The in vivo assay is a key step in the development of a new compound as a drug. In the present work, bis-4-aminocoumarin derivative 3,3'-(p-tolylmethylene)bis(4-amino-2H-chromen-2-one) (PTBAC) and bis-4-hydroxycoumarin derivative 3,3'-((4-((1-(2-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)methylene)bis(4-hydroxy-2H-chromen-2-one) (2CTMBHC) that showed high anti-α-glucosidase activity on the yeast form of this enzyme were selected for in vivo anti-hyperglycemic assay.

The in vivo anti-hyperglycemic effect of PTBAC and 2CTMBHC was assessed using oral starch tolerance test in streptozotocin-induced diabetic albino mouse model, and the results were compared with acarbose as a representative inhibitor of intestinal α-glucosidase enzyme. Toxicity of the selected compounds was also evaluated in vivo.

The obtained results revealed that both selected compounds, PTBAC and 2CTMBHC, showed more anti-diabetic effects when compared with acarbose as a standard drug. In vivo anti-diabetic assays also demonstrated that bis-4-hydroxycoumarin derivative 2CTMBHC was more potent than bis-4-aminocoumarin derivative PTBAC. In vivo results were also confirmed by in vitro and in silico studies. Moreover, there was not any apparent signs of toxicity and mortality in in vivo toxicity assay.

In summary, in vivo anti-hyperglycemic effects of two synthetic compounds PTBAC and 2CTMBHC was confirmed in this study. Given that these compounds exhibited no evidences of toxicity and mortality in mice, therefore, they are good candidates for further investigations.

Maternal diabetes mellitus is linked to neurobiological and cognitive impairments, increasing the risk of brain and cerebellar defects in diabetic pregnant rats and their offspring. Momordica charantia (bitter melon) possesses antidiabetic properties due to its bioactive compounds, including phenolics, alkaloids, proteins, steroids, inorganic compounds, and lipids. Forty pregnant rats were randomly assigned to four groups: control; M charantia (BM); diabetic (DM); and diabetic treated with M charantia (BM+DM). Diabetic maternal rats showed significantly elevated serum glucose, insulin, leptin, and homeostasis model assessment of insulin resistance (HOMA-IR) levels, with a concomitant decrease in insulin sensitivity check index (QUICKI), glucose transporter 4 (GLUT4), adenosine monophosphate-activated protein kinase (AMPK), acetylcholine (ACh), and dopamine. Oxidative stress markers in cerebellar tissue indicated increased malondialdehyde (MDA) and decreased glutathione (GSH) levels. Cerebellar tissue analysis revealed significantly reduced superoxide dismutase (SOD), catalase (CAT), B-cell lymphoma 2 (Bcl-2), and nerve growth factor (NGF), while Bcl-2-associated X protein (BAX) and glial fibrillary acidic protein (GFAP) were elevated. Histological and ultrastructural analysis of the diabetic maternal cerebellum showed moderate vacuolation of the neuropil in all cerebellar cortical layers, along with Purkinje cell degeneration and necrosis, including Nissl substance loss. Offspring of diabetic mothers exhibited multifocal Purkinje cell loss, empty baskets, and cerebellar cortical dysplasia with abnormal tissue development and organization. In conclusion, M. charantia supports central nervous system health in diabetic pregnant rats and their offspring by enhancing antioxidant markers, regulating GFAP and NGF, and mitigating apoptosis, ultimately improving cerebellar pathology and neural development.

Diabetic foot ulcer (DFU) is a severe diabetic complication. Transplantation of skin substitutes, stem cells, and platelet-rich plasma (PRP) treatments are promising tools to promote ulcer healing in diabetes. An important aspect of the remodeling phase of wound healing is collagen deposition. miR-192 increases the expression of COL1A2 by specifically targeting Smad-interacting protein 1 (SIP1). This study was designed to investigate the impact of combined treatment with platelet-rich plasma and fibroblast cells expressing miR-192 on the healing process of wounds using an experimental diabetic animal model.

After transfection of HDF cells and induction of increased miR-192 expression, relative changes in COL1A2 gene expression were determined by the RT-PCR method. Rats were randomly divided into 6 groups: non-diabetic control group, diabetic control, backbone, PRP, miR-192, and PRP + miR-192 groups. Diabetes was induced in male Wistar rats of all treated groups except non-diabetic control through a 21-day high-fat diet and an intraperitoneal injection of 40 mg/kg streptozotocin. A 10-mm skin biopsy punch was used to create two full-thickness wounds on the dorsal part of the upper body in all six groups of animals. Hematoxylin-eosin and Mason's trichrome staining were used to evaluate the wounds and analyze histological changes.

The overexpression of miR-192 in HDF cells resulted in a significant increase in COL1A2 gene expression, which was 15.77-fold higher than the control group. PRP and pLenti-III-miR-192-GFP-expressing cells significantly increased wound closure rates, granulation tissue area, and collagen fiber density in rats, according to a histological examination.

The combined use of PRP and HDFs expressing pLenti-III-miR-192-GFP speeds up the healing of wounds by increasing collagen expression, demonstrating the efficacy of this approach in improving wound healing results.

Type 2 Diabetes (T2D) is a chronic metabolic disorder, considered the fastest growing pandemic of the 21stcentury. Meta-inflammation is a pivotal characteristic of T2D. Hyperactivated PTP1B, NLRP3, and AIM2 inflammasomes are considered the major regulators of metabolic inflammation. The concept of diabetes as an inflammatory disease has changed the pathogenic vision of T2D and hence, the compounds that mitigateinflammation in the setting of T2D are under the limelight of research. Current study aimed to evaluatethe anti-inflammatory potency of Viscosol, a novel PTP1B inhibitor, isolated from Dodonaea viscosa, in the STZ-HFD-induced T2D mouse model. Herein, male mice(C57BL/6), were administrated with Streptozotocin (STZ) (40mg/kg) and Viscosol (33mg/kg), intraperitoneally. Computational profiling revealed good absorption, distribution, metabolism and excretion (ADME) properties, least toxicity, and high docking score of Viscosol with PTP1B(-6.4 kcal/mol), NLRP3(-7.2 kcal/mol), and AIM2(-7.4 kcal/mol). Viscosol treatment significantly restored normal body weight (p < 0.0001), decreased the blood glucose level (p < 0.001), serum ROS level(p < 0.05) and diminished the severity of histopathological lesions, inflammatory lobules and increased the cell count of both brain and kidney tissues. The RT-qPCR analysis showed that Viscosol significantly reduced the mRNA expression of PTP1B, NF-κB, NLRP3, and AIM2up to 2.7-folds, 2.6-folds, 5.7-folds and 14.2-folds in the kidney tissues and 1.6-folds, 1.2-folds, 10.2-folds and 1.5-folds in brain tissues. Conclusively, inhibition of PTP1B via Viscosol could attenuate meta-inflammation by suppressing the aberrant NLRP3 and AIM2 inflammasome signaling in diabetes-linked pathophysiology.

Cerebral ketone bodies are crucial for understanding both physiological brain metabolism and pathological states, such as diabetic ketoacidosis (DKA). However, the metabolic consequences of elevated ketone body levels on brain metabolism during DKA remain poorly described to date. In this study, we utilized non-invasive magnetic resonance spectroscopy to detect and quantify ketone bodies and their correlation with neurotransmitter and neurotransmitter precursor levels in situ in the living brain of the streptozotocin (STZ)-induced type 1 diabetes (T1D) rat model. This well-characterized T1D model develops insulin deficiency with chronic hyperglycemia, which can trigger DKA. We report the detection and quantification of the acetone signal at 2.22 ppm in the STZ-induced T1D rat brain, along with two other ketone bodies, β-hydroxybutyrate and acetoacetate at 9.4 T. Cerebral levels of all three ketone bodies significantly increased as diabetes progressed compared to baseline levels prior to STZ injection. Moreover, ketone body levels correlated strongly with the inhibitory neurotransmitter γ-aminobutyric acid (GABA) and glutamine, as well as several other neurochemicals. Overall, DKA is characterized by a marked increase in brain ketone bodies as T1D progresses, accompanied by elevated GABA and glutamine levels. This study demonstrates the direct measurement of ketone bodies in the brain in vivo, enabling further investigation of their impact on brain metabolism in both health and disease.

Diabetic encephalopathy (DE) is a common central nervous system complication resulting from diabetes mellitus (DM). While the exact pathogenesis remains unclear, a homeostatic imbalance of mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) within neurons has been shown to be closely associated with the dysfunctional cognitive pathology of this condition. Our previous work has revealed that phosphatidate phosphatase Lipin1 plays a critical role in the cognitive processes of DE via regulating mitochondrial function. In this study, we reported that the integrity of neuronal MAMs was disrupted in DE mice, which was accompanied by a decrease in the expression of hippocampal Lipin1. With a knock-down of hippocampal Lipin1 in normal mice, ER stress was induced, MAMs structures were impaired and Ca2+ transfer was suppressed. Such effects resulted in mitochondrial dysfunction, synaptic plasticity impairments, and finally cognitive dysfunctions. In contrast, an up-regulation of hippocampal Lipin1 in the DE model partially alleviated these dysfunctions. These results suggest that Lipin1 may ameliorate the cognitive dysfunctions associated with DE via regulating Ca2+ transfers through MAMs. Therefore, targeting Lipin1 may serve as a therapeutic strategy for the clinical treatment of DE.

Here, we present StimExo as a rational design strategy allowing various user-defined control signals to trigger calcium-dependent exocytosis and mediate on-demand protein secretion in cell-therapy settings. Using a modular framework incorporating inducible protein-protein interactions into an engineered bipartite activator of calcium release-activated calcium (CRAC) channels, Ca2+ influx mediated by the STIM/Orai1 machinery was flexibly adjusted to depend on different user-defined input signals. Application of StimExo to various endocrine cells enables instant secretion of therapeutic hormones upon administration of safe and patient-compliant trigger compounds. StimExo also mediated insulin exocytosis using a cell-based gene delivery strategy in vivo, accounting for real-time control of blood glucose homeostasis in male diabetic mice in response to the FDA-approved drug grazoprevir. This study achieves true "sense-and-respond" cell-based therapies and provides a platform for remote control of in vivo transgene activities using various trigger signals of interest.

Insulin supply is the golden standard for type 1 diabetes mellitus (T1DM) therapy. Is there a drug-reduction application for reversing glucose metabolism disabled and diabetic neuropathy (DN), and is it suitable for the young and elderly populations? Reducing T1DM-associated DN, and maintaining glucose metabolism require using the anti-aging gene Klotho to regulate specific signaling cascades. This study applied five 16:8 intermittent fasting (16-h fasting, 8-h eating; 168if) protocols by different executing times to young and elderly diabetic mice to evaluate whether 168if is age-dependent and how it alters Klotho-related signaling molecules. Blood glucose levels were efficiently reduced when 168if was implemented in the early stage of T1DM onset (DNf group) of young and elderly mice. Another four groups failed to reduce blood sugar. However, the DNf protocol was unsuitable for diabetic elderly mice because it posed a higher mortality risk for this population. Young DNf mice exhibited reduced thermal hyperalgesia and mechanical allodynia and reversed Klotho downregulation and protein kinase C epsilon (PKCε) upregulation compared with DN mice. Furthermore, young DNf mice exhibited normalization of fibroblast growth factor receptor 1 (FGFR1) and nuclear factor κB (NF-κB) expression, which is involved in Klotho-related glucose metabolism and anti-inflammation. The expression densities of PKCε, Klotho, FGFR1, and NF-κB were linear to neuropathic manifestations. This study demonstrated the effectiveness of 168if application in the early stage of T1DM onset, a straightforward and convenient dietary control method, as a blood glucose control for achieving pharmaceutical reduction and relieving neuropathic pain in young T1DM patients.

Background/Objectives: Disrupted intracellular calcium (Ca2+i) regulation and renin-angiotensin system (RAS) activation are pathogenetic factors in diabetic cardiomyopathy, a major complication of type 1 (T1D) and type 2 (T2D) diabetes. This study explored their potential link in diabetic rat hearts. Methods: Experiments were conducted on T1D and T2D Sprague-Dawley rats induced by streptozotocin and fructose-rich diet, respectively. In T1D, rats were treated with Enalapril (Ena) or Losartan (Los) for six weeks, whereas T2D animals received high-dose (HD) or low-dose (LD) Ena for 8 weeks. Heart function was assessed via echocardiography, Ca2+i transients by Indo-1 fluorometry in Langendorff-perfused hearts, and key Ca2+i cycling proteins by Western blot. Data: mean ± SD. Results: Diabetic hearts exhibited reduced contractile performance that was improved by RAS inhibition both in vivo (ejection fraction (%): T1D model: Control: 79 ± 7, T1D: 54 ± 11, T1D + Ena: 65 ± 10, T1D + Los: 69 ± 10, n = 18, 18, 15, 10; T2D model: Control: 73 ± 8, T2D: 52 ± 6, T2D + LDEna: 62 ± 8, T2D + HDEna: 76 ± 8, n = 9, 8, 6, 7) and ex vivo (+dPressure/dtmax (mmHg/s): T1D model: Control: 2532 ± 341, T1D: 2192 ± 208, T1D + Ena: 2523 ± 485, T1D + Los: 2643 ± 455; T2D model: Control: 2514 ± 197, T2D: 1930 ± 291, T2D + LDEna: 2311 ± 289, T2D + HDEna: 2614 ± 268). Analysis of Ca2+i transients showed impaired Ca2+i release and removal dynamics and increased diastolic Ca2+i levels in both models that were restored by Ena and Los treatments. We observed a decrease in sarcoendoplasmic reticulum Ca2+-ATPase2a (SERCA2a) expression, accompanied by a compensatory increase in 16Ser-phosphorylated phospholamban (P-PLB) in T2D that was prevented by both LD and HD Ena (expression level (% of Control): SERCA2a: T2D: 36 ± 32, T2D + LDEna: 112 ± 32, T2D + HDEna: 106 ± 30; P-PLB: T2D: 557 ± 156, T2D + LDEna: 129 ± 38, T2D + HDEna: 108 ± 42; n = 4, 4, 4). Conclusions: The study highlights the critical role of RAS activation, most likely occurring at the tissue level, in disrupting Ca2+i homeostasis in diabetic cardiomyopathy. RAS inhibition with Ena or Los mitigates these disturbances independent of blood pressure effects, underlining their importance in managing diabetic heart failure.

This study presents the development of two novel injectable dual-responsive polyanionic hydrogels (DRPHs) based on N-isopropylacrylamide (NIPAM), incorporating carboxylic acid comonomers for temperature- and pH-responsive drug release. These hydrogels were designed for the sustained and localized delivery of the antimicrobial peptide MP-L [I5R8], targeting multidrug-resistant bacteria (MDRB) in wound infections. The physicochemical characterization confirmed polymer formation and comonomer integration through Fourier-transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR). Rheological analysis demonstrated a temperature-dependent sol-gel transition at ∼35°C, making the hydrogels suitable for in situ gelation at physiological conditions. The hydrogels exhibited tunable swelling behavior and a controlled dual-phase release profile of MP-L [I5R8], ensuring both immediate bactericidal activity and prolonged antimicrobial effect. In vitro assays confirmed sustained antimicrobial efficacy against Staphylococcus aureus and Pseudomonas aeruginosa, while biocompatibility tests validated their safety for biomedical applications. An in vivo diabetic wound infection model demonstrated rapid infection clearance, enhanced wound healing, and organized tissue regeneration following treatment with MP-L [I5R8]-loaded DRPHs. These results highlight the potential of dual-stimuli-responsive hydrogels as a next-generation antimicrobial delivery platform for the treatment of chronic infected wounds, such as diabetic foot ulcers.

Type 2 diabetes mellitus (T2DM) arises from a complex interplay of genetic and environmental factors. Patients with T2DM are susceptible to hyperglycemia-related complications that can impair organ function, underscoring the need to explore the metabolic profiles of affected organs.

In this study, a comprehensive metabolomic analysis was conducted on the serum, kidney, and heart tissues from a rat model of diabetic complications (DC). Pattern recognition and multivariate statistical analyses were applied to identify the potential biomarkers of DC, and metabolic network analysis served to understand the specific metabolic pathways associated with DC.

Fourteen significantly altered metabolites were identified in serum, 20 in the kidney, and 14 in the heart. The corresponding metabolic pathways included mineral absorption, mTOR signaling pathway, taurine and hypotaurine metabolism, glycine, serine and threonine metabolism, ABC transporters, glucagon signaling pathway, protein degradation and uptake, galactose metabolism, purine metabolism, nicotinic acid and nicotinamide metabolism, and glycolysis and gluconeogenesis. Differential metabolite network analysis revealed instinct metabolic patterns among the serum, kidney, and heart. Notably, the serum's metabolic correlation patterns were found to be somewhat similar to those observed in the kidney, whereas the heart exhibited less pronounced metabolite correlations compared to the other two biological matrices.

These findings provide insights into the mechanism underlying the development of diabetic complications. The integration of metabolomics and biological network analyses into diabetes research can potentially revolutionize the field by revealing novel biomarkers for early detection and personalized treatment of diabetes and its associated complications.

Multidrug resistance (MDR) infectious wounds are a major concern due to drug resistance, leading to increased patient morbidity. Lichenysin (LCN), a lipopeptide and biosurfactant obtained from certain strains of Bacillus licheniformis, has demonstrated an excellent antimicrobial property. The present study focuses on the fabrication and comprehensive evaluation of LCN-incorporated poly(vinyl alcohol) (PVA)/polycaprolactone (PCL)-based nanofiber scaffolds using an electrospinning technique as a potential wound healing biomaterial for the treatment of MDR infectious wounds in diabetic rats. The LCN-loaded PVA-PCL nanofiber scaffolds were characterized for their physicochemical, antimicrobial, in vitro cell line on L-929, hemocompatibility, flow cytometry, in vivo infectious wound healing, and enzyme-linked immuno sorbent assay (ELISA). Morphological analysis via scanning electron microscopy (SEM) images confirmed smooth and porous nanofibers with diameters in the range 200-300 nm. Fourier transform infrared and X-ray diffraction (XRD) results demonstrated the structural integrity, chemical compatibility, and amorphous nature of developed scaffolds. The scaffolds loaded with LCN demonstrated excellent water retention, moderate biodegradability, and sustained release of LCN for up to 72 h. Mechanical characterization demonstrated a robust tensile strength conducive to wound healing applications. Antimicrobial activity against Pseudomonas aeruginosa (P. aeruginosa) and Staphylococcus aureus (S. aureus) showed substantial antibacterial and antibiofilm activity. In vitro cell line studies showed enhanced cell adhesion, proliferation, migration, and viability, signifying the cytocompatibility of these scaffolds. In vivo studies demonstrated exceptional infectious wound healing potential in diabetic rats. These findings indicate that LCN-enriched PVA-PCL scaffolds hold significant potential as a therapeutic strategy for the treatment of MDR infectious wounds in diabetic rats through a multifaceted approach.

Diabetes mellitus (DM) is a metabolic disorder characterized by high blood sugar levels due to insufficient insulin production or insulin resistance. Recently, metabolic biomarkers, such as glycated albumin (GA) and methylglyoxal (MGO), have been successfully employed for the management of diabetes and its complications. The main goal of this study was to investigate the relationship between metabolic parameters, related to diabetic conditions, and the recognition memory, a declarative episodic long-term memory, in a streptozotocin (STZ)-induced diabetes mouse model. The longitudinal experimental plan scheduled five experimental timepoints, starting from 9 months and lasting until 19 months of age, and included different evaluations: i) fasting serum glucose, GA, and MGO, ii) recognition memory performance; iii) histological examinations of pancreas and hippocampus. At 13 months of age, mice were randomly divided into two groups, and STZ (50 mg/kg i.p.) or vehicle was administered for 5 consecutive days. Mice were fed with a normal diet but, starting from 14 months, half of them were given water with a high sugar (HS) to explore the potential detrimental effects of HS intake to hyperglycemia. Our main outcomes are as follows: i) HS intake alone does not contribute to worsened diabetic condition/hyperglycemia; ii) GA emerges as a reliable biomarker for monitoring diabetic conditions, consistently increasing with hyperglycemia; iii) diabetic conditions correlate with a worsening of recognition memory; iv) diabetic mice display mild-to-severe insulitis and injured hippocampal cytoarchitecture, detectable in Ammon's horns regions CA1 and CA3; v) correlation among recovered normal fasting glycemic level and recognition memory, partial regaining of physiological pancreatic morphology, and hippocampal cytoarchitecture.

The study of type 2 diabetes mellitus (T2DM) pathophysiology relies mainly on the use of animal models, the most common of which involves the consumption of high-fat diets comprising 60% calories from fat. Although these models reproduce the onset and most complications associated with T2DM, they do not accurately mimic human dietary patterns, as they lack the addition of carbohydrates such as fructose. This study aimed to develop a C57BL/6 mouse model of T2DM that mimics the disease, as occurs in younger individuals, via a medium-fat diet (34.5% kcal from fat) combined with a 20% fructose solution as drinking water and a single low-dose of streptozotocin (STZ) (100 mg/kg), a diabetogenic drug. At week 20, D + T mice exhibited significant weight gain and elevated fasting blood glucose levels compared with those of control mice and the development of insulin resistance. Similarly, the circulating levels of hepatic enzymes (GPT, GOT, and alkaline phosphatase), total cholesterol, and LDL increased. Multi-organ damage, including reduced pancreatic islet size and number, severe hepatic steatosis, inflammatory infiltration in visceral adipose tissue, and cardiac and renal dysfunction, were also detected. The proposed model replicates T2DM in young mice by combining a medium-fat diet with fructose and STZ.

Diabetic cystopathy (DCP) is linked to bladder nerve conduction disorders, with diabetes-induced neuropathy impairing nerve signal transmission and causing bladder dysfunction. Myosin 5a, vital for neuronal transport, has been linked to neurological disorders, though its role in DCP remains unclear. The objective of this study was to investigate whether Myosin 5a plays a potential regulatory role in Diabetic Cystopathy.

Bladder strips from diabetic rats were use to assess heightened responsiveness to external stimuli. Urodynamic assessments were conducted to track the progression of bladder voiding dysfunction over time, following streptozotocin (STZ) injection. Single-cell RNA-Seq mining was employed to identify associations between Myosin 5a and bladder overactivity. Cellular and tissue analyses were performed to determine the co-localization of Myosin 5a with neurotransmitter-related proteins. The impact of Myosin 5a knockdown on ChAT and SP expression in bladder neurons was also evaluated. Additionally, Myosin 5a-deficient DBA mice were studied for voiding function and sensitivity to stimuli. Student's t-test (two-tailed) or Mann-Whitney's U test analysis of variance was used to analyze the difference between groups.

Bladder strips from diabetic rats exhibit increased responsiveness to external stimuli, with urodynamic assessments showing a progressive decline in bladder function, culminating in overactivity by the fourth week post-STZ injection. Co-localization of Myosin 5a with neurotransmitter-related proteins was observed, and the knockdown of Myosin 5a in bladder neurons led to a significant reduction in ChAT and SP expression. Myosin 5a-deficient DBA mice exhibited abnormal voiding function and reduced sensitivity to stimuli, along with significant downregulation of SLC17A9. Single-cell RNA-Seq analysis revealed a significant link between Myosin 5a and bladder overactivity, with Myosin 5a expression escalating in tandem with the severity of bladder dysfunction.

Myosin 5a's dysregulation in diabetic rats may worsen bladder overactivity, suggesting its potential as a therapeutic target for diabetic OAB.

Mitochondrial dysfunction and brain insulin resistance have been related to Alzheimer's disease (AD) development. Streptozotocin (STZ) is commonly employed to disrupt glucose and insulin metabolism, even causing cognitive impairment in animal models. We aimed at studying the protective effect of JM-20 on STZ-induced memory impairment and brain mitochondrial dysfunction.

Male C57Bl6 mice received 3 mg/kg STZ intracerebroventricularly and JM-20 (0.25 mg/kg or 4 mg/kg) was administered daily by gastric gavage. Episodic memory was evaluated through Y-maze, novel object recognition, and Morris water maze. Endogenous antioxidant systems (catalase and superoxide dismutase activities), total sulfhydryl groups, malondialdehyde levels were also studied and acetylcholinesterase (AChE) activity were assessed in the prefrontal cortex (PC) and hippocampus (HO).

demonstrated that STZ injection impaired recognition and spatial learning and memory and oxygen flow in all mitochondrial respiration states. Additionally, STZ increased AChE, superoxide dismutase, and catalase activity in the PC but not in HO tissue. A neuroprotective effect of JM-20 on STZ-induced memory decline, and mitochondrial dysfunction was observed, suggesting an important causal interaction. In addition, JM-20 was able to decreased AChE enzyme hyperactivity, rescued endogenous antioxidant systems, and prevented histologically observed neuronal damage CONCLUSION: Our results indicate that JM-20 protects against STZ-induced impairment in brain bioenergetic metabolism and memory, confirming its potential as a candidate for treating neurodegenerative disorders associated with mitochondrial dysfunction like AD.

Diabetic nephropathy (DN) represents the primary cause of chronic kidney disease (CKD) worldwide. Orientin is a natural bioactive flavonoid with profound immunomodulatory, anti-inflammatory, and antioxidative effects. This study aimed to investigate the nephroprotective effect of orientin on rat prototypes of high-fat diet (HFD) and streptozotocin (STZ)-induced DN. 75 male rats were divided into 5 groups of 15 rats each. Rats were fed a HFD for 4 weeks, injected with a single dose of STZ 30 mg/kg, and continued on HFD for 15 weeks. Orientin was administered daily at 40 mg/kg for 15 weeks. The diabetic group reported substantially greater fasting blood glucose, HbA1c, and renal function measures than normal controls, as well as notable kidney histological abnormalities such as interstitial inflammation, glomerular shrinkage, and tubular necrosis. Additionally, the diabetic group showed dramatically greater amounts of IL-1β, IL-6, TNF-α, TGF-β1, MDA, and a much lower level of GSH than the control group. However, orientin had no effect on the glycaemic parameters, but it dramatically reduced blood creatinine levels, prevented the development of histopathological irregularities, and minimized the renal concentrations of inflammatory and oxidative markers. Orientin may be a promising natural medication for improving diabetic nephropathy thanks to its robust anti-inflammatory and anti-proliferative properties.

Background: The efficacy of banaba leaf extract was tested against carboxymethyllysine (CML)-induced toxicity in embryos and adult zebrafish. Additionally, the individual and combined effects of banaba (BNB) and policosanol (PCO) were analyzed to alleviate dyslipidemia, hyperglycemia, and associated effects in streptozotocin (STZ)-induced hyperlipidemic diabetic zebrafish. Methodology: The high cholesterol diet (HCD, final 4%, w/w)-fed zebrafish were injected with STZ to develop diabetes and were subsequently fed with either HCD or HCD+BNB (final 0.1% w/w) or HCD+PCO (final 0.1% w/w) or HCD+BNB+PCO (each final 0.1%, w/w) each for 14 days. The zebrafish tail fin was amputated to assess tissue regeneration, while the organs and blood were collected for histological and biochemical analysis. Results: Severely compromised embryo survivability and developmental defects were noticed in the CML-injected group that significantly improved following BNB exposure. Similarly, CML-induced acute paralysis and mortality of adult zebrafish were effectively mitigated by the treatment with BNB. In the hyperlipidemic diabetic zebrafish, both BNB and PCO supplementation displayed the hypoglycemic effect; however, a remarkable reduction (p < 0.05) in blood glucose levels was observed in the BNB+PCO group, around 14% and 16% less than the BNB group and PCO group, respectively. Likewise, higher tail fin regeneration was noticed in response to BNB+PCO supplementation. Both BNB and PCO have a substantial counter-effect against HCD+STZ-induced dyslipidemia. However, the combined supplementation (BNB+PCO) displayed a significantly better effect than that of BNB and PCO alone to alleviate total cholesterol (TC), triglycerides (TGs), and low-density lipoprotein cholesterol (LDL-C). The most impressive impact of BNB+PCO was noticed in the elevation of high-density lipoprotein cholesterol (HDL-C), which was ~1.5 times higher than the HDL-C level in response to BNB and PCO. Also, BNB+PCO effectively reduced the malondialdehyde (MDA) and elevated the plasma sulfhydryl content, paraoxonase (PON), and ferric ion reduction (FRA) activity. Histological analyses revealed a significant effect of BNB+PCO in preventing inflammatory infiltration, fatty liver changes, and interleukin-6 production. Similarly, a notably better effect of BNB+PCO compared to their individual effect was noticed in preventing kidney damage and mitigation of ROS generation, apoptosis, and cellular senescence. Conclusions: The finding establishes the substantial effect of BNB and PCO in countering hyperglycemia, dyslipidemia, and associated disorders, which synergistically improved following the combined supplementation with BNB+PCO.

To investigate the effect of Tongmai Hypoglycemic Capsule (THC) on myocardium injury in diabetic cardiomyopathy (DCM) rats.

A total of 24 Sprague Dawley rats were fed for 4 weeks with high-fat and high-sugar food and then injected with streptozotocin intraperitoneally for the establishment of the DCM model. In addition, 6 rats with normal diets were used as the control group. After modeling, 24 DCM rats were randomly divided into the model, L-THC, M-THC, and H-THC groups by computer generated random numbers, and 0, 0.16, 0.32, 0.64 g/kg of THC were adopted respectively by gavage, with 6 rats in each group. After 12 weeks of THC administration, echocardiography, histopathological staining, biochemical analysis, and Western blot were used to detect the changes in myocardial structure, oxidative stress (OS), biochemical indexes, protein expressions of myocardial fibrosis, and nuclear factor erythroid 2-related faactor 2 (Nrf2) element, respectively.

Treatment with THC significantly decreased cardiac markers such as creatine kinase, lactate dehydrogenase, and creatine kinase-MB, etc., (P<0.01); enhanced cardiac function indicators including heart rate, ejection fraction, cardiac output, interventricular septal thickness at diastole, and others (P<0.05 or P<0.01); decreased levels of biochemical indicators such as fasting blood glucose, total cholesterol, triglycerides, low-density lipoprotein cholesterol, aspartate transaminase, (P<0.05 or P<0.01); and decreased the levels of myocardial fibrosis markers α-smooth muscle actin (α-SMA), and collagen I (Col-1) protein (P<0.01), improved myocardial morphology and the status of myocardial interstitial fibrosis. THC significantly reduced malondialdehyde levels in model rats (P<0.01), increased levels of catalase, superoxide dismutase, and glutathione (P<0.01), and significantly increased the expression of Nrf2, NAD(P)H:quinone oxidoreductase 1, heme oxygenase-1, and superoxide dismutase 2 proteins in the left ventricle of rats (P<0.01).

THC activates the Nrf2 signaling pathway and plays a protective role in reducing OS injury and cardiac fibrosis in DCM rats.

Wound healing in diabetic patients is often compromised due to excessive inflammation, oxidative stress, and impaired angiogenesis, leading to delayed recovery and increased susceptibility to complications. This study aimed to develop an emulgel formulation of guava leaf oil, derived from Psidium guajava (Myrtaceae), and evaluate its wound healing potential in nondiabetic and diabetic rats. Preliminary phytochemical analysis of guava leaf oil identified active compounds such as D-limonene, β-caryophyllene, and 1,8-cineole, which are known for their anti-inflammatory and antioxidant properties. The emulgel was formulated and assessed for physical attributes, including pH, viscosity, spreadability, and stability. The emulgel demonstrated potent antimicrobial activity, with the 1% concentration showing significant efficacy. In vivo studies revealed enhanced wound contraction in diabetic rats treated with the emulgel, supporting its role in promoting excision wound healing. These findings underscore the therapeutic potential of guava leaf oil emulgel as an effective agent for managing nondiabetic and diabetic wounds, providing a foundation for future clinical applications.

Oral insulin has therapeutic advantages, as it can mimic the endogenous insulin pathway and relieve patients from daily self-injections. Among the many investigated oral insulin delivery systems, lipid nanoparticle (LNP)-based drug delivery systems are considered promising platforms for improving oral insulin absorption due to their unique in vivo properties and high design flexibility. However, challenges such as toxicity and low oral bioavailability persist. Dioleoylglycerophosphate-diethylenediamine (DOP-DEDA) is a pH-responsive and charge-reversible lipid for cytosolic cargo delivery. In this study, an insulin-encapsulated DOP-DEDA-based LNP (Ins-LNP) system was developed to achieve highly biocompatible and efficient oral insulin delivery. The Ins-LNPs exhibited a positive charge at gastrointestinal pH levels of 1.2 and 6.8, suggesting enhanced stability in the acidic stomach environment and facilitating efficient absorption in the small intestine. In addition, they are noncationic at a physiological pH level of 7.4, indicating low toxicity. PEGylated Ins-LNPs had a particle size of 125.4 nm, a polydispersity index of 0.047, and an encapsulation efficiency of 57.2 %. PEGylated Ins-LNPs maintained their particle characteristics for more than 2 h in simulated gastrointestinal fluid containing digestive enzymes. They also retained 89 %, 51 %, and 44 % of insulin for 60 min in simulated gastrointestinal/physiological fluid at pH levels of 1.2, 6.8, and 7.4, respectively. Furthermore, in vivo studies using streptozocin-induced diabetic mice demonstrated a pronounced and sustained hypoglycemic effect following oral administration, characterized by a ∼40 % reduction in blood glucose levels for over 10 h, indicative of an optimal pharmacodynamic profile. This favorable pharmacodynamic profile may mitigate the risk of clinically relevant hypoglycemia, enhancing patient compliance and overall treatment outcomes. Consequently, this research presents a promising LNP system for oral insulin delivery.

Effective methods for establishing an aged animal model of diabetes and glycemic fluctuation have rarely been investigated. The aim of the study was to explore the feasibility of inducing glycemic fluctuation in aged Sprague-Dawley rats and to evaluate the corresponding changes in cognitive function.

Male rats aged 48 weeks were fed a high-fat and high-glucose diet and given streptozotocin intraperitoneally to establish a rat model of type 2 diabetes mellitus (T2DM). Then, glycemic fluctuation was induced via three different protocols: (1) intraperitoneal injection of glucose; (2) sequential fasting, insulin injection, and normal diet; and (3) intermittent intraperitoneal injections of glucose and insulin.

All three protocols were effective at inducing glycemic fluctuation in aged rats with T2DM, with successful modeling rates of 60 %, 90 %, and 70 %, respectively. Aged T2DM rats with glycemic fluctuation showed significant increases in glycemic variability compared with controls, including in the mean blood glucose, postprandial glycemic excursion, largest amplitude of glycemic excursion, and standard deviation of blood glucose values (all P < 0.05). Additionally, rats with glycemic fluctuation had more severe insulin resistance and dyslipidemia (P < 0.05). Morris water maze testing showed a trend of longer escape latency in the navigation test for rats in the glycemic fluctuation groups, suggesting impaired cognitive function. Pathological analysis showed degenerative changes in the CA1 hippocampal region of rats in the glycemic fluctuation groups. Finally, differential gene expression analysis revealed 1323 significantly altered genes in the GV group, with 691 upregulated and 632 downregulated. The dysregulated genes were predominantly associated with the axon guidance pathway and potassium channel regulation.

The proposed protocols were effective at establishing an aged T2DM rat model with glycemic fluctuation, and rats with glycemic fluctuation exhibited diminished cognitive function.

Type 1 diabetes mellitus is defined by the autoimmune destruction of pancreatic β cells, with diabetic nephropathy being a significant consequence. Recently, cuminaldehyde has been shown protective ability against various pathophysiology. However, its nephroprotective and anti-diabetic potential has not yet been fully understood. We, therefore, conducted the present study to evaluate the anti-hyperglycemic potential of cuminaldehyde in NRK52E cells without (control) or with high glucose medium to emulate hyperglycemic conditions. Cuminaldehyde pre-treatment at an optimal concentration of 175 μM prior to high glucose addition restricted excessive reactive oxygen species (ROS) production and maintained cellular morphology to almost normal. The inhibitor study using N-acetyl-l-cysteine confirmed that blocking of ROS assists NRK52E cells in evading apoptosis. In addition, hyperglycemia was induced in 6-week-old Swiss albino mice in this investigation through the intraperitoneal injection of streptozotocin (150 mg kg-1 body weight). Hyperglycemia increased the kidney-to-body weight ratio, lowered serum insulin levels, and led to significant renal tissue damage compared to control mice. Moreover, hyperglycemia disturbs cellular redox equilibrium by decreasing antioxidant enzyme functions and promoting inflammatory cytokines in kidney tissue. Administering cuminaldehyde at a dosage of 10 mg kg-1 body weight for 5 weeks daily after the onset of diabetes effectively ameliorated the aforementioned anomalies and reversed kidney damage by regulating inflammation-induced cell death. Overall, the research demonstrated that cuminaldehyde has hypoglycemic, antioxidant, anti-inflammatory, and anti-apoptotic properties. We believe that after conducting extensive research, this unique molecule can be used in clinical trials against diabetic nephropathy in future.

Diabetic wound healing remains a healthcare challenge due to co-occurring multidrug-resistant (MDR) bacterial infections and the constraints associated with sustained drug delivery. Here, we integrate two new species of phages designated as PseuPha1 and RuSa1 respectively lysing multiple clinical MDR strains of P. aeruginosa and S. aureus into a novel polyvinyl alcohol-eudragit (PVA-EU†) nanofiber matrix through electrospinning for rapid diabetic wound healing. PVA-EU† evaluated for characteristic changes that occurred due to electrospinning and subjected to elution, stability and antibacterial assays. The biocompatibility and wound healing ability of PVA-EU† were assessed through mouse fibroblast cell line NIH3T3, followed by validation through diabetic mice excision wound co-infected with P. aeruginosa and S. aureus. The electrospinning resulted in the incorporation of ~ 75% active phages at PVA-EU†, which were stable at 25 °C for 30 days and at 4 °C for 90 days. PVA-EU† showed sustained release of phages for 18 h and confirmed to be detrimental to both mono- and mixed-cultures of target pathogens. The antibacterial activity of PVA-EU† remained unaltered in the presence of high amounts of glucose, whereas alkaline pH promoted the activity. The matrix exerted no cytotoxicity on NIH3T3, but showed significant (p < 0.0001) wound healing in vitro and the process was rapid as validated through a diabetic mice model. The sustained release, quick wound closure, declined abundance of target MDR bacteria in situ and histopathological signs of recovery corroborated the therapeutic efficacy of PVA-EU†. Taken together, our data signify the potential application of PVA-EU† in the rapid treatment of diabetic wounds without the aid of antibiotics.

Cellular and gene therapy (CGT) products have emerged as a popular approach in regenerative medicine, showing promise in treating various pancreatic and liver diseases in numerous clinical trials. Before these therapies can be tested in human clinical trials, it is essential to evaluate their safety and efficacy in relevant animal models. Such preclinical testing is often required to obtain regulatory approval for investigational new drugs. However, there is a lack of detailed guidance on selecting appropriate animal models for CGT therapies targeting specific pancreatic and liver conditions, such as pancreatitis and chronic liver diseases. In this review, the gastrointestinal committee for the International Society for Cell and Gene Therapy provides a summary of current recommendations for animal species and disease model selection, as outlined by the US Food and Drug Administration, with references to EU EMA and Japan PMDA. We discuss a range of small and large animal models, as well as humanized models, that are suitable for preclinical testing of CGT products aimed at treating pancreatic and liver diseases. For each model, we cover the associated pathophysiology, commonly used metrics for assessing disease status, the pros and limitations of the models, and the relevance of these models to human conditions. We also summarize the use and application of humanized mouse and other animal models in evaluating the safety and efficacy of CGT products. This review aims to provide comprehensive guidance for selecting appropriate animal species and models to help bridge the gap between the preclinical research and clinical trials using CGT therapies for specific pancreatic and liver diseases.

Diabetic wounds face challenges like infection, prolonged inflammation, and poor vascularization. To address these, we developed an injectable hydrogel for diabetic wound dressing by grafting palmitoyl tetrapeptide-7 (Pal-7) onto chitosan (CS) to form CS/Pal-7 (CP7). Glutaraldehyde (GA) was used to enhance crosslinking between CS, creating the CP7 hydrogel. The hydrogel showed rapid gelation, good mechanical properties, biocompatibility, and strong antibacterial effects. Additionally, stem cells derived from human deciduous teeth (SHED) were loaded into the CP7 hydrogel to form SHED@CP7. This complex promoted human umbilical vein endothelial cell (HUVEC) migration and tube formation, aiding angiogenesis, and induced macrophage polarization toward the M2 phenotype, exerting anti-inflammatory effects. In streptozotocin-induced diabetic mouse wounds, SHED@CP7 significantly improved wound healing with over 95 % wound closure, increased collagen deposition, and reduced tumor necrosis factor-α (TNF-α) expression by approximately 75 % and Interleukin-6 (IL-6) expression by around 81 %. It also increased Interleukin-10 (IL-10) expression by approximately 58 %, modulating the inflammatory microenvironment for regeneration. Moreover, SHED@CP7 enhanced angiogenesis, as shown by a 69 % increase in endothelial cell marker CD31 staining, supporting faster wound healing. These results highlight the potential of SHED@CP7 as an effective treatment for diabetic wounds.

Background/Objectives: Diabetic cardiomyopathy is a distinct myocardial dysfunction characterized by structural and functional changes in the heart that occur in diabetic patients independently of coronary artery disease or hypertension. It is closely associated with oxidative stress, inflammation, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress, and contributes to progressive cardiac damage. This study aimed to evaluate the cardioprotective effects of dapagliflozin (DAPA) and trimetazidine (TMZ) in a rat model of doxorubicin-induced cardiomyopathy with streptozotocin-induced diabetes, focusing on their potential mechanisms related to ER stress. Methods: A total of 48 Sprague Dawley rats aged 6-8 weeks were randomly distributed equally into six cages. The diabetes model was induced by intraperitoneal administration of streptozotocin (STZ) and rats with blood glucose levels above 250 mg/dL were considered diabetic. For those rats with diabetes, cardiotoxicity was induced by intraperitoneal injection of 5 mg/kg/week doxorubicin (DOXO) for 4 weeks. After a cumulative dose of 20 mg/kg doxorubicin, a week break was given, followed by the administration of TMZ (10 mg/kg) and/or DAPA (10 mg/kg) to the treatment groups. Results: STZ administration caused diabetes and significant degeneration in cardiomyocytes. With the addition of DOXO (STZ + DOXO), cardiomyocyte degeneration became more severe. When the study groups were histopathologically evaluated based on parameters of degenerative cardiomyocytes, vascular congestion, and edema, it was shown that both TMZ and DAPA, whether applied alone or in combination, reduced damage in heart tissue. Both TMZ and DAPA reduced cardiomyocyte damage, and their combination provided the lowest level of damage through the reduced ER stress pathway by reducing GRP 78 and CHOP positivity. Conclusions: TMZ and DAPA reduce ER stress and have protective effects against diabetic-induced cardiotoxicity. Combination therapy or TMZ was found to be more effective than DAPA in alleviating ER stress. Combination therapy appears to carry potential effects for reducing cardiac cell damage in individuals with diabetes.

Diabetes-associated dry eye syndrome (DMDES) affects 20-54 % of diabetes, leading to ocular irritation and blurry vision. Decreased conjunctival goblet cell mucus secretion is one of the major pathological processes of DMDES. This study aims to investigate the mechanism of mucus granule maturation and secretion disturbance in DMDES.

Tear samples from diabetic patients with and without dry eye syndrome were analyzed by mass spectrometry to identify proteins associated with ocular mucous layer reduction. The N-terminal domain fragment of Mucin1 (MUC1-ND) was transfected into the mouse conjunctiva to investigate alterations in goblet cell mucus secretion. Protein localization and granule morphology were explored through transmission electron microscopy with colloidal gold labeling and immunohistochemistry. Immunofluorescence, co-immunoprecipitation, and integrative computational modeling of protein interactions were employed to explore protein-protein interactions.

Tear proteomic analysis revealed significantly elevated MUC1-ND levels in tears from DMDES patients, which correlated with reduced goblet cell mucus secretion and tear film instability. Upregulation of MUC1-ND in mice conjunctiva inhibited the maturation of secretory mucus granules, contributing to tear mucous layer reduction. Protein docking and co-immunoprecipitation analysis demonstrated that the binding of MUC1-ND and Syntaxin6 prevents granule fusion and maintains the immature state of secretory granules, which leads to reduced mucus secretion.

In DMDES, MUC1-ND binds with Syntaxin6 to disrupt the fusion and maturation of secretory mucus granules in conjunctival goblet cells, which provides a new insight into DMDES pathophysiology.

Peripheral neuropathy caused by diabetes is closely related to the vicious cycle of oxidative stress and mitochondrial dysfunction resulting from metabolic abnormalities. The effects mediated by the silent information regulator type 2 homolog-1 (SIRT1)/peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) axis present new opportunities for the treatment of type 2 diabetic peripheral neuropathy (T2DPN), potentially breaking this harmful cycle.

To validate the effectiveness of electroacupuncture (EA) in the treatment of T2DPN and investigate its potential mechanism based on the SIRT1/PGC-1α axis.

The effects of EA were evaluated through assessments of metabolic changes, morphological observations, and functional examinations of the sciatic nerve, along with measurements of inflammation and oxidative stress. Proteins related to the SIRT1/PGC-1α axis, involved in the regulation of mitochondrial biogenesis and antioxidative stress, were detected in the sciatic nerve using Western blotting to explain the underlying mechanism. A counterevidence group was created by injecting a SIRT1 inhibitor during EA intervention to support the hypothesis.

In addition to diabetes-related metabolic changes, T2DPN rats showed significant reductions in pain threshold after 9 weeks, suggesting abnormal peripheral nerve function. EA treatment partially restored metabolic control and reduced nerve damage in T2DPN rats. The SIRT1/PGC-1α axis, which was downregulated in the model group, was upregulated by EA intervention. The endogenous antioxidant system related to the SIRT1/PGC-1α axis, previously inhibited in diabetic rats, was reactivated. A similar trend was observed in inflammatory markers. When SIRT1 was inhibited in diabetic rats, these beneficial effects were abolished.

EA can alleviate the symptoms of T2DNP in experimental rats, and its effects may be related to the mitochondrial biogenesis and endogenous antioxidant system mediated by the SIRT1/PGC-1α axis.

Full-thickness burn wounds in diabetes often present significant challenges in terms of timely progression of healing and even mortality. Multifunctional dressings that possess strong absorptivity and mechanical property while effectively regulating inflammation and promoting angiogenesis is therefore crucial. We have developed a novel sponge (CCGE) comprising carboxymethyl chitosan, gelatin, and glycerin for the purpose of promoting accelerated healing of scald wounds in diabetic rats. This sponge is loaded with epigallocatechin-3-gallate, which possesses antioxidant and anti-inflammatory properties. The incorporation of the crosslinker BDDE reinforces its mechanical characteristics by augmenting the interplay between the sponge structure through hydrogen bonding and covalent bonding. Moreover, the crosslinked sponges provide a highly absorptive layer, carboxymethyl chitosan show good biocompatibility and angiogenic effects, and the gelatin provide matrix metalloproteinases-9 targeting. The CCGE sponges exhibit high biocompatibility, facilitate fibroblast migration, and promote tube formation. The application of the CCGE sponges significantly accelerates wound healing of full-thickness scald wounds in diabetic rats, exhibits enhanced collagen synthesis, reduced levels of pro-inflammatory cytokines, and increased blood vessel formation within the wounded area. In summary, this study presents a multifunctional composite CCGE sponge dressing that effectively modulates ROS, inflammation, and angiogenesis to facilitate comprehensive burn wound tissue repair in diabetes.

Diabetic nephropathy (DN) is a serious complication of diabetes mellitus; oxidative stress plays a key role in the pathogenesis of DN. The objective of this study was to evaluate the antioxidant effect of vitamin E on diabetic nephropathy. A control group and three groups of rats with streptozotocin-induced diabetes mellitus (untreated diabetic rats and diabetic rats treated with vitamin E 250 and 500 mg/kg) were studied. After 4 weeks of treatment, the kidneys were removed under anesthesia with sodium pentobarbital. The kidneys were weighed, the AT1 and AT2 receptor expression was measured by Western blot, and the activities of glutathione peroxidase, catalase, and superoxide dismutase were determined in the renal cortex. Rats with diabetes mellitus had hyperglycemia, increased food and water consumption, and higher urinary volume than control rats. In diabetic rats (DM), kidney hypertrophy was observed and measured by kidney weight, protein/DNA ratio in the renal cortex, and proximal tubular cell area; proteinuria and reduced creatinine clearance were observed. AT1 and AT2 receptor expression in the kidney cortex of DM rats increased significantly compared to normoglycemic rats; antioxidant enzyme activities were decreased; treatment with vitamin E reversed kidney hypertrophy and reduced proteinuria; reduction in expression of AT1 and AT2 receptors was associated with increased antioxidant activity. Thus, treatment with vitamin E slows the progress of DN.

The development of type 2 diabetes (T2D) is largely dependent on the maintenance of pancreatic islet function and mass. Sexual dimorphism in T2D is evident in many areas, such as pathophysiology, treatment, and prevention. Mitogen-activated protein kinase phosphatase-2 (MKP-2) has a distinct role in the regulation of cell proliferation and the development of metabolic disorders. However, whether there is a causal relationship between MKP-2 and diabetes onset is unclear. The aim of this study was to determine the role of MKP-2 in the regulation of whole-body glucose homeostasis and the impact on pancreatic islet function using streptozotocin-induced pancreatic injury. Here, we show that female mice with whole-body deletion of MKP-2 exhibit hyperglycemia in mouse models treated with multiple low doses of streptozotocin (STZ). In comparison, both male MKP-2 wild-type and knockout mice were hyperglycemic. Consistent with the hyperglycemia, female MKP-2-deficient mice exhibited reduced islet size. Under T2D conditions, MKP-2-deficient mice display enhanced pancreatic JNK and ERK phosphorylation that is associated with the downregulation of genes important for pancreatic islet development and function, Pdx-1 and MafA. Furthermore, we found impaired metabolic flux in adipose tissue that is consistent with hyperglycemia and dysfunctional pancreas. MKP-2 deletion results in reduced Akt activation that is associated with increased adiposity and insulin resistance in female MKP-2 KO mice. These studies demonstrate the critical role of MKP-2 in the development of T2D diabetes in vivo. This suggests that MKP-2 may have a gender-specific role in diabetes development. This discovery raises the possibility that postmenopausal prevention of T2D may benefit from the activation of MKP-2 activity in islet cells.

Vanadium is a transition metal with important industrial, technological, biological, and biomedical applications widespread in the environment and in living beings. The different reactions that vanadium compounds (VCs) undergo in the presence of proteins, nucleic acids, lipids and metabolites under mild physiological conditions are reviewed. In the environment vanadium is present naturally or through anthropogenic sources, the latter having an environmental impact caused by the dispersion of VCs in the atmosphere and aquifers. Vanadium has a versatile chemistry with interconvertible oxidation states, variable coordination number and geometry, and ability to form polyoxidovanadates with various nuclearity and structures. If a VC is added to a water-containing environment it can undergo hydrolysis, ligand-exchange, redox, and other types of changes, determined by the conditions and speciation chemistry of vanadium. Importantly, the solution is likely to differ from the VC introduced into the system and varies with concentration. Here, vanadium redox, hydrolytic and ligand-exchange chemical reactions, the influence of pH, concentration, salt, specific solutes, biomolecules, and VCs on the speciation are described. One of our goals with this work is highlight the need for assessment of the VC speciation, so that beneficial or toxic species might be identified and mechanisms of action be elucidated.

Cubebin, a dibenzyl butyrolactone lignan belonging to several distinct families, including Aristolochiaceae, Myristicaceae, Piperaceae, and Rutaceae, and possesses several pharmacological activities, including analgesic, anti-inflammatory, antioxidant, and vasodilatory. The current study aimed to evaluate the effect of cubebin on streptozotocin (STZ)-evoked diabetic nephropathy (DN). DN is a well-identified complication of diabetes mellitus (DM) characterized by renal hypertrophy that progressively declines kidney function. Wistar rats were randomly divided into groups- normal, STZ control (65 mg/kg/body weight), and STZ + cubebin (10 and 20 mg/kg). Biochemical parameters such as glucose levels, kidney parameters, lipid profile, oxidative stress, endogenous antioxidant markers, inflammatory cytokines and histopathology were performed. Molecular docking [(PDB ID: TNF-α (7JRA), NF-κB (1SVC), TGF-β1 (3TZM)] and dynamic simulation (MDS) were also performed with the selected target. STZ-induced DN was changes in these parameters. In contrast, DN + cubebin at 10 and 20 mg/kg doses improved the biochemical parameters and histological changes. Furthermore, molecular docking and simulation studies showed a binding affinity with negative binding energy with TNF-α (7jra, - 11.342 kcal/mol), TGF-β1 (3tzm, - 9.162 kcal/mol) and NF-κB (1svc, - 6.665 kcal/mol). The results of MDS provided insight into the mechanisms that associate proteins TNF-α, NF-κB, and TGF-β1 in conformational dynamics upon binding to cubebin. In conclusion, these findings exhibit a potential effect of cubebin in STZ-evoked DN rats.

Depression is a prevalent and disabling disorder that poses serious problems in mental health care, and rapid antidepressants are novel treatments for this disorder. Cannabidiol (CBD), a nonintoxicating phytocannabinoid, is thought to have therapeutic potential due to its important neurological and anti-inflammatory properties. Despite major advances in pharmacotherapy in experimental animals, the exact mechanism of antidepressant-like effects remains to be elucidated.

In this paper, we review the current state of knowledge on the antidepressant properties of CBD in numerous experimental and clinical studies.

Accumulating evidence suggests that CBD has antidepressant properties in humans and animals with few side effects, suggesting that CBD may be a potential antidepressant. Furthermore, we discuss that CBD may therefore provide a potential treatment to exert antidepressant-like effects through various molecular targets, reducing inflammation, and enhancing neurogenesis.

Taken together with the growing popularity of CBD as a medicine, these findings extend the limited knowledge on the antidepressant effects of CBD. This potentially opens up new therapeutic means for the patients with depression.

This study aimed to investigate the long-term physiological and morphological changes in the bladders of diabetic rats. Sixty-nine female Sprague-Dawley rats were divided into a control and six diabetic (3 days and 2, 4, 8, 12, and 24 weeks after induction of type 1 diabetes) groups. Metabolic cages and cystometry were used to evaluate bladder function. Bladder contractility was assessed using an organ bath test, and Masson's trichrome staining was performed. In the metabolic cage study, the urination frequency during the dark period significantly increased in the early stages at 3 days of diabetes (p < 0.05). The voiding interval significantly increased (p < 0.05) at 8-12 weeks of diabetes, while the residual urine volume and voiding efficiency worsened at 24 weeks. In the organ bath study, the dose-response curve of carbachol for median effective concentration did not change; however, the bladder contractile force was enhanced at 8 weeks (p = 0.028). Histological analysis revealed increased fibrosis at 4 weeks of diabetes. Diabetic bladder dysfunction is characterized by storage and voiding bladder activity changes in the early stages that induces urinary frequency and reduced voiding efficiency in the late phase; this turning point occurs at 8 weeks after diabetes.

For patients who have difficulty controlling blood glucose even with insulin administration, xenogeneic islet cells, including human stem cell-derived pancreatic islets (hSC-islet) and porcine islets, have garnered attention as potential solutions to challenges associated with donor shortages. For the development of diabetes treatment modalities that use cell transplantation therapy, it is essential to evaluate the efficacy and safety of transplanted cells using experimental animals over the long term.

We developed permanent diabetic immune-deficient mice by introducing the Akita (C96Y) mutation into the rodent-specific Insulin1 gene of NOD/Shi-scid IL2rγc null (NOG) mice ( Ins1 C96Y/C96Y NOG). Their body weight, nonfasting blood glucose, and survival were measured from 4 wk of age. Insulin sensitivity was assessed via tolerance tests. To elucidate the utility of these mice in xenotransplantation experiments, we transplanted hSC-islet cells or porcine islets under the kidney capsules of these mice.

All male and female homozygous mice exhibited persistent severe hyperglycemia associated with β-cell depletion as early as 4 wk of age and exhibited normal insulin sensitivity. These mice could be stably engrafted with hSC-islets, and the mice that received porcine islet grafts promptly exhibited lowered blood glucose levels, maintaining blood glucose levels below the normal glucose range for at least 52 wk posttransplantation.

The Ins1C96Y/C96Y NOG mouse model provides an effective platform to assess both the efficacy and safety of long-term xenograft engraftment without the interference of their immune responses. This study is expected to contribute essential basic information for the clinical application of islet cell transplantation.

Hepatocellular carcinoma is one of the deadliest and fastest-growing cancers. Among HCC etiologies, metabolic dysfunction-associated fatty liver disease (MAFLD) has served as a major HCC driver due to its great potential for increasing cirrhosis. The obesogenic environment fosters a positive energy balance and results in a continuous rise of obesity and metabolic syndrome. However, it is difficult to understand how metabolic complications lead to the poor prognosis of liver diseases and which molecular mechanisms are underpinning MAFLD-driven HCC development. Thus, suitable preclinical models that recapitulate human etiologies are essentially required. Numerous preclinical models have been created but not many mimicked anthropometric measures and the course of disease progression shown in the patients. Here we review the literature on adipose tissues, liver-related HCC etiologies and recently discovered genetic mutation signatures found in MAFLD-driven HCC patients. We also critically review current rodent models suggested for MAFLD-driven HCC study.