Diabetic Conditions Research Articles

Exacerbation of diabetes due to F. Nucleatum LPS-induced SGLT2 overexpression in the renal proximal tubular epithelial cells

BackgroundDiabetes treatments by the control of sodium-glucose cotransporter 2 (SGLT2) is commonly conducted while there are still uncertainties about the mechanisms for the SGLT2 overexpression in kidneys with diabetes. Previously, we have reported that glomeruli and proximal tubules with diabetic nephropathy express toll-like receptor TLR2/4, and that the TLR ligand lipopolysaccharide (LPS) of periodontal pathogens have caused nephropathy in diabetic model mice. Recently, many researchers suggested that the periodontal pathogenic bacteria Fusobacterium (F.) nucleatum has the TLR4-associated strong activator of the colorectal inflammation and cancer. The present study aimed to investigate the possibility of F. nucleatum as an exacerbation factor of diabetes through the renal SGLT2 induction.MethodsThe induction of the SGLT2 by F. nucleatum LPS (Fn-LPS) were investigated in the streptozotocin-induced diabetic mouse renal tissue and cultured renal proximal epithelial cells. The changes of blood glucose levels and survival curves in diabetic mice with Fn-LPS were analyzed. The Fn-LPS-induced SGLT2 production in the diabetic mouse renal tissue and in the cultured proximal epithelial cells was examined by ELISA, quantitative RT-PCR, and immunohistochemical analysis.ResultsThe SGLT2 expression in the cultured mouse tubular epithelial cells was significantly increased by TNF- or co-culture with Fn-LPS-supplemented J774.1 cells. The period to reach diabetic condition was significantly shorter in Fn-LPS-administered diabetic mice than in diabetic mice. All Fn-LPS-administered-diabetic mice reached humane endpoints during the healthy period of all of the mice administered Fn-LPS only. The promotion of the SGLT2 expression at the inner lumen of proximal tubules were stronger in the Fn-LPS-administered-diabetic mice than in diabetic mice. The renal tissue SGLT2 mRNA amounts and the number of renal proximal tubules with overexpressed SGLT2 in the lumen were more in the Fn-LPS-administered-diabetic mice than in diabetic mice.ConclusionsThis study suggests that F. nucleatum causes the promotion of diabetes through the overexpression of SGLT2 in proximal tubules under the diabetic condition. Periodontitis with F. nucleatum may be a diabetic exacerbating factor.

In vitro evaluation of silver-zinc oxide-eugenol nanocomposite for enhanced antimicrobial and wound healing applications in diabetic conditions

Diabetic wounds with chronic infections present a significant challenge, exacerbated by the growing issue of antimicrobial resistance, which often leads to delayed healing and increased morbidity. This study introduces a novel silver-zinc oxide-eugenol (Ag+ZnO+EU) nanocomposite, specifically designed to enhance antimicrobial activity and promote wound healing. The nanocomposite was thoroughly characterized using advanced analytical techniques, confirming its nanoscale structure, stability and chemical composition. The Ag+ZnO+EU nanocomposite demonstrated potent antimicrobial efficacy against a range of wound associated pathogens, including standard and clinical isolates of Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans. Minimum inhibitory concentrations of Ag+ZnO+EU for standard and clinical isolates were significantly lower than those of the individual components, highlighting the synergistic effect of the nanocomposite. Time-kill assays revealed rapid microbial eradication, achieving complete sterility within 240-min. Importantly, the nanocomposite effectively eliminated persister-like cells, which are typically resistant to conventional treatments, suggesting a potential solution for persistent infections. In vitro scratch assays using human keratinocyte cells demonstrated that the Ag+ZnO+EU nanocomposite significantly accelerated wound closure, with near-complete healing observed within 24-h, indicating enhanced cell migration and tissue regeneration. Additionally, the nanocomposite showed potential antidiabetic effects by increasing glucose uptake up to 97.21% in an in vitro assay using 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-D-glucose, a fluorescent glucose analog, suggesting potential applications beyond wound healing. These findings highlight the Ag+ZnO+EU nanocomposite as a promising candidate for addressing both antimicrobial resistance and impaired wound healing in diabetic contexts.Graphical

ERK1/2 Inhibition Alleviates Diabetic Cardiomyopathy by Suppressing Fatty Acid Metabolism.

Diabetes mellitus is associated with morphological and functional impairment of the heart primarily due to lipid toxicity caused by increased fatty acid metabolism. Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) have been implicated in the metabolism of fatty acids in the liver and skeletal muscles. However, their role in the heart in diabetes remains unclear. In this study, we tested our hypothesis that pharmacological inhibition of ERK1/2 alleviates cardiac remodeling in diabetic mice through a reduction in fatty acid metabolism. ERK1/2 phosphorylation in diabetes was determined both in vitro and in vivo. H9C2 cells were subjected to high glucose, high palmitic acid, or both high glucose and palmitic acid. db/db and streptozotocin (STZ)-induced diabetic mice were analyzed for ERK1/2 phosphorylation levels as well as the effects of U0126 treatment on cardiac remodeling. Administration of STZ and U0126 in mice was performed via intraperitoneal injection. Blood glucose levels in mice were measured using a glucometer. Mouse heart total RNAs were purified for reverse transcription. Real-time polymerase chain reaction (PCR) analysis of the messenger ribonucleic acid (mRNA) expression was performed for hypertrophy (ANF, BNP, and βMHC), fibrosis (Col3α1), and fatty acid metabolism genes (PPARα, CPT1A, and FACS). Interstitial fibrosis of the myocardium was analyzed using Masson's trichrome staining of the paraffin-embedded tissues. ERK1/2 phosphorylation was significantly increased in diabetic conditions. Inhibition of ERK1/2 by U0126 in both streptozotocin-induced diabetic mice and db/db mice resulted in a significant reduction in the expression of genes associated with hypertrophy and fibrosis. In contrast, elevated phosphorylation of ERK1/2 in Dusp6/8 knockout (DKO) mice resulted in fibrosis. Mechanistically, ERK1/2 activation enhanced the expression of fatty acid metabolism genes PPARα, CPT1A, and FACS in the heart, which was reversed by U0126 treatment. ERK1/2 are potential therapeutic targets for diabetic cardiomyopathy by modulating fatty acid metabolism in the heart.

Nε-carboxyethyl-lysin influences atherosclerotic plaque stability through ZKSCAN3 acetylation-regulated macrophage autophagy via the RAGE/LKB1/AMPK1/SIRT1 pathway

Atherosclerosis, a chronic inflammatory condition characterized by plaque formation, often leads to instability, particularly under Type 2 diabetes mellitus (T2DM) conditions, which exacerbate cardiovascular risks. However, the molecular mechanisms underlying this process remain incompletely understood. In this study, we investigated the correlation between acute coronary syndrome (ACS) and serum levels of Nε-carboxyethyl-lysin (CEL), a prominent advanced glycation end product (AGE) elevated in T2DM, in a cohort of 225 patients with coronary artery disease. Using a murine model of atherosclerosis complicated by T2DM, we examined the effects of CEL on plaque stability and macrophage autophagy. Our findings revealed that elevated serum CEL levels are independently associated with increased ACS incidence. Metabolomic profiling identified CEL as a key AGE contributing to plaque instability in diabetic conditions. Mechanistically, CEL disrupted macrophage autophagy and plaque stability by perturbing the Receptor for Advanced Glycation End products (RAGE)/Liver Kinase B1 (LKB1)/AMP-activated Protein Kinase 1 (AMPK1)/Sirtuin 1 (SIRT1) signaling cascade. This pathway further regulated autophagic activity through SIRT1-mediated acetylation of Zinc Finger with KRAB and SCAN Domains 3 (ZKSCAN3). These findings highlight CEL’s critical role in promoting plaque instability in T2DM by impairing key molecular pathways that regulate autophagy, offering potential therapeutic targets for managing atherosclerosis in diabetic patients.

Anti-oxidant Effects of Chromatographic Fractions of Abrus precatorius (Linn.) Leaf Extract in Wistar Rats

Aims: Plant antioxidants are considered safe, nutritional, and therapeutic, offering promising solutions to oxidative stress-related health issues. This study explores the antioxidant potential of column fractions derived from the methanol extract of Abrus precatorius, a plant with limited prior evaluation of its bioactive fractions. Study Design: The study used an experimental design. Place and Duration of Study: Orlu LGA, Imo State, Nigeria Methodology: Plant materials were collected from Orlu LGA, Imo State, Nigeria. The dried, powdered leaves were screened for phytochemical constituents using standard methods. Methanol extract was obtained through cold maceration and further fractionated using column chromatography packed with silica gel (60–120 mesh), with elution performed using a gradient mixture of hexane, ethyl acetate, and methanol. The phytochemical analysis confirmed the presence of alkaloids, flavonoids, tannins, cardenolides, and saponins, compounds known for their antioxidative properties. Column chromatography yielded five fractions (F1–F5), which were assessed for antioxidant activity using both in vivo (rat models) and in vitro methods, including 2,2-diphenyl-1-picryl hydrazyl (DPPH) and nitric oxide assays. Results: Notably, fraction F1 demonstrated a significant increase in glutathione and catalase activity, while F4 showed a marked elevation in superoxide dismutase activity in erythrocytes. In liver tissue, F1 and F5 showed exceptional catalase activity, with respective increases of 258 % and 290 %. Fraction F3 exhibited a 290 % increase in superoxide dismutase activity. Furthermore, F3 effectively reduced DPPH radical activity with an IC50 of 0.2 mg/mL, while F4 significantly lowered nitric oxide levels with an IC50 of 0.3 mg/ml. Conclusion: This study highlights the novel identification of potent antioxidant fractions from Abrus precatorius methanol extract, offering valuable insights for developing plant-based therapies for oxidative stress-related disorders such as cardiovascular diseases, diabetes, and neurodegenerative conditions. It underscores the plant's potential as a safe, natural antioxidant source for further pharmacological exploration.

The Abnormal Expression of Tubular SGLT2 and GULT2 in Diabetes Model Mice with Malocclusion-Induced Hyperglycemia

Background: A relationship between malocclusion and the promotion of diabetes has been suggested. In hyperglycemia, the expression of sodium–glucose cotransporter 2 (SGLT2) and the facilitative glucose transporter 2 (GLUT2) is upregulated in proximal tubular cells, leading to an increase in renal glucose reabsorption. The present study aimed to investigate whether malocclusion contributes to diabetic exacerbation. Methods: Streptozotocin (STZ)-induced diabetic mice with malocclusion due to cutting molars were investigated based on increased blood glucose levels. PCR and immunohistochemical analyses were performed on diabetic mice kidneys to investigate the expression of SGLT2 and GLUT2. Results: Animal experiments were performed using 32 mice for 21 days. The time to reach a diabetic condition in STZ-administered mice was shorter with malocclusion than without malocclusion. The increase and mean blood glucose levels in STZ-administered mice were steeper and higher with malocclusion than without malocclusion. Urea albumin, BUN, and CRE levels were higher in diabetic mice with malocclusion than in diabetic mice without. Immunoreaction with anti-SGLT2 and anti-GLUT2 in the renal tissue of STZ-administered mice was stronger with malocclusion than without malocclusion. The amounts of SGLT2 and GLUT2 mRNA in the renal tissue in STZ-administered mice were higher with malocclusion than without malocclusion. The amounts of TNF-a and IL-6 mRNA in the large intestinal tissue in STZ-administered mice were higher with malocclusion than without malocclusion. Conclusions: Our results indicate that malocclusion accelerates the tubular expression of SGLT2 and GLUT2 under hyperglycemia. Malocclusion may be a diabetes-exacerbating factor with increased poor glycemic control due to shortened occlusion time resulting from swallowing food without chewing.

Relation of Insulin Resistance to Brain Glucose Metabolism in Fasting and Hyperinsulinemic States: A Systematic Review and Meta-analysis.

Abnormal brain glucose metabolism may cause cognitive disease in type 2 diabetes, yet the relation between insulin resistance and brain glucose metabolism has not been systematically described. We evaluated the impact of metabolic condition (fasting vs insulin stimulation, eg, from hyperinsulinemic clamp) on the association between insulin resistance of different etiologies and brain glucose metabolism. PubMed, Embase, Cochrane Library, and Web of Science were systematically searched from inception until February 2022. Of 656 unique records, we deemed 31 eligible. Criteria were studies assessing brain glucose metabolism (uptake or metabolic rate) by 18F-2-fluoro-2-deoxy-D-glucose-positron emission tomography in individuals characterized by measures of or clinical proxies for insulin resistance (eg, type 2 diabetes and obesity). Two independent investigators extracted data and assessed study quality. We applied random-effects models to pool Hedge's g standardized mean differences. Insulin resistance was associated with decreased brain glucose metabolism during fasting [-0.47 SD, 95% confidence interval (CI): -0.73 to -0.22, P < .001, I2 = 71%] and increased metabolism during insulin stimulation (1.44 SD, 95% CI 0.79 to 2.09, P = .002, I2 = 43%). Contrary to type 2 diabetes and other insulin resistance-related conditions, obesity was not associated with brain hypometabolism in fasting states (0.29 SD, 95% CI -.81 to 1.39). Metabolic conditions modify associations between insulin resistance and brain glucose metabolism; ie, most individuals with insulin resistance display hypometabolism during fasting and hypermetabolism during insulin stimulation.

Fructose-derived glycation and immune function: Effects on antigen binding in human IgG and lymphocytes.

Diabetes Mellitus (DM), one of the oldest known metabolic disorders, dates back to 3000 BC and continues to have a profound impact on health and the economy. Nutrition plays a critical role in managing diabetes and enhancing overall quality of life. It is also vital for immune system function, as well as in the prevention and treatment of aging-related diseases. A key factor contributing to the global rise in obesity is the excessive consumption of fructose/glucose (corn) syrup, which leads to various metabolic complications. Uncontrolled intake of carbohydrates, particularly sugars like fructose, triggers the Maillard Reaction, a chemical process that occurs between sugars and proteins, resulting in advanced glycation end-products (AGEs). This process is accelerated in diabetic patients due to hyperglycemia, leading to increased glycation of plasma proteins such as immunoglobulins, which play an essential role in the immune system. Studies show that individuals with Diabetes Mellitus experience a higher susceptibility to infections due to increased viral entry, impaired immune responses, reduced viral clearance, and dysregulated inflammatory cytokine production. In this study, human IgG proteins were glycated in vitro using fructose, simulating the damaging effects seen in diabetic conditions. A mixture containing antioxidants like glutathione, oleuropein, and selenium was prepared and incubated with the glycated IgG to assess its protective properties. Lymphocyte cells from healthy volunteers were also treated with fructose and subjected to similar experiments. Results demonstrated that fructose significantly compromises immune function by damaging key proteins, but the antioxidant mixture effectively mitigates this damage, offering a protective mechanism against glycation in the immune system.

New Insights into Chemical Profiles and Health-Promoting Effects of Edible Mushroom Dictyophora indusiate (Vent ex. Pers.) Fischer: A Review.

Mushrooms are valued for their culinary and medicinal benefits, containing bioactive compounds like polysaccharides, terpenoids, phenolics, lectins, and ergosterols. This review aims to encourage research on D. indusiata by summarizing its chemistry, health benefits, pharmacology, and potential therapeutic applications. Molecules from D. indusiata offer anti-diabetic, antioxidant, anti-tumor, hepatoprotective, and anti-bacterial effects. In particular, polysaccharides from Dictyophora indusiata (DIP) enhance immune function, reduce oxidative stress, and promote gut health as prebiotics. DIP shows neuroprotective effects by reducing oxidative damage, improving mitochondrial function, and regulating apoptosis, making them beneficial for neurodegenerative diseases. They also activate immune responses through TLR4 and NF-κB pathways. Additionally, compounds like dictyophorines and quinazoline from D. indusiata support nerve growth and protection. Mushrooms help regulate metabolism and improve lipid profiles, with potential applications in managing metabolic disorders, cancer, cardiovascular diseases, diabetes, and neurodegenerative conditions. Their wide range of bioactive compounds makes D. indusiata mushrooms functional foods with significant therapeutic potential.

G-protein coupled receptor GPR124 protects against podocyte senescence and injury in diabetic kidney disease.

Although emerging studies highlight the pivotal role of podocyte senescence in the pathogenesis of diabetic kidney disease (DKD) and aging-related kidney diseases, therapeutic strategies for preventing podocyte senescence are still lacking. Here, we identified a previously unrecognized role of GPR124, a novel adhesion G protein-coupled receptor, in maintaining podocyte structure and function by regulation of cellular senescence in DKD. Podocyte GPR124 was significantly reduced in db/db diabetic (a type 2 diabetic mouse model) and streptozocin-induced diabetic mice (a type 1 diabetic model), which was further confirmed in kidney biopsies from patients with DKD. The level of GPR124 in glomeruli was positively correlated with the estimated glomerular filtration rate and negatively correlated with serum creatinine levels. Podocyte-specific deficiency of GPR124 significantly aggravated podocyte injury and proteinuria in the two models of diabetic mice. Moreover, GPR124 regulated podocyte senescence in both diabetic and aged mice. Mechanistically, GPR124 directly bound with vinculin and negatively regulated focal adhesion kinase (FAK) signaling, thereby mediating podocyte senescence and function. Importantly, overexpression of GPR124 or pharmacological inhibition of FAK protected against podocyte senescence and injury under diabetic conditions. Our studies suggest that targeting GPR124 may be an innovative therapeutic strategy for patients with DKD and aging-related kidney diseases.

Enhancing Therapy Adherence: Impact on Clinical Outcomes, Healthcare Costs, and Patient Quality of Life.

Adherence to therapy, defined as the extent to which a patient follows prescribed therapeutic recommendations, is a pivotal factor in the effective management of chronic diseases such as diabetes, hypertension, and cardiovascular conditions. This review highlights the profound influence of adherence on clinical outcomes, healthcare costs, and patient quality of life. Despite its critical importance, non-adherence remains a pervasive challenge globally, contributing to suboptimal treatment results, higher rates of complications, increased hospitalizations, and substantial healthcare expenditures. This narrative review examines the multifaceted impact of adherence, focusing on its role in achieving clinical efficacy, mitigating economic burdens, and enhancing patient well-being. The findings reveal that poor adherence exacerbates the risk of disease progression, complications, and higher healthcare costs. Conversely, improved adherence promotes better disease control, fewer complications, and enhanced patient quality of life. Interventions such as patient education, streamlined treatment regimens, and the integration of digital health tools have shown promise in addressing adherence barriers. Furthermore, the role of healthcare professionals is underscored as fundamental, with their continuous support, effective communication, and efforts to build patient trust being essential to fostering better adherence. In conclusion, adherence significantly affects clinical outcomes, healthcare costs, and patient quality of life. Addressing barriers to adherence requires a comprehensive and personalized approach, considering individual patient needs and circumstances. Future research should prioritize the long-term evaluation of emerging technologies and the development of tailored strategies to improve adherence across diverse patient populations. Strengthening adherence is not only crucial for individual patient outcomes, but also for enhancing the sustainability and efficiency of healthcare systems.

Effect of Chrysin, a Flavonoid Present in Food, on the Skeletal System in Rats with Experimental Type 1 Diabetes.

It seems that some substances of plant origin may exert health-promoting activities in diabetes and its complications, including those concerning bones. Chrysin (5,7-dihydroxyflavone), present in honey, some plants, and food of plant origin, has been reported to exert, among others, antioxidative, anti-inflammatory and antidiabetic effects. The aim of this study was to investigate the effects of chrysin on the skeletal system of rats with experimental type 1 diabetes (T1D). The experiments were carried out on mature male Wistar rats. T1D was induced by a single streptozotocin injection. Administration of chrysin (50 or 100 mg/kg p.o., once daily) began two weeks later and lasted four weeks. Serum bone turnover markers, bone mass, density and mineralization, mechanical properties and histomorphometric parameters of cancellous and compact bone were examined. T1D profoundly affected bone metabolism, leading to worsening of bone strength in comparison with the healthy controls. After administration of chrysin, slight improvement of only some parameters was demonstrated in relation to the diabetic controls. Results of the present study indicate that chrysin may exert some very limited favorable effects on the skeletal system in diabetic conditions.

Phytochemical investigation and evaluation of antioxidant and antidiabetic activities in aqueous extracts of Cedrus atlantica

Abstract Diabetes mellitus is a global health problem requiring innovative approaches for effective management. Natural compounds derived from medicinal plants offer promising avenues due to their diverse biological activities. The aim of this study was to assess the inhibitory effects of Cedrus atlantica extracts on the enzymes α-amylase and α-glucosidase, which play a crucial role in the regulation of postprandial glucose levels, as well as to investigate their phytochemical composition and antioxidant capabilities. Aqueous extract of bark (EA), aqueous extract of cones (CA), and aqueous extract of leaves (FA) of C. atlántica were prepared and evaluated for enzyme inhibition using acarbose as a standard. The CA extract showed potent α-amylase inhibition (IC50 307 ± 0.02 μg/mL) and remarkable α-glucosidase inhibition (IC50 70 ± 0.04 μg/mL), outperforming the FA and EA extracts. Quantitative analysis revealed that EA and CA extracts had higher total phenolic content, flavonoid content, and tannin content than FA extract. Antioxidant assessments highlighted the outstanding performance of CA extract, with a low IC50 ABTS (30.65 ± 0.1 μg/mL) and an impressive EC50 FRAP (59.43 ± 1.19 μg/mL), outperforming FA extract. The results demonstrate the remarkable antidiabetic potential of C. atlantica extracts, particularly the CA extract, by inhibiting key enzymes involved in carbohydrate digestion. These extracts possess various phytochemical compounds with significant antioxidant capacities, suggesting that they are suitable for pharmaceutical, nutraceutical, and cosmetic applications. Further research to isolate and identify the bioactive compounds in CA extract could lead to new therapeutic strategies for managing diabetes and oxidative stress-related conditions.

Abnormality detection in nailfold capillary images using deep learning with EfficientNet and cascade transfer learning

Nailfold Capillaroscopy (NFC) is a simple, non-invasive diagnostic tool used to detect microvascular changes in nailfold. Chronic pathological changes associated with a wide range of systemic diseases, such as diabetes, cardiovascular disorders, and rheumatological conditions like systemic sclerosis, can manifest as observable microvascular changes in the terminal capillaries of nailfolds. The current gold standard relies on experts performing manual evaluations, which is an exhaustive time-intensive, and subjective process. In this study, we demonstrate the viability of a deep learning approach as an automated clinical screening tool. Our dataset consists of NFC images from a total of 225 participants, with normal images accounting for 6% of the dataset. This study introduces a robust framework utilizing cascade transfer learning based on EfficientNet-B0 to differentiate between normal and abnormal cases within NFC images. The results demonstrate that pre-trained EfficientNet-B0 on the ImageNet dataset, followed by transfer learning from domain-specific classes, significantly enhances the classifier’s performance in distinguishing between Normal and Abnormal classes. Our proposed model achieved superior performance, with accuracy, precision, recall, F1 score, and ROC_AUC of 1.00, significantly outperforming both models of single transfer learning on the pre-trained EfficientNet-B0 and cascade transfer learning on a convolutional neural network, which each attained an accuracy, precision, recall, and F1 score of 0.67 and a ROC_AUC of 0.83. The framework demonstrates the potential to facilitate early preventive measures and timely interventions that aim to improve healthcare delivery and patients’ quality of life.

Polyphenolic Hispolon Derived from Medicinal Mushrooms of the Inonotus and Phellinus Genera Promotes Wound Healing in Hyperglycemia-Induced Impairments.

Background: This study investigated the wound-healing potential of hispolon, a polyphenolic pigment derived from medicinal mushrooms, under diabetic conditions using both in vitro and in vivo models. Methods: In the in vitro assays, L929 fibroblast cells exposed to high glucose (33 mmol/L) were treated with hispolon at concentrations of 2.5, 5, 7.5, or 10 μmol/L. In the in vivo assays, streptozotocin-induced diabetic rats with excision wounds received daily topical applications of 0.2 g of 5% (w/w) hispolon ointment. Results: Hispolon improved cell viability; suppressed oxidative stress by reducing reactive oxygen species, lipid peroxidation, and oxidative DNA damage; and restored the reduced glutathione/oxidized glutathione ratio. The scratch assay demonstrated that hispolon at 10 μmol/L enhanced fibroblast migration impaired by high-glucose conditions. Treatment with 5% (w/w) hispolon ointment accelerated wound contraction, reduced the epithelialization time, and enhanced tissue regeneration with an efficacy comparable to that of Fespixon® cream, as shown by histological findings of increased fibroblast activity, collagen deposition, and capillary growth. Hispolon ointment also modulated macrophage polarization in diabetic wounds by reducing M1 markers and enhancing M2 markers. In a diabetic rat dead-space-wound model, 5% (w/w) hispolon ointment reduced the levels of pro-inflammatory cytokines, increased those of anti-inflammatory cytokines and growth factors, and stimulated Type I and III collagen synthesis, effectively promoting wound healing. In incisional wounds, hispolon ointment improved the wound-breaking strength, showing results comparable to that of Fespixon® cream. Safety assessments confirmed that hispolon ointment showed no acute dermal toxicity. These findings underscore hispolon's potential as a promising candidate for diabetic wound management by mitigating oxidative stress, enhancing tissue regeneration, and accelerating wound healing.

Rnd3 Ameliorates Diabetic Cardiac Microvascular Injury via Facilitating Trim40-mediated Rock1 Ubiquitination.

Diabetic microvascular dysfunction is evidenced by disrupted endothelial cell junctions and increased microvascular permeability. However, effective strategies against these injuries remain scarce. In this study, the type 2 diabetes mouse model was established by high-fat diet combined with streptozotocin injection in Rnd3 endothelial- specific transgenic and knockout mice. Echocardiography was employed to evaluate cardiac function. Microvascular corrosion casts, lanthanum nitrate perfusion, trans- endothelial electrical resistance, FITC-dextran permeability assay and laser speckle contrast imaging were performed to evaluate the integrity of endothelial cell junctions and microvascular function. RNA sequencing, mass spectrometry, co-immunoprecipitation, immunofluorescence and molecular docking were used to explore the downstream regulators of Rnd3. Evidence from gain/loss-of-function studies denoted a protective role for Rnd3 against microvascular dysfunction in diabetic heart. Endothelial-specific deletion of Rnd3 significantly exacerbated coronary microvascular barrier dysfunction under diabetic conditions, while Rnd3 overexpression effectively prevented these effects. Furthermore, Rnd3 overexpression also attenuated cardiac dysfunction in diabetic mice, as indicated by increased LVEF, LVFS, and E/A ratio. Rnd3 overexpression inhibited CMECs apoptosis and increased CMECs migration in response to HG-PA challenge. Rnd3 overexpression inhibited Rock1 activity and MLC phosphorylation in CMECs treated with HG-PA stimulus. Mechanically, Rnd3 recruited and interacted with the E3 ubiquitin ligase Trim40 which further facilitated the degradation of Rock1, thus inhibiting endothelial barrier hyperpermeability in HG-PA-stimulated CMECs. However, the cardioprotective effects of Rnd3 were largely abrogated by Trim40 deficiency in diabetic conditions. Collectively, Rnd3 alleviates microvascular hyperpermeability, maintains endothelial barrier integrity, and mitigates cardiac dysfunction by regulating the Rock1/MLC signaling pathway in the state of DCM.

Smart Imitator: Learning from Imperfect Clinical Decisions.

This study introduces Smart Imitator (SI), a 2-phase reinforcement learning (RL) solution enhancing personalized treatment policies in healthcare, addressing challenges from imperfect clinician data and complex environments. Smart Imitator's first phase uses adversarial cooperative imitation learning with a novel sample selection schema to categorize clinician policies from optimal to nonoptimal. The second phase creates a parameterized reward function to guide the learning of superior treatment policies through RL. Smart Imitator's effectiveness was validated on 2 datasets: a sepsis dataset with 19711 patient trajectories and a diabetes dataset with 7234 trajectories. Extensive quantitative and qualitative experiments showed that SI significantly outperformed state-of-the-art baselines in both datasets. For sepsis, SI reduced estimated mortality rates by 19.6% compared to the best baseline. For diabetes, SI reduced HbA1c-High rates by 12.2%. The learned policies aligned closely with successful clinical decisions and deviated strategically when necessary. These deviations aligned with recent clinical findings, suggesting improved outcomes. Smart Imitator advances RL applications by addressing challenges such as imperfect data and environmental complexities, demonstrating effectiveness within the tested conditions of sepsis and diabetes. Further validation across diverse conditions and exploration of additional RL algorithms are needed to enhance precision and generalizability. This study shows potential in advancing personalized healthcare learning from clinician behaviors to improve treatment outcomes. Its methodology offers a robust approach for adaptive, personalized strategies in various complex and uncertain environments.

ADAMTS13 Improves Endothelial Function and Reduces Inflammation in Diabetic Retinopathy.

The protease, a disintegrin and metalloproteinase with thrombospondin type 1 motif member 13 (ADAMTS13), known to cleave only the von Willebrand factor (VWF), has powerful regulatory effects on microvascular platelet adhesion, thrombosis, inflammation, and endothelial dysfunction. We study the protection against diabetes-induced retinal injury in experimental rats by supplementation with recombinant ADAMTS13. We compare human epiretinal membranes and vitreous samples from nondiabetic subjects and patients with proliferative diabetic retinopathy (PDR) and extend in vitro analyses with the use of various immunodetection and spectrofluorimetric methods on rat retina and human retinal glial and endothelial cell cultures. Functional studies include the assessment of the blood-retinal barrier (BRB), cell adhesion, and in vitro angiogenesis. In epiretinal membranes, endothelial cells and monocytes/macrophages express ADAMTS13. The levels of VWF, the platelet marker CD41, ADAMTS13, and the biomarkers of endothelial cell injury soluble VE-cadherin and soluble syndecan-1 are increased in PDR vitreous. ADAMTS13 is downregulated in diabetic rat retinas. The intravitreal administration of ADAMTS13 attenuates diabetes-induced BRB breakdown, the downregulation of VE-cadherin and β-catenin, and the upregulation of VWF, CD41, phospho-ERK1/2, HMGB1, VCAM-1, and ICAM-1. In Müller cells, ADAMTS13 attenuates MCP-1, MMP-9, and ROS upregulation induced by diabetic mimetic conditions. In HRMECs, ADAMTS13 attenuates the shedding of the soluble VE-cadherin and soluble syndecan-1 and the levels of phospho-ERK1/2, MCP-1, fractalkine, and ROS induced by diabetic mimetic conditions, the upregulation of ICAM-1 and VCAM-1 elicited by TNF-α, the adherence of monocytes induced by TNF-α, and VEGF-induced migration of human retinal microvascular endothelial cells. Our findings suggest that enhancing ADAMTS13 levels in situ ameliorates diabetes-induced retinal inflammation and vascular dysfunction.

Methylglyoxal compromises callus mineralization and impairs fracture healing through suppression of osteoblast terminal differentiation.

Impaired fracture healing in diabetic patients leads to prolonged morbidity and increased healthcare costs. Methylglyoxal (MG), a reactive metabolite elevated in diabetes, is implicated in various complications, but its direct impact on bone healing remains unclear. Here, using a non-diabetic murine tibial fracture model, we demonstrate that MG directly impairs fracture healing. Micro-computed tomography revealed decreased volumetric bone mineral density in the callus, while callus volume remained unchanged, resulting in a brittle bone structure. This was accompanied by reduced expression of osteocalcin and bone sialoprotein, both critical for mineralization. Biomechanical analysis indicated that MG reduced the mechanical resilience of the fracture site without altering its elastic strength, suggesting that the impairment was not primarily due to the accumulation of advanced glycation end-products in the bone extracellular matrix. In vitro studies confirmed that non-cytotoxic concentrations of MG inhibited osteoblast maturation and mineralization. Transcriptomic analysis identified downregulation of Osterix, a key transcription factor for osteoblast maturation, without altering Runx2 levels, leading to decreased expression of key mineralization-related factors like osteocalcin. These findings align with clinical observations of reduced circulating osteocalcin levels in diabetic patients, suggesting that the detrimental effects of MG on osteoblasts may extend beyond bone metabolism. Our study highlights MG and MG-sensitive pathways as potential therapeutic targets for improving bone repair in individuals with diabetes and other conditions characterized by elevated MG levels.

Unraveling the AMPK-SIRT1-FOXO Pathway: The In-Depth Analysis and Breakthrough Prospects of Oxidative Stress-Induced Diseases.

Oxidative stress (OS) refers to the production of a substantial amount of reactive oxygen species (ROS), leading to cellular and organ damage. This imbalance between oxidant and antioxidant activity contributes to various diseases, including cancer, cardiovascular disease, diabetes, and neurodegenerative conditions. The body's antioxidant system, mediated by various signaling pathways, includes the AMPK-SIRT1-FOXO pathway. In oxidative stress conditions, AMPK, an energy sensor, activates SIRT1, which in turn stimulates the FOXO transcription factor. This cascade enhances mitochondrial function, reduces mitochondrial damage, and mitigates OS-induced cellular injury. This review provides a comprehensive analysis of the biological roles, regulatory mechanisms, and functions of the AMPK-SIRT1-FOXO pathway in diseases influenced by OS, offering new insights and methods for understanding OS pathogenesis and its therapeutic approaches.