Exploring the pharmacological mechanism of Xianlingubao against diabetic osteoporosis based on network pharmacology and molecular docking: An observational study.

Xianlinggubao formula (XLGB), is a traditional Chinese compound Medicine that has been extensively used in osteoarthritis and aseptic osteonecrosis, but its curative effect on diabetic osteoporosis (DOP) and its pharmacological mechanisms remains not clear. The aim of the present study was to investigate the possible mechanism of drug repurposing of XLGB in DOP therapy. We acquired XLGB active compounds from the traditional Chinese medicine systems pharmacology and traditional Chinese medicines integrated databases and discovered potential targets for these compounds by conducting target fishing using the traditional Chinese medicine systems pharmacology and Swiss Target Prediction databases. Gene Cards and Online Mendelian Inheritance in Man® database were used to identify the DOP targets. Overlapping related targets between XLGB and DOP was selected to build a protein-protein interaction network. Next, the Metascape database was utilized to enrich the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways. In addition, Auto-Dock Vina software was used to verify drug and target binding. In total, 48 hub targets were obtained as the candidate targets responsible for DOP therapy. The anti-DOP effect mediated by XLGB was primarily centralized on the advanced glycation end products (AGEs)-receptor for AGE signaling pathway in diabetic complications and osteoclast differentiation. In addition, AKT serine/threonine kinase 1, tumor necrosis factor, Interleukin-6, vascular endothelial growth factor A and peroxisome proliferator activated receptor gamma, which were considered as potential therapeutic targets. Furthermore, molecular docking results confirm the credibility of the predicted therapeutic targets. This study elucidates that XLGB may through regulating AGEs formation and osteoclast differentiation as well as angiogenesis and adipogenesis against DOP. And this study provides new promising points to find the exact regulatory mechanisms of XLGB mediated anti-DOP effect.

Mechanisms of Flavonoids and Their Derivatives in Endothelial Dysfunction Induced by Oxidative Stress in Diabetes.

Diabetic complications pose a significant threat to life and have a negative impact on quality of life in individuals with diabetes. Among the various factors contributing to the development of these complications, endothelial dysfunction plays a key role. The main mechanism underlying endothelial dysfunction in diabetes is oxidative stress, which adversely affects the production and availability of nitric oxide (NO). Flavonoids, a group of phenolic compounds found in vegetables, fruits, and fungi, exhibit strong antioxidant and anti-inflammatory properties. Several studies have provided evidence to suggest that flavonoids have a protective effect on diabetic complications. This review focuses on the imbalance between reactive oxygen species and the antioxidant system, as well as the changes in endothelial factors in diabetes. Furthermore, we summarize the protective mechanisms of flavonoids and their derivatives on endothelial dysfunction in diabetes by alleviating oxidative stress and modulating other signaling pathways. Although several studies underline the positive influence of flavonoids and their derivatives on endothelial dysfunction induced by oxidative stress in diabetes, numerous aspects still require clarification, such as optimal consumption levels, bioavailability, and side effects. Consequently, further investigations are necessary to enhance our understanding of the therapeutic potential of flavonoids and their derivatives in the treatment of diabetic complications.

Multifunctional Nanosystem for Dual Anti-Inflammatory and Antibacterial Photodynamic Therapy in Infectious Diabetic Wounds.

Infectious diabetic wounds present a substantial challenge, characterized by inflammation, infection, and delayed wound healing, leading to elevated morbidity and mortality rates. In this work, we developed a multifunctional lipid nanoemulsion containing quercetin, chlorine e6, and rosemary oil (QCRLNEs) for dual anti-inflammatory and antibacterial photodynamic therapy (APDT) for treating infectious diabetic wounds. The QCRLNEs exhibited spherical morphology with a size of 51 nm with enhanced encapsulation efficiency, skin permeation, and localized delivery at the infected wound site. QCRLNEs with NIR irradiation have shown excellent wound closure and antimicrobial properties in vitro, mitigating the nonselective cytotoxic behavior of PDT. Also, excellent biocompatibility and anti-inflammatory and wound healing responses were observed in zebrafish models. The infected wound healing properties in S. aureus-infected diabetic rat models indicated re-epithelization and collagen deposition with no signs of inflammation. This multifaceted approach using QCRLNEs with NIR irradiation holds great promise for effectively combating oxidative stress and bacterial infections commonly associated with infected diabetic wounds, facilitating enhanced wound healing and improved clinical outcomes.

A Review of Experimental Studies on Natural Chalcone-Based Therapeutic Targeting of Genes and Signaling Pathways in Type 2 Diabetes Complications.

Diabetes mellitus type 2 (T2DM) is a common chronic condition that presents as unsettled hyperglycemia (HG) and results from insulin resistance (IR) and ß-cell dysfunction. T2DM is marked by an increased risk of microvascular and macrovascular complications, all of which can be the cause of increasing mortality. Diabetic nephropathy (DNE), neuropathy (DNU), and retinopathy (DR) are the most common complications of diabetic microangiopathy, while diabetic cardiomyopathy (DCM) and peripheral vascular diseases are the major diabetic macroangiopathy complications. Chalcones (CHs) are in the flavonoid family and are commonly found in certain plant species as intermediate metabolites in the biosynthesis of flavonoids and their derivatives. Natural CHs with different substituents exert diverse therapeutic activities, including antidiabetic ones. However, the therapeutic mechanisms of natural CHs through influencing genes and/or signaling pathways in T2DM complications remain unknown. Therefore, this review summarizes the existing results from experimental models which highlight the mechanisms of natural CHs as therapeutic agents for T2DM complications.

Effects of ondansetron on symptoms during a gastric emptying study and enteral lipid challenge and on daily symptoms in diabetic gastroenteropathy.

BACKGROUND: This study compared the effects of ondansetron and placebo in patients with diabetes mellitus and symptoms of dyspepsia (diabetic gastroenteropathy [DGE]). METHODS: We performed a randomized, double-blinded, placebo-controlled study of ondansetron tablets (8 mg) three times daily for 4 weeks in DGE patients. Symptoms were assessed with the Gastroparesis Cardinal Symptom Index daily diaries. Gastric emptying (GE) of solids (scintigraphy) and duodenal lipid infusions (300 kcal over 2 h) were each assessed twice, with placebo and ondansetron. Drug effects on GE, symptoms during the GE study and during lipid infusion, and daily symptoms were analyzed. KEY RESULTS: Of 41 patients, 37 completed both GE studies and one completed 1; 31 completed both lipid infusions and four only placebo; and all 35 randomized patients completed 4 weeks of treatment. Compared to placebo, ondansetron reduced the severity of fullness (p = 0.02) and belching (p = 0.049) during lipid infusion but did not affect GE T1/2. Both ondansetron and placebo improved daily symptoms versus the baseline period (p < 0.05), but the differences were not significant. In the analysis of covariance of daily symptoms during the treatment period, the interaction term between treatment and the acute effect of ondansetron on symptoms during lipid challenge was significant (p = .024). CONCLUSIONS & INFERENCES: Ondansetron significantly reduced fullness during enteral lipid infusion in patients with DGE. Overall, ondansetron did not improve daily symptoms versus placebo. But patients in whom ondansetron improved symptoms during enteral lipid challenge were perhaps more likely to experience symptom relief during daily treatment.

Improving the bioavailability and therapeutic efficacy of felodipine for the control of diabetes-associated atherosclerosis: In vitro and in vivo characterization.

Felodipine has proven to be effective as an atherosclerosis therapy because it increases blood flow to the vessel wall. However, the poor solubility, low bioavailability, and hepatic first-pass metabolism of oral felodipine compromise its therapeutic effectiveness. The study's goal is to create a nasal pH-sensitive hydrogel of felodipine-loaded invasomes (IPHFI) that will improve felodipine's release, permeation, bioavailability, and efficacy as a potential diabetes-associated atherosclerosis therapy. According to the pre-formulation study, the felodipine-loaded invasomes formulation composed of phospholipid (3%w/v), cholesterol (0.16%w/v), ethanol (3%v/v) and cineole (1%v/v) was chosen as the optimum formulation. The optimum formulation was characterized in vitro and then mixed with a mixture of chitosan and glyceryl monooleate to make the IPHFI formulation. The IPHFI formulation enhanced the release and permeation of felodipine by 2.99 and 3-fold, respectively. To assess the efficacy and bioavailability of the IPHFI formulation, it was studied in vivo using an experimental atherosclerosis rat model. Compared to oral free felodipine, the nasal administration of the IPHFI formulation increased the bioavailability by 3.37-fold and decreased the serum cholesterol, triglycerides, LDL, and calcification score by 1.56, 1.53, 1.80, and 1.18 ratios, respectively. Thus, nasal IPHFI formulation may represent a promising diabetes-associated atherosclerosis therapy.

Histone deacetylases and inhibitors in diabetes mellitus and its complications.

Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia, with its prevalence linked to both genetic predisposition and environmental factors. Epigenetic modifications, particularly through histone deacetylases (HDACs), have been recognized for their significant influence on DM pathogenesis. This review focuses on the classification of HDACs, their role in DM and its complications, and the potential therapeutic applications of HDAC inhibitors. HDACs, which modulate gene expression without altering DNA sequences, are categorized into four classes with distinct functions and tissue specificity. HDAC inhibitors (HDACi) have shown efficacy in various diseases, including DM, by targeting these enzymes. The review highlights how HDACs regulate ß-cell function, insulin sensitivity, and hepatic gluconeogenesis in DM, as well as their impact on diabetic cardiomyopathy, nephropathy, and retinopathy. Finally, we suggest that targeted histone modification is expected to become a key method for the treatment of diabetes and its complications. The study of HDACi offers insights into new treatment strategies for DM and its associated complications.

Qiju Dihuang Pill protects the lens epithelial cells via alleviating cuproptosis in diabetic cataract.

ETHNOPHARMACOLOGICAL RELEVANCE: Qiju Dihuang Pill (QDP) is a traditional Chinese medicine prescription for the treatment of eye diseases. Novel literature reports that copper-induced cell death, called as cuproptosis, is a copper-dependent and differs distinctly from other types of cell death. AIM OF THE STUDY: The present study aims to investigate whether QDP could protect lens epithelial cells via alleviating copper-induced death in diabetic cataract. MATERIALS AND METHODS: The different concentration of QDP medicated serum was administrated on high glucose (HG)-induced human lens epithelial cells (HLECs). The copper concentration was tested using Elabscience Copper Assay kit. The proliferation was detected using CCK-8 and EdU assays. The molecular binding was identified using RIP-PCR and luciferase reporter assay. RESULTS: Results indicated that HG culture condition triggered the copper concentration and repressed the proliferation of HLECs. Then, the elesclomol-Cu (Es-Cu) administration up-regulated the copper concentration and inhibited the proliferation, and cuproptosis inhibitor tetrathiomolybdate (TTM) could specifically reverse the consequence. QDP treatment reduced the copper concentration and cuproptosis-related genes (SLC31A1, FDX1). MeRIP-Seq and RIP-PCR confirmed that QDP reduced the stability of SLC31A1 mRNA through m6A modified site, and copper actually synergized the molecular binding efficiency. Rescue assay verified the role of QDP and SLC31A1 on HLECs' cuproptosis characteristic. CONCLUSION: This research identified the protective role of QDP on HG-induced HLECs in DC through decreasing m6A/SLC31A1-mediated cuproptosis in DC. This finding provides novel insights into mechanisms for QDP and sheds light on the multifaceted role of traditional prescription on DC.

Copper metabolism and its role in diabetic complications: A review.

Disturbances in copper (Cu) homeostasis have been observed in diabetes and associated complications. Cu is an essential micronutrient that plays important roles in various fundamental biological processes. For example, diabetic cardiomyopathy is associated with elevated levels of Cu in the serum and tissues. Therefore, targeting Cu may be a novel treatment strategy for diabetic complications. This review provides an overview of physiological Cu metabolism and homeostasis, followed by a discussion of Cu metabolism disorders observed during the occurrence and progression of diabetic complications. Finally, we discuss the recent therapeutic advances in the use of Cu coordination complexes as treatments for diabetic complications and their potential mechanisms of action. This review contributes to a complete understanding of the role of Cu in diabetic complications and demonstrates the broad application prospects of Cu-coordinated compounds as potential therapeutic agents.

Targeting starvation therapy for diabetic bacterial infections with endogenous enzyme-triggered hyaluronan-modified nanozymes in the infection microenvironment.

The high-glycemic microenvironment of diabetic wounds promotes bacterial proliferation, leading to persistent infections and delayed wound healing. This poses a significant threat to human health, necessitating the development of new nanodrug visualization platforms. In this study, we designed and synthesized cascade nano-systems modified with targeted peptide and hyaluronic acid for diabetic infection therapy. The nano-systems were able to target the site of infection using LL-37, and in the microenvironment of wound infection, the hyaluronic acid shell of the nano-systems was degraded by endogenous hyaluronidase. This precise degradation released a cascade of nano-enzymes on the surface of the bacteria, effectively destroying their cytoskeleton. Additionally, the metals in the nano-enzymes provided a photo-thermal effect, accelerating wound healing. The cascade nano-visualization platform demonstrated excellent bactericidal efficacy in both in vitro antimicrobial assays and in vivo diabetic infection models. In conclusion, this nano-system employs multiple approaches including targeting, enzyme-catalyzed therapy, photothermal therapy, and chemodynamic therapy to kill bacteria and promote healing. The Ag@Pt-Au-LYZ/HA-LL-37 formulation shows great potential for the treatment of diabetic wounds.

The Role of Selenium Nanoparticles in Addressing Diabetic Complications: A Comprehensive Study.

Diabetes, as an emerging epidemic, has put forward a significant spotlight on the evolving population worldwide grounded upon the remarkable affliction of healthcare along with economical conflict. Various studies suggested that, in modern society, lack of maintenance of a healthy life style leads to the occurrence of diabetes as insulin resistant, later having a damaging effect on the pancreatic ß-cells, suggesting various complications. Furthermore, diabetes management is controversial owing to different opinions based on the prevention of complications. For this purpose, nanostructured materials (NSM) like selenium nanoparticles (SeNPs) have proved their efficiency in the therapeutic management of such serious diseases. This review offers an in- -depth idea regarding the pathophysiology, diagnosis and various conventional therapeutics of type 1 and type 2 diabetes, shedding light on Diabetic Nephropathy (DN), a case study of type 1 diabetes. Moreover, this review provides an exhaustive study by highlighting the economic and healthcare burdens associated with diabetes along with the controversies associated with conventional therapeutic management and the promising role of NSM like selenium nanoparticles (SeNPs), as a novel weapon for encountering such fatal diseases.

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.

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.

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.

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.

Relieving Macrophage Dysfunction by Inhibiting SREBP2 Activity: A Hypoxic Mesenchymal Stem Cells-Derived Exosomes Loaded Multifunctional Hydrogel for Accelerated Diabetic Wound Healing.

Macrophage dysfunction is one of the primary factors leading to the delayed healing of diabetic wounds. Hypoxic bone marrow mesenchymal stem cells-derived exosomes (hyBMSC-Exos) have been shown to play an active role in regulating cellular function through the carried microRNAs. However, the administration of hyBMSC-Exos alone in diabetic wounds usually brings little effect, because the exosomes are inherently unstable and have a short retention time at the wounds. In this study, a multifunctional hydrogel based on gallic acid (GA) conjugated chitosan (Chi-GA) and partially oxidized hyaluronic acid (OHA) is prepared for sustained release of hyBMSC-Exos. The hydrogel not only exhibits needs-satisfying physicochemical properties, but also displays outstanding biological performances such as low hemolysis rate, strong antibacterial capacity, great antioxidant ability, and excellent biocompatibility. It has the ability to boost the stability of hyBMSC-Exos, leading to a continuous and gradual release of the exosomes at wound locations, ultimately enhancing the exosomes' uptake efficiency by target cells. Most importantly, hyBMSC-Exos loaded hydrogel shows an excellent ability to promote diabetic wound healing by regulating macrophage polarization toward M2 phenotype. This may be because exosomal miR-4645-5p and antioxidant property of the hydrogel synergistically inhibit SREBP2 activity in macrophages. This study presents a productive approach for managing diabetic wounds.

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.

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.