Novel 1,2,4-triazoles derived from Ibuprofen: synthesis and in vitro evaluation of their mPGES-1 inhibitory and antiproliferative activity.

Some novel triazole-bearing ketone and oxime derivatives were synthesized from Ibuprofen. In vitro cytotoxic activities of all synthesized molecules against five cancer lines (human breast cancer MCF-7, human lung cancer A549, human prostate cancer PC-3, human cervix cancer HeLa, and human chronic myelogenous leukemia K562 cell lines) were evaluated by MTT assay. In addition, mouse embryonic fibroblast cells (NIH/3T3) were also evaluated to determine the selectivity. Compounds 18, 36, and 45 were found to be the most cytotoxic, and their IC50 values were in the range of 17.46-68.76 µM, against the tested cancer cells. According to the results, compounds 7 and 13 demonstrated good anti-inflammatory activity against the microsomal enzyme prostaglandin E2 synthase-1 (mPGES-1) enzyme at IC50 values of 13.6 and 4.95 µM. The low cytotoxicity and non-mutagenity of these compounds were found interesting. Also, these compounds significantly prevented tube formation in angiogenesis studies. In conclusion, the anti-inflammatory and angiogenesis inhibitory activities of these compounds without toxicity suggested that they may be promising agents in anti-inflammatory treatment and they may be supportive agents for the cancer treatment.

Exercise improves testicular morphology and oxidative stress parameters in rats with testicular damage induced by a high-fat diet.

Obesity and male infertility are problems that affect population. Exercise is a nonpharmacological way to reduce the negative health effects of obesity. The purpose of this study was to examine the effects of exercise on hormone levels, blood-testis barrier, and inflammatory and oxidative biomarkers in rats that became obese due to a high-fat diet (HFD). Male rats received a standard diet (STD group) or a HFD (HFD group) for 18 weeks. During the final 6 weeks of the experiment, swimming exercises (1 h/5 days/week) were given to half of these animals (STD + EXC and HFD + EXC groups). Finally, blood and testicular tissues were analysed by biochemical and histological methods. Body weight, leptin, malondialdehyde, interleukin-6, TNF-alpha and myeloperoxidase levels, apoptotic cells and DNA fragmentation were increased, and testis weight, insulin, FSH, LH, testosterone, glutathione and superoxide dysmutase levels, proliferative cells, ZO-1, occludin, and gap junction protein Cx43 immunoreactivity were decreased in the HFD group. All these hormonal, morphological, oxidative and inflammatory biomarkers were enhanced in the HFD + EXC group. It is thought that exercise protected testicular cytotoxicity by regulating hormonal and oxidant/antioxidant balances and testicular function, inhibiting inflammation and apoptosis, as well as preserving blood-testis barrier.

Investigation of 3D-printed chitosan-xanthan gum patches.

In this study, using a new polymer combination of Chitosan(CH)/Xanthan Gum(XG) has been exhibited for wound dressing implementation by the 3D-Printing method, which was fabricated due to its biocompatible, biodegradable, improved mechanical strength, low degradation rate, and hydrophilic nature to develop cell-mimicking, cell adhesion, proliferation, and differentiation. Different concentrations of XG were added to the CH solution as 0.25, 0.50, 0.75, 1, and 2 wt% respectively in the formic acid/distilled water (1.5:8.5) solution and rheologically characterized to evaluate their printability. The results demonstrated that high mechanical strength, hydrophilic properties, and slow degradation rate were observed with the presence and increment of XG concentration within the 3D-Printed patches. Moreover, in vitro cell culture research was conducted by seeding NIH 3T3 fibroblast cells on the patches, proving the cell proliferation rate, viability, and adhesion. Finally, 1% XG and 4% CH containing 3D-Printed patches were great potential for wound dressing applications.

Investigation of the protective effect of gel incorporating Eugenia jambolana leaf extract on 5-fluorouracil-induced oral mucositis: an animal study.

PURPOSE: The study aimed to evaluate the possible preventive effect of two concentrations (3 and 5% w/w) of Eugenia jambolana (EJ) extract against 5-FU-induced mucositis. METHOD: Sixteen adult rats were separated into four groups: two control and two preventive groups. Animals in Groups 1, 2, and 3 were injected intraperitoneally with 60 mg/kg/day of 5-FU on Day 1 followed by 150 mg/kg/day on Day 5. The rats in Group 4 (negative control) were given physiological saline at the same times and doses. Furthermore, on the fifth day of the study, the cheek and sublingual mucosa were irritated by external superficial scratches using the tip of an 18-G needle, followed by the application 15 µL of 20% acetic acid, after which 3 and 5% EJ w/w gels were applied topically for animals in Groups 2 and 3, respectively. RESULTS: The weight and the mucositis scores were recorded. Antioxidant and anti-inflammatory markers and biochemical tests were analyzed. Significant differences were found between the study groups in weight loss, clinical mucositis scores, mortality rates, and antioxidant and anti-inflammatory parameters. CONCLUSION: The preventive effect of 3% gel was significant, with no mortality rate, making it an option for preventive strategies.

Protective effect of ferulic acid on cisplatin induced nephrotoxicity in rats.

This study aims to determine the potential protective effects of ferulic acid against cisplatin-induced nephrotoxicity and to compare its effect with curcumin, a well-known protective agent against cisplatin- induced toxicity in rats. Administration of cisplatin resulted in high BUN (Blood Urea Nitrogen), creatinine, MDA (Malondialdehyde), MPO (Myeloperoxidase), TOS (Total Oxidative Status), PtNT (Protein Nitrotyrosine) levels (p<0.05). Histological observations showed abnormal morphology of kidney; in addition with appearance of TUNEL positive cells indicating apoptosis in cisplatin administered group. HO-1 (Heme Oxygenase-1) levels measured by RT-PCR (Real Time Polymerase Chain Reaction), and TAS (Total Antioxidative Status) revealed antioxidant depletion due to cisplatin toxicity in animals (p<0.05). All parameters showed improvement in groups treated with ferulic acid (p<0.05). Ferulic acid treatment was found significant in preventing oxidative stress, increasing antioxidative status and regaining histological parameters to normal, indicating nephroprotective and antioxidant effects of this phenolic compound.

Association between the growth arrest-specific 6 (Gas6) gene polymorphism c.834 + 7G>A and preeclampsia.

OBJECTIVE: Preeclampsia (PE) is a hypertensive disease of pregnancy complicating 2-8% of all pregnancies. The exact pathophysiology still remains unknown. Growth arrest-specific 6 (Gas6) is a member of the vitamin K-dependent protein family and it has been suggested as a novel atherothrombotic risk factor with anti-angiogenic and pro-atherogenic properties. The goal of the our study was to investigate the relationships between the c.834 + 7G > A polymorphism of GAS6, plasma Gas6 levels and PE. METHODS: A total of 150 women, including 82 preeclamptic pregnant women and 68 normotensive pregnant (NP) women, were recruited in the current study. Blood samples were taken from all participants. Plasma Gas6 levels measured by an enzyme-linked immunosorbent assay. GAS6 polymorphism was determined using a PCR-RFLP method. RESULTS: The plasma Gas6 levels of preeclamptic patients were significantly lower than those of NP women (8.65 ± 3.70 ng/ml and 10.89 ± 4.23 ng/ml respectively, p < 0.001). The GG genotype was the most prevalent, and the risk of PE was 3.5-fold higher in pregnant women with GG genotype compared to woman with AA genotype (p < 0.01). The A allele was less frequent in preeclamptic patients than in control subjects (OR = 2.118, 95% CI = 1.330-3.371, p < 0.001). CONCLUSIONS: Our results suggest that GAS6 c.834 + 7G > A polymorphism may have a pivotal role in the pathogenesis of PE suggesting that the A allele has a protective role for PE.

Remifentanil protects uterus against ischemia-reperfusion injury in rats.

PURPOSE: To investigate the effects of remifentanil as an antioxidant and analyze the histopathologic, biochemical changes in experimental ischemia-reperfusion (I/R) exposed rat uteri. METHODS: Wistar albino rats were assigned to three groups (n = 7). 2h period of ischemia was followed by 1h of reperfusion in the I/R and the I/R-remifentanil groups. After ischemia, no drug was administered in the sham and I/R groups. In the I/R-remifentanil group, remifentanil infusion (2 µg/kg/min) was started in the ischemia period, and continued until the end of reperfusion. After the ischemic and reperfusion period, the ischemic uterine horns were removed surgically for biochemical and histopathologic examination. Tissue damage scores (endometrial epithelial glandular leukocytosis, degeneration, and endometrial stromal changes) were examined. Malondialdehyde levels and catalase, superoxide dismutase enzyme activities in tissue were measured. RESULTS: We found significantly lower epithelial leukocytosis and cell degeneration in the I/R-remifentanil group (p<0.05). Remifentanil administration significantly decreased concentrations of malondialdehyde, and increased catalase and superoxide dismutase enzyme activities (p<0.05). CONCLUSION: Remifentanil appears to protect the uterine tissue against ischemia-reperfusion and can be used safely in uterus transplantation.

Remifentanil protects uterus against ischemia-reperfusion injury in rats

PURPOSE: To investigate the effects of remifentanil as an antioxidant and analyze the histopathologic, biochemical changes in experimental ischemia-reperfusion (I/R) exposed rat uteri. METHODS: Wistar albino rats were assigned to three groups (n = 7). 2h period of ischemia was followed by 1h of reperfusion in the I/R and the I/R-remifentanil groups. After ischemia, no drug was administered in the sham and I/R groups. In the I/R-remifentanil group, remifentanil infusion (2 μg/kg/min) was started in the ischemia period, and continued until the end of reperfusion. After the ischemic and reperfusion period, the ischemic uterine horns were removed surgically for biochemical and histopathologic examination. Tissue damage scores (endometrial epithelial glandular leukocytosis, degeneration, and endometrial stromal changes) were examined. Malondialdehyde levels and catalase, superoxide dismutase enzyme activities in tissue were measured. RESULTS: We found significantly lower epithelial leukocytosis and cell degeneration in the I/R-remifentanil group (p<0.05). Remifentanil administration significantly decreased concentrations of malondialdehyde, and increased catalase and superoxide dismutase enzyme activities (p<0.05). CONCLUSION: Remifentanil appears to protect the uterine tissue against ischemia-reperfusion and can be used safely in uterus transplantation.

Ovarian stem cells: From basic to clinical applications.

The field of reproductive biology has undergone significant developments in the last decade. The notion that there is a fixed reserve pool of oocytes before birth was established by Zuckerman in 1951. However, in 2004, an article published in nature challenged this central dogma of mammalian reproductive biology. Tilly's group reported the existence of ovarian germline stem cells (GSCs) in postnatal ovaries of mice and suggested that the bone marrow could be an extragonadal source of ovarian GSCs. These findings were strongly criticized; however, several independent groups have since successfully isolated and characterized ovarian GSCs in postnatal mice. The ovarian GSCs are located in the ovarian surface epithelium and express markers of undifferentiated GSCs. When transplanted into mouse ovaries, mouse ovarian GSCs could differentiate and produce embryos and offspring. Similarly, in a recent study, ovarian GSCs were found to be present in the ovaries of women of reproductive age. Conversely, there is increasing evidence that stem cells responsible for maintaining a healthy state in normal tissue may be a source of some cancers, including ovarian cancer. Cancer stem cells (CSCs) have been found in many tissues, including ovaries. Some researchers have suggested that ovarian cancer may be a result of the transformation and dysfunction of ovarian GSCs with self-renewal properties. Drug resistant and metastasis-generating CSCs are responsible for many important problems affecting ovarian cancer patients. Therefore, the identification of CSCs will provide opportunities for the development of new therapeutic strategies for treatments for infertility and ovarian cancer. In this article, we summarize the current understanding of ovarian GSCs in adult mammals, and we also discuss whether there is a relationship between GSCs and CSCs.

The impact of platelet functions and inflammatory status on the severity of preeclampsia.

OBJECTIVE: To find out whether there is a correlation between the extent of platelet activation and inflammation and the severity of preeclampsia (PE) in the third trimester of pregnancy. METHODS: Forty-one women with PE (n = 23 severe, n = 18 mild) and 80 normotensive pregnant (NP) women were included in the study. Their blood samples were obtained and interleukin (IL)-8 and IL-10 levels measured by an enzyme-linked immunosorbent assay. Basal CD61 and CD62P expressions on CD41-positive platelets were analyzed with the use of flow-cytometry. Platelet aggregation was induced by adenosine diphosphate and determined by aggregometry. RESULTS: CD62P expression was increased in severely preeclamptic women, and the platelet aggregation was decreased in both mildly and severely preeclamptic women in comparison with NP women. However, CD61 expression was similar among the groups. An enhanced inflammatory response was seen in severely preeclamptic women demonstrated by increased levels of IL-8 and decreased levels of IL-10. However, the intensity of platelet activation did not correlate directly with the change in plasma levels of IL-8 and IL-10 in preeclamptic women. CONCLUSIONS: Platelets may have a role in the inflammatory response in PE. However, the severity of inflammation is found to be independent from the intensity of platelet activation in preeclamptic women. This seems to be related to mechanisms causing alterations of cytokine levels such as IL-8 and IL-10, rather than platelet activation.

Blood serum and seminal plasma selenium, total antioxidant capacity and coenzyme q10 levels in relation to semen parameters in men with idiopathic infertility.

In this case-control study, we aimed to evaluate the serum and seminal plasma levels of Selenium (Se), total antioxidant capacity (TAC), and Coenzyme Q10 (CoQ-10) and determine their relationship with sperm concentration, motility, and morphology in men with idiopathic infertility. A total of 59 subjects were enrolled in the study. Forty four patients were diagnosed with idiopathic male infertility and had abnormal sperm parameters, and 15 subjects had normal sperm parameters with proven fertility. Serum Se, semen Se, and semen TAC levels were significantly different in the fertile and infertile groups (p<0.01, p<0.001, and p<0.001, respectively). However, serum TAC, serum, and seminal plasma CoQ-10 levels did not differ between fertile and infertile groups. When the levels of the measured parameters were compared in serum and seminal plasma, serum levels of Se were found to be correlated positively with the semen levels in all subjects included into the study (N=59) (r=0.46, p<0.01). A relationship was found between neither serum and semen levels of TAC nor between serum and semen levels of CoQ-10. Correlations among measured serum and semen parameters with sperm parameters demonstrated that both the serum and semen levels of Se were correlated positively with spermatozoa concentration, motility, and morphology. Additionally, seminal plasma levels of TAC correlated positively with all these sperm parameters. On the other hand, seminal plasma levels of CoQ-10 correlated only with sperm morphology but not with concentration or motility. No relationship was observed between serum levels of TAC or serum levels of CoQ-10 and sperm parameters. In conclusion, serum and seminal plasma Se deficiency may be a prominent determinant of abnormal sperm parameters and idiopathic male infertility. Measurement of serum Se levels may help determine nutritional status and antioxidant capacity in infertile patients, which may help distinguish those patients who will benefit from supplementation therapy.

The protective effects of tacrolimus on rat uteri exposed to ischemia-reperfusion injury: a biochemical and histopathologic evaluation.

OBJECTIVE: To evaluate the effects of the immunosuppressant tacrolimus as an antioxidant and analyze the histopathologic changes in rat uteri exposed to experimental ischemia-reperfusion (I/R) injury. DESIGN: Experimental study. SETTING: Experimental surgery laboratory in a university. ANIMAL(S): Twenty-eight female rats exposed to experimentally induced uterine I/R injury. INTERVENTION(S): Group I: control group; group II: uterine I/R injury-induced group; group III: pre-ischemia tacrolimus group; group IV: post-ischemia tacrolimus group. MAIN OUTCOME MEASURE(S): Uterine tissue malondialdehyde (MDA) level as a marker of lipid peroxidation and glutathione (GSH) level and superoxide dismutase (SOD) and catalase (CAT) activities as markers of tissue antioxidant capacity; histopathologic examination of all uterine rat tissue. RESULT(S): Following aortic I/R injury, MDA levels were significantly increased whereas GSH levels and CAT and SOD activities were found to be decreased compared with control animals. MDA levels were found to recover prominently after the administration of tacrolimus in both groups III and IV. Administration of tacrolimus improved uterine GSH levels and CAT activity in the tacrolimus-treated groups. CONCLUSION(S): Our results indicate that tacrolimus reduces oxidative damage in rat uteri exposed to I/R injury induced by distal abdominal aortic occlusion. Histologic evaluation reveals that tacrolimus attenuates the inflammatory response and protects the tissue damage induced by I/R injury.

Obestatin alleviates subarachnoid haemorrhage-induced oxidative injury in rats via its anti-apoptotic and antioxidant effects.

OBJECTIVE: The aim was to investigate the putative anti-inflammatory and anti-apoptotic effect of obestatin in a rat model of subarachnoidal haemorrhage (SAH). METHODS: To induce SAH, rats were injected with 0.3 mL blood into their cisterna magna. At 48 hours rats were decapitated after neurological examination. Blood-brain barrier (BBB) permeability, brain water content, oxidative stress markers and histological analysis were done in brain tissue. RESULTS: The results showed that neurological examination scores were increased in the SAH group and, moreover, BBB permeability was impaired and oedema formed. SAH resulted in increased levels of plasma tumour necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6 levels and caspase-3 activity. Lipid peroxidation and protein oxidation levels and myeloperoxidase activity were all increased in the brain tissue, with concomitant decreases in antioxidant enzymes. On the other hand, SAH-induced neurological impairment and oxidative brain injury were ameliorated in the obestatin-treated group. CONCLUSION: The present study provides the first evidence that peripheral administration of obestatin exerts potent anti-inflammatory and neuroprotective effects in SAH-induced oxidative damage by maintaining a balance in oxidant-antioxidant status through the augmentation of endogenous antioxidants and the inhibition of pro-inflammatory mediators.

Synthesis and characterization of celecoxib derivatives as possible anti-inflammatory, analgesic, antioxidant, anticancer and anti-HCV agents.

A series of novel N-(3-substituted aryl/alkyl-4-oxo-1,3-thiazolidin-2-ylidene)-4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamides 2a-e were synthesized by the addition of ethyl a-bromoacetate and anhydrous sodium acetate in dry ethanol to N-(substituted aryl/alkylcarbamothioyl)-4-[5-(4-methylphenyl)-3-(trifluoro-methyl)-1H-pyrazol-1-yl]benzene sulfonamides 1a-e, which were synthesized by the reaction of alkyl/aryl isothiocyanates with celecoxib. The structures of the isolated products were determined by spectral methods and their anti-inflammatory, analgesic, antioxidant, anticancer and anti-HCV NS5B RNA-dependent RNA polymerase (RdRp) activities evaluated. The compounds were also tested for gastric toxicity and selected compound 1a was screened for its anticancer activity against 60 human tumor cell lines. These investigations revealed that compound 1a exhibited anti-inflammatory and analgesic activities and further did not cause tissue damage in liver, kidney, colon and brain compared to untreated controls or celecoxib. Compounds 1c and 1d displayed modest inhibition of HCV NS5B RdRp activity. In conclusion, N-(ethylcarbamothioyl)-4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (1a) may have the potential to be developed into a therapeutic agent.

The novel function of nesfatin-1 as an anti-inflammatory and antiapoptotic peptide in subarachnoid hemorrhage-induced oxidative brain damage in rats.

BACKGROUND: There is substantial evidence to suggest that oxidative stress plays a significant role in the development of acute brain injury after subarachnoid hemorrhage (SAH). OBJECTIVE: To investigate the putative neuroprotective effect of nesfatin-1, a novel peptide with anorexigenic properties, in a rat model of SAH. METHODS: Male Wistar albino rats were randomly divided into control, saline-treated SAH, and nesfatin-1 (10 µg/kg IP)-treated SAH groups. To induce SAH, rats were injected with 0.3 mL blood into their cisterna magna. Forty-eight hours after SAH induction, neurological examination scores were recorded and the rats were decapitated. Brain tissue samples were taken for the determination of blood-brain barrier (BBB) permeability, brain water content, and oxidative stress markers and for histological analysis. RESULTS: The neurological examination scores were increased on the second day of SAH induction. SAH resulted in impaired blood-brain barrier and edema, along with increased levels of brain tumor necrosis factor-α, interleukin-1ß, interleukin-6, lipid peroxidation, protein carbonylation, and myeloperoxidase activity with concomitant decreases in antioxidant enzymes. Conversely, in the nesfatin-1-treated SAH group, SAH-induced neurological impairment and oxidative brain injury were ameliorated by nesfatin treatment. Furthermore, SAH-induced morphological changes in the basilar arteries were improved by nesfatin-1 treatment, whereas caspase-3 activity and SAH-induced elevations in the plasma levels of proinflammatory cytokines were also depressed by nesfatin-1 treatment. CONCLUSION: These findings suggest that nesfatin-1, which appears to have antiapoptotic and anti-inflammatory properties, exerts neuroprotection in SAH-induced injury in rats by inhibiting neutrophil infiltration and subsequent release of inflammatory mediators.