Scutellarin alleviates lipopolysaccharide-provoked septic nephrotoxicity via attenuation of inflammatory and oxidative events and mitochondrial dysfunction.

BACKGROUND: Sepsis-associated acute kidney injury (AKI) is highlighted by high incidence of mortality and morbidity. Scutellarin is a flavone extracted from certain medicinal plants with anti-inflammatory and anti-oxidative properties. This research study was done to investigate the beneficial effect of scutellarin on lipopolysaccharide (LPS) murine model of AKI. MATERIALS AND METHODS: Five groups of mice were used including control (without LPS injection), LPS group (LPS injection, 10 mg/kg), and LPS + Scutellarin25, 50, and/or 100 groups (receiving scutellarin orally at different doses of 25, 50, or 100 mg/kg before LPS injection). RESULTS: Scutellarin pretreatment effectively lowered kidney function markers (BUN, creatinine, and cystatin C), improved superoxide dismutase (SOD) besides enhancement of level, and/or gene expression for nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase 1 (HO-1) and also reduced oxidative stress factors including reactive oxygen species (ROS) and malondialdehyde (MDA). In addition, scutellarin reduced tissue level and/or gene expression of inflammatory markers comprising toll-like receptor 4 (TLR4), nuclear factor-kappaB (NF-κB), and tumor necrosis factor α (TNF-α) and properly raised anti-inflammatory factor IL-10. Moreover, scutellarin enhanced mitochondrial membrane potential (MMP) and attenuated histopathological changes in renal tissue subsequent to LPS challenge. Beneficial effects of scutellarin was associated with improvement of gene expression regarding peroxisome proliferator-activated receptor gamma (PPARγ) and its coactivator PGC-1α as specific markers of mitochondrial biogenesis. CONCLUSION: These results indicate that scutellarin could protect against LPS-provoked AKI through restraining inflammation and oxidative stress and maintenance of mitochondrial health and biogenesis which is partly mediated through its regulation of Nrf2/PPAR-γ/PGC-1α/NF-kB/TLR4.

Cardioprotective effect of silymarin nanoemulsion on 5-fluorouracil-induced cardiotoxicity in rats.

5-Fluorouracil (5-FU)-associated cardiotoxicity has been ranked as the second most common cause of cardiotoxicity induced by chemotherapeutic drugs after anthracyclines. In the present study, we investigated the protective impacts of silymarin (SIL) and silymarin nanoemulsion (SLN) against cardiotoxicity caused by 5-FU in rats. Thirty male Wistar rats were divided into six groups as follows: control, SLN (5 mg/kg), SIL (5 mg/kg), 5-FU + SLN, 5-FU + SIL, and 5-FU. Cardiotoxicity was induced by a single intraperitoneal injection of 5-FU (100 mg/kg). The control group received an intraperitoneal injection (ip) of normal saline and the treatment groups received ips of SIL and SLN for 14 days. 5-FU resulted in significant cardiotoxicity, represented by an increase in the serum levels of cardiac enzymes and malondialdehyde, as well as cyclooxygenase-2 (COX-2) and tumor necrosis factor-α (TNF-α) expression, and histopathological degeneration. 5-FU treatment also induced a decrease in body weight, total antioxidant capacity (TAC), and catalase values. Evaluation of electrocardiographic parameters in 5-FU-treated rats showed increases in the ST segment, QRS duration, and RR interval. Treatment with SIL and SLN reduced oxidative stress, cardiac enzymes, histopathological degeneration, and the expression of TNF-α and COX-2 in cardiac tissue. Our results demonstrated that treatment with SIL and SLN significantly improved cardiotoxicity induced by 5-FU in rats.

The potential neuroprotective roles of olive leaf extract in an epilepsy rat model induced by kainic acid.

BACKGROUND AND PURPOSE: Epilepsy is recognized as a chronic neurologic disease. Increasing evidence has addressed the antioxidant and anti-inflammatory roles of olive leaf extract (OLE) in neurodegenerative diseases. So, the current study aimed to investigate the neuroprotective roles of OLE in epilepsy. EXPERIMENTAL APPROACH: Forty rats were divided into 4 groups including a control group, sham group, kainic acid (KA) group, and KA + OLE group. KA (4 µg/rat) was injected intrahippocampal, and OLE (300 mg/kg) was orally administrated for 4 weeks. Animals were sacrificed, and their hippocampi were isolated. KA- induced seizure activity was recorded. Oxidative stress index was assessed by measuring its indicators including malondialdehyde (MDA), nitrite, nitrate, and glutathione (GSH) as well as the catalase (CAT) activity. The supernatant concentration of tumor necrosis factor-α (TNF-α) and the apoptosis rate in neurons were measured. FINDINGS/RESULTS: Treatment with OLE significantly reduced the seizure score. OLE decreased oxidative stress index by reducing the concentration of MDA, nitrite, and nitrate as well as increasing the level of GSH. OLE had a significant anti-apoptotic effect on neurons. However, CAT activity and the level of TNF-α were not affected. CONCLUSION AND IMPLICATIONS: Our findings indicated neuroprotective properties of OLE, which is mainly mediated by its antioxidant and anti-apoptotic effects, therefore, could be considered as a valuable therapeutic supplement for epilepsy.

Exogenous Ghrelin Could Not Ameliorate 3,4-methylenedioxymethamphetamine-induced Acute Liver Injury in The Rat: Involved Mechanisms.

MDMA (3,4-methylenedioxymethamphetamine, ecstasy) is often abused by youth as a recreational drug. MDMA abuse is a growing problem in different parts of the world. An important adverse consequence of the drug consumption is hepatotoxicity of different intensities. However, the underlying mechanism of this toxicity has not been completely understood. Ghrelin is a gut hormone with growth hormone stimulatory effect. It expresses in liver, albeit at a much lower level than in stomach, and exerts a hepatoprotective effect. In this study, we investigated hepatotoxicity effect of MDMA alone and its combination with ghrelin as a hepatoprotective agent. MDMA and MDMA+ ghrelin could transiently increase serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) followed by tissue necrosis. However, they could significantly decrease liver tumor necrosis factor-a (TNF-±) in both treatment groups. Unexpectedly, in MDMA treated rats, Bax, Bcl-xl, Bcl-2, Fas, Fas ligand (Fas-L), caspase 8, cytochrome c, caspase 3 gene expression, and DNA fragmentation were nearly unchanged. In addition, apoptosis in MDMA+ ghrelin group was significantly reduced when compared with MDMA treated animals. In all, MDMA could transiently increase serum transaminases and induce tissue necrosis and liver toxicity. Ghrelin, however, could not stop liver enzyme rise and MDMA hepatotoxicity. MDMA hepatotoxicity seems to be mediated via tissue necrosis than apoptotic and inflammatory pathways. Conceivably, ghrelin as an anti-inflammatory and anti-apoptotic agent may not protect hepatocytes against MDMA liver toxicity.

Evaluation of Nanocarrier Targeted Drug Delivery of Capecitabine-PAMAM Dendrimer Complex in a Mice Colorectal Cancer Model.

Capecitabine, an effective anticancer drug in colorectal cancer chemotherapy, may create adverse side effects on healthy tissues. In the present study, we first induced colon adenocarcinoma with azoxymethane, a carcinogen agent, and then investigated the potentiality of polyamidoamine (PAMAM) dendrimer to improve capecitabine therapeutic index and decrease its adverse side effects on healthy tissues like liver and bone marrow. Other variables such as nanoparticle concentrations have also been investigated. Drug loading concentration (DLC) and encapsulation efficiency (EE) were calculated for capecitabine/dendrimer complex. Experimental results showed an increase in DLC percentage resulted from elevated capecitabine/dendrimer ratio. Capecitabine/dendrimer complex could reduce tumor size and adverse side effects in comparison with free capecitabine form.