Antioxidant Effects of Trehalose in an Experimental Model of Type 2 Diabetes.

BACKGROUND: Oxidative stress that occurs as a consequence of the imbalance between antioxidant activity and free radicals can contribute in the pathogenesis of metabolic disorders, such as type 2 diabetes mellitus (T2DM). Antioxidant therapies have been proposed as possible approaches to treat and attenuate diabetic complications. The purpose of this study was to evaluate potential antioxidant effects of trehalose on oxidative indices in a streptozotocin (STZ)-induced diabetic rat model. METHODS: Diabetic rats were divided randomly into five treatment groups (six rats per group). One test group received 45 mg/kg/day trehalose via intraperitoneal injection, and another received 1.5 mg/kg/day trehalose via oral gavage for 4 weeks. Three control groups were also tested including nondiabetic rats as a normal control (NC), a nontreated diabetic control (DC), and a positive control given 200 mg/kg/day metformin. Levels of thiol groups (-SH), and serum total antioxidant capacity were measured between control and test groups. In addition, superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzyme activities were assessed. RESULTS: In both oral and injection trehalose-treated groups, a marked increase was observed in serum total antioxidant capacity (TAC) (p > 0.05) and thiol groups (-SH) (p < 0.05). Also, SOD and GPx activities were increased after 4 weeks of treatment with trehalose. CONCLUSION: In conclusion, the present results indicate ameliorative effects of trehalose on oxidative stress, with increase antioxidant enzyme activities in STZ-induced diabetic rats.

Investigation of the Effects of Difluorinated Curcumin on Glycemic Indices in Streptozotocin-Induced Diabetic Rats.

BACKGROUND: Curcumin is an antioxidant agent that improves glycemia in animal models of diabetes. Clinically curcumin use is limited due to poor solubility, weak absorption, and low bioavailability; therefore, this study to investigate the effects of curcumin's analog, difluorinated curcumin (CDF), on fasting blood glucose (FBG), oral glucose tolerance test (OGTT), and insulin tolerance test (ITT), in streptozotocin (STZ)-induced diabetic rats was undertaken. METHODS: STZ-induced diabetes rats were randomly assigned to six groups (7 rats per group). They were treated daily by oral gavage with curcumin (200 and 100 mg/kg/day), CDF (200 and 100 mg/kg/day), and metformin (200 mg/kg/day) as a positive control group, for 4 weeks. Two diabetic control (DC) and normal control (NC) groups (non-diabetic rats) received normal saline and citrate buffer, respectively. FBG was measured at the beginning and end of the treatment (Day 0 and week 4) and OGTT and ITT were performed to determine glucose tolerance and insulin sensitivity. RESULTS: Cur100, CDF 100, and CDF200 significantly decreased FBG levels after 4 weeks oral administration by -34% (-150 mg/dL ± 70, p = 0.02), -36% (123 mg/dL ±67, p < 0.04), and - 40% (-189 mg/dL ± 91, p = 0.03), respectively. Glucose sensitivity by OGTT showed a significant improvement in glucose tolerance ability in all treated groups compared with DC group. ITT demonstrated that insulin response improved significantly in Cur100 and CDF 200 groups. CONCLUSION: Overall, CDF improved glucose tolerance and insulin sensitivity, while reducing FBG compared to curcumin, suggesting that curcumin analogs may have therapeutic utility in diabetes.

Investigation of the Effects of Trehalose on Glycemic Indices in Streptozotocin-Induced Diabetic Rats.

BACKGROUND AND AIM: Diabetes is a chronic metabolic disorder with considerable morbidity and mortality because of its associated complications that has become a challenging health problem worldwide. Trehalose (mycose) is a nonreducing disaccharide with a unique therapeutic potency without adverse effects, which has been found to improve glucose metabolism and homeostasis in different diabetes models. We hypothesized that trehalose can reduce blood glucose and improve insulin sensitivity. We have conducted this study to evaluate the effect of trehalose on glycemic indices in streptozotocin (STZ)-induced diabetic rats. METHOD: Fourteen diabetic rats were randomly assigned in two treatment groups (seven rats per group) that received trehalose at a dose of 1.5 g/kg/day via oral gavage and a dose of 45 mg/kg/day via intraperitoneal (i.p.) injection. Three control groups, including a positive control, diabetic control (DC), and nondiabetic rats as a normal control group (NC), received metformin (200 mg/kg/day), normal saline, and citrate buffer, respectively. The levels of fasting blood glucose (FBG) were measured at baseline (week 0) and after 4 weeks of treatment. Moreover, an oral glucose tolerance test (OGTT) was performed at the end of the study to determine glucose tolerance. RESULTS: The results showed that FBG levels were significantly decreased by -66% (-221 ± 65 mg/dL, p = 0.01), -40% (-114 ± 46 mg/dL, p = 0.02), and - 72% (-191 ± 68 mg/dL, p = 0.01) in trehalose-oral, trehalose-i.p., and metformin groups, respectively, after 4 weeks of administration. Evaluating the results of glucose tolerance test and analysis of corresponding areas under the glucose curve (AUCglucose) over 180 min indicated that glucose tolerance was significantly improved in the trehalose-i.p. group (p = 0.03) compared to DC group. CONCLUSION: Our findings suggested that trehalose administered via i.p. route might reduce FBG levels and improve glycemic control in STZ-induced diabetic rats.

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.

Evaluation of vitamin D3 deficiency: A population-based study in northeastern Iran.

BACKGROUND AND AIM: In recent years, vitamin D deficiency has become a major worldwide problem that can exert harmful effects. The aim of the present study was to evaluate the sex- and age-related prevalence of vitamin D deficiency in people from Mashhad, northeastern Iran. METHODS: In this cross-sectional study conducted over a period of 1 year (2015-2016), 7504 subjects who referred to Mashhad medical centers were randomly enrolled in the study. The study population was divided into four groups based on sex and age, as following: group 1, 6 to 18 years; group 2, 19 to 35 years; group 3, 36 to 50 years; and group 4, 51 to 65 years. Since vitamin D levels <10, 10 to 20, and 20 to 30 ng/mL are considered as severe, moderate, and mild deficiency, respectively, we used these criteria for categorizing our population. RESULTS: Of the total population in our study, 65.26% (4902; 57.81% of men and 72.07% of women) showed some degree of vitamin D deficiency. In addition, we found that vitamin D deficiency was common in all age groups (6-18, 19-35, 36-50, and 51-65 years), and more common in women (58.5%, 80.12%, 63.83%, and 88.44%, respectively) than men (41.66%, 59.86%, 44.97%, and 84.75%, respectively). CONCLUSION: Vitamin D deficiency is a major health problem in all age groups and is more common in women. This information would help to provide a progressive prevention program to maintain health and manage some of the vitamin-related disorders and diseases that especially affect women.

The effects of curcumin on Brain-Derived Neurotrophic Factor expression in neurodegenerative disorders.

Brain-Derived Neurotrophic Factor (BDNF) is a crucial molecule implicated in plastic modifications related to learning and memory. The expression of BDNF is highly regulated, which can lead to significant variability in BDNF levels in healthy subjects. Changes in BDNF expression might be associated with neuropsychiatric diseases, particularly in structures important for memory processes, including the hippocampus and parahippocampal areas. Curcumin is a natural polyphenolic compound that has great potential for the prevention and treatment of age-related disorders by regulating and activating the expression of neural protective proteins such as BDNF. This review discusses and analyzes the available scientific literature on the effects of curcumin on BDNF production and function in both in vitro and in vivo models of disease.

The effect of intravenous trehalose administration in a patient with multiple sulfatase deficiency.

Introduction: We describe the case of a female child with multiple sulfatase deficiency (MSD) who received intravenous (IV) trehalose (15 g/week) for 3 months. Methods: The efficacy of trehalose was evaluated by comparing serum biomarkers, a quality-of-life questionnaire (HRQoL), and imaging (brain MRI and ultrasonography of liver and spleen) at weeks 0 (W0) and 12 (W12). Results: The improvement in quality of life assessments along with a slight decrease in the spleen dimensions were observed after 3-month intervention. Conclusions: Future research with a larger MSD population and a longer-term follow-up is warranted to determine whether trehalose can improve MSD patient health and clinical outcomes.

Effects of Trehalose Administration in Patients with Mucopolysaccharidosis Type III.

BACKGROUND AND AIM: Mucopolysaccharidosis type III (MPS III) is a rare autosomal recessive lysosomal storage disease (LSD) caused by a deficiency of lysosomal enzymes required for the catabolism of glycosaminoglycans (GAGs), mainly in the central nervous system. Trehalose has been proposed as a potential therapeutic agent to attenuate neuropathology in MPS III. We conducted a single-arm, open-label study to evaluate the efficacy of trehalose treatment in patients with MPS IIIA and MPS IIIB. METHODS: Five patients with MPS III were enrolled. Trehalose was administrated intravenously (15 g/week) for 12 weeks. Health-related quality of life and cognitive function, serum biomarkers, liver, spleen, and lung imaging were assessed to evaluate trehalose efficacy at baseline and trial end (week 12). RESULTS: TNO-AZL Preschool children Quality of Life (TAPQOL) scores increased in all patients, and the mean scores for quality of life were increased after the intervention. Serum GAG levels were reduced in all treated patients (however, the differences were not statistically significant). Alanine aminotransferase (ALT) levels were reduced in all patients post-treatment (p=0.0039). The mean levels of aspartate transaminase (AST) were also decreased after 12 weeks of treatment with Trehalose. Decreased serum pro-oxidant-antioxidant balance and increased GPX activity were observed at the end of the study. Decreases in mean splenic length were observed, whereas the liver volume did not change. CONCLUSION: Improvements in health-related quality of life and serum biomarkers (GAGs, liver aminotransferase levels, antioxidant status), as well as liver and spleen size, were found following 3 months of trehalose administration in patients with MPS IIIA and MPS IIIB.

The effects of oral trehalose on glycaemia, inflammation, and quality of life in patients with type 2 diabetes: a pilot randomized controlled trial.

Introduction: Trehalose is a naturally occurring disaccharide of 2 glucose molecules, which has been suggested as a potential therapeutic agent to reduce blood glucose and ameliorate diabetes-related complications in type 2 diabetes (T2D). This study aimed to determine the efficacy of medium-term trehalose treatment in patients with T2D. Material and methods: A double-blind, randomized, placebo-controlled trial in 40 patients with T2D was undertaken; 20 ingested trehalose 3.3 g/day and 20 placebo (sucrose), for 3 months. Parameters of glycaemic indices, high-sensitivity C-reactive protein (CRP), mood status, and quality of life were measured. Results: CRP was significantly lower with trehalose treatment (-0.62 ±0.3 mg/l, p = 0.02); however, no differences in glycaemic indices of fasting blood glucose (FBG) (-7.1 ±10.7 mg/dl, p = 0.15), glycated hemoglobin (HbA1c) (-0.1 ±0.4%, p = 0.73), insulin (0.73 ±0.8 µU/ml, p = 0.39), or insulin resistance (HOMA-IR) (0.19 ±0.33, p = 0.56) were seen between groups after 12 weeks. Depression and stress scores were lower with trehalose compared to the placebo group (p = 0.02 and p = 0.05, respectively), whilst the quality-of-life score was higher with trehalose compared to placebo (p = 0.03) at the end of study. Between-group differences in these indices did not reach statistical significance (-2.36 ±1.20, -2.21 ±1.39 and 3.00 ±1.76 for depression, stress, and quality-of-life score, respectively) (p > 0.05). The pro-oxidant antioxidant balance (PAB) did not differ between groups (-4.6 ±12.8, p = 0.72). Conclusions: 12 weeks of treatment with 3.3 g/day of oral trehalose significantly improves CRP as a marker of inflammation, with potential favourable effects on quality of life, depression, and stress levels, but overall glycaemic control and pro-oxidant-antioxidant balance were unaltered during this time frame.

Regulating NETosis: An emerging facet of statin pleiotropy.

NETosis has emerged as a new player in the pathogenesis of several diseases including atherosclerotic cardiovascular disease. There is accumulating evidence suggesting that NETosis is regulated by statins, thereby justifying an important lipid-independent pleiotropic action of statin drugs in reducing the risk of atherothrombosis as well as other pathologies.

Effects of statins on specialized pro-resolving mediators: An additional pathway leading to resolution of inflammation.

Statins are a class of cholesterol-lowering drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Anti-inflammatory and antioxidant properties, as well as improvement of endothelial function and plaque stabilization have also been proposed as parts of the pleiotropic effects of statins. Specialized pro-resolving mediators (SPMs) are endogenous lipid-derived molecules originating from ω-6 and ω-3 polyunsaturated fatty acids, such as arachidonic, docosahexaenoic and eicosapentaenoic acid that trigger and modulate the resolution of inflammation. Impaired SPM biosynthesis can lead to excessive or chronic inflammation and is implicated in the pathogenesis of several diseases. Exogenous administration of SPMs, including lipoxin, maresin, protectin, have been shown to improve both bacterial and viral infections, mainly in preclinical models, thus minimizing inflammation. Statin-triggered-SPM production in several in vitro and in vivo models may represent another anti-inflammatory pathway involving these drugs. This commentary discusses scientific publications on the effects of statins on SPMs and the resolution of inflammation process.

Antioxidant Effects of Statins by Modulating Nrf2 and Nrf2/HO-1 Signaling in Different Diseases.

Statins are competitive inhibitors of hydroxymethylglutaryl-CoA (HMG-CoA) reductase and have been used to treat elevated low-density lipoprotein cholesterol (LDL-C) for almost four decades. Antioxidant and anti-inflammatory properties which are independent of the lipid-lowering effects of statins, i.e., their pleiotropic effects, might be beneficial in the prevention or treatment of many diseases. This review discusses the antioxidant effects of statins achieved by modulating the nuclear factor erythroid 2 related factor 2/ heme oxygenase-1 (Nrf2/HO-1) pathway in different organs and diseases. Nrf2 and other proteins involved in the Nrf2/HO-1 signaling pathway have a crucial role in cellular responses to oxidative stress, which is a risk factor for ASCVD. Statins can significantly increase the DNA-binding activity of Nrf2 and induce the expression of its target genes, such as HO-1 and glutathione peroxidase) GPx, (thus protecting the cells against oxidative stress. Antioxidant and anti-inflammatory properties of statins, which are independent of their lipid-lowering effects, could be partly explained by the modulation of the Nrf2/HO-1 pathway.

Impact of Intravenous Trehalose Administration in Patients with Niemann-Pick Disease Types A and B.

BACKGROUND AND AIMS: Niemann-Pick disease (NPD) types A (NPA) and B (NPB) are caused by deficiency of the acid sphingomyelinase enzyme, which is encoded by the SMPD1 gene, resulting in progressive pathogenic accumulation of lipids in tissues. Trehalose has been suggested as an autophagy inducer with therapeutic neuroprotective effects. We performed a single-arm, open-label pilot study to assess the potential efficacy of trehalose treatment in patients with NPA and NPB patients. METHODS: Five patients with NPD type A and B were enrolled in an open-label, single-arm clinical trial. Trehalose was administrated intravenously (IV) (15 g/week) for three months. The efficacy of trehalose in the management of clinical symptoms was evaluated in patients by assessing the quality of life, serum biomarkers, and high-resolution computed tomography (HRCT) of the lungs at the baseline and end of the interventional trial (day 0 and week 12). RESULTS: The mean of TNO-AZL Preschool children Quality of Life (TAPQOL) scores increased in all patients after intervention at W12 compared to the baseline W0, although the difference was not statistically significant. The serum levels of lyso-SM-509 and lyso-SM were decreased in three and four patients out of five, respectively, compared with baseline. Elevated ALT and AST levels were decreased in all patients after 12 weeks of treatment; however, changes were not statistically significant. Pro-oxidant antioxidant balance (PAB) was also decreased and glutathione peroxidase (GPX) activity was increased in serum of patients at the end of the study. Imaging studies of spleen and lung HRCT showed improvement of symptoms in two patients. CONCLUSIONS: Positive trends in health-related quality of life (HRQoL), serum biomarkers, and organomegaly were observed after 3 months of treatment with trehalose in patients with NPA and NPB. Although not statistically significant, due to the small number of patients enrolled, these results are encouraging and should be further explored.

The role of incretins and incretin-based drugs in autoimmune diseases.

Incretin hormones, including glucagon-like peptide (GLP)-1, GLP-2 and glucose-dependent insulinotropic polypeptide (GIP), are gastrointestinal peptides secreted from enteroendocrine cells. These hormones play significant roles in many physiological processes via binding to G-protein coupled receptors (GPCRs) on different organs and tissues; one of them is the immunomodulatory effect on the immune system and its molecular components such as cytokines and chemokines. Anti-inflammatory effects of incretins and dependent molecules involving long-acting analogs and DPP4 inhibitors through regulation of T and B cell activation may attenuate autoimmune diseases caused by immune system disorders in mistakenly recognizing self as the foreign agent. In this review, we investigate incretin effects on the immune system response and the potential benefits of incretin-based therapy for treating autoimmune diseases.

Curcumin: A small molecule with big functionality against amyloid aggregation in neurodegenerative diseases and type 2 diabetes.

Amyloidosis is a concept that implicates disorders and complications that are due to abnormal protein accumulation in different cells and tissues. Protein aggregation-associated diseases are classified according to the type of aggregates and deposition sites, such as neurodegenerative disorders and type 2 diabetes mellitus. Polyphenolic phytochemicals such as curcumin and its derivatives have anti-amyloid effects both in vitro and in animal models; however, the underlying mechanisms are not understood. In this review, we summarized possible mechanisms by which curcumin could interfere with self-assembly processes and reduce amyloid aggregation in amyloidosis. Furthermore, we discuss clinical trials in which curcumin is used as a therapeutic agent for the treatment of diseases linking to protein aggregates.

Circular RNA and Diabetes: Epigenetic Regulator with Diagnostic Role.

Circular RNAs, a group of endogenous non-coding RNAs, are characterized by covalently closed cyclic structures with no poly-adenylated tails. It has been recently recommended that cirRNAs have an essential role in regulating genes expression by functioning as a translational regulator, RNA binding protein sponge and microRNA sponge. Due to their close relation to the progression of various diseases such as diabetes, circRNAs have become a research hotspot. A number of circRNAs (i.e., circRNA_0054633, circHIPK3, circANKRD36, and circRNA11783-2) have been shown to be associated with initiation and progression of diabetes. Based on reports, in a tissue, some circRNAs are expressed in a developmental stage-specific manner. In this study, we reviewed research on circular RNAs involved in the pathogenesis and diagnosis of diabetes and their prognostic roles.