Alternate-day fat diet and exenatide modulate the brain leptin JAK2/STAT3/SOCS3 pathway in a fat diet-induced obesity and insulin resistance mouse model.

Introduction: Obesity is one of the most burdensome health problems and is closely linked to leptin resistance. The study examined whether an alternate-day high-fat diet (ADF) and/or GLP-1 agonist (exenatide) modulate brain leptin resistance caused by a high-fat diet (HFD). Material and methods: Sixty adult male mice were divided into 6 groups: (i) normal palatable diet (NPD), (ii) exenatide control (NPD received exenatide) (iii) HFD, (iv) ADF treated, (v) exenatide treated, (vi) ADF and exenatide treated. All animal groups were fed a HFD for 8 weeks, before they received treatment (ADF and/or exenatide) for 8 additional weeks. Body weight was assessed at the start and at the end of the experiment. Lipid profile, brain leptin and its receptor expression with the leptin-sensitive pathway, JAK2/STAT3/SOCS3/PTP1B, fasting blood glucose (FBG), serum insulin, liver metabolic handling via its regulators IRS1/PI3K/GLUT4 for hyperinsulinemia/obesity-induced PDK3/NAFLD2 modification, and liver enzymes were determined at the end of the experiment. Results: ADF and exenatide reduced body weight and FBG in HFD-obese mice (p < 0.05). The combined ADF and exenatide regimen enhanced the brain anorexic leptin/JAK2/STAT3 and attenuated the SOCS3/PTP1B pathway (p < 0.05). The ADF/exenatide anorexigenic brain effect also modulated liver glucose via IRS1/PI3K/GLUT4 expression (p < 0.05), attenuating NAFLD2 and PDK3 expression (p < 0.05). Liver enzymes and the histopathological profile confirmed the improvement. Conclusions: In HFD caloric consumption, a combination of ADF and GLP-1 agonist enhances the brain leptin anorexigenic effect with the improvement of the metabolic sequelae of hyperinsulinemia, hyperlipidemia and liver steatosis.

Is Adynamic Bone Always a Disease? Lessons from Patients with Chronic Kidney Disease.

Renal osteodystrophy (ROD) is a common complication of end-stage kidney disease that often starts early with loss of kidney function, and it is considered an integral part in management of patients with chronic kidney disease (CKD). Adynamic bone (ADB) is characterized by suppressed bone formation, low cellularity, and thin osteoid seams. There is accumulating evidence supporting increasing prevalence of ADB, particularly in early CKD. Contemporarily, it is not very clear whether it represents a true disease, an adaptive mechanism to prevent bone resorption, or just a transitional stage. Several co-players are incriminated in its pathogenesis, such as age, diabetes mellitus, malnutrition, uremic milieu, and iatrogenic factors. In the present review, we will discuss the up-to-date knowledge of the ADB and focus on its impact on bone health, fracture risk, vascular calcification, and long-term survival. Moreover, we will emphasize the proper preventive and management strategies of ADB that are pivotal issues in managing patients with CKD. It is still unclear whether ADB is always a pathologic condition or whether it can represent an adaptive process to suppress bone resorption and further bone loss. In this article, we tried to discuss this hard topic based on the available limited information in patients with CKD. More studies are needed to be able to clearly address this frequent ROD finding.

Kidneys in SARS-CoV-2 era: A challenge of multiple faces.

INTRODUCTION: With the evolution of SARS-CoV-2 pandemic, it was believed to be a direct respiratory virus. But, its deleterious effects were observed on different body systems, including kidneys. AIM OF WORK: In this review, we tried as much as we can to summarize what has been discussed in the literature about the relation between SARS-CoV-2 infection and kidneys since December, 2019. METHODS: Each part of the review was assigned to one or two authors to search for relevant articles in three databases (Pubmed, Scopus, and Google scholar) and collected data were summarized and revised by two independent researchers. CONCLUSION: The complexity of COVID-19 pandemic and kidney could be attributed to the direct effect of SARS-CoV-2 infection on the kidneys, different clinical presentation, difficulties confronting dialysis patients, restrictions of the organ transplant programs, poor outcomes and bad prognosis in patients with known history of kidney diseases who got infected with SARS-CoV-2.

Thyroid dysfunction and insulin resistance in end-stage renal disease patients before and 1 year after starting maintenance hemodialysis: A prospective multicenter study.

BACKGROUND: Thyroid dysfunction and insulin resistance (IR) are common findings in patients with ESRD. We aimed to evaluate thyroid dysfunction and IR in ESRD before and after 1 year of starting hemodialysis (HD). METHODS: This was a prospective study that recruited newly starting HD patients who fulfilled the inclusion criteria. Patients were evaluated for TSH, free T4, free T3, fasting insulin, fasting glucose, HOMA-IR, serum ferritin, and hs-CRP levels before starting their first dialysis session and after 1 year of regular HD. RESULTS: Eighty-one patients have completed the 1-year follow-up period. After 1 year of regular HD, there were statistically significant increments of hs-CRP, serum ferritin, and TSH levels. On the other hand, fasting insulin level and HOMA-IR showed statistically significant increments after 1 year of starting HD. After 1 year of regular HD, TSH level showed a positive correlation with hs-CRP and serum ferritin level, while free T3 was negatively correlated with HOMA-IR. On the other hand, there was a significant positive correlation between HOMA-IR, hs-CRP, and serum ferritin levels, while HOMA-IR was negatively correlated with Kt/V. CONCLUSIONS: This study suggests overlapping complex pathogenesis of thyroid dysfunction, chronic inflammation, and IR in chronic HD patients.

Upregulation of antioxidant nuclear factor erythroid 2-related factor 2 and its dependent genes associated with enhancing renal ischemic preconditioning renoprotection using levosimendan and cilostazol in an ischemia/reperfusion rat model.

INTRODUCTION: Ischemic preconditioning (Ipre) provides protection against renal ischemia-reperfusion (I/R) injury with its associated remote organ damage. This study examined the enhancing protective effect of Ipre with levosimendan or cilostazol in I/R-induced kidney and lung injury in a rat model. MATERIAL AND METHODS: Rats were divided into: sham-operated, I/R control, Ipre control, I/R + cilostazol or levosimendan and Ipre + cilostazol or levosimendan. Drugs were given 30 min before left renal I/R or 4 cycles of Ipre just before renal ischemia. RESULTS: The Ipre combined with the implemented drugs enhanced physiological antioxidant defense genes including renal nuclear factor erythroid 2-related factor 2 (Nrf2) and its dependent genes heme oxygenase-1 (HO-1) and NADPH-quinone oxidoreductase-1 (NQO-1) and improved malondialdehyde and superoxide dismutase renal tissue levels. The combined effect improved I/R consequences for blood urea, creatinine, and creatinine clearance and improved blood oxygenation and metabolic acidosis. Moreover, the combination improved the renal soluble intercellular adhesion molecule (ICAM), tumor necrosis factor α (TNF-α) and interlukin-6 (IL-6) with histopathological improvement of tubular necrosis with a decrease in the apoptotic marker caspase-3 and an increase in the anti-apoptotic Bcl-2 expression. CONCLUSIONS: Cilostazol or levosimendan potentiates the renoprotective effect of Ipre against renal I/R injury, associated with upregulation of antioxidant genes Nrf2, HO-1, and NOQ-1 expression.

Nifuroxazide Mitigates Angiogenesis in Ehlrich's Solid Carcinoma: Molecular Docking, Bioinformatic and Experimental Studies on Inhibition of Il-6/Jak2/Stat3 Signaling.

Nifuroxazide is an antidiarrheal medication that has promising anticancer activity against diverse types of tumors. The present study tested the anticancer activity of nifuroxazide against Ehrlich's mammary carcinoma grown in vivo. Furthermore, we investigated the effect of nifuroxazide on IL-6/jak2/STAT3 signaling and the possible impact on tumor angiogenesis. The biological study was supported by molecular docking and bioinformatic predictions for the possible effect of nifuroxazide on this signaling pathway. Female albino mice were injected with Ehrlich carcinoma cells to produce Ehrlich's solid tumors (ESTs). The experimental groups were as follows: EST control, EST + nifuroxazide (5 mg/kg), and EST + nifuroxazide (10 mg/kg). Nifuroxazide was found to reduce tumor masses (730.83 ± 73.19 and 381.42 ± 109.69 mg vs. 1099.5 ± 310.83) and lessen tumor pathologies. Furthermore, nifuroxazide downregulated IL-6, TNF-α, NFk-ß, angiostatin, and Jak2 proteins, and it also reduced tumoral VEGF, as indicated by ELISA and immunohistochemical analysis. Furthermore, nifuroxazide dose-dependently downregulated STAT3 phosphorylation (60% and 30% reductions, respectively). Collectively, the current experiment shed light on the antitumor activity of nifuroxazide against mammary solid carcinoma grown in vivo. The antitumor activity was at least partly mediated by inhibition of IL-6/Jak2/STAT3 signaling that affected angiogenesis (low VEGF and high angiostatin) in the EST. Therefore, nifuroxazide might be a promising antitumor medication if appropriate human studies will be conducted.

Blocking angiotensin 2 receptor attenuates diabetic nephropathy via mitigating ANGPTL2/TL4/NF-κB expression.

BACKGROUND: Diabetic nephropathy (DN) is a consequence of diabetes mellitus (DM) and is associated with early changes in renal angiotensin II (ANG II). These changes were evaluated using ANG II blocker valsartan early from week two of diabetes (experiment I, renoprotective) and late from week nine of diabetes (experiment II, renotherapeutic) to the end of both experiments at week twelve. METHODS AND RESULTS: In both experiments, adult male Wister rats were divided into (i) vehicle group; (ii) valsartan received oral 30 mg/Kg/day; (iii) diabetic received single 50 mg/Kg intraperitoneal streptozotocin injection; (iv) renoprotection, diabetic rats received valsartan treated in experiments I and II. DM effects on urine albumin excretion, blood pressure, and renal ANG II were measured. Urinary nephrin, kidney injury molecule-1 (KIM-1), renal angiopoietin-like protein 2 (ANGPTL2), and toll-like receptor 4 (TLR 4) mRNA expression were tested. DM-initiated fibrotic markers integrin, α-smooth muscle actin expression, and collagen IV and apoptotic protein caspase 3 were tested. DM induced early changes starting from week four in the tested variables. At week twelve, in both experiments, valsartan intervention showed a significant reduction in ANG II, ANGPTL2, TLR 4 and integrin expression and improvement in albuminuria, blood pressure, urinary biomarkers, fibrotic and apoptotic markers. CONCLUSIONS: Changes leading to DN starts early in the disease course and ANG II reduction decreased the expression of ANGPTL2 and integrin which preserve the glomerular barrier. Blocking ANG II was able to decrease TLR 4 and inflammatory cytokines leading to decreasing DN.

Chemopreventive Effect of 5-Flurouracil Polymeric Hybrid PLGA-Lecithin Nanoparticles against Colon Dysplasia Model in Mice and Impact on p53 Apoptosis.

The use of 5-fluorouracil (5FU) is associated with multifaceted challenges and poor pharmacokinetics. Poly(lactic-co-glycolic acid)-lipid hybrid nanoparticles (PLNs)-based therapy has received attention as efficient carriers for a diversity of drugs. This study evaluated the in vivo chemotherapeutic and anti-proliferative efficacy of 5FU-loaded PLNs against 1,2-dimethylhydrazine (Di-MH) prompted colon dysplasia in mice compared to free 5FU. 5FU PLNs were prepared. Male Swiss albino mice were distributed to six experimental groups. Group 1: Saline group. All the other groups were injected weekly with Di-MH [20 mg/kg, s.c.]. Group 2: Di-MH induced colon dysplasia control group. Groups 3 and 4: Di-MH + free 5FU treated group [2.5 and 5 mg/kg]. Groups 5 and 6: Di-MH + 5FU-PLNs treated group [2.5 and 5 mg/kg]. Free 5FU and 5FU-PLNs doses were administered orally, twice weekly. Treatment with 5FU-PLNs induced a higher cytoprotective effect compared to free 5FU as indicated by lower mucosal histopathologic score and reduction in number of Ki-67 immunpositive proliferating nuclei. Additionally, there was significant upregulation of p53 and caspase 3 genes in colon specimens. Our results support the validity of utilizing the PLNs technique to improve the chemopreventive action of 5FU in treating colon cancer.

Kidney injury molecule-1: A potential marker of renal recovery after laparoscopic sleeve gastrectomy.

BACKGROUND: Bariatric surgeries were reported to improve diabetes and hypertension; however, the effect on renal recovery has not been fully explored. The aim of this study was to evaluate the effect of laparoscopic sleeve gastrectomy (LSG) in morbidly obese patients on renal function, degree of albuminuria, and kidney injury molecule-1 (KIM-1) level. METHODS: This was a prospective observational study conducted at Mansoura University Hospitals from January to June 2017. Forty-four morbidly obese patients (29 females and 15 males) who met the 1991 WHO criteria for obesity surgery were included. Patients underwent surgical LSG for treatment of morbid obesity, and all were followed for 6 months after surgery. Demographic, clinical, and laboratory data were collected and compared before and after surgery. Primary endpoints were the differences of albuminuria, estimated glomerular filtration rate (eGFR) and serum KIM-1 between baseline (pre-surgery) and 6-month post-surgery values. RESULTS: Six-month post-surgery data showed significant reduction of body mass index, HbA1c, microalbuminuria, and serum KIM-1, and a significant increase in eGFR (all, P < 0.001). The serum KIM-1 level positively correlated with microalbuminuria and serum creatinine (r = 0.596, P = 0.001 and r = 0.402, P = 0.034, respectively). Postoperative data showed that patients with microalbuminuria had significantly lower eGFR and higher KIM-1 values than those without microalbuminuria (P = 0.003 and 0.049, respectively). CONCLUSION: We showed potential benefits of LSG against obesity-associated kidney damage. This is evidenced by improving eGFR and reducing levels of both KIM-1 and microalbuminuria. The serum level of KIM-1 may be a potential marker for renal recovery after LSG.

Could intraoperative magnesium sulphate protect against postoperative cognitive dysfunction?

BACKGROUND: Although there is much concern about the pathogenesis of postoperative cognitive dysfunction (POCD); no effective prevention strategies are currently described. The aim of this work was to study whether intraoperative magnesium sulphate could have a protective effect against developing POCD and to study its impact on serum level of S100B, a marker of neuronal degeneration. METHODS: This is a prospective randomized controlled trial carried out on 80 participants undergoing elective laparoscopic cholecystectomy, 40 participants received conventional general anesthesia (conventional anesthesia group) and 40 participants received conventional general anesthesia with extra administration of intraoperative magnesium sulphate (Mg sulphate group). Cognitive assessment for both groups was done preoperatively and 1 week postoperatively using Paired Associate Learning test (PALT) and Benton Visual Retention Test (BVRT). Quantitative determination of serum S100B was done for both groups preoperatively and one week postoperatively by using an enzyme- linked immunoabsorbent assay technique. RESULTS: Postoperative PALT and BVRT were significantly lower than preoperative PALT and BVRT in the conventional anesthesia group (P value =0.043, P value =0.015 respectively), but not in the Mg sulphate group (P value =0.134, P value =0.151 respectively). Postoperative S100B was significantly higher than preoperative S100B in the conventional anesthesia group (P value =0.006), but not in the Mg sulphate group (P value =0.293). CONCLUSIONS: Administration of intravenous infusion of magnesium sulphate during conventional general anesthesia can protect against POCD and attenuate the post operative elevation of serum S100B.

Endothelin-1/Nitric Oxide Ratio as a Predictive Factor of Response to Therapy With Terlipressin and Albumin in Patients With Type-1 Hepatorenal Syndrome.

BACKGROUND AND PURPOSE: Predictors of response to type-1 hepatorenal syndrome (HRS) therapy are urgently needed. This study's purpose is to evaluate the proposed predictors in these patients. METHODS: Forty-two type-1 HRS patients with cirrhosis were treated with albumin and terlipressin. Clinical, biochemical, and demographic parameters taken at the onset of therapy and changes in endothelin-1/nitric oxide (ET-1/NO) ratio during therapy were analyzed to check their predictive value. RESULTS: Response to treatment (serum creatinine level <1.5 mg/dL at the end of therapy) was shown in 20 patients (48%). Independent predictive variables of response to therapy were early reduction of ET-1/NO ratio ≥0.15 at day 3 of therapy and serum bilirubin baseline <8 mg/dL (area under the receiver operating characteristic curve, 0.751; P < 0.001; specificity, 55%; sensitivity, 85%). Response rates in patients with serum bilirubin level <8 and ≥8 mg/dL were 63% and 20%, respectively (P = 0.008). The corresponding values in patients with an early reduction of ET-1/NO ratio ≥0.15 and <0.15 on day 3 were 85% and 13.6%, respectively (P < 0.001). CONCLUSIONS: Early reduction of ET-1/NO ratio and lower serum bilirubin baseline can predict response to type-1 HRS therapy with albumin and terlipressin. Alternative therapy should be investigated for nonresponder type-1 HRS patients.

Recurrence of spontaneous bacterial peritonitis in cirrhosis: novel predictors.

BACKGROUND AND AIMS: Recurrence of spontaneous bacterial peritonitis (SBP) is still a matter of debate. We conducted this study to evaluate the probable factors that predict the recurrence of SBP in patients who recovered from the first episode of SBP and the long-term outcomes of SBP recurrence. METHODS: One hundred twenty-four patients diagnosed with liver cirrhosis, SBP and did not receive secondary prophylaxis either with norfloxacin or other antibiotics were included in this prospective cohort pilot study. Clinical, biochemical and ascitic fluid analysis parameters were evaluated. Ascitic fluid interferon-γ-induced protein (IP-10), calprotectin, interleukin-6 and tumor necrosis factor-α were measured by ELISA. RESULTS: Of these, 76 patients survived with an in-hospital mortality rate of 38.7%. The survivors were classified into two groups according to recurrence and nonrecurrence of SBP and survival time, clinical parameters and cause of death were investigated. Thirty-one participants had one or more attacks of SBP, with a recurrence rate of 40.8% within one-year follow-up. Before discharge, multivariate analysis showed that ascitic IP-10 (≥1220 pg/ml), ascitic calprotectin (≥550 ng/ml), serum albumin (≤2.5 g/dl), nonuse of prophylactic ß-blockers and use of proton-pump inhibitors (PPIs) were the independent variables in predicting recurrent SBP. Sepsis-related organ failure was the most common etiology of mortality in the recurrent SBP group within 3 and 6 months. CONCLUSION: Increased ascitic calprotectin and IP-10, hypoalbuminemia, nonuse of prophylactic ß-blockers and use of PPI were independently associated with increased SBP recurrence rate. Sepsis-related organ failure was the most common etiology of mortality.

Leflunomide-induced liver injury in mice: Involvement of TLR4 mediated activation of PI3K/mTOR/NFκB pathway.

AIMS: Leflunomide is a disease modifying anti-rheumatic drug (DMARD) beneficial in refractory cases of rheumatoid arthritis. Since leflunomide approval, hepatotoxicity and instructions of liver function monitoring have been recommended. The current work aimed to explore the possible role of inflammation in leflunomide-induced hepatotoxicity with a focus on the TLR4-mediated stimulation of PI3K/mTOR/NFκB pathway. MAIN METHODS: Forty-eight male albino mice were allocated into four different groups (n; 12 mice/group). Group (i): normal mice, Group (ii-iv) mice received escalating dosed/s of leflunomide (2.5, 5 or 10 mg/kg, p.o.) every 48 h for eight weeks. At the end of the study, mice were sacrificed, and blood samples were collected for determination of liver enzymes. Liver samples were collected; (1) formalin-fixed for histologic examination, (2) frozen for PI3K and mTOR genes PCR assays. KEY FINDINGS: Results indicated a significant elevation of liver enzymes in leflunomide-treated mice (10 mg/kg); AST and ALT activities were 218.17 ±â€¯6.83 U/L and 99.83 ±â€¯9.82 U/L versus 130.5 ±â€¯12.79 U/L and 44.72 ±â€¯3.58 U/L in the vehicle group. Additionally, histopathological examination revealed higher necro-inflammatory scores in leflunomide-treated mice. Immunohistochemistry indicated dose-dependent increased staining of TLR4 and caspase 3. Furthermore, leflunomide-treated mice (5 or 10 mg/kg) showed greater staining for NFκB compared to vehicle control. RT-PCR results revealed upregulations in genes expressing PI3K and mTOR by leflunomide. SIGNIFICANCE: The current study highlights the possible role of TLR4-PI3K/mTOR/NFκB in the pathogenesis of leflunomide-induced hepatic injury. A better understanding of mechanisms of leflunomide-induced hepatotoxicity may be of translational implication for the predictive, preventive and therapeutic purposes.

Insulin Resistance and Hepatitis C Virus-Associated Subclinical Inflammation Are Hidden Causes of Pruritus in Egyptian Hemodialysis Patients: A Multicenter Prospective Observational Study.

BACKGROUND: Pruritus is one of the most common and disturbing symptoms in hemodialysis (HD) patients. The pathogenesis of pruritus in HD patients is multifactorial; however, a little progress in understanding this pathogenesis has been achieved. OBJECTIVES: To evaluate the frequency and risk factors of pruritus among HD patients in Dakahlia, Egypt. METHODS: A total of 193 patients from 4 HD centers were included in this study. Pruritus intensity was assessed by visual analog scale. All patients were assessed by clinical and laboratory parameters, such as age, sex, duration of dialysis, dialysis adequacy, urea, calcium, phosphorus, parathyroid hormone, fasting insulin, fasting sugar, HOMA-IR, serum ferritin, high-sensitive C-reactive protein (hs-CRP) and hemoglobin. They were also investigated for hepatitis C virus (HCV) infection by HCV enzyme-linked immunosorbent assay, HCV-PCR for plasma and buffy coat for further detection of occult HCV infection. RESULTS: Male gender, dialysis duration, inadequate dialysis, anemia, high ferritin, hyperphosphatemia, hypocalcemia, hs-CRP, and insulin resistance were characteristic features in pruritic patients (p = 0.01, 0.006, 0.0001, 0.047, 0.01, 0.0001, 0.024, 0.000, and 0.0001, respectively). Significant positive correlations were found between pruritus score and each of age (p = 0.002, r = 0.222), duration of dialysis (p = 0.03, r = 0.151), serum ferritin (p = 0.001, r = 0.213), serum phosphorus (p = 0.0001, r = 0.59), fasting insulin (p = 0.001, r= 0.273), and HOMA-IR (p = 0.0001, r = 0.349), while there was a negative correlation with Kt/V (p= 0.0001, r = -0.459). Linear multivariate regression analysis showed that age, duration of dialysis, serum phosphorus, Kt/v, and hs-CRP were good predictors for pruritic score in HD patients. All HCV-infected patients (who were positive for both plasma and buffy coat HCV-PCR) had pruritus with -significantly higher pruritus score than non-infected patients (p = 0.009), they also showed significantly higher fasting insulin, HOMA-IR, and hs-CRP levels (p = 0.0001). CONCLUSIONS: Uremic pruritus (UP) is a serious problem in HD patients. hs-CRP, male gender, dialysis duration, insulin resistance, dialysis inadequacy, and hyperphosphatemia are positively correlated with the intensity of UP. HCV infection is associated with severe UP, insulin resistance, and inflammation.

Cardioprotective effect of ranolazine in nondiabetic and diabetic male rats subjected to isoprenaline-induced acute myocardial infarction involves modulation of AMPK and inhibition of apoptosis.

Diabetes increases the sensitivity of myocardium to ischemic damage and impairs response of the myocardium to cardioprotective interventions. The present study aimed to elucidate the potential cardioprotective effect provided by ranolazine during myocardial infarction in nondiabetic and diabetic male rats. As AMP-activated protein kinase (AMPK) has been shown to be involved in the cellular response to ischemic injury, in this context, the present animal study evaluated the modulating role of ranolazine in the AMPK expression in isoprenaline-induced myocardial ischemic rat model. Male rats were divided into 2 experiments: experiment I and II (nondiabetic and diabetic rats) and assigned to normal control, saline control for isoprenaline, isoprenaline control, and ranolazine-treated groups. Ranolazine administration revealed effectiveness in attenuating the severity of isoprenaline-induced myocardial injury in both nondiabetic and diabetic rats as revealed by ECG signs, histopathological score, and apoptotic markers via abrogating the increments in the inflammatory and oxidative stress markers and modulating AMPK expression. Therefore, the current cardioprotective effect of ranolazine was, at least in part, mediated through inhibition of apoptosis and modulation of AMPK expression, encouraging considering the utility of ranolazine in protection from acute myocardial infarction.

Angiotensin blockade attenuates diabetic nephropathy in hypogonadal adult male rats.

This study examined the effect of the aromatase inhibitor letrozole (0.5 mg/kg) alone or in combination with the angiotensin-receptor blocker valsartan (30 mg/kg) against streptozocin-induced diabetic nephropathy (DN) in hypogonadal (HG) rats for 12 weeks. First, we tested the HG effect on hormone levels, inflammatory cytokines, and oxidative stress in nondiabetic (ND) and diabetic (D) rats. HG was induced with the luteinizing hormone-releasing hormone antagonist cetrorelix (0.71 mg/kg). Diabetes enhanced hormonal hypogonadism and increased inflammation and oxidative stress. Next, experiments examined the effect of early letrozole and valsartan intervention on DN in HG rats. HG-ND and HG-D rats were treated with letrozole alone or in combination with valsartan. HG-D rats developed proteinuria and had increased blood urea nitrogen and creatinine, and histopathological evidence of renal injury, including glomerular hypertrophy and mesangial expansion. Valsartan alone or in combination with letrozole reduced proteinuria, improved renal functions, and reduced diabetes-induced renal angiotensin II. Both agents ameliorated nuclear factor kappa light chain enhancer of activated B cells, interleukin 1ß, interleukin 6, and tumor necrosis factor alpha levels. The combination decreased superoxide dismutase, malondialdehyde, and glutathione peroxidase levels, and prevented glomerular hypertrophy. In HG-D rats, valsartan reduced renal collagen IV and transforming growth factor-beta 1, especially when the testosterone level was corrected by letrozole. Thus, normalizing testosterone and inhibiting renal angiotensin II have a renoprotective effect against DN in HG male rats.

Community Acquired Acute Kidney Injury in Mansoura Nephrology Dialysis Unit: One Year Prospective Observational Study.

AIM: Acute kidney injury (AKI) is a major health problem with poor patient prognosis. We evaluated the clinical characteristics, risk factors, associated comorbidities, and outcomes of AKI patients. METHODOLOGY: A single-center prospective observational study. The patients were admitted in Mansoura Nephrology and Dialysis Unit over a period of 1 year from January to December, 2016. Patients were diagnosed as AKI or AKI in addition to chronic kidney disease according to the creatinine criteria of KDIGO 2013. All patients were subjected to complete history taking, physical examination, and full laboratory and pelvi-abdominal ultrasound investigations. The study outcomes were all-cause hospital mortality, and recovery of renal function. Predictors of mortality were assessed using multivariate logistic regression analysis. The study was reviewed and approved by local Ethical Committee of IBR. RESULTS: We evaluated 199 (96 males plus 103 females) aged between 18 and 88 years old. Dehydration was the commonest precipitating factor for AKI in our patients (68.8%) and Oliguria was the commonest symptom present in 47.7% of patients. Intravenous fluids were received by 79.9% of patients, 22.6% of patients received diuretics, and 33.7% received renal replacement therapy in the form of intermittent hemodialysis. Death occurred in 25 patients (13.16%) and 69 (36.32%) showed no renal recovery. Shock and sepsis were the most significant predictors of mortality. Conclusion: Community acquired AKI is a major health problem with high morbidity and mortality.

Obesity may be erythropoietin dose-saving in hemodialysis patients.

BACKGROUND: In dialysis patients, the obesity-survival paradox still requires an explanation. Anemia and high doses of erythropoiesis-stimulating agents (ESAs) are associated with worse outcomes in the hemodialysis (HD) population. In the present study, we explored the relation between obesity and anemia control in a sample of maintenance HD patients in Egypt. METHODS: This multicenter observational study included 733 patients on maintenance HD from 9 hemodialysis centers in Egypt. Clinical and laboratory data as well as average doses of ESAs and parenteral iron were recorded. The erythropoietin resistance index (ERI) was calculated. RESULTS: Obesity, defined as a body mass index (BMI) ≥ 30 kg/m2, was present in 22.6% of the studied population. The target hemoglobin level (10.0-11.5 g/dL) was achieved in 27.3% of non-obese and 25.3% of obese patients, with no significant difference. The median serum ferritin and the values of transferrin saturation index did not differ significantly between these two groups. The weekly ESA dose was significantly lower in obese than in non-obese patients (P = 0.0001). A trend toward higher ESA doses and ERI values was observed in patients with lower BMIs (P < 0.0001). Multiple linear regression revealed that the BMI and urea reduction ratio were the strongest predictors of the ERI. CONCLUSION: Our study adds more evidence to obesity-associated advantages in HD patients. BMI may determine ESA response, with better responses observed in patients with higher BMIs.

An optimized dose of raspberry ketones controls hyperlipidemia and insulin resistance in male obese rats: Effect on adipose tissue expression of adipocytokines and Aquaporin 7.

Obesity constitutes a major worldwide problem in which hyperlipidemia and insulin resistance represents adverse metabolic consequences of it. The present study was conducted to elucidate the role of raspberry ketones (RKs) in controlling body weight gain, hyperlipidemia and insulin resistance in male obese rats through affecting the expression of various adipocytokines. As Aquaporin-7 is co-related with the expression of various adipocytokines and has recently emerged as a modulator of adipocyte metabolism, the present study evaluated the effect of RKs on adipose tissue expression of aquaporin-7(AQP7) in high-fat (HF) diet-fed rats. Groups of male rats were assigned to normal, HF diet-fed control rats and RKs-treated (250 and 500 mg/kg) groups. RKs administration effectively abrogated hyperlipidemia and oxidative burden and enhanced insulin sensitivity. In addition, treatment with RKs ameliorated adipose tissue and liver indices and the reduced adipocyte diameters. Moreover, administration of the low dose of RKs ameliorated the expression of apelin and its receptor, and visfatin with upregulating adiponectin expression compared to HF diet control rats. However, both doses effectively downregulated leptin expression. It was obvious that both RKs doses revealed effectiveness in upregulating the AQP7 expression. The present data suggest the promising therapeutic role of RKs in HF diet-induced obesity that is likely attributable, at least in part, to upregulation of AQP7 expression.

Neuroprotective effect of duloxetine in a mouse model of diabetic neuropathy: Role of glia suppressing mechanisms.

AIMS: Painful diabetic neuropathy (PDN) is one of the most frequent complications of diabetes and the current therapies have limited efficacy. This study aimed to study the neuroprotective effect of duloxetine, a serotonin noradrenaline reuptake inhibitor (SNRI), in a mouse model of diabetic neuropathy. MAIN METHODS: Nine weeks after developing of PDN, mice were treated with either saline or duloxetine (15 or 30 mg/kg) for four weeks. The effect of duloxetine was assessed in terms of pain responses, histopathology of sciatic nerve and spinal cord, sciatic nerve growth factor (NGF) gene expression and on the spinal expression of astrocytes (glial fibrillary acidic protein, GFAP) and microglia (CD11b). KEY FINDINGS: The present results highlighted that duloxetine (30 mg/kg) increased the withdrawal threshold in von-Frey test. In addition, both doses of duloxetine prolonged the licking time and latency to jump in the hot-plate test. Moreover, duloxetine administration downregulated the spinal expression of both CD11b and GFAP associated with enhancement in sciatic mRNA expression of NGF. SIGNIFICANCE: The current results highlighted that duloxetine provided peripheral and central neuroprotective effects in neuropathic pain is, at least in part, related to its downregulation in spinal astrocytes and microglia. Further, this neuroprotective effect was accompanied by upregulation of sciatic expression of NGF.