Molecular mechanisms by which GLP-1 RA and DPP-4i induce insulin sensitivity

Glucagon-like peptide-1 is a peptide of incretin family which is used in the management of diabetes as glucagon-like peptide-1 receptor agonist (GLP-1RA). Dipeptidyl peptidase-4 enzyme metabolizes glucagon-like peptide-1 and various dipeptidyl peptidase-4 enzyme inhibitors (DPP-4i) are also used in the management of diabetes. These antidiabetic agents provide anti-hyperglycemic effects via several molecular mechanisms including promoting insulin secretion, suppression of glucagon secretion and slowing the gastric emptying. There is some research suggesting that they can induce insulin sensitivity in peripheral tissues. In this study, we review the possible molecular mechanisms by which GLP-1RA and DPP-4i can improve insulin resistance and increase insulin sensitivity in insulin-dependent peripheral tissues

siRNA Therapeutics: Future Promise for Neurodegenerative Diseases

Neurodegenerative diseases (ND), as a group of central nervous system (CNS) disorders, are among the most prominent medical problems of the 21st century. They are often associated with considerable disability, motor dysfunction and dementia and are more common in the aged population. ND imposes a psychologic, economic and social burden on the patients and their families. Currently, there is no effective treatment for ND. Since many ND result from the gain of function of a mutant allele, small interference RNA (siRNA) can be a potential therapeutic agent for ND management. Based on the RNA interference (RNAi) approach, siRNA is a powerful tool for modulating gene expression through gene silencing. However, there are some obstacles in the clinical application of siRNA, including unfavorable immune response, off-target effects, instability of naked siRNA, nuclease susceptibility and a need to develop a suitable delivery system. Since there are some issues related to siRNA delivery routes, in this review, we focus on the application of siRNA in the management of ND treatment from 2000 to 2020

Molecular mechanisms of trehalose in modulating glucose homeostasis in diabetes

Diabetes mellitus is the most prevalent metabolic disorder contributing to significant morbidity and mortality in humans. Many preventative and therapeutic agents have been developed for normalizing glycemic profile in patients with diabetes. In addition to various pharmacologic strategies, many non-pharmacological agents have also been suggested to improve glycemic control in patients with diabetes. Trehalose is a naturally occurring disaccharide which is not synthesized in human but is widely used in food industries. Some studies have provided evidence indicating that it can potentially modulate glucose metabolism and help to stabilize glucose homeostasis in patients with diabetes. Studies have shown that trehalose can significantly modulate insulin sensitivity via at least 7 molecular pathways leading to better control of hyperglycemia. In the current study, we concluded about possible anti-hyperglycemic effects of trehalose suggesting trehalose as a potentially potent non-pharmacological agent for the management of diabetes

Therapeutic effects of Crocin in autoimmune diseases: A review

The immune system when acts against selfmolecules results in an imbalance in immunologic tolerance leading to the development of several autoimmune diseases (ADs) such as rheumatoid arthritis, asthma, ulcerative colitis, type 1 diabetes, and multiple sclerosis. Improved recognition of the mechanisms of ADs has led to the advancement of the management of these diseases. The principal mediators of ADs are inflammatory molecules. The herbal medicines due to their antioxidant and antiinflammatory properties have an important role in the management of ADs. Crocin is the principal chemical component extracted from saffron, which is a medicinal plant. This review focuses on the therapeutic effects of Crocin in various ADs

Impacts of Sodium/Glucose Cotransporter-2 Inhibitors on Circulating Uric Acid Concentrations: A Systematic Review and Meta-Analysis

Background: Several trials have assessed the antihyperglycemic effects of sodium/glucose cotransporter-2 inhibitors (SGLT2i) in patients with type 2 diabetes mellitus (T2DM). We conducted a quantitative analysis to assess the impact of SGLT2is on serum uric acid (SUA) in patients with T2DM. Methods: Placebo-controlled trials published before 13 August 2021 were identified by searching PubMed, Embase, Web of Science, and Scopus. The intervention group received SGLT2i as monotherapy or add-on treatment, and the control group received a placebo that was replaced with SGLT2i. Clinical trials providing changes in SUA were included. The mean change of SUA, glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and body weight were calculated (PROSPERO CRD42021287019). Results: After screening of 1172 papers, 59 papers were included in the systematic review. A total of 55 trials (122 groups) of 7 types of SGLT2i on patients with T2DM were eligible for meta-analysis. All SGLT2is significantly decreased SUA levels compared with the placebo groups: empagliflozin mean difference (MD) = -40.98 μmol/L, 95% CI [-47.63, -34.32], dapagliflozin MD = -35.17 μmol/L, 95% CI [-39.68, -30.66], canagliflozin MD = -36.27 μmol/L, 95% CI [-41.62, -30.93], luseogliflozin MD = -24.269 μmol/L, 95% CI [-33.31, -15.22], tofogliflozin MD = -19.47 μmol/L, 95% CI [-27.40, -11.55], and ipragliflozin MD = -18.85 μmol/L, 95% CI [-27.20, -10.49]. SGLT2i also decreased FPG, body weight, and HbA1c levels. SUA reduction persisted during long-term treatment with SGLT2i (except for empagliflozin), while the SUA reduction was affected by the duration of diabetes. Conclusions: SGLT2i can be a valid therapeutic strategy for patients with T2DM and comorbid hyperuricemia. Besides reducing FPG, body weight, and HbA1c, SGLT2i can significantly decrease SUA levels compared to placebo (Total MD = -34.07 μmol/L, 95% CI [-37.00, -31.14])

Incretins and microRNAs: Interactions and physiological relevance

MicroRNAs (miRNA) are one class of the small regulatory RNAs that can impact the expression of numerous genes including incretin hormones and their G protein-coupled receptors. Incretin peptides, including GLP-1, GLP-2, and GIP, are released from the gastrointestinal tract and have an crucial role in the glucose hemostasis and pancreatic beta-cell function. These hormones and their analogs with a longer half-life, glucagon like peptide-1 receptor agonists (GLP1RA), modify the expression of miRNAs. Dipeptidyl peptidase IV (DPP-4) is an enzyme that degrades the incretin hormones and is inactivated by DPP-4 inhibitors, which are a class of compounds used in the management of type 2 diabetes. DPP-4 inhibitors may also increase or reduce the expression of miRNAs. In this review, we describe the possible interactions between miRNAs and incretin hormones and the relevance of such interactions to physiological processes and diseases

The effect of C-peptide on diabetic nephropathy: A review of molecular mechanisms

C-peptide is a small peptide connecting two chains of proinsulin molecule and is dissociated before the release of insulin. It is secreted in an equimolar amount to insulin from the pancreatic beta-cells into the circulation. Recent evidence demonstrates that it has other physiologic activities beyond its structural function. C-peptide modulates intracellular signaling pathways in various pathophysiologic states and, could potentially be a new therapeutic target for different disorders including diabetic complications. There is growing evidence that c-peptide has modulatory effects on the molecular mechanisms involved in the development of diabetic nephropathy. Although we have little direct evidence, pharmacological properties of c-peptide suggest that it can provide potent renoprotective effects especially, in a c-peptide deficient milieu as in type 1 diabetes mellitus. In this review, we describe possible molecular mechanisms by which c-peptide may improve renal efficiency in a diabetic milieu

Counteracting arsenic toxicity: Curcumin to the rescue?

Arsenicosis leads to various irreversible damages in several organs and is considered to be a carcinogen. The effects of chronic arsenic poisoning are a result of an imbalance between pro- and antioxidant homeostasis, oxidative stress, as well as DNA and protein damage. Curcumin, the polyphenolic pigment extracted from the rhizome of Curcuma longa, is well-known for its pleiotropic medicinal effects. Curcumin has been shown to have ameliorative effects in arsenic-induced genotoxicity, nephrotoxicity, hepatotoxicity, angiogenesis, skin diseases, reproductive toxicity, neurotoxicity, and immunotoxicity. This review aims to summarize the scientific evidence on arsenic toxicity in various organs and the ameliorative effects of curcumin on the arsenic toxicity

A Comprehensive Review of the Development of Carbohydrate Macromolecules and Copper Oxide Nanocomposite Films in Food Nanopackaging

Background. Food nanopackaging helps maintain food quality against physical, chemical, and storage instability factors. Copper oxide nanoparticles (CuONPs) can improve biopolymers' mechanical features and barrier properties. This will lead to antimicrobial and antioxidant activities in food packaging to extend the shelf life. Scope and Approach. Edible coatings based on carbohydrate biopolymers have improved the quality of packaging. Several studies have addressed the role of carbohydrate biopolymers and incorporated nanoparticles to enhance food packets' quality as active nanopackaging. Combined with nanoparticles, these biopolymers create film coatings with an excellent barrier property against transmissions of gases such as O2 and CO2. Key Findings and Conclusions. This review describes the CuO-biopolymer composites, including chitosan, agar, cellulose, carboxymethylcellulose, cellulose nanowhiskers, carrageenan, alginate, starch, and polylactic acid, as food packaging films. Here, we reviewed different fabrication techniques of CuO biocomposites and the impact of CuONPs on the physical, mechanical, barrier, thermal stability, antioxidant, and antimicrobial properties of carbohydrate-based films

Capacity of HDL to Efflux Cellular Cholesterol from Lipid-Loaded Macrophages Is Reduced in Patients with Familial Hypercholesterolemia

: This study aimed to evaluate the high-density lipoprotein (HDL) capacity to efflux cellular cholesterol from lipid-loaded macrophages to find a reliable and low-cost biomarker with the purpose of better evaluating the risk of premature cardiovascular (CV) events in FH patients. This case-controlled study comprised 16 homozygous (HOFH) and 18 heterozygous (HEFH) FH patients, as well as 20 healthy subjects recruited as controls. Two main subfractions of HDL (HDL2 (d = 1.063-1.125 g/mL) and HDL3 (d = 1.125-1.210 g/mL)) were isolated from the patients' serum samples using sequential ultracentrifugation. After compositional characterization, the capacity of HDL to efflux cholesterol (CEC%) from lipid-laden macrophages was measured. The HDL2 and HDL3 subfractions showed some differences in lipid and protein composition between the studied groups. In addition, both HDL subfractions (p < 0.001) revealed significantly reduced CEC% in HOFH patients (HDL2: 2.5 ± 0.1 and HDL3: 3.2 ± 0.2) in comparison with the HEFH (HDL2: 3.2 ± 0.1% and HDL3: 4.1 ± 0.2%) and healthy (HDL2: 3.3 ± 0.2% and HDL3: 4.5 ± 0.3%) subjects. Additionally, multinomial logistic regression results indicated that the CEC% of both HDL2 (OR: 0.091; 95% CI: 0.018-0.452, p < 0.01) and HDL3 (OR: 0.118; 95% CI: 0.035-0.399, p < 0.01) subfractions are strongly and inversely associated with the homozygous form of FH. A decreased capacity of HDL particles to efflux cholesterol from macrophages might identify homozygous FH patients who are at elevated risk for premature CVDs. Prospective studies with a large sample size are warranted to evaluate this hypothesis