Publications by authors named "Zekai Halıcı"

145 Publications

Roflumilast as a Potential Therapeutic Agent for Cecal Ligation and Puncture-Induced Septic Lung Injury.

J Invest Surg 2021 Apr 11:1-9. Epub 2021 Apr 11.

Department of Pharmacology, Ataturk University, Erzurum, Turkey.

Purpose/aims: This study focused on delineating the possible effects of roflumilast (ROF), a selective phosphodiesterase 4 (PDE4) inhibitor, in rats with cecal ligation and puncture (CLP)-induced polymicrobial sepsis, and investigated whether ROF can act as a protective agent in sepsis-induced lung damage.

Material And Methods: Four experimental groups were organized, each comprising eight rats: Control, Sepsis, Sepsis + ROF 0.5 mgkg, and Sepsis + ROF 1 mgkg groups. A polymicrobial sepsis model was induced in the rats by cecal ligation and puncture under anesthesia. Twelve hours after sepsis induction, the lungs were obtained for biochemical, molecular, and histopathological analyses.

Results: In the sepsis group's lungs, the TNF-α, IL-1β, and IL-6 mRNA expression levels peaked in the sepsis group's lung tissues, and ROF significantly decreased these levels compared with the sepsis group dose-dependently. ROF also significantly decreased MDA levels in septic lungs and increased antioxidant parameters (SOD and GSH) compared with the sepsis group. Histopathological analysis results supported biochemical and molecular results.

Conclusions: ROF, a PDE4 inhibitor, suppressed the expression levels of pro-inflammatory cytokines, alleviated lung damage (probably by blocking neutrophil infiltration), and increased the capacity of the antioxidant system.
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http://dx.doi.org/10.1080/08941939.2021.1908462DOI Listing
April 2021

Neuroprotective effect of roflumilast under cerebral ischemia/reperfusion injury in juvenile rats through NLRP-mediated inflammatory response inhibition.

Clin Exp Pharmacol Physiol 2021 Mar 8. Epub 2021 Mar 8.

Department of Pharmacology, Ataturk University Faculty of Medicine, 25240, Erzurum, Turkey.

To investigate the protective effect of roflumilast, a PDE-4 enzyme inhibitor, and show its possible role in preventing cerebral ischemia/reperfusion injury (CI/RI) developing after a stroke induced by carotid artery ligation in juvenile rats. The rats were randomly divided into five groups: healthy group not administered any treatment, healthy group administered 1 mg/kg roflumilast, cerebral ischemia group administered no roflumilast, cerebral ischemia group administered 0.5 mg/kg roflumilast, and cerebral ischemia group administered 1 mg/kg roflumilast. In the cerebral ischemia groups, reperfusion was achieved two hours after ischemia induction. In the three roflumilast groups, this drug was intraperitoneally administered immediately after reperfusion and at the 12 hour. At the end of the 24 hour, the rats were sacrificed and their brain tissues were removed for examination. The expressions of IL-1β, TNF-α and NLRP3 significantly increased in the CI/RI-induced groups, and this increase was significantly lower in the groups administered roflumilast. The histopathological studies revealed that the values closest to those of the healthy group were obtained from the roflumilast groups. Our study showed that roflumilast, a PDE-4 inhibitor, reduced cellular damage caused by CI/RI in juvenile rats, and this effect may be mediated by NLRP3.
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http://dx.doi.org/10.1111/1440-1681.13493DOI Listing
March 2021

5-HT7 receptors as a new target for prostate cancer physiopathology and treatment: an experimental study on PC-3 cells and FFPE tissues.

Naunyn Schmiedebergs Arch Pharmacol 2021 Feb 2. Epub 2021 Feb 2.

Department of Pharmacology, Faculty of Medicine, Atatürk University, 25240, Erzurum, Turkey.

Prostate cancer (PCa) is one of the most common types of cancer seen among men worldwide. Previous studies have demonstrated that serotonin regulates cell proliferation, migration, and invasion in vitro; the presence of 5-HT receptors in cancer cells; and the role of serotonin in tumor development. The most recently discovered of these receptors is 5-HT7 but also least characterized receptors of serotonin. The aim of this study is to investigate the existence and possible role of 5-HT7 receptors in healthy and cancerous prostate tissues and also investigate effects of receptor agonists and antagonists on PC-3 cells to evaluate potential therapeutic effects. PC-3 cells were cultured and effects of 5-HT7 receptor agonist (LP-44) and antagonist (SB-269970) were evaluated on these cells. After proliferation analyses, relative expression of apoptotic markers and 5-HT7 receptor mRNA expression levels were determined through real-time PCR. Annexin V-FITC/PI double staining and Hoechst 33258 staining assay methods were applied to determine apoptosis. Additional PCR studies were performed on healthy and cancerous prostate tissue to see existence of receptors in human samples. The viability of PC-3 cells was decreased by SB-269970 after 48 and 72 h of incubation. However, LP-44 increased PC-3 cell proliferation at all time points. In 10 M SB-269970 treated PC-3 cells, there was significant increase in the expression of CAS-3 (4-fold), CAS-9 (2.5-fold), BAX (1.9-fold), and Tp-53 (4.8-fold) gene mRNA levels when compared to non-treated control group. Conversely, there was a significant decrease in NF-κB (2.9-fold) and 5-HT7 receptor (3.6-fold) mRNA expression in cells treated with SB-269970 when compared to control. SB-269970 that antagonized 5-HT7 receptors also induced apoptosis in Annexin V-FITC/PI double staining assay and Hoechst 33258 staining assays when compared with other groups. In human samples, 5-HT7 receptor mRNA expression was approximately 200-fold higher than that of heathy ones. In this study, for the first time, the 5-HT7 receptor antagonist SB-269970 has been shown to inhibit proliferation in PC-3 cells and to be associated with an apoptosis-inducing effect. These results suggest blocking 5-HT7 receptors can be a novel therapeutic target for the treatment of prostate cancer.
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http://dx.doi.org/10.1007/s00210-021-02051-zDOI Listing
February 2021

Effects of soy isoflavonoids (genistein and daidzein) on endometrial receptivity.

Iran J Basic Med Sci 2020 Dec;23(12):1603-1609

Ataturk University, Faculty of Medicine, Department of Pharmacology, Erzurum.

Objectives: This study aimed to examine the effects of genistein and daidzein on endometrial receptivity by histopathological, immunohistochemical, and biochemical techniques.

Materials And Methods: In this study, 72 female Sprague-Dawley rats were randomly divided into 8 groups. The endometrial receptivity model was applied to identified groups. Experimental animals were given periorally 10 mg/kg and high 40 mg/kg doses of genistein and daidzein for 5 days by gavage. At the end of the experiment, uterine tissues were evaluated histopathologically, immunohistochemically, and biochemically.

Results: When histopathological findings were examined, significant decreases in pinopod formation were observed in high dose genistein and daidzein groups. When compared with the endometrial receptivity group, immunohistochemical staining findings showed a significant decrease in the expression of integrin β3, integrin αvβ3, LIF, and HOXA10 and an increase in MUC 1 expression in the high dose of genistein and daidzein groups. In biochemical evaluations, it was determined that genistein and daidzein increased estrogen levels and decreased progesterone levels in a dose-dependent manner.

Conclusion: Genistein and daidzein have a negative effect on endometrial receptivity. Therefore, individuals with a risk of infertility should pay attention to the consumption of genistein and daidzein.
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http://dx.doi.org/10.22038/ijbms.2020.48294.11089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811811PMC
December 2020

Phloretin and phloridzin guard against cisplatin-induced nephrotoxicity in mice through inhibiting oxidative stress and inflammation.

Life Sci 2021 Feb 9;266:118869. Epub 2020 Dec 9.

Ataturk University, Faculty of Medicine, Department of Pharmacology, Erzurum, Turkey; Clinical Research, Development and Design Application and Research Center, Ataturk University, Erzurum, Turkey.

Aim: Cisplatin (Cis) is widely used chemotherapeutic and has some serious side effects as nephrotoxicity. Phloretin (PH) and Phloridzin (PZ) are known their anti-oxidant anti-inflammatory effects. We aimed to examine the protective effects of PH and PZ on cisplatin-induced nephrotoxicity.

Main Methods: Totally, 48 Balb/C female mice were separated into eight groups (n = 6). First day, single dose of cisplatin (20 mg/kg intraperitoneal) was administered to induce toxicity. PH and PZ were given (50 and 100 mg/kg orally) to treatment groups during 3 days. After the experimental procedures serum renal function enzymes (BUN and Creatinine), oxidative parameters (SOD, GSH and MDA), nuclear agent NFKβ, inflammatory cytokines (Tnf-α and IL1β) and HSP70 expressions and histopathological assessments were analyzed.

Key Findings: Serum enzymes, tissue cytokines and oxidative stress were increased after the Cis treatment. PH and PZ treatments normalized all parameters compared to Cis administrated group. After the treatments, SOD activities and GSH levels were increased while MDA levels were decreased. PH and PZ treatments decreased Tnf-α, IL1β and NFKβ mRNA expressions. Cis significantly increased the HSP70 expression while PH and PZ administrations significantly decreased. Similar the biochemical and molecular results, PH and PZ showed positive effects on tissue pathological parameters. Cisplatin cause a lot of abnormal structures as tubular and glomeruli damages on the kidney.

Significance: PH and PZ play important physiological roles in the prevention of nephrotoxicity. Antioxidant and anti-inflammatory effects of PH and PZ demonstrated visible protective effects in the cisplatin-induced nephrotoxicity model.
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http://dx.doi.org/10.1016/j.lfs.2020.118869DOI Listing
February 2021

Investigation of the Role of Stimulation and Blockade of 5-HT Receptors in Ketamine Anesthesia.

J Mol Neurosci 2020 Nov 16. Epub 2020 Nov 16.

Department of Pharmacology, Faculty of Medicine, Ataturk University, Erzurum, 25240, Turkey.

Although several pieces of evidence have indicated the ability of the serotonin-7 receptor (5-HTR) to modulate N-methyl--aspartate receptor (NMDAR) activation, the possible impact on ketamine anesthesia has not been examined directly. The purpose of the present study is thus to investigate the possible role of the 5-HTR in ketamine anesthesia using a 5-HTR agonist and/or antagonist. The influence of a 5-HTR agonist/antagonist on ketamine anesthesia for behavioral impact was assessed by testing potential anesthetic parameters. Its functional impact was assessed by mRNA expression with real-time PCR and immunostaining in the hippocampus and prefrontal cortex of mice. Two different doses of ketamine-high and low-were administered to induce anesthesia. In the high-dose ketamine-applied group in particular, the administration of both the 5-HTR agonist and antagonist intensified the anesthetic effect of ketamine. The reflection of the change in anesthesia parameters to 5-HTR expression was observed as an increase in the hippocampus and a decrease in the prefrontal cortex in the anesthetized groups by stimulation of 5-HTR. It is noteworthy that the results of NMDAR expressions are parallel to the results of the 5-HTR expressions of both the hippocampus and the prefrontal cortex. The 5-HTR may play a role in ketamine anesthesia. It may act through NMDAR in ketamine anesthesia, depending on the parallelism between both receptors.
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http://dx.doi.org/10.1007/s12031-020-01732-3DOI Listing
November 2020

Protective effect of luteolin on acute lung injury in a rat model of sepsis.

Biotech Histochem 2020 Nov 12:1-7. Epub 2020 Nov 12.

Faculty of Medicine, Department of Biochemistry, Ataturk University , Erzurum, Turkey.

We investigated the effects of luteolin (LUT) treatment on acute lung injury caused by cecal ligation and puncture (CLP) induced septic rats. We also investigated the relation between LUT and the cytokines, interleukin-10 (IL-10) and tumor necrosis factor-α (TNF-α). LUT was administered 1 h after CLP surgery. Administration of LUT reduced the glutathione level and superoxide dismutase activity in rat lung tissues. We also found significant reduction of malondialdehyde following LUT treatment. LUT administration also reduced TNF-α and IL-10 mRNA expression in lung tissue. Histopathologic investigation of lung tissue supported our biochemical and molecular findings. Administration of LUT ameliorated lung injury in CLP induced septic rats owing to its antioxidant and anti-inflammatory properties.
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http://dx.doi.org/10.1080/10520295.2020.1846787DOI Listing
November 2020

Investigation of serum and brain superoxide dismutase levels depending on atomoxetine used in attention-deficit/hyperactivity disorder treatment: A combination of in vivo and molecular docking studies.

Bioorg Chem 2020 12 27;105:104435. Epub 2020 Oct 27.

Department of Medical Services and Techniques, Health Services Vocational School, Atatürk University, 25240 Erzurum, Turkey.

This study aims to determine whether atomoxetine (ATX), used as an alternative to methylphenidate, affects superoxide dismutase (SOD) activity besides glutathione (GSH) and malondialdehyde (MDA) levels, apart from determining possible effects of ATX on SOD activity through molecular docking studies. 24 male Wistar rats were divided into 4 groups, each containing 6 members. After a 6-week application of ATX, blood samples and brain tissues were obtained from the rats for biochemical analyses. Besides, molecular docking studies were conducted using PyRx and Discovery Studio 3.0 programs. No significant difference occurred in GSH and MDA levels after ATX application. A high-dose application of ATX caused a statistically significant change only in the serum-SOD activity compared to that of Control Group. Molecular docking studies revealed that ATX settled in the biggest space rather than the catalytic regions of CuZn-SOD. Our biochemical and molecular docking data showed that ATX, an alternative drug to stimulant methylphenidate, showed no significant changes in the antioxidant defence system at either low or therapeutic doses after long-term use. Therefore, we suggest ATX could be used as a substitute for methylphenidate in the long-term treatment of ADHD.
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http://dx.doi.org/10.1016/j.bioorg.2020.104435DOI Listing
December 2020

Biochemical Research of the Effects of Essential Oil Obtained from the Fruit of Myrtus communis L. on Cell Damage Associated with Lipopolysaccharide-Induced Endotoxemia in a Human Umbilical Cord Vein Endothelial Cells.

Biochem Genet 2021 Feb 12;59(1):315-334. Epub 2020 Oct 12.

Department of Pharmacology, Faculty of Medicine, Ataturk University, 25240, Erzurum, Turkey.

The aim of this study to investigate the potential effects of essential oils and compounds obtained from MC fruit on sepsis induced endothelial cell damage in human umbilical cord vein endothelial cells (HUVECs) at molecular and cellular levels on in vitro sepsis model. A sepsis model was induced by the application of LPS. The HUVEC treatment groups were as follows: control, LPS, MC, MC plus LPS, 1.8 cineole, 1.8 cineole plus LPS, α-pinene, α-pinene plus LPS, α-terpineol, and α-terpineol plus LPS. Following the treatments, cell proliferation was analyzed using the xCELLigence® system. The mRNA expression of various cytokines [tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), and IL-6] and endothelial nitric oxide (eNOS) were determined by quantitative polymerase chain reaction (qPCR) analysis. The 1.8 cineole and α-pinene treatments at specific doses showed toxic effects on α-terpineine, although it did not result in a change in the cellular index as compared with that of the control group. The application of LPS to HUVECs led to a significant decrease in the cellular index, depending on the treatment time. It did not correct the decreased cell index of MC plus LPS and α-terpineol plus LPS groups as compared with that of the LPS-only group. The 1.8 cineole plus LPS treatment and α-pinene plus LPS treatment significantly increased the cell index as compared with that of the LPS-only treatment, and the cell index in these groups was closer to that of the control. According to the results of the qPCR analysis, neither the MC-only treatment nor the α-terpineol-only treatment significantly reduced cellular damage caused by LPS-induced increases in TNF-α, IL-1β, IL-6, and eNOS mRNA expression. However, both the 1.8 cineole treatment and α-pinene treatments significantly decreased TNF-α, IL-1β, IL-6, and eNOS mRNA expression induced by LPS. Volatile oil obtained from MC fruit and the MC compound α-terpineol had no effect on the decreased cell index and increased cytokine response due to LPS-induced endothelial cell damage. However, 1.8 cineole and α-pinene, other major components of MC fruit, ameliorated LPS-induced damage in HUVECs at cellular and biomolecular levels (TNF-α, IL-1β, IL-6, and eNOS).
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http://dx.doi.org/10.1007/s10528-020-10005-yDOI Listing
February 2021

Do peripheral melatonin agonists improve bone fracture healing? The effects of agomelatine and ramelteon on experimental bone fracture.

Eur J Pharmacol 2020 Nov 17;887:173577. Epub 2020 Sep 17.

Faculty of Medicine, Department of Histology and Embryology Department, Kafkas Univeristy, Kars, Turkey.

Melatonin improves fracture healing, but the long-term use of melatonin seems impracticable in the treatment of fracture due to side effects caused by hormonal stress on chronological rhythm. Ramelteon (RAMEL) and agomelatine (AGO) are non-selective peripheral melatonin receptor (MT) agonists. This study investigated the effects on bone fracture healing of these MT agonists, which do not affect the central nervous system. The rats were divided into 6 groups, including Group 1 (SHAM): sham operated group; Group 2 (FRACTURE): femoral fracture control; Group 3 (FR + AGO30): femoral fracture + agomelatine 30 mg/kg; Group 4 (FR + AGO60): femoral fracture + agomelatine 60 mg/kg; Group 5 (FR + RAMEL3): femoral fracture + ramelteon 3 mg/kg; and Group 6 (FR + RAMEL6): femoral fracture + ramelteon 6 mg/kg. After 21 days, the rats were subjected to X-ray imaging. Bone healing was evaluated with hematoxylin-eosin (HE) staining. Messenger RNA (mRNA) expressions of bone formation markers, such as bone alkaline phosphatase (ALP), osteocalcin (OC), and osteopontin (OP), were evaluated by real-time polymerase chain reaction (RT-PCR) and with immunohistochemistry (IHC) staining. The radiographic fracture healing scores were statistically significantly higher in the FR + AGO60 group and the FR + RAMEL3 group than in the FRACTURE group. The histopathology and molecular results supported the radiographic results. It was shown that agomelatine and ramelteon increase bone fracture healing, leading to the conclusion that a preference for agomelatine, an antidepressant, and ramelteon, a sleep aid, will increase bone fracture healing in patients with fractures.
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http://dx.doi.org/10.1016/j.ejphar.2020.173577DOI Listing
November 2020

Protective Effect of Lycopene against Reperfusion Injury in Rats with Ovarian Torsion: A Biochemical and Histopathological Evaluation.

J Lab Physicians 2020 Mar 11;12(1):32-37. Epub 2020 Aug 11.

Department of Pharmacology, Faculty of Medicine, Ataturk University, Erzurum, Turkey.

 The aim of our study was to evaluate the effect of two different doses of lycopene, an antioxidant, on experimentally induced ovarian ischemia/reperfusion (IR) injury in rat model.  Twenty-four female rats were randomly divided into four groups: sham operation (group 1), 3-hour ischemia, 3-hour reperfusion (IR) (group 2), and IR + 100 mg/kg lycopene (PO) (group 3), IR + 200 mg/kg of lycopene (group 4). The rats' superoxide dismutase (SOD), myeloperoxidase (MPO) activities, malondialdehyde (MDA), and glutathione (GSH) levels were calculated. Ovarian tissue damage was assessed using a histopathological scoring system.  Serum parameter levels and histological scores showed that treatment with lycopene may be conservative approach to prevent IR injury after the ovarian detorsion procedure.The improvement with lycopene was higher at 200 mg than at 100 mg. The MPO and MDA values were significantly lower in groups 3 and 4 as compared with group 2 ( < 0.05), whereas the MPO and MDA values were lower in group 4 as compared with group 3.The SOD and GSH values were significantly higher in groups 3 and 4 as compared with group 2 ( < 0.05), whereas the SOD and GSH values were higher in group 4 as compared with group 3.Tissue damage scores were elevated in the IR group compared with the sham group, but the treatment with different lycopene doses after reperfusion improved the histopathological tissue damage scores.  The results showed that lycopene treatment reduced ovarian IR damage. Antioxidant activity was found to increase in a dose-dependent manner. Lycopene treatment may be conservative approach for ovarian torsion patients after the detorsion procedure to prevent IR damage.
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http://dx.doi.org/10.1055/s-0040-1715553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419174PMC
March 2020

Can aprepitant used for nausea and vomiting be good gastrointestinal complaints?

Naunyn Schmiedebergs Arch Pharmacol 2020 12 3;393(12):2463-2472. Epub 2020 Aug 3.

Department of Pharmacology, Faculty of Medicine, Ataturk University, Erzurum, Turkey.

Aprepitant is a selective SP/NK-1 receptor antagonist and used in postoperative and chemotherapeutics induced emesis and vomiting. The aim of our study is to show aprepitant may have beneficial effects on gastrointestinal complaints in cancer patients undergoing chemotherapeutics by indomethacin-induced gastric ulcer model. A total of 48 rats were fasted 24 h for ulcer experiment. Aprepitant doses of 5, 10, 20, and 40 mg/kg were evaluated for their antiulcer activity. Omeprazole (20 mg/kg) was used as a positive control group. Six hours after 25 mg/kg indomethacin administration, all stomachs were dissected out. After macroscopic analyses, tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), COX-1, and COX-2 mRNA levels and SOD activity, and GSH and MDA levels of stomachs were determined. Histopathological examinations were evaluated. Aprepitant administration exerted 48.14%, 49.62%, 65.92%, and 76.77% ulcer inhibition effects at 5, 10, 20, and 40 mg/kg, respectively. Aprepitant administration decreased oxidative stress and inflammatory parameters in stomach tissues dose dependently. Aprepitant administration increased stomach COX-2 mRNA levels at 20 and 40 mg/kg doses. Although aprepitant appears to be disadvantageous in terms of treating gastric ulcer due to COX enzyme inhibition according to the previous studies, aprepitant has been shown to have ulcer healing effect in our study. When aprepitant is given as an anti-nausea and vomiting drug to cancer patients undergoing chemotherapy, we can argue that it will not be necessary to add a new gastric protective agent as it also shows beneficial effects in gastrointestinal complaints.
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http://dx.doi.org/10.1007/s00210-020-01956-5DOI Listing
December 2020

Possible contribution of the neprilysin/ACE pathway to sepsis in mice.

Life Sci 2020 Oct 30;258:118177. Epub 2020 Jul 30.

Ataturk University Faculty of Medicine, Department of Pharmacology, Erzurum, Turkey; Ataturk University Clinical Research, Development and Design Application and Research Center, Erzurum, Turkey.

Aim: Omapatrilat is an antagonist of angiotensin-converting (ACE) and neprilysin-neuropeptidase (NEP) enzymes. The aim of our study is to show that omapatrilat may have beneficial effects as a treatment for polymicrobial sepsis.

Main Methods: A cecal ligation and puncture (CLP) sepsis model was used to evaluate 10 and 20 mg/kg doses of omapatrilat in mice (n = 30) fasted for 12 h. The lungs were removed 12 h after CLP, and lung levels of cytokines (tumor necrosis factor-alpha [TNF-α], interleukin-6 [IL-6], NF-κB), iNOS and eNOS mRNA expression, GSH and MDA levels, and ACE and NEP activities were determined. Histopathological examinations were also performed.

Key Findings: Omapatrilat treatment provided a dose-dependent reduction in oxidative stress and inflammatory parameters in lung tissues. Omapatrilat administration decreased lung iNOS and eNOS mRNA levels at 20 mg/kg dose. Histopathological analysis revealed a decline in the thickening and edema areas in the alveolar septa in the Sepsis+OMA20 group.

Significance: Omapatrilat, a dual ACE and NEP inhibitor, protected lung tissue from sepsis damage by reducing ACE and NEP activities, by decreasing the mRNA expression levels of pro-inflammatory cytokines (TNF-α, IL-6, and NF-κB), by suppressing leukocyte infiltration and edema, by restoring iNOS and eNOS levels, and by restoring SOD activity and GSH and MDA levels, thereby reducing oxidative stress.
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http://dx.doi.org/10.1016/j.lfs.2020.118177DOI Listing
October 2020

Is Ebselen A Therapeutic Target in Fracture Healing?

Eurasian J Med 2020 Jun 2;52(2):171-175. Epub 2020 Jun 2.

Department of Histology and Embryology, Ataturk University, School of Medicine, Erzurum, Turkey.

Objective: We investigated the effect of ebselen on fracture healing in an experimental fracture model.

Materials And Methods: We divided rats into two groups, 6 rats in each: the experimental femur fracture control group and the ebselen treatment group with an experimental femur fracture. In the experimental femur fracture control group, we created only experimental femur fracture. In the ebselen treatment group, we administered ebselen treatment with creating an experimental femur fracture. We administered ebselen intraperitoneally at 5 mg/kg once daily for 1 month after the 1st day of experimental femur fracture in the ebselen treatment group. We evaluated the recovery status of fractured femurs at the end of 1st month with radiographic, histopathological, and immunohistochemical methods.

Results: According to the radiographic fracture healing scores, ebselen treatment increased the extent of new bone formation and fracture cartilage callus significantly compared to the control group. According to the histopathological recovery scores, ebselen treatment significantly improved healing scores compared to the control group. Ebselen treatment increased the expression scores of bone healing markers in the ebselen treatment group, such as vascular endothelial growth factor and osteocalcin, compared to the control group.

Conclusion: We demonstrated that ebselen treatment increases the formation of new bone in the femur in an experimentally created femoral fracture model. Ebselen has been shown to improve the bone fracture healing in a radiological and histopathological manner, and more detailed studies are needed.
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http://dx.doi.org/10.5152/eurasianjmed.2020.18443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311129PMC
June 2020

LP44 (4-[2-(methylthio)phenyl]-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide) exerts anti-ulcer effects via 5-hydroxytryptamine receptor 7 activation on indomethacin-induced gastric ulcers in rats.

Inflammopharmacology 2020 Aug 5;28(4):893-902. Epub 2020 Jun 5.

Department of Pharmacology, Faculty of Medicine, Ataturk University, 25240, Erzurum, Turkey.

Aim: This study aimed to demonstrate the role of serotonin 7 receptor (5-HT) and the effects of 5-HT agonists and antagonists in an indomethacin-induced gastric ulcer.

Material And Method: Male albino Wistar rats (n = 60) were used in the experiments. LP44 (5-HT agonist) and SB269970 (5-HT antagonist) were administered at 10 mg/kg as a pre-treatment. One hour after the drug treatments, 25 mg/kg of indomethacin (INDO) was administered to all groups except the healthy control group. Six hours after indomethacin administration, all the rats were euthanized.

Results: We analyzed the iNOS, eNOS, and 5-HT receptor mRNA levels in the stomach tissue of rats by real-time PCR. 5-HT mRNA expression was increased in the INDO group compared to the healthy group. LP44 administration exerted a significant upregulatory effect on eNOS mRNA expression and downregulatory effects on iNOS and 5-HT mRNA expression compared to the INDO group. However, antagonist (SB269970) administration did not result in such difference in gene expression, but even partially decreased the agonist's effect in combination. Famotidine and agonist exerted similar effects. Histopathological findings supported the beneficial effects of 5-HT agonist on gastric tissue.

Conclusion: The study suggested that activation of 5-HT receptor showed a significant anti-ulcerogenic effect in the indomethacin-induced gastric ulcer model.
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http://dx.doi.org/10.1007/s10787-020-00725-3DOI Listing
August 2020

A novel effect of Aprepitant: Protection for cisplatin-induced nephrotoxicity and hepatotoxicity.

Eur J Pharmacol 2020 Aug 11;880:173168. Epub 2020 May 11.

Ataturk University, Faculty of Medicine, Department of Pharmacology, Erzurum, Turkey; Clinical Research, Development and Design Application and Research Center, Ataturk University, Erzurum, Turkey.

Cisplatin is widely used chemotherapeutic drug and have some serious side effects as tissue toxicity and nausea and vomiting. Aprepitant is used in clinic as an anti-emetic drug for cisplatin treated patient to prevent nausea and vomiting. We aimed to investigate the protective effects of Aprepitant on cisplatin-induced nephrotoxicity and hepatotoxicity. In total 42 male rats were separated into six groups (n = 7). A single dose of cisplatin (10 mg/kg i.p.) was administered to induce toxicity on first day. Different doses of Aprepitant (5, 10 and 20 mg/kg, p.o.) were given to treatment groups during 3 days. After the experimental procedures serum enzymes (ALT, AST, ALP, BUN and Creatinin), kidney and liver oxidative parameters (SOD, GSH and MDA), inflammatory cytokines (TNF-α and NF-κB) and Cyp2e1 expressions analyzed. Histopathological investigations also performed for all groups. Cisplatin caused tissue toxicity in both kidney and liver. Serum enzymes, tissue cytokines and oxidative stress were increased after the Cis treatment. Aprepitant treatment normalized all parameters compared to cisplatin treated group. Cisplatin significantly increased the Cyp2e1 expression in the kidney while significantly decreased in the liver compared to Healthy group. Histopathologically, it was shown that cisplatin causes a lot of abnormal structures as inflammatory infiltration and necrosis on the liver and kidney. Similar the biochemical and molecular results, aprepitant showed positive effects on tissue pathological parameters. With its main anti-emetic effect, Aprepitant treatment may be an effective option for cancer patients if they have additional injury as nephrotoxicity and hepatotoxicity due to cisplatin.
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http://dx.doi.org/10.1016/j.ejphar.2020.173168DOI Listing
August 2020

5-HT7 receptorsare over-expressed in patients with nasal polyps.

Ear Nose Throat J 2020 May 12:145561320919603. Epub 2020 May 12.

Department of Ear, Nose and Throat Diseases, Faculty of Medicine, Ataturk University, Erzurum, Turkey.

Nasal polyposis (NP) is an inflammatory disease of the paranasal sinuses and nasal cavity. The primary purpose of our study is to determine the expression of 5-HT receptors both in nasal polyps and in healthy tissue in the nasal cavity. The subsequent aim is to compare the expression of 5-HT receptors in patients with NP and in inferior turbinate tissue (control).The study included 60 participants (40 with NP and 20 controls) aged 35 to 62 years. Nasal polyp samples were collected from all patients and relative expression analyses were performed. RT-PCR analysis of nasal polyps and control tissue identified 5-HT receptor expression in the nasal cavities of controls. This expression was approximately 67 times higher in nasal polyp tissue than in healthy tissue. Our study identifies the expression of 5-HT receptors in the nasal cavity for the first time. It is also the first demonstration of increased 5-HT receptor expression in tissue from nasal polyps, which occur in the paranasal sinuses and nasal cavity.
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http://dx.doi.org/10.1177/0145561320919603DOI Listing
May 2020

Olfactory bulbectomy and raphe nucleus relationship: a new vision for well-known depression model.

Nord J Psychiatry 2020 Apr 14;74(3):194-200. Epub 2019 Nov 14.

Department of Pharmacology, Medical Faculty, University of Ataturk, Erzurum, Turkey.

The olfactory bulbectomy (OBX) technic is a well-known animal model for depression. According to serotonin hypothesis of depression, one of the possible explanations to this mechanism is the destroying effect of OBX on raphe nuclei which especially include serotonergic neurons. In this study, we aimed to explore histopathological findings in raphe nuclei in OBX rats. Forty-eight rats (8 control group, 10 sham group, and 30 as the study group) were used. No procedure was applied to the control group. Only frontal burr holes were performed at the level of olfactory bulbs (OBs) on the sham group. Mechanical OBX by compression was applied to 20 rats and the OBs of 10 rats were cauterized. Their OBs, olfactory cortices, raphe nuclei were extracted, tissue specimens were taken than examined by using histopathological methods including hematoxylin and eosin, S-100, and TUNEL staining. Physical dissector method was used to evaluate the number of living and apoptotic neurons in the raphe nuclei. Prominent neuronal loss and morphological changes in the dorsal raphe nuclei were detected in study groups. Raphe nuclei degeneration, related alterations in neurotransmitter system activities and functional brain connectivity might be related to neurobiology of depression.
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http://dx.doi.org/10.1080/08039488.2019.1689294DOI Listing
April 2020

Evaluation of the Roflumilast Effect Supplemented with Linezolid in Pleural Empyema in Rats Caused by Intrapleural Staphylococcus aureus Inoculation.

Jpn J Infect Dis 2020 Jan 30;73(1):1-7. Epub 2019 Aug 30.

Department of Pulmonary Diseases, Ataturk University School of Medicine.

In addition to tube drains, pleural empyema is treated with antibiotics and anti-inflammatory drugs. We aimed to evaluate the anti-inflammatory activity of roflumilast combined with linezolid in a rat model of pleural empyema induced by Staphylococcus aureus. A total of 40 rats were divided into 7 groups: sham (n = 4), S. aureus inoculation (n = 6), S. aureus + 10 mg/kg linezolid (n = 6), S. aureus + 5 mg/kg roflumilast (n = 6), S. aureus + 10 mg/kg linezolid + 5 mg/kg roflumilast (n = 6), S. aureus + 10 mg/kg roflumilast (n = 6), and S. aureus + 10 mg/kg linezolid + 10 mg/kg roflumilast (n = 6). Animals were administered linezolid 1 h before and 12 h after inoculation with S. aureus. Roflumilast was administered orally as a single dose 30 min before inoculation with S. aureus. Compared to linezolid treatment alone, linezolid combined with 5 mg/kg roflumilast significantly improved TNF-α, IL-1β, vasodilation/congestion, and tissue/pleural polynuclear leukocyte (PNL) infiltration (p < 0.05). Linezolid combined with 10 mg/kg roflumilast also provided a significant improvement in TNF-α, IL-1β, IL-6, endothelin-1, vasodilation/congestion, mesothelial cell damage, lung tissue PNL, and pleural PNL compared to linezolid alone (p < 0.05). Due to its anti-inflammatory effects and significant impact on recovery, roflumilast can be used in conjunction with antibiotherapy for the treatment of pleural empyema.
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http://dx.doi.org/10.7883/yoken.JJID.2019.164DOI Listing
January 2020

Regenerative Effect of Resorbable Scaffold Embedded Boron-Nitride/Hydroxyapatite Nanoparticles in Rat Parietal Bone.

J Nanosci Nanotechnol 2020 Feb;20(2):680-691

Department of Moleculary Science and Biotechnology, Faculty of Science, Yeditepe University, 34100 Istanbul, Turkey.

BN has important roles in several physiological events, including bone growth and immune system. New infection-free cranioplasty and has an osteogenic activities material that are compatible with tissue are being developed. We aimed in our study to examine whether different combinations of Boron-nitride/Hydroxyapatite are embedded into the scaffold in the treatment of calvarial defects. 200 adult female Sprague-Dawley rats divided into 10 equal groups. Osteotomy was made by trepan drill in 8 mm diameter. The scaffolds were placed in the rats and were left to recovery for 2 months. During the experiment, CT scans were taken from the calvarial areas of the rats in the 2nd, 4th and 8th weeks. Significant healing was observed in defect diameters in 2.5% BN+10% HA, 2.5% BN and 5% BN+10% HA, respectively. After 8 weeks, it was seen that the amounts of OPN, BMP-2, RunX2 and ALP mRNA expression significantly decreased in 2.5% BN+10% HA, 2.5% BN, 5% BN+10% HA and 5% BN groups. It was shown that bone recovery was at the best grade in the groups, which contained 2.5% BN and 2.5% BN+10% HA when compared to the other groups. BN is a very promising agent that will be used in reconstructive surgery for the treatment of calvarial bone defects.
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http://dx.doi.org/10.1166/jnn.2020.17128DOI Listing
February 2020

The investigation of possible roles of central 5-HT receptors in antipyretic effect mechanism of paracetamol in LPS-induced hyperthermia model of mice.

Inflammopharmacology 2019 Dec 15;27(6):1169-1178. Epub 2019 Jul 15.

Department of Pharmacology, Faculty of Pharmacy, Binali Yıldırım University, 24100, Erzincan, Turkey.

Aim: This study aimed to investigate the role of the 5-HT receptor in fever mechanisms and its possible effect on the antipyretic mechanism of paracetamol.

Materials And Methods: The study consisted of eight experimental groups and one control group. Group I: healthy, II: LPS, III: LPS + PARA, IV: LPS + AGO, V: LPS + ANTA, VI: LPS + AGO + ANTA, VII: LPS + AGO + PARA, VIII: LPS + ANTA + PARA, and IX: LPS + AGO + ANTA + PARA. Rectal temperatures were measured with a rectal thermometer. At the end of the experiment, tissues were examined molecularly. Real-time PCR mRNA expression analyses were performed for the 5-HT7 receptor, IL-6, and TNF-α in hypothalamus tissue.

Results: The mean differences in rectal temperature increased in the LPS, LPS + ANTA, and LPS + AGO + ANTA groups when compared to the healthy group and decreased in the LPS + PARA, LPS + AGO, LPS + AGO + PARA, and LPS + AGO + ANTA + PARA groups when compared to the healthy group. The IL-6 and TNF-α mRNA expression increased in the LPS, LPS + ANTA, and LPS + AGO + ANTA groups when compared to the healthy group in the 2nd and 4th hours. The IL-6 and TNF-α expression decreased in the LPS + PARA, LPS + AGO, LPS + AGO + PARA, and LPS + AGO + ANTA + PARA groups when compared to the LPS group in the 2nd and 4th hours. The 5-HT receptor mRNA expression increased in the LPS group when compared to the healthy group in the 2nd hour. The 5-HT receptor mRNA expression decreased in the LPS + AGO and LPS + AGO + PARA groups when compared to the LPS group in the 2nd hour. The 5-HT receptor mRNA expression increased the in LPS + ANTA and LPS + ANTA + PARA groups when compared to the LPS group in the 2nd hour.

Conclusion: The 5-HT receptor is a potential defense mechanism in stopping fever and the antipyretic property of paracetamol is not due to the 5-HT receptor.
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http://dx.doi.org/10.1007/s10787-019-00617-1DOI Listing
December 2019

The effects of Beeswax, Olive oil and Butter impregnated bandage on burn wound healing.

Burns 2019 09 22;45(6):1410-1417. Epub 2019 May 22.

Faculty of Medicine, Department of Pharmacology, Ataturk University, Erzurum, Turkey.

Background: Beeswax, Olive oil and Butter (BOB) are nutritive products that could support wound healing by adsorption to bandage. This study demonstrated the therapeutic effects of BOB on second degree burn.

Methods: Second degree burn model was created in rats. Experimental groups were assigned to Healthy, Burn, Silver Sulfadiazine (SS) and BOB. The effects of BOB were evaluated on skin regeneration, vesicles and bullae and fibroblast activity by histopathological analyses and wound contraction percent were determined. Transforming Growth Factor-Beta1 (TGF-β1) and Vascular Endothelial Growth Factor-alpha (VEGF-α) mRNA expressions were analyzed with Real Time-Polymerase Chain Reaction. All parameters analyzed at 3rd, 7th, 14th days.

Results: The BOB treatment increased TGF-β1 and VEGF-α expressions compared to Burn group. The histopathological analyses showed that epidermis and dermis layers injured due to burn. BOB treatment augmented the regeneration of these layers and increased fibroblast activity and keratinization which are play important role on the new blood vessels production. Also with the BOB treatment we showed wound contraction levels were higher than Burn and SS treatment.

Conclusion: This study demonstrated that beeswax-olive oil-butter mixture impregnated bandage treatment in a second-degree burn rat model improved burn wound healing and encouraged skin renewal via modulating tissue TGF-β1 and VEGF-α.
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http://dx.doi.org/10.1016/j.burns.2018.03.004DOI Listing
September 2019

Evaluation of Endothelial Dysfunction in Bipolar Affective Disorders: Serum Endocan and Urotensin-II Levels.

Clin Psychopharmacol Neurosci 2019 May;17(2):211-221

Department of Biochemistry, Faculty of Pharmacy, Ataturk University.

Objective: This study investigated changes in urotensin-II (U-II) and endocan levels which can be used as an early biological marker of endothelial injury in the episode and remission phases of bipolar affective disorder (BAD).

Methods: We compared endocan and U-II levels, which has been shown to be closely associated with neurotransmitter systems in addition to continuity of endothelial structure and inflammatory response, in patients with BAD in remission for at least one year (n=42) and in patients still in manic or depressive episodes (n=16) with healthy controls (n=30).

Results: Both endocan and U-II levels were significantly higher in the bipolar patients than in the controls. Endocan and U-II levels were also significantly correlated with one another ( =0.000, r=0.833). Both endocan ( =0.000) and U-II levels ( =0.000) were significantly higher in the bipolar attack group compared to the subjects in remission, and in the remission group compared to the controls.

Conclusion: In this study we determined significantly higher endocan and U-II levels in BAD compared to the controls, while serum endocan and U-II levels of patients undergoing attacks were also significantly higher than those of the controls and also those of patients in remission.
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http://dx.doi.org/10.9758/cpn.2019.17.2.211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478082PMC
May 2019

Ameliorative effect of gossypin against acute lung injury in experimental sepsis model of rats.

Life Sci 2019 Mar 20;221:327-334. Epub 2019 Feb 20.

Ataturk University, Faculty of Medicine, Department of Pharmacology, Erzurum, Turkey. Electronic address:

Aims: 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.

Main Methods: 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.

Key Findings: 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.

Significance: 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.
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http://dx.doi.org/10.1016/j.lfs.2019.02.039DOI Listing
March 2019

Protective effect of 5-HT7 receptor activation against glutamate-induced neurotoxicity in human neuroblastoma SH-SY5Y cells via antioxidative and antiapoptotic pathways.

Neurotoxicol Teratol 2019 Mar - Apr;72:22-28. Epub 2019 Jan 24.

Ataturk University, Faculty of Medicine, Department of Pharmacology, Erzurum, Turkey.

Serotonin exerts anti-inflammatory, antioxidant and antiapoptotic effects through 5-HT7 receptors. The present study determined the role of 5-HT7 receptors in glutamate-induced neurotoxicity by using human SH-SY5Y neuroblastoma cells. The cells were pretreated with different concentrations of 5-HT7 receptor agonist LP44 and antagonist SB269970 for 60 min, followed by treatment with glutamate. Cell proliferation was measured using xCELLigence system. Treatment with all the concentrations of LP44 significantly protected the cells from the toxic effects of glutamate after 24, 48 and 72 h. Although 5-HT7 receptor expression was significantly upregulated in glutamate-treated cells, it was downregulated in LP44-pretreated cells. Furthermore, LP44 treatment significantly decreased malondialdehyde levels and increased superoxide dismutase activities and glutathione levels. Moreover, LP44 treatment significantly decreased tumor necrosis factor alpha (TNF-α) levels and inhibited caspase 3 and caspase 9 mRNA expression. In contrast, SB269970 treatment exerted an insignificant effect on oxidative stress, inflammation and apoptosis. These findings suggest that exogenous stimulation of the 5-HT7 receptors may be protective in glutamate-induced neurotoxicity and that 5-HT7 receptor agonists can be used as therapeutic agents for preventing glutamate-induced neurological disorders.
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http://dx.doi.org/10.1016/j.ntt.2019.01.002DOI Listing
May 2020

Effects of Aliskiren, an RAAS inhibitor, on a carrageenan-induced pleurisy model of rats.

An Acad Bras Cienc 2019 17;91(1):e20180106. Epub 2018 Dec 17.

Faculty of Medicine, Department of Pharmacology, Ataturk University Campus 25240, Erzurum, Turkey.

Our aim is to investigate the potentially preventive effects of Aliskiren in a carrageenan-induced lung pleurisy model and to compare the standard anti-inflammatory agents, indomethacin and dexamethasone. The pleurisy model was induced through the injection of carrageenan (0.2 ml-%2) into the pleural cavity. After the experiment, serum and lung tissues were collected and biochemical, molecular and pathological examinations were performed. In our study, pleural inflammation decreased superoxide dismutase activity and the glutathione level and increased the malondialdehyde level in the lung of rats, while Aliskiren increased the superoxide dismutase activity and glutathione level and decreased the malondialdehyde level. In addition, carrageenan-induced pleurisy caused a significant increase in pro-inflammatory cytokines mRNA expressions (TNF-α, IL-1β, and NF-KB), while Aliskiren administration decreased their expressions as well as the standard treatments, indomethacin and dexamethasone, did. Aliskiren administration at the 200 mg/kg dose protected the lungs in the pathological evaluation, especially against inflammatory cell infiltration and edematous lesions. It appears that Aliskiren protects the lung from carrageenan-induced pleurisy damage by regulating inflammation and antioxidant-oxidant balance via Renin Angiotensin Aldosterone System inhibition.
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http://dx.doi.org/10.1590/0001-3765201820180106DOI Listing
February 2019

Urotensin receptors as a new target for CLP induced septic lung injury in mice.

Naunyn Schmiedebergs Arch Pharmacol 2019 02 24;392(2):135-145. Epub 2018 Oct 24.

Department of Pharmacology, Faculty of Medicine, Ataturk University, Erzurum, Turkey.

Sepsis is a life-threatening organ dysfunction condition response resulting in acute lung injury. Urotensin II (UII), an endogenous vasoactive peptide, is widely distributed in pulmonary, cardiovascular, central nervous, renal and metabolic systems, and especially in inflammatory regions. This study aimed to investigate whether urotensin II (UII) and UII receptor (UTR) antagonists play a role in the inflammatory response to sepsis-induced lung damage and they are possible therapeutic targets. In the study, 78 male Balb-c mice were used. A cecal ligation and puncture (CLP)-induced polymicrobial sepsis model was applied, and the effects of human urotensin II (agonist) and urantide and palosuran (antagonists) were investigated on lung tissues. Glutathione and malondialdehyde levels and SOD activity of lung tissues were investigated in addition to TNF-α, IL-1β, IL-6, NF-κB, and UTR mRNA levels. Also, lung sections were histopathologically evaluated. Urantide and palosuran, UII receptor antagonists, decreased proinflammatory cytokines such as TNF-α, IL-1β, IL-6, NF-κB, and also decreased oxidative stress parameters in lung tissue, which are markers of damage. UTR mRNA expression was increased in septic lungs, and both antagonists significantly decreased the elevated receptor level. Also, histopathological examination showed beneficial effects of both agonists on lung tissue. The results of this study help to understand the inflammatory and therapeutic contribution of the UII/UTR system on sepsis-induced lung damage. We can suggest that UTR receptor antagonists may be evaluated as a potential drug which reduces sepsis-induced lung damage in the future.
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http://dx.doi.org/10.1007/s00210-018-1571-8DOI Listing
February 2019

5-HT receptors are over-expressed in patients with nasal polyps.

Ear Nose Throat J 2017 Dec;96(12):E14-E18

Department of Pharmacology, Kafkas University Faculty of Medicine Kars, Turkey.

Nasal polyposis (NP) is an inflammatory disease of the paranasal sinuses and nasal cavity. The primary purpose of our study is to determine the expression of 5-HT receptors both in nasal polyps and in healthy tissue in the nasal cavity. The subsequent aim is to compare the expression of 5-HT receptors in patients with NP and in inferior turbinate tissue (control). The study included 60 participants (40 with NP and 20 controls) aged 35 to 62 years. Nasal polyp samples were collected from all patients and relative 5-HT receptor expression analyses were performed. Reverse transcription polymerase chain reaction analysis of nasal polyps and control tissue identified 5-HT receptor expression in the nasal cavities of controls. This expression was approximately 67 times higher in nasal polyp tissue than in healthy tissue. Our study identifies the expression of 5-HT receptors in the nasal cavity for the first time and the first demonstration of increased 5-HT receptor expression in tissue from nasal polyps, which occur in the paranasal sinuses and nasal cavity.
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http://dx.doi.org/10.1177/014556131709601204DOI Listing
December 2017

The role of urotensin-II and its receptors in sepsis-induced lung injury under diabetic conditions.

Eur J Pharmacol 2018 Jan 10;818:457-469. Epub 2017 Nov 10.

Ataturk University, Faculty of Medicine, Department of Pharmacology, Erzurum, Turkey.

This study aimed to investigate the potential role of urotensin-II receptors in sepsis-induced lung injury in diabetic mice using urotensin-II receptor agonists and antagonists. A total of 110 male CD1 mice were used in this study. Diabetes was induced by 200mg/kg streptozotocin. One month after diabetes induction, the cecal ligation and puncture-induced polymicrobial sepsis model was applied in the diabetic and non-diabetic mice. Low and high doses of human urotensin-II agonist (HU-II) and antagonist (palosuran) were administered one hour after sepsis induction. HU-II administration was repeated in two-hour intervals. Blood and tissue samples were collected at 6 and 12H after sepsis induction for biochemical, molecular, and histopathologic examinations. Regarding to the lungs mRNA expression and immunohistochemistry results of TNF-α, IL1 β, IL6, and NF-κB, it was observed that cytokine levels significantly increased in the diabetes group and the sepsis groups compared to the healthy group; this increase was significantly higher in the diabetes-sepsis groups. Our biochemical (superoxide dismutase, glutathione, and malondialdehyde) and histopathological findings in the lungs also supported these results. All increased parameters were significantly reduced dose-dependently by the administration of palosuran, an urotensin receptor antagonist. mRNA expression of urotensin-II and its receptor were examined in the lung tissue. Palosuran administration significantly reduced the urotensin-II and urotensin-II receptor levels that increased in the damaged tissue. This study has shown that urotensin-II and urotensin-II receptors contribute to the aggravation of sepsis-induced lung injury in diabetic mice; palosuran prevents this damage by antagonizing urotensin-II receptors.
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http://dx.doi.org/10.1016/j.ejphar.2017.11.011DOI Listing
January 2018

Dose-dependent effect of radiation on resorbable blast material titanium implants: an experimental study in rabbits.

Acta Odontol Scand 2018 Mar 23;76(2):130-134. Epub 2017 Oct 23.

b Department of Pharmacology , Ataturk University, Faculty of Medicine , Erzurum , Turkey.

Background: Radiotherapy is a commonly used treatment modality in head and neck cancer; however, it also negatively affects healthy structures. Direct damage to oral soft and hard tissue frequently occurs with radiotherapy. In this study, we aimed to evaluate the effect of radiotherapy on bone surrounding titanium dental implants via biomechanical and molecular methods.

Materials And Methods: Fifty-four implants were inserted in the left tibiae of 18 adult male New Zealand rabbits (3 implants in each rabbit). After 4 weeks of the implant surgery, the left tibiae of 12 rabbits were subjected to a single dose of irradiation (15 Gy or 30 Gy). Four weeks after the irradiation, rabbits were sacrificed and removal torque test was done for the biomechanical evaluation. Bone morphogenetic protein-2 (Bmp-2) and fibroblast growth factor-2 (Fgf-2) expression analyses were performed with Real-time PCR. Statistical analysis was done using SPSS.

Results: The control group showed significantly higher removal torque value than the 15 and 30 Gy irradiation groups, and the 15 Gy irradiation group had higher removal torque value than the 30 Gy irradiation group (p < .001). The 15 Gy and 30 Gy irradiation groups had significantly lower Bmp-2 and Fgf-2 mRNA expressions than the control group (p < .001). In addition, the 30 Gy irradiation group had significantly lower Bmp-2 (p < .01) and Fgf-2 mRNA expressions (p < .001) than the 15 Gy group.

Conclusion: Radiotherapy with 15 and 30 Gy doses can adversely affect osseointegration of implants by reducing the quality of bone and impairing the bone-to-implant contact. The mechanism of action seems to be related to alterations in Bmp-2 and Fgf-2 mRNA expressions.
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http://dx.doi.org/10.1080/00016357.2017.1392601DOI Listing
March 2018