Pharmacological induction of diabetes mellitus in pregnant female mice: a comparison of two doses and routes of administration.

OBJECTIVE: This study aimed to compare two routes of administration and different dosages of streptozotocin (STZ) for the pharmacological induction of gestational diabetes mellitus (GDM) in pregnant CD1 females. MATERIALS AND METHODS: 35 female CD1 mice were divided into 5 groups (n = 7). Diabetes mellitus (DM) was induced with STZ by two routes and two doses: 1) Control Group without administration of STZ (CL), 2) Intraperitoneal Group with 200 mg of STZ/Kg of weight (IP200), 3) Intraperitoneal Group with 230 mg of STZ/Kg of weight (IP230), 4) Subcutaneous Group with 200 mg of STZ/Kg of weight (SC200) and 5) Subcutaneous Group with 230 mg of STZ/Kg of weight (SC230). Body weight, food and water intake, glycemia, Homeostatic Model Assessment of Insulin Resistance Index (HOMA-IR), survival, and birth rate were identified. RESULTS: The SC230 group turned out to be the most effective dose and route for the induction of GDM in pregnant females. This scheme managed to reproduce sustained hyperglycemia with high HOMA-IR, the presence of polyphagia, polydipsia, and weight loss. In addition, the birth rate and survival were high compared to the other doses and routes of administration. CONCLUSIONS: The administration of a single dose of 230 mg/kg of weight by subcutaneous route supposes advantages compared to previously used models since it decreases the physiological stress due to manipulation and the costs since it does not require repeated doses or adjuvants such as high lipid diets to potentiate the diabetogenic effect of STZ. Graphical Abstract: https://www.europeanreview.org/wp/wp-content/uploads/Graphical-abstract-12.jpg.

Polystyrene nanoplastics with different functional groups and charges have different impacts on type 2 diabetes.

BACKGROUND: Increasing attention is being paid to the environmental and health impacts of nanoplastics (NPs) pollution. Exposure to nanoplastics (NPs) with different charges and functional groups may have different adverse effects after ingestion by organisms, yet the potential ramifications on mammalian blood glucose levels, and the risk of diabetes remain unexplored. RESULTS: Mice were exposed to PS-NPs/COOH/NH2 at a dose of 5 mg/kg/day for nine weeks, either alone or in a T2DM model. The findings demonstrated that exposure to PS-NPs modified by different functional groups caused a notable rise in fasting blood glucose (FBG) levels, glucose intolerance, and insulin resistance in a mouse model of T2DM. Exposure to PS-NPs-NH2 alone can also lead the above effects to a certain degree. PS-NPs exposure could induce glycogen accumulation and hepatocellular edema, as well as injury to the pancreas. Comparing the effect of different functional groups or charges on T2DM, the PS-NPs-NH2 group exhibited the most significant FBG elevation, glycogen accumulation, and insulin resistance. The phosphorylation of AKT and FoxO1 was found to be inhibited by PS-NPs exposure. Treatment with SC79, the selective AKT activator was shown to effectively rescue this process and attenuate T2DM like lesions. CONCLUSIONS: Exposure to PS-NPs with different functional groups (charges) induced T2DM-like lesions. Amino-modified PS-NPs cause more serious T2DM-like lesions than pristine PS-NPs or carboxyl functionalized PS-NPs. The underlying mechanisms involved the inhibition of P-AKT/P-FoxO1. This study highlights the potential risk of NPs pollution on T2DM, and provides a new perspective for evaluating the impact of plastics aging.

Aloe juvenna Brandham & S.Carter as α-Amylase Inhibitor and Hypoglycaemic Agent with Anti-inflammatory Properties for Diabetes Management.

Despite Aloe's traditional use, Aloe juvenna Brandham & S.Carter is poorly characterized. Other Aloes are known for their antidiabetic activity. This study describes the antidiabetic potentials and phytoconstituents of the A. juvenna leaves methanolic extract (AJME). Twenty-six phytoconstituents of AJME were described using HPLC/MS-MS. Lupeol and vitexin were isolated using column chromatography. The antidiabetic activity of AJME was investigated using an in vivo high-fat diet/streptozotocin-induced diabetic rat model and in vitro α-glucosidase and α-amylase inhibitory activity assays. AJME demonstrated its α-amylase inhibitory activity (IC50=313±39.9 ppm) with no effect on α-glucosidase. In vivo, AJME dose-dependently improved hyperglycaemia in a high-fat diet/streptozotocin-induced diabetic rat model. Notably, the higher dose (1600 mg/kg) of AJME significantly downregulated serum interleukin-6, tumor necrosis factor-α, and matrix metalloproteinase-1 genes, suggesting its anti-inflammatory effect. These findings indicate AJME's potential as a significant antidiabetic agent through its α-amylase inhibition, hypoglycaemic, and anti-inflammatory properties.

Nrf-2-dependent antioxidant and anti-inflammatory effects underlie the protective effect of esculeoside A against retinal damage in streptozotocin-induced diabetic rats.

Esculeoside A (ESA) is a tomato-derived glycoside with antioxidant and anti-inflammatory properties. The protective effect of ESA against diabetic retinopathy is not well-investigated and was the core objective of this study. In addition, we tested if such protection involves the activation of Nrf2 signaling. Type 1 diabetes mellitus (T1DM) was induced in adult Wistar male rats by an intraperitoneal injection of streptozotocin (65 mg/kg). Non-diabetic and T1DM rats were divided into two subgroup groups given either the vehicle or ESA (100 mg)/kg. An additional T1DM group was given ESA (100 mg/kg) and an Nrf2 inhibitor (2 mg/kg) (n=8 rats/group). Treatments continued for 12 weeks. In this study, according to the histological features, ESA improved the structure of ganglionic cells and increased the number of cells of the inner nuclear and plexiform layers in the retinas of T1DM rats. Concomitantly, it reduced the retina levels of malondialdehyde (lipid peroxides), vascular endothelial growth factor, interleukin-6, tumor necrosis factor-α, Bax, and caspase-3. In the retinas of the control and diabetic rats, ESA boosted the levels of total glutathione, superoxide dismutase, heme-oxygenase-1, and Bcl2, reduced the mRNA levels of REDD1, and enhanced cytoplasmic and nuclear levels of Nrf2. However, ESA failed to alter the mRNA levels of Nrf2 and keap1, protein levels of keap1, plasma glucose, plasma insulin, serum triglycerides, cholesterol, and LDL-c in both the control and T1DM rats. In conclusion, ESA alleviates retinopathy in T1DM rats by suppressing REDD1-associated degradation and inhibiting the Nrf2/antioxidant axis.

Are insulin sensitizers the new strategy to treat Type 1 diabetes? A long-acting dual amylin and calcitonin receptor agonist improves insulin-mediated glycaemic control and controls body weight.

BACKGROUND AND PURPOSE: Insulin therapies for Type 1 diabetes (T1D) have limitations, such as glucose fluctuations, hypoglycaemia, and weight gain. Only pramlintide is approved with insulin. However, its short half-life limits efficacy, requiring multiple daily injections and increasing hypoglycaemia risk. New strategies are needed to improve glycaemic control. Dual amylin and calcitonin receptor agonists are potent insulin sensitizers developed for Type 2 diabetes (T2D) as they improve glucose control, reduce body weight, and attenuate hyperglucagonemia. However, it is uncertain if they could be used to treat T1D. EXPERIMENTAL APPROACH: Sprague Dawley rats received a single intravenous injection of streptozotocin (STZ) (50 mg·kg-1) to induce T1D. Humulin (1 U/200 g·day-1 or 2 U/200 g·day-1) was continuously infused, while half of the rats received additional KBP-336 (4.5 nmol·kg-1 Q3D) treatment. Bodyweight, food intake, and blood glucose were monitored throughout the study. An oral glucose tolerance test was performed during the study. KEY RESULTS: Treatment with Humulin or Humulin + KBP-336 improved the health of STZ rats. Humulin increased body weight in STZ rats, but KBP-336 attenuated these increases and maintained a significant weight loss. The combination exhibited greater blood glucose reductions than Humulin-treated rats alone, reflected by improved HbA1c levels and glucose control. The combination prevented hyperglucagonemia, reduced amylin levels, and increased pancreatic insulin content, indicating improved insulin sensitivity and beta-cell preservation. CONCLUSION AND IMPLICATIONS: The insulin sensitizer KBP-336 lowered glucagon secretion while attenuating insulin-induced weight gain. Additionally, KBP-336 may prevent hypoglycaemia and improve insulin resistance, which could be a significant advantage for individuals with T1D seeking therapeutic benefits.

Unveiling the chemical profiling and remarkable modulation of carbohydrate metabolism by costus root, Dolomiaea costus (Falc.) in streptozotocin (STZ)-induced diabetic rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Dolomiaea costus (Falc.), formerly Saussurea costus (Falc.) Lipsch., an ayurvedic medicinal plant, has long been recognized and utilized in diverse indigenous systems of medicine for its multifaceted therapeutic properties, including anti-inflammatory, carminative, expectorant, antiarthritic, antiseptic, aphrodisiac, anodyne, and antidiabetic effects. AIM OF THE STUDY: The potential and underlying mechanisms of D. costus root as an antidiabetic agent were investigated in this study. Additionally, the quantification of phenolic and flavonoid compounds, which dominate the extracts, was of particular interest in order to elucidate their contribution to the observed effects. MATERIALS AND METHODS: High-performance liquid chromatography/electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) was employed to analyze the chemical constituents in D. costus root aqueous extract (DCA) and D. costus root ethanolic extract (DCE). Furthermore, the inhibitory potentials of DCE and its respective fractions as well as DCA against α-amylase, α-glucosidase, and lipase enzymes were assessed. Subsequently, the efficacy of DCA and DCE extracts was evaluated using an established streptozotocin (STZ)-induced diabetic animal model; this involved administering the extracts at doses of 200 and 400 mg/kg bwt. and comparing them with a positive control (glibenclamide (Glib.) at 0.6 mg/kg bwt.). After induction of diabetes (except for negative control), all animals received the treatments orally for 21 days consecutively, followed by the collection of rat serum to assess various parameters including, glycemic and lipid profiles, liver and kidney functions, antioxidant activity, glycolysis, and gluconeogenesis pathways. RESULTS: The results of HPLC-ESI-MS/MS revealed that isochlorogenic acid A (8393.64 µg/g) and chlorogenic acid (6532.65 µg/g) were the predominant compounds in DCE and DCA, respectively. Both extracts exhibited notable antidiabetic properties, as evidenced by their ability to regulate blood glycemic and lipid profiles (glucose, insulin, HBA1C; HDL, TC, TGs), liver enzymes (ALT, ALP, AST), kidney function (urea, creatinine, uric acid), oxidative stress biomarkers (MDA), antioxidant enzymes (CAT, GSH, SOD), as well as glycolysis (glucokinase) and gluconeogenesis (G-6-P, FBP1) pathways. CONCLUSIONS: Furthermore, the administration of D. costus extracts significantly mitigated STZ-induced diabetic hyperglycemia. These results can be attributed, at least partially, to the presence of several polyphenolic compounds with potent antioxidant and anti-inflammatory activities.

Lung molecular and histological changes in type 2 diabetic rats and its improvement by high-intensity interval training.

BACKGROUND: Type 2 diabetes (T2D) leads to serious respiratory problems. This study investigated the effectiveness of high-intensity interval training (HIIT) on T2D-induced lung injuries at histopathological and molecular levels. METHODS: Forty-eight male Wistar rats were randomly allocated into control (CTL), Diabetes (Db), exercise (Ex), and Diabetes + exercise (Db + Ex) groups. T2D was induced by a high-fat diet plus (35 mg/kg) of streptozotocin (STZ) administration. Rats in Ex and Db + Ex performed HIIT for eight weeks. Tumor necrosis factor-alpha (TNFα), Interleukin 10 (IL-10), BAX, Bcl2, Lecithin, Sphingomyelin (SPM) and Surfactant protein D (SPD) levels were measured in the bronchoalveolar lavage fluid (BALF) and malondialdehyde (MDA) and total antioxidant capacity (TAC) levels were measured in lung tissue. Lung histopathological alterations were assessed by using H&E and trichrome mason staining. RESULTS: Diabetes was significantly associated with imbalance in pro/anti-inflammatory, pro/anti-apoptosis and redox systems, and reduced the SPD, lecithin sphingomyelin and alveolar number. Performing HIIT by diabetic animals increased Bcl2 (P < 0.05) and IL10 (P < 0.01) levels as well as surfactants components and TAC (P < 0.05) but decreased fasting blood glucose (P < 0.001), TNFα (P < 0.05), BAX (P < 0.05) and BAX/Bcl2 (P < 0.001) levels as well as MDA (P < 0.01) and MDA/TAC (P < 0.01) compared to the diabetic group. Furthermore, lung injury and fibrosis scores were increased by T2D and recovered in presence of HIIT. CONCLUSION: These findings suggested that the attenuating effect of HIIT on diabetic lung injury mediated by reducing blood sugar, inflammation, oxidative stress, and apoptosis as well as improving pulmonary surfactants components.

Berberine ameliorates glucocorticoid-induced hyperglycemia: an in vitro and in vivo study.

Berberine (BBR), a bioactive compound isolated from Coptidis Rhizoma, possesses diverse pharmacological activities including anti-bacterial, anti-inflammatory, antitumor, hypolipidemic, and anti-diabetic. However, its role as an anti-diabetic agent in animal models of dexamethasone (Dex)-induced diabetes remains unknown. Studies have shown that natural compounds including aloe, caper, cinnamon, cocoa, green and black tea, and turmeric can be used for treating Type 2 diabetes mellitus (DM). Compared to conventional drugs, natural compounds have less side effects and are easily available. Herein, we studied the anti-diabetic effects of BBR in a mice model of Dex-induced diabetes. HepG2 cell line was used for glucose release and glycogen synthesis studies. Cell proliferation was measured by methylthiotetrazole (MTT) assay. For animal studies, mice were treated with Dex (2 mg/kg, i.m.) for 30 days and effect of BBR at the doses 100, 200, and 500 mg/kg (p.o.) was analyzed. Glucose, insulin, and pyruvate tests were performed for evaluating the development of the diabetic model. Echo MRI was performed to assess the fat mass. Further, to elucidate the mechanism of action of BBR, mRNA expression of genes regulating gluconeogenesis, glucose uptake, and glycolysis was analyzed. In vitro BBR had no impact on cell viability up to a concentration of 50 µM. Moreover, BBR suppressed the hepatic glucose release and improved glucose tolerance in HepG2 cells. In vivo, BBR improved glucose homeostasis in diabetic mice as evidenced by enhanced glucose clearance, increased glycolysis, elevated glucose uptake, and decreased gluconeogenesis. Further, Dex treatment increased the total fat mass in mice, which was ameliorated by BBR treatment. BBR improves glucose tolerance by increasing glucose clearance, inhibiting hepatic glucose release, and decreasing obesity. Thus, BBR may become a potential therapeutic agent for treating glucocorticoid-induced diabetes and obesity in the future.

GMFB/AKT/TGF-ß3 in Müller cells mediated early retinal degeneration in a streptozotocin-induced rat diabetes model.

Retinal degeneration, characterized by Müller cell gliosis and photoreceptor apoptosis, is considered an early event in diabetic retinopathy (DR). Our previous study proposed that GMFB may mediate diabetic retinal degeneration. This study identified GMFB as a sensitive and functional gliosis marker for DR. Compared to the wild type (WT) group, Gmfb knockout (KO) significantly improved visual function, attenuated gliosis, reduced the apoptosis of neurons, and decreased the mRNA levels of tumor necrosis factor α (Tnf-α) and interleukin-1ß (Il-1ß) in diabetic retinas. Tgf-ß3 was enriched by hub genes using RNA sequencing in primary WT and KO Müller cells. Gmfb KO significantly upregulated the transforming growth factor (TGF)-ß3 protein level via the AKT pathway. The protective effect of TGF-ß3 in the vitreous resulted in significantly improved visual function and decreased the number of apoptotic cells in the diabetic retina. The protection of Gmfb KO in primary Müller cells against high glucose (HG)-induced photoreceptor apoptosis was partially counteracted by TGF-ß3 antibody and administration of TGFBR1/2 inhibitors. Nuclear receptor subfamily 3 group C member 1 (NR3C1) binds to the promoter region of Gmfb and regulates Gmfb mRNA at the transcriptional level. NR3C1 was increased in the retinas of early diabetic rats but decreased in the retinas of late diabetic rats. N'-[(1E)-(3-Methoxyphenyl)Methylene]-3-Methyl-1H-Pyrazole-5-Carbohydrazide (DS-5) was identified as an inhibitor of GMFB, having a protective role in DR. We demonstrated that GMFB/AKT/TGF-ß3 mediated early diabetic retinal degeneration in diabetic rats. This study provides a novel therapeutic strategy for treating retinal degeneration in patients with DR.

Observation of the neuroprotective efficacy of vitamin K in a streptozocin-induced diabetes model in chick embryos.

Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia due to insulin deficiency and/or resistance. Vitamin K (VK) is a group of fat-soluble molecules, including naturally occurring vitamin K1 (phylloquinone). vitamin K2 (menaquinone), and synthetic vitamin K3 (menadione). Beyond coagulation, the health benefits of VK have been described to play different roles in both physiological and pathological processes such as inflammation, energy metabolism, neuroprotection, cellular growth, and survival. It was aimed to observe the antioxidant and/or neuroprotective activity of vitamin K1 in our model of chick embryo diabetic neuropathy (DN) induced by streptozotocin (STZ). Ninety White Leghorn, fertile and 0-day-old SPF (specific pathogen-free) eggs (57 ± 4 gr) were used in the study. Chick embryo blood brain tissues were taken for biochemical evaluation. Plasma insulin and glucose levels were measured. In addition, brain tissue total antioxidant level (TAS), total oxidant level (TOS), malondialdehyde (MDA), and vascular endothelial growth factor (VEGF) levels were measured. Plasma glucose levels were higher in the STZ-treated groups and lower in the treatment groups. Plasma insulin levels were observed to be higher in STZ groups in groups treated with high VK. Low TAS, high MDA, TOS, and VEGF levels were recorded in brain tissue STZ groups. Low VEGF, TOS, and MDA levels were recorded in the group treated with the highest VK, while high TAS levels were observed. In our STZ-induced chick embryo diabetic neuropathy model, we observed that VK1 reduced oxidant damage by showing antioxidant properties or by modulating antioxidant enzymes.

Exploring effect of M2 macrophages on experimental full-thickness wound healing in streptozotocin-induced diabetic rats.

Diabetes mellitus is one of the most prevalent medical conditions, in both humans and animals. People with diabetes mellitus often experience slower than normal wound healing, making it a serious health concern. This study investigates the effect of M2 differentiated macrophages on full-thickness wound healing in white Westar rats exposed to streptozocin 70 mg/kg. A full-thickness skin defect with dimensions of 2 × 2 cm was created on the back of all the animals, and their blood sugar was simultaneously assessed. The monocytes were isolated from blood samples using the plastic adherence method and were exposed to dexamethasone (5-10 µ) for 24 h. Subsequently, they were washed with PBS and incubated in fresh cell culture medium for 5 days. The differentiated M2 cells were injected into four points of the experimental ulcers of the treatment group. Macroscopic and microscopic changes were evaluated and compared over a period of two weeks between the test and control groups. The infusion of these cells a few days after wounding enhances wound healing parameters significantly, as evidenced by an increase in germinating tissue formation, wound contraction, inflammation reduction, and collagen increase in the treated group.

Erythritol attenuates testicular dysfunction in diabetic rat via suppression of oxidative stress, inflammation and apoptosis.

Hyperglycemia -induced oxidative stress and inflammation have been closely associated with diabetes complications including testicular dysfunction. Conversely, reducing blood glucose and/or use of antioxidant have been associated with reduced diabetes complications. The present study investigated the effect of erythritol (which has both antioxidant and blood glucose lowering function) on diabetes -induced testicular dysfunction in rats. Thirty male Wistar rats (170-200g) were randomly divided into 5 groups: 1) control; 2) erythritol; 3) diabetic; 4) diabetic + erythritol 1000 mg/kg; and 5) diabetic + metformin 300 mg/kg. After 8 weeks of treatment period, blood sample, testes and epididymis were collected for reproductive hormones, biochemical and histological examinations, and sperm analysis respectively. There was a significant (p < 0.05) decrease in sperm count, sperm motility, sperm morphology and serum reproductive hormones (Follicle stimulating hormone (FSH), Leutinizing hormone (LH), testosterone and gonadotropin releasing hormone (GnRH)) of diabetes rat compared to control. Also, diabetes rat showed increase in sperm and testicular malonaldehyde (MDA) and decrease in sperm and testicular superoxide dismutase (SOD) activity and glutathione (GSH) level. Further, diabetes rat showed reduced testicular weight, decreased testicular 17ß-HSD and 3ß-HSD activity and testicular histo-architectural alteration which were accompanied by decrease testicular vascular endothelial growth factor (VEGF) and concomitant increase in testicular myeloperoxidase activity and level of caspase 3. The present results indicates that induction of diabetes in rat causes reduction in the level of reproductive hormones (Testosterone, LH and FSH) as well as sperm and testicular oxidative stress causing abnormal sperm parameters, and biochemical and histo-architectural alterations in the testes of rats. In addition, the present results suggest that erythritol administration reduced blood glucose and ameliorated hyperglycemia -induced oxidative stress -mediated alterations in both sperm and testes of diabetes rat. Further, the present study suggests that erythritol improved testicular oxidative stress, inflammation and apoptosis by up-regulating VEGF.

Crocetin ameliorative effect on diabetic nephropathy in rats through a decrease in transforming growth factor-ß and an increase in glyoxalase-I activity.

BACKGROUND & AIMS: Glycation, oxidative stress, and inflammation due to the elevation of transforming growth factor-ß1 (TGF-ß1) participate in diabetic nephropathy (DN). Thus, we investigated for the first time the effect of crocetin (Crt) on the renal histopathological parameters, TGF-ß1 and glycation, oxidative stress, as well as inflammatory markers in the DN rat model. METHODS: Forty male Wistar rats were randomly divided into 4 equal groups: normal (N), N + Crt, DN, and DN + Crt. DN was induced in rats with a combination of nephrectomy and streptozotocin. Treated groups received 100 mg/kg of Crt via intraperitoneal injection monthly for 3 months. Different glycation (glycated albumin, glycated LDL, Methylglyoxal, and pentosidine), oxidative stress (advanced oxidation protein products, malondialdehyde, glutathione, and paraoxonase-I (PON-1)), and inflammatory markers (tumor necrosis factor-α, myeloperoxidase, and TGF-ß1), blood glucose, insulin, lipid profile, creatinine in the serum, and proteinuria, as well as the glyoxalase-1 (GLO-1) activity, was determined. RESULTS: Crt decreased renal biochemical (Cre and PU) and histopathological (glomerulosclerosis) renal dysfunction parameters, diverse glycation, oxidative stress, and inflammatory markers in the DN rats. Furthermore, the treatment corrected glycemia, insulin resistance, and dyslipidemia as well as induced the activities of GLO-1 and PON-1. Over and above, the treatment decreased TGF-ß1 in their serum (p > 0.001). CONCLUSIONS: Crocetin improved DN owing to an advantageous effect on metabolic profile. Further, the treatment with a reducing effect on TGF-ß1, oxidative stress, glycation, and inflammation markers along with an increase in Glo-1 activity showed multiple protective effects on kidney tissue.

Phytochemical analysis and antihyperglycemic activity of Carissa grandiflora leaves extract on streptozotocin-induced diabetic mice.

Diabetes mellitus (DM), a prevalent metabolic condition that impairs glucose metabolism, causes morbidity and hospitalization. Thus, there is need to establish novel therapeutics against DM. The current study examined the phytochemical analysis and antidiabetic effects of Carissa grandiflora leave extracts (CGLE) on streptozotocin (STZ)-induced DM in mice. CGLE (n-hexane, chloroform, ethanol) was extracted and phytochemically examined for primary and secondary metabolites. Fourier transformed infrared spectroscopy (FTIR) detected functional groups, while 2,2-diphenyl-1-picrylhydrazyl (DPPH) test assessed antioxidant capacity. Later, antidiabetic potential of CGLE extract was investigated in vivo in STZ induced diabetic mice. Phytochemical investigation revealed sugars, ketones, alkaloids, triterpenoids, and glycosides. FTIR indicated phenol, aldehyde, ketone, alkene, alkyne, alcohol, benzene ring and amines, while DPPH assay demonstrated antioxidant potential of extract. Oral CGLE treatment significantly improved body weight (P<0.05), polyphagia and polydipsia (P<0.05) and FBG (P<0.001). Moreover, CGLE extract reversed histopathological alterations in the pancreas, liver, and kidney of diabetic mice. These outcomes highlighted that C. grandiflora extract could be effective therapeutic approach against DM.

Effect of lawsone-preconditioned mesenchymal stem cells on the regeneration of pancreatic ß cells in Type 1 diabetic rats.

Diabetes is one of the major health issues globally. Type 1 diabetes mellitus develops due to the destruction of pancreatic ß cells. Mesenchymal stem cells (MSCs) having remarkable self-renewal and differentiation potential, can regenerate ß cells. MSCs preconditioned with bioactive small molecules possess enhanced biological features and therapeutic potential under in vivo environment. Interestingly, compounds of naphthoquinone class possess antidiabetic and anti-inflammatory properties, and can be explored as potential candidates for preconditioning MSCs. This study analyzed the effect of lawsone-preconditioned human umbilical cord MSCs (hUMSCs) on the regeneration of ß cells in the streptozotocin (STZ)-induced Type 1 diabetes (T1D) rats. hUMSCs were isolated and characterized for the presence of surface markers. MSCs were preconditioned with optimized concentration of lawsone. T1D rat model was established by injecting 50 mg/kg of STZ intraperitoneally. Untreated and lawsone-preconditioned hUMSCs were transplanted into the diabetic rats via tail vein. Fasting blood sugar and body weight were monitored regularly for 4 weeks. Pancreas was harvested and ß cell regeneration was evaluated by hematoxylin and eosin staining, and gene expression analysis. Immunohistochemistry was also done to assess the insulin expression. Lawsone-preconditioned hUMSCs showed better anti-hyperglycemic effect in comparison with untreated hUMSCs. Histological analysis presented the regeneration of islets of Langerhans with upregulated expression of ßcell genes and reduced expression of inflammatory markers. Immunohistochemistry revealed strong insulin expression in the preconditioned hUMSCs compared with the untreated hUMSCs. It is concluded from the present study that lawsone-preconditioned hMSCs were able to exhibit pronounced anti-hyperglycemic effect in vivo compared with hUMSCs alone.

Adding SGLT2 Cotransporter Inhibitor to PPARγ Activator Does Not Provide an Additive Effect in the Management of Diabetes-Induced Vascular Dysfunction.

INTRODUCTION: Endothelial dysfunction (ED) plays a key role in the pathogenesis of diabetic vascular complications. In monotherapy, dapagliflozin (Dapa) as well as pioglitazone (Pio) prevent the progression of target organ damage in both type 1 (T1DM) and type 2 diabetes. We investigated whether the simultaneous PPAR-γ activation and SGLT2 cotransporter inhibition significantly alleviate ED-related pathological processes and thus normalize vascular response in experimental T1DM. METHODS: Experimental diabetes was induced by streptozotocin (STZ; 55 mg/kg, i.p.) in Wistar rats. Dapa (10 mg/kg), Pio (12 mg/kg), or their combination were administrated to the STZ rats orally. Six weeks after STZ administration, the aorta was excised for functional studies and real-time qPCR analysis. RESULTS: In the aorta of diabetic rats, impaired endothelium-dependent and independent relaxation were accompanied by the imbalance between vasoactive factors (eNos, Et1) and overexpression of inflammation (Tnfα, Il1b, Il6, Icam, Vcam) and oxidative stress (Cybb) markers. Pio monotherapy normalized response to vasoactive substances and restored balance between Et1-eNos expression, while Dapa treatment was ineffective. Nevertheless, Dapa and Pio monotherapy significantly reverted inflammation and oxidative stress markers to normal values. The combination treatment exhibited an additive effect in modulating Il6 expression, reaching the effect of Pio monotherapy in other measured parameters. CONCLUSION: Particularly, Pio exerts a vasoprotective character when used in monotherapy. When combined with Dapa, it does not exhibit an expected additive effect within modulating vasoreactivity or oxidative stress, though having a significant influence on IL6 downregulation.

Investigation of the effect of addition of Momordica charantia to glibenclamide on amelioration of endothelial dysfunction in diabetic rats by activating Takeda G protein-coupled receptor 5.

Endothelial dysfunction (ED) is a significant risk factor of blood vessel related diseases of diabetes and this study evaluate the effect of adding Momordica charantia (Mc) to glibenclamide (GLB) on ED markers in diabetic rats. Streptozotocin (STZ-40mg/kg b. w.) induced diabetic rats were randomly put into 3 groups with 10 rats/group; diabetic control [DC] group, glibenclamide treated group (GLB -2.5mg/kg) and GLB-Mc treated group (2.5mg/kg + 400mg/kg). Serum glucose was measured weekly for eight weeks whereas insulin, sVCAM-1, vWF-Ag and interleukin-6 [IL-6] were measured at week 0 and week 8. Luciferase assay was performed to determine luminescence. At week 8, GLB and GLB-Mc groups revealed improvements in blood glucose and insulin concentrations (P≤0.05) when compared to corresponding baseline values with GLB-Mc group showing slightly greater improvements. GLB-M c group also revealed improvement (P≤0.05) in vWF-Ag, sVCAM-1 and IL-6 concentrations but was non-significant in GLB group when compared to corresponding baseline values. Comparison between GLB and GLB-Mc group showed significantly high concentration of sVCAM-1 in GLB group (P≤0.05) due to its minimal effect on TGR5 activation. We conclude that adding M. charantia to GLB may be a useful choice for modulating diabetes induced ED due to its stimulatory effect on TGR5 receptors.

Esculeoside A Decreases Diabetic Cardiomyopathy in Streptozotocin-Treated Rats by Attenuating Oxidative Stress, Inflammation, Fibrosis, and Apoptosis: Impressive Role of Nrf2.

Background and Objectives: This experiment evaluated the preventative influence of the tomato-derived Esculeoside A (ESA) on diabetic cardiomyopathy in type 1 diabetes mellitus (T1DM) in rats induced by streptozotocin (STZ). It also examined whether the activation of Nrf2 signaling affords this protection. Materials and Methods: Adult male Wistar control nondiabetic rats and rats with T1DM (STZ-T1DM) were given either carboxymethylcellulose as a vehicle or ESA (100 mg/kg) (eight rats/group) orally daily for 12 weeks. A group of STZ-T1DM rats was also treated with 100 mg/kg ESA and co-treated i.p. with 2 mg/kg (twice/week), brusatol, and Nrf2 inhibitors for 12 weeks. Results and Conclusions: Treatment with ESA prevented the gain in heart weight and cardiomyocyte hypertrophy and improved the left ventricular (LV) systolic and diastolic function (LV) in the STZ-T1DM rat group. Likewise, it reduced their serum levels of triglycerides, cholesterol, and low-density lipoproteins (LDL-c), as well as their LV mRNA, cytoplasmic total, and nuclear total levels of NF-κB. ESA also reduced the total levels of malondialdehyde, tumor necrosis factor-α, interleukine-6 (IL-6), Bax, cytochrome-c, and caspase-3 in the LV of the STZ-T1DM rats. In parallel, ESA enhanced the nuclear and cytoplasmic levels of Nrf2 and the levels of superoxide dismutase, glutathione, and heme oxygenase-1, but decreased the mRNA and cytoplasmic levels of keap-1 in the LVs of the STZ-T1DM rats. Interestingly, ESA did not affect the fasting insulin and glucose levels of the diabetic rats. All of these beneficially protective effects of ESA were not seen in the ESA-treated rats that received brusatol. In conclusion, ESA represses diabetic cardiomyopathy in STZ-diabetic hearts by activating the Nrf2/antioxidant/NF-κB axis.

Ectopic expression of insulin in a type 1 diabetic rat model by injection of manipulated mesenchymal stem cells with an insulin construct driven by a glucose-sensitive promoter in the port vein.

The treatment of type 1 diabetes through islet cell transplantation is a complex process, facing challenges such as allograft rejections and a limited supply of donors. One potential solution is to utilize the liver as an alternative for natural insulin production, as hepatocytes can secrete proteins and respond to glucose levels. Recent research has shown promising results in using mesenchymal stem cells as a potential cure for diabetes. The study utilized a diabetic rat model, confirmed through blood sugar measurement. A plasmid vector was designed with specific genetic components, synthesized by biotech company, and then Inserted vector into a plasmid with resistance genes and bacterial origin. Bone marrow-derived mesenchymal stem cells (BM-MSCs) were cultured and transfected with the plasmid using Lipofectamine 3000. Polymerase chain reaction was employed to confirm successful transfection using specific primers. For the animal study, 30 male Wistar rats were divided into six groups, each comprising five rats. The control group did not receive any treatment, while the second group received MSCs via Portal Vein Injection. The third group received MSCs transfected with a specific construct via Portal Vein Injection. The fourth group was induced to develop diabetes through streptozotocin (STZ) injection, the fifth group developed diabetes and received untransfected MSCs via Portal Vein Injection, and the sixth group received MSCs transfected with the specific construct via Portal Vein Injection. To manage Pain, appropriate pain control was administered to the rats for 3 days after the surgery. Fixed liver tissues obtained from the euthanized rats were utilized for immunohistochemistry. In this study, immunohistochemical techniques were used to examine insulin expression in different groups of rats. The control groups showed high levels of insulin expression, while the diabetic groups exhibited lower expression. However, there was a significant difference between the diabetic groups treated with MSC and transgenic MSC cells. All groups had similar baseline glucose levels, but the diabetic groups showed a significant increase after STZ injection, whereas the control and MSC groups did not. Postintervention, both the control and MSC groups had similar glucose levels to the post-STZ levels. However, diabetes-induced groups experienced a significant decrease in glucose levels, with the transfected MSCs showing a greater decrease than the untransfected MSCs. The study suggested that treatment with MSCs, especially transfected ones, can effectively reduce glucose levels in rats with diabetes. In this research, rat BM-MSCs were utilized to create insulin-producing mesenchymal cells with glucose-sensitive insulin expression. The cells were transferred to the liver of diabetic rats via portal vein injection, leading to an increase in insulin expression. This study proposes a novel approach for cell therapy and delivery in the treatment of type 1 diabetes.

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.