The combined effect of zinc oxide nanoparticles and milrinone on acute renal ischemia/reperfusion injury in rats: Potential underlying mechanisms.

AIM: To investigate the efficacy of zinc oxide nanoparticles (ZnO-NPs) and/or milrinone (MIL) on renal ischemia/reperfusion injury (I/RI) in rats and their possible underlying mechanisms. MATERIALS AND METHODS: Forty-eight adult male Sprague-Dawley albino rats were randomly assigned into six equal-sized groups (n = 8): normal control, sham-operated, I/R group (45 min/24 h), ZnO-NPs group (10 mg/kg i.p.), MIL group (0.5 mg/kg i.p.), and ZnO-NPs + MIL group in the same previous doses. KEY FINDINGS: In comparison to the I/R-operated group, administration of either ZnO-NPs or MIL significantly decreased serum creatinine and urea concentrations, and renal vascular permeability (p < 0.05). The oxidative stress was significantly declined, as evidenced by increased GPx, CAT, and SOD activities and decreased MDA and NO concentrations. Renal expressions of TNF-α, NF-κB, KIM-1, NGAL, and caspase-3 decreased significantly, while Nrf2 increased significantly. Histopathology investigation revealed improvement with minimal renal lesions and fibrosis after ZnO-NPs or MIL treatments. The combined treatments synergistically improved the studied parameters more than either treatment alone. These findings were validated by molecular modeling, which revealed that MIL inhibited TNF-α, NF-kB, caspase-3, KIM-1 and NGAL. SIGNIFICANCE: Both ZnO-NPs and MIL exerted cytoprotective effects against acute renal I/RI, and a combination of both was found to be even more effective. This renoprotective effect is suggested to be mediated through activation of Nrf2 and the prevention of the NF-κB activation-induced oxidative stress and inflammation, which may strengthen the potential role of ZnO-NPs or MIL in renal I/RI protection during surgical procedures.

The Potential Safe Antifibrotic Effect of Stem Cell Conditioned Medium and Nilotinib Combined Therapy by Selective Elimination of Rat Activated HSCs.

Hepatic fibrosis is a progressive disease with serious clinical complications that arise from abnormal propagation and activation of multiple inflammatory pathways. Nilotinib is an oral tyrosine kinase inhibitor with antifibrotic activity. Mesenchymal stem cells (MSCs) are blank cells and can differentiate into specific cell types. They have the potential to repair and regenerate cells. MSCs have a special paracrine fashion where they produce special exosomes, microvesicles, and cytokines like IL-6, transforming growth factor-beta (TGF-ß), and HGF as well as hepatic stellate cell suppressors. This paracrine fashion can decrease collagen deposition, enhance antifibrotic, anti-inflammatory, and angiogenic activity in vitro and in vivo. In our study, the rat's hepatic stellate cells (HSCs) in addition to different normal cell lines were treated with Nilotinib alone and in combination with liver mesenchymal stem cells conditioned medium (LMSCs-CM) for 24 h. Mono and combined therapy antifibrotic and cytotoxicity effects were evaluated using different parameters including α-SMA, cytochrome c, P53 expression, collagen deposition, DNA content, oxidative stress parameters, cell viability, and apoptosis by flow cytometry analysis. Our results showed that Nilotinib and LMSCs-CM in combination had a significantly potent antifibrotic and anti-inflammatory effect on activated hepatic stellate cells than Nilotinib alone; otherwise, this combination showed the best safety with minimal cytotoxicity on different normal cell lines.

Antifibrotic Effect of Combination of Nilotinib and Stem Cell-Conditioned Media on CCl4-Induced Liver Fibrosis.

Liver fibrosis is the excessive extracellular matrix accumulation of proteins, such as collagen, which follows the chronic liver diseases. Advanced liver fibrosis leads to cirrhosis and liver failure. Nilotinib is a second-generation tyrosine kinase inhibitor, which showed antifibrotic efficacy. Stem cell therapy still has some limitations such as oncogenesis, unexpected differentiation, and ethical consideration. Stem cells secrete cytokines and growth factors that showed paracrine-mediated antifibrotic and anti-inflammatory effects in vivo and in vitro. Thus, stem cell-conditioned medium (SC-CM), which contains the secretory proteins of stem cells, may have an antifibrotic role. This study was carried out to examine the antifibrotic effect of Nilotinib and stem cell exosomes on CCl4-induced liver fibrosis in rats. Male Wistar rats were injected intraperitoneally with CCl4 twice a week for 9 weeks and given daily treatments of Nilotinib (20 mg/kg), stem cell exosomes (0.5 ml/rat), and the combination treatment of Nilotinib and stem cell exosomes during the last 5 weeks of CCl4 intoxication. Liver fibrosis and also antifibrotic efficacy of the treatments were estimated with liver function tests, oxidative stress parameters, apoptotic parameters, histopathological examination, and hydroxyproline contents. Results showed that the combination of Nilotinib and stem cell-conditioned media had more antifibrotic effects than each one alone (P value < 0.001).

A simple diagnostic index comprising epithelial membrane antigen and fibronectin for hepatocellular carcinoma.

UNLABELLED: Background and rationale for the study. Continuing search for suitable tumor-markers is of clinical value in managing patients with various malignancies. These markers may be presented as intracellular substances in tissues or may be released into the circulation and appear in serum. Therefore, this work is concerned with identification and quantitative determination of epithelial membrane antigen (EMA) and fibronectin and estimating their performances as surrogate markers for identifying hepatocellular carcinoma (HCC). RESULTS: A total of 627 individuals constituted this study [fibrosis (F1-F3) = 217; cirrhosis = 191; HCC = 219]. Western-blot was used for identifying EMA and fibronectin in sera. As a result, a single immunoreactive band was shown at 130-kDa and 90-kDa corresponding to EMA and fibronectin, respectively. They were quantified using ELISA providing values in HCC higher than fibrosis or cirrhosis with a significant difference (P < 0.0001). For identifying HCC, EMA showed 0.82 area under receiver-operating characteristic curve (AUC) with sensitivity = 70% and specificity = 78% while fibronectin yielded AUC = 0.70 with sensitivity = 67% and specificity = 82%. FEBA-Test comprising fibronectin and EMA together with total-bilirubin and AFP was constructed yielding AUC = 0.92 for identifying HCC from cirrhosis with sensitivity = 89% and specificity = 85%. FEBA-Test was then tested for differentiating HCC from fibrosis showing AUC = 0.97 with sensitivity = 90% and specificity = 89%. FEBA-Test enabled the correct identification of HCC patients with CLIP 0-1 and size ≤ 3 cm with AUC = 0.80 and AUC = 0.84, respectively, indicating its ability in identifying early HCC. CONCLUSIONS: A four-marker index may improve the early detection of HCC with a high degree of accuracy.