Assessing the potential fasting and postprandial mechanisms involved in the acute hypoglycemic and anti-hyperglycemic effects of four selected plants from Iran used in traditional Persian medicine.

ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Persian medicine (TPM), people often use herbal infusions as a dosage form to treat diseases related to hyperglycemia, known as 'dam-kardeh'. Traditionally, herbal preparations of Eryngium bungei Boiss. (E. b), Tragopogon buphthalmoides (DC.) Boiss. (T. b), Salvia hydrangea DC. ex Benth. (S. h), and Juniperus polycarpos K. Koch. (J. p) are used to manage diabetes in Iran. However, there is no evidence of their effectiveness in controlling glucose levels and their mechanisms remain unclear. AIM OF THE STUDY: This study aimed to investigate whether traditional doses of plant infusions can have hypoglycemic and/or anti-hyperglycemic effects during fasting and/or postprandial states and establish the basis for future research on their potential mechanisms of action. MATERIALS AND METHODS: The effects of traditional doses of herbal extracts on blood glucose levels in STZ-NA-induced hyperglycemic rats were investigated in 2-h acute tests during fasting and postprandial states (with a glucose load). In addition, the potential inhibitory effect in vitro of enzymes involved in relevant pathways, such as gluconeogenesis (fructose-1,6-bisphosphatase, FBPase and glucose-6-phosphatase, G6Pase), carbohydrate breakdown (intestinal α-glucosidases), and insulin sensitivity (protein tyrosine phosphatase 1B, PTP-1B) was evaluated. Acute toxicity tests were carried out and HPLC-SQ-TOF was used to analyze the chemical profiles of the plant extracts. RESULTS: In the fasting state, T. b, S. h, and E. b were as effective as glibenclamide in lowering blood glucose levels in hyperglycemic rats. Moreover, all three suppressed G6Pase and FBPase enzymatic activity by 90-97% and 80-91%, respectively. On the other hand, significant postprandial hypoglycemic efficacy was observed for E. b, S. h, and T. b. Based on the AUC values, T. b caused a reduction comparable to the therapeutic efficacy of repaglinide. When investigating the possible mechanisms of action involved in this activity, E. b, S. h, and T. b showed significant inhibition of PTP-1B in vitro (>70%). Finally, all plant extracts showed no signs of acute toxicity. Several compounds that may contribute to biological activities were identified, including phenolic acids and flavonoid glycosides. CONCLUSIONS: The present study supports the traditional use of T. b, E. b and S. h for the control of diabetes in the fasting and postprandial state. Moreover, these plants were found to be rich in bioactive compounds with hypoglycemic and antihyperglycemic activities. On the other hand, J. p, showed a modest effect only in the fasting state and after 90 min. Further studies are needed to expand these results by analyzing the chemical composition and using complementary experimental models.

Syzygium cumini (L.) skeels mitigate diabetic nephropathy by regulating Nrf2 pathway and mitocyhondrial dysfunction: In vitro and in vivo studies.

ETHNOPHARMACOLOGICAL PREVALENCE: Hyperglycemia in diabetes increases the generation of advanced glycation end products (AGEs) through non-enzymatic reactions. The interaction between AGEs and their receptors (RAGE) leads to oxidative and inflammatory stress, which plays a pivotal role in developing diabetic nephropathy. Syzygium cumini (SC) L. (DC.) homeopathic preparations viz. 200C, 30C, and mother tincture [MT] are used to treat diabetes. This study aimed to elucidate the regulatory effects of SC preparations (200C, 30C, and MT) on the nuclear factor erythroid 2-related factor 2 (Nrf2) - nuclear factor-κB (NF-κB) pathways and mitochondrial dysfunction in mitigating diabetic nephropathy (DN). MATERIALS AND METHODS: Streptozotocin-induced diabetic rats were treated with SC preparations (200C, 30C, MT; 1:20 dilution in distilled water; 600 µL/kg body weight) and metformin (45 mg/kg body weight) twice daily for 40 days. DN was evaluated through biochemical parameters and histological examination. Renal tissue lysates were analyzed for glycation markers. Protein and gene levels of Nrf2, NF-κB, and mitochondrial dysfunctional signaling were determined via western blotting and RT-qPCR. An immunohistochemical analysis of the kidneys was performed. In vitro, human serum albumin (HSA - 10 mg/ml) was glycated with methylglyoxal (MGO - 55 mM) in the presence of SC preparations (200C, 30C, MT) for eight days. Glycated samples (400 µg/mL) were incubated with renal cells (HEK-293) for 24 h. Further reactive oxygen species production, Nrf2 nuclear translocation, and protein or gene expression of Nrf2 and apoptosis markers were analyzed by western blotting, RT-qPCR, and flow cytometry. Molecular docking of gallic and ellagic acid with the HSA-MGO complex was performed. RESULT: In vivo experiments using streptozotocin-induced diabetic rats treated with SC preparations exhibited improved biochemical parameters, preserved kidney function, and reduced glycation adduct formation in a dose-dependent manner. Furthermore, SC preparations downregulated inflammatory mediators such as RAGE, NF-κB, vascular endothelial growth factor (VEGF), and Tumor necrosis factor α (TNF-α) while upregulating the Nrf2-dependent antioxidant and detoxification pathways. They downregulated B-cell lymphoma 2 (Bcl-2) associated X-protein (BAX), C/EBP homologous protein (CHOP), Dynamin-related protein 1 (DRP1), and upregulated BCL 2 gene expression. Notably, SC preparations facilitated nuclear translocation of Nrf2, leading to the upregulation of antioxidant enzymes and the downregulation of oxidative stress markers. Molecular docking studies revealed favorable interactions between gallic (-5.26 kcal/mol) and ellagic acid (-4.71 kcal/mol) with the HSA-MGO complex. CONCLUSION: SC preparations mitigate renal cell apoptosis and mitochondrial dysfunction through Nrf2-dependent mechanisms.

Ozone Administration Reduces Myocardial Ischemia Reperfusion Injury in Streptozotocin Induced Diabetes Mellitus Rat Model.

Objective: This study aimed to demonstrate whether ozone has cardioprotective effects on the myocardial ischemia-reperfusion injury (IRI) in rats with streptozotocin(STZ)-induced diabetes. Methods: A total of 38 male Wistar Albino rats were divided into five groups as follows: control group (group C,n=6), diabetic group (group D,n=6), diabetic ozone group (group DO,n=6), diabetic-ischemia/reperfusion (group DIR,n=6), diabetic-ischemia/reperfusion-ozone (group DIRO,n=6). Six rats died during this period and two died because of surgical complications. A myocardial ischemia-reperfusion model was created using a thoracotomy incision from 4th intercostal space. The LAD was ligated using an 8-0 prolene suture for 30min. Ozone was administered intraperitoneally(1mg/kg) 5min before reperfusion. The reperfusion time was 120 min. At the end of the reperfusion procedure, myocardial tissue histopathological examinations, and serum biochemical analyses were performed. Results: The percentage of TUNEL(+) cardiomyocytes/HPF was significantly higher in the DIR group than in the C, D, and DO groups. Conversely, TUNEL positivity was significantly lower in the DIRO group than in the DIR group. The IRI score was significantly higher in the DIR and DIRO groups than that in the C, D, and DO groups. In contrast, the IRI damage score in the DIRO group was significantly lower than that in the DIR group. Serum MDA levels were significantly higher in the DIR group than in the C, D, and DO groups. Similarly, MDA levels were significantly higher in the DIRO group than in the C and D groups. CAT activity was significantly higher in the DIR group than in the C and D groups. SOD activity was significantly higher in the DIR group than in the C and DO groups. Conclusion: Our study showed that ozone exerts cardioprotective effects in STZ-induced diabetic rats through its antioxidant role against oxidative stress. Both biochemical and histological analyses clearly revealed that ozone has beneficial effects against IRI in the diabetic rat myocardium.

The modulatory effects of tyrosol and nano-tyrosol on anxiety-like behavior and emotional memory in streptozotocin-induced diabetic rats.

The effects of tyrosol and nano-tyrosol on the modulation of anxiety-like behavior and memory processes were evaluated in streptozotocin-induced diabetic rats. Male diabetic rats were orally treated with 1 ml of saline, nano-niosome, tyrosol, and nano-tyrosol (20 mg/dl) for 30 days. Anxiety-like behavior and memory process were evaluated by an elevated plus-maze (EPM) test-retest paradigm. The results showed that a single intraperitoneal (i.p.) administration of streptozotocin (50 mg/kg) raised blood glucose. While daily intragastric administration of tyrosol and nano-tyrosol reduced blood glucose. Induction of type II diabetes produced a distorted cellular arrangement whereas treatment with tyrosol and nano-tyrosol showed a typical cellular arrangement in the liver. Furthermore, induction of type II diabetes decreased %OAT (%open-arm time) but daily intragastric application of tyrosol (20 mg/dl) and nano-tyrosol (20 mg/dl) enhanced %OAT and %OAE (%open-arm entry) in the EPM when compared to the saline groups, showing anxiogenic- and anxiolytic-like effects, respectively. Also, induction of type II diabetes increased %OAT while daily intragastric administration of tyrosol (20 mg/dl) and nano-tyrosol (20 mg/dl) decreased %OAT and %OAE in the EPM in comparison to the saline groups, displaying impairment and improvement of emotional memory, respectively. Interestingly, nano-tyrosol exhibited the highest significant effect rather than tyrosol. Upon these results, we proposed the beneficial effects of tyrosol and nano-tyrosol on the modulation of anxiety-like behavior and memory processes in streptozotocin-induced diabetic rats.

Mitigation of Diabetes Mellitus Using Euphorbia helioscopia Leaf Ethanolic Extract by Modulating GCK, GLUT4, IGF, and G6P Expressions in Streptozotocin-Induced Diabetic Rats.

Diabetes mellitus is a metabolic disorder. Synthetic antidiabetics are the commonly used treatment options associated with complications. The objective of this study was to explore the antioxidative and antidiabetic potential of Euphorbia helioscopia whole plant ethanolic extract using in vitro and in vivo models. For that purpose, the antioxidative potential was explored by using 2,2-diphenyl-1-picrylhydrazyl analysis. In vitro antidiabetic potential of the extract was evaluated using amylase inhibitory analysis. In vivo antidiabetic activity of the extract was assessed in diabetic rats using streptozotocin/nicotinamide (60 mg/kg/120 mg/kg) as an inducing agent. Metformin was used as standard. The results indicated the presence of significant quantities of phenolic 82.18 ± 1.28 mgg-1 gallic acid equivalent (GAE) and flavonoid 66.55±1.22 mgg-1 quercetin equivalent (QE) contents in the extract. Quantitation of phytoconstituents exhibited the presence of sinapic acid, myricetin, and quercetin using HPLC analysis. The extract inhibited α-amylase by 84.71%, and an antiglycemic potential of 50.34% was assessed in the OGTT assay. Biochemical analysis demonstrated a reduction in urea, creatinine, cholesterol, low-density lipoprotein, and alkaline phosphatase (p < 0.001) as compared to diabetic control rats at the dose of 500 mg/kg. An upregulation in the expressions of glucokinase, glucose transporter 4, peroxisome proliferator-activated receptor γ, and insulin-like growth factor was observed in treated rats in contrast to G6P expression, which was downregulated upon treatment. In conclusion, this study provided evidence of the antioxidative and antidiabetic potential of E. helioscopia whole plant ethanolic extract through in vitro and in vivo analysis and emphasized its promising role as a natural alternative.

Bovine umbilical mesenchymal stem cell-conditioned medium increased expression of GLUT-4 in pancreas of diabetic rats induced by nicotinamide-streptozotocin.

Background: Diabetes is a degenerative disease associated with metabolic disorders. The majority of people have type 2 diabetes mellitus (DM) insulin resistance due to an unhealthy lifestyle. The development of DM treatment is also growing, one of which is using conditioned medium. Aim: This study aims to determine the effect of Bovine umbilical mesenchymal stem cell-conditioned medium (BUMSC-CM) on nicotinamide (NA) and streptozotocin (STZ) induced rats as an animal model of DM. Methods: The study began with the in vitro docking of Cholecalciferol with aldolase reductase and glucokinase. In the in vivo study, animal models were divided into five groups: group A (negative control), group B (diabetic rats), group C (NA+STZ+Metformin), group D (NA+STZ+ BUMSC-CM 0.2 ml/kg BW), and group E (NA+STZ+ BUMSC-CM 0.5 ml/kg BW). Blood sugar levels were checked, and BUMSC-CM was administered by intramuscular injection at four-day intervals for a duration of 16 days. Blood sugar levels were also sampled, and GLUT4 histochemical and immunohistochemical staining was performed. Results: The results showed that Cholecalciferol can bind to aldolase reductase ASP43 and TYR48 and bind to glucokinase at TYR214 with hydrogen bonds. BUMSC-CM administration was able to reduce blood sugar well. In addition, BUMSC-CM also helped repair the tissue structure of the pancreas damaged by inflammation from STZ administration. Conclusion: This study can be concluded that the administration of BUMSC-CM can be an alternative cell-free therapy for patients with DM.

The wound healing and hypoglycemic activates of date palm (Phoenix dactylifera) leaf extract and saponins in diabetic and normal rats.

INTRODUCTION: Indigenous plants have historically been crucial in treating human diseases across various cultures worldwide. Research continues to uncover new therapeutic uses for indigenous plants, from treating infectious diseases to managing chronic conditions such as diabetes and wound care. This study aimed to examine the effect of palm tree leaves "Phoenix dactylifera L" extract and its topical film formulation on wound healing and blood glucose levels. METHODS: Palm leaves were collected, authenticated, powdered, and extracted with ethanol by cold maceration. Saponins were isolated. The dried extract was analyzed using reverse-phase high-pressure liquid chromatography to identify the phytochemicals present. Diabetes mellitus was induced by a single intraperitoneal injection of Streptozotocin (40mg/kg). Rats with blood glucose levels ≥ 200 mg/dl were used to determine the reduction in blood glucose with or without the oral extract. Incision and excision wounds were induced in both diabetic and normal rats. Topical films containing extract or saponin and inert films were applied to the wounds every other day, and wound sizes were recorded until the wound was completely healed. RESULTS: The presence of six flavonoids, Naringin, Rutin, Quercetin, Kaempferol, Apigenin, and Catechin, and five phenolic acids, Syringic acid, p Coumaric acid, Caffeic acid, Ferulic acid, Ellagic acid were detected in the dried extract. A significant reduction in blood sugar in diabetic rats and wound diameter in the treated group compared to the control group in both diabetic and normal rats was observed, confirming the promising role of palm leaf extract on diabetes and wound care. Macroscopic, morphometric, and histological data suggested that the cutaneous wound healing in rats treated with the leaf extract was better and faster than the control or inert groups. CONCLUSIONS: Our research findings highlight the marked effect of Phoenix dactylifera extract as a supportive or alternative treatment for both hyperglycemia and incision or excision wounds. Further research and clinical trials are warranted to validate these findings and explore the underlying mechanisms of action.

Effects of combustible cigarettes and electronic nicotine delivery systems on immune cell-driven inflammation: Evidences from diabetic patients and multiple low dose streptozotocin-treated diabetic mice.

Considering detrimental impacts of combustible cigarettes (CCs) on the exacerbation of diabetes mellitus (DM), a significant number of DM patients have substituted CCs with electronic nicotine delivery systems (ENDS). Herewith, we compared CCs and ENDS-dependent modulation of immune cell-driven inflammation in DM patients who used ENDS (DMENDS), CCs (DMCC) or were non-smokers (DMAIR), paving the way for the better understanding of ENDS-induced biological effects. Multiple low dose streptozotocin (MLD-STZ)-induced mice model of DM was used to support clinical findings. Both CCs and ENDS aggravated MLD-STZ-induced DM. Pancreatic injury and inflammation were more severe in CC-exposed than in ENDS-exposed diabetic mice. CCs promoted activation of NLRP3 inflammasome, enhanced production of inflammatory cytokines in neutrophils, macrophages and remarkably improved antigen presenting capacity of dendritic cells which resulted in the expansion of TNF-α, IFN-γ and IL-17-producing Th1 and Th17 lymphocytes, NK and NKT cells. Compared to CCs, ENDS more intensively promoted expansion of FoxP3-expressing, IL-10-producing NK and NKT cells and triggered less intense systemic inflammatory response in diabetic animals. Similar findings were observed in DM patients. The highest numbers of inflammatory, TNF-α and IL-1ß-producing neutrophils and monocytes, TNF-α and IFN-γ-producing T lymphocytes, NK and NKT cells were determined in the blood of DMCC patients, while total number of immunosuppressive, TGF-ß-producing CD3 + CD4 + T cells was the highest in the blood of DMENDS patients. In conclusion, although both CC and ENDS aggravate on-going inflammation in DM, ENDS have weaker capacity to induce production of inflammatory cytokines in immune cells than CCs.

ED-71 Ameliorates Bone Loss in Type 2 Diabetes Mellitus by Enhancing Osteogenesis Through Upregulation of the Circadian Rhythm Coregulator BMAL1.

Purpose: Bone loss is a common complication of type 2 diabetes mellitus (T2DM). Circadian rhythms play a significant role in T2DM and bone remodeling. Eldecalcitol (ED-71), a novel active vitamin D analog, has shown promise in ameliorating T2DM. We aimed to investigate whether the circadian rhythm coregulator BMAL1 mediates the anti-osteoporotic effect of ED-71 in T2DM and its associated mechanisms. Methods: A T2DM mouse model was established using high-fat diet (HDF) and streptozotocin (STZ) injection, and blood glucose levels were monitored weekly. HE staining, Masson staining, and Micro-CT were performed to assess the changes in bone mass. IHC staining and IF staining were used to detect osteoblast status and BMAL1 expression and RT-qPCR was applied to detect the change of oxidative stress factors. In vitro, high glucose (HG) stimulation was used to simulate the cell environment in T2DM. RT-qPCR, Western blot, IF, ALP staining and AR staining were used to detect osteogenic differentiation and SIRT1/GSK3ß signaling pathway. DCFH-DA staining was used to detect reactive oxygen species (ROS) levels. Results: ED-71 increased bone mass and promoted osteogenesis in T2DM mice. Moreover, ED-71 inhibited oxidative stress and promoted BMAL1 expression in osteoblasts The addition of STL1267, an agonist of the BMAL1 transcriptional repressor protein REV-ERB, reversed the inhibitory effect of ED-71 on oxidative stress and the promotional effect on osteogenic differentiation. In addition, ED-71 facilitated SIRT1 expression and reduced GSK3ß activity. The inhibition of SIRT1 with EX527 partially attenuated ED-71's effects, whereas the GSK3ß inhibitor LiCl further enhanced ED-71's positive effects on BMAL1 expression. Conclusion: ED-71 ameliorates bone loss in T2DM by upregulating the circadian rhythm coregulator BMAL1 and promoting osteogenesis through inhibition of oxidative stress. The SIRT1/GSK3ß signaling pathway is involved in the regulation of BMAL1.

Therapeutic potential of aquatic Stevia extract in alleviating endoplasmic reticulum stress and liver damage in streptozotocin-induced diabetic rats.

BACKGROUND: Misfolded proteins accumulate in the liver due to endoplasmic reticulum stress (ERS) caused by high blood glucose levels in diabetes. This triggers the unfolded protein response (UPR), which if persistently activated, results in cellular dysfunction. Chronic ER stress increases inflammation, insulin resistance, and apoptosis. There is growing interest in using native plants and traditional medicine for diabetes treatment. The stevia plant has recently gained attention for its potential therapeutic effects. This study investigates the protective effects of aquatic stevia extract on liver damage, ER stress, and the UPR pathway in streptozotocin (STZ)-induced diabetic rats. METHODS: Rats were randomly divided into four groups: a control group that received 1 ml of water; a diabetic group induced by intraperitoneal injection of STZ (60 mg/kg); a diabetic group treated with metformin (500 mg/kg); and a diabetic group treated with aquatic extracts of stevia (400 mg/kg). After 28 days, various parameters were assessed, including inflammatory markers, oxidative stress indices, antioxidant levels, gene expression, stereology, and liver tissue pathology. RESULT: Compared to the diabetic control group, treatment with stevia significantly decreased serum glucose, liver enzymes, inflammatory markers, and oxidative stress while increasing body weight and antioxidant levels. Additionally, stevia extract manipulated UPR gene expression and reduced apoptosis pathway activation. Histological examination revealed improved liver tissue morphology in stevia-treated diabetic rats. CONCLUSION: These findings suggest that aquatic stevia extract mitigates ER stress in diabetic rats by modulating the IRE-1 arm of the UPR and apoptosis pathways, highlighting its potential therapeutic benefits for diabetes-related liver complications.

Exploring the analgesic potential of isorhamnetin: insights from formalin-induced pain and diabetic neuropathy models.

OBJECTIVE: Isorhamnetin, a naturally occurring flavonoid compound, holds paramount importance as a primary constituent within several medicinal plants, exhibiting profound pharmacological significance. The aim of this study is to investigate the pain-relieving attributes of isorhamnetin in murine models through both formalin-induced pain and diabetic neuropathy scenarios. MATERIALS AND METHODS: To achieve our objective, isorhamnetin was orally administered to mice at varying dosage levels (10 to 100 mg/kg). Pain-related behaviors were assessed using the formalin test during its secondary phase. Additionally, the potential pain-alleviating effect of isorhamnetin was evaluated in a diabetic neuropathy model induced by streptozotocin. Additionally, we carried out advanced interventions using naloxone, which is a well-known antagonist of opioid receptors, yohimbine, which blocks α2-adrenergic receptors, and methysergide, which inhibits serotonergic receptors, during the formalin test. RESULTS: The oral intake of isorhamnetin showed a decrease in behaviors associated with pain that was proportional to the dose observed during the second phase of the formalin test when induced by formalin. In the diabetic neuropathy model, isorhamnetin administration effectively reversed the reduced pain threshold observed. Notably, naloxone, the opioid receptor antagonist, effectively counteracted the pain-relieving effect produced by isorhamnetin in the formalin test, whereas yohimbine and methysergide did not yield similar outcomes. Isorhamnetin also led to a reduction in elevated spinal cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) levels triggered by formalin, with this effect reversed by pre-treatment with naloxone. The compound also suppressed heightened spinal phosphorylated CREB (p-CREB) levels caused by diabetic neuropathy. CONCLUSIONS: This research determined that isorhamnetin has notable abilities to relieve pain in models of formalin-induced pain and diabetic neuropathy. The pain-relieving mechanism of isorhamnetin in the formalin-induced pain model seems to be connected to the activation of spinal opioid receptors and the adjustment of CREB protein amounts. This insight improves our knowledge of how isorhamnetin could be used therapeutically to treat pain conditions stemming from formalin-induced pain and diabetic neuropathy.

Evaluation of Peripheral Neuropathy in Rat Models of Metabolic Syndrome and Diabetes Mellitus.

The dynamics of nephropathy development in rats with type 2 diabetes mellitus, caused by a high-fat diet and the streptozotocin administration (25 mg/kg), and metabolic syndrome, caused by addition of 20% fructose solution to the diet, was evaluated during the experiment. Models with moderate severity of metabolic changes without significant changes in body weight were obtained after 24 weeks. To study neuropathy severity, the method of electroneuromyography was used; the velocities of motor and sensory excitation propagation along the caudal nerve fibers were measured. In modeled diabetes mellitus against the background of hyperglycemia, a marked decrease in motor and sensory propagation rates was observed, and an increase in the response durations was noted from week 12 to week 24, indicating pronounced neuropathy. In the fructose model, the motor response duration increased from week 12, which possibly indicates the development of peripheral neuropathy.

Acute effects of empagliflozin on open-loop baroreflex function and urine output in streptozotocin-induced type 1 diabetic rats.

Although sympathetic suppression is considered one of the mechanisms for cardioprotection afforded by sodium-glucose cotransporter 2 (SGLT2) inhibitors, whether SGLT2 inhibition acutely modifies sympathetic arterial pressure (AP) regulation remains unclear. We examined the acute effect of an SGLT2 inhibitor, empagliflozin (10 mg/kg), on open-loop baroreflex static characteristics in streptozotocin (STZ)-induced type 1 diabetic and control (CNT) rats (n = 9 each). Empagliflozin significantly increased urine flow [CNT: 25.5 (21.7-31.2) vs. 55.9 (51.0-64.5), STZ: 83.4 (53.7-91.7) vs. 121.2 (57.0-136.0) µL·min-1·kg-1, median (1st-3rd quartiles), P < 0.001 for empagliflozin and STZ]. Empagliflozin decreased the minimum sympathetic nerve activity (SNA) [CNT: 15.7 (6.8-18.4) vs. 10.5 (2.9-19.0), STZ: 36.9 (25.7-54.9) vs. 32.8 (15.1-37.5) %, P = 0.021 for empagliflozin and P = 0.003 for STZ], but did not significantly affect the peripheral arc characteristics assessed by the SNA-AP relationship. Despite the significant increase in urine flow and changes in several baroreflex parameters, empagliflozin preserved the overall sympathetic AP regulation in STZ-induced diabetic rats. The lack of a significant change in the peripheral arc may minimize reflex sympathetic activation, thereby enhancing a cardioprotective benefit of empagliflozin.

Sema4D deficiency enhances glucose tolerance through GLUT2 retention in hepatocytes.

BACKGROUND: The glucose transporter 2 (GLUT2) is constitutively expressed in pancreatic beta cells and hepatocytes of mice. It is the most important receptor in glucose-stimulated insulin release and hepatic glucose transport. The Sema4D is a signalin receptor on cell membranes. The correlation between Sema4D and GLUT2 has not been reported previously. We investigated whether knockdown of Sema4D could exert a hypoglycemic effect based on the increased GLUT2 expression in Sema4D -/- mice hepatocytes. METHODS: The glucose tolerance test and insulin tolerance test in sema4D -/- and sema4D +/+ mice were compared before and after streptozotocin (STZ) injection; the expression of GLUT2 content on the membrane surface of both groups was verified by Western blot. Then, the levels of insulin and C-peptide in the serum of the two groups of mice after STZ injection were measured by ELISA; the differentially expressed mRNAs in the liver of the two groups of mice were analyzed by transcriptomic analysis; then the differences in the expression of GLUT2, glycogen, insulin and glucagon in the two groups of mice were compared by tissue section staining. Finally, metabolomics analysis was performed to analyze the metabolites differentially expressed in the two groups of mice. KEY FINDINGS: First, Sema4D -/- male mice exhibited significantly greater glucose tolerance than wild-type mice in a hyperglycemic environment. Secondly, Sema4D -/- mice had more retained GLUT2 in liver membranes after STZ injection according to an immunofluorescence assay. After STZ injection, Sema4D -/- male mice did not exhibit fasting hyperinsulinemia like wild-type mice. Finally, analysis of metabolomic and immunohistochemical data also revealed that Sema4D -/- mice produce hypoglycemic effects by enhancing the pentose phosphate pathway, but not glycogen synthesis. CONCLUSIONS: Thus, Sema4D may play an important role in the regulation of glucose homeostasis by affecting GLUT2 synthesis.

Impact of streptozotocin-induced diabetes on experimental masseter pain in rats.

This study aimed to assess the influence of streptozotocin (STZ)-induced diabetes on the nociceptive behavior evoked by the injection of hypertonic saline (HS) into the masseter muscle of rats. Forty male rats were equally divided into four groups: a) isotonic saline control, which received 0.9% isotonic saline (IS), (Ctrl-IS); b) hypertonic saline control, which received 5% HS (Ctrl-HS); c) STZ-induced diabetic, which received IS, (STZ-IS); d) STZ-induced diabetic, which received HS (STZ-HS). Experimental diabetes was induced by a single intraperitoneal injection of STZ at dose of 60 mg/kg dissolved in 0.1 M citrate buffer, and 100 µL of HS or IS were injected into the left masseter to measure the nociceptive behavior. Later on, muscle RNA was extracted to measure the relative expression of the following cytokines: cyclooxygenase-2 (COX-2), tumor necrosis factor (TNF-α), and interleukins (IL)-1ß, -2, -6, and -10. One-way analysis of variance (ANOVA) was applied to the data (p < 0.050). We observed a main effect of group on the nociceptive response (ANOVA: F = 11.60, p < 0.001), where the Ctrl-HS group presented the highest response (p < 0.001). However, nociceptive response was similar among the Ctrl-IS, STZ-IS, and STZ-HS group (p > 0.050). In addition, the highest relative gene expression of TNF-α and IL-6 was found in the masseter of control rats following experimental muscle pain (p < 0.050). In conclusion, the loss of somatosensory function can be observed in deep orofacial tissues of STZ-induced diabetic rats.

The potential protective effect of propolis on diabetic nephropathy induced by streptozotocin in adult albino rats.

Diabetes mellitus is a common metabolic disorder. It is associated with serious life-threatening complications if not properly managed. The current study aimed at investigating the possible protective role of propolis on streptozotocin-induced diabetic nephropathy. A diabetic rat model was induced by a single intraperitoneal injection of 55 mg/kg streptozotocin. After 4 days, the diabetic rats received oral propolis (300 mg/kg/day) via gastric gavage for 28 days. Biochemical, histopathological and ultrastructural evaluations were performed. The results showed that: streptozotocin-induced diabetes was associated with a marked decrease in the serum high-density lipoproteins and antioxidant enzymes. However, a significant elevation in the levels of serum creatinine, blood urea nitrogen, uric acid, cholesterol, triglycerides and low-density lipoproteins was detected. Furthermore, streptozotocin treatment induced histopathological alterations of the renal cortex; in the form of distorted glomerular capillaries, widened Bowman's space and signs of epithelial tubular degeneration. Ultra-structurally, thickening and irregularity of the glomerular basement membrane and podocytes foot processes effacement were observed. The tubular epithelial cells showed swollen vacuolated mitochondria, scarce basal infoldings and loss of microvilli. Conversely, propolis partially restored the normal lipid profile, antioxidant biomarkers and renal cortical morphology. Propolis exhibited a sort of renoprotection through hypoglycemic, anti-hyperlipidemic and antioxidant effects.

Docosahexaenoic acid eliminates endoplasmic reticulum stress and inflammatory pathways in diabetic rat keratopathy.

Diabetic keratopathy, characterized by corneal structural changes, is a common complication of diabetes mellitus (DM). Docosahexaenoic acid (DHA), an omega-3 fatty acid, has shown potential therapeutic benefits in various diabetic complications. This study aimed to investigate the protective effect of DHA on corneal tissue in streptozotocin (STZ)-induced type 2 DM in rats. Forty male Sprague-Dawley rats were randomly assigned to four groups (n = 10 per group): Control, DHA, DM, and DM + DHA. The DHA group received DHA by oral gavage at a dose of 100 mg/kg daily for 10 days. In the DM group, diabetes was induced by a single intraperitoneal injection of STZ at 50 mg/kg. Confirmation of diabetes induction was based on monitoring fasting blood glucose levels on the third day post-injection. The DM + DHA group underwent the same diabetes induction protocol with STZ and received DHA at 100 mg/kg daily via oral gavage for 10 consecutive days. Corneal tissue samples were collected at the end of the study period for histopathological, immunohistochemical, qRT-PCR, and ELISA analyses. Histopathological analysis showed significant edema, angiogenesis, and degeneration in the DM group compared to the control (p < 0.001). DHA treatment significantly mitigated these changes, approaching control levels (p < 0.01). Immunohistochemistry showed increased VEGFR2 and iNOS expression in the DM group, which was significantly reduced in the DM + DHA group (p < 0.01). qRT-PCR results indicated a significant decrease in Bcl-2 expression (p < 0.001) and an increase in ATF-6, IRE1, NF-κB, TNF-α, IL-1ß, NLRP3, Bax, and Caspase-3 expressions in the DM group (p < 0.001). ELISA analyses revealed significantly elevated levels of inflammatory markers NF-κB, TNF-α, IL-1ß, and IL-6 in the DM group compared to the control (p < 0.001). DHA treatment significantly upregulated Bcl-2 and downregulated apoptotic and inflammatory markers (p < 0.01). DHA demonstrated significant protective effects against STZ-induced corneal damage in diabetic rats by modulating apoptotic and inflammatory pathways. These findings suggest that DHA may be a promising therapeutic agent for preventing diabetic keratopathy.

Hypoglycemic effect of orally administered resistant dextrins prepared with different acids on type 2 diabetes mice induced by high-fat diet and streptozotocin.

A comparative study was performed to investigate the physicochemical properties and protective effects of hydrochloric acid-resistant dextrin (H-RD), citric acid-resistant dextrin (C-RD) and tartaric acid-resistant dextrin (T-RD) on the metabolic disorders and intestinal microbiota for type 2 diabetes mellitus (T2DM) mice. T-RD had the minimum molecular weight, with the highest short chain (DP 6-12) proportion and resistant starch content. After 4-week intervention with the three resistant dextrins, the body weight and fasting blood glucose of T2DM mice were improved significantly, accompanied by the reduction of serum indexes (TG, TC, LDL-C, ALT, AST, CRE, BUN, FINS, and GSP), but the serum HDL-C and liver glycogen levels increased. Among the three RDs intervention groups, T-RD showed the most significant improvement, followed by C-RD and finally H-RD. The 16 s rDNA results indicated that oral administration of resistant dextrins favored the proliferation of specific gut microbiota, including Faecalibaculum, Parabacteroides and Dubosiella, and reduced the ratio of Firmicutes/Bacteroidota, which is beneficial for reducing insulin resistance. Herein, the findings supported that the resistant dextrins exhibited a remission effect on T2DM, providing a basis for the development of functional food adjuvants for T2DM treatment.

Evaluation of terpenes rich Hura crepitans extract on glucose regulation and diabetic complications in STZ-induced diabetic rats.

The continual increase in global diabetic statistics portends decreased productivity and life spans, thus making it a disease of concern requiring more effective and safe therapeutic options. While several reports on antidiabetic plants, including Hura crepitans, are available, there is still a dearth of information on the holistic antidiabetic properties of H. crepitans and its associated complications. This study evaluated the antidiabetic potential of methanolic extract of Hura crepitans using in vitro, in vivo, and in silico approaches. The extract revealed a dose-dependent in vitro effect, with a 47.97 % and 65.34 % decrease in the fasting blood sugar levels of streptozotocin (STZ) induced diabetic rats at 150 and 300 mg/kg BW, respectively. Likewise, the extract increased serum and pancreatic insulin levels, and significantly ameliorated neuronal oxidative stress and inflammation by reducing the expression levels of cholinesterase, NF-κB, and COX-2 in the brain of hyperglycemic rats. Serum dyslipidemia, liver, and kidney biomarker indices, and hematological alterations in diabetic rats were also significantly attenuated by the extract. Several constituents, mainly terpenes, were identified in the extract. To further predict the drug-likeness, pharmacokinetics, and binding properties of the compounds, in silico analysis was conducted. Ergosta-2,24-dien-26-oicacid,18-(acetyloxy)-5,6-epoxy-4, 22-dihydroxy-1-oxo-,delta.-lactone-4.beta., displayed the highest docking scores for acetylcholinesterase, butyrylcholinesterases, alpha-amylase, and nuclear factor-kB with values of -12.4, -10.9, -10.3, and -9.4 kcal/mol, while ergost-25-ene-6,12-dione,3,5-dihydroxy-, (3.beta.,5.alpha.) topped for cyclooxygenase-2 (-9.0 kcal/mol). The top-ranked compounds also presented significant oral drug-likeness, pharmacokinetics, and safety properties. Altogether, our data provide preclinical evidence of the potential of Hura crepitans in ameliorating diabetes and its associated complications.

Blue mussel (Mytilus edulis) water extract ameliorates intestinal immune response in high-fat diet-streptozotocin-induced diabetic mice.

Diabetes mellitus is a metabolic disease characterized by high blood glucose levels or hyperglycemia. Diabetes causes a decrease in immune function in the human body. Mytilus edulis has been identified as having anti-inflammatory properties and the ability to improve inflammation. Thus, this study aimed to investigate the function of Matsu M. edulis water extract (MWE) in mediating the regulation of immune responses and dysregulating the intestinal immune system in hyperglycemia mouse models. The mice were treated with MWE for seven weeks. The results showed that treatment with MWE has the ability to decrease triglyceride and total cholesterol concentrations. MWE also increases the interleukin (IL)-10 concentration and natural killer cell activation. It also improves the phagocytic capacity of monocytes in the colon and the proliferative capacity of lymphocytes in the mesentery. Furthermore, MWE also regulates the IL-6 concentration and the ratio of T helper 17 cells to regulatory T cells. Collectively, this extract can improve dyslipidemia, inflammatory responses, and dysregulation of the intestinal immune system. Therefore, M. edulis water extract can be used as an alternative treatment to reduce diabetes complications.