Non-diabetic Animals Research Articles

Renal outcomes with sodium-glucose cotransporters 2 inhibitors.

Diabetic nephropathy (DN) is one of the most serious complications of diabetes. Therefore, delaying and preventing the progression of DN becomes an important goal in the clinical treatment of type 2 diabetes mellitus. Recent studies confirm that sodium-glucose cotransporters 2 inhibitors (SGLT2is) have been regarded as effective glucose-lowering drugs with renal protective effect. In this review, we summarize in detail the present knowledge of the effects of SGLT2is on renal outcomes by analyzing the experimental data in preclinical study, the effects of SGLT2is on estimated glomerular flitration rates (eGFRs) and urinary albumin-creatinine ratios (UACRs) from clinical trials and observational studies, and renal events (such as renal death or renal failure requiring renal replacement therapy) in some large prospective cardiovaslucar outcomes trials. The underlying mechanisms for renoprotective activity of SGLT2is have been demondtrated in multiple diabetic and nondiabetic animal models including kidney-specific effects and secondary kidney effects related to amelioration in blood glucose and blood pressure. In conclusion, these promising results show that SGLT2is act beneficially in terms of the kidney for diabetic patients.

Co-transplantation of pancreatic islets and microvascular fragments effectively restores normoglycemia in diabetic mice

Insufficient revascularization of pancreatic islets is one of the major obstacles impairing the success of islet transplantation. To overcome this problem, we introduce in the present study a straightforward strategy to accelerate the engraftment of isolated islets. For this purpose, we co-transplanted 250 islets and 20,000 adipose tissue-derived microvascular fragments (MVF) from donor mice under the kidney capsule as well as 500 or 1000 islets with 40,000 MVF into the subcutaneous space of diabetic mice. We found that the co-transplantation of islets and MVF markedly accelerates the restoration of normoglycemia in diabetic recipients compared with the transplantation of islets alone. In fact, the transplantation of 250 islets with 20,000 MVF under the kidney capsule reversed diabetes in 88% of mice and the subcutaneous transplantation of 500 or 1000 islets with 40,000 MVF restored normoglycemia in 100% of mice. Moreover, diabetic mice receiving islets and MVF exhibited plasma insulin levels similar to nondiabetic control animals. Additional immunohistochemical analyses of the grafts revealed a significantly higher number of islet cells and microvessels in the co-transplantation groups. These findings demonstrate that the co-transplantation of islets and MVF is a promising strategy to improve the success rates of islet transplantation, which could be easily implemented into future clinical practice.

Buffer glucose adjustment affects myocardial function after ischemia-reperfusion in long-term diabetic rat isolated hearts.

Due to its comorbidities type 2 diabetes mellitus (T2DM) and hypertension, the Zucker Spontaneous Hypertensive Fatty (ZSF1) rat is a clinically relevant animal model when assessing ischemia-reperfusion (IR) injury. Most IR studies in hearts isolated from diabetic animals have been conducted at normal glucose concentrations, providing a different environment compared to in-vivo. We hypothesized IR injury to be attenuated in isolated hearts of diabetic ZSF1 rats when adjusting the Krebs-buffer (KB) to their in-vivo, i.e., elevated blood glucose (BG) levels. Diabetic and non-diabetic ZSF1 rats were anesthetized, hearts isolated and Langendorff-prepared. While standard KB was used for the non-diabetic and diabetic unadjusted groups, KB with glucose levels increased to each rat's prior BG level was used for the adjusted diabetic group. All hearts underwent 30 min ischemia and 120 min reperfusion. Diastolic contracture during ischemia and early reperfusion was delayed and temporarily attenuated in the adjusted compared to the unadjusted diabetic and the non-diabetic groups. The decrease in coronary flow on reperfusion was attenuated in diabetic animals. Left ventricular developed pressure and contractility were not different among the three groups. Infarct size was significantly lower in non-diabetic animals; buffer adjustment made no difference in diabetic animals. In our study, T2DM did not worsen myocardial function in ZSF1 rat isolated hearts. Since our results reveal that hearts with an adjusted glucose level exhibit an at least temporary improvement of function following IR, further studies should consider adapting glucose levels to create more realistic conditions in isolated, perfused hearts.

Antidiabetic Potential and Antioxidant Activity of Olea europaea subsp. Cuspidata (Indian Olive) Seed Extracts.

The aim of the present study was to evaluate the antioxidant and antidiabetic potential of Indian olive seed extracts. Plant seeds were sequentially extracted with n-hexane, chloroform, methanol, and water. 2,2-Diphenyl-1-picrylhydrazyl (DPPH) scavenging and alpha-amylase inhibitory activities of extracts were carried out. Olea europaea methanolic extract (MEOE) and aqueous extract (AEOE) were orally administered to normoglycemic and alloxan-treated diabetic rats so as to determine their hypoglycemic effect. High-performance liquid chromatography (HPLC) analysis showed gallic acid, ferulic acid, quercetin, and vanillic acid in MEOE. It was found that the methanolic and aqueous extracts exhibited the maximum DPPH and alpha-amylase inhibition activities, respectively. MEOE and AEOE exerted a significant decline in the fasting blood sugar in diabetic animals (p < 0.05); however, they did not cause hypoglycemia in nondiabetic animals. Treatment with MEOE and AEOE reduced the aggravated liver and kidney function biomarkers. Aggravated levels of oxidative stress biomarkers including superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), and malondialdehyde (MDA) were restored by treatment with MEOE. Moreover, MEOE improved the count of islets of Langerhans in the pancreas, fatty changes, and enlarged sinusoidal spaces in the liver and necrosis of the glomerulus and tubular cells of the kidney in diabetic rats. This study showed that the African olive seed extract effectively managed experimental diabetes and restored the normal functions and histology of the liver and kidney in diabetic rats through the reduction of oxidative stress.

Borassus aethiopum (Mart.) ethanol fruit extract reverses alloxan-treatment alterations in experimental animals

BACKGROUND: Borassus aethiopum fruit is claimed to be used for the management of diabetes without scientific validation. OBJECTIVE: This study seeks to evaluate the antihyperglycaemic activity of ethanol fruit extract of Borassus aethiopum in alloxan-induced diabetic rats. METHODS: 36 rats were placed in six groups (i-vi) (n = 6). Animals in group i (standard) were given 0.4 mls of distilled water (d.w) whereas the ones assigned to group ii, iii, iv, v and vi which were induced into diabetes (by intake of 140 mg/kg body weight [b.w] of alloxan) were also respectively given d.w, 50 mg/kg b.w of metformin, 25, 50 and 100 mg/kg b.w of ethanol fruit extract of Borassus aethiopum, once daily for 14 days. RESULTS: Flavonoid found in the extract (24.04 mg/ml) occurred the most with phenolic (0.35 mg/ml) being the least. While alloxan substantially (p &lt; 0.05) increased the levels of some biological molecules and enzyme activity, it lowered those of others. The extract however significantly (p &lt; 0.05) reversed all the alloxan-induced alterations, with the extract at 100 mg/kg b.w producing figures that compared (p &gt; 0.05) well with those of the d.w treated non-diabetic animals and metformin-treated diabetic animals. The extract also renewed the wholeness of histological damage in the pancreas. CONCLUSION: The bioactive agents of B. aethiopum presented antihyperglycaemic property by preventing diabetes via reversal of alloxan-treatment alterations in the animals.

Effects of Neural Mobilization on Sensory Dysfunction and Peripheral Nerve Degeneration in Rats With Painful Diabetic Neuropathy.

ObjectiveThis study aims to evaluate the effectiveness of neural mobilization (NM) in the management of sensory dysfunction and nerve degeneration related to experimental painful diabetic neuropathy (PDN).MethodsThis is a pre-clinical animal study performed in the streptozocin (STZ)-induced diabetic rat model. 3 groups were included; a treatment group of rats with PDN receiving NM under anesthesia (PDN-NM, n=10), a sham treatment group of rats with PDN that only received anesthesia (PDN-Sham, n=9) and a vehicle control group with nondiabetic animals (Vehicle, n=10). Rats in the PDN-NM and PDN-Sham groups received 1 treatment sessions on day-10, 12 and 14 after STZ injection, with a 48-hour rest period between sessions. Behavioral tests were performed using von Frey and Plantar tests. Evaluation for peripheral nerve degeneration was performed through measuring protein gene product 9.5-positive (PGP9.5+) intra-epidermal nerve fiber density (IENFD) in hind-paw skin biopsies. All measurements were performed by a blinded investigator.ResultsThe behavioral tests showed that a single NM session could reduce hyperalgesia which was maintained for 48 hours. The second treatment session further improved this treatment effect, and the third session maintained it. These results suggest that it requires multiple treatment sessions to produce and maintain hypoalgesic effects. Skin biopsy analysis showed that the PGP9.5+ IENFD was higher on the experimental side of the PDN-NM group compared to the PDN-Sham group, suggesting NM may mitigate the degeneration of peripheral nerves.ConclusionsThis study demonstrated that NM may be an effective method to manage experimentally induced PDN, potentially through mitigation of nerve degeneration.Further studies are needed to develop standardized protocols for clinical use.ImpactThese findings provide neurophysiological evidence for the use of NM in PDN and can form the basis for the development of physical therapy-based programs in clinics.

Analysis of Keratinocytic Exosomes from Diabetic and Nondiabetic Mice by Charge Detection Mass Spectrometry.

Unresolved inflammation compromises diabetic wound healing. Recently, we reported that inadequate RNA packaging in murine wound-edge keratinocyte-originated exosomes (Exoκ) leads to persistent inflammation [Zhou, X. ACS Nano 2020, 14(10), 12732-12748]. Herein, we use charge detection mass spectrometry (CDMS) to analyze intact Exoκ isolated from a 5 day old wound-edge tissue of diabetic mice and a heterozygous nondiabetic littermate control group. In CDMS, the charge (z) and mass-to-charge ratio (m/z) of individual exosome particles are measured simultaneously, enabling the direct analysis of masses in the 1-200 MDa range anticipated for exosomes. These measurements reveal a broad mass range for Exoκ from ∼10 to >100 MDa. The m and z values for these exosomes appear to fall into families (subpopulations); a statistical modeling analysis partially resolves ∼10-20 Exoκ subpopulations. Complementary proteomics, immunofluorescence, and electron microscopy studies support the CDMS results that Exoκ from diabetic and nondiabetic mice vary substantially. Subpopulations having high z (>650) and high m (>44 MDa) are more abundant in nondiabetic animals. We propose that these high m and z particles may arise from differences in cargo packaging. The veracity of this idea is discussed in light of other recent CDMS results involving genome packaging in vaccines, as well as exosome imaging experiments. Characterization of intact exosome particles based on the physical properties of m and z provides a new means of investigating wound healing and suggests that CDMS may be useful for other pathologies.

Evaluation of Wound Healing Activity (Excision Wound Model) of Ointment Prepared from Infusion Extract of Polyherbal Tea Bag Formulation in Diabetes-Induced Rats

In the present investigation, Ichnocarpus frutescens, Ficus dalhousiae, Crateva magna, Alpinia galanga, and Swertia chirata plants were selected to formulate polyherbal tea bag. The infusion obtained from these polyherbal tea bags was used to formulate 5% and 10% ointment formulation to perform its wound healing activity. The excision wound model was used to assess the wound healing activity in diabetic as well nondiabetic rats. The mean percentage closure of wound area was calculated on the 3rd, 6th, 9th, 12th, 15th, 18th, and finally 21st day. The wound healing activity of formulation was found to be significantly compared with that of the reference standard and untreated groups. The percentages of closure of excision wound area on the 21st day in diabetic animals treated with ointment formulations (F1 and F2) were found to be 93.91 ± 1.65% and 99.12 ± 5.21% respectively, whereas the chloramphenicol sodium drug solution was found to be 99.81 ± 3.16%. The percentages of closure of excision wound area in nondiabetic animals treated with ointment formulations (F1 and F2) were found to be 96.81 ± 2.04% and 98.13 ± 1.14%, respectively, whereas the chloramphenicol sodium drug solution was found to be 99.15 ± 1.41% at 21st day. Therefore, from the above results, we have concluded that this polyherbal ointment can be used clinically for the treatment of diabetic and nondiabetic wounds.

VLA4-Enhanced Allogeneic Endothelial Progenitor Cell-Based Therapy Preserves the Aortic Valve Function in a Mouse Model of Dyslipidemia and Diabetes.

The number and function of endothelial progenitor cells (EPCs) are reduced in diabetes, contributing to deteriorated vascular repair and the occurrence of cardiovascular complications. Here, we present the results of treating early diabetic dyslipidemic mice or dyslipidemic with disease-matched EPCs modified to overexpress VLA4 (VLA4-EPCs) as compared with the treatment of EPCs transfected with GFP (GFP-EPCs) as well as EPCs from healthy animals. Organ imaging of injected PKH26-stained cells showed little pulmonary first-pass effects and distribution in highly vascularized organs, with splenic removal from circulation, mostly in non-diabetic animals. Plasma measurements showed pronounced dyslipidemia in all animals and glycaemia indicative of diabetes in streptozotocin-injected animals. Echocardiographic measurements performed 3 days after the treatment showed significantly improved aortic valve function in animals treated with VLA4-overexpressing EPCs compared with GFP-EPCs, and similar results in the groups treated with healthy EPCs and VLA4-EPCs. Immunohistochemical analyses revealed active inflammation and remodelling in all groups but different profiles, with higher MMP9 and lower P-selectin levels in GFP-EPCs, treated animals. In conclusion, our experiments show that genetically modified allogeneic EPCs might be a safe treatment option, with bioavailability in the desired target compartments and the ability to preserve aortic valve function in dyslipidemia and diabetes.

Effect of exercising in water on the fibrocartilage of the deep digital flexor tendon in rats with induced diabetes

Individuals with diabetes mellitus (DM) are affected four times more by tendinopathies than non-diabetics. On the other hand, physical activity helps to DM control. However, the effects of physical exercise in water (PEW) on the fibrocartilages present in the tendons of animals affected by DM are unknown. In this sense, the aim of this study was to analyze the structural organization and chemical composition of fibrocartilage present in the intermediate region of the deep digital flexor tendon (DDFT) of Wistar rats with alloxan-induced DM. Diabetic and non-diabetic animals were randomly separated into four experimental groups (n = 10): Non-Trained Control (NTC), Trained Control (TC), Non-Trained Diabetic (NTD), and Trained Diabetic (TD). TC and TD animals underwent the exercise protocol (total weekly training load - week 1: 14,375; 2: 16,500; 3: 18,375; 4: 20,000) and then were euthanized to collect tendon samples for analysis. The matrix basophilia was more intense in the TC and TD groups. The Decorin immunohistochemical test results showed greater intensity in the NTD and TD groups. The wet weight of the fibrocartilaginous region of the tendon (NTC:19.9 ± 0.06; TC:22.3 ± 0.05; NTD:20.3 ± 0.08; TD:21.8 ± 0.04 mg - p = 0.048), glycosaminoglycan amounts (NTC:3.21 ± 0.18; TC:3.98 ± 0.44; NTD:3.32 ± 0.19; TD:3.79 ± 0.28 μg/mg of fresh tissue - p = 0.046), and intumescence in water (NTC:13.8 ± 3.8; TC:24.3 ± 3.9; NTD:14.9 ± 3.9; TD:28.2 ± 5.3 % w/w - p = 0.042) were higher in the TC and TD groups. The TD group showed the highest levels of type I collagen and matrix metalloproteinase (MMP)-13. The TC group showed the highest and TD the lowest TGF-β1 levels. In conclusion, the PEW was able to stimulate the deposition of proteoglycans, without inducing chemical changes that would cause histopathological modifications in fibrocartilage in the DDFT of adult rats. Thus, PEW preserves the structural organization of these tissues in tendons of animals affected by DM.

Effects of Creatine Supplementation on Histopathological and Biochemical Parameters in the Kidney and Pancreas of Streptozotocin-Induced Diabetic Rats.

Diabetes mellitus (DM) is a worldwide health concern, and projections state that cases will reach 578 million by 2030. Adjuvant therapies that can help the standard treatment and mitigate DM effects are necessary, especially those using nutritional supplements to improve glycemic control. Previous studies suggest creatine supplementation as a possible adjuvant therapy for DM, but they lack the evaluation of potential morphological parameters alterations and tissue injury caused by this compound. The present study aimed to elucidate clinical, histomorphometric, and histopathological consequences and the cellular oxidative alterations of creatine supplementation in streptozotocin (STZ)-induced type 1 DM rats. We could estimate whether the findings are due to DM or the supplementation from a factorial experimental design. Although creatine supplementation attenuated some biochemical parameters, the morphological analyses of pancreatic and renal tissues made clear that the supplementation did not improve the STZ-induced DM1 injuries. Moreover, creatine-supplemented non-diabetic animals were diagnosed with pancreatitis and showed renal tubular necrosis. Therefore, even in the absence of clinical symptoms and unaltered biochemical parameters, creatine supplementation as adjuvant therapy for DM should be carefully evaluated.

Efficacy and safety of small extracellular vesicle interventions in wound healing and skin regeneration: A systematic review and meta-analysis of animal studies.

Small extracellular vesicles (sEVs) have been proposed as a possible solution to the current lack of therapeutic interventions for endogenous skin regeneration. We conducted a systematic review of the available evidence to assess sEV therapeutic efficacy and safety in wound healing and skin regeneration in animal models. 68 studies were identified in Web of Science, Scopus, and PubMed that satisfied a set of prespecified inclusion criteria. We critically analyzed the quality of studies that satisfied our inclusion criteria, with an emphasis on methodology, reporting, and adherence to relevant guidelines (including MISEV2018 and ISCT criteria). Overall, our systematic review and meta-analysis indicated that sEV interventions promoted skin regeneration in diabetic and non-diabetic animal models and influenced various facets of the healing process regardless of cell source, production protocol and disease model. The EV source, isolation methods, dosing regimen, and wound size varied among the studies. Modification of sEVs was achieved mainly by manipulating source cells via preconditioning, nanoparticle loading, genetic manipulation, and biomaterial incorporation to enhance sEV therapeutic potential. Evaluation of potential adverse effects received only minimal attention, although none of the studies reported harmful events. Risk of bias as assessed by the SYRCLE's ROB tool was uncertain for most studies due to insufficient reporting, and adherence to guidelines was limited. In summary, sEV therapy has enormous potential for wound healing and skin regeneration. However, reproducibility and comprehensive evaluation of evidence are challenged by a general lack of transparency in reporting and adherence to guidelines. Methodological rigor, standardization, and risk analysis at all stages of research are needed to promote translation to clinical practice.

Drag-Reducing Polymers Improve Vascular Hemodynamics and Tissue Oxygen Supply in Mouse Model of Diabetes Mellitus.

Diabetes mellitus (DM) is a chronic metabolic disease characterised by hyperglycaemia and glucose intolerance caused by impaired insulin action and/or defective insulin secretion. Long-term hyperglycaemia leads to various structural and functional microvascular changes within multiple tissues, including the brain, which involves blood-brain barrier alteration, inflammation and neuronal dysfunction. We have shown previously that drag-reducing polymers (DRP) improve microcirculation and tissue oxygen supply, thereby reducing neurologic impairment in different rat models of brain injury. We hypothesised that DRP could improve cerebral and skin microcirculation in the situation of progressive microangiopathies associated with diabetes using a mouse model of diabetes mellitus. Diabetes was induced in C57BL/6 J mice with five daily consecutive intraperitoneal injections of streptozotocin (50mg/kg/day). Animals with plasma glucose concentrations greater than 250mg/dL were considered diabetic and were used in the study following four months of diabetes. DRP (2ppm) was injected biweekly during the last two weeks of the experiment. Cortical and skin (ear) microvascular cerebral blood flow (mCBF) and tissue oxygen supply (NADH) were measured by two-photon laser scanning microscopy (2PLSM). Cerebrovascular reactivity (CVR) was evaluated by measuring changes in arteriolar diameters and NADH (tissue oxygen supply) during the hypercapnia test. Transient hypercapnia was induced by a 60-second increase of CO2 concentration in the inhalation mixture from 0% to 10%. Compared to non-diabetic animals, diabetic mice had a significant reduction in the density of functioning capillaries per mm3 (787±52 vs. 449±25), the linear velocity of blood flow (1.2±0.31 vs. 0.54±0.21mm/sec), and the tissue oxygen supply (p<0.05) in both brain and skin. DRP treatment was associated with a 50% increase in all three parameters (p<0.05). According to the hypercapnia test, CVR was impaired in both diabetic groups but more preserved in DRP mice (p<0.05). Our study in a diabetic mouse model has demonstrated the efficacy of hemorheological modulation of blood flow by DRP to achieve increased microcirculatory flows and tissue oxygen supply.

The mineralocorticoid receptor in chronic kidney disease.

Chronic kidney disease (CKD) is a major public health concern, affecting approximately 10% of the population worldwide. CKD of glomerular or tubular origin leads to the activation of stress mechanisms, including the renin-angiotensin-aldosterone system and mineralocorticoid receptor (MR) activation. Over the last two decades, blockade of the MR has arisen as a potential therapeutic approach against various forms of kidney disease. In this review, we summarize the experimental studies that have shown a protective effect of MR antagonists (MRAs) in nondiabetic and diabetic CKD animal models. Moreover, we review the main clinical trials that have shown the clinical application of MRAs to reduce albuminuria and, importantly, to slow CKD progression. Recent evidence from the FIDELIO trial showed that the MRA finerenone can reduce hard kidney outcomes when added to the standard of care in CKD associated with type 2 diabetes. Finally, we discuss the effects of MRAs relative to those of SGLT2 inhibitors, as well as the potential benefit of combination therapy to maximize organ protection. LINKED ARTICLES: This article is part of a themed issue on Emerging Fields for Therapeutic Targeting of the Aldosterone-Mineralocorticoid Receptor Signaling Pathway. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.13/issuetoc.

Doxorubicin-induced apoptosis enhances monocyte infiltration and adverse cardiac remodeling in diabetic animals.

Diabetic cancer patients were treated with doxorubicin (DOX), a potent chemotherapeutic drug that induces cardiac toxicity; however, molecular mechanisms of cardiac toxicity in this specific disease progression in patients and animal models are completely unknown. Therefore, we designed a study to understand the effects of DOX-induced cardiac toxicity in diabetic animals and the involved pathophysiological mechanisms. C57BL/6 J mice were divided into four DOX- and diabetic (streptozotocin; STZ) - treated groups; control, STZ, DOX, and DOX+STZ. At day 14, animals were sacrificed, echocardiography was used to examine heart function, and heart and blood samples were collected to investigate apoptotic mechanisms (caspase 3, BAX, B-Cell leukemia/lymphoma 2 (Bcl2)), inflammation, and cardiac remodeling. Our data shows a significant (p < 0.05) increase in glucose levels, apoptotic markers, and monocyte infiltration at the site of apoptosis and triggered inflammatory immune response (tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6)), in DOX+STZ animals compared with control and experimental groups. We also observed significant (p < 0.05) increase in myofibrillar area, fibrosis, and significantly decreased (p < 0.05) cardiac function in DOX-treated diabetic animals compared with controls. In conclusion, our data suggest that DOX induces significantly increased apoptosis, fibrosis, and structural alterations in diabetic hearts compared with non-diabetic animals.

Antidiabetic and Antioxidant Activities of the Twigs of Andrograhis paniculata on Streptozotocin-Induced Diabetic Male Rats

Background: Diabetes is associated with chronic hyperglycaemia, long-term damage, dysfunction, and organ failure. This study aims to evaluate the antidiabetic activity of the twigs of Andrographis paniculata and its toxicological markers on Streptozotocin (STZ)-induced diabetic Albino rats. Methods: A total of thirty rats were randomly divided into five groups of six animals each. Non-diabetic animals were treated with distilled water as non-diabetic sham control group 1, while diabetic animals (group 2, 3, 4 and 5) were treated with 60 mg/kg bw STZ intravenous (iv) and 100 mg/kg body weight (bwt) of metformin orally for group 2, distilled water for group 3, and 250 and 500 mg/kg bwt of Andrograhis paniculata (A. paniculata) for groups 4 and 5, respectively. The animals were dosed for 28 days, after which they were sacrificed. Liver and kidney function tests as well as livid profile tests were used as the biomarkers of toxicological assessment. Fasting blood glucose was carried out weekly. Oral Glucose Tolerance Test (OGTT) was conducted on the 28th day of the antidiabetic assessment. Results: A. paniculata groups 4 and 5 were significant at different doses (p &lt; 0.05) in reducing the blood glucose level in comparison with metformin. There were significant changes in total and direct bilirubin, total protein, potassium, triglyceride and inorganic phosphorus in 500 mg/kg bwt of the treated group in comparison with the metformin and diabetic group groups. A. paniculata at 500 mg/kg bwt is most effective for its antidiabetic and organ protecting effects.

Dose-response effect of prebiotic ingestion (\u03b2-glucans isolated from Saccharomyces cerevisiae) in diabetic rats with periodontal disease

BackgroundPeriodontal disease is one of the most frequent comorbidities in diabetic patients and can contribute to poor blood glucose control.ObjectiveTo evaluate the effects of ingesting different doses of beta-glucans (BG) isolated from Saccharomyces cerevisiae on alveolar bone loss (ABL) and inflammatory/metabolic parameters in normal and diabetic rats with ligature-induced periodontal disease (PD).DesignSixty male rats were assigned into two groups: non-diabetic or diabetic (i.p. 70 mg/kg streptozotocin) with PD. Then, groups were subdivided into five subgroups according BG doses: 0 mg/Kg; 10 mg/Kg; 20 mg/Kg; 40 mg/Kg or 80 mg/Kg. Animals received BG for 28 days and ligatures were placed on lower first molars during the last 14 days.ResultsABL of diabetic and non-diabetic animals receiving BG 40 mg/kg (1.33 ± 0.03 mm and 0.77 ± 0.07 mm, respectively) and 80 mg/kg (1.26 ± 0.07 mm and 0.78 ± 0.05 mm, respectively) doses was lower (p < 0.05) in comparison to respective controls (1.59 ± 0.11 mm and 0.90 mm ±0.08). COX-2 (Control: 1.66 ± 0.12; 40 mg/kg: 1.13 ± 0.07; 80 mg/kg: 0.92 ± 0.18) and RANKL expressions (Control: 1.74 ± 0.34; 40 mg/kg: 1.03 ± 0.29 ;80 mg/kg: 0.75 ± 0.21), together with the RANKL/OPG ratio (Control: 1.17 ± 0.08; 40 mg/kg: 0.67 ± 0.09; 80 mg/kg: 0.63 ± 0.28) were attenuated above the same dose (p < 0.05). BG did not influence (p > 0.05) metabolic parameters in non-diabetic rats. In diabetic animals, doses above 40 mg/kg reduced IL-1β (Control: 387 ± 66; 40 mg/kg: 309 ± 27; 80 mg/kg: 300 ± 14) and TNF-α (Control: 229 ± 19; 40 mg/kg: 128 ± 53; 80 mg/kg: 71 ± 25), blood glucose levels (Control: 402 ± 49; 40 mg/kg: 334 ± 32; 80 mg/kg: 287 ± 56), total cholesterol (Control: 124 ± 8; 40 mg/kg: 120 ± 10; 80 mg/kg: 108 ± 9), LDL-c + VLDL-c (Control: 106 ± 8; 40 mg/kg: 103 ± 10; 80 mg/kg: 87 ± 10) and triacylglycerols (Control: 508 ± 90; 40 mg/kg: 301 ± 40; 80 mg/kg: 208 ± 61), whereas increased HDL-c (Control: 18 ± 0.5; 40 mg/kg: 19 ± 1; 80 mg/kg: 21 ± 1) (p < 0.05). Optimal dose needed to reduce ABL was higher in diabetic animals with PD.ConclusionsBG ingestion reduced ABL and improved inflammatory profile in a dose-dependent manner. Best effects were achieved with doses above 40 mg/kg.

Systematic Review of the Application of Perinatal Derivatives in Animal Models on Cutaneous Wound Healing.

Knowledge of the beneficial effects of perinatal derivatives (PnD) in wound healing goes back to the early 1900s when the human fetal amniotic membrane served as a biological dressing to treat burns and skin ulcerations. Since the twenty-first century, isolated cells from perinatal tissues and their secretomes have gained increasing scientific interest, as they can be obtained non-invasively, have anti-inflammatory, anti-cancer, and anti-fibrotic characteristics, and are immunologically tolerated in vivo. Many studies that apply PnD in pre-clinical cutaneous wound healing models show large variations in the choice of the animal species (e.g., large animals, rodents), the choice of diabetic or non-diabetic animals, the type of injury (full-thickness wounds, burns, radiation-induced wounds, skin flaps), the source and type of PnD (placenta, umbilical cord, fetal membranes, cells, secretomes, tissue extracts), the method of administration (topical application, intradermal/subcutaneous injection, intravenous or intraperitoneal injection, subcutaneous implantation), and the type of delivery systems (e.g., hydrogels, synthetic or natural biomaterials as carriers for transplanted cells, extracts or secretomes). This review provides a comprehensive and integrative overview of the application of PnD in wound healing to assess its efficacy in preclinical animal models. We highlight the advantages and limitations of the most commonly used animal models and evaluate the impact of the type of PnD, the route of administration, and the dose of cells/secretome application in correlation with the wound healing outcome. This review is a collaborative effort from the COST SPRINT Action (CA17116), which broadly aims at approaching consensus for different aspects of PnD research, such as providing inputs for future standards for the preclinical application of PnD in wound healing.

Glucosamine protects against neuronal but not vascular damage in experimental diabetic retinopathy

ObjectiveGlucosamine, an intermetabolite of the hexosamine biosynthesis pathway (HBP), is a widely used nutritional supplement in osteoarthritis patients, a subset of whom also suffer from diabetes. HBP is activated in diabetic retinopathy (DR). The aim of this study is to investigate the yet unclear effects of glucosamine on DR. MethodsIn this study, we tested the effect of glucosamine on vascular and neuronal pathology in a mouse model of streptozotocin-induced DR in vivo and on cultured endothelial and Müller cells to elucidate the underlying mechanisms of action in vitro. ResultsGlucosamine did not alter the blood glucose or HbA1c levels in the animals, but induced body weight gain in the non-diabetic animals. Interestingly, the impaired neuronal function in diabetic animals could be prevented by glucosamine treatment. Correspondingly, the activation of Müller cells was prevented in the retina as well as in cell culture. Conversely, glucosamine administration in the normal retina damaged the retinal vasculature by increasing pericyte loss and acellular capillary formation, likely by interfering with endothelial survival signals as seen in vitro in cultured endothelial cells. Nevertheless, under diabetic conditions, no further increase in the detrimental effects were observed. ConclusionsIn conclusion, the effects of glucosamine supplementation in the retina appear to be a double-edged sword: neuronal protection in the diabetic retina and vascular damage in the normal retina. Thus, glucosamine supplementation in osteoarthritis patients with or without diabetes should be taken with care.

Melatonin protects against focal cerebral ischemia-reperfusion injury in diabetic mice by ameliorating mitochondrial impairments: involvement of the Akt-SIRT3-SOD2 signaling pathway.

Diabetic patients are more vulnerable to cerebral ischemia-reperfusion (CIR) injury and have a worse prognosis and higher mortality after ischemic stroke than non-diabetic counterparts. Melatonin can exert neuroprotective effects against CIR injury in nondiabetic animal models. However, its effects on diabetic CIR injury and the underlying mechanisms remain unclarified. Herein, we found that melatonin administration improved neurological deficit, cerebral infarct volume, brain edema, and cell viability, reduced mitochondrial swelling, reactive oxygen species generation, and cytoplasmic cytochrome C release, and increased mitochondrial antioxidant enzymes activities, adenosine triphosphate production, and mitochondrial membrane potential in both streptozotocin-induced diabetic mice and high glucose-treated HT22 cells. Importantly, melatonin also activated protein kinase B (Akt) and sirtuin 3 (SIRT3)/superoxide dismutase 2 (SOD2) signaling and upregulated mitochondrial biogenesis-related transcription factors. However, these effects were largely attenuated by LY294002 (a specific Akt signaling blocker) administration. Additionally, 3-TYP (a selective SIRT3 inhibitor) and SIRT3 siRNA inhibited the above protective effects of melatonin as well as the upregulation of SIRT3 and the decrease of SOD2 acetylation but did not affect the p-Akt/Akt ratio. Overall, we demonstrate that melatonin can alleviate CIR injury in diabetic mice by activating Akt-SIRT3-SOD2 signaling and subsequently improving mitochondrial damage.