Liraglutide abrogates nephrotoxic effects of chemotherapies.

Acute kidney injury (AKI) is a common clinical complication. Cisplatin (Cis) is an effective chemotherapeutic drug; however, its acute nephrotoxicity often limits its application. The role of liraglutide (Lir), an agonist of the glucagon-like peptide-1 receptor (GLP-1R), has recently attracted increasing attention beyond glycemic regulation. This study showed that Lir significantly ameliorated Cis-induced kidney dysfunction and renal damage. However, this renoprotective effect was partially abolished in GLP-1R knockout (GLP-1R-/-) mice. Furthermore, we synthesized Lir metabolites, GLP-1 (9-37) and GLP-1 (28-37), and found that they also exerted reno-protective effects that were not impaired in GLP-1R-/- mice. We also demonstrated that Lir and its metabolites reduced cisplatin-induced apoptosis in human renal tubular epithelial cells (HK-2). After silencing GLP-1R expression in HK-2 cells with small interfering ribose nucleic acid (siRNA), the protective effect of Lir on HK-2 cells was inhibited, while the protective effects of GLP-1 (9-37) and GLP-1 (28-37) were not affected. Additionally, we demonstrated that Lir and its metabolites inhibited Cis-induced high-mobility group box 1 (HMGB1) nuclear-cytoplasmic translocation and release, and reduced inflammatory cytokines and HMGB1 receptor expression. The exogenous use of recombinant HMGB1 (rHMGB1) dramatically weakened the protective effects of Lir and its metabolites. In conclusion, our study shows that Lir significantly attenuated Cis-induced AKI through GLP-1R dependent and independent pathways, mediated by inhibiting nuclear-cytoplasmic translocation and release of HMGB1. Lir and its metabolites may be effective drugs for treating cisplatin-induced nephrotoxicity.

The anti-inflammatory and immunological properties of GLP-1 Receptor Agonists.

In the last few years, a great interest has emerged in investigating the pleiotropic effects of Glucagon Like Peptide-1 Receptor Agonists (GLP-1RAs). While GLP-1RAs ability to lower plasma glucose and to induce weight loss has allowed them to be approved for the treatment of diabetes and obesity, consistent evidences from in vitro studies and preclinical models suggested that GLP-1RAs have anti-inflammatory properties and that may modulate the immune-system. Notably, such anti-inflammatory effects target different pathways in different tissues, underling the broad spectrum of GLP-1RAs actions. This review examines some of the currently proposed molecular mechanisms of GLP-1RAs actions and explores their potential benefits in reducing inflammatory responses, which may well suggest a future therapeutic use of GLP-1RAs in new indications.

Liraglutide protects against lethal renal ischemia-reperfusion injury by inhibiting high-mobility group box 1 nuclear-cytoplasmic translocation and release.

Liraglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, has been reported to exert protective effects against myocardial, hepatic, and gastric ischemia-reperfusion injury (IRI), but whether it can protect against renal IRI remains unknown. Here, a lethal renal IRI model was established with a 100% mortality rate in untreated mice. Treatment with liraglutide involving a regimen of multiple doses resulted in 100% survival, remarkable preservation of renal function, a significant reduction in pathological damage, and blunted upregulation of TNF-α, IL-1ß, IL-6, MCP-1, TLR-2, TLR-4, and RAGE mRNA. We found that liraglutide treatment dramatically inhibited ischemia-induced nucleocytoplasmic translocation and release of HMGB1. This inhibition was associated with a marked decrease (~ 60%) in nuclear histone acetyltransferase activity. In addition, the protective effects of liraglutide on renal IRI were largely abolished by the administration of exogenous HMGB1. When the GLP-1R antagonist exendin (9-39) was given to mice before each liraglutide administration, or GLP-1R-/- mice were used for the renal IRI experiments, the protective effect of liraglutide on renal IRI was partially reversed. Moreover, liraglutide pretreatment significantly inhibited HMGB1 nucleocytoplasmic translocation during hypoxic culture of HK-2 cells in vitro, but the addition of exendin (9-39) significantly eliminated this inhibition. We demonstrate here that liraglutide can exert a strong protective effect on lethal renal IRI in mice. This protection appears to be related to the inhibition of HMGB1 nuclear-cytoplasmic translocation and release and partially depends on GLP-1R. Thus, liraglutide may be therapeutically useful for the clinical prevention and treatment of organ IRI.

Anti-diabetic drugs and weight loss in patients with type 2 diabetes.

INTRODUCTION: Obesity is frequently a comorbidity of type 2 diabetes. Even modest weight loss can significantly improve glucose homeostasis and lessen cardiometabolic risk factors in patients with type 2 diabetes, but lifestyle-based weight loss strategies are not long-term effective. There is an increasing need to consider pharmacological approaches to assist weight loss in the so called diabesity syndrome. Aim of this review is to analyze the weight-loss effect of non-insulin glucose lowering drugs in patients with type 2 diabetes. MATERIAL AND METHODS: A systematic analysis of the literature on the effect of non-insulin glucose lowering drugs on weight loss in patients with type 2 diabetes was performed. For each class of drugs, the following parameters were analyzed: kilograms lost on average, effect on body mass index and body composition. RESULTS: Our results suggested that anti-diabetic drugs can be stratified into 3 groups based on their efficacy in weight loss: metformin, acarbose, empagliflozin and exenatide resulted in a in a mild weight loss (less than 3.2% of initial weight); canagliflozin, ertugliflozin, dapagliflozin and dulaglutide induces a moderate weight loss (between 3.2% and 5%); liraglutide, semaglutide and tirzepatide resulted in a strong weight loss (greater than 5%). CONCLUSIONS: This study shows that new anti-diabetic drugs, particularly GLP1-RA and Tirzepatide, are the most effective in inducing weight loss in patients with type 2 diabetes. Interestingly, exenatide appears to be the only GLP1-RA that induces a mild weight loss.

Epigenetics in NAFLD/NASH: Targets and therapy.

Recently non-alcoholic fatty liver disease (NAFLD) has grabbed considerable scientific attention, owing to its rapid increase in prevalence worldwide and growing burden on end-stage liver diseases. Metabolic syndrome including obesity, diabetes, and hypertension poses a grave risk to NAFLD etiology and progression. With no drugs available, the mainstay of NAFLD management remains lifestyle changes with exercise and dietary modifications. Nonselective drugs such as metformin, thiazolidinediones (TZDs), ursodeoxycholic acid (UDCA), silymarin, etc., are also being used to target the interrelated pathways for treating NAFLD. Considering the enormous disease burden and the unmet need for drugs, fresh insights into pathogenesis and drug discovery are required. The emergence of the field of epigenetics offers a convincing explanation for the basis of lifestyle, environmental, and other risk factors to influence NAFLD pathogenesis. Therefore, understanding these epigenetic modifications to target the primary cause of the disease might prove a rational strategy to prevent the disease and develop novel therapeutic interventions. Apart from describing the role of epigenetics in the pathogenesis of NAFLD as in other reviews, this review additionally provides an elaborate discussion on exploiting the high plasticity of epigenetic modifications in response to environmental cues, for developing novel therapeutics for NAFLD. Besides, this extensive review provides evidence for epigenetic mechanisms utilized by several potential drugs for NAFLD.

Pharmacotherapy of obesity: An update.

Several pharmacological approaches to controlling body weight have been developed over the last decades, albeit with limited success. Currently available agents include centrally acting appetite suppressants and peripherally acting compounds. Efficacy and safety of these agents in the clinical setting require a difficult balance. Further strategies including multiagonists able to simultaneously target multiple actors involved in obesity initiation and expansion such as the glucagon receptor family are under investigation. The results of recent clinical trials are encouraging and highlight emerging compounds as potential game changers. In view of the rising prevalence of obesity and the associated burden of comorbidities worldwide, and compared with other areas of pharmacological intervention, we feel that the field of obesity has been affected by therapeutic inertia. Of note, obesity may also affect the response to concomitant medications such as low-dose aspirin. Lessons from withdrawn agents such as the cannabinoid receptor antagonist rimonabant include developing compounds with a more targeted action profile (i.e., central vs peripheral, or antagonist versus inverse agonist) as well as careful selection of patients based on individual risk factors. We anticipate that the expanding knowledge base and clinical testing will result in improved outcomes for patients with obesity in the near future.

Therapeutic potential of blood flow mimetic compounds in preventing endothelial dysfunction and atherosclerosis.

Endothelial cells (ECs), as one of the most important types of vascular cells, line the innermost layer of all blood vessels throughout human body and regulate vascular tone and homeostasis. ECs are constantly exposed to different types of shear stress (one form of mechanical forces) generated by the flowing blood. Various mechanosensing molecules or complexes existing on EC membrane serve as versatile sensors (termed as mechanosensors) of different patterns and pattern alternation of blood flow. Via these mechanosensors, ECs sense and transduce flow-induced biomechanical signal into different mechano-transduction pathways, leading to altered expression/activity of mechanosensitive transcription factors (TFs), epigenetic modification enzymes, non-coding RNAs, and genes, thereby generating biological responses (i.e., the regulation of endothelial function). Dysfunction of ECs (i.e., endothelial dysfunction) represents one of the most important pathomechanisms for atherosclerosis, hypertension and diabesity. Emerging studies have demonstrated that pharmacological modulators of mechanosensors/TFs/enzymes improve endothelial dysfunction and reduce the incidence of experimental atherosclerosis. Here, I overviewed the important role of endothelial mechanoregulators in vascular endothelium, highlighting the potential of blood flow mimetic compounds to treat endothelial dysfunction and associated atherosclerotic cardiovascular diseases.

Management of diabetes mellitus in patients undergoing liver transplantation.

Diabetes is a common feature in cirrhotic individuals both before and after liver transplantation and negatively affects prognosis. Certain aetiological agents of chronic liver disease and loss of liver function per se favour the occurrence of pre-transplant diabetes in susceptible individuals, whereas immunosuppressant treatment, changes in lifestyle habits, and donor- and procedure-related factors contribute to diabetes development/persistence after transplantation. Challenges in the management of pre-transplant diabetes include the profound nutritional alterations characterizing cirrhotic individuals and the limitations to the use of drugs with liver metabolism. Special issues in the management of post-transplant diabetes include the diabetogenic potential of immunosuppressant drugs and the increased cardiovascular risk characterizing solid organ transplant survivors. Overall, the pharmacological management of cirrhotic patients undergoing liver transplantation is complicated by the lack of specific guidelines reflecting the paucity of data on the impact of glycaemic control and the safety and efficacy of anti-hyperglycaemic agents in these individuals.

The glucagon-like peptide-1 (GLP-1) analog liraglutide attenuates renal fibrosis.

Renal fibrosis is recognized as the common route of all chronic kidney disease (CKD) progressing to end-stage renal disease (ESRD). Additionally, accumulating evidence suggests that epithelial-mesenchymal transition (EMT) plays a significant role in the process of renal fibrogenesis. Liraglutide is a long-acting glucagon-like peptide-1 (GLP-1) analog that has been widely used to treat type 2 diabetes. Recent studies have demonstrated that the GLP-1 analogs could also exert protective effects in cardiac fibrosis models. However, the effects of liraglutide on the progression of CKD remain largely unknown. In the present study, we investigated the effects of liraglutide on the progression to renal fibrosis induced by unilateral ureteral obstruction (UUO) and EMT of rat renal tubular epithelial cells (NRK-52E) induced with recombinant transforming growth factor-beta 1 (TGF-ß1). The results indicated that UUO increased collagen deposition and the mRNA expression of fibronectin (FN) and collagen type I alpha 1 (Col1α1) in the obstructed kidney tissues. The effects were blunted in liraglutide-treated UUO mice compared with control mice. The upregulation of Snail1 and alpha smooth muscle actin (α-SMA), and downregulation of E-cadherin revealed that EMT occurred in the UUO kidneys, and these effects were ameliorated following liraglutide treatment. Additionally, liraglutide treatment decreased the expression of TGF-ß1 and its receptor (TGF-ß1R) and inhibited the activation of its downstream signaling molecules (pSmad3 and pERK1/2). The in vitro results showed that the EMT and extracellular matrix (ECM) secretion of NRK-52E cells were induced by TGF-ß1. In addition, the Smad3 and ERK1/2 signaling pathways were highly activated in cells cultured with TGF-ß1. All these effects were attenuated by liraglutide treatment. However, the protective effects of liraglutide were abolished by co-incubation of the GLP-1 receptor (GLP-1R) antagonist exendin-3 (9-39). These results suggest that liraglutide attenuates the EMT and ECM secretion of NRK-52E cells induced by TGF-ß1 and EMT and renal fibrosis induced by UUO. The potential mechanism involves liraglutide binding to and activating GLP-1R, which prevents EMT by inhibiting the activation of TGF-ß1/Smad3 and ERK1/2 signaling pathways, thereby decreasing the ECM secretion and deposition. Therefore, liraglutide is a promising therapeutic agent that may halt the progression of renal fibrosis.

BPI-3016, a novel long-acting hGLP-1 analogue for the treatment of Type 2 diabetes mellitus.

Glucagon-like peptide-1 (GLP-1) analogues have been commonly used as add-on medications for patients with Type 2 diabetes mellitus (T2DM). Currently, the development of long-acting GLP-1 analogues which allow the freedom and flexibility of once-weekly injections while maintaining their potency for a relatively long period has become the mainstream. Here, we successfully developed a long-acting human GLP-1(7-37) analogue (BPI-3016) with significantly extended half-life and increased resistance to dipeptidyl peptidase IV (DPP-IV) cleavage by structural modifications of human GLP-1. In vitro activity of BPI-3016 including GLP-1 receptor affinity and stimulation of cyclic adenosine monophosphate (cAMP) production was measured. In vivo activity of BPI-3016 such as its effects on glycemic control, ß-cell mass and body weight was evaluated in ob/ob mice, db/db mice, and spontaneous diabetic cynomolgus monkeys. The results indicated that BPI-3016 preserved receptor affinity to GLP receptors, and was capable of stimulating cAMP production. In in vivo pharmacokinetic study, the half-life of BPI-3016 was more than 95h after single dosing in diabetic cynomolgus monkeys. Also, BPI-3016 reduced fasting and post-prandial plasma glucose levels for up to a week after a single dose; It reduced body mass index (BMI), body fat, improved glucose tolerance and showed insulinotropic effects after once-weekly injection for 7 weeks. In conclusion, BPI-3016 retains the effects of GLP-1 with significantly prolonged half-life, making it a promising therapy for type 2 diabetes with once-weekly treatment in the clinic.

Efficacy and risk profile of anti-diabetic therapies: Conventional vs traditional drugs-A mechanistic revisit to understand their mode of action.

An increasing array of anti-diabetic drugs are available today, yet Type-2 diabetes mellitus (T2DM) - remains a life threatening disease, causing high mortality and morbidity in developing and developed countries. As of now, no effective therapy is available for the complete eradication/cure of diabetes and its associated complications. Therefore, it is time to re-think and revisit molecular pathways and targets of each existing drug in order to identify multiple targets from different signaling pathways that may be manipulated simultaneously to treat or manage T2DM effectively. Bearing this goal in mind, the article reviews the mechanisms of action of available anti-diabetic drugs with in-depth mechanistic analysis of each therapy. The conventional and herbal strategies are analysed and compared for their benefits and the associated possible side effects. This critical information is necessary not only for the development of better, novel and potent anti-diabetic therapy in future but also for best possible combinational therapies and strategies with the available drugs.

Potentially active compounds that improve PAD through angiogenesis: A review.

Peripheral arterial disease (PAD) has been historically neglected, which has resulted in a lack of effective drugs in clinical practice. However, with the increasing prevalence of diseases like atherosclerosis and diabetes, the incidence of PAD is rising and cannot be ignored. Researchers are exploring the potential of promoting angiogenesis through exogenous compounds to improve PAD. This paper focuses on the therapeutic effect of natural products (Salidroside, Astragaloside IV, etc.) and synthetic compounds (Cilostazol, Dapagliflozin, etc.). Specifically, it examines how they can promote autocrine secretion of vascular endothelial cells, enhance cell paracrine interactions, and regulate endothelial progenitor cell function. The activation of these effects may be closely related to PI3K, AMPK, and other pathways. Overall, these exogenous compounds have promising therapeutic potential for PAD. This study aims to summarize the potential active compounds, provide a variety of options for the search for drugs for the treatment of PAD, and bring light to the treatment of patients.

Role of Dapagliflozin and Liraglutide on Diabetes-Induced Cardiomyopathy in Rats: Implication of Oxidative Stress, Inflammation, and Apoptosis.

The current study aims to assess the protective effects of dapagliflozin (Dapa; a sodium-glucose cotransporter-2 inhibitor) and/or liraglutide (Lira; a glucagon-like peptide 1 agonist) in an experimental model of diabetic cardiomyopathy (DCM). A single dose of streptozotocin (STZ) was administrated to male Sprague-Dawley rats by intraperitoneal injection at a dose of 50 mg/kg to induce diabetes mellitus (DM). Dapa (1 mg/kg, orally), Lira (0.4 mg/kg, s.c.), and Dapa-Lira combination were administrated for 8 weeks once-daily. Blood samples were evaluated for glucose level and biochemical markers of cardiac functions. Cardiac tissue was dissected and assessed for redox homeostasis (malondialdehyde (MDA), glutathione (GSH), and catalase (CAT)), pro-inflammatory mediators (NF-κB and tumor necrosis factor-α (TNF-α)), and apoptotic effectors (caspase-3). Moreover, the effect of treatments on the cardiac cellular structure was studied. Dapa and/or Lira administration resulted in significant improvement of biochemical indices of cardiac function. Additionally, all treatment groups demonstrated restoration of oxidant/antioxidant balance. Moreover, inflammation and apoptosis key elements were markedly downregulated in cardiac tissue. Also, histological studies demonstrated attenuation of diabetes-induced cardiac tissue injury. Interestingly, Dapa-Lira combination treatment produced a more favorable protective effect as compared to a single treatment. These data demonstrated that Dapa, Lira, and their combination therapy could be useful in protection against DM-accompanied cardiac tissue injury, shedding the light on their possible utilization as adjuvant therapy for the management of DM patients.

Xenopus GLP-1-inspired discovery of novel GLP-1 receptor agonists as long-acting hypoglycemic and insulinotropic agents with significant therapeutic potential.

We here report the discovery and therapeutic efficacy of a novel series of glucagon-like peptide-1 (GLP-1) receptor agonists derived from Xenopus GLP-1. First, five amino acid-mutated Xenopus GLP-1s were synthesized, and xGLP-3 with the best acute and long-acting hypoglycemic activity was selected for further modification. Next, PEGylation of xGLP-3 was performed at specific sites, which were determined using cysteine mutagenesis scanning. Twelve PEGylated conjugates tethered with Mal-PEGs of 1, 2, and 5kDa were synthesized. Conjugates 7b and 7c, which exhibited comparable hypoglycemic and insulinotropic effects to Gly8-GLP-1, were selected for in-depth evaluation. It was found that 7b and 7c exhibited prolonged in vivo half-life and improved pharmacokinetic behaviors. The long-term hypoglycemic effects of 7b and 7c were further confirmed by pre-OGTT and multiple OGTT. Importantly, long-term administration of 7b or 7c in db/db mice achieved beneficial effects on body weight loss, food intake and HbA1c reduction, and glucose tolerance normalization. These preclinical studies indicate the promising role of 7b and 7c as long-acting type 2 diabetes therapeutics. In addition, our research demonstrated the feasibility of developing novel antidiabetic agents based on Xenopus GLP-1.