Nano-Oxy: Diabetic ulcer treatment using oxygen nanoparticles concept as innovation in reducing amputation rates and antibiotics usage

Diabetes mellitus is a metabolic disease characterized by chronic hyperglycemia caused by defects in insulin secretion, insulin reactions, or both. More than one third of diabetic patients have complications in the form of diabetic ulcers, and half are infected, and 15% of these infections require limb amputation. High cost expenditure and risks of microbial resistance to antibiotics also adds the complexity of the problem. The purpose of this literature review is to offer Nano-Oxy, using oxygen in nanoparticle size, as an alternative diabetic ulcer treatment. Literature searching was conducted through online search method. Oxygen therapy has been widely used to treat diabetic ulcers, including hyperbaric oxygen therapy (HOT) and topical oxygen therapy (TOT). Both of them have good results on diabetic ulcer therapy. Oxygen can act as an antimicrobial agent through the activation mechanism of neutrophils and macrophages which play a role in phagocytosis process and ROS regeneration. Nano-Oxy has advantages than the previous therapy, such as it does not cause barotrauma, oxygen poisoning, and low risk of burning. The mechanism of how Nano-Oxy works is similar with the Micro-nanobubbles (MNBs) concept. The negatively charged surface of MNBs can prevent them from aggregating, attracts particles, and help remove debris. MNBs also generate free radicals while shrinking in water, which contribute to its antibacterial effect. In addition, Nano-oxygen technology can be applied externally, but still have effect on the intended target cells. Therefore, Nano-oxygen can be used as a diabetic ulcer therapy to replace the role of antibiotics.

Anti-α-Glucosidase and Antiglycation Activities of α-Mangostin and New Xanthenone Derivatives: Enzymatic Kinetics and Mechanistic Insights through In Vitro Studies

Diabetes mellitus is characterized by chronic hyperglycemia that promotes ROS formation, causing severe oxidative stress. Furthermore, prolonged hyperglycemia leads to glycation reactions with formation of AGEs that contribute to a chronic inflammatory state. This research aims to evaluate the inhibitory activity of α-mangostin and four synthetic xanthenone derivatives against glycation and oxidative processes and on α-glucosidase, an intestinal hydrolase that catalyzes the cleavage of oligosaccharides into glucose molecules, promoting the postprandial glycemic peak. Antiglycation activity was evaluated using the BSA assay, while antioxidant capacity was detected with the ORAC assay. The inhibition of α-glucosidase activity was studied with multispectroscopic methods along with inhibitory kinetic analysis. α-Mangostin and synthetic compounds at 25 µM reduced the production of AGEs, whereas the α-glucosidase activity was inhibited only by the natural compound. α-Mangostin decreased enzymatic activity in a concentration-dependent manner in the micromolar range by a reversible mixed-type antagonism. Circular dichroism revealed a rearrangement of the secondary structure of α-glucosidase with an increase in the contents of α-helix and random coils and a decrease in β-sheet and β-turn components. The data highlighted the anti-α-glucosidase activity of α-mangostin together with its protective effects on protein glycation and oxidation damage.

Glucose Regulates m6A Methylation of RNA in Pancreatic Islets

Type 2 diabetes is characterized by chronic hyperglycemia associated with impaired insulin action and secretion. Although the heritability of type 2 diabetes is high, the environment, including blood components, could play a major role in the development of the disease. Amongst environmental effects, epitranscriptomic modifications have been recently shown to affect gene expression and glucose homeostasis. The epitranscriptome is characterized by reversible chemical changes in RNA, with one of the most prevalent being the m6A methylation of RNA. Since pancreatic β cells fine tune glucose levels and play a major role in type 2 diabetes physiopathology, we hypothesized that the environment, through variations in blood glucose or blood free fatty acid concentrations, could induce changes in m6A methylation of RNAs in pancreatic β cells. Here we observe a significant decrease in m6A methylation upon high glucose concentration, both in mice and human islets, associated with altered expression levels of m6A demethylases. In addition, the use of siRNA and/or specific inhibitors against selected m6A enzymes demonstrate that these enzymes modulate the expression of genes involved in pancreatic β-cell identity and glucose-stimulated insulin secretion. Our data suggest that environmental variations, such as glucose, control m6A methylation in pancreatic β cells, playing a key role in the control of gene expression and pancreatic β-cell functions. Our results highlight novel causes and new mechanisms potentially involved in type 2 diabetes physiopathology and may contribute to a better understanding of the etiology of this disease.

Current Management of Diabetic Macular Edema

Diabetic macular edema is a complication of diabetes mellitus (DM) which contributes significantly to the burden of visual impairment amongst persons living with diabetes. Chronic hyperglycemia triggers a cascade of pathologic changes resulting in breakdown of the retinal blood barrier. Understanding the pathophysiological and biochemical changes occurring in diabetes has led to developing novel therapeutics and effective management strategies for treating DME. The clinical utility of optical coherence tomography (OCT) imaging of the retina provides a detailed assessment of the retina microstructure, valid for individualization of patient treatment and monitoring response to treatment. Similarly, OCT angiography (dye-less angiography), another innovation in imaging of DME, provides an understanding of retinal vasculature in DME. From the earlier years of using retinal laser photocoagulation as the gold standard for treating DME, to the current use of intravitreal injection of drugs, several clinical trials provided evidence on safety and efficacy for the shift to intravitreal steroids and anti-vascular endothelial growth factor use. The short durability of available drugs leading to frequent intravitreal injections and frequent clinic visits for monitoring constitute an enormous burden. Therefore, extended durability drugs are being designed, and remote monitoring of DME may be a solution to the current challenges.

Assessment of Glycemic Control, Renal Function, and Oxidative Stress Parameters in Type 2 Diabetes MellitusPatients

Diabetes mellitus (T2DM) is a multifactorial syndrome that israpidly rising in all the continents ofthe globe, causing elevated blood sugar levels in affected people. A sample of 81 Iraqi T2DM patients was investigated based on several parameters. Glycemic control parameters includedlevels of fasting blood glucose (FBG),glycated hemoglobin (HbA1C), and insulin, along with insulin resistance (IR) and insulin sensitivity (IS). Renal function tests includedmeasuring the blood levels of urea and creatinine. Oxidative stress parameters included total antioxidant capacity (TAC) and thelevel of reactive oxygen species (ROS). The results of the presentstudy showed a highly significant (P˂0.01) increase in FBG, HbA1c, insulin and IR levels in T2DM patients as compared to control.Insulin sensitivity showed a highly significant (p˂0.01) decrease in patients compared with control.Urea and creatinine levelsincreased in T2DM patients, but the differences were insignificant. TAC levelsignificantly (P<0.05) increased in patients compared with control. Also, the levels of ROSrevealed a highly significant (P<0.01) increasein T2DM patients compared with the control. Correlation analysis showedthat FBG has a highly significant (P<0.01) positive correlation with IR, urea, creatinine and ROS, as well as a significant (P<0.05) positive correlation with TAC. However, FBG shows a highlysignificant (P< 0.01) inverse correlation with IS. The levels of HbA1C show a significant (P<0.05) positive correlation with IR, creatinine, and TAC, whereas ithas a highly significant (P<0.01) positive relation with ROS. However, HbA1C level has a highly significant (P<0.01) inverse relation with IS. Insulin has highly significant (P<0.01) positive and negative associations with IR and IS, respectively.IR showshighlya significant (P<0.01) inverse correlation with IS, significant (P<0.05) positive correlation with creatinine, and highly significant (P<0.01) positive correlation with ROS. IS has a significant(P< 0.05) inverse correlation with urea. Urea shows a highly significant (P<0.01) positive correlation with creatinine. TAC has a significant (P<0.05) inverse correlation with ROS. Conclusion: diabetic patients revealed poor glycemic control. Fluctuating blood glucose concentrations may contribute significantly to oxidative stress, probablyeven more than chronic hyperglycemia. The observed significant positive correlation between FBG and the other tested parameters revealed that hyperglycemia is an obvious independent risk factor for T2DM progression.

The Impact of Incretin-Based Medications on Lipid Metabolism

Pathophysiological pathways that are induced by chronic hyperglycemia negatively impact lipid metabolism. Thus, diabetes is commonly accompanied by varying degrees of dyslipidemia which is itself a major risk factor for further macro- and microvascular diabetes complications such as atherosclerosis and nephropathy. Therefore, normalizing lipid metabolism is an attractive goal for therapy in patients with diabetes. Incretin-based medications are a novel group of antidiabetic agents with potent hypoglycemic effects. While the impact of incretins on glucose metabolism is clear, recent evidence indicates their positive modulatory roles on various aspects of lipid metabolism. Therefore, incretins may offer additional beneficial effects beyond that of glucose normalization. In the current review, how these antidiabetic medications can regulate lipid homeostasis and the possible cellular pathways involved are discussed, incorporating related clinical evidence about incretin effects on lipid homeostasis.

Mice with Type 2 Diabetes Present Significant Alterations in Their Tissue Biomechanical Properties and Histological Features

Type 2 diabetes mellitus (T2DM) is a complex metabolic disease often associated with severe complications that may result in patient morbidity or death. One T2DM etiological agent is chronic hyperglycemia, a condition that induces damaging biological processes, including impactful extracellular matrix (ECM) modifications, such as matrix components accumulation. The latter alters ECM stiffness, triggering fibrosis, inflammation, and pathological angiogenesis. Hence, studying ECM biochemistry and biomechanics in the context of T2DM, or obesity, is highly relevant. With this in mind, we examined both native and decellularized tissues of obese B6.Cg-Lepob/J (ob/ob) and diabetic BKS.Cg-Dock7m+/+LeprdbJ (db/db) mice models, and extensively investigated their histological and biomechanical properties. The tissues analyzed herein were those strongly affected by diabetes—skin, kidney, adipose tissue, liver, and heart. The referred organs and tissues were collected from 8-week-old animals and submitted to classical histological staining, immunofluorescence, scanning electron microscopy, rheology, and atomic force microscopy. Altogether, this systematic characterization has identified significant differences in the architecture of both ob/ob and db/db tissues, namely db/db skin presents loose epidermis and altered dermis structure, the kidneys have clear glomerulopathy traits, and the liver exhibits severe steatosis. The distribution of ECM proteins also pinpoints important differences, such as laminin accumulation in db/db kidneys and decreased hyaluronic acid in hepatocyte cytoplasm in both obese and diabetic mice. In addition, we gathered a significant set of data showing that ECM features are maintained after decellularization, making these matrices excellent biomimetic scaffolds for 3D in vitro approaches. Importantly, mechanical studies revealed striking differences between tissue ECM stiffness of control (C57BL/6J), obese, and diabetic mice. Notably, we have unveiled that the intraperitoneal adipose tissue of diabetic animals is significantly stiffer (G* ≈ 10,000 Pa) than that of ob/ob or C57BL/6J mice (G* ≈ 3000–5000 Pa). Importantly, this study demonstrates that diabetes and obesity selectively potentiate severe histological and biomechanical alterations in different matrices that may impact vital processes, such as angiogenesis, wound healing, and inflammation.

Role of Circulating Microparticles in Type 2 Diabetes Mellitus: Implications for Pathological Clotting

Type 2 diabetes mellitus (T2DM) is a multifactorial chronic metabolic disease characterized by chronic hyperglycemia due to insulin resistance and a deficiency in insulin secretion. The global diabetes pandemic relates primarily to T2DM, which is the most prevalent form of diabetes, accounting for over 90% of all cases. Chronic low-grade inflammation, triggered by numerous risk factors, and the chronic activation of the immune system are prominent features of T2DM. Here we highlight the role of blood cells (platelets, and red and white blood cells) and vascular endothelial cells as drivers of systemic inflammation in T2DM. In addition, we discuss the role of microparticles (MPs) in systemic inflammation and hypercoagulation. Although once seen as inert by-products of cell activation or destruction, MPs are now considered to be a disseminated storage pool of bioactive effectors of thrombosis, inflammation, and vascular function. They have been identified to circulate at elevated levels in the bloodstream of individuals with increased risk of atherothrombosis or cardiovascular disease, two significant hallmark conditions of T2DM. There is also general evidence that MPs activate blood cells, express proinflammatory and coagulant effects, interact directly with cell receptors, and transfer biological material. MPs are considered major players in the pathogenesis of many systemic inflammatory diseases and may be potentially useful biomarkers of disease activity and may not only be of prognostic value but may act as novel therapeutic targets.

Old and New Biomarkers Associated with Endothelial Dysfunction in Chronic Hyperglycemia

Chronic hyperglycemia and vascular damage are strictly related. Biomarkers of vascular damage have been intensively studied in the recent years in the quest of reliable cardiovascular risk assessment tools able to facilitate risk stratification and early detection of vascular impairment. The present study is a narrative review with the aim of revising the available evidence on current and novel markers of hyperglycemia-induced vascular damage. After a discussion of classic tools used to investigate endothelial dysfunction, we provide an in-depth description of novel circulating biomarkers (chemokines, extracellular vesicles, and epigenetic and metabolomic biomarkers). Appropriate use of a single as well as a cluster of the discussed biomarkers might enable in a near future (a) the prompt identification of targeted and customized treatment strategies and (b) the follow-up of cardiovascular treatment efficacy over time in clinical research and/or in clinical practice.

Decorin Concentrations in Aqueous Humor of Patients with Diabetic Retinopathy

Diabetic retinopathy (DR) is a microvascular complication of diabetes in the retina. Chronic hyperglycemia damages retinal microvasculature embedded into the extracellular matrix (ECM), causing fluid leakage and ischemic retinal neovascularization. Current treatment strategies include intravitreal anti-vascular endothelial growth factor (VEGF) or steroidal injections, laser photocoagulation, or vitrectomy in severe cases. However, treatment may require multiple modalities or repeat treatments due to variable response. Though DR management has achieved great success, improved, long-lasting, and predictable treatments are needed, including new biomarkers and therapeutic approaches. Small-leucine rich proteoglycans, such as decorin, constitute an integral component of retinal endothelial ECM. Therefore, any damage to microvasculature can trigger its antifibrotic and antiangiogenic response against retinal vascular pathologies, including DR. We conducted a cross-sectional study to examine the association between aqueous humor (AH) decorin levels, if any, and severity of DR. A total of 82 subjects (26 control, 56 DR) were recruited. AH was collected and decorin concentrations were measured using an enzyme-linked immunosorbent assay (ELISA). Decorin was significantly increased in the AH of DR subjects compared to controls (p = 0.0034). AH decorin levels were increased in severe DR groups in ETDRS and Gloucestershire classifications. Decorin concentrations also displayed a significant association with visual acuity (LogMAR) measurements. In conclusion, aqueous humor decorin concentrations were found elevated in DR subjects, possibly due to a compensatory response to the retinal microvascular changes during hyperglycemia.