Anti-inflammatory effects of sodium-glucose cotransporter-2 inhibitors in COVID-19.

The ongoing pandemic of COVID-19 is intrinsically a systemic inflammatory disorder; hence, those patients suffering an underlying chronic inflammatory disease such as diabetes mellitus are at high risk of severe complications. Preventing or suppressing the inflammatory responses are of importance in diabetic patients. Sodium-glucose cotransporters-2 inhibitors (SGLT2i) are a newly introduced anti-diabetic drugs that have hypoglycemic effects through the urinary excretion of glucose. They also have an anti-inflammatory potential in diabetes patients, in addition to improving glycemic control, and while there is no direct data available in diabetic patients with COVID-19 disease, there is evidence that suggests that SGLT2i can reduce systemic inflammation and diminish the cytokine storm effect via several cellular mechanisms. In the current review, our aim was to classify and describe the molecular and cellular pathways by which SGLT2i have anti-inflammatory effects in diabetic patients with COVID-19 disease.

SGLT2 inhibitors and autophagy in diabetes.

Autophagy is a physiological event in mammalian cells to promote cell survival and efficiency in tissues, but it may turn to be a pathological process in disease conditions such as in diabetes. Chronic hyperglycemia induces aberrant autophagy and promotes cellular death as a main underlying cause of diabetes-related complications. Therefore, autophagy-modifying therapy may be of value to prevent the development of complications. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are a class of newly introduced antidiabetic drugs that achieve normoglycemia through causing overt glycosuria. There is evidence that these drugs may have pleiotropic extra-glycemic benefits, but their effect on the autophagy process is unclear; therefore, this review was undertaken to clarify the possible effects of SGLT2is on autophagy.

Sodium-glucose co-transporter 2 inhibitors and hematopoiesis.

Many patients with diabetes mellitus, especially those with chronic kidney disorders, have some degree of anemia due to a spectrum of causes and underlying pathophysiologic pathways. As such, enhancement in erythropoiesis is important in these patients. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a relatively new class of antidiabetic drugs with confirmed protective effects in kidney and cardiovascular tissues. Recent evidence suggests that these drugs may provide additional benefits in enhancing hematopoietic processes in diabetic patients. Though the exact mediating pathways have not been fully elucidated, cellular mechanisms are likely involved. In the current study, we present the potential pathways by which SGLT2i may modulate hematopoiesis and stimulate erythropoiesis.

New insights into cellular links between sodium-glucose cotransporter-2 inhibitors and ketogenesis.

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a newly developed class of highly effective antidiabetic therapies that normalize hyperglycemia via urinary glucose excretion. However, they may be accompanied by certain side effects that negatively impact their therapeutic benefits. SGLT2is induce a metabolic shift from glucose to fatty acids and thus increase lipolysis which, in turn, induces ketogenesis. The complete pathways linking SGLT2is to ketoacidosis have not yet been fully elucidated, though much is now known. Therefore, in this mechanistic study, we present the current knowledge and shed light upon the possible cellular pathways involved. A deeper understanding of the possible links between SGLT2is and ketogenesis could help to prevent adverse side effects in diabetic patients treated with these drugs.

Renoprotective Roles of Curcumin.

The use of herb-based therapies is increasing over the past decades. These agents have been reported to provide many beneficial effects in many experimental and clinical studies. Curcumin is one of these agents which has potent pharmacological effects enabling it for the prevent and treatment of many diseases and pathologies such as renal disorders, hyperglycemia, oxidative stress, hypertension, and dyslipidemia. However, the exact molecular mechanisms mediating these renoprotective effects of curcumin are not well established. So, in the current study, we surveyed for possible renoprotective roles of curcumin and concluded how curcumin protects against renal injuries.

Crocin Improves Diabetes-Induced Oxidative Stress via Downregulating the Nox-4 in Myocardium of Diabetic Rats.

BACKGROUND: Oxidative stress has a crucial role in the pathophysiology of cardiac dysfunction in the diabetic milieu. Crocin is a natural compound that acts as an antioxidant which could potentially ameliorate oxidative damages in various tissues. The potential role of crocin in the myocardial tissue is not clear yet. This study was aimed to evaluate the possible antioxidative properties of crocin in the myocardium of diabetic rats. MATERIALS AND METHODS: Male Wistar rats were randomly divided into four groups as normal, normal-treated, diabetic, and diabetic-treated. Diabetes was induced by a single intravenous injection of STZ (40 mg/kg). Two treated groups of animals (diabetic and non-diabetic) were treated with crocin daily for 8 weeks (40 mg/kg/IP). At the end of day 56, animals were sacrificed under deep anesthesia, and blood and tissue samples were collected. After tissue preparation, the level of nitrate, malondialdehyde, and glutathione and the activity of superoxide dismutase and catalase enzymes were measured via standard protocols. In addition, the level of Nox-4 mRNA expression was examined by RT-PCR method. The data were analyzed via one-way ANOVA, and P < 0.05 was considered as a significant difference. RESULTS: Diabetes induces oxidative damages by upregulating the Nox-4 enzyme and increasing nitrate and malondialdehyde levels in the myocardium. Diabetes reduced the superoxide dismutase, catalase, and glutathione activities in the myocardial tissues. Treatment with crocin reversed these changes, reduced Nox-4 mRNA expression, and reduced the nitrate and malondialdehyde content in the myocardium of diabetic rats. CONCLUSION: Diabetes induces oxidative stress in myocardium via the upregulating Nox-4 enzyme, and the treatment with crocin reversed these changes. Thus, crocin could be considered as a novel agent for potentially protecting myocardial tissues against diabetes-induced oxidative damages.

The predictive performance of short-linear motif features in the prediction of calmodulin-binding proteins.

BACKGROUND: The prediction of calmodulin-binding (CaM-binding) proteins plays a very important role in the fields of biology and biochemistry, because the calmodulin protein binds and regulates a multitude of protein targets affecting different cellular processes. Computational methods that can accurately identify CaM-binding proteins and CaM-binding domains would accelerate research in calcium signaling and calmodulin function. Short-linear motifs (SLiMs), on the other hand, have been effectively used as features for analyzing protein-protein interactions, though their properties have not been utilized in the prediction of CaM-binding proteins. RESULTS: We propose a new method for the prediction of CaM-binding proteins based on both the total and average scores of known and new SLiMs in protein sequences using a new scoring method called sliding window scoring (SWS) as features for the prediction module. A dataset of 194 manually curated human CaM-binding proteins and 193 mitochondrial proteins have been obtained and used for testing the proposed model. The motif generation tool, Multiple EM for Motif Elucidation (MEME), has been used to obtain new motifs from each of the positive and negative datasets individually (the SM approach) and from the combined negative and positive datasets (the CM approach). Moreover, the wrapper criterion with random forest for feature selection (FS) has been applied followed by classification using different algorithms such as k-nearest neighbors (k-NN), support vector machines (SVM), naive Bayes (NB) and random forest (RF). CONCLUSIONS: Our proposed method shows very good prediction results and demonstrates how information contained in SLiMs is highly relevant in predicting CaM-binding proteins. Further, three new CaM-binding motifs have been computationally selected and biologically validated in this study, and which can be used for predicting CaM-binding proteins.

Anti-inflammatory benefits of semaglutide: State of the art.

Individuals with diabetes often have chronic inflammation and high levels of inflammatory cytokines, leading to insulin resistance and complications. Anti-inflammatory agents are proposed to prevent these issues, including using antidiabetic medications with anti-inflammatory properties like semaglutide, a GLP-1 analogue. Semaglutide not only lowers glucose but also shows potential anti-inflammatory effects. Studies suggest it can modulate inflammatory responses and benefit those with diabetes. However, the exact mechanisms of its anti-inflammatory effects are not fully understood. This review aims to discuss the latest findings on semaglutide's anti-inflammatory effects and the potential pathways involved.

Raspberry-like PLA/PGS biodegradable microparticles with urethane linkages: Unlocking tailored release of magnesium ions and oxygen for bone tissue engineering.

Designing biodegradable microparticles with finely controlled release properties for tissue engineering systems remains a significant scientific challenge. This study introduces a novel approach by fabricating urethane-linked PLA/PGS microparticles loaded with magnesium peroxide. The microparticles offer potential applications in bone tissue engineering due to their ability to provide a controlled release of oxygen and magnesium ions while maintaining physiological pH. The PGS pre-polymer was synthesized via polycondensation and characterized using FTIR, 1H NMR, and GPC. Microparticle morphology transformed from smooth to raspberry-like upon incorporation of PGS, as observed by SEM. Microparticle size was tuned by varying PGS and PLA concentrations. FTIR analysis confirmed the successful formation of urethane links within the microparticles. MgO2-loaded PLA/PGS microparticles exhibited sustained release of dissolved oxygen and magnesium ions for 21 days while maintaining physiological pH better than PLA microparticles. Cell viability assays confirmed microparticle cytocompatibility, and ALP and Alizarin red assays demonstrated their ability to induce osteogenic differentiation. These findings highlight the potential of pH-controlled MgO2-loaded microparticles as an effective system for bone tissue engineering. In conclusion, this study presents a novel approach to designing biodegradable microparticles with adjustable release properties for bone tissue engineering. The urethane-based MgO2-loaded microparticles provide controlled release of oxygen and magnesium ions and regulate the environment's pH, making them a promising system for bone tissue engineering applications.

Glp-1 Mimetics and Autophagy in Diabetic Milieu: State-of-the-Art.

The diabetic milieu is associated with cascades of pathophysiological pathways that culminate in diabetic complications and tissue injuries. Autophagy is an essential process mandatory for cell survival and tissue homeostasis by degrading damaged organelles and removing injured cells. However, it may turn into a pathological process in an aberrant mode in the diabetic and/or malignant milieu. Moreover, autophagy could serve as a promising therapeutic target for many complications related to tissue injury. Glp-1 mimetics are a class of newer antidiabetic agents that reduce blood glucose through several pathways. However, some evidence suggests that they can provide extra glycemic benefits by modulating autophagy, although there is no complete understanding of this mechanism and its underlying molecular pathways. Hence, in the current review, we aimed to provide new insights on the possible impact of Glp-1 mimetics on autophagy and consequent benefits as well as mediating pathways.

Modulating effects of crocin on lipids and lipoproteins: Mechanisms and potential benefits.

Dyslipidemia poses a significant risk to cardiovascular health in both diabetic and non-diabetic individuals. Therefore, it is crucial to normalize lipid homeostasis in order to prevent or minimize complications associated with dyslipidemia. However, pharmacological interventions for controlling lipid metabolism often come with adverse effects. As an alternative, utilizing herbal-based agents, which typically have fewer side effects, holds promise. Crocin, a naturally occurring nutraceutical, has been shown to impact various intracellular pathways, reduce oxidative stress, and alleviate inflammatory processes. Recent evidence suggests that crocin may also confer lipid-related benefits and potentially contribute to the normalization of lipid homeostasis. However, the specific advantages and the cellular pathways involved are not yet well understood. In this review, we present the latest findings regarding the lipid benefits of crocin, which could be instrumental in preventing or reducing disorders associated with dyslipidemia. Additionally, we explore the potential cellular mechanisms and pathways that mediate these lipid benefits.

The role of electrostatic energy in prediction of obligate protein-protein interactions.

BACKGROUND: Prediction and analysis of protein-protein interactions (PPI) and specifically types of PPIs is an important problem in life science research because of the fundamental roles of PPIs in many biological processes in living cells. In addition, electrostatic interactions are important in understanding inter-molecular interactions, since they are long-range, and because of their influence in charged molecules. This is the main motivation for using electrostatic energy for prediction of PPI types. RESULTS: We propose a prediction model to analyze protein interaction types, namely obligate and non-obligate, using electrostatic energy values as properties. The prediction approach uses electrostatic energy values for pairs of atoms and amino acids present in interfaces where the interaction occurs. The main features of the complexes are found and then the prediction is performed via several state-of-the-art classification techniques, including linear dimensionality reduction (LDR), support vector machine (SVM), naive Bayes (NB) and k-nearest neighbor (k-NN). For an in-depth analysis of classification results, some other experiments were performed by varying the distance cutoffs between atom pairs of interacting chains, ranging from 5Å to 13Å. Moreover, several feature selection algorithms including gain ratio (GR), information gain (IG), chi-square (Chi2) and minimum redundancy maximum relevance (mRMR) are applied on the available datasets to obtain more discriminative pairs of atom types and amino acid types as features for prediction. CONCLUSIONS: Our results on two well-known datasets of obligate and non-obligate complexes confirm that electrostatic energy is an important property to predict obligate and non-obligate protein interaction types on the basis of all the experimental results, achieving accuracies of over 98%. Furthermore, a comparison performed by changing the distance cutoff demonstrates that the best values for prediction of PPI types using electrostatic energy range from 9Å to 12Å, which show that electrostatic interactions are long-range and cover a broader area in the interface. In addition, the results on using feature selection before prediction confirm that (a) a few pairs of atoms and amino acids are appropriate for prediction, and (b) prediction performance can be improved by eliminating irrelevant and noisy features and selecting the most discriminative ones.

Renal Effects of Empagliflozin in Patients with Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) is one of the main causes of mortality and morbidity worldwide. It leads to various long-term complications such as diabetic nephropathy. Diabetes nephropathy is the leading cause of renal failure in patients with chronic kidney diseases undergoing hemodialysis. Hence preventing the development and progression of diabetic nephropathy is one of the main goals in the management of patients with type 2 diabetes. Sodium-glucose cotransporter 2 inhibitors of empagliflozin is a potent anti-hyperglycemic agents. In addition, it has been shown to have some pharmacologic potentials to provide renoprotective effects in patients with T2DM. In the current study, we review the available clinical data on the potential renoprotective effects of this drug from a mechanistic and molecular viewpoint.

Sodium-glucose cotransporter 2 inhibitors and mitochondrial functions: state of the art.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are a class of newly introduced antidiabetic drugs with potent hypoglycemic effects. Recent evidence suggests that these drugs have extraglycemic impacts and are therefore able to provide additional benefits beyond glucose lowering. Mitochondrial dysfunction is a central facet of many disorders that negatively impacts many tissues and organs, especially in the setting of diabetes. Therefore, it would be hugely beneficial if an antidiabetic drug could also provide mitochondrial benefits to improve cellular function and reduce the risk of diabetic complications. In this review, we have surveyed the literature for possible mitochondrial benefits of SGLT2is and we discuss the possible mechanisms involved.

Sodium-glucose co-transporter-2 inhibitors and epicardial adiposity.

Epicardial adipose tissue is a layer of adipocytes that physiologically surround the myocardium and play some physiologic roles in normal heart function. However, in pathologic conditions, the epicardial adipose tissue can present a potent cardiac risk factor that is capable of impairing heart function through several pathways, increasing the risk of dysrhythmia and creating an inflammatory milieu around the heart tissues. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are a relatively newly introduced class of antidiabetes drugs which effectively normalize blood glucose via overt glycosuria. Some recent reports suggest that these drugs are able to modulate epicardial adiposity and decrease the risk of cardiac complications in diabetic patients who are at higher risk of epicardial adiposity-dependent cardiac disorders. If proven to be true, these antidiabetic drugs can provide dual benefits as both hypoglycemic agents and as epicardial adiposity normalizing agents, thus providing cardiac benefits. In this study, we discuss the physiological and pathophysiological importance of epicardial adiposity and the potential positive effects of SGLT2is in the diabetic milieu.

Hepatic benefits of sodium-glucose cotransporter 2 inhibitors in liver disorders.

Diabetic patients are at higher risk of liver dysfunction compared with the normal population. Thus, using hypoglycemic agents to improve liver efficiency is important in these patients. Sodium-glucose cotransporters-2 inhibitors (SGLT2i) are newly developed antidiabetic drugs with potent glucose-lowering effects. However, recent limited evidence suggests that they have extra-glycemic benefits and may be able to exert protective effects on the liver. Hence, these drugs could serve as promising pharmacological agents with multiple benefits against different hepatic disorders. In this review, the current knowledge about the possible effects of SGLT2 inhibitors on different forms of liver complications and possible underlying mechanisms are discussed.

Brain insulin signaling and cognition: Possible links.

Poor cognitive ability is a consequence of a wide variety of neurobehavioral disorders and is a growing health problem, especially among the elderly and patients with diabetes. The precise underlying cause of this complication is not well-defined. However, recent studies have highlighted the possible role of insulin hormone signaling in brain tissue. Insulin is a metabolic peptide integral to whole body energy homeostasis; it does, however, have extrametabolic impacts, such as upon neuronal circuits. Therefore, it has been suggested that insulin signaling may modify cognitive ability by yet unknown pathways. In the current review, we discuss the cognitive role of brain insulin signaling and consider the possible links between brain insulin signaling and cognitive ability.

The Beneficial Effects of Curcumin on Lipids: Possible Effects on Dyslipidemia-Induced Cardiovascular Complications.

Dyslipidemia and altered lipid metabolism are closely involved in the pathogenesis and clinical manifestation of many metabolic and non-metabolic diseases. Therefore, mitigation of pharmacological and nutritional factors together with lifestyle modifications is paramount. One potential nutraceutical exhibiting cell signaling and lipid-modulating properties implicated in dyslipidemias is curcumin. Specifically, recent evidence suggest that curcumin may improve lipid metabolism and prevent dyslipidemia-induced cardiovascular complications via several pathways. Although the exact molecular mechanisms involved are not well understood, the evidence presented in this review suggests that curcumin can provide significant lipid benefits via modulation of adipogenesis and lipolysis, and prevention or reduction of lipid peroxidation and lipotoxicity via different molecular pathways. Curcumin can also improve the lipid profile and reduce dyslipidemia-dependent cardiovascular problems by impacting important mechanisms of fatty acid oxidation, lipid absorption, and cholesterol metabolism. Although only limited direct supporting evidence is available, in this review we assess the available knowledge regarding the possible nutraceutical effects of curcumin on lipid homeostasis and its possible impacts on dyslipidemic cardiovascular events from a mechanistic viewpoint.

Benefits of GLP-1 Mimetics on Epicardial Adiposity.

The epicardial adipose tissue, which is referred to as fats surrounding the myocardium, is an active organ able to induce cardiovascular problems in pathophysiologic conditions through several pathways, such as inflammation, fibrosis, fat infiltration, and electrophysiologic problems. So, control of its volume and thickness, especially in patients with diabetes, is highly important. Incretin-based pharmacologic agents are newly developed antidiabetics that could provide further cardiovascular benefits through control and modulating epicardial adiposity. They can reduce cardiovascular risks by rapidly reducing epicardial adipose tissues, improving cardiac efficiency. We are at the first steps of a long way, but current evidence demonstrates the sum of possible mechanisms. In this study, we evaluate epicardial adiposity in physiologic and pathologic states and the impact of incretin-based drugs.

Nanoparticles with SGLT2 inhibitory activity: Possible benefits and future.

AIM: Nano-drug delivery is a rapidly growing approach in medicine that helps design and develop newer forms of drugs with more efficacy and lower adverse effects. Sodium-glucose cotransporter-2 inhibitors are an emerging class of antidiabetic agents that reduce the blood glucose levels by damping glucose reabsorption in renal proximal tubules. METHODS AND RESULTS: This mechanism might be followed by some adverse effects that could be prevented by nano-drug delivery. Although we have still limited evidence about nanoforms of sodium-glucose cotransporter-2 inhibitors, current knowledge strongly suggests that nanotechnology can help us design more effective drugs with lower side effects. In recent years, several studies have explored the possible benefits of nanoforms of sodium-glucose cotransporter-2 inhibitors. However, clinical trials are yet to be conducted. CONCLUSION: In the current review, we present the latest findings on the development and benefits of nanoforms of sodium-glucose cotransporter-2 inhibitors.