Arbutin abrogates cisplatin-induced hepatotoxicity via upregulating Nrf2/HO-1 and suppressing genotoxicity, NF-κB/iNOS/TNF-α and caspase-3/Bax/Bcl2 signaling pathways in rats.

BACKGROUND: Cisplatin is a potent anticancer agent widely employed in chemotherapy. However, cisplatin leads to toxicity on non-targeted healthy organs, including the liver. We investigated the hepatoprotective mechanism of arbutin (ARB), a glycosylated hydroquinone, against cisplatin-induced hepatotoxicity. METHODS: Rats were orally administered with ARB (ARB1 = 50 mg/kg; ARB2 = 100 mg/kg) for 14 consecutive days against hepatotoxicity induced by a single dose of cisplatin (10 mg/kg) on day 15. Three days after the intraperitoneal cisplatin injection, serum and liver tissue were collected for subsequent analyses. RESULTS: Cisplatin triggered marked increases in serum AST, ALT, and ALP activities, hepatic malondialdehyde (MDA) and reactive oxygen species (ROS) coupled with a considerable diminution in hepatic activities of superoxide dismutase (SOD), catalase (CAT) and the concentration of reduced glutathione (GSH). The gene expressions of interleukin-1ß (IL-1ß), tumor necrosis factor (TNF-α), and IL-6 were notably increased. The pre-administration of ARB1 and ARB2 reduced AST, ALT and ALP in serum and restored SOD, CAT, GSH, ROS, MDA and cytokine levels which was also evidenced by alleviated hepatic lesions. Further, cisplatin-induced prominent alterations in the gene expressions of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), iNOS, NF-κB, Bax, Bcl-2, caspase-3 and 8-OHdG in the liver. Interestingly, ARB protected the liver and mitigated the cisplatin-induced alterations in serum AST, ALT, ALP, and reduced hepatic redox markers, 8-OdG, inflammatory markers and gene expressions. CONCLUSION: The findings demonstrate that ARB is a potential protective adjuvant against cisplatin-induced hepatotoxicity via inhibition of hepatic oxidative stress, inflammation, and apoptosis.

DEL-1: a promising treatment for AMD-associated ER stress in retinal pigment epithelial cells.

BACKGROUND: Age-related macular degeneration (AMD) is an irreversible eye disease that can cause blurred vision. Regular exercise has been suggested as a therapeutic strategy for treating AMD, but how exercise improves AMD is not yet understood. This study investigated the protective effects of developmental endothelial locus-1 (DEL-1), a myokine upregulated during exercise, on endoplasmic reticulum (ER) stress-induced injury in retinal pigment epithelial cells. METHODS: We evaluated the levels of AMPK phosphorylation, autophagy markers, and ER stress markers in DEL-1-treated human retinal pigment epithelial cells (hRPE) using Western blotting. We also performed cell viability, caspase 3 activity assays, and autophagosome staining. RESULTS: Our findings showed that treatment with recombinant DEL-1 dose-dependently reduced the impairment of cell viability and caspase 3 activity in tunicamycin-treated hRPE cells. DEL-1 treatment also alleviated tunicamycin-induced ER stress markers and VEGF expression. Moreover, AMPK phosphorylation and autophagy markers were increased in hRPE cells in the presence of DEL-1. However, the effects of DEL-1 on ER stress, VEGF expression, and apoptosis in tunicamycin-treated hRPE cells were reduced by AMPK siRNA or 3-methyladenine (3-MA), an autophagy inhibitor. CONCLUSIONS: Our study suggests that DEL-1, a myokine, may have potential as a treatment strategy for AMD by attenuating ER stress-induced injury in retinal pigment epithelial cells.

Cerebrolysin Alleviating Effect on Glutamate-Mediated Neuroinflammation Via Glutamate Transporters and Oxidative Stress.

Glutamate, one of the most important excitatory neurotransmitters, acts as a signal transducer in peripheral tissues and endocrine cells. Excessive glutamate secretion has been shown to cause excitotoxicity and neurodegenerative disease. Cerebrolysin is a mixture of enzymatically treated peptides derived from pig brain including neurotrophic factors, like brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and ciliary neurotrophic factor (CNTF). The present study investigated the protective effects of cerebrolysin on glutamate transporters (EAAT 1, EAAT 2) and cytokines (IL-1ß and IL-10) activity in glutamate-mediated neurotoxicity. Primary cortex neuron culture was exposed to glutamate and successively treated with various cerebrolysin concentrations for 24 and 48 h. Our data showed that cerebrolysin primarily protects neurons by decreasing glutamate concentration in the synaptic cleft. In addition, Cerebrolysin can decrease oxidative stress and neuron cell damage by increasing antioxidant activity and decreasing inflammation cytokine levels.

Ulipristal-temozolomide-hydroxyurea combination for glioblastoma: in-vitro studies.

BACKGROUND: Glioblastoma multiforme (GBM) is a brain malignancy with worst survival. Low dose progesterone stimulates GBM growth, while progesterone receptor (PR)-antagonist mifepristone was shown to reduce growth and to enhance temozolomide sensitivity in GBM cells. Mifepristone is not available in all countries due to ethical reasons and may cause adrenal insufficiency and pelvic infections. Ulipristal is also a PR-antagonist used in treatment of uterine leiomyomas with higher biosafety. Ulipristal is demonstrated to suppress growth of breast cancer, yet it is not tested as yet whether it can also block growth and sensitize to temozolomide in glioblastoma as it was previously shown with mifepristone. Our first aim was to detect whether ulipristal exerts antiproliferative and chemotherapy-sensitizing effects in glioblastoma. Hydroxyurea inhibits DNA replication via blocking ribonucleotide reductase (RR) and it was demonstrated to increase temozolomide antineoplasticity in GBM. Progesterone receptor-activation in the uterus enhances RR transcription. Hence, we have hypothesized that PR-inactivation with ulipristal would further enhance hydroxyurea antineoplasticity by shutting down DNA synthesis mechanisms through further suppression of RR. Lastly, there exists no study as yet whether ulipristal, hydroxyurea and temozolomide could exert ternary antineoplastic efficacy, which was our last aim to define. METHODS: To reveal interactions between ulipristal, hydroxyurea and temozolomide, we treated human U251 GBM cell line with these agents alone and in combination and measured cell proliferation, total antioxidant capacity (TAC) and total oxidant status (TOS) in conditioned medium and cellular cytokine gene expressions. RESULTS: All agents significantly reduced cell proliferation significantly, yet the most significant decrease of GBM cells occured with the triple drug combination at the 96th hour. All agents significantly decreased TAC and increased TOS in culture media, which was mostly relevant for the triple combination at the 96th hour. All these 3 agents tend to reduce the expression of immunosuppressive and/or GBM-growth stimulating cytokines TGFß, IL-10 and IL-17 while increasing the expression of GBM-growth suppressing cytokine IL-23. CONCLUSIONS: Repurposal of these agents in treatment of GBM would be a plausible approach if future studies prove their efficacy.