Impact of Cerium Oxide Nanoparticles on Metabolic, Apoptotic, Autophagic and Antioxidant Changes in Doxorubicin-Induced Cardiomyopathy: Possible Underlying Mechanisms.

Background: In the current study, the effects of cerium oxide nanoparticles (nanocerium; NC) on doxorubicin (DOX)-induced cardiomyopathy and its possible underlying mechanisms were addressed. Methods: 32 adult male rats were allocated into 4 groups; i) control group, ii) NC group; rats received NC (0.2 mg/kg, i.p., daily), iii) DOX group; rats received DOX 4 mg/kg (2 injections with a 14-day interval), and iv) DOX+NC group as DOX but rats received NC. At the end of the experiment, ECG and ECHO recordings and assessments of the levels of cardiac enzymes (CK-MB, LDH), and myocardial oxidative stress (MDA, catalase, and GSH), the expression of LC3 and beclin1 (markers of autophagy), caspase3 (marker of apoptosis) by immunohistochemistry, the expression of acetyl-CoA carboxylase alpha (ACCA) by PCR, and 5'adenosine monophosphate-activated protein kinase (AMPK) levels in the heart tissues were performed. Results: The DOX group displayed a prolonged corrected QT interval, an increase in cardiac enzymes (CK-MB and LDH), myocardial oxidative stress (high MDA with low catalase and GSH), expression of ACCA, caspase-3, beclin1, and LC3 in myocardial tissues, with reduction in myocardial AMPK levels, and myocardial contractility (low ejection fraction, and fractional shortening). On the other hand, administration of NC with DOX resulted in significant improvement of all studied parameters. Conclusion: NC offers a cardioprotective effect against DOX-induced cardiomyopathy. This effect might be due to its antioxidant and antiapoptotic effects as well as to the modulation of autophagy and metabolic dysfunctions induced by DOX in the heart tissues.

Vitamin K2 (MK-7) Intercepts Keap-1/Nrf-2/HO-1 Pathway and Hinders Inflammatory/Apoptotic Signaling and Liver Aging in Naturally Aging Rat.

Aging is a naturally occurring physiological process with a deleterious impact on various body organs and humans' well-being. The aging population is increasing worldwide, which imposes the need for the exploration of nutritional options that can intercept the impact of the aging processed on various body organs. Vitamin K2 (VK2) is a fat-soluble vitamin with emerging evidence on its therapeutic merits. In the current study, natural aging induced a significant liver deterioration with a disrupted Keap-1/Nrf-2/HO-1 axis and increased COX-2, iNOS and TNF-α expression and apoptotic and fibrotic changes. VK2 administration, on the other hand, improved the biochemical indices of liver function (total protein, albumin, ALT and AST); the suppressed hepatic expression of Keap-1 and increased the hepatic expression of Nrf-2 with a parallel increase in the hepatic activity of HO-1. Subsequently, the liver content and hepatic expression of TNF-α, COX-2 and iNOS were significantly retracted. In context, the liver content and hepatic expression of the fibrotic biomarkers TGFß and TIMP significantly retracted as well. Moreover, the TUNEL assay confirmed the retraction of liver apoptotic changes. Of notice, electron transmission microscope examination confirmed the preservation of mitochondrial functions and preservation of the ultra-microscopical structures. In conclusion, the VK2-mediated interception of aging-induced Keap-1/Nrf-2/HO-1 signaling suppressed the hepatic contents of inflammatory and fibrotic biomarkers, as well as apoptotic changes with preservation of the hepatic architectural and functional status. VK2 can be presumed to be an effective nutritional supplement to the aging population to spare the liver, amongst other body organs, against aging-induced deleterious injury.

α-Lipoic Acid Protects against Cyclosporine A-Induced Hepatic Toxicity in Rats: Effect on Oxidative Stress, Inflammation, and Apoptosis.

The clinical application of cyclosporine A (CsA) as an immunosuppressive agent is limited by its organ toxicity. We aimed to evaluate the effectiveness of α-lipoic acid against CsA-induced hepatotoxicity and to delineate the underlying molecular mechanisms. Male Wistar rats (n = 24, 8 per each group) received the vehicle, CsA (25 mg/kg) and/or ALA (100 mg/kg, p.o.) for 3 weeks. Biochemical markers of liver function (serum ALT, AST, ALP < GGT), oxidative stress (MDA, TAC, SOD, GSH, Nrf2/HO-1), inflammation (NF-κB, CD68, iNOS, NO, COX-2), and apoptosis (caspase-3) were assessed in serum and tissue. Liver histological analysis using H&E and Sirius red was performed. The development of liver injury in CsA-treated animals was indicated by elevated levels of liver enzymes, oxidants/antioxidants imbalance, inflammatory cells infiltration, up-regulated expression of inflammatory mediators, and apoptosis. These changes were associated with altered architecture of hepatic cells and fibrous connective tissue. ALA co-administration protected against CsA-induced liver damage and ameliorated biochemical changes and cellular injury. In conclusion, ALA demonstrated hepatoprotective potential against CsA-induced liver injury through combating oxidative stress, inflammation, and apoptosis, highlighting ALA as a valuable adjunct to CsA therapy.

Effect of bone marrow mesenchymal stem cells-derived exosomes on diabetes-induced retinal injury: Implication of Wnt/ b-catenin signaling pathway.

BACKGROUND: Diabetic retinopathy (DR) is a serious microvascular complication of diabetes mellitus. Mesenchymal stem cells are currently studied as therapeutic strategy for management of DR. Exosomes, considered as a promising cell-free therapy option, display biological functions similar to those of their parent cells. In retinal development, Wnt/b-catenin signaling provides key cues for functional progression. The present study aimed to evaluate the potential efficacy of bone marrow-derived mesenchymal stem cell-derived exosomes (BM-MSCs-Ex) in diabetes-induced retinal injury via modulation of the Wnt/ b-catenin signaling pathway. METHODS: Eighty-one rats were allocated into 6 groups (control, DR, DR + DKK1, DR + exosomes, DR + Wnt3a and DR + exosomes+Wnt3a). Evaluation of each group was via histopathological examination, assessment of gene and/or protein expression concerned with oxidative stress (SOD1, SOD2, Nox2, Nox4, iNOS), inflammation (TNF-α, ICAM-1, NF-κB) and angiogenesis (VEGF, VE-cadherin). RESULTS: Results demonstrated that exosomes blocked the wnt/b-catenin pathway in diabetic retina concomitant with significant reduction of features of DR as shown by downregulation of retinal oxidants, upregulation of antioxidant enzymes, suppression of retinal inflammatory and angiogenic markers. These results were further confirmed by histopathological results, fundus examination and optical coherence tomography. Additionally, exosomes ameliorative effects abrogated wnt3a-triggered retinal injury in DR. CONCLUSION: Collectively, these data demonstrated that exosomes ameliorated diabetes-induced retinal injury via suppressing Wnt/ b-catenin signaling with subsequent reduction of oxidative stress, inflammation and angiogenesis.

Dapagliflozin, Liraglutide, and Their Combination Attenuate Diabetes Mellitus-Associated Hepato-Renal Injury-Insight into Oxidative Injury/Inflammation/Apoptosis Modulation.

In this study, we aim to explore the beneficial therapeutic impacts of dapagliflozin (Dapa), a highly potent, reversible, and selective sodium-glucose cotransporter-2 inhibitor, and liraglutide (Lira), a glucagon-like peptide-1 (GLP-1) receptor agonist, as hypoglycaemic agents for the management of diabetes mellitus (DM), as well as their combination against DM-induced complications, including hepato-renal injury. Indeed, the progression of DM was found to be associated with significant hepatic and renal injury, as confirmed by the elevated biochemical indices of hepatic and renal functions, as well as histopathological examination. Dapa, Lira, and their combination effectively attenuated DM-induced hepatic and renal injury, as confirmed by the recovery of hepatic and renal functional biomarkers. The administration of both drugs significantly reduced the tissue contents of MDA and restored the contents of GSH and catalase activity. Moreover, NF-κB and TNF-α expression at the protein and gene levels was significantly reduced in the liver and the kidney. This was in parallel with the significant reduction in the caspase-3 content in the liver and the kidney, as well as suppressed cleaved caspase-3 expression in the hepatic and renal specimens, as confirmed by immune-histochemical analysis. Notably, the combined Dapa/Lira treatment demonstrated an additive superior hepato-renal protective impact compared with the use of either drug alone. Thus, it appears that Dapa and Lira, through the coordinated modulation of oxidative, inflammatory, and apoptotic signalling, confer a significant hepato-renal protective impact against DM-induced complications and tissue injury.

Effect of vanillic acid and exercise training on fatty liver and insulin resistance in rats: Possible role of fibroblast growth factor 21 and autophagy.

BACKGROUND AND AIMS: The prevalence of non-alcoholic fatty liver disease has been alarmingly increased with no lines of effective treatment. Vanillic acid is a naturally occurring polyphenol with promising therapeutic effects. Exercise is well known to be an effective tool against obesity and its consequences. Thus, we aim to study the effect of vanillic acid alone and along with exercise on fatty liver induced by a high-fat diet in a rat model and to investigate possible novel mechanisms involved in their action. METHODS: In this study, 40 male rats were divided equally into five groups: control (standard chow diet), HFD (high-fat diet), HFD+VA (HFD+ vanillic acid (50 mg/kg/day orally), HFD+EX (HFD+ swimming exercise 5 days/week), HFD+VA+EX (HFD+ vanillic acid+ swimming exercise) for eight weeks. RESULTS: Body mass, liver weight, liver enzymes, cholesterol, and triglycerides were significantly decreased in the combined VA+EX group, with marked improvement in hyperglycemia, hyperinsulinemia, and consequently HOMA-IR index compared to the HFD group. These improvements were also reflected in the pathological view. VA and swimming, either solely or in combination, markedly increased hepatic and circulating fibroblast growth factor 21. Additionally, VA and swimming increased the immunohistochemical expression of the autophagosomal marker LC3 and decreased the expression of P62, which is selectively degraded during autophagy. CONCLUSIONS: These results suggest the hepatoprotective effect of VA and swimming exercise against fatty liver and the involvement of FGF21 and autophagy in their effect.

Vitamin D Status in Egyptian Adolescent Females with Iron Deficiency Anemia and Its Correlation with Serum Iron Indices.

BACKGROUND: In Egypt, it seems that adolescent girls are a candidate for Vitamin D Deficiency (VDD), mostly due to inadequate sun exposure as a result of the culture and social dress codes and dietary factors. Currently, there is growing evidence that VDD is associated with Iron Deficiency Anemia (IDA). AIM: To investigate the frequency of VDD in adolescent females with IDA in comparison to healthy control and demonstrate whether VD level was correlated with serum iron indices. SUBJECTS AND METHODS: Forty adolescent females with known cases of IDA (group 1) and 30 healthy females matched for age as a control (group 2) were selected. We compared the differences between the two groups to determine the degree of VD level; where VDD was defined as 25-hydroxyvitamin D [25(OH)D] ≤20 ng/mL, vitamin D insufficiency (VDI) as 25(OH) D of 20-30 ng/mL, and vitamin D sufficiency (VDS) as 25(OH)D >30 ng/mL. Body mass index (BMI), complete blood count (CBC), serum iron, total iron binding capacity (TIBC), serum ferritin, serum creatinine, ionized calcium and 25(OH)D were measured for all participants. RESULTS: We found that subnormal vitamin D (VDD and VDI) was more frequent in the IDA group (75%) than control (40%), (p = 0.025); where 19 adolescent female patients (47.5%) were VDD, 11 (27.5%) were VDI and 10 (25%) were VDS, while in the control group, VDD was present in 4 (20%), VDI in 4 (20%) and VDS in 12 (60%) respectively. There was not any significant correlation between serum VD and serum iron indices (r =0.168, p < 0.05) and Hb (r = 0.360, p < 0.001). There was no significant difference in serum hemoglobin level between IDA patients with subnormal VD and those with VDS. The mean level of serum 25(OH) D was significantly lower in winter months than summer in both groups; (16.87 vs. 31.57 mg/dL, p < 0.001) and (31.9 vs. 35.04 mg/dL, p < 0.001) respectively. BMI, Iron, TIBC and seasonal variation were not predictors of 25(OH) D levels in adolescent girls with IDA. CONCLUSION: VDD has a higher frequency in Egyptian adolescent females with IDA than healthy control. However, vitamin D levels were not significantly correlated with iron indices. Our result might direct the attention for measuring vitamin D level in patients with IDA with the possibility of VD supplementation with iron.

Th17 and IL-17 as Predictors of Hepatic Inflammation in Patients with Chronic Hepatitis C Virus Infection and Treated With Direct Antiviral Therapy.

Limited data exists on the role of Th17 cells in chronic HCV infected patients, particularly with regard to hepatic inflammation and fibrosis. We aimed to investigate the relationship between circulating and intrahepatic frequency of Th17 cells and IL-17 serum level and degrees of hepatic inflammation and fibrosis in chronic HCV patients, as well as to evaluate the effect of successful anti-viral therapy on these parameters. This nested longitudinal case control study included 30 treatment-naïve chronic HCV patients and 20 healthy individuals as control. All patients were investigated for circulating Th17 cell percentage (flow cytometry) and intrahepatic Th17 cell percentage (immunohistochemistry) and serum IL-17 (ELISA) at baseline and at week 12 after discontinuation of therapy. Circulating and intrahepatic Th17 cell percentage and serum IL17 level were found to be significantly higher in chronic HCV patients when compared with controls, with significant correlation with Metavir activity score. No patients required discontinuation of therapy due to any adverse event allowing for sustained virological response at 12 weeks (SVR12) in 24 patients while the remaining six patients were considered "non-responders". Circulating Th17 cells and serum IL17 levels were significantly decreased after successful Sofosbuvir-Ribavirin therapy (P < 0.0001). The extent of liver inflammation is positively correlated with frequencies of circulating Th17 cells, and their HCV-specific IL17 secretion, and intrahepatic Th17 cells. This data may also provide the basis for the potential use of Th17 as a new marker for disease advancement of chronic hepatitis C.

Iron overload detection using pituitary and hepatic MRI in thalassemic patients having short stature and hypogonadism.

OBJECTIVE: to assess the growth and pubertal development among a group of patients with ß-Thalassemia Major (ß-TM) and to evaluate the role of the pituitary gland and liver MRI signal intensity (SI) reduction in assessing and predicting the clinical severity of growth and pubertal dysfunctions. METHODS: Thirty-eight patients with ß-TM were examined and divided into two groups: Group I patients were of normal height and puberty and Group II patients had short statures and hypogonadism. Laboratory investigations included serum ferritin, LH, FSH, prolactin, TSH, and basal and dynamic growth hormones. Pituitary and liver MRIs were performed to assess the pituitary to fat (P/F) and liver to muscle (L/M) signal intensities (SI), respectively. Fifteen healthy and sex- and age-matched subjects were included as controls. RESULTS: Both patient groups had significantly elevated serum ferritin and significantly decreased prolactin and IGF1 compared to control subjects. Group II showed a significant reduction in LH, FSH, and IGF1 and a significant increase in ferritin in comparison with Group I and the control group, and it had a highly significant reduction in both P/F and L/M SI in comparison with Group I (p<0.001 and 0.008, respectively). The reduced P/F ratio was significantly correlated with FSH and LH, and a cutoff for a P/F ratio ≥0.94 was obtained to differentiate between Group I and II. CONCLUSION: MRI in conjunction with the P/F signal intensity ratio is a useful and noninvasive tool for the early diagnosis of pituitary iron overload.