Effects of garlic (Allium sativum L) and Citrullus colocynthis (L.) Schrad individually and in combination on male reproductive damage due to diabetes: suppression of the AGEs/RAGE/Nox-4 signaling pathway.

BACKGROUND: Diabetes Mellitus is associated with disturbances in male reproductive function and fertility. Studies have shown that oxidative stress with the subsequent inflammation and apoptosis cause these complications in diabetes. Garlic (G) (Allium sativum L) and Citrullus colocynthis (L.) Schrad (C) both have antidiabetic and antioxidant properties. Recently, we demonstrated their synergistic effects in alleviating reproductive complications when administered concomitantly. However, as even medicinal plants in long term usage may lead to some unwanted side effects of their own, we examined whether with half the original doses of these two medicinal plants we could achieve the desired results. METHODS: Thirty-five male Wistar rats were divided into five groups (n = 7/group): Control, Diabetic, Diabetic + G (0.5 ml/100 g BW), Diabetic + C (5 mg/kg BW) and Diabetic + GC (0.5 ml/100 g BW of garlic and 5 mg/kg BW of C. colocynthis) groups. The experimental period was 30 days. RESULTS: Oxidative stress, advanced glycation end products (AGEs), immunoexpression of caspase-3, and expression of mRNAs for receptor for advanced glycation end products (RAGE), NADPH oxidase-4 (NOX-4) and nuclear factor kappa B increased in testis of diabetic rats. Treatment with garlic and C. colocynthis alone showed some beneficial effects, but in the combination form the effectiveness was more profound. CONCLUSIONS: We conclude that the combination therapy of diabetic rats with lower doses is still as efficient as higher doses; therefore, the way forward for reducing complications in long term consumption.

Effects of sevoflurane and fullerenol C60 on lower limb ischemia-reperfusion injury in streptozocin-induced diabetic mice.

BACKGROUND: Ischemia-reperfusion injury (IRI) poses a significant challenge for physicians, necessitating the management of cell damage and the preservation of organ functions. Various surgical procedures, such as vascular surgery on extremities, temporary cross-clamping of the abdominal aorta in aortic surgery, and the use of a tourniquet in extremity surgeries, may induce lower limb IRI. The susceptibility to IRI is heightened in individuals with diabetes. This study aimed to investigate the effects of fullerenol C60 and sevoflurane on mouse muscle tissue in a lower limb IRI model and to assess their potential in preventing complications arising from ischemia-reperfusion in mice with streptozocin-induced diabetes. METHODS: A total of 36 adult Swiss albino mice were randomly divided into six groups, each consisting of six mice: control group (group C), diabetes group (group D), diabetes-ischemia/reperfusion group (group DIR), diabetes-ischemia/reperfusion-fullerenol C60 group (group DIR-FC60), diabetes-ischemia/reperfusion-sevoflurane group (group DIR-S), and diabetes-ischemia/reperfusion-sevoflurane-fullerenol C60 group (DIR-S-FC60). Streptozocin (55 mg/kg) was intraperitoneally administered to induce diabetes in the relevant groups, with mice displaying blood glucose levels of 250 mg/dL or higher at 72 h were considered diabetic. After 4 weeks, all groups underwent laparotomy under anesthesia. In DIR-FC60 and DIR-S-FC60 groups, fullerenol C60 (100 mg/kg) was intraperitoneally administrated 30 min before the ischemia period. Sevoflurane, delivered in 100% oxygen at a rate of 2.3% and 4 L/min, was administered during the ischemia period in DIR-S and DIR-S-FC60 groups. In the IR groups, a microvascular clamp was placed on the infrarenal abdominal aorta for 120 min during the ischemia period, followed by the removal of the clamp and a 120-min reperfusion period. At the end of the reperfusion, gastrocnemius muscle tissues were removed for histopathological and biochemical parameter examinations. RESULTS: Histopathological examination revealed a significant reduction in the disorganization and degeneration of muscle cells in the DIR-S-FC60 group compared to the DIR group (p = 0.041). Inflammatory cell infiltration was notably lower in the DIR-S, DIR-FC60, and DIR-S-FC60 groups than in the DIR group (p = 0.031, p = 0.011, and p = 0.013, respectively). The total damage scores in the DIR-FC60 and DIR-S-FC60 groups were significantly lower than in the DIR group (p = 0.018 and p = 0.008, respectively). Furthermore, the levels of malondialdehyde (MDA) in the DIR-S, DIR-FC60, and DIR-S-FC60 groups were significantly lower than in the DIR group (p < 0.001, p < 0.001, and p < 0.001, respectively). Catalase (CAT) enzyme activity in the DIR-S, DIR-FC60, and DIR-S-FC60 groups was higher than in the DIR group (p = 0.001, p = 0.014, and p < 0.001, respectively). Superoxide dismutase (SOD) enzyme activity in the DIR-FC60 and DIR-S-FC60 groups was also higher than in the DIR group (p < 0.001 and p = 0.001, respectively). CONCLUSION: Our findings indicate that administering fullerenol C60 30 min prior to ischemia in diabetic mice, in combination with sevoflurane, led to a reduction in oxidative stress and the correction of IR-related damage in muscle tissue histopathology. We believe that the administration of fullerenol C60 before IR, coupled with sevoflurane administration during IR, exerts a protective effect in mice.

Static Strength Training Method for Type 2 Diabetic Mice.

The treatment of type 2 diabetes mellitus (T2DM) is a major difficulty in improving patient health. Exercise is one of the main interventions for T2DM. Static strength training is one of the key forms of traditional sports in China. Research shows that static strength training is an effective clinical method for T2DM intervention, but there is no experimental device suitable for static training in mice. One of the difficulties in moving from clinical to basic research is to design appropriate experimental devices. In order to further study the mechanism of static training intervention in T2DM, a simple method for making a static training device for mice is introduced in this paper. This device has the advantages of simple operation, cheap material, and high feasibility. Previous studies conducted under this protocol have shown that static training can effectively reduce blood glucose levels and improve the mitochondrial function of skeletal muscle cells in T2DM mice. The purpose of introducing this device is to promote research on the mechanism of traditional exercise in the intervention of T2DM and to lay a foundation for the quantitative intervention of exercise.

AESIS-1, a Rheumatoid Arthritis Therapeutic Peptide, Accelerates Wound Healing by Promoting Fibroblast Migration in a CXCR2-Dependent Manner.

In patients with autoimmune disorders such as rheumatoid arthritis (RA), delayed wound healing is often observed. Timely and effective wound healing is a crucial determinant of a patient's quality of life, and novel materials for skin wound repair, such as bioactive peptides, are continuously being studied and developed. One such bioactive peptide, AESIS-1, has been studied for its well-established anti-rheumatoid arthritis properties. In this study, we attempted to use the anti-RA material AESIS-1 as a therapeutic wound-healing agent based on disease-modifying antirheumatic drugs (DMARDs), which can help restore prompt wound healing. The efficacy of AESIS-1 in wound healing was assessed using a full-thickness excision model in diabetic mice; this is a well-established model for studying chronic wound repair. Initial observations revealed that mice treated with AESIS-1 exhibited significantly advanced wound repair compared with the control group. In vitro studies revealed that AESIS-1 increased the migration activity of human dermal fibroblasts (HDFs) without affecting proliferative activity. Moreover, increased HDF cell migration is mediated by upregulating chemokine receptor expression, such as that of CXC chemokine receptor 2 (CXCR2). The upregulation of CXCR2 through AESIS-1 treatment enhanced the chemotactic reactivity to CXCR2 ligands, including CXC motif ligand 8 (CXCL8). AESIS-1 directly activates the ERK and p38 mitogen-activated protein kinase (MAPK) signaling cascades, which regulate the migration and expression of CXCR2 in fibroblasts. Our results suggest that the AESIS-1 peptide is a strong wound-healing substance that increases the movement of fibroblasts and the expression of CXCR2 by turning on the ERK and p38 MAPK signaling cascades.

Calorie Restriction Using High-Fat/Low-Carbohydrate Diet Suppresses Liver Fat Accumulation and Pancreatic Beta-Cell Dedifferentiation in Obese Diabetic Mice.

In diabetes, pancreatic ß-cells gradually lose their ability to secrete insulin with disease progression. ß-cell dysfunction is a contributing factor to diabetes severity. Recently, islet cell heterogeneity, exemplified by ß-cell dedifferentiation and identified in diabetic animals, has attracted attention as an underlying molecular mechanism of ß-cell dysfunction. Previously, we reported ß-cell dedifferentiation suppression by calorie restriction, not by reducing hyperglycemia using hypoglycemic agents (including sodium-glucose cotransporter inhibitors), in an obese diabetic mice model (db/db). Here, to explore further mechanisms of the effects of food intake on ß-cell function, db/db mice were fed either a high-carbohydrate/low-fat diet (db-HC) or a low-carbohydrate/high-fat diet (db-HF) using similar calorie restriction regimens. After one month of intervention, body weight reduced, and glucose intolerance improved to a similar extent in the db-HC and db-HF groups. However, ß-cell dedifferentiation did not improve in the db-HC group, and ß-cell mass compensatory increase occurred in this group. More prominent fat accumulation occurred in the db-HC group livers. The expression levels of genes related to lipid metabolism, mainly regulated by peroxisome proliferator-activated receptor α and γ, differed significantly between groups. In conclusion, the fat/carbohydrate ratio in food during calorie restriction in obese mice affected both liver lipid metabolism and ß-cell dedifferentiation.

Advancing diabetes treatment: the role of mesenchymal stem cells in islet transplantation.

Diabetes mellitus, a prevalent global health challenge, significantly impacts societal and economic well-being. Islet transplantation is increasingly recognized as a viable treatment for type 1 diabetes that aims to restore endogenous insulin production and mitigate complications associated with exogenous insulin dependence. We review the role of mesenchymal stem cells (MSCs) in enhancing the efficacy of islet transplantation. MSCs, characterized by their immunomodulatory properties and differentiation potential, are increasingly seen as valuable in enhancing islet graft survival, reducing immune-mediated rejection, and supporting angiogenesis and tissue repair. The utilization of MSC-derived extracellular vesicles further exemplifies innovative approaches to improve transplantation outcomes. However, challenges such as MSC heterogeneity and the optimization of therapeutic applications persist. Advanced methodologies, including artificial intelligence (AI) and single-cell RNA sequencing (scRNA-seq), are highlighted as potential technologies for addressing these challenges, potentially steering MSC therapy toward more effective, personalized treatment modalities for diabetes. This review revealed that MSCs are important for advancing diabetes treatment strategies, particularly through islet transplantation. This highlights the importance of MSCs in the field of regenerative medicine, acknowledging both their potential and the challenges that must be navigated to fully realize their therapeutic promise.

MicroRNA Regulatory Pattern in Diabetic Mouse Cortex at Different Stages Following Ischemic Stroke.

After ischemic stroke, microRNAs (miRNAs) participate in various processes, including immune responses, inflammation, and angiogenesis. Diabetes is a key factor increasing the risk of ischemic stroke; however, the regulatory pattern of miRNAs at different stages of diabetic stroke remains unclear. This study comprehensively analyzed the miRNA expression profiles in diabetic mice at 1, 3, and 7 days post-reperfusion following the middle cerebral artery occlusion (MCAO). We identified differentially expressed (DE) miRNAs in diabetic stroke and found significant dysregulation of some novel miRNAs (novel_mir310, novel_mir89, and novel_mir396) post-stroke. These DEmiRNAs were involved in apoptosis and the formation of tight junctions. Finally, we identified three groups of time-dependent DE miRNAs (miR-6240, miR-135b-3p, and miR-672-5p). These have the potential to serve as biomarkers of diabetic stroke. These findings provide a new perspective for future research, emphasizing the dynamic changes in miRNA expression after diabetic stroke and offering potential candidates as biomarkers for future clinical applications.

Nephro-protective effects of alpha-lipoic acid in type I diabetes.

Type 1 diabetes (T1D) is an insulin-dependent autoimmune condition. Short chain fatty acids (SCFAs) are volatile fatty acids with 1-6 carbon atoms that influence glucose storage in the body and can reduce appetite, potentially decreasing T1D risk. Alpha-lipoic acid (α-LA), a type of SCFA, has previously been used to treat diabetic neuropathy and inflammation due to its antioxidant properties. This study aims to assess α-LA's protective effects against T1D and associated kidney damage in rats induced with streptozotocin. Diabetic rats were treated with α-LA orally for 15 days, resulting in improved blood glucose (56% decrease) and kidney function markers like blood urea nitrogen, creatinine and uric acid. α-LA also showed significant antioxidant effects by decreasing LPO as well as improving activities of antioxidant enzymes like superoxide dismutase, catalase and glutathione-S transferase and alleviated kidney damage caused by diabetes. Docking experiments suggest that α-LA may regulate diabetes-related changes at the epigenetic level through interactions with the SIRT1 protein, indicating its potential as a target for future antidiabetic drug development.

Molecular Modeling, Synthesis, and Antihyperglycemic Activity of the New Benzimidazole Derivatives - Imidazoline Receptor Agonists.

Introduction: The paper presents the results of a study on the first synthesized benzimidazole derivatives obtained from labile nature carboxylic acids. The synthesis conditions of these substances were studied, their structure was proved, and some components were found to have sugar-reducing activity on the model of alloxan diabetes in rats. Methods: The study used molecular modeling methods such as docking based on the evolutionary model (igemdock), RP_HPLC method to monitor the synthesis reaction, and 1H NMR and 13C NMR, and other methods of organic chemistry to confirm the structures of synthesized substances. Results & Discussion: The docking showed that the ursodeoxycholic acid benzimidazole derivatives have high tropics to all imidazoline receptor carriers (PDB ID: 2XCG, 2bk3, 3p0c, 1QH4). The ursodeoxycholic acid benzimidazole derivative and arginine and histidine benzimidazole derivatives showed the highest sugar-lowering activity in the experiment on alloxan-diabetic rats. For these derivatives, the difference in glucose levels of treated rats was significant against untreated control. Therefore, the new derivatives of benzimidazole and labile natural organic acids can be used to create new classes of imidazoline receptor inhibitors for the treatment of diabetes mellitus and hypertension.

Development of chitosan lipid nanoparticles to alleviate the pharmacological activity of piperine in the management of cognitive deficit in diabetic rats.

The aim of the present study was to prepare and evaluate Piperine (PP) loaded chitosan lipid nanoparticles (PP-CLNPs) to evaluate its biological activity alone or in combination with the antidiabetic drug Metformin (MET) in the management of cognitive deficit in diabetic rats. Piperine was successfully loaded on CLNPs prepared using chitosan, stearic acid, Tween 80 and Tripolyphosphate (TPP) at different concentrations. The developed CLNPs exhibited high entrapment efficiency that ranged from 85.12 to 97.41%, a particle size in the range of 59.56-414 nm and a negatively charged zeta potential values (- 20.1 to - 43.9 mV). In vitro release study revealed enhanced PP release from CLNPs compared to that from free PP suspensions for up to 24 h. In vivo studies revealed that treatment with the optimized PP-CLNPs formulation (F2) exerted a cognitive enhancing effect and ameliorated the oxidative stress associated with diabetes. PP-CLNPs acted as an effective bio-enhancer which increased the potency of metformin in protecting brain tissue from diabetes-induced neuroinflammation and memory deterioration. These results suggested that CLNPs could be a promising drug delivery system for encapsulating PP and thus can be used as an adjuvant therapy in the management of high-risk diabetic cognitive impairment conditions.

Cold-induced FOXO1 nuclear transport aids cold survival and tissue storage.

Cold-induced injuries severely limit opportunities and outcomes of hypothermic therapies and organ preservation, calling for better understanding of cold adaptation. Here, by surveying cold-altered chromatin accessibility and integrated CUT&Tag/RNA-seq analyses in human stem cells, we reveal forkhead box O1 (FOXO1) as a key transcription factor for autonomous cold adaptation. Accordingly, we find a nonconventional, temperature-sensitive FOXO1 transport mechanism involving the nuclear pore complex protein RANBP2, SUMO-modification of transporter proteins Importin-7 and Exportin-1, and a SUMO-interacting motif on FOXO1. Our conclusions are supported by cold survival experiments with human cell models and zebrafish larvae. Promoting FOXO1 nuclear entry by the Exportin-1 inhibitor KPT-330 enhances cold tolerance in pre-diabetic obese mice, and greatly prolongs the shelf-life of human and mouse pancreatic tissues and islets. Transplantation of mouse islets cold-stored for 14 days reestablishes normoglycemia in diabetic mice. Our findings uncover a regulatory network and potential therapeutic targets to boost spontaneous cold adaptation.

Insulin eye drops improve corneal wound healing in STZ-induced diabetic mice by regulating corneal inflammation and neuropeptide release.

INTRODUCTION: In recent years, insulin eye drops have attracted increasing attention from researchers and ophthalmologists. The aim of this study was to investigate the efficacy and possible mechanism of action of insulin eye drops in diabetic mice with corneal wounds. METHODS: A type 1 diabetes model was induced, and a corneal epithelial injury model of 2.5 mm was established. We used corneal fluorescein staining, hematoxylin-eosin (H-E) staining and the Cochet-Bonnet esthesiometer to examine the process of wound healing. Subsequently, the expression levels of Ki-67, IL-1ß, ß3-tubulin and neuropeptides, including substance P (SP) and calcitonin gene-related peptide (CGRP), were examined at 72 h after corneal injury. RESULTS: Fluorescein staining demonstrated an acceleration of the recovery of corneal epithelial injury in diabetic mice compared with the saline treatment, which was further evidenced by the overexpression of Ki-67. Moreover, 72 h of insulin application attenuated the expression of inflammatory cytokines and neutrophil infiltration. Remarkably, the results demonstrated that topical insulin treatment enhanced the density of corneal epithelial nerves, as well as neuropeptide SP and CGRP release, in the healing cornea via immunofluorescence staining. CONCLUSIONS: Our results indicated that insulin eye drops may accelerate corneal wound healing and decrease inflammatory responses in diabetic mice by promoting nerve regeneration and increasing levels of neuropeptides SP and CGRP.

Hyperbaric oxygen therapy promotes the browning of white fat and contributes to the healing of diabetic wounds.

Non-healing wounds are one of the chronic complications of diabetes and have remained a worldwide challenge as one of the major health problems. Hyperbaric oxygen (HBO) therapy is proven to be very successful for diabetic wound treatment, for which the molecular basis is not understood. Adipocytes regulate multiple aspects of repair and may be therapeutic for inflammatory diseases and defective wound healing associated with aging and diabetes. Endothelial cell-derived extracellular vesicles could promote wound healing in diabetes. To study the mechanism by which HBO promotes wound healing in diabetes, we investigated the effect of HBO on fat cells in diabetic mice. A diabetic wound mouse model was established and treated with HBO. Haematoxylin and eosin (H&E) staining and immunofluorescence were used for the analysis of wound healing. To further explore the mechanism, we performed whole-genome sequencing on extracellular vesicles (EVs). Furthermore, we conducted in vitro experiments. Specifically, exosomes were collected from human umbilical vein endothelial cell (HUVEC) cells after HBO treatment, and then these exosomes were co-incubated with adipose tissue. The wound healing rate in diabetic mice treated with HBO was significantly higher. HBO therapy promotes the proliferation of adipose precursor cells. HUVEC-derived exosomes treated with HBO significantly promoted fat cell browning. These data clarify that HBO therapy may promote vascular endothelial cell proliferation and migration, and promote browning of fat cells through vascular endothelial cells derived exosomes, thereby promoting diabetic wound healing. This provides new ideas for the application of HBO therapy in the treatment of diabetic trauma.

Nafamostat mesylate decreases skin flap necrosis in a mouse model of type 2 diabetes by protecting the endothelial glycocalyx.

The success rate of flap tissue reconstruction has increased in recent years owing to advancements in microsurgical techniques. However, complications, such as necrosis, are still more prevalent in diabetic patients compared to non-diabetic individuals, presenting an ongoing challenge. To address this issue, many previous studies have examined vascular anastomoses dilation and stability, primarily concerning surgical techniques or drugs. In contrast, in the present study, we focused on microvascular damage of the peripheral microvessels in patients with diabetes mellitus and the preventative impact of nafamostat mesylate. Herein, we aimed to investigate the effects of hyperglycemia on glycocalyx (GCX) levels in mice with type 2 diabetes. We examined the endothelial GCX (eGCX) in skin flap tissue of 9-12-week-old type 2 diabetic mice (db/db mice) using a perforator skin flap and explored treatment with nafamostat mesylate. The growth rates were compared after 1 week. Heterotype (db/+) mice were used as the control group. Morphological examination of postoperative tissues was performed at 1, 3, 5, and 7 days post-surgery. In addition, db/db mice were treated with 30 mg/kg/day of nafamostat mesylate daily and were evaluated on postoperative day 7. Seven days after surgery, all db/db mice showed significant partial flap necrosis. Temporal observation of the skin flaps revealed a stasis-like discoloration and necrosis starting from the contralateral side of the remaining perforating branch. The control group did not exhibit flap necrosis, and the flap remained intact. In the quantitative assessment of endothelial glycans using lectins, intensity scoring showed that the eGCX in the db/db group was significantly thinner than that in the db/+ group. These results were consistent with the scanning electron microscopy findings. In contrast, treatment with nafamostat mesylate significantly improved the flap engraftment rate and suppressed eGCX injury. In conclusion, treatment with nafamostat mesylate improves the disrupted eGCX structure of skin flap tissue in db/db mice, potentially ameliorating the impaired capillary-to-venous return in the skin flap tissue.

Improvement of diabetes-induced spinal cord axon injury with taurine via nerve growth factor-dependent Akt/mTOR pathway.

Diabetic neuropathy (DN) is a common neurological complication caused by diabetes mellitus (DM). Axonal degeneration is generally accepted to be the major pathological change in peripheral DN. Taurine has been evidenced to be neuroprotective in various aspects, but its effect on spinal cord axon injury (SCAI) in DN remains barely reported. This study showed that taurine significantly ameliorated axonal damage of spinal cord (SC), based on morphological and functional analyses, in a rat model of DN induced by streptozotocin (STZ). Taurine was also found to induce neurite outgrowth in cultured cerebral cortex neurons with high glucose exposure. Moreover, taurine up-regulated the expression of nerve growth factor (NGF) and neurite outgrowth relative protein GAP-43 in rat DN model and cultured cortical neurons/VSC4.1 cells. Besides, taurine increased the activating phosphorylation signals of TrkA, Akt, and mTOR. Mechanistically, the neuroprotection by taurine was related to the NGF-pAKT-mTOR axis, because either NGF-neutralizing antibody or Akt or mTOR inhibitors was found to attenuate its beneficial effects. Together, our results demonstrated that taurine promotes spinal cord axon repair in a model of SCAI in STZ-induced diabetic rats, mechanistically associating with the NGF-dependent activation of Akt/mTOR pathway.

The analgesic effects of insulin and its disorders in streptozotocin-induced short-term diabetes.

Evidence suggests that insulin resistance plays an important role in developing diabetes complications. The association between insulin resistance and pain perception is less well understood. This study aimed to investigate the effects of peripheral insulin deficiency on pain pathways in the brain. Diabetes was induced in 60 male rats with streptozotocin (STZ). Insulin was injected into the left ventricle of the brain by intracerebroventricular (ICV) injection, then pain was induced by subcutaneous injection of 2.5% formalin. Samples were collected at 4 weeks after STZ injection. Dopamine (DA), serotonin, reactive oxygen species (ROS), and mitochondrial glutathione (mGSH) were measured by ELISA, and gene factors were assessed by RT-qPCR. In diabetic rats, the levels of DA, serotonin, and mGSH decreased in the nuclei of the thalamus, raphe magnus, and periaqueductal gray, and the levels of ROS increased. In addition, the levels of expression of the neuron-specific enolase and receptor for advanced glycation end genes increased, but the expression of glial fibrillary acidic protein expression was reduced. These results support the findings that insulin has an analgesic effect in non-diabetic rats, as demonstrated by the formalin test. ICV injection of insulin reduces pain sensation, but this was not observed in diabetic rats, which may be due to cell damage ameliorated by insulin.

Phenotypes of streptozotocin-induced gestational diabetes mellitus in mice.

Gestational diabetes mellitus (GDM) in human patients disrupts glucose metabolism post-pregnancy, affecting fetal development. Although obesity and genetic factors increase GDM risk, a lack of suitable models impedes a comprehensive understanding of its pathology. To address this, we administered streptozotocin (STZ, 75 mg/kg) to C57BL/6N mice for two days before pregnancy, establishing a convenient GDM model. Pregnant mice exposed to STZ (STZ-pregnant) were compared with STZ-injected virgin mice (STZ-virgin), citrate buffer-injected virgin mice (CB-virgin), and pregnant mice injected with citrate buffer (CB-pregnant). STZ-pregnant non-obese mice exhibited elevated blood glucose levels on gestational day 15.5 and impaired glucose tolerance. They also showed fewer normal fetuses compared to CB-pregnant mice. Additionally, STZ-pregnant mice had the highest plasma C-peptide levels, with decreased pancreatic islets or increased alpha cells compared to CB-pregnant mice. Kidneys isolated from STZ-pregnant mice did not display histological alterations or changes in gene expression for the principal glucose transporters (GLUT2 and SGLT2) and renal injury-associated markers. Notably, STZ-pregnant mice displayed decreased gene expression of insulin-receiving molecules (ISNR and IGFR1), indicating heightened insulin resistance. Liver histology in STZ-pregnant mice remained unchanged except for a pregnancy-related increase in lipid droplets within hepatocytes. Furthermore, the duodenum of STZ-pregnant mice exhibited increased gene expression of ligand-degradable IGFR2 and decreased expression of GLUT5 and GLUT12 (fructose and glucose transporters, respectively) compared to STZ-virgin mice. Thus, STZ-pregnant mice displayed GDM-like symptoms, including fetal abnormalities, while organs adapted to impaired glucose metabolism by altering glucose transport and insulin reception without histopathological changes. STZ-pregnant mice offer a novel model for studying mild onset non-obese GDM and species-specific differences in GDM features between humans and animals.

Garlic oil improves small intestinal motility in experimentally induced type II diabetes mellitus in female Wistar rats.

Diabetes mellitus adversely affects the contractile ability of the small intestine. However, there is a paucity of studies investigating the impact of garlic oil on small intestinal motility. This study aimed to evaluate the potential beneficial effects of garlic oil on type 2 diabetes mellitus in rats. Thirty-six adult female Wistar rats (n = 36) were divided into four groups: control, non-diabetic rats supplemented with garlic oil, diabetic rats, and diabetic rats treated with garlic oil. The rats were anesthetized using pentobarbitone (40 mg/kg BW); various motility parameters and oxidative markers were determined in small intestinal segments. Measurements were taken for naso-anal length, waist circumference, fasting blood glucose level (FBG), and plasma insulin level. Compared to the control group, the diabetic rats exhibited a reduction in the average force of contraction and motility index in all small intestinal segments. Furthermore, the rats exhibited a reduction in the average duration of muscle contraction only in the jejunum. The rats also exhibited hyperglycemia, insulin resistance, significant oxidative stress, and obesity. This was proven by changes in motility parameters, fasting blood glucose levels, HOMA-IR values, intestinal MDA levels, and waist circumference. The non-diabetic rats supplemented with garlic oil also exhibited a decrease in the average force of contraction and motility index in all small intestinal segments, despite having consistently higher Lee index and waist circumference values. However, the diabetic rats treated with garlic oil demonstrated improved small intestinal motility in nearly all small intestinal segments and a reduction in oxidative stress. In conclusion, rats with diabetes mellitus experienced a decrease in small intestinal motility, which is primarily driven by oxidative stress. Normal rats administered with garlic oil supplements exhibited similar effects. In contrast, garlic oil treatment in diabetic rats led to enhanced small intestinal motility and a notable anti-hyperglycemic effect, which can be attributed to the potent antioxidant properties of garlic oil.

Aberrant splicing of CaV1.2 calcium channel induced by decreased Rbfox1 enhances arterial constriction during diabetic hyperglycemia.

Diabetic hyperglycemia induces dysfunctions of arterial smooth muscle, leading to diabetic vascular complications. The CaV1.2 calcium channel is one primary pathway for Ca2+ influx, which initiates vasoconstriction. However, the long-term regulation mechanism(s) for vascular CaV1.2 functions under hyperglycemic condition remains unknown. Here, Sprague-Dawley rats fed with high-fat diet in combination with low dose streptozotocin and Goto-Kakizaki (GK) rats were used as diabetic models. Isolated mesenteric arteries (MAs) and vascular smooth muscle cells (VSMCs) from rat models were used to assess K+-induced arterial constriction and CaV1.2 channel functions using vascular myograph and whole-cell patch clamp, respectively. K+-induced vasoconstriction is persistently enhanced in the MAs from diabetic rats, and CaV1.2 alternative spliced exon 9* is increased, while exon 33 is decreased in rat diabetic arteries. Furthermore, CaV1.2 channels exhibit hyperpolarized current-voltage and activation curve in VSMCs from diabetic rats, which facilitates the channel function. Unexpectedly, the application of glycated serum (GS), mimicking advanced glycation end-products (AGEs), but not glucose, downregulates the expression of the splicing factor Rbfox1 in VSMCs. Moreover, GS application or Rbfox1 knockdown dynamically regulates alternative exons 9* and 33, leading to facilitated functions of CaV1.2 channels in VSMCs and MAs. Notably, GS increases K+-induced intracellular calcium concentration of VSMCs and the vasoconstriction of MAs. These results reveal that AGEs, not glucose, long-termly regulates CaV1.2 alternative splicing events by decreasing Rbfox1 expression, thereby enhancing channel functions and increasing vasoconstriction under diabetic hyperglycemia. This study identifies the specific molecular mechanism for enhanced vasoconstriction under hyperglycemia, providing a potential target for managing diabetic vascular complications.

Edible wild plants, chicory and purslane, alleviated diabetic testicular dysfunction, and insulin resistance via suppression 8OHdg and oxidative stress in rats.

Testicular dysfunction is a prevalent health problem frequently reported in individuals with diabetes mellitus (DM). Oxidative-inflammatory reactions, hormonal and spermatic abnormalities often accompany this illness. Herbal remedies "particularly wild plants" including chicory (Chicorium Intybus) and purslane (Portulaca Oleracea) are emerging as popular agents for people dealing with these issues due to their ability to act as antioxidants, reduce inflammation, and exhibit antidiabetic effects. According to the collected data, the daily administration of chicory (Ch) seed-extract (250 mg/kg) or purslane (Pu) seed-extract (200 mg/kg) to streptozotocin (STZ)-induced diabetic rats (50 mg/kg) for 30 days resulted in the normalization of fasting blood glucose (FBG), serum fructosamine, insulin levels, and insulin resistance (HOMA-IR), as well as reducing lipid peroxidation end-product malondialdehyde (MDA) level, aldehyde oxidase (AO) and xanthene oxidase (XO) activities. While caused a considerable improvement in glutathione (GSH) content, superoxide dismutase (SOD), catalase (CAT) activity, and total antioxidant capacity (TAC) when compared to diabetic rats. Ch and Pu extracts had a substantial impact on testicular parameters including sperm characterization, testosterone level, vimentin expression along with improvements in body and testis weight. They also mitigated hyperlipidemia by reducing total lipids (TL), total cholesterol (TC) levels, and low-density lipoprotein cholesterol (LDL-C), while increasing high-density lipoprotein cholesterol (HDL-C). Furthermore, oral administration of either Ch or Pu notably attuned the elevated proinflammatory cytokines as tumor necrotic factor (TNF-α), C-reactive protein (CRP), and Interleukin-6 (IL-6) together with reducing apoptosis and DNA damage. This was achieved through the suppression of DNA-fragmentation marker 8OHdG, triggering of caspase-3 immuno-expression, and elevation of Bcl-2 protein. The histological studies provided evidence supporting the preventive effects of Ch and Pu against DM-induced testicular dysfunction. In conclusion, Ch and Pu seed-extracts mitigate testicular impairment during DM due to their antihyperglycemic, antilipidemic, antioxidant, anti-inflammatory, and antiapoptotic properties.