Xanthones with multiple roles against diabetes: their synthesis, structure-activity relationship, and mechanism studies.

A four-step synthetic process has been developed to prepare 1,3,5,8-tetrahydroxyxanthone (2a) and its isomer 1,3,7,8-tetrahydroxyxanthone (2b). 25 more xanthones were also synthesized by a modified scheme. Xanthone 2a was identified as the most active inhibitor against both α-glucosidase and aldose reductase (ALR2), with IC50 values of 7.8 ± 0.5 µM and 63.2 ± 0.6 nM, respectively, which was far active than acarbose (35.0 ± 0.1 µM), and a little more active than epalrestat (67.0 ± 3.0 nM). 2a was also confirmed as the most active antioxidant in vitro with EC50 value of 8.9 ± 0.1 µM. Any structural modification including methylation, deletion, and position change of hydroxyl group in 2a will cause an activity loss in inhibitory and antioxidation. By applying a H2 O2 -induced oxidative stress nematode model, it was confirmed that xanthone 2a can be absorbed by Caenorhabditis elegans and is bioavailable to attenuate in vivo oxidative stress, including the effects on lifespan, superoxide dismutase, Catalase, and malondialdehyde. 2a was verified with in vivo hypoglycemic effect and mitigation of embryo malformations in high glucose. All our data support that xanthone 2a behaves triple roles and is a potential agent to treat diabetic mellitus, gestational diabetes mellitus, and diabetic complications.

Acute Diabetes Complications After Transition to a Value-Based Medication Benefit.

Importance: The association of value-based medication benefits with diabetes health outcomes is uncertain. Objective: To assess the association of a preventive drug list (PDL) value-based medication benefit with acute, preventable diabetes complications. Design, Setting, and Participants: This cohort study used a controlled interrupted time series design and analyzed data from a large, national, commercial health plan from January 1, 2004, through June 30, 2017, for patients with diabetes aged 12 to 64 years enrolled through employers that adopted PDLs (intervention group) and matched and weighted members with diabetes whose employers did not adopt PDLs (control group). All participants were continuously enrolled and analyzed for 1 year before and after the index date. Subgroup analysis assessed patients with diabetes living in lower-income and higher-income neighborhoods. Data analysis was performed between August 19, 2020, and December 1, 2023. Exposure: At the index date, intervention group members experienced employer-mandated enrollment in a PDL benefit that was added to their follow-up year health plan. This benefit reduced out-of-pocket costs for common cardiometabolic drugs, including noninsulin antidiabetic agents and insulin. Matched control group members continued to have cardiometabolic medications subject to deductibles or co-payments at follow-up. Main Outcomes and Measures: The primary outcome was acute, preventable diabetes complications (eg, bacterial infections, neurovascular events, acute coronary disease, and diabetic ketoacidosis) measured as complication days per 1000 members per year. Intermediate measures included the proportion of days covered by and higher use (mean of 1 or more 30-day fills per month) of antidiabetic agents. Results: The study 10 588 patients in the intervention group (55.2% male; mean [SD] age, 51.1 [10.1] years) and 690 075 patients in the control group (55.2% male; mean [SD] age, 51.1 [10.1] years) after matching and weighting. From baseline to follow-up, the proportion of days covered by noninsulin antidiabetic agents increased by 4.7% (95% CI, 3.2%-6.2%) in the PDL group and by 7.3% (95% CI, 5.1%-9.5%) among PDL members from lower-income areas compared with controls. Higher use of noninsulin antidiabetic agents increased by 11.3% (95% CI, 8.2%-14.5%) in the PDL group and by 15.2% (95% CI, 10.6%-19.8%) among members of the PDL group from lower-income areas compared with controls. The PDL group experienced an 8.4% relative reduction in complication days (95% CI, -13.9% to -2.8%; absolute reduction, -20.2 [95% CI, -34.3 to -6.2] per 1000 members per year) compared with controls from baseline to follow-up, while PDL members residing in lower-income areas had a 10.2% relative reduction (95% CI, -17.4% to -3.0%; absolute, -26.1 [95% CI, -45.8 to -6.5] per 1000 members per year). Conclusions and Relevance: In this cohort study, acute, preventable diabetes complication days decreased by 8.4% in the overall PDL group and by 10.2% among PDL members from lower-income areas compared with the control group. The results may support a strategy of incentivizing adoption of targeted cost-sharing reductions among commercially insured patients with diabetes and lower income to enhance health outcomes.

The favorable impacts of cardamom on related complications of diabetes: A comprehensive literature systematic review.

BACKGROUND AND AIM: Complementary and alternative medicine plays an increasing role in preventing, and regulatory, complications associated with diabetes. There are plenty of polyphenolic compounds found in Elettaria cardamomum (Cardamom) such as luteolin, limonene, pelargonidin, caffeic acid, kaempferol, gallic acid, and quercetin which can be used in many metabolic diseases. METHOD: The objective of this systematic review was to appraise evidence from clinical and in vivo studies on the effects of cardamom on inflammation, blood glucose, oxidative stress and dyslipidemia of diabetes mellitus. According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statements, the present study was carried out. Studies were conducted by searching databases such as EMBASE, Scopus, PubMed, Google Scholar, web of sciences, and Cochrane Library from the commencement until April 2022. RESULTS: All available human and animal studies examining the effects of cardamom on diabetes were published in the form of English articles. Finally, only 14 of the 241 articles met the criteria for analysis. Of the 14 articles, 8 were in vivo studies, and 6 were clinical trial studies. Most studies have indicated the beneficial effects of cardamom on insulin resistance, oxidative stress and inflammation. Cardamom also improved dyslipidemia, but had no substantial effect on weight loss. CONCLUSION: According to most studies, cardamom supplementation enhanced antioxidant enzyme production and activity in diabetes mellitus and decreased oxidative stress and inflammatory factors. Despite this, the exact mechanism of the disease needs to be identified through more clinical trials.

Therapeutic Delivery of Soluble Fractalkine Ameliorates Vascular Dysfunction in the Diabetic Retina.

Diabetic retinopathy (DR)-associated vision loss is a devastating disease affecting the working-age population. Retinal pathology is due to leakage of serum components into retinal tissues, activation of resident phagocytes (microglia), and vascular and neuronal damage. While short-term interventions are available, they do not revert visual function or halt disease progression. The impact of microglial inflammatory responses on the neurovascular unit remains unknown. In this study, we characterized microglia-vascular interactions in an experimental model of DR. Early diabetes presents activated retinal microglia, vascular permeability, and vascular abnormalities coupled with vascular tortuosity and diminished astrocyte and endothelial cell-associated tight-junction (TJ) and gap-junction (GJ) proteins. Microglia exclusively bind to the neuronal-derived chemokine fractalkine (FKN) via the CX3CR1 receptor to ameliorate microglial activation. Using neuron-specific recombinant adeno-associated viruses (rAAVs), we therapeutically overexpressed soluble (sFKN) or membrane-bound (mFKN) FKN using intra-vitreal delivery at the onset of diabetes. This study highlights the neuroprotective role of rAAV-sFKN, reducing microglial activation, vascular tortuosity, fibrin(ogen) deposition, and astrogliosis and supporting the maintenance of the GJ connexin-43 (Cx43) and TJ zonula occludens-1 (ZO-1) molecules. The results also show that microglia-vascular interactions influence the vascular width upon administration of rAAV-sFKN and rAAV-mFKN. Administration of rAAV-sFKN improved visual function without affecting peripheral immune responses. These findings suggest that overexpression of rAAV-sFKN can mitigate vascular abnormalities by promoting glia-neural signaling. sFKN gene therapy is a promising translational approach to reverse vision loss driven by vascular dysfunction.

Emphysematous pyelonephritis with progression to necrotising fasciitis of the posterior cervical region and the retropharyngeal space.

A man in his 50s with diabetes presented with backache, left flank pain and fever. On evaluation, he was found to have emphysematous pyelonephritis of the left kidney with a paranephric abscess extending into the posterior abdominal wall and superiorly up to the posterior chest wall and inferiorly extending up to the posterior superior iliac spine. The management involved the initiation of broad-spectrum antibiotics and percutaneous drainage of the abscess. However, as he continued to worsen symptoms-wise, he underwent computed-enhanced CT of the abdomen and thorax. The imaging revealed the presence of a purulent collection in the left lumbar region with an extension along the posterior cervical region and the retropharyngeal space. He underwent a fasciotomy of the lumbar region. The occurrence of emphysematous pyelonephritis along with necrotising fasciitis is uncommon and requires early aggressive management with broad-spectrum antibiotics and adequate drainage. This emphasises the need for early reimaging if the patient does not settle with antibiotics or percutaneous drainage.

Natural products as pharmacological modulators of mitochondrial dysfunctions for the treatment of diabetes and its complications: An update since 2010.

Diabetes, characterized as a well-known chronic metabolic syndrome, with its associated complications pose a substantial and escalating health and healthcare challenge on a global scale. Current strategies addressing diabetes are mainly symptomatic and there are fewer available curative pharmaceuticals for diabetic complications. Thus, there is an urgent need to identify novel pharmacological targets and agents. The impaired mitochondria have been associated with the etiology of diabetes and its complications, and the intervention of mitochondrial dysfunction represents an attractive breakthrough point for the treatments of diabetes and its complications. Natural products (NPs), with multicenter characteristics, multi-pharmacological activities and lower toxicity, have been caught attentions as the modulators of mitochondrial functions in the therapeutical filed of diabetes and its complications. This review mainly summarizes the recent progresses on the potential of 39 NPs and 2 plant-extracted mixtures to improve mitochondrial dysfunction against diabetes and its complications. It is expected that this work may be useful to accelerate the development of innovative drugs originated from NPs and improve upcoming therapeutics in diabetes and its complications.

5-Year simulation of diabetes-related complications in people treated with tirzepatide or semaglutide versus insulin glargine.

AIM: This study compared the 5-year incidence rate of macrovascular and microvascular complications for tirzepatide, semaglutide and insulin glargine in individuals with type 2 diabetes, using the Building, Relating, Assessing, and Validating Outcomes (BRAVO) diabetes simulation model. RESEARCH DESIGN AND METHODS: This study was a 5-year SURPASS-2 trial extrapolation, with an insulin glargine arm added as an additional comparator. The 1-year treatment effects of tirzepatide (5, 10 or 15 mg), semaglutide (1 mg) and insulin glargine on glycated haemoglobin, systolic blood pressure, low-density lipoprotein and body weights were obtained from the SUSTAIN-4 and SURPASS-2 trials. We used the BRAVO model to predict 5-year complications for each study arm under two scenarios: the 1-year treatment effects persisted (optimistic) or diminished to none in 5 years (conservative). RESULTS: When compared with insulin glargine, we projected a 5-year risk reduction in cardiovascular adverse events [rate ratio (RR) 0.64, 95% confidence interval (CI) 0.61-0.67] and microvascular composite (RR 0.67, 95% CI 0.64-0.70) with 15 mg tirzepatide, and 5-year risk reduction in cardiovascular adverse events (RR 0.75, 95% CI 0.72-0.79) and microvascular composite (RR 0.79, 95% CI 0.76-0.82) with semaglutide (1 mg) under an optimistic scenario. Lower doses of tirzepatide also had similar, albeit smaller benefits. Treatment effects for tirzepatide and semaglutide were smaller but still significantly higher than insulin glargine under a conservative scenario. The 5-year risk reduction in diabetes-related complication events and mortality for the 15 mg tirzepatide compared with insulin glargine ranged from 49% to 10% under an optimistic scenario, which was reduced by 17%-33% when a conservative scenario was assumed. CONCLUSION: With the use of the BRAVO diabetes model, tirzepatide and semaglutide exhibited potential to reduce the risk of macrovascular and microvascular complications among individuals with type 2 diabetes, compared with insulin glargine in a 5-year window. Based on the current modelling assumptions, tirzepatide (15 mg) may potentially outperform semaglutide (1 mg). While the BRAVO model offered insights, the long-term cardiovascular benefit of tirzepatide should be further validated in a prospective clinical trial.

Hypoglycemia unawareness among insulin-treated diabetic patients in Madinah, Saudi Arabia: prevalence and risk factors.

Background: Hypoglycemia unawareness (HU) is associated with significant risks. Screening for impaired awareness of hypoglycemia in patients with diabetes is important to minimize those risks. There are limited data on the prevalence of HU in patients with diabetes in Saudi Arabia (KSA). In the current study, we investigated the frequency of HU and its risk factors among insulin treated diabetic patients in Madinah, KSA. Methods: A cross-sectional study was conducted in a diabetes center and four primary healthcare centers at Madinha, KSA. Patients ≥14 years old with type 1 or type 2 diabetes treated with insulin for more than a year were included. HU was assessed by Clarke's and modified Pedersen-Bjergaard's scores. The risk factors for HU were determined. Results: Of the 413 included patients, 60.3% were women, and 60.8% were on insulin alone. One-third of the participants had T1DM, while 68.5% had T2DM, with median ages of 25 and 56 years, diabetes durations of 10 and 15 years, and durations of insulin use of 10 and 5 years, respectively. The prevalence of HU was 25.2% by Clarke's survey. The risk factors for HU were poor knowledge of the patient's latest HbA1c, type of insulin, and dose of insulin. Poor medical follow-up, previous stroke, and ischemic heart disease were the other risk factors for HU. When the modified Pedersen-Bjergaard method was used, the prevalence of HU was 48.9%. Conclusion: Despite the advances in diabetes management, HU continues to be prevalent among diabetic patients on insulin, and poor diabetes knowledge is a major risk factor. Diabetes education on self-management is of utmost importance to reduce hypoglycemia and HU.

Advancements of fish-derived peptides for mucormycosis: a novel strategy to treat diabetic compilation.

Mucormycosis, an extremely fatal fungal infection, is a major hurdle in the treatment of diabetes consequences. The increasing prevalence and restricted treatment choices urge the investigation of novel therapeutic techniques. Because of their effective antimicrobial characteristics and varied modes of action, fish-derived peptides have lately emerged as viable options in the fight against mucormycosis. This review examines the potential further application of fish-derived peptides in diagnosing and managing mucormycosis in relation to diabetic complications. First, we examine the pathophysiology of mucormycosis and the difficulties in treating it in diabetics. We emphasize the critical need for alternative therapeutic methods for tackling the limitations of currently available antifungal medicines. The possibility of fish-derived peptides as an innovative approach to combat mucormycosis is then investigated. These peptides, derived from several fish species, provide wide antimicrobial properties against a variety of diseases. They also have distinct modes of action, such as rupture of cell membranes, suppression of development, and modification of the host immunological response. Furthermore, we investigate the problems and prospects connected with the clinical application of fish-derived peptides. Ultimately, future advances in fish-derived peptides, offer interesting avenues for the management of mucormycosis in the context of diabetic comorbidities. More research and clinical trials are needed to properly investigate these peptide's therapeutic potential and pave the way for their adoption into future antifungal therapies.

RIPK1 and RIPK3 inhibitors: potential weapons against inflammation to treat diabetic complications.

Diabetes mellitus is a metabolic disease that is characterized by chronic hyperglycemia due to a variety of etiological factors. Long-term metabolic stress induces harmful inflammation leading to chronic complications, mainly diabetic ophthalmopathy, diabetic cardiovascular complications and diabetic nephropathy. With diabetes complications being one of the leading causes of disability and death, the use of anti-inflammatories in combination therapy for diabetes is increasing. There has been increasing interest in targeting significant regulators of the inflammatory pathway, notably receptor-interacting serine/threonine-kinase-1 (RIPK1) and receptor-interacting serine/threonine-kinase-3 (RIPK3), as drug targets for managing inflammation in treating diabetes complications. In this review, we aim to provide an up-to-date summary of current research on the mechanism of action and drug development of RIPK1 and RIPK3, which are pivotal in chronic inflammation and immunity, in relation to diabetic complications which may be benefit for explicating the potential of selective RIPK1 and RIPK3 inhibitors as anti-inflammatory therapeutic agents for diabetic complications.

Comparing the Effect of Moringa Aqueous Extract and Selenium Nanoparticles Against Complications of Type 2 Diabetes Mellitus.

<b>Background and Objective:</b> Plant extracts were widely used to maintain postprandial levels and minimize diabetes complications. The main goal of this study was to evaluate the therapeutic effect of selenium nanoparticles and aqueous extract of the <i>Moringa</i> plant against diabetes mellitus complications and compare their therapeutic effects. <b>Materials and Methods:</b> Fifty six Wistar male rats were divided randomly into 8 groups (7 rats each): (i) Control, (ii): Received corn oil, (iii): Treated with Se-NPs, (iv): Injected orally with <i>Moringa</i> aqueous extract (MAE), (v): Treated with a single i.p., dose of streptozotocin (STZ), (vi): Single i.p., dose of STZ followed by Se-NPs, (vii): Treated with a single i.p., dose of STZ then MAE orally and (viii): Injected with STZ and then received Se-NPs. After 4 weeks the blood sera were isolated and stored at -20°C for investigation of values of insulin, GSH, MDA, SOD, GSH-PX, triglycerides, T-cholesterol, HDL-cholesterol and LDL-cholesterol. <b>Results:</b> The STZ treatment decreased insulin, HDL cholesterol and body weight values while increasing glucose, total cholesterol, LDL cholesterol and triglycerides and mild degeneration of islets of Langerhans. The single treatment of diabetic rats with either MAE or Se-NPs exhibited a decline in the levels of serum glucose, LDL-cholesterol, triglycerides, MDA and GSH, improving the HDL-cholesterol, insulin level and body weight. <b>Conclusion:</b> The co-administration of diabetic rats with MAE and Se-NPs resulted in a prominent improvement that was revealed by restoring beta-cell function, reducing blood glucose levels and stimulating insulin production rather than their single therapeutic use.

CysLTR1 antagonism by montelukast can ameliorate diabetes-induced aortic and testicular inflammation.

AIMS: Montelukast, a cysteinyl leukotriene receptor (CysLTR)1 antagonist, is emerging as an attractive strategy to curtail diabetic complications; however, its role in aortic and testicular tissues is unknown. This study investigated the effect of CysLTR1 antagonism by montelukast on toll-like receptor (TLR)4 and nuclear factor kappa B (NF-κB) pathways in diabetes-induced aortic and testicular injury. METHODS: Adult male Sprague-Dawley rats were made diabetic with Streptozotocin (STZ, 55 mg/kg). Following this, Streptozotocin-induced diabetic (SD) rats were administered montelukast (10 and 20 mg/kg, orally) for 8 weeks. Blood glucose, serum malondialdehyde (MDA), inflammatory markers, and histopathology were evaluated. RESULTS: Montelukast showed protection against diabetic complications, as evidenced by the ameliorative effect against STZ-induced alterations in oxidative stress as indicated by serum MDA levels. Moreover, montelukast conferred a significant decrease in the aortic and testicular levels of CysLTR1, TLR4, and NF-κB with a subsequent decrease in the levels of NOD-like receptor family pyrin domain containing (NLRP)3, caspase 1, interleukin (IL)-1ß, IL-6, monocyte chemoattractant protein (MCP)-1, and tumor necrosis factor (TNF)-α. Additionally, administration of montelukast resulted in autophagy stimulation, as shown by decreased p62/Sequestosome (SQSTM)1 levels. Finally, montelukast protection resulted in normal thickness of whole aortic wall, regular tunica (t.) intima, mild vacuolation of smooth muscle fibers in aorta, increased size of seminiferous tubules, and increased spermatogenesis in testis as demonstrated by histopathology. CONCLUSIONS: The protective effect of montelukast against diabetes-induced aortic and testicular injury is due to its antioxidant, anti-inflammatory, and autophagy stimulation characteristics.

Five-Year Follow-Up of Diabetic Complications and Geriatric Alterations in French Older Patients with Type 2 Diabetes According to Treatment Modalities: The Observational Prospective GERODIAB Cohort.

BACKGROUND: Little is known about clinical events occurring in older patients with type 2 diabetes mellitus according to their therapeutic modalities based on the prescription of insulin and/or oral antidiabetic drugs. OBJECTIVE: The aim of this study was to compare the complications of diabetes and geriatric alterations that occurred according to three therapeutic modalities prescribed over 5 years. METHODS: A total of 616 patients from the GERODIAB cohort (mean age 77.1 years) were divided into three groups: an insulin-only group (n = 200), a group receiving insulin and one or more oral antidiabetic drug (n = 169), and an oral antidiabetic drug group without insulin (n = 247). We compared the diabetic complications and geriatric alterations that occurred over 5 years in patients without these pre-existing complications. RESULTS: At inclusion, there was a significant difference between glycosylated hemoglobin values, and between the frequencies of most diabetic complications and geriatric alterations, with higher frequencies in the insulin group and lower frequencies in the oral antidiabetic drug group. At the end of the follow-up, there was still a significant difference between the mean glycosylated hemoglobin of the three groups (mean for all patients 7.4 ± 0.8%). The frequencies of new clinical events were high and they were generally higher in the insulin group. They were not significantly different between the three groups, with the exception of four events: heart failure, retinopathy, transfer to a nursing home (more frequent in the insulin group), and hypoglycemia (more frequent in the insulin + oral antidiabetic drug group). Some frequencies of the total diabetic complications (including complications at inclusion and at the follow-up) in the oral antidiabetic drug group were close to those in the insulin group, although only at inclusion. Mortality was higher in the insulin group and lower in the oral antidiabetic drug group. CONCLUSIONS: The increased frequency of hypoglycemia in the insulin + oral antidiabetic drug group raises doubts about the value of continuing a secretagogue drug when insulin is introduced. As the vast majority of patients were not yet receiving antidiabetic drugs with cardiovascular action, our results on heart failure could help in conducting specific studies on these drugs in older patients with type 2 diabetes.

Association of Strict Versus Lenient Cholesterol Lowering with Cardiac Outcomes, Diabetes Progression and Complications, and Mortality in Patients with Diabetes Treated with Statins: Is Less More?

INTRODUCTION: Whereas some guidelines recommend statin use to achieve low-density lipoprotein cholesterol (LDL-C) goal < 70 mg/dL for primary prevention of atherosclerotic cardiovascular disease (ASCVD) in patients at higher risk, others recommend against a target LDL-C level. Achieving a target level < 70 mg/dL commonly requires the use of high intensity statins, which has been associated with higher risk of diabetes progression. The objective of this study is to assess the association of strict (≤ 70 mg/dL) versus lenient (> 70 to100 mg/dL) LDL-C lowering on major adverse cardiovascular events (MACE), diabetes progression, diabetes microvascular complications, and total mortality in patients with diabetes. METHODS: This was a retrospective propensity score (PS)-matched study from a national cohort of, predominantly male, veterans diagnosed with diabetes without prior cardiovascular disease (from fiscal years 2003-2015), who were initiated on a statin. We created PS to match strict (mean LDL-C during follow-up ≤ 70 mg/dL) versus lenient (mean LDL-C during follow up > 70-100 mg/dL) using 65 baseline characteristics including comorbidities, risk scores, medication classes usage, vital signs, and laboratory data. Outcomes included MACE, diabetes progression, microvascular diabetes complications, and total mortality. RESULTS: From 80,110 eligible patients, we PS-matched 21,294 pairs of statin initiators with strict or lenient LDL-C lowering. The mean (SD) age was 64 (9.5) years and mean (SD) duration of follow-up was 6 (3) years. MACE was similar in the PS-matched groups [6.1% in strict versus 5.8% in lenient; odds ratio (OR): 1.06; 95% confidence interval (95% CI) 0.98-1.15, P = 0.17]. Diabetes progression was higher among the strict vs lenient group (66.7% in strict versus 64.1% in lenient; OR 1.12; 95% CI 1.08-1.17, P < 0.001). There was no difference in microvascular diabetes complications (22.3% in strict versus 21.9% in lenient; OR 1.02; 95% CI 0.98-1.07, P = 0.31) and no difference in total mortality (14.6% in strict versus 15% in lenient; OR 0.97; 95% CI 0.92-1.02, P = 0.20). CONCLUSION: Strict compared with lenient lowering of LDL-C with statins in men with diabetes without preexisting ASCVD did not decrease the risk of MACE but was associated with an increased diabetes progression. Clinicians should monitor their patients for diabetes progression upon escalating statins to achieve LDL-C levels ≤ 70 mg/dL.

Enhanced diabetic wound healing using platelet-derived extracellular vesicles and reduced graphene oxide in polymer-coordinated hydrogels.

Impaired wound healing is a significant complication of diabetes. Platelet-derived extracellular vesicles (pEVs), rich in growth factors and cytokines, show promise as a powerful biotherapy to modulate cellular proliferation, angiogenesis, immunomodulation, and inflammation. For practical home-based wound therapy, however, pEVs should be incorporated into wound bandages with careful attention to delivery strategies. In this work, a gelatin-alginate hydrogel (GelAlg) loaded with reduced graphene oxide (rGO) was fabricated, and its potential as a diabetic wound dressing was investigated. The GelAlg@rGO-pEV gel exhibited excellent mechanical stability and biocompatibility in vitro, with promising macrophage polarization and reactive oxygen species (ROS)-scavenging capability. In vitro cell migration experiments were complemented by in vivo investigations using a streptozotocin-induced diabetic rat wound model. When exposed to near-infrared light at 2 W cm- 2, the GelAlg@rGO-pEV hydrogel effectively decreased the expression of inflammatory biomarkers, regulated immune response, promoted angiogenesis, and enhanced diabetic wound healing. Interestingly, the GelAlg@rGO-pEV hydrogel also increased the expression of heat shock proteins involved in cellular protective pathways. These findings suggest that the engineered GelAlg@rGO-pEV hydrogel has the potential to serve as a wound dressing that can modulate immune responses, inflammation, angiogenesis, and follicle regeneration in diabetic wounds, potentially leading to accelerated healing of chronic wounds.

Attenuation of epithelial-mesenchymal transition via SGLT2 inhibition and diabetic cataract suppression by dapagliflozin nanoparticles treatment.

AIMS: Chronic hyperglycemia triggers overproduction of AKR1B1 (aldo-keto reductase family 1 member B) and receptor for advanced glycation end product (RAGE), which causes epithelial-mesenchymal transition (EMT) in the lens epithelial cells (LECs) of diabetic mellitus (DM) cataracts. However, it is unclear whether EMT in LECs is related to abnormal increase of SGLT2. Sodium glucose cotransporter 2 (SGLT2) inhibitor, also known as dapagliflozin (Dapa) can be used to treat diabetes. Here, we examined how Dapa or nano eye-drops (DapaN) reduce EMT in LECs of DM cataracts. The nano eye-drop provides an ophthalmic treatment that suppressed diabetic cataract progression and improved potency with reduced side effects. MAIN METHODS: SD rats were injected with streptozocin (STZ) (65 mg/kg, ip), nano-Dapa drops (0.456 mg/10 ml/eye) or Dapa (1.2 mg/kg/day) treatment for 6-12 weeks. Immunofluorescence staining was used for protein quantification of RAGE, SGLT2, N-cadherin and E-cadherin in the LECs of rats. KEY FINDINGS: In this study, Dapa applies nanotechnology-based delivery system and it contains polyvinylpyrrolidone (PVP) and HPBCD. Dapa showed therapeutic effect on DM cataracts, wherein it targeted EMT biomarker, E-cadherin. The nano-Dapa drops or oral Dapa inhibited SGLT2, suppressed AKR1B1 expression, decreased AcSOD2- and RAGE-induced EMT in diabetic cataracts. Our findings suggest that nanotechnology-based Dapa eye drops (Dapa-PVP-HPBCD) can effectively improve solubility of Dapa in aqueous solution. SIGNIFICANCE: Taken together, results suggest that the SGLT2-mediated DM cataract therapy may involve the AKR1B1-RAGE-AcSOD2-EMT pathway. The nano eye drops and Dapa show potential beneficial effects for cataract prevention. This study conveys new insights into cataract treatment and supplementation of nano-Dapa drops shows promising result in preventing diabetic cataracts.

rhFGF-21 accelerates corneal epithelial wound healing through the attenuation of oxidative stress and inflammatory mediators in diabetic mice.

Diabetic keratopathy, commonly associated with a hyperactive inflammatory response, is one of the most common eye complications of diabetes. The peptide hormone fibroblast growth factor-21 (FGF-21) has been demonstrated to have anti-inflammatory and antioxidant properties. However, whether administration of recombinant human (rh) FGF-21 can potentially regulate diabetic keratopathy is still unknown. Therefore, in this work, we investigated the role of rhFGF-21 in the modulation of corneal epithelial wound healing, the inflammation response, and oxidative stress using type 1 diabetic mice and high glucose-treated human corneal epithelial cells. Our experimental results indicated that the application of rhFGF-21 contributed to the enhancement of epithelial wound healing. This treatment also led to advancements in tear production and reduction in corneal edema. Moreover, there was a notable reduction in the levels of proinflammatory cytokines such as TNF-α, IL-6, IL-1ß, MCP-1, IFN-γ, MMP-2, and MMP-9 in both diabetic mouse corneal epithelium and human corneal epithelial cells treated with high glucose. Furthermore, we found rhFGF-21 treatment inhibited reactive oxygen species production and increased levels of anti-inflammatory molecules IL-10 and SOD-1, which suggests that FGF-21 has a protective role in diabetic corneal epithelial healing by increasing the antioxidant capacity and reducing the release of inflammatory mediators and matrix metalloproteinases. Therefore, we propose that administration of FGF-21 may represent a potential treatment for diabetic keratopathy.

Molecular implications of glycosaminoglycans in diabetes pharmacotherapy.

Diabetes mellitus causes a wide range of metabolic derangements with multiple organ damage. The microvascular and macrovascular complications of diabetes result partly from the damage to the glycosaminoglycans (GAG) in the basement membrane. GAGs are negatively charged polysaccharides with repeating disaccharide units. They play a significant role in cellular proliferation and signal transduction. Destruction of extracellular matrix results in diseases in various organs including myocardial fibrosis, retinal damage and nephropathy. To substitute the natural GAGs pharmacotherapeutically, they have been synthesized by using basic disaccharide units. Among the four classes of GAGs, heparin is the most widely studied. Recent studies have revealed multiple significant GAG-protein interactions suggesting their use for the management of diabetic complications. Moreover, they can act as biomarkers for assessing the disease progression. A number of GAG-based therapeutic agents are being evaluated for managing diabetic complications. The current review provides an outline of the role of GAGs in diabetes while covering their interaction with different molecular players that can serve as targets for the diagnosis, management and prevention of diabetes and its complications. The medicinal chemistry and clinical pharmacotherapeutics aspects have are covered to aid in the establishment of GAG-based therapies as a possible avenue for diabetes.

[Research advances in role of angiogenesis in diabetic ulcer and traditional Chinese medicine intervention].

Diabetic ulcer(DU) is one of the common complications of diabetes often occurring in the peripheral blood vessels of lower limbs or feet with a certain degree of damage. It has high morbidity and mortality, a long treatment cycle, and high cost. DU is often clinically manifested as skin ulcers or infections in the lower limbs or feet. In severe cases, it can ulcerate to the surface of tendons, bones or joint capsules, and even bone marrow. Without timely and correct treatment, most of the patients will have ulceration and blackening of the extremities. These patients will not be able to preserve the affected limbs through conservative treatment, and amputation must be performed. The etiology and pathogenesis of DU patients with the above condition are complex, which involves blood circulation interruption of DU wound, poor nutrition supply, and failure in discharge of metabolic waste. Relevant studies have also confirmed that promoting DU wound angiogenesis and restoring blood supply can effectively delay the occurrence and development of wound ulcers and provide nutritional support for wound healing, which is of great significance in the treatment of DU. There are many factors related to angiogenesis, including pro-angiogenic factors and anti-angiogenic factors. The dynamic balance between them plays a key role in angiogenesis. Meanwhile, previous studies have also confirmed that traditional Chinese medicine can enhance pro-angiogenic factors and down-regulate anti-angiogenic factors to promote angiogenesis. In addition, many experts and scholars have proposed that traditional Chinese medicine regulation of DU wound angiogenesis in the treatment of DU has broad prospects. Therefore, by consulting a large number of studies available, this paper expounded on the role of angiogenesis in DU wound and summarized the research advance in traditional Chinese medicine intervention in promoting the expression of angiogenic factors [vascular endothelial growth factor(VEGF), fibroblast growth factor(FGF), and angiopoietin(Ang)] which played a major role in promoting wound angiogenesis in the treatment of DU to provide ideas for further research and new methods for clinical treatment of DU.

Impact of Nutrition or FDA-Approved Medicine Repurposing on Metabolic Syndrome and Diabetic Complications.

Both obesity and diabetes are global health threats due to their high risk of developing different complications [...].