Oleuropein attenuates the nephrotoxic effect of sunitinib in rats: Unraveling the potential role of SIRT6/Notch-1/NLRP-3/IL-1ß axis.

Sunitinib (SUN) is a chemotherapeutic agent clinically approved for treatment of metastatic renal carcinoma. Despite its remarkable benefits, various renal toxicities have been reported that limit its clinical uses. Oleuropein (OLE) is the main polyphenolic constituent of olive tree and mediates the majority of its valuable pharmacological activities. The current study examined the probable renoprotective effects of OLE against SUN-induced nephrotoxicity. Adult male albino rats were co-treated by SUN (25 mg/kg, 3 times/week, PO) with either a drug vehicle or OLE (60 mg/kg/day, daily, PO) for four weeks. A control group comprising of age-matched rats was used. Four weeks later, blood specimens were collected to assess kidney functions. Kidneys were harvested for biochemical and histopathological analyses. Administration of SUN induced kidney dysfunction, along with marked rises in endothelin-1 (ET-1) and monocyte chemotactic protein-1 (MCP-1) levels in renal tissues. Histological abnormalities were also detected in kidneys of SUN-treated rats including glomerular and tubular interstitial congestion along with interstitial fibrosis. On molecular levels, there was a decline in renal SIRT6 expression along with significant up-regulation of Notch-1, NLRP-3, interleukin -1ß (IL-1ß) and cleaved caspsase-3. All these changes were almost alleviated by OLE co-treatment. These findings suggest the implication of SIRT6/Notch-1/NLRP3/IL-1ß axis in the pathogenesis of SUN-induced nephrotoxicity and highlight OLE as a prospective renoprotective agent during SUN chemotherapy to halt its renal toxicity likely through promotion of SIRT6 and suppression of Notch-1/NLRP3/IL-1ß signaling pathway.

Histological and biochemical evaluation of the effects of silver nanoparticles (AgNps) versus titanium dioxide nanoparticles (TiO2NPs) on rat parotid gland.

The unlimited use of nanoparticles (NPs) results in toxic impacts on different tissues. The current study aimed to compare the adverse effects of AgNPs and TiO2NPs on the parotid gland of adult male albino rats as regards the histopathological, immunohistochemical, and biochemical changes, exploring the possible underlying mechanisms and the degree of improvement after cessation of administration. Fifty-four adult male albino rats were divided into control group (I), AgNPs-injected group (II), and TiO2NPs-injected group (III). We measured the levels of tumor necrosis factor-alpha (TNF-α) and interleukin (IL-6) in the serum, and levels of MDA and GSH in parotid tissue homogenate. Quantitative real-time polymerase-chain reaction (qRT-PCR) was used to measure the expression levels of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC1-α), nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), mouse double minute 2 (MDM2), Caspase-3 Col1a1, and Occludin. Parotid tissue sections were examined by light microscope (Hematoxylin & Eosin and Mallory trichrome stains), electron microscope, and immunohistochemical examination of CD68 and anti-caspase-3 antibodies. Both NPs severely affected the acinar cells and damaged the tight junction between them by enhancing expression of the inflammatory cytokines, inducing oxidative stress, and disturbing the expression levels of the studied genes. They also stimulated fibrosis, acinar cell apoptosis, and inflammatory cells infiltration in parotid tissue. TiO2NPs effects were less severe than AgNPs. Cessation of exposure to both NPs, ameliorated the biochemical and structural findings with more improvement in TiO2NPs withdrawal. In conclusion: AgNPs and TiO2NPs adversely affected the parotid gland, but TiO2NPs were less toxic than AgNPs.

Dulaglutide mitigates high dietary fructose-induced renal fibrosis in rats through suppressing epithelial-mesenchymal transition mediated by GSK-3ß/TGF-ß1/Smad3 signaling pathways.

AIMS: High dietary fructose consumption has been linked to the development of renal fibrosis. Dulaglutide is a long acting glucagon like peptide-1 (GLP-1) analog, showing some renoprotective properties; however its action on renal fibrosis remains uncertain. We investigated the effect of dulaglutide on fructose-induced renal fibrosis in comparison to pirfenidone, as well-established anti-fibrotic drug, and the contribution of epithelial-mesenchymal transition (EMT) process and its upstream signaling. MAIN METHODS: Six week-old male Wistar albino rats received 10%w/v fructose solution in drinking water for 24 weeks and co-treated with either pirfenidone (100 mg/kg/day, orally) or dulaglutide (0.2 mg/kg/week, s.c) for the last four weeks. Lipid profile, glucose homeostasis, kidney functions were assessed. Kidneys were harvested for biochemical and histological analyses. KEY FINDINGS: High dietary fructose consumption for 24 weeks induced insulin resistance, dyslipidemia and renal dysfunction that were ameliorated by dulaglutide and pirfenidone to lesser extent. Histological examination revealed histological lesions and interstitial fibrosis in renal sections of high fructose-fed rats, which were reversed by dulaglutide or pirfenidone treatment. Both drugs modulated the EMT-related proteins by increasing the epithelial marker, E-cadherin, while suppressing the mesenchymal markers, vimentin and alpha-smooth muscle actin (α-SMA) in renal tissue. Moreover, both drugs attenuated fructose-induced upregulation of GSK-3ß/TGF-ß1/Smad3 signaling. SIGNIFICANCE: These findings suggest that dulaglutide can emerge as a promising therapeutic agent for fructose-induced renal fibrosis. These results add mechanistic insights into the anti-fibrotic action of dulaglutide through suppressing EMT and the upstream GSK-3ß/TGF-ß1/Smad3 signaling.

Mesenchymal stem cells microvesicles versus granulocytes colony stimulating factor efficacy in ameliorating septic induced acute renal cortical injury in adult male albino rats (Histological and Immunohistochemical Study).

Sepsis is the most common cause of acute kidney injury in ICU patients, with increasing mortalities. Treatment septic AKI is unsatisfactory; therefore, more effective therapies must be investigated. MSCs-MVs have the same effectiveness in tissue repair as their original cells. Granulocyte colony-stimulating factor (G-CSF) is considered a simple and convenient tool in regenerative medicine. This study aimed to compare the probable therapeutic effect of MSCs-MVs versus G-CSF on septic AKI in rats. Forty-eight adult male rats were divided into four groups; I control group (IA-ID), II induced-sepsis group, III G-CSF, and IV MSC-MVs groups. Sepsis was induced in groups II, III, IV through a single IV injection of 10 mg/ kg of E.Coli-LPS dissolved in 1 ml saline. Four hours later, group IV received a single IV injection of MSCs-MVs, while group III received a SC injection of Neupogen for 5 days. All animals were sacrificed 7 days from the start. Serum and tissue samples of each group were used for biochemical study. Sections from all groups were subjected to light and electron microscopic examination. A fluorescent microscope examination for subgroup ID and group IV was done. Morphometric and statistical analyses were performed. Group II showed features of acute tubular injury. Group III showed some improvement (biochemically, LM & EM level) however, group IV showed more improvement. MVs injection caused a marked improvement in septic AKI; G-CSF can also meliorate the degenerative effect of sepsis on renal cortex, but to a lesser extent than MSCs-MVs.

Duration-dependent effects induced by titanium dioxide nanoparticles on pancreas of adult male albino rats (histological and biochemical study).

Titanium dioxide nanoparticles (TiO2NPs) have been widely used in numerous applications and enter the human body through different routes. This study aimed to investigate the effect of intraperitoneal TiO2NPs on the histological and biochemical structure of rat pancreas. Fifty adult male albino rats were divided into four groups. Group I (control) was equally divided into two subgroups. Groups II, III, and IV: rats received intraperitoneal TiO2NPs for 7, 14, and 45 days, respectively. Blood samples were taken for the estimation of blood glucose, serum insulin, serum α-amylase, and lipase activity levels. Sections of the pancreas were processed for light, electron microscope examination, and immunohistochemical detection of insulin protein. Other parts were exposed to Real-Time Polymerase Chain Reaction for Bax, Bcl-2, SOD, and GST mRNA gene expression. Results showed pancreatic tissue damage, including acinar and islet cells, which became worse with increased duration of exposure to TiO2NPs. Decreased immune expression of the insulin protein together with decreased serum insulin and increased blood glucose levels indicated the alteration of ß cells. Decreased serum α-amylase and lipase activities indicated alteration of acinar cells. Increased Bax and decreased Bcl-2 mRNA expression levels showed the apoptotic effect of TiO2NPs caused by oxidative stress and evidenced by a significant reduction in the mRNA expression of SOD and GST in a duration-dependent manner. In conclusion: the present study stated that TiO2NPs exposure for long durations had toxic effects on both exocrine and endocrine pancreas mediated by apoptotic and oxidative stress pathways.

Infliximab ameliorates tumor necrosis factor-alpha exacerbated renal insulin resistance induced in rats by regulating insulin signaling pathway.

Infliximab (IFX), a monoclonal antibody for tumor necrosis factor-alpha (TNF-α), is known to restore blood glucose homeostasis. However, its effects on improving renal insulin resistance (IR) are not yet studied. So we investigate the impact of infliximab on renal insulin signaling pathway in IR rat model regarding to metformin (MET). The induced IR was confirmed by a high oral glucose tolerance test, an elevation of lipid profile and the homeostatic model assessment of insulin resistance 2 (HOMA-IR 2) values. Subsequently, IR rats were concurrently treated with either MET (100 mg/kg/day) or IFX (one dose 5 mg/kg) besides IR and normal control (NC) groups. Four weeks later, IR control rats displayed hyperglycemia, hyperinsulinemia and elevation in HOMA-IR 2, renal function markers and renal tissue TNF-α, interleukins-1ß and 6 (Il-1ß, IL-6) and suppressor of cytokines signaling 3 (SOCS3) contents as well as glomerulosclerosis when compared to NC group. Additionally, the phosphorylation of renal insulin receptor substrate 1 (IRS1), phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt) were markedly impaired. Treatment with either MET or IFX significantly improved IR and kidney functions. The effects of the drugs were achieved by the downregulation of renal inflammatory cytokines and SOCS3 levels and the amelioration of the renal IRS1/PI3K/Akt pathway. In conclusion, MET and IFX ameliorated the TNF-α worsening effect on IR in rat renal tissues by regulating insulin signaling. Interestingly, infliximab was superior to metformin in regulating insulin signaling pathway. Therefore, infliximab could be used as an adjuvant therapy in improving renal IR.

Umbilical cord blood-mesenchymal stem cells and carvedilol reduce doxorubicin- induced cardiotoxicity: Possible role of insulin-like growth factor-1.

In this study, we tried to demonstrate the effects of adding human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) to carvedilol in improving the doxorubicin- induced cardiotoxicity in rats. Rats were randomly divided into four groups: group 1: control group, group 2: doxorubicin untreated group, group 3: rats injected with doxorubicin and received carvedilol, and group 4: rats injected with doxorubicin and received carvedilol and stem cell-treated. Electrocardiography (ECG) was performed to assess cardiac function after animals were sacrificed. Cardiac muscle sections were examined histologically using H&E, Masson trichrome and immunohistochemically using caspase 3 immunostaining. The morphometric and statistical analysis was performed. Levels of malondialdehyde (MDA), superoxide dismutase (SOD), insulin-like growth factor (IGF-1), and vascular endothelial growth factor (VEGF) were measured. We concluded that combination of hUCB-MSCs and carvedilol markedly improves histological and immunohistochemical structure of cardiac muscle fibers and restores cardiac function in doxorubicin- induced cardiotoxicity in rats.

Mesenchymal stem cells: In vivo therapeutic application ameliorates carbon tetrachloride induced liver fibrosis in rats.

BACKGROUND: Egypt has the highest prevalence of hepatitis C virus in the world with infection rate up to 60%, for which liver fibrosis or hepatic carcinoma is the final outcome. Stem cell therapy provides a new hope for hepatic repair instead of traditional treatment, liver transplantation, as it is safer, gives long term engraftment and avoid expensive immunosuppressive drugs and unexpected hazardous effects. AIM: This work aimed at determining the therapeutic potential of mesenchymal stem cells (MSC) in hepatic repair as a new line of therapy for liver fibrosis. METHODS: 33 female albino rats were divided into three groups: Group I: 10 rats injected subcutaneously with olive oil, Group II: 13 rats injected with carbon tetrachloride (CCl4) and Group III: 10 rats injected with CCl4 then bone marrow derived MSC from male rats. Blood and liver tissue samples were taken from all rats for biochemical and histological study. RESULTS: Liver functions for group II rats showed significant deterioration in response to CCl4 in addition to significant histological changes in liver lobules and portal areas. Those parameters tend to be normal in MSC-treated group. Group III rats revealed normalized liver function and histological picture. Meanwhile, most of the pathological lesions were still detected in rats of second group. CONCLUSION: Undifferentiated MSCs have the ability to ameliorate CCl4 induced liver injury in albino rats in terms of liver functions and histological features. So, stem cell therapy can be considered clinically to offer a hope for patients suffering from liver fibrosis.