Activation of angiotensin-converting enzyme 2 ameliorates metabolic syndrome-induced renal damage in rats by renal TLR4 and nuclear transcription factor κB downregulation.

Background: Metabolic syndrome (MetS) is an independent risk factor for chronic kidney disease (CKD) through many mechanisms, including activation of the renin-angiotensin system. The deleterious effects of angiotensin II (Ang II) can be counterbalanced by angiotensin-converting enzyme 2 (ACE2). Diminazene aceturate (DIZE), an anti-trypanosomal drug, can activate ACE2. Objective: This study aimed to investigate the possible reno-protective effects of DIZE in MetS rats with elucidation of related mechanisms. Materials and methods: Thirty adult male Wistar albino rats were divided equally into control, MetS, and MetS + DIZE groups. Body weight, systolic blood pressure (SBP), and urinary albumin levels were measured. Serum levels of fasting blood glucose (FBG), insulin, uric acid, lipid profile, urea, and creatinine were measured. Homeostasis Model Assessment Index (HOMA-IR) was estimated. Subsequently, renal levels of ACE2, Ang II, malondialdehyde (MDA), reduced glutathione (GSH), and tumor necrosis factor-α (TNF-α) were measured with histopathological and immunohistochemical assessment of TLR4 and NF-κB in renal tissues. Results: MetS caused dyslipidemia with significant increases in body weight, SBP, FBG, serum insulin, HOMA-IR, uric acid, urea, creatinine, urinary albumin, and renal levels of Ang II, MDA, and TNF-α, whereas renal ACE2 and GSH were significantly decreased. Renal TLR4 and NF-κB immunoreactivity in MetS rats was upregulated. DIZE supplementation of MetS rats induced significant improvements in renal function parameters; this could be explained by the ability of DIZE to activate renal ACE2 and decrease renal Ang II levels with downregulation of renal TLR4 and NF-κB expression. Conclusion: DIZE exerts a reno-protective effect in MetS, mainly by downregulating renal TLR4 and NF-κB levels.

Combination of magnesium supplementation with treadmill exercise improves memory deficit in aged rats by enhancing hippocampal neurogenesis and plasticity: a functional and histological study.

This study aimed to investigate the possible ameliorative effects of co-supplementation with Mg2+ and treadmill exercise on memory deficit in aged rats. Fifty male albino rats (10 young and 40 aged rats) were divided into 5 groups (10 rats/group): young, aged sedentary, aged exercised, aged Mg2+-supplemented, and aged exercised and Mg2+-supplemented. Memory was assessed using the Y-maze and novel object recognition tests. Plasma samples were collected for measurement of C-reactive protein (CRP). Subsequently, brain malondialdehyde and catalase levels were measured. Histological and immunohistochemical analyses of the hippocampi were performed. Our results showed impaired memory in aged sedentary rats, with significantly elevated plasma CRP and brain malondialdehyde levels and decreased brain catalase. The hippocampus of aged sedentary rats showed cellular degeneration, downregulation of synaptophysin (SYP) and proliferating cell nuclear antigen (PCNA), and upregulation of glial fibrillary acidic protein (GFAP) and caspase-3. Mg2+ supplementation and/or treadmill exercise significantly improved memory tests in aged rats, which could be explained by the upregulation of hippocampal SYP and PCNA expression and downregulation of GFAP and caspase-3 expression with antioxidant and anti-inflammatory mechanisms. The combined therapy had a better effect than both treatments alone, confirming the role of Mg2+ supplementation with physical exercise in enhancing age-related memory deficit. Novelty: Magnesium supplementation with treadmill exercise improves memory deficit in aged rats. The possible mechanisms are upregulation of the hippocampal synaptophysin and PCNA, downregulation of GFAP and caspase-3, the antioxidant and anti-inflammatory mechanisms.

Changes in Plasma Growth Differentiation Factor-15 After Laparoscopic Sleeve Gastrectomy in Morbidly Obese Patients: A Prospective Study.

PURPOSE: This study aimed to assess the potential changes of Growth differentiation factor 15 (GDF15) after laparoscopic sleeve gastrectomy (LSG) in morbidly obese patients. METHODS: We conducted a prospective study on 68 patients who underwent LSG and 58 cases, who were enrolled as a control group, to whom conservative measures of weight loss were adopted. Both groups were followed for 12 months. RESULTS: At the baseline, the serum GDF15 was comparable between LSG and conservative groups (409.93±119 versus 385.8±120.2 pg/mL, p =0.246). However, at 12 months after the operation, the serum GDF15 was significantly higher in the LSG than conservative groups (699.941 ±193.5 versus 559 ±159.7; p <0.001). The degree of serum GDF15 increase was higher in the LSG group (290.01 ±189.9 versus 173.14 ±116.7; p <0.001). The degree of serum GDF15 increase correlated negatively with the final BMI (r = -0.352, p =0.001) and weight loss (r = -0.793, p =0.001) at 12 months after the operation. The correlation analysis demonstrated that the initial GFD15 did not correlate with any baseline parameters. Multiple regression analysis of change in serum GDF15 showed a statistical significance of the weight loss after 12 months. CONCLUSION: The present work confirms the impact of successful weight loss on the circulating level of GDF15. Our study demonstrated that the circulating GDF15 increased significantly after LSG and it was correlated to the degree of weight loss.

Effect of laparoscopic sleeve gastrectomy on vasoactive mediators in obese hypertensive patients: A prospective study.

INTRODUCTION: The causal relationship between obesity and high blood pressure is established; however, the detailed pathways for such association are still under research. This work aims to assess the changes in neprilysin, vasoconstrictor and vasodilatory molecules in obese hypertensive patients undergoing laparoscopic sleeve gastrectomy (LSG). PATIENTS: The present prospective study was done on 59 hypertensive obese patients in whom LGS was performed. Blood pressure, as well as blood samples for neprilysin, angiotensinogen, angiotensin II, renin, endothelin-1 "ET-1", aldosterone, atrial natriuretic peptide "ANP" and B-type natriuretic peptide "BNP", were assessed before and 15 months after surgery. Patients were divided into two groups according to the remission of hypertension (HTN). RESULTS: After 15 months, remission of hypertension was seen in 42 patients (71%). The declines in the following measurements were significantly higher in patients with remission than those with persistent HTN: aldosterone (p = .029567), angiotensin II (p < .000001), angiotensinogen (p = .000021), neprilysin (p = .000601), renin (p = .000454) and endothelin-1(p = .000030). There was a significantly higher increment in ANP (p = .000002) and a non-significant increment in BNP (p = .081740). Angiotensin II 15 months after LSG and Δ ANP % were significant independent predictors of persistent HTN. CONCLUSION: In the setting of LSG, aldosterone, angiotensinogen, angiotensin II, renin and neprilysin were significantly lower in patients with remission of HTN after 15 months than those with persistent HTN, and natriuretic peptides were significantly higher. A lower postoperative level of angiotensin II and a larger percentage increment of ANP are independently associated with hypertension remission after LSG.

Dapagliflozin, a sodium glucose cotransporter 2 inhibitors, protects cardiovascular function in type-2 diabetic murine model.

Diabetes mellitus and its complications are major international health problems in which there are many limitations to the orthodox approaches in the treatment. Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of diabetic medications, with a different mechanism of action that may reduce risk of cardiovascular complications. To evaluate the effect of SGLT2 inhibitor monotherapy on cardiovascular complications in patients with type-2 diabetes and to compare its effect with the first-line therapy, metformin. Eighty rats divided into four groups were used: nondiabetic, diabetic nontreated, diabetic + met and diabetic + dapa. At the end, the arterial blood pressure and cardiac performance were assessed. Glycemic index, lipid profile, total antioxidant capacity, malondialdehyde, tumour necrosis factor a were measured. DNA changes were assessed from the hearts and aortae. Aortic tissue changes recorded using haematoxylin and eosin, Masson trichrome and iNOS immune stain. Glycemic index, lipid profile, oxidative stress and inflammatory parameters were significantly improved in both metformin and dapagliflozin treated groups with significant improvement in blood pressure and cardiac performance. Also, there were noticeable significant reduction in DNA fragmentation in aortic and cardiac tissues and reduction in collagen deposition and iNOS expression in aortic tissue. Dapagliflozin treatment results' significantly surpassed improvement of metformin treatment nearly in all parameters. Total genomic DNA extraction proved that SGL2 inhibitor (dapagliflozin) has superior glycemic control and cardiovascular protective effect over metformin especially in type-2 diabetes with high fat intake.