gossypin and Disease-Models--Animal

The aim of the study was to examine the protective effects and possible mechanism of gossypin against isoproterenol (ISO)-mediated myocardial damage in vivo and H9c2 cell damage in vitro. H9c2 cells were categorized into five groups. Viability was evaluated with MTT and LDH release in H9c2 cells. Apoptotic parameter analysis was performed with cytochrome c (Cyt-c), caspase-3 (CASP-3), and BCL2/Bax mRNA expression levels. In vivo, gossypin was administered orally to mice at doses of 5, 10, and 20 mg/kg for 7 days. ISO groups were injected with isoproterenol (150 mg/kg) subcutaneously (on 8th and 9th) for 2 days. Afterward, lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB) levels and Troponin-I (Tn-I) amount from their serum, oxidative stress parameters superoxide dismutase (SOD) activity, glutathione (GSH) and malondialdehyde (MDA) levels, and tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1 β), and NF-kB mRNA expression levels with inflammatory markers from heart tissue were evaluated. In addition, IL-1B, BCL-2, and cas-3 immunohistochemical staining was performed from heart tissue and TNF-a level was measured by ELISA method. Administration of Gossypin protected the cells by dose-dependent, eliminating the reduced cell viability and increased LDH release of ISO in H9c2 cells. In mice serum analyses, increased LDH, CK-MB levels, and Tn-I levels were normalized by gossypin. ISO administration in heart tissue is regulated by gossypin with increased SOD activity, GSH amount, TNF-α, IL-6, IL-1β, and NF-kB mRNA expression levels and decreased MDA amount. Overall, the present results demonstrated that gossypin has a potential cardioprotective treatment for ischemic heart disease on in vivo and in vitro.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Apoptosis Regulatory Proteins; Cardiotoxicity; Cell Line; Cytokines; Disease Models, Animal; Flavonoids; Inflammation Mediators; Isoproterenol; Male; Mice, Inbred BALB C; Myocardial Infarction; Myocytes, Cardiac; Oxidative Stress; Rats

Sepsis is a complex pathophysiological event involving systemic inflammatory response syndrome, multiple organ dysfunction syndrome and tissue damage such as acute lung injury (ALI). Although many new mechanisms are being investigated to enlighten the pathophysiology of sepsis, there is no effective treatment protocol yet. Antioxidant, antibacterial and antiinflammatory effects of gossypin (GOS)-like flavonoids have been shown and we have hypothesized that GOS have roles in sepsis induced inflammation of lungs.. Cecal ligation and puncture (CLP) induced sepsis model was induced in rats. Effects of GOS on oxidative stress, histopathology, nuclear factor kappa B (NF-κB), IL-6 positivity and NLRP3, HMGβ1, TNF-α, NF-κB, IL-1β mRNA expression levels were evaluated in lung tissues of the septic rats.. GOS 20 (20 mg/kg) administration to septic rats decreased oxidative stress and supported antioxidant system in lungs. GOS administration also decreased the tissue NF-κB and IL-6 immunopositivity, which is high in septic rats; and decreased the sepsis-induced lung injury. HMGβ1, NLRP3, NF-κB, IL-1β, and TNF-α mRNA expression significantly increased in the CLP group. Both doses of GOS significantly reduced these mRNA expression as compared with the levels in the CLP group demonstrating its anti-inflammatory potential.. GOS administration, may represent a novel treatment for the prevention of lung damage occurred after sepsis induction. This effect of GOS might be related to its anti-inflammatory potential that result in decreased cytokine response and improved oxidative status.

Topics: Acute Lung Injury; Animals; Antioxidants; Cytokines; Disease Models, Animal; Female; Flavonoids; HMGB Proteins; Inflammation; Interleukin-1beta; Interleukin-6; Lung; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative Stress; Rats; Rats, Wistar; Sepsis; Tumor Necrosis Factor-alpha

Mutation in the BRAF gene (BRAFV600E) exists in nearly 70% of human melanomas. Targeted therapy against BRAFV600E kinase using a recently identified RAF-selective inhibitor, PLX4032, has been successful in early clinical trials. However, in patients with the normal BRAF allele (wild-type), PLX4032 is protumorigenic. This conundrum identifies the unmet need for novel therapeutic agents to target BRAFV600E kinase that are not counterproductive. We have identified gossypin, a pentahydroxy flavone, as a potent antimelanoma agent. Gossypin inhibited human melanoma cell proliferation, in vitro, in melanoma cell lines that harbor both BRAFV600E kinase and cyclin-dependent kinase 4 (CDK4) as well as in cells with BRAF wild-type allele. Gossypin inhibited kinase activities of BRAFV600E and CDK4, in vitro, possibly through direct binding of gossypin with these kinases, as confirmed by molecular docking studies. For cells harboring the BRAFV600E, gossypin inhibited cell proliferation through abrogation of the MEK-ERK-cyclin D1 pathway and in cells with BRAF wild-type allele, through attenuation of the retinoblastoma-cyclin D1 pathway. Furthermore, gossypin significantly inhibited melanoma growth in an organotypic three-dimensional skin culture mimicking human skin. Gossypin (10 and 100 mg/kg) treatment for 10 days in human melanoma (A375) cell xenograft tumors harboring BRAFV600E significantly reduced tumor volume through induction of apoptosis and increased survival rate in mice, and the effect was significantly superior to that of PLX4032 (10 mg/kg) or roscovitine 10 mg/kg. In summary, this study identified gossypin as a novel agent with dual inhibitory effects for BRAFV600E kinase and CDK4 for treatment of melanoma.

Topics: Animals; Cell Cycle; Cell Line, Tumor; Cell Movement; Cyclin-Dependent Kinase 4; Disease Models, Animal; Female; Flavonoids; Humans; MAP Kinase Signaling System; Melanoma; Mice; Molecular Docking Simulation; Mutation; Protein Binding; Proto-Oncogene Proteins B-raf; Transplantation, Heterologous; Tumor Burden

The mast cell-mediated allergic reactions are involved in many allergic diseases, such as asthma, allergic rhinitis and sinusitis. Stimulation of mast cells initiates the process of degranulation, resulting in the release of mediators such as histamine and an array of inflammatory cytokines. In this report, we investigated the effect of gossypin (a biflavonoid) and suramin (a synthetic polysulphonated naphtylurea) on the mast cell-mediated allergy model, and studied the possible mechanism of their action. Both gossypin and suramin inhibited (P<0.001) compound 48/80-induced systemic anaphylaxis reactions, antiprurities (P<0.001) and reduced the histamine release in rats. Further, both showed significant (P<0.001) protection against rat peritoneal mast cells activated by compound 48/80. Thus, our findings provide evidence that gossypin and suramin inhibit mast cell-derived allergic reactions.

Topics: Anaphylaxis; Animals; Anti-Allergic Agents; Antipruritics; Ascitic Fluid; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Female; Flavonoids; Histamine Release; Hypersensitivity; Male; Mast Cells; Mice; Nitrogen Oxides; p-Methoxy-N-methylphenethylamine; Rats; Suramin