Isosteviol attenuates streptozotocin-mediated diabetic nephropathy in rats by upregulating and stimulating adenosine monophosphate-activated protein kinase.

Diabetic nephropathy (DN) is the major microvascular complication of type 1 diabetes mellitus (T1DM). Impairment in adenosine monophosphate-activated protein kinase (AMPK) activity was shown to mediate the pro-oxidant and inflammatory mechanisms underlying DN. Isosteviol (ISV), isolated from Stevia rebaudiana, has antioxidant and anti-inflammatory properties and alleviates non-alcoholic fatty liver disease and lethal septic shock by activating AMPK. The effect of ISV on DN is unknown. This study examined if ISV alleviates DN in T1DM in adult male rats by activating AMPK. Diabetes was induced in rats by a single intraperitoneal (i.p.) injection of streptozotocin (STZ) (65 mg/kg). Five groups of rats (n=8 each) were designed and included: control, ISV (20 mg/kg orally), STZ (diabetic), STZ + ISV (20 mg/kg orally), STZ + ISV + CC (compound C/an AMPK inhibitor) (0.2 mg/kg, i.p). Fasting glucose and insulin levels, assessment of kidney function tests, lipid profile analysis, measurements of markers of oxidative stress and inflammation, PCR and Western blotting analysis, and histological studies of the kidneys were conducted. With no effect on fasting glucose or insulin levels (p>0.05), ISV reduced serum levels of cholesterol, triglycerides (TGs), and low-density lipoprotein cholesterol (LDL-c) (p<0.01). ISV also increased urinary creatinine excretion, reduced urinary albumin levels, and alleviated tubular and glomerular damage of STZ-diabetic kidneys. ISV also lowered the renal levels of malondialdehyde (MDA) (p<0.01), tumor necrosis factor-alpha (TNF-α) (p<0.01), interleukin-6 (IL-6) (p<0.01), and mRNA and nuclear protein levels of nuclear factor kappaB (NF-κB) in both the control and diabetic rats. Concomitantly, ISV increased the phosphorylation of AMPK (p<0.05), levels of superoxide dismutase (SOD) (p<0.01), catalase (CAT) (p<0.01), total glutathione (GSH) (p<0.01), and mRNA and nuclear protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2) (p<0.01) in the kidneys of the control and diabetic rats. Co-administration of CC prevented all renal protective effects of ISV and reversed all these effects. In conclusion, AMPK-induced inhibition of NF-κB and activation of Nrf2 entails the nephroprotective effect of ISV in STZ-diabetic rats.

Ellagic acid prevents streptozotocin-induced hippocampal damage and memory loss in rats by stimulating Nrf2 and nuclear factor-κB, and activating insulin receptor substrate/PI3K/Akt axis.

This study examined the protective effect of ellagic acid (EA) against streptozotocin (STZ)-induced hippocampal damage and memory loss and investigated some mechanisms of action. Adult male rats were divided into 4 groups (n = 12) as control, control + EA (50 mg/kg), STZ-DM, and STZ-DM + EA. Treatments were given orally and daily for 8 weeks. Memory function was assessed by the Morris water maze (MWM) and passive learning avoidance test. In addition, blood samples were used to measure glucose and insulin levels. Also, the hippocampus was used to measure markers of oxidative stress, inflammation, and insulin signaling. Associated with the improved memory, EA preserved the structure of the CA1 area of rats' hippocampus and suppressed the hippocampal expression of Bax and cleaved caspase 3. Concomitantly, EA increased rats' weekly weights gain and fasting plasma insulin levels and reduced the hippocampal levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and plasma glucose levels in diabetic rats. In both the control and STZ-DM rats, EA significantly lowered the hippocampal levels of reactive oxygen species (ROS) and malondialdehyde (MDA) but significantly increased the hippocampal levels of glutathione (GSH) and manganese superoxide dismutase (MnSOD), as well as the nuclear levels of NF-κB and nuclear factor-erythroid 2-related factor (Nrf-2). Besides, and in the hippocampus of both groups, EA increased the phosphorylation of insulin receptor substrate (IRS), PI3K, Akt, GS3Kß, and CREB, and increased levels of BDNF and Bcl-2. In conclusion, these data suggest that the neuroprotective effect of EA on rats' hippocampus and memory function is associated with upregulation of Nrf2 and Bcl-2, suppression of NF-κB, and activation of CREB and IRS/PI3K/Akt/ GS3Kß axis.

Ellagic acid protects against diabetic cardiomyopathy in rats by stimulating cardiac silent information regulator 1 signaling.

This study investigated the protective effect of ellagic acid (EA) against diabetic cardiomyopathy (DC) in streptozotocin (STZ)-treated rats and examined if the mechanism of protection involves modulating silent information regulator 1 (SIRT1). Adult male rats were divided into 5 groups (n = 12/each) as control, control + EA, diabetes mellitus (DM), STZ + EA, and STZ + EA + EX-527 (a SIRT1 inhibitor). With a hypoglycemic and insulin-releasing effect, EA preserved cardiomyocyte structure and suppressed the increase in heart weights and collagen deposition in the left ventricle (LV) of DM rats. Concomitantly, EA improved LV systolic and diastolic functions; reduced serum levels of creatinine kinase-MB (CK-MB), brain natriuretic peptide (BNP), and troponin-I, downregulated transforming growth factor beta 1 (TGF-ß1), smad3, and cleaved caspase-3, and increased Bax/Bcl-2 ratio. Of note, EA increased the expression and activity of SIRT1 and suppressed the acetylation of nuclear factor erythroid-derived 2-like 2 (Nrf2), nuclear factor kappa B (NF-κB), smad2, and forkhead box, class O (FOXO1) in the LVs of both the control and diabetic groups. These effects were associated with a significant reduction in the levels of reactive oxygen species (ROS), malondialdehyde (MDA), tumor necrosis factor kappa (TNF-κ), and interleukin 6 (IL-6) levels and activity of NF-κB but with increased activity Nrf2 and levels of glutathione (GSH), superoxide dismutase (SOD), and Bcl-2. All these effects were abolished by EX-527. In conclusion, EA protected against DC by its hypoglycemic, antioxidant, anti-inflammatory, and anti-fibrotic, and anti-apoptotic effects through upregulation and activation of SIRT1.

A randomized controlled trial of lorcaserin and lifestyle counselling for weight loss maintenance: changes in emotion- and stress-related eating, food cravings and appetite.

Anti-obesity medication may help people maintain diet-induced reductions in appetite. The present exploratory analysis assessed the effects of lorcaserin on changes at 24 weeks post-randomization in emotion- and stress-related eating, food cravings and other measures of appetite (i.e. binge eating, cognitive restraint, disinhibition, hunger, preoccupation with eating and fullness). The parent study investigated the efficacy of combined lorcaserin and behavioural treatment in facilitating weight loss maintenance (WLM) in 137 adults (mean age = 46.1 years, 86.1% female, 68.6% black) who had lost ≥5% of initial weight during a 14-week, low-calorie diet (LCD) run-in. Participants were randomly assigned to lorcaserin or placebo and were provided with group WLM counselling sessions. Emotion- and stress-related eating, food cravings and appetite were measured at the start of the LCD (week -14), randomization (0) and week 24. From randomization, lorcaserin-treated participants had significantly greater improvements in emotion- and stress-related eating compared to placebo-treated participants (P = 0.04). However, groups did not differ significantly after randomization in changes in the frequency of food cravings, binge eating or other measures of appetite (Ps > 0.05). Compared to placebo, lorcaserin may improve emotion- and stress-related eating.