Hyperglycemic Animals Research Articles

Effect of photobiomodulation with different wavelengths on periodontal repair in non-hyperglycemic and hyperglycemicrats.

Hyperglycemic conditions is associated with more severe periodontitis and poorer outcomes after nonsurgical periodontal treatment (NPT). Then, these patients are candidates for adjunctive therapy associated with NPT. This study evaluates the effect of photobiomodulation (PBMT) at different wavelengths on periodontal repair in non-hyperglycemic/hyperglycemic animals. Sixty-four rats were submitted to induction of periodontitis by ligatures. Hyperglycemia was induced in half of these animals, whereas the other half remained non-hyperglycemic. The animals were subdivided into 4 groups according to the PBMT protocol applied at the time of ligature removal (n = 8): CTR: Without PBMT; IRL: PBMT with infrared laser (808 nm); RL: PBMT with red laser (660 nm); and RL-IRL: PBMT with red (660 nm) and infrared laser (808 nm). After a period of 7 days, the animals were euthanized. The parameters assessed by microtomography were the bone volume relative to total tissue volume (BV/TV%), distance from the cemento-enamel junction to the top of the bone crest (CEJ-CB), trabecular thickness, space between trabeculae, and number of trabeculae. Additionally, the percentage of inflammatory cells, blood vessels, and connective tissue matrix were assessed by histomorphometric analysis. PBMT reduced bone loss and increased trabecular density in hyperglycemic animals (p < .05), with RL being more effective in reducing linear bone loss (CEJ-CB), whereas RL-IRL was more effective in maintaining BV/TV%. PBMT reduced blood vessels and increased the connective tissue component in hyperglycemic animals (p < .05). RL-IRL reduced inflammatory cells regardless of the systemic condition of the animal (p < .05). PBMT (RL, RL-IRL) improves the repair of periodontal tissues in hyperglycemic animals.

Anti-hyperglycemic Activity of the Piper longum Dried Fruit Extract on the Experimental Animal Model

Predominately, in the Indian tradition, the species Piper longum could play a significant role in the management of several severe disorders such as asthma, tuberculosis, rheumatism, and epilepsy. Mostly, the plant root would be responsible for treating insomnia, rheumatism, and epilepsy, as well as plant leaves for a prevailing stimulant for both the digestive and the respiratory systems. The alcoholic extract of P. longum fruits showed antiamoebic, anti-inflammatory, and immunomodulatory potential in experimental animals. In addition to these benefits, the current study concluded that the examination of the ethanolic extract of P. longum fruits as an anti-hyperglycemic in streptozotocin (STZ)-induced diabetic animal model (Wistar rats). A diabetic condition could be induced in an animal model by dissolving STZ in a 0.1 M citrate buffer of pH 4.5. It was injected intraperitoneally at a dose of 50 mg/kg body weight in the animal test model. All the test animals were fed with a 5% dextrose solution to control overnight hypoglycemic conditions. Subsequently, 48 hours of hyperglycemic test animals were selected for the study. The observed anti-hyperglycemic effect of ethanolic extract of P. longum dried fruits should correspond to that of the reference standard, i.e., glibenclamide. The study reveals that the ethanolic extract of P. longum fruits has a promising potential as an anti-hyperglycemic in the STZ-induced diabetic animal test model. So, it is presumed that the ethanolic extract of P. longum could be a promising alternative for severe diabetes complications such as hyperglycemia, oxidative stress, etc., in the near future

Hyperglycemia influences the cell proliferation and death of the rat endocrine pancreas in the neonatal period

AimsTo evaluate the cell proliferation and death, and structural morphology of the pancreatic islet cells of the rats with hyperglycemia in the first month of life and compare to those of the control rats. Main methodsFemale Sprague-Dawley newborn rats received Streptozotocin (a beta-cytotoxic drug) at birth for diabetes induction. Control and hyperglycemic animals were euthanized on different days of life: 5, 10, 15, and 30. The pancreas was collected and processed for immunohistochemical analysis of cleaved Caspase-3 (cell death), Ki-67 (cell proliferation), PDX-1 (transcription factor responsible for insulin synthesis), and endocrine hormones (insulin, glucagon, and somatostatin). Key findingsControl females showed a higher percentage (%) of Ki-67-positive(+) cells on D10 and D15, a higher % of insulin+ and somatostatin+ cells on D15 and D30, a lower % of PDX-1+ cells on D10, and a higher % of glucagon+ cells on D10 and D30. Hyperglycemic females showed a lower % of Ki-67+ cells on D15, a higher % of cleaved Caspase-3+ cells on D15, and insulin+ cells on D15 and D30. In the comparison among the experimental groups, the hyperglycemic females showed an increased % of cleaved Caspase-3+ and Ki-67+ cells and a lower % of PDX-1+ cells. SignificanceThis study enabled a better understanding of the abnormal pancreas development regarding cellular proliferation, apoptosis, and hormonal synthesis in the neonatal period. Thus, the pancreatic islets of hyperglycemic rats do not reestablish the normal endocrine cell population, and cellular apoptosis overcame the proliferative activity of these cells.

Hyperglycemia and circadian disruption lead to retinal dysfunction in a stabilized colony of the fat sand rat Psammomys obesus

PurposeThe Fat Sand Rat (Psammomys obesus) recapitulates several features of human pre-proliferative diabetic retinopathy, but data are restricted to wild animals, incompatible with stringent biomedical research criteria. To overcome this barrier, we characterized retinal changes in a colony of P. obsesus maintained under strictly controlled housing conditions. MethodsAnimals were maintained on low or high caloric energy diets, and raised under either standard (12 h light/12 h dark) or shortened (5 h light/5 h dark) photoperiods. Visual responses were tested by electroretinography, while structural/molecular changes were assayed by immunochemistry and molecular biology (RNAseq and qPCR). ResultsWhereas high calorie diet alone did not induce hyperglycemia, coupled with short photoperiod >80 % animals developed severe hyper-insulinemia by 15 weeks, and 16 % animals further developed hyperglycemia. In these groups, electroretinography showed significant declines in visual responses in both hyper-insulinemic and hyperglycemic animals, especially in photopic (cone) responses. Transcriptomics analysis of hyperglycemic compared to low caloric controls revealed major upregulation in pathways involved in glial activation, extracellular matrix remodeling, inflammation, cytokine production, partial ischemic responses and angiogenesis. Western blotting against rhodopsin and cone opsin also showed decreased levels in both groups, overall decreases being greater for cones than rods in hyperglycemic animals. ConclusionsP. obesus maintained in rigorously monitored captive conditions, albeit showing attenuated responses to dietary overload compared to wild counterparts, nevertheless do develop some retinal features of diabetic retinopathy-like degeneration. Such a colony with known sanitary status opens their broader use for biomedical research.

Improving stroke outcomes in hyperglycemic mice by modulating tPA/NMDAR signaling to reduce inflammation and hemorrhages

AbstractThe pharmacological intervention for ischemic stroke hinges on intravenous administration of the recombinant tissue-type plasminogen activator (rtPA, Alteplase/Actilyse) either as a standalone treatment or in conjunction with thrombectomy. However, despite its clinical significance, broader use of rtPA is constrained because of the risk of hemorrhagic transformations (HTs). Furthermore, the presence of diabetes or chronic hyperglycemia is associated with an elevated risk of HT subsequent to thrombolysis. This detrimental impact of tPA on the neurovascular unit in patients with hyperglycemia has been ascribed to its capacity to induce endothelial N-methyl-D-aspartate receptor (NMDAR) signaling, contributing to compromised blood-brain barrier integrity and neuroinflammatory processes. In a mouse model of thromboembolic stroke with chronic hyperglycemia, we assessed the effectiveness of rtPA and N-acetylcysteine (NAC) as thrombolytic agents. We also tested the effect of blocking tPA/NMDAR signaling using a monoclonal antibody, Glunomab. Magnetic resonance imaging, speckle contrast imaging, flow cytometry, and behavioral tasks were used to evaluate stroke outcomes. In hyperglycemic animals, treatment with rtPA resulted in lower recanalization rates and increased HTs. Conversely, NAC treatment reduced lesion sizes while mitigating HTs. After a single administration, either in standalone or combined with rtPA-induced thrombolysis, Glunomab reduced brain lesion volumes, HTs, and neuroinflammation after stroke, translating into improved neurological outcomes. Additionally, we demonstrated the therapeutic efficacy of Glunomab in combination with NAC or as a standalone strategy in chronic hyperglycemic animals. Counteracting tPA-dependent endothelial NMDAR signaling limits ischemic damages induced by both endogenous and exogenous tPA, including HTs and inflammatory processes after ischemic stroke in hyperglycemic animals.

Targeting hypoxia-inducible factors with 32-134D safely and effectively treats diabetic eye disease in mice.

Many patients with diabetic eye disease respond inadequately to anti-VEGF therapies, implicating additional vasoactive mediators in its pathogenesis. We demonstrate that levels of angiogenic proteins regulated by HIF-1 and -2 remain elevated in the eyes of people with diabetes despite treatment with anti-VEGF therapy. Conversely, by inhibiting HIFs, we normalized the expression of multiple vasoactive mediators in mouse models of diabetic eye disease. Accumulation of HIFs and HIF-regulated vasoactive mediators in hyperglycemic animals was observed in the absence of tissue hypoxia, suggesting that targeting HIFs may be an effective early treatment for diabetic retinopathy. However, while the HIF inhibitor acriflavine prevented retinal vascular hyperpermeability in diabetic mice for several months following a single intraocular injection, accumulation of acriflavine in the retina resulted in retinal toxicity over time, raising concerns for its use in patients. Conversely, 32-134D, a recently developed HIF inhibitor structurally unrelated to acriflavine, was not toxic to the retina, yet effectively inhibited HIF accumulation and normalized HIF-regulated gene expression in mice and in human retinal organoids. Intraocular administration of 32-134D prevented retinal neovascularization and vascular hyperpermeability in mice. These results provide the foundation for clinical studies assessing 32-134D for the treatment of patients with diabetic eye disease.

Pre-hyperglycemia immune cell trafficking underlies subclinical diabetic cataractogenesis

BackgroundThis work elucidates the first cellular and molecular causes of cataractogenesis. Current paradigm presupposes elevated blood glucose as a prerequisite in diabetic cataractogenesis. Novel evidence in our model of diabetic cataract challenges this notion and introduces immune cell migration to the lens and epithelial-mesenchymal transformation (EMT) of lens epithelial cells (LECs) as underlying causes.MethodsPaucity of suitable animal models has hampered mechanistic studies of diabetic cataract, as most studies were traditionally carried out in acutely induced hyperglycemic animals. We introduced diabetic cataract in the Nile grass rat (NGR) that spontaneously develops type 2 diabetes (T2D) and showed its closeness to the human condition. Specialized stereo microscopy with dual bright-field illumination revealed novel hyperreflective dot-like microlesions in the inner cortical regions of the lens. To study immune cell migration to the lens, we developed a unique in situ microscopy technique of the inner eye globe in combination with immunohistochemistry.ResultsContrary to the existing paradigm, in about half of the animals, the newly introduced hyper reflective dot-like microlesions preceded hyperglycemia. Even though the animals were normoglycemic, we found significant changes in their oral glucose tolerance test (OGTT), indicative of the prediabetic stage. The microlesions were accompanied with significant immune cell migration from the ciliary bodies to the lens, as revealed in our novel in situ microscopy technique. Immune cells adhered to the lens surface, some traversed the lens capsule, and colocalized with apoptotic nuclei of the lens epithelial cells (LECs). Extracellular degradations, amorphous material accumulations, and changes in E-cadherin expressions showed epithelial-mesenchymal transformation (EMT) in LECs. Subsequently, lens fiber disintegration and cataract progression extended into cortical, posterior, and anterior subcapsular cataracts.ConclusionsOur results establish a novel role for immune cells in LEC transformation and death. The fact that cataract formation precedes hyperglycemia challenges the prevailing paradigm that glucose initiates or is necessary for initiation of the pathogenesis. Novel evidence shows that molecular and cellular complications of diabetes start during the prediabetic state. These results have foreseeable ramifications for early diagnosis, prevention and development of new treatment strategies in patients with diabetes.

Bioactivity Guided Study for the Isolation and Identification of Antidiabetic Compounds from Edible Seaweed-Ulva reticulata.

Managing diabetes is challenging due to the complex physiology of the disease and the numerous complications associated with it. As part of the ongoing search for antidiabetic chemicals, marine algae have been demonstrated to be an excellent source due to their medicinal properties. In this study, Ulva reticulata extracts were investigated for their anti-diabetic effect by examining its inhibitory effects on α-amylase, α-glucosidase, and DPP-IV and antioxidant (DPPH) potential in vitro and its purified fraction using animal models. Among the various solvents used, the Methanolic extract of Ulva reticulata (MEUR) displayed the highest antidiabetic activity in both in vitro and in vivo; it showed no cytotoxicity and hence was subjected to bioassay-guided chromatographic separation. Among the seven isolated fractions (F1 to F7), the F4 (chloroform) fraction exhibited substantial total phenolic content (65.19 μg mL-1) and total flavonoid content (20.33 μg mL-1), which showed the promising inhibition against α-amylase (71.67%) and α-glucosidase (38.01%). Active fraction (F4) was further purified using column chromatography, subjected to thin-layer chromatography (TLC), and characterized by spectroscopy techniques. Upon structural elucidation, five distinct compounds, namely, Nonane, Hexadecanoic acid, 1-dodecanol, Cyclodecane methyl, and phenol, phenol, 3,5-bis(1,1-dimethylethyl) were identified. The antidiabetic mechanism of active fraction (F4) was further investigated using various in vitro and in vivo models. The results displayed that in in vitro both 1 and 24 h in vitro cultures, the active fraction (F4) at a concentration of 100 μg mL-1 demonstrated maximum glucose-induced insulin secretion at 4 mM (0.357 and 0.582 μg mL-1) and 20 mM (0.848 and 1.032 μg mL-1). The active fraction (F4) reduces blood glucose levels in normoglycaemic animals and produces effects similar to that of standard acarbose. Active fraction (F4) also demonstrated outstanding hypoglycaemic activity in hyperglycemic animals at a dose of 10 mg/kg B.wt. In the STZ-induced diabetic rat model, the active fraction (F4) showed a (61%) reduction in blood glucose level when compared to the standard drug glibenclamide (68%). The results indicate that the marine algae Ulva reticulata is a promising candidate for managing diabetes by inhibiting carbohydrate metabolizing enzymes and promoting insulin secretion.

Protective Effect of High-Intensity Interval Training (HIIT) and Moderate-Intensity Continuous Training (MICT) against Vascular Dysfunction in Hyperglycemic Rats.

Hyperglycemia is a major risk factor for endothelial dysfunction. Endothelial dysfunction is associated with the inability of endothelial cells to maintain homeostasis of the cardiovascular system. Regular exercise may be considered as an effective and low-cost nonpharmacological tool for improving vascular function, though there is no agreement on the best type of exercise. To determine how high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) may prevent endothelial dysfunction under hyperglycemic conditions, and to compare these two interventions. Twenty-four eight-week-old male Wistar rats were randomly assigned into four groups: healthy nonexercising control (C), hyperglycemic control (HG-C), hyperglycemic + HIIT (HG-IT), and hyperglycemic + MICT (HG-CT). Hyperglycemia was induced by a single injection of streptozotocin. Hyperglycemic animals were subjected to HIIT or MICT protocols six days a week for six weeks. Decapitation was performed the day after the exercise protocols were completed. The ascending aorta (until the abdominal artery) was examined. An enzyme-linked immunosorbent assay (ELISA) was used to measure the glucagon-likepeptide-1 (GLP-1), endothelial nitric oxide synthase (eNOS), and tumor necrosis factor-alpha (TNFα) levels. A colorimetric assay was used to measure superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels. Quantitative real-time polymerase chain reaction (PCR) was used to measure the expression of the receptor for advanced glycation end-products (RAGE) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Hematoxylin and eosin (H&E) staining was used to histologically analyze the aortas. There was a significantly higher level of GLP-1 and lower expression of RAGE, NF-κB, and TNFα in the HG-IT and HG-CT group compared to the HG-C group. Microscopic examination of aortic tissue showed a better tissue arrangement in both treatment groups than in the HG-C group. Except for the MDA level, there were no significant differences in any of the measured parameters between the HG-IT and HG-CT groups. Under hyperglycemic conditions, both HIIT and MICT have a protective role against endothelial dysfunction.

Implants with hydrophilic surfaces equalize the osseointegration of implants in normo- and hyperglycaemic rats.

The purpose of this study was to evaluate the effect of a surface modified by blasting and acid attack and maintained in an isotonic solution compared to a machined surface on osseointegration in normo- and hyperglycaemic animals. Sixty-four animals were allocated into 4 groups with 16 animals each, and they were subdivided into two experimental periods (15 and 45 days), with 8 animals in each group. The groups were divided according to the type of implant that was installed in the animals' tibia and the animals' systemic condition: CM - Machined implants placed in Healthy animals; CH - Hydrophilic implants placed in Healthy animals, HM - Machined implants placed in animals with hyperglycaemia; HH- Hydrophilic implants installed in animals with hyperglycaemia. The following analyses were performed: biomechanical (removal torque), microtomographic (evaluation of the bone volume around the implants- BV/TV), and histomorphometric (evaluation of bone-implant contact BIC% and of the bone formation area between the threads BBT%). It was found that the implants with hydrophilic surfaces presented higher removal torques and quantities of BV/TV% and higher BIC% and BBT% values in normo- and hyperglycaemic animals. The results of this study indicated that the hydrophilic surface accelerates the osseointegration process (~ 15% BIC/BBT at 15-day period), especially in animals with hyperglycaemia. The hydrophilic surface equaled the osseointegration between normo- and hyperglycaemic animals, reversing the negative potential of hyperglycaemia on the osseointegration process.

LC-MS-based metabolite profiling of aqueous extract of Pergularia tomentosa L. and its anti-hyperglycemic effect.

In this study, to find scientific evidence for the traditional use of Pergularia tomentosa as an anti-diabetic remedy, the effects of its aqueous extract on streptozotocin-induced diabetes mellitus in rats were evaluated. Wistar rats were fasted overnight and diabetes mellitus was induced using streptozotocin (50 mg/kg body weight). The rats were randomly and equally divided into four groups (n=5): group I (normoglycaemic control), group II (diabetic rats), group III (diabetic rats treated with 200 mg/kg BW of an aqueous extract of P. tomentosa), group IV (normoglycemic rats treated with 200 mg/kg BW of an aqueous extract of P. tomentosa). Chemical profiling of the aqueous extract was carried out using liquid chromatography coupled with electrospray ionization and multiple-stage linear ion-trap and orbitrap high-resolution mass spectrometry (LC-ESI/LTQOrbitrap/MS/MS). In addition, the quantitative determination of the main cardenolides in the extract was carried out by an analytical approach based on LC coupled to tandem mass spectrometry with ESI source and hybrid triple quadrupole-linear ion trap mass analyzer (LC-ESI/QTrap/MS/MS). Aqueous extract of P. tomentosa showed a reasonable reduction in blood glucose level. Probably, the P. tomentosa effect on hyperglycemic and hyperlipidemic diabetic animals was associated with antioxidant properties, triglyceride levels, as well as liver enzymes. Meanwhile, LC-ESI/LTQOrbitrap/MS/MS analysis led to identification of double-linked cardenolides along with cardenolides and flavone glycosides as the main bioactive compounds. The extract decreased the glucose level and induced a beneficial effect on the lipid profile, probably due to the presence of cardenolide glycosides.

Histological and Molecular Evidence of the Positive Performance of Glycerol-Plasticized Chitosan-Alginate Membranes on Skin Lesions of Hyperglycemic Mice.

The purpose of this study was to investigate tissue repair of excisional wounds in hyperglycemic animals treated with chitosan-alginate membranes (CAM) produced in the presence of glycerol. 8-week C57B1 male mice were divided into normoglycemic animals with a 0.9% saline solution topical treatment (CTSF); hyperglycemic animals with 0.9% saline solution topical treatment (DMSF) and hyperglycemic animals with glycerol-plasticized chitosan-alginate membrane topical treatment (DMCAM). On post-wound day three, the DMCAM group presented a lower number of leukocytes, mature mastocytes, a higher number of vessels (p < 0.05), and active mastocytes (p < 0.05) when compared to the CTSF and DMSF groups. There were no differences regarding the distribution, deposition, organization, and thickness of collagen fibers. On day 7 there were no differences in the analysis of fibroblasts, mastocytes, and TGF−β1 and VEGF expressions among the groups. Regarding collagen fibers, the DMCAM group presented slight red-orange birefringence when compared to the CTSF and DMSF groups. On day 14 there was a slight concentration of thinner elastic fibers for the DMCAM group, with a greater reorganization of papillary skin and improved red-orange birefringence collagen fibers, as well as net-shaped orientation, similar to intact skin. In addition, improved elastic fiber organization distributed in the entire neo-dermis and a larger presence of elaunin fibers were observed, in a similar pattern found in the intact skin. The use of CAM in cutaneous lesions boosted tissue repair since there was a smaller number of inflammatory cells and mastocytes, and an improvement in collagen deposition and collagen fibers. These results demonstrate the high potential of plasticized chitosan-alginate membrane for skin wound dressing of hyperglycemic patients.

Ameliorative Effects of Vanadyl Sulfate on Some Biochemical Parameters of Experimental Diabetic Rat Kidneys

Diabetes mellitus (DM), closely related to diabetic nephropathy, is one of the major public health problems worldwide. Today, with the increasing understanding of the underlying pathophysiology of DM, new oral anti-diabetic treatment strategies are being developed. Vanadium is a transition element that is widely distributed in nature, and its oral administration has been reported to improve DM in humans and a variety of diabetic animal models. The purpose of the research is to explore the effect of vanadyl sulfate (VS) administration on the different enzyme activities associated with kidney injury in streptozotocin- (STZ) induced diabetic rats. Male rats were assigned into groups as follows: untreated control, control animals given VS (100 mg/kg), diabetic (a single dose of intraperitoneal STZ, 65 mg/kg), and diabetic + VS (same dose) group. VS was administered orally for 60 days after the induction of diabetes. On the 60th day of experiment, kidney samples were taken for analysis. According to the data obtained from the biochemical analysis, the activities of transaminases, alkaline phosphatase, carbonic anhydrase, and γ-glutamyl transpeptidase decreased, whereas superoxide dismutase activity elevated in the kidney tissue of VS treated hyperglycemic animals. The results suggested that VS improved the diabetic renal injury, probably by VS insulin-mimic and antioxidant behavior through decreased oxidative stress and increased antioxidant capacity. Therefore, vanadyl sulfate might be used as a potential oral anti-diabetic compound in the treatment of the diabetic nephropathy, and as an important control for elevated blood glucose levels in the diabetic state.

Assessment of Pancreatic and Hepatic Histological Changes in Streptozotocin Induced Diabetic Rats Fed with Morizella Juice

Background: Hibiscus sabdariffa and Moringa oleifera has been reported to have ant diabetic effect on hyperglycemic animals. However, there are no reports on its histological and physiological changes in diabetic animals.&#x0D; Objective: To assess the pancreatic and hepatic histological changes in streptozotocin-induced diabetic rats fed with Morizella juice.&#x0D; Methods: A Completely Randomized Block Design (CRBD) was used for this study, 40 adult male Wistar rats, 9 to 10 weeks with a bodyweight 190g – 250g were selected for the study. The animals were divided into four main groups (A, B, C, and D), each group was further subdivided into two groups with 5 rats. The experiments were divided into acute and sub-acute tests of 10 animals per group. At the end of the experiment, animals were sacrificed, pancreatic and liver tissues were harvested and histologically processed. Sections were examined and photographed using a light microscope (Leica® DM 750) with an in-built camera ((Icc50 HD-47142065) and the number of Islet cells was measured in 40 high-power fields.&#x0D; Results: Microscopic structures of the pancreas revealed that the number of Islets of Langerhans was significantly higher in the Morizella treated groups at the dosages of 50mg/kg and 100 mg/kg body weight. The microscopic structure of the liver in both treated groups presented with normal histological architecture when compared with both control groups&#x0D; Conclusion: There was a dose-dependent increase of islets of Langerhans cells in the acute and sub-acute group treated with Morizella extracts compared to the control group. Additionally, the liver architecture was reversed back to the normal in Morizella-treated group.

Experimentally Induced Hyperglycemia in Prepubertal Phase Impairs Oocyte Quality and Functionality in Adult Mice.

Reproductive abnormalities in women with a history of childhood diabetes are believed to be partially attributed to hyperglycemia. Prolonged hyperglycemia can negatively affect ovarian function and fertility during reproductive life. To address this in an experimental setting, the present study used streptozotocin-induced hyperglycemic prepubertal mouse model. The impact of prolonged hyperglycemic exposure during prepubertal life on ovarian function, oocyte quality, and functional competence was assessed in adult mice. The ovarian reserve was not significantly altered; however, the in vitro maturation potential (P < 0.001), mitochondrial integrity (P < 0.01), and meiotic spindle assembly (P < 0.05-0.001) in oocytes were significantly affected in hyperglycemic animals in comparison to control groups. The results from the study suggest that prepubertal hyperglycemia can have adverse effects on the oocyte functional competence and spindle integrity during the reproductive phase of life. Because these changes can have a significant impact on the genetic integrity and developmental potential of the embryos and fetus, the observation warrants further research both in experimental and clinical settings.

Embryonic nutritional hyperglycemia decreases cell proliferation in the zebrafish retina.

Diabetic retinopathy (DR) is one of the leading causes of blindness in the world. While there is a major focus on the study of juvenile/adult DR, the effects of hyperglycemia during early retinal development are less well studied. Recent studies in embryonic zebrafish models of nutritional hyperglycemia (high-glucose exposure) have revealed that hyperglycemia leads to decreased cell numbers of mature retinal cell types, which has been related to a modest increase in apoptotic cell death and altered cell differentiation. However, how embryonic hyperglycemia impacts cell proliferation in developing retinas still remains unknown. Here, we exposed zebrafish embryos to 50mM glucose from 10h postfertilization (hpf) to 5days postfertilization (dpf). First, we confirmed that hyperglycemia increases apoptotic death and decreases the rod and Müller glia population in the retina of 5-dpf zebrafish. Interestingly, the increase in cell death was mainly observed in the ciliary marginal zone (CMZ), where most of the proliferating cells are located. To analyze the impact of hyperglycemia in cell proliferation, mitotic activity was first quantified using pH3 immunolabeling, which revealed a significant decrease in mitotic cells in the retina (mainly in the CMZ) at 5 dpf. A significant decrease in cell proliferation in the outer nuclear and ganglion cell layers of the central retina in hyperglycemic animals was also detected using the proliferation marker PCNA. Overall, our results show that nutritional hyperglycemia decreases cellular proliferation in the developing retina, which could significantly contribute to the decline in the number of mature retinal cells.

The Intestinal and Biliary Metabolites of Ibuprofen in the Rat with Experimental Hyperglycemia.

Hyperglycemia is reported to be associated with oxidative stress. It can result in changes in the activities of drug-metabolizing enzymes and membrane-integrated transporters, which can modify the fate of drugs and other xenobiotics; furthermore, it can result in the formation of non-enzyme catalyzed oxidative metabolites. The present work aimed to investigate how experimental hyperglycemia affects the intestinal and biliary appearance of the oxidative and Phase II metabolites of ibuprofen in rats. In vivo studies were performed by luminal perfusion of 250 μM racemic ibuprofen solution in control and streptozotocin-treated (hyperglycemic) rats. Analysis of the collected intestinal perfusate and bile samples was performed by HPLC-UV and HPLC-MS. No oxidative metabolites could be detected in the perfusate samples. The biliary appearance of ibuprofen, 2-hydroxyibuprofen, ibuprofen glucuronide, hydroxylated ibuprofen glucuronide, and ibuprofen taurate was depressed in the hyperglycemic animals. However, no specific non-enzymatic (hydroxyl radical initiated) hydroxylation product could be detected. Instead, the depression of biliary excretion of ibuprofen and ibuprofen metabolites turned out to be the indicative marker of hyperglycemia. The observed changes impact the pharmacokinetics of drugs administered in hyperglycemic individuals.

Effect of Prosopis ruscifolia on incretin and insulin secretion in alloxan-induced hyperglycemic rats

Background: Diabetes mellitus treatment is based on oral hypoglycemic agents or insulin. Medicinal plants constitute an option, and the leaves of Prosopis ruscifolia (Pr) were shown to be effective in reducing glycemia in hyperglycemic animals. Objective: In this paper, we report the effect of P. rusciofolia (Pr) on insulin and incretin secretion in alloxan-induced hyperglycemic rats. Methodology: The effective dose was selected, and four groups (n=10) of Wistar rats were used. Two groups with normal glycemia received water or Pr (75 mg/Kg, per os, p.o.), and two groups with hyperglycemia induced by alloxan (intraperitoneal, ip), received water or Pr (75 mg/Kg, p.o.) for 2 weeks. Oral glucose tolerance test, and incretin and insulin levels were measured at the end of the experimental period. Results: The results showed that extract promotes better tolerance to oral glucose overload, in addition to a statistically significant (p&lt;0.001) increase in blood levels of incretin and insulin, compared to the hyperglycemic rats. Conclusion: It is concluded that the ethanolic extract of P. ruscifolia leaves has a hypoglycemic effect in hyperglycemic animals by a mechanism that involves the incretin-insulin system.

The effects of taxifolin on neuropathy related with hyperglycemia and neuropathic pain in rats: A biochemical and histopathological evaluation.

Hyperglycemia can be considered a determining factor in the development of diabetic neuropathy as well as neuropathic pain. There is a relationship between the excessive production of reactive oxygen species (ROS) and the pathogenesis of diabetic neuropathic pain. Taxifolin, on the other hand, is a flavonoid that has been documented to inhibit ROS production. To investigate the effects of taxifolin, which has antioxidant and neuroprotective effects, on alloxan-induced hyperglycemia-induced neuropathy and neuropathic pain, biochemically and histopathologically. The albino Wistar male rats were divided into 3 groups: healthy group (HG), only alloxan group (AXG) and alloxan+taxifolin group (ATG). Hyperglycemia in animals was caused through intraperitoneal injection of alloxan at a dose of 120 mg/kg. Paw pain thresholds of animals were measured using Basile algesimeter. Sciatic nerve tissues were examined biochemically and histopathologically in order to evaluate neuropathy. Our experimental results revealed that taxifolin significantly prevented the increase of plasma glucose concentration level with alloxan administration, the decrease of the paw pain threshold related to hyperglycemia, the change of oxidant-antioxidant balance in the sciatic nerve tissue in favor of oxidants, and the deterioration of tissue morphology in animals. Our experimental results indicate that taxifolin alleviates alloxan-induced hyperglycemia-related neuropathy and neuropathic pain.

MicroRNA Transcriptomics Analysis Identifies Dysregulated Hedgehog Signaling Pathway in a Mouse Model of Acute Intracerebral Hemorrhage Exposed to Hyperglycemia

Objective: Hyperglycemia is often observed in the patients after acute stroke. This study aims to elucidate the potential effect and mechanism of hyperglycemia by screening microRNAs expression in intracerebral hemorrhage mice. Methods: We employed the collagenase model of intracerebral hemorrhage. Twenty male C57BL/6 mice were used and randomly divided in normo- and hyperglycemic. The hyperglycemia was induced by intraperitoneally injection of 50% of Dextrose (8 mL/kg) 3 hours after intracerebral hemorrhage. The neurologic impairment was investigated by neurologic deficit scale. To study the specific mechanisms of hyperglycemia, microRNAs expression in perihematomal area was investigated by RNA sequencing. MicroRNAs expression in hyperglycemic intracerebral hemorrhage animals were compared normoglycemic mice. Functional annotation analysis was used to indicate potential pathological pathway, underlying observed effects. Finally, polymerase chain reaction validation was administered. Results: Intraperitoneal injection of dextrose significantly increased blood glucose level. That was associated with aggravation of neurological deficits in hyperglycemic compared to normoglycemic animals. A total of 73 differentially expressed microRNAs were identified via transcriptomics analysis. Bioinformatics analyses showed that these microRNAs were significantly altered in several signaling pathways, of which the hedgehog signaling pathway was regarded as the most potential pathway associated with the effect of hyperglycemia on acute intracerebral hemorrhage. Furthermore, polymerase chain reaction results validated the correlation between microRNAs and hedgehog signaling pathway. Conclusions: MicroRNA elevated in hyperglycemia group may be involved in worsening the neurological function via inhibiting the hedgehog signaling, which provides a novel molecular physiological mechanism and lays the foundation for treatment of intracerebral hemorrhage.