In vitro inhibition of uterine contractions using electrospun nanofibers loaded with nifedipine and ML7.

OBJECTIVE: To formulate a nanofiber-based controlled drug delivery system that could be effective in preventing uterine contractions and can be used for the treatment of preterm labor. PATIENTS AND METHODS: We utilized uterine tissue samples obtained from ten pregnant women who underwent cesarean section at term to investigate the effect of nanofibers on spontaneous and induced myometrial contractions. We prepared nifedipine and ML7-loaded nanofibers using the electrospinning method with Poly(D,L-lactide-co-glycolide) (PLGA) polymer, resulted in seven groups of nanofibers, including a control group. Group I served as the control, Group II was non-drug loaded nanofiber, Group III was nifedipine (10-5 M) loaded nanofiber, Group IV was ML7 (3x10-5 M) loaded nanofiber, Group V was ML7 (3x10-5 M) and nifedipine (10-5 M) nanofiber, Group VI was ML7 (3x10-5 M) and nifedipine (3x10-5 M) nanofiber, and Group VII was ML7 (3x10-5 M) and nifedipine (10-4 M) nanofiber. To evaluate the contractile response, the nanofibers loaded with different doses of ML7 and nifedipine were applied onto the tissue strips, and in vitro organ bath experiments were performed. Full-thickness uterine samples were cleared of the serosa and surrounding tissues, and eight strips (3x10 mm) were prepared from each sample. The seven different nanofiber formulations were gently placed and sutured onto the strips, with one strip always kept as the time control. We recorded spontaneous, KCl-induced, and stimulated cumulative oxytocin-induced contractions from all samples in all groups. After completing all experiments, the viability of the strips was checked, and weight measurement was recorded. RESULTS: The administration of drug-loaded polymers resulted in a significant decrease in both the frequency and intensity of spontaneous and induced contractions in all groups (p<0.01). No significant difference was observed between the control group and the non-drug-loaded nanofiber group in post hoc analysis (p=0.704). In terms of amplitude and frequency of contractions, the most significant decrease was observed in group VII at cumulative oxytocin doses compared to the control and non-drug-loaded nanofiber groups (p<0.05). Moreover, group VI also showed a significant decrease in contraction intensity and frequency compared to the control and non-drug-loaded nanofiber groups (p<0.05). While the use of nifedipine and/or ML7-loaded nanofibers decreased both intensity and frequency of contraction, this attenuation was not significant compared to the control and empty polymer groups. However, a more significant inhibition was observed when ML7 was used with nifedipine at doses of 3x10-5 M and 10-4 M. CONCLUSIONS: The results indicate that human uterine contractions can be inhibited using calcium channel blocker (nifedipine) and myosin light chain kinase inhibitor (ML7) loaded nanofibers in uterine tissue strips. These results strongly suggested the potential for the development of locally effective and safe controlled drug release systems to prevent premature birth.

A new marker of coronary collateral flow in patients presenting with acute myocardial infarction.

OBJECTIVE: Multimerin-2 is an adhesion substrate between pericytes and basal membranes during angiogenesis. The present study aimed to assess the relationship between serum Multimerin-2 and coronary collateral flow grade. PATIENTS AND METHODS: Between April 2022 and August 2022, 88 patients with subacute ST-elevation myocardial infarction were included in this study. The main inclusion criteria were patients who present 12-48 hours after symptom onset and aged between 18 and 90 years. The patients were divided into two groups according to the Rentrop classification: poor collateral group (Rentrop grade 0-1) and good collateral group (Rentrop grade 2-3). Biochemical and hematological parameters were measured before coronary angiography. RESULTS: Serum Multimerin-2 levels were found to be significantly different between the two groups, and levels were higher in the Rentrop 2-3 group than in the Rentrop 0-1 group (3,527.9 ± 1,194.2 pg/ml and 946.7 ± 249.1 pg/ml; p < 0.00). Receiver operating characteristic curve analysis indicated that the area under the curve was 0.918 (p = 0.001), and the best cut-off value of 849 pg/ml had a sensitivity of 90.1% and a specificity of 84.1% for predicting Rentrop grade 2-3 coronary flow. The number of patients with low left ventricular ejection fraction (LVEF) by echocardiography at 30 days was significantly higher in patients with poor collateralization. CONCLUSIONS: Multimerin-2 levels were found to be higher in patients with Rentrop grade 2-3 coronary flow than Rentrop grade 0-1 coronary flow after myocardial infarction. We detected a potential relationship between MMR-2 and good coronary collateral formation.

Carotid arteries and vertebrobasilary system intracranial stenosis correlates with multi vessel coronary artery disease.

BACKGROUND: The goal of this study was to show the importance of the identifying potential carotid and vertebrobasilar stenosis with Computed Tomography Angiography (CTA) in severe coronary artery disease. METHODS: In 109 patients, CTA of the carotid and the vertebrobasilar system were taken in the six months following the Coronary Angiography (CA). Coronary arteries and carotid vertebrobasilar system stenosis were considered significant at more than ≥ 50 %. RESULTS: A significant statistical relationship was found between a coronary artery group of three-vessel disease (3-VD) and stenosis of the cervical segments of the right (p = 0.022) and left internal carotid artery (ICA) (p = 0.001); intracranial segments of the right (p = 0.007) and left ICA (p = 0.020), and the right vertebral artery (VA) (p = 0.008). There was a significant statistical relationship between Gensini score and stenosis of both the right (p = 0.030) and the left ICA cervical segments (p = 0.003). CONCLUSION: In patients with severe coronary artery disease especially in 3-VD, CTA scan may be useful diagnostic tool for identifying stenosis of the carotid arteries, particularly in the intracranial segments of the ICA and in the preforaminal (V1) segment of the VA (Tab. 4, Fig. 3, Ref. 22).

Protective effects of Urtica dioica L. on experimental testicular ischaemia reperfusion injury in rats.

In this study, it was aimed to examine the effects of Urtica dioica L. (UD) that has antioxidant feature in the experimental testicular I/R model in rats in terms of anti-apoptotic and antioxidative effects. In our study, 24 male rats were divided into three groups: control group, I/R group and I/R + UD (2 mg kg-1 ) group. Seminiferous tubule calibre measurement, Johnson score, haematoxylin-eosin staining, proliferative cell nucleus antigen (PCNA) immunohistochemical staining and TUNEL as histopathological have been conducted. The structural deterioration in the testicular on I/R group has reduced after the treatment of UD. Our data indicate a significant reduction in the activity of in situ identification of apoptosis using terminal dUTP nick end labelling (TUNEL), and there was a rise in the expression of proliferating cell nuclear antigen (PCNA) in testis tissues of UD-treated rats in the I/R group. The I/R + UD group showed a decrease in malondialdehyde levels and an increase in the activities of superoxide dismutase, catalase and glutathione peroxidase in comparison with the I/R group. It could be concluded that protective effects of UD on the I/R testicles are via reduction of histological damage, apoptosis, oxidative stress and lipid peroxidation.

Protective effects of thymoquinone on experimental testicular ischaemia-reperfusion injury: an apoptotic, proliferative and biochemical study.

The objective of this study was to examine the effects of thymoquinone (TQ), which has antioxidant properties in the experimental testicular I/R model in rats in terms of its anti-apoptotic, proliferative and biochemical attributes. In our study, 24 male rats were divided into three groups: control group, I/R group and I/R+TQ group. Testicular torsion was created by rotating the left testis 720° in a clockwise direction. The ischaemia period was 4 h, and an orchiectomy was performed after 4 h of detorsion. Spermatogenesis and the mean seminiferous tubule diameter were significantly decreased in the I/R groups compared to the control group. Furthermore, TQ-treated animals displayed an improved histological appearance in the I/R group. It was also observed that treatment with TQ increased the activity of PCNA, which decreased as a result of I/R, and this treatment also reduced the number of TUNEL-positive cells. The I/R+TQ group showed a decrease in malondialdehyde levels and an increase in the activities of superoxide dismutase, catalase and glutathione peroxidase in comparison with the I/R group. It could be concluded that cytoprotective effects of TQ on the I/R testicles are via reduction of apoptosis, oxidative stress and lipid peroxidation.

Atherosclerosis, some serum inflammatory markers in psoriasis.

AIM: Psoriasis is an autoimmune inflammatory disease which is associated with increased inflammatory markers and atherosclerosis. We wanted to investigate whether there is a relationship between some inflammatory markers and subclinical atherosclerosis markers. METHODS: We studied 60 psoriasis patients and 50 healthy controls. Demographic, biochemical parameters, C3, C4, d-dimer, CRP, fibrinogen and YKL-40 (human cartilage glycoprotein-39) levels were measured. After measuring carotid intima-media thickness (cIMT) and aortic elasticity parameters such as aortic strain, (beta) stiffness index and compliance, statistical comparisons were done. RESULTS: Patients with psoriasis had significantly higher diastolic blood pressure, CRP, fibrinogen, C3, uric acid levels, ß-stiffness index, and cIMT values than the control group. cIMT was correlated with CRP, YKL-40 and psoriasis area and severity index (PASI) score (r=0.219, P=0.038; r=0.225, P=0.033 and r=0.275, P=0.034). Aortic strain (%), aortic compliance and aortic stiffness index were correlated with C3 (r=-0.349, r=-0.526 and r=0.235) and fibrinogen (r=-0.354, r=-0.275 and r=0.289), all P values <0.05, but not with PASI score. The presence of psoriasis was related to aortic strain (ß±SE: -2.055±0.861, P=0.019) and ß-stiffness index (ß±SE: 2.934±1.143, P=0.012). CONCLUSION: Serum C3, CRP, fibrinogen and YKL-40 levels are elevated as well as increased cIMT and impaired aortic elasticity in psoriasis. CRP, YKL-40 and PASI score are correlated with cIMT. Increased serum C3 and fibrinogen levels correlate negatively with aortic strain and aortic compliance, and correlate positively with the ß-stiffness index.

Association of colon adenomas and skin tags: coincidence or coexistence?

OBJECTIVES: Skin tag (STs) are benign connective tissue tumors of the dermis. Some researchers have argued that there is a relationship between skin tag and colon polyps, although the physiopathological mechanisms underlying this relation were not well elucidated. In this study we aimed to investigate the co-existence of colonic adenomatous polyps and ST, additionally to shed light on the physiopathological mechanisms underlying this coincidence. PATIENTS AND METHODS: A total of 45 patients aged between 18 and 60 diagnosed with adenomatous colonic polyps and 45 sex, age, and socio-demographically matched subjects, had no polyps, were enrolled as the control group. Routine blood analysis of all participants, including serum glucose, total cholesterol, low-density lipoprotein cholesterol (LDL-C), (high-density lipoprotein cholesterol (HDL-C), triglyceride, insulin, IGF-1, and EGF, were performed. The chi-square and independent sample t or Mann Whitney U test were used to determine differences between groups. RESULTS: The number of participants with ST was significantly higher in the patient group (OR 7.067, p < 0.01). Serum levels of IGF-1 and EGF were statistically similar between the groups. In the subgroup analyses, no difference was found in serum levels of insulin, IGF-1, or EGF between patients with and without ST. However, higher serum levels of insulin and EGF were found in control subjects with ST (p < 0.01 and p < 0.01, respectively). For the entire study group, 67 participants had ST and 23 patients did not. Serum insulin, and IGF-1 were similar, while serum EGF levels were higher in patients with ST (p < 0.01). CONCLUSIONS: Findings of the present study may show a co-existence of colonic polyps and ST. Although previous studies have indicated that insulin resistance may play a role in the pathogenesis of both lesions in diabetic and obese patients, we found no indication of a relationship in nondiabetic and nonobese patients with increased levels of EGF in patients with ST, suggesting an alternative pathogenesis in this patient group.

Protective effects of fish omega-3 fatty acids on doxorubicin-induced testicular apoptosis and oxidative damage in rats.

The aim of this study was to examine the protective effects of fish omega-3 (n-3) fatty acids on acute doxorubicin (DOX)-induced testicular apoptosis and oxidative damage. 24 male rats were divided into three groups: control, DOX-treated and DOX+fish n-3 fatty acids. Fish n-3 fatty acids (400 mg kg(-1) ) were given for 30 days by intragastric gavage. The rats received a single intraperitoneal injection of DOX (30 mg kg(-1) ) and were sacrificed after 48 h. The DOX+fish n-3 fatty acids group showed a decrease in malondialdehyde levels and increased activities of superoxide dismutase and glutathione peroxidase in comparison with the DOX-treated group. Acute DOX treatment caused severe damage such as disorganisation and separation of germ cells. The fish n-3 fatty acids-pretreated rats showed an improved histological appearance in the DOX-treated group. Our data indicate a reduction in the activity of terminal deoxynucleotidyl transferase mediated dUTP nick end labelling; there was a rise in the expression of proliferating cell nuclear antigen in testis tissues of the DOX+fish n-3 fatty acids group compared with DOX-treated group. These data suggested that fish n-3 fatty acids pre-treatment may be beneficial for spermatogenesis following acute DOX-induced testicular damage by decreasing germ cell apoptosis and oxidative stress.

Cardioprotective effects of fish omega-3 fatty acids on doxorubicin-induced cardiotoxicity in rats.

The aim of this study was to investigate the protective effects of fish omega-3 (n-3) fatty acids on doxorubicin (DOX)-induced acute cardiotoxicity. A total of 24 rats were divided into three groups: control, DOX-treated, and DOX treated with fish n-3 fatty acids. Control group received 0.4 ml/kg/day of saline intragastrically. The rats in the fish n-3 fatty acid-pretreated group were given 400 mg/kg/day fish n-3 fatty acids for 30 days by intragastric intubation. To induce acute cardiotoxicity, DOX (30 mg/kg) was injected intraperitoneally by a single dose and the rats were killed after 48 h. DOX treatment caused severe damage in heart tissues. Disorganization of myocardial muscle fibers, myofibrillar loss, and cardiotoxic myocardial fibers with cytoplasmic vacuoles were seen. Fish n-3 fatty acid-treated rats showed an improved histological appearance in the DOX-treated group. Our data indicate a significant reduction in the activity of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling in cardiomyocytes of the DOX-treated group with fish n-3 fatty acids therapy. The DOX-treated with fish n-3 fatty acids group showed a significant decrease in malondialdehyde levels, and an increase in superoxide dismutase and glutathione peroxidase activities in comparison with the DOX-treated group. This study showed that fish n-3 fatty acids may be a suitable cardioprotector against acute toxic effects of DOX.

Carotid intima-media thickness and serum paraoxonase-1 activity in patients with Helicobacter pylori.

AIM: To evaluate serum paraoxonase(PON)-1 activity and carotid intima-media thickness (CIMT) in patients with Cytotoxin-associated antigen(CagA)-positive and negative Helicobacter pylori strains. PATIENTS AND METHODS: The study group included a total of 134 individuals, of whom 103 were H. pylori positive, and 31 were H. pylori negative. Five biopsies were collected from each patient for histological examination: two from the antrum, two from the corpus, and one from the incisura angularis. The presence of H. pylori was determined using a modified Gram staining protocol. Peripheral blood was collected from each patient to determine levels of triglyceride, TC, HDL-cholesterol and LDL-cholesterol. IgG antibodies against CagA protein were analyzed by enzyme immunoassays. PON-1 activity was measured by colorimetric method. Carotid intima-media thickness and atherogenic plaques were measured using a grey scale color Doppler ultrasound. Data were analyzed by descriptive and inferential statistics. RESULTS: The right, the left and the mean CIMT were significantly higher in H. pylori (+) group versus H. pylori (-) group (p < 0.001 for all). However, the mean PON-1 concentration was significantly lower in H. pylori (+) group versus H. pylori (-) group (p < 0.001). The right, the left and the mean CIMT of CagA (+) group were significantly higher than that of CagA (-) group and controls, while PON-1 concentrations of CagA (+) group were significantly lower than that of CagA (-) group and controls (for all p = 0.0001). The right, the left and the mean CIMT of CagA (-) group were significantly higher than that of the control group, while the mean PON-1 concentration were significantly lower (for all p = 0.0001). CONCLUSIONS: Decreased PON-1 activity may be an etiopathogenetic factor in increased atherosclerosis in patients with H. pylori infection, especially in those infected with the CagA positive strain.

Acute tamoxifen treatment increases nitric oxide level but not total antioxidant capacity and adenosine deaminase activity in the plasma of rabbits.

Tamoxifen is a synthetic non steroidal anti-estrogen used to treat patients with breast cancer and healthy subjects with high risk of breast cancer. It was aimed to study the short term effects of tamoxifen on the plasma total antioxidant capacity (TAC), nitric oxide (NO) and the adenosine deaminase activity (ADA) in healthy rabbits. Sixteen healthy New Zealand rabbits were allocated to 2 groups including controls and tamoxifen treated animals. Controls received a single application of 0.9% saline via oral route while the treated rabbits received orally tamoxifen (dissolved in 0.9% saline, at a dose of 5 mg/kg). Blood samples were collected at 6 and 24 hours following the treatments. Plasma TAC and ADA were not affected by Tamoxifen treatment. However, NO level in tamoxifen treated group was increased at 24 hours following tamoxifen treatment as compared to controls. In conclusion, acute tamoxifen treatment may not affect the antioxidant status and cellular immunity, as evidenced by unaltered TAC and ADA. However, NO level was increased as early as 24 hours following tamoxifen treatment.

Investigation of oral selegiline and rasagiline administration on QT interval in conscious rabbits.

Rasagiline (RSG) and selegiline (SEL) are potent selective monoamine oxidase-B inhibitors and used in the treatment of Parkinson's disease. Selegiline is metabolized in vivo to I-methamphetamine and I-amphetamine which effect cardiovascular system. Therefore, the aim of this study was to evaluate and to compare the effects of long-term use of these drugs on QT interval in conscious rabbits. The study involved 17 New Zealand rabbits of both sexes, aged between 7 and 14 months. Control group (CG, n = 6) was orally given isotonic saline solution at dose of 0.5 cc/per rabbit. The SEL group (SG, n = 6) received 5 mg/per rabbit SEL orally twice daily (09:00 am and 09:00 pm) for 14 days. The RSG group (RG, n = 5) was orally given of RSG at 1 mg/per rabbit daily for 14 days. Electrocardiographic records were taken before the experiment (baseline) and at 1st, 7th, and 14th days of experiment by direct writing electrocardiograph for two groups. Heart rate (HR), QT and QTc values were determined from ECG records. HR did not significantly differ in both treatment groups through the experimental period when compared to baseline values. The significant prolongation of QT and QTc values were observed at 7th, and 14th day (p < 0.01) in SG and 1st day of experiment in RG (p < 0.05) as compared to baseline values. In conclusion, the results obtained suggest a statistically significant effect of SEL on QTc prolongation when compared to RAS. QTc prolongations should be taken into account in Parkinson's disease where autonomic system is involved.

Effects of therapeutic dose of ivermectin on plasma nitric oxide and total antioxidant capacity in rabbits.

BACKGROUND: Ivermectin, an acaricide and anthielmintic drug of the family of avermectins may produce free radicals thus resulting cytotoxic effect on the parasite. Nitric oxide (NO) acts as free radicals and as host defense mechanisms. The antioxidant capacity (TAC) can be described by the analysis of single components in the defense systems against free radicals. It was aimed to study the effects of therapeutic doses of ivermectin on the plasma adenosine deaminase (ADA) and gamma glutamyl transpeptidase activities (GGT), total antioxidant capacity (TAC), nitric oxide (NO) and total protein, albumin, globulin levels in rabbits. MATERIAL AND METHODS: Twenty healthy New Zealand rabbits were allocated to 2 equal groups. Group I received 0.5 mg/kg and Group II received 1 mg/kg of ivermectin via subcutaneous injection. Blood samples were collected before the experiment, at 24 and 120 hours following the treatments. RESULTS: Ivermectin at therapeutic doses increased plasma NO level at 24 h while decreased TAC at 120 h and did not alter other parameters. CONCLUSION: These findings may suggest that ivermectin is a safe antiparasitic drug for mammals but to less extent, it may have an effect on the oxidant/antioxidant balance.

Effects of therapeutic doses of Pregabalin on QTc interval in conscious rabbits.

Pregabalin (PRG) is a new antiepileptic drug that has been used as supportive therapy for partial seizures in patients. Although many neuro-psychiatric and non-cardiac drugs are known to prolong ventricular repolarization as manifested by QTc prolongation on ECG of which provokes torsades de pointes, there is limited data available regarding the characteristics of QT interval in conscious laboratory animals after PRG administration. For that purpose, effects of different therapeutic doses of oral PRG administration on Heart Rate (HR), QT and QTc values in rabbits were evaluated at a predefined time interval in this research. The study involved 28 New Zealand rabbits of both sexes, aged between 8 and 12 months. Animals were divided into four equal groups. Rabbits in control group (CG) received saline 0.5 ml/per animal orally. Group I, II and III were orally given single dose of PRG at 1.25 mg/kg, 2.5 mg/kg and 5 mg/kg, respectively. ECG records were taken before experiment (baseline) and at 1st, 2nd, 4th, and 6th hour (h) of experiment by direct writing electrocardiograph. HR, QT and QTc values were determined from ECG records. Heart rates increased in all groups when compared to baseline values. The increases were evident at 4th h in group II (p < 0.001), at 2nd h (p < 0.05) and 4th h (p < 0.001) in group III compared with CG. After application of PRG, QTc began to prolong at 1st h through the 4th of experiment and then turned to baseline values at 6th h of the experiment. The QTc values obtained at 2nd h in Group II and III (p < 0.05) and 4th h (p < 0.001) of application in group III were significantly different from CG. Changes obtained in HR, QT and QTc values in PRG treated rabbits were time and dose dependent (p < 0.001). Increase in HR and QTc prolongation determined in PRG given rabbits may implied that clinicians should take care of these changes when using this drug and further studies are required to fully understand the mechanism involved.