential of the C. anthelminticum seed's fixed oil (FO) and its fractions in high fat-high fructose-streptozotocin (HF-HFr-STZ) induced T2DM rat model. METHODS: The T2DM rat model was developed by giving a high-fat and high-fructose diet followed by a single intraperitoneal injection of streptozotocin (STZ 60 mg/kg) on 28th day of the trial. After 72 hours of this injection, rats showing fasting blood glucose (FBG) levels≥230 mg/dL were recruited into six groups. These groups were orally administered distilled water (1 mL/kg), Gliclazide (200 mg/kg), Centratherum anthelminticum seed (FO) and its hexane (HF), chloroform (CF) and ethanol (EF) soluble fractions (200 mg/kg each), respectively for 4 weeks (i.e. 28 days). Blood, serum, and kidney tissue samples of euthanized animals were used for biochemical, pro-inflammatory, and antioxidant markers (ELISA, qRT-PCR, and spectrophotometric assays) and histology, respectively. RESULTS: C. anthelminticum FO and its fractions reduced the lipid peroxidation, and improved the antioxidant parameters: enzymatic (SOD, CAT, and GPx), non-enzymatic (GSH), and mRNA expression of anti-inflammatory markers (Nrf-2, keap1, and HO-1). mRNA expression of inflammatory and apoptotic markers (TNF-α, IL-1ß, COX-1, NF-κB, Bax, and Bcl-2) were attenuated along with improved kidney architecture. CONCLUSION: C. anthelminticum can mitigate inflammation and oxidative stress in early DN. The anti-nephropathic effect can be attributed to its ability to down-regulate NF-κB and by bringing the Nrf-2 expression levels to near normal.

Relaxin-3 Ameliorates Diabetic Cardiomyopathy by Inhibiting Endoplasmic Reticulum Stress.

Background: This study is aimed at investigating whether relaxin-3 exhibits protective effects against cardiomyopathy in diabetic rats by suppressing ERS. Methods: Eighty male SD rats were randomly divided into two groups: controls (n = 20) and diabetes (n = 60). The streptozotocin-treated rats were randomly divided into three groups: diabetic group (DM), low-dose relaxin-3 group (0.2 µg/kg/d), and high-dose relaxin-3 group (2 µg/kg/d). The myocardial tissues and collagen fiber were observed by hematoxylin and eosin (H&E) and Masson staining. Serum brain natriuretic peptide (BNP), troponin (TNI), myoglobin, interleukin (IL-17), interleukin (IL)-1α, and tumor necrosis factor (TNF)-α were determined by ELISA. The protein expression of glucose regulatory protein 78 (GRP78) and C/EBP homologous protein (CHOP) in the heart tissue of each group was detected by Western blot analysis. Results: (1) HE and Masson staining indicated that relaxin-3 could attenuate myocardial lesions and myocardial collagen volume fraction. (2) BNP, TnI, and myoglobin in the DM group at four and eight weeks were significantly higher than in the controls (P < 0.01). The relaxin-3-treated groups showed significantly reduced serum BNP, TnI, and myoglobin levels compared with the DM group (P < 0.05). (3) IL-17, IL-1α, and TNF-α levels in the DM rats at 4 weeks were higher than in the controls (P < 0.05). Low or high dose of relaxin-3-treated groups showed reduced serum IL-17 and TNF-α levels compared with the DM group at four and eight weeks (P < 0.05). (4) CHOP and GRP78 protein expression was increased in the DM group at four and eight weeks compared with the controls (P < 0.01), and small and large doses of relaxin-3 significantly reduced GRP78 and CHOP protein expression. Conclusions: Exogenous relaxin-3 ameliorates diabetic cardiomyopathy by inhibiting ERS in diabetic rats.

Exploring Anti-Type 2 Diabetes Mellitus Mechanism of Gegen Qinlian Decoction by Network Pharmacology and Experimental Validation.

Purpose: Gegen Qinlian Decoction (GGQL) has been employed to treat type 2 diabetes mellitus (T2DM) in the clinical practice of traditional Chinese medicine. However, the underlying mechanism of GGQL in the treatment of T2DM remains unknown. This study was aimed at exploring the pharmacological mechanisms of GGQL against T2DM via network pharmacology analysis combined with experimental validation. Methods: The effective components of GGQL were screened, and the target was predicted by using traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP). The candidate targets of GGQL were predicted by network pharmacological analysis, and crucial targets were chosen by the protein-protein interaction (PPI) network. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses were performed to predict the core targets and pathways of GGQL against T2DM. Then, T2DM mice were induced by a high-fat diet combined with streptozotocin. The model and GGQL groups were given normal saline and GGQL aqueous solution (10 and 20 g/kg/d) intragastric administration, respectively, for 8 weeks. The mice in the GGQLT groups were administered with GGQLT at 10 and 20 g/kg/d, respectively. The pathological changes in liver tissues were observed by hematoxylin-eosin staining. The protein expression of TNF-α and NF-κB was verified by western blotting. Results: A total of 204 common targets of GGQL for the treatment of T2DM were obtained from 140 active ingredients and 212 potential targets of T2DM. GO and KEGG enrichment analysis involved 119 signaling pathways, mainly in inflammatory TNF signaling pathways. Animal experiments showed that GGQL significantly reduced the serum levels of body mass, fasting blood glucose, fasting insulin, HOMA-IR, TNF-α, and IL-17. The liver pathological section showed that GGQL could improve the vacuolar degeneration and lipid deposition in the liver of T2DM mice. Mechanistically, GGQL downregulated the mRNA expression of TNF-α and NF-κB. Conclusions: This study demonstrated that GGQL may exert antidiabetic effects against T2DM by suppressing TNF-α signaling pathway activation, thus providing a basis for its potential use in clinical practice and further study in treating T2DM.

Effects of zinc supplementation on glycemic control and oxidative stress in experimental diabetes: A systematic review.

INTRODUCTION: Diabetes mellitus (DM), an important public health problem worldwide, can cause imbalances in the homeostasis of trace elements such as zinc (Zn). It is possible that an adequate nutritional status related to nutrients is essential for the normal functioning of antioxidant defense systems, and any change in the concentration of these substances could increase the chances of DM complications. OBJECTIVE: To present a review on the effect of zinc supplementation on glycemic control and oxidative stress in experimental diabetes. METHODS: This is a systematic review of articles that investigated the effects of zinc supplementation on glycemic control and oxidative stress in diabetic rats. The PICOS strategy was used for the development of the research question, and the Syrcle tool for the quality assessment of the studies included in the review. Articles available in the PubMed, Scopus, and Web of Science databases were included without restriction on year of publication. The Syrcle tool was used to assess the risk of bias of the included studies. RESULTS: Fifteen studies were included in the review, seven of which evaluated glycemic control and oxidative stress after zinc supplementation, five only oxidative stress and three only glycemic control after zinc treatment. In all the studies included, diabetes was induced by the administration of streptozotocin (STZ) at doses ranging from 40 to 100 mg/kg. Zinc supplementation was made in the diet or drinking water or by gavage or intraperitoneal injection. The most used doses were 100 mg/kg of body weight by gavage and 0.32 and 0.64 g/kg in diet. The supplementation period ranged from 14 days to 8 weeks. Six studies revealed that zinc supplementation decreased fasting blood glucose as well as insulin resistance; nine studies included in this review reported decreased MDA concentration; in five studies, there was an increase in the activity of antioxidant enzymes (GPx, SOD, GSH and catalase); and one of the studies reported a reduction in glycated hemoglobin. CONCLUSION: Zinc supplementation improved hyperglycemia and revealed a protective potential against oxidative stress associated with experimental diabetes.

Luteolin-Rich Extract of Thespesia garckeana F. Hoffm. (Snot Apple) Contains Potential Drug-Like Candidates and Modulates Glycemic and Oxidoinflammatory Aberrations in Experimental Animals.

The present study evaluated the polyphenolic contents and hypoglycemic, antioxidant, and anti-inflammatory effects of the diethyl ether fraction of Thespesia garckeana using various in vitro and in vivo models. Total phenol and flavonoid contents of the extract were 613.65 ± 2.38 and 152.83 ± 1.56 mg/100 g dry weight, respectively. The extract exhibited in vitro antioxidant activities against DPPH, FRAP, LPO, and ABTS with respective half-maximal inhibitory concentration (IC50) values of 30.91 ± 0.23, 16.81 ± 0.51, 41.29 ± 1.82, and 42.39 ± 2.24 µg/mL. In vitro anti-inflammatory studies using membrane stabilization, protein denaturation, and proteinase activities revealed the effectiveness of the extract with respective IC50 values of 54.45 ± 2.89, 93.62 ± 3.04, and 56.60 ± 2.34 µg/mL, while in vitro hypoglycemic analysis of the extract revealed inhibition of α-amylase (IC5064.59 ± 3.29 µg/mL) and enhancement of glucose uptake by yeast cells. Interestingly, the extract demonstrated in vivo hypoglycemic and anti-inflammatory effects in streptozotocin- (STZ-) induced diabetic and xylene-induced ear swelling models, respectively. In addition, the extract improved insulin secretion, attenuated pancreatic tissue distortion and oxidative stress, and increased the activities of superoxide dismutase (SOD), catalase, and reduced glutathione (GSH), while reducing the concentration of LPO in the diabetic rats. A high-performance liquid chromatography (HPLC) analysis identified the presence of catechin (6.81e - 1 ppm), rutin (8.46 e - 1 ppm), myricetin, apigenin (4.019 e - 1 ppm), and luteolin (15.09 ppm) with respective retention times (RTs) of 13.64, 24.269, 27.781, 29.58, and 32.23 min, and these were subjected to a pharmacoinformatics analysis, which revealed their drug-likeness and good pharmacokinetic properties. A docking analysis hinted at the potential of luteolin, the most abundant compound in the extract, for targeting glucose-metabolizing enzymes. Thus, the present study provides preclinical insights into the bioactive constituents of T. garckeana, its antioxidant and anti-inflammatory effects, and its potential for the treatment of diabetes.