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.

Saffron and crocin ameliorate prenatal valproic acid-induced autistic-like behaviors and brain oxidative stress in the male offspring rats.

Autism is a neurobehavioral disease that induces cognitive and behavioral alterations, usually accompanied by oxidative stress in the brain. Crocus sativus (saffron) and its active ingredient, crocin, have potent antioxidative effects that may benefit autistic behaviors. This study aimed to determine the effects of saffron extract and crocin against brain oxidative stress and behavioral, motor, and cognitive deficits in an animal model of autism in male offspring rats. 14 female rats were randomly divided into the saline and valproic acid (VPA) groups. Then, they were placed with mature male rats to mate and produce offspring. VPA (500 mg/kg, i.p.) was injected on day 12.5 of pregnancy (gestational day, GD 12.5) to induce an experimental model of autism. 48 male pups were left undisturbed for 29 days. First-round behavioral tests (before treatments) were performed on 30-33 post-natal days (PND), followed by 28 days of treatment (PND 34-61) with saffron (30 mg/kg, IP), crocin (15 or 30 mg/kg, i.p.), or saline (2 ml/kg, i.p.). The second round of behavioral tests (after treatments) was performed on PND 62-65 to assess the effects of the treatments on behavioral and cognitive features. In the end, animals were sacrificed under deep anesthesia, and their brains were dissected to evaluate the brain oxidative stress parameters, including malondialdehyde (MDA), glutathione (GSH), and catalase (CAT). VPA injection into female rats increased anxiety-like behaviors, enhanced pain threshold, impaired motor functions, disturbed balance power, increased MDA, and decreased GSH and CAT in their male offspring. 28 days of treatment with saffron or crocin significantly ameliorated behavioral abnormalities, reduced MDA, and increased GSH and CAT levels. Brain oxidative stress has been implicated in the pathophysiology of autistic-like behaviors. Saffron and crocin ameliorate anxiety-like behaviors, pain responses, motor functions, and brain oxidative stress parameters in an experimental model of autism. Saffron and crocin may hold promise as herbal-based pharmacological treatments for individuals with autism. However, further histological evidence is needed to confirm their efficacy.

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.

Natural Insulin Sensitizers for the Management of Diabetes Mellitus: A Review of Possible Molecular Mechanisms.

Diabetes mellitus is a growing health challenge globally which is increasing in epidemic proportion. Naturally occurring pharmacological agents are more likely to provide beneficial therapeutic effects without undesirable side effects compared to the synthetic agents. There is a growing evidence that some naturally occurring pharmacological agents derived from plants have potential antihyperglycemic effects. In this study, we have reviewed the molecular mechanism behind potential hypoglycemic properties of four well-known herbal-based agents, namely, ginger, curcumin, garlic, and cinnamon. Also, we present the related clinical data confirming experimental results aiming to develop novel therapeutic strategies based on these herbal agents potentially for the management of patients with diabetes.

Crocin Improves Oxidative Stress in Testicular Tissues of Streptozotocin-Induced Diabetic Rats.

Crocin has been shown to have potent antioxidant properties, but its potential antioxidative effects on testicular tissue during uncontrolled diabetes is unknown. Wistar rats were randomly divided into four separate groups; normal, normal-treated, diabetic and diabetic treated (n = 6 per group). Diabetes was induced by a single intravenous injection of streptozotocin (45 mg/kg). Two treated groups of animals (diabetic and non-diabetic) received Crocin daily for 56 days (40 mg/kg/intraperitoneally). At the end of the 56th day, animals were sacrificed and blood and testicular tissue obtained. The level of nitrate, malondialdehyde, glutathione, and the activities of superoxide dismutase and catalase enzymes were determined. Crocin therapy moderated the increased oxidative stress in testicular tissue induced by diabetes with a significant reduction in nitrate and malondialdehyde, whilst reducing superoxide dismutase and catalase enzyme activities in diabetes (p < 0.001), though glutathione was unaffected. Treatment by Crocin in normal rats also modestly improved parameters of oxidative stress (p < 0.05). Crocin has a protective effect on diabetes induced oxidative stress in testicular tissue in an animal model, though it is unclear if this is a direct antioxidant effect.

The Effects of Ginsenosides on the Nrf2 Signaling Pathway.

Nuclear factor erythroid-2 related factor 2 (Nrf2) is a major signaling pathway for the maintenance of homeostasis and redox balance. This pathway also plays a significant role in proteostasis, xenobiotic/drug metabolism, apoptosis, and lipid and carbohydrate metabolism. Conversely, the Nrf2 signaling pathway is impaired in several pathological conditions including cancer. Although various drugs have been developed to target the Nrf2 pathway, plant-derived chemicals than can potentially impact this pathway and are particularly attractive due to their minimal side effects. Ginsenosides are active components of ginseng and have been shown to exert pharmacological effects including antioxidant, anti-inflammatory, antitumor, antidiabetes, neuroprotective, and hepatoprotective activities. In this article, we have reviewed the effects of ginsenosides on Nrf2 signaling pathway.

Antitumor and Protective Effects of Melatonin: The Potential Roles of MicroRNAs.

MicroRNAs (miRNAs) are endogenous short noncoding RNAs with approximately 22 nucleotides. The primary function of miRNAs is the negative regulation of target gene expression via mRNA degradation or translation inhibition. During recent years, much attention has been made toward miRNAs' role in different disorders; particularly cancer and compounds with modulatory effects on miRNAs are of interest. Melatonin is one of these compounds which is secreted by the pineal gland. Also, melatonin is present in the leaves, fruits, and seeds of plants. Melatonin has several valuable biological activities such as antioxidant, anti-inflammation, antitumor, and antiaging activities. This important agent is extensively used to treat different disorders such as cancer and neurodegenerative and cardiovascular diseases. This review aims to describe the modulatory effect of melatonin on miRNAs as novel targets.

Boosting GLP-1 by Natural Products.

The prevalence of diabetes mellitus is growing rapidly. Diabetes is the underlying cause of many metabolic and tissue dysfunctions, and, therefore, many therapeutic agents have been developed to regulate the glycemic profile. Glucagon-like peptide-1 (GLP-1) receptor agonists are a newly developed class of antidiabetic drugs that have potent hypoglycemic effects via several molecular pathways. In addition to synthetic GLP-1 receptor agonists, some evidence suggests that natural products may have modulatory effects on GLP-1 expression and secretion. In the current study, we conclude that certain herbal-based constituents, such as berberine, tea, curcumin, cinnamon, wheat, soybean, resveratrol, and gardenia, can exert an influence on GLP-1 release.

Naturally Occurring SGLT2 Inhibitors: A Review.

With an increasing incidence of diabetes mellitus globally due to various factors, including unhealthy lifestyle, there is a need for developing novel drugs for the management of diabetes. This chronic metabolic disorder results in high blood glucose levels due to the body's inability to reduce the concentration of glucose. The decreased secretion of insulin and increased resistance to insulin action contribute to the development of diabetes mellitus. There have been efforts to target pathways involved in the metabolism of blood glucose. It seems that most of the currently applied antidiabetic medications are associated with unwanted side effects. Hence, it appears that plant-derived chemicals can be considered as potential candidates in the management of diabetes. Sodium-glucose cotransporter inhibitors (SGLT2i) are synthetic hypoglycemic medications approved for managing patients with diabetes in lowering blood glucose. SGLT2i reduces blood glucose concentration by enhancing its urinary excretion and inhibition of its absorption through the kidney. It has been demonstrated that some of the naturally occurring nutraceutical agents can imitate the action of SGLT2i and, consequently, diminish the level of blood glucose. At the present review, we have discussed the phytochemicals that act like SGLT2i to decrease blood glucose level.

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.

Paving the Road Toward Exploiting the Therapeutic Effects of Ginsenosides: An Emphasis on Autophagy and Endoplasmic Reticulum Stress.

Programmed cell death processes such as apoptosis and autophagy strongly contribute to the onset and progression of cancer. Along with these lines, modulation of cell death mechanisms to combat cancer cells and elimination of resistance to apoptosis is of great interest. It appears that modulation of autophagy and endoplasmic reticulum (ER) stress with specific agents would be beneficial in the treatment of several disorders. Interestingly, it has been suggested that herbal natural products may be suitable candidates for the modulation of these processes due to few side effects and significant therapeutic potential. Ginsenosides are derivatives of ginseng and exert modulatory effects on the molecular mechanisms associated with autophagy and ER stress. Ginsenosides act as smart phytochemicals that confer their effects by up-regulating ATG proteins and converting LC3-I to -II, which results in maturation of autophagosomes. Not only do ginsenosides promote autophagy but they also possess protective and therapeutic properties due to their capacity to modulate ER stress and up- and down-regulate and/or dephosphorylate UPR transducers such as IRE1, PERK, and ATF6. Thus, it would appear that ginsenosides are promising agents to potentially restore tissue malfunction and possibly eliminate cancer.

PPAR-α Agonist Fenofibrate Ameliorates Oxidative Stress in Testicular Tissue of Diabetic Rats.

BACKGROUND: Oxidative stress has the potential to induce impotence, especially in diabetic patients. Peroxisome proliferator-activated receptor alpha (PPAR-α) agonists can potentiate antioxidants in a wide variety of tissues. However, no available evidence exists showing a direct antioxidant effect on testicular tissue in the setting of diabetes. Therefore, the aim of this study was to evaluate whether PPAR-α agonists can act directly to protect testicular tissue from oxidative damage. METHODS: Male Wistar rats (180-200 g) were randomly allocated into four groups: normal control (N), normal treated (NF), diabetic (D), and diabetic treated (DF) (n = 6 for each group). Diabetes was induced by a single intravenous injection of streptozotocin STZ (40 mg/kg). Two treatment groups (diabetic and nondiabetic) were treated with fenofibrate daily for 8 weeks (80 mg/kg orally). At the end of 8 weeks, the animals were sacrificed and blood and testicular tissue samples collected. Nitrate, malondialdehyde, and glutathione levels, and the activity of superoxide dismutase and catalase enzymes were evaluated. The data were analyzed via two-way analysis of variance (ANOVA), with P < 0.05 taken as significant. RESULTS: Diabetes significantly augmented free radicals, as attested by an increase in nitrate levels in testicular tissue, reduced activity of superoxide dismutase and catalase enzymes, and enhanced malondialdehyde content. These changes lead to oxidative stress in testicular tissues. Treatment with fenofibrate in the diabetic group improved oxidative stress by potentiation of antioxidant elements and a reduction in nitrate and malondialdehyde production. CONCLUSION: Diabetes has a potent effect in promoting the development of oxidative damage in testicular tissue. The PPAR-a agonist fenofibrate improves the redox state and may prevent oxidative stress in the setting of diabetes-induced oxidative stress.

Neuromodulatory effects of anti-diabetes medications: A mechanistic review.

Diabetes mellitus is a potent upstream event in the molecular pathophysiology which gives rise to various diabetes-related complications. There are several classes of anti-diabetic medications that have been developed to normalize blood glucose concentrations through a variety of molecular mechanisms. Beyond glucose-lowering effects, these agents may also provide further therapeutic potential. For instance, there is a high incidence of diabetes-induced neuronal disorders among patients with diabetes, who may also develop neurodegenerative and psychological complications. If anti-diabetic agents can modify the molecular mechanisms involved in the pathophysiology of neuronal comorbidities, this could potentially be translated to reducing the risk of other neurological conditions such as Alzheimer's disease, Parkinson's disease, depression, memory deficits and cognition impairments among patients with diabetes. This review aimed to shed light on some of the potentially beneficial aspects of anti-diabetic agents in lowering the risk or treating neuronal disorders by reviewing the molecular mechanisms by which these agents can potentially modulate neuronal behaviors.

A review of the molecular mechanisms of hyperglycemia-induced free radical generation leading to oxidative stress.

The prevalence of diabetes is growing worldwide with an increasing morbidity and mortality associated with the development of diabetes complications. Free radical production is a normal biological process that is strictly controlled and has been shown to be important in normal cellular homeostasis, and in the bodies response to pathogens. However, there are several mechanisms leading to excessive free radical production that overcome the normal protective quenching mechanisms. Studies have shown that many of the diabetes complications result from excessive free radical generation and oxidative stress, and it has been shown that chronic hyperglycemia is a potent inducer for free radical production, generated through several pathways and triggering multiple molecular mechanisms. An understanding of these processes may help us to improving our preventive or therapeutic strategies. In this review, the major molecular pathways involved in free radical generation induced by hyperglycemia are described.

Interleukin-18 and diabetic nephropathy: A review.

The inflammatory response has an important role in the pathophysiology of diabetic nephropathy that is contributed to by inflammatory mediators such as interleukin-1 (IL-1), IL-6, IL-18, tumor necrosis factor-α, and macrophage chemotactic protein-1; however, the role of IL-18 seems to be more specific than other cytokines in the inflammatory process. IL-18 is expressed in renal tissue and is upregulated by several stimuli including hyperglycemia. The expression/urinary level of IL-18 is positively correlated with the progression of diabetic nephropathy and the urinary albumin excretion rate. In this review, we have focused on the molecular pathways modulating the relationship between IL-18 and diabetic nephropathy.

Mitochondrial dysfunction in diabetes and the regulatory roles of antidiabetic agents on the mitochondrial function.

The prevalence of type 2 diabetes mellitus (T2DM) is increasing rapidly with its associated morbidity and mortality. Many pathophysiological pathways such as oxidative stress, inflammatory responses, adipokines, obesity-induced insulin resistance, improper insulin signaling, and beta cell apoptosis are associated with the development of T2DM. There is increasing evidence of the role of mitochondrial dysfunction in the onset of T2DM, particularly in relation to the development of diabetic complications. Here, the role of mitochondrial dysfunction in T2DM is reviewed together with its modulation by antidiabetic therapeutic agents, an effect that may be independent of their hypoglycemic effect.

Wingless-type inducible signaling pathway protein-1 (WISP1) adipokine and glucose homeostasis.

Whilst the growing global prevalence of diabetes mellitus is a major healthcare problem, the exact pathophysiology of insulin resistance leading to diabetes mellitus remains unclear. Studies have confirmed that increased adiposity is linked to lower insulin sensitivity through the expression and release of adipocyte-derived proteins such as adipokines. Wingless-type (Wnt) inducible signaling pathway protein-1 (WISP1) is a newly identified adipokine that has important roles in many molecular pathways and cellular events, with the suggestion that WISP1 adipokine is closely correlated to the progression of insulin resistance. Studies have shown that circulatory levels of WISP adipokine are higher in obese patients accompanied with increased insulin resistance. However, the exact role of WISP1 adipokine in the induction of insulin resistance is not completely understood. In this review, we detail the latest evidence showing that the WIPS1 adipokine impairs glucose homeostasis and induces diabetes mellitus.