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    Doxycycline and meloxicam can treat neuroinflammation by increasing activity of antioxidant enzymes in rat brain
    (Univ Karachi, 2019) Dik, Burak; Coskun, Devran; Bahcivan, Emre; Er, Ayse
    The aim of this study is to determine the effects of alone or combined usage of doxycycline and meloxicam on brain superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), and matrix metalloproteinase (MMP)-9 levels of lipopolysaccharide (LPS)-induced brain inflammation. Totally 78 rats were divided into 5 groups; Healthy control (n=6), LPS (n=18, 0.05 mu g/mu L/rat, intracranially), LPS+D (n=18, LPS 0.05 mu g/mu L/rat, intracranially and doxycycline 40 mg/kg, intraperitoneally), LPS+M (n=18, LPS 0.05 mu g/mu L/rat, intracranially and meloxicam 2 mg/kg, intraperitoneally), LPS+Combination (n=18, LPS 0.05 mu g/mu L/rat, intracranially and simultaneously both drug combination) groups. Animals were euthanized at 1, 3 and 6 hours following injections and the brains were removed. Brain SOD, CAT, MDA and MMP-9 levels were determined by ELISA reader. Parameters of LPS groups generally different from Healthy control group. When compared to LPS group, increased SOD level of LPS+D at 3 hours and CAT levels of LPS+M and LPS+D groups were determined (P<0.05) at 3 and 6 hours, respectively. In addition, all treatments statistically significantly (P<0.05) decreased MMP-9 levels at 6 hours. In conclusion, doxycycline and meloxicam may show antioxidant effect via increasing antioxidant enzyme production in the brain; however combined usage of drugs may show more beneficial effect for neuroinflammation.
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    Effect of doxycycline and meloxicam on cytokines, brain-derived neurotrophic factor, matrix metalloproteinase-3, tissue inhibitor of metalloproteinase-3 and cyclooxygenase-2 in brain
    (Mashhad Univ Med Sciences, 2020) Er, Ayse; Coskun, Devran; Bahcivan, Emre; Dik, Burak
    Objective(s): Prevention of inflammation in early stages will be useful in maintaining vitality of the organism. The objective of this study was to evaluate the effects of doxycycline (DOX) or meloxicam (MLX) monotherapy and combination therapy on the levels of inflammatory mediators in the brain tissues of rats with Escherichia coli lipopolysaccharide (LPS)-induced brain inflammation. Materials and Methods: Seventy-eight rats were divided into the following groups: control (n=6), LPS (0.5 mu g/10 mu l intracranial) (n=18), LPS (0.5 mu g/10 mu l intracranial)+DOX (40 mg/kg intraperitoneal) (n=18), LPS (0.5 mu g/10 mu l intracranial)+MLX (2 mg/kg intraperitoneal) (n=18) and LPS (0.5 mu g/10 mu l intracranial)+DOX (40 mg/kg intraperitoneal)+MLX (2 mg/kg intraperitoneal) (n=18) groups. Brain tissues were harvested from all rats in the control group and from six rats each in the four experimental groups at 1, 3 and 6 hr under anaesthesia. The levels of tumor necrosis factor alpha (TNF alpha), interleukin 4 (IL-4), IL-6, IL-10, IL-17, brain-derived neurotrophic factor (BDNF), matrix metalloproteinase 3 (MMP-3), tissue inhibitor of metalloproteinase 3 (TIMP-3) and cyclooxygenase 2 (COX-2) in the brain tissues were measured using ELISA kits with ELISA device. Results: LPS administration increased proinflammatory cytokines (TNF, IL-6, IL-17), and MMP-3 levels and decreased anti-inflammatory cytokines (IL-10, IL-4), and BDNF levels. The lowest TNF alpha levels were detected in the LPS+MLX group (P<0.05). All the drug treatment groups showed decreased IL-17 and COX-2 levels compared to the LPS groups. Conclusion: DOX or MLX monotherapy exerts neuroprotective effects against brain inflammation by decreasing proinflammatory cytokine levels and by increasing anti-inflammatory cytokines levels.
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    Pentoxifylline May Restore Kanamycin-Induced Renal Damage in Rats
    (Univ Fed Rio Grande Do Sul, 2018) Corum, Orhan; Ozdemir, Ozgur; Hitit, Mustafa; Corum, Duygu Durna; Coskun, Devran; Er, Ayse
    Background: Kidney damage can be caused by many factors, such as using certain drugs in high doses or over the long term. The use of one such group of drugs, aminoglycosides, which act as Gram-negative antibacterial therapeutic agents, can lead to nephrotoxicity. It has been hypothesized that aminoglycoside-induced nephrotoxicity might be prevented by using pentoxifylline, which has antioxidant and anti-inflammatory effects and improves microcirculation. The objective of this present research was to determine the protective effects of pentoxifylline on kanamycin-induced kidney damage. Materials, Methods & Results: Thirty-two male Wistar rats were divided into four groups as follows: control, pentoxifylline, kanamycin, and kanamycin + pentoxifylline. The control group received intraperitoneal (IP) injections of 0.5 mL normal saline solution once a day (d) (SID) for 20 d; the pentoxifylline group received IP injections of 50 mg/kg pentoxifylline twice a day (BID) for 20 d, the kanamycin group received subcutaneous (SC) injections of 500 mg/kg kanamycin SID for 20 d, and the kanamycin + pentoxifylline group received both SC injections of 500 mg/kg kanamycin SID and IP injections of 50 mg/kg pentoxifylline BID for 20 d. At the end of 20 d, blood samples were taken from the heart by cardiac puncture under general anesthesia. After euthanizing the rats by cervical dislocation under anesthesia, the kidneys were immediately removed, relative kidney weights were calculated, and routine pathologic evaluations were conducted. Hemogram parameters were measured using a blood cell count apparatus and serum biochemical parameters were measured using an autoanalyzer. Kanamycin also caused (P < 0.05) tubular degeneration and tubular dilatation. Although pentoxifylline significantly reduced the level of kanamycin-induced tubular degeneration (P < 0.05), it did not significantly reduce tubular dilatation. Increases in relative kidney weights (P < 0.05) and in interstitial mononuclear cell (MNC) infiltrates were observed in the kanamycin and kanamycin + pentoxifylline groups compared to those in the control and pentoxifylline groups. Statistically significant changes were determined in the levels of some hemogram and biochemical parameters within reference ranges (P < 0.05). Discussion: In this study, both tubular degeneration and dilatation were observed in the kanamycin group. Pentoxifylline inhibited (P < 0.05) kanamycin-induced tubular degeneration and appeared to also reduce tubular dilatation, although this reduction was not significant. Tubular necrosis, epithelial edema of proximal tubules, tubular fibrosis, and perivascular inflammation might also be observed in aminoglycoside-induced nephrotoxicity. In current research, pentoxifylline prevented tubular damage induced by kanamycin, but did not inhibit infiltration by MNCs. Pentoxifylline also ameliorated amikacin-or gentamycin-induced histopathologic changes, especially those associated with tubular structures. The protective effects of pentoxifylline on kanamycin-induced tubular nephrotoxicity in this research might be a result of its stimulating the production of prostaglandin, a vasodilator, and of its improving microcirculation. Although the anti-inflammatory effects of pentoxifylline have been reported, these did not inhibit kanamycin-induced infiltration by interstitial MNCs in the present study. These results could indicate that the anti-inflammatory effects of pentoxifylline are not obvious and/or are dose dependent. Statistically significantly changes were determined in the levels of some hemogram and biochemical parameters in reference ranges. However, these changes were within the reference ranges for rats. These results suggested that kanamycin-induced tubular degeneration and dilatation might be prevented by administering pentoxifylline.
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    Protective Effect of Nerium oleander Distillate and Tarantula cubensis Alcoholic Extract on Cancer Biomarkers in Colon and Liver Tissues of Rats with Experimental Colon Cancer
    (Bentham Science Publ Ltd, 2022) Dik, Burak; Coskun, Devran; Er, Ayse
    Background: Colon cancers are among the top three causes of cancer-related deaths. This study is a continuation of previous research aiming to identify effective treatments. Objective: This study investigated the effects of Tarantula cubensis alcoholic extract (TCAE) and Nerium oleander (NO) distillate on the levels of midkine, transforming growth factor (TGF)-beta, vascular endothelial growth factor (VEGF), alpha-fetoprotein (AFP), cyclooxygenase (COX)-2, insulin-like growth factor (IGF) and caspase-3 in the liver and colon tissues of rats with experimentally induced colon cancer. Methods: The liver and colon tissues of rats were homogeneously divided into control, colon cancer (azoxymethane, AZM), AZM + TCAE, and AZM + NO distillate groups. The levels of midkine, TGF-beta, VEGF, AFP, COX-2, IGF, and caspase-3 in the colon and liver tissues were measured by ELISA. Results: The levels of all parameters in colon and liver tissues in the AZM group were higher (p<0.05) than those in the control group. TCAE and NO distillate prevented (p < 0.05) increases in midkine, TGF-beta, VEGF, AFP, COX-2, IGF, and caspase-3 levels in the colon. NO distillate prevented the increase in all parameters except IGF, whereas TCAE prevented the increase in all values apart from COX-2 and IGF levels in the liver (p<0.05). Conclusion: NO distillate and TCAE may prevent the studied markers from reaching specified levels observed in the colon in AZM-induced colon cancer. The increases in the levels of the parameters in the liver were not as severe as those in the colon; however, an 18-week study period may not be sufficient for liver metastasis formation. Future molecular studies should investigate the mechanisms and pathways of these treatments in greater detail.
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    The impact of ambroxol on the anti-inflammatory effect of azithromycin in lung tissue
    (Univ Zagreb Vet Faculty, 2021) Er, Ayse; Dik, Burak; Coskun, Devran; Faki, Hatice Eser; Bahcivan, Emre
    The aim of this study was to compare the effects of two different doses of ambroxol (AMB) co-administered with azithromycin (AZIT) on the concentrations of bronchoalveolar lavage fluid (BALF) cytokines and serum biochemical parameters in an lipopolysaccharide (LPS)-induced acute lung injury mouse model. A total of 78 male Swiss albino mice were used for this investigation. After six mice had been separated as the control group (0 hours), the remaining animals were divided into the following three equal groups: LPS, LPS+AZIT+AMB30 and LPS+AZIT+AMB70. LPS, AZIT and AMB were administered intraperitoneally. BALF and serum samples were collected before (0 hour) and after applications at 4, 8, 16 and 24 hours under general anaesthesia, and then all mice were euthanised by cervical dislocation. Concentrations of tumor necrosis factor (TNF)alpha, interleukin (IL)-6 and IL-10 in BALF and aspartate aminotransferase (AST), alkaline phosphatase (ALP), urea and creatinine concentrations in serum were determined. Elevated TNF alpha and IL-6 concentrations in the LPS group were prevented at 8 and 16 hours in LPS+AZIT+AMB30 group. In addition, both treatment groups inhibited elevated IL-6 concentrations in the LPS group at 16 hours. LPS+AZIT+AMB30 and LPS+AZIT+AMB70 increased IL-10 concentrations at 16 and 4 hours, respectively. LPS caused significant elevations in urea concentrations at all sampling times and statistical fluctuations in other parameters at different sampling times. The increased ALP concentration in LPS group decreased in the treatment groups at 8 hours. In conclusion, the combination of low-dose AMB and AZIT may achieve beneficial effects in pulmonary infections by influencing the cytokine network.