The effect of aromatase inhibitors against possible testis toxicity in pembrolizumab treated rats.

Pembrolizumab is a monoclonal antibody. Anastrozole is an infertility inhibitor of aromatase. Resveratrol is an antioxidant polyphenol in the reproductive system. This study was planned to demonstrate the protective effects of anastrozole and resveratrol against pembrolizumab-induced reproductive damage. Forty-two Sprague-Dawley rats were used in the study. Groups: The control, Pembrolizumab (PEMB), PEMB + Anastrazol (ANAST), PEMB + Resveratrol (RES), RES, and ANAST groups. At the end of the experiment, rats were euthanased under anaesthesia. Tissue samples were taken from rats for biochemical, histological, and ELISA evaluations. Tissues were subjected to routine tissue follow-up for histological analysis. Biochemically, thiobarbituric acid reactive substance (TBARS), glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) levels were measured. Sperm motility, abnormal sperm rate, and epididymal sperm concentration were examined spermatologically. Serum testosterone and programmed cell death-1 (PD-1) levels were measured using the ELISA. TBARS levels were significantly increased and GSH, SOD, GPx, and CAT levels were mitigated in PEMB-treated rats. Histologically; Control, ANAST, and RES groups testis samples were observed with normal histological appearance. Histological damage was detected in seminiferous tubule structures in testicular tissue in the PEMB group. In treatment groups, this damage was decreased. In addition, PD-1 and testosterone levels were evaluated by the ELISA method. ANAST and RES have therapeutic effects against reproductive damage caused by PEMB.

EGFR blocker lapatinib inhibits the synthesis of matrix metalloproteinases from synovial fibroblasts.

BACKGROUND: Epidermal growth factor receptor (EGFR) family members and their associated ligands may be related to bone and joint destruction in rheumatoid arthritis. Matrix metalloproteinases are responsible for joint and bone tissue degradation. This study is intended to investigate the effect of epidermal growth factor receptor inhibition by lapatinib on the synthesis of matrix metalloproteinases in in vitro. METHODS: Synovial fibroblast cell culture was obtained from a patient with rheumatoid arthritis who underwent knee arthroplasty. Interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) were added to the cell culture to stimulate synovial fibroblast cells and create an inflammatory character. Understimulated and nonstimulated conditions, lapatinib was applied to the culture in four different concentrations of 25, 50, 100, and 200 µmol. Then, matrix metalloproteinase -1, -3, and, -13 levels were assessed. RESULTS: When stimulated with IL-1ß and TNF-α, the synthesis of matrix metalloproteinases from synovial fibroblast was increased significantly. When lapatinib is added to the stimulated synovial fibroblasts, matrix metalloproteinases synthesis is significantly suppressed. DISCUSSION: Inhibition of the EGFR pathway with lapatinib suppresses matrix metalloproteinases synthesis. Our results suggest EGFR pathway inhibition may be a promising option to prevent joint destruction in the treatment of rheumatoid arthritis.

Schiff Base-Poloxamer P85 Combination Prevents Prostate Cancer Progression in C57/Bl6 Mice.

BACKGROUND: Prostate cancer which is the second most common cause of death among men has a high incidence in recent years. Current therapeutic regimens should be improved to overcome drug resistance. At the metastatic stage, tumors become refractory to established chemotherapeutic treatments and cause serious problems at the clinics. Development of new drug molecules that are able to transport through the membrane easily and kill tumor cells rapidly is of great interest. METHOD: In the current study, a novel Heterodinuclear copper(II)Mn(II) Schiff base complex combined with P85 was used for prostate cancer treatment in vivo. Tramp-C1 cells injected animals were subjected to chemotherapeutic formulation treatment and results were analyzed by toxicology analysis, tumor volume measurements, and histopathological analysis. 0.5 mg/kg Schiff base was selected and combined with 0.05% P85 according to the toxicology analysis showing the enzyme levels, blood parameters, and multiple organ toxicity. RESULTS: Results demonstrated that Heterodinuclear copper(II)Mn(II) complex-P85 combination decreased tumor formation and tumor volume steadily over the course of experiments. CONCLUSIONS: Overall, Heterodinuclear copper(II)Mn(II) complex-P85 exerted remarkable anti-cancer activity in vivo in C57/B16 mice. Prostate 76:1454-1463, 2016. © 2016 Wiley Periodicals, Inc.

Nerolidol attenuates dehydroepiandrosterone-induced polycystic ovary syndrome in rats by regulating oxidative stress and decreasing apoptosis.

AIMS: Although nerolidol (NRL) is a naturally occurring sesquiterpene alcohol with many pharmacological activities, its role in dehydroepiandrosterone DHEA-induced polycystic ovary syndrome PCOS is unknown. This study aims to explore the potential beneficial effects and underlying molecular mechanisms of nerolidol treatment on polycystic ovary syndrome. MAIN METHODS: Pre-pubertal female Sprague-Dawley rats were randomly assigned into four groups (n = 8/group); group I: control; group II: PCOS; group III: P + NRL; group IV: NRL. Biochemical parameters related to oxidative stress, inflammation, apoptosis, and hormones were estimated in the blood and ovarian tissues. Histopathological, ultrastructural, and immunohistochemical analyses were performed. Bax, P53, Cas-3, and Bcl-2 gene expression levels were detected with RT-PCR. The membrane array analysis detected chemokine, cytokine, and growth factor protein profiles. KEY FINDINGS: In light of the available data, it can deduce that nerolidol has a significant ameliorating effect on lipid peroxidation, oxidative stress, inflammation, histopathological damage, and apoptosis accompanying PCOS in female rats. SIGNIFICANCE: PCOS is not only a reproductive pathology but also a systemic condition and its etiopathogenesis is still not fully understood. Since changes in PCOS have important long-term effects on health, this study evaluated the efficacy of nerolidol, a phytotherapeutic for the control of biochemical, apoptotic, histopathological, and metabolic changes.

The Ameliorate Effects of Nerolidol on Thioacetamide-induced Oxidative Damage in Heart and Kidney Tissue

Objectives: Thioacetamide (TAA) is an organosulfur, white crystalline compound having liver injury. However, it shows toxic effects on many organs. The reverts the oxidative stress created by TAA on the heart and kidney, and decreased lipid peroxide peroxidation back with antioxidant-properties nerolidol (NRL). This study hypothesized that NRL treatment a potential ameliorate nephrotoxicity and cardiotoxicity caused by TAA. Materials and Methods: Thirty-two Wistar Albino male rats (3-4 months old and 280-300 g in weight) were divided into four groups. (a) Control, (b) TAA was administered 200 mg/kg i.p. twice a weekly (c) NRL was orally administered at the dose of 100 mg/kg per every other day by gavages. (d) TAA and NRL-treated groups were assigned 200 mg/kg TAA and 100 mg/kg NRL for three weeks. Results: As a result of these dose administration thiobarbituric acid reactive substances (TBARS) levels, superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and glutathione peroxidase (GPx) levels were detected. The results were shown that TAA leads to a significant rise in TBARS level and a significant decrease in GPx, CAT, SOD, and GSH levels in the heart and kidney tissue according to the control group. The finding of this study the NRL treatment reduced TBARS levels and increased antioxidant level. Administration of NRL prevents the biochemical and histopathological alterations induced by TAA. Conclusion: The findings of this study show that the antioxidant activity of NRL can protect against biochemical and histological damage caused by TAA in heart and kidney tissue.

Evaluation of serum neopterin, periostin, Tenascin-C, tissue inhibitor of metalloproteinase-1 and matrix metalloproteinase-2 levels in obese pregnant women

Objective: To investigate the role of extracellular matrix proteins in the molecular mechanism of inflammatory response in obese pregnant women by comparing serum levels of neopterin, periostin, Tenascin-C, tissue inhibitor of metalloproteinase-1, and matrix metalloproteinase-2 between obese and normal weight pregnant women in the third trimester. Materials and Methods: A prospective cross-sectional study was conducted between April 2021 and December 2021. A total of 84 pregnant women were included and three groups were formed with 28 participants in each group. Results: Serum levels of neopterin, periostin, Tenascin-C and tissue inhibitor of metalloproteinase-1 were significantly higher in class II-III obese pregnant women than in class I obese and normal-weight women (p=0.002, p<0.001, p<0.001, and p<0.001, respectively). There was no significant difference in serum matrix metalloproteinase-2 levels between the groups (p=0.769). Receiver operating characteristic curve analysis showed that Tenascin-C and periostin were effective in predicting pre-eclampsia [area under the curve (AUC)=0.82, 95% confidence interval (CI), 0.72-0.90, p<0.001 and AUC=0.71, 95% CI, 0.60-0.80, p=0.007, respectively]. Conclusion: This study demonstrated that class II-III obese pregnant women had significantly higher serum levels of neopterin, periostin, Tenascin-C, and tissue inhibitor of metalloproteinase-1 in the third trimester. These higher serum levels may be associated with the adverse perinatal effects of obesity during pregnancy.

Secukinumab Ameliorates Oxidative Damage Induced by Cerebral Ischemia-Reperfusion in Rats.

AIM: To investigate the histological and biochemical neuroprotective effects of secukinumab (SEC) on cerebral ischemia-reperfusion (IR) injury in Sprague-Dawley male rats. MATERIAL AND METHODS: A total of 28 Sprague-Dawley male rats were randomly and equally divided into the following four groups: Sham, SEC, IR, and IR+SEC groups. Bilateral common carotid arteries were simultaneously separated and blocked for 15 minutes using two vascular mini clips in the IR and IR+SEC groups. The surgical procedure was similarly repeated in the Sham and SEC groups, but the carotid arteries were not clipped. Secukinumab was administered intraperitoneally to the SEC and IR+SEC groups once a week after the surgical procedure. Rat brain tissues were collected for biochemical analysis and histopathological examination 14 days after surgery. RESULTS: Cerebral IR caused abnormal changes in oxidative stress parameters by increasing the malondialdehyde (MDA) level and by decreasing the glutathione (GSH), catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD) levels. IR also induced histopathological alterations, such as vascular congestion, hemorrhage, and cell infiltration in the rat brain tissues. Secukinumab treatment significantly decreased the MDA levels and increased the GPx, GSH, CAT, and SOD levels. In addition, secukinumab partially prevented histopathological alterations in the brain tissues. The percentage of immunohistochemically Caspase-3-positive cells was high in the IR group; however, SEC decreased the density of cells stained with Caspase-3. CONCLUSION: IR injury was found to cause oxidative and histopathological changes in rat brain tissues, and secukinumab treatment ameliorated these pathological effects. Therefore, secukinumab may be useful to prevent and treat oxidative stressinduced brain damage in patients with ischemic stroke.

Molecular docking and in vitro anticancer studies of silver(I)-N-heterocyclic carbene complexes.

A series of symmetric and unsymmetrical benzimidazolium-based N-heterocyclic carbene (NHC) precursors (1a-i) and their silver complexes (2a-i) have been synthesized. The Ag(I)-NHC complexes were characterized by 1H, 13C{1H} NMR, FTIR, LC/MS-QTOF, and elemental analysis. Anticancer and cytotoxic activity of all Ag(I)-NHC complexes were tested against healthy fibroblast cell line (L929), breast cancer cell line (MCF-7), and neuroblastoma cell line (SH-SY5Y) by MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4sulfophenyl)-2H-tetrazolium] assay. The 2b, 2c, 2e, 2g, 2h, and 2i complexes showed higher cytotoxicity than cisplatin against SH-SY5Y and MCF-7 and lower cytotoxic activity against L929 cell lines. Because of their high cytotoxic activity against cancer cells and low cytotoxicity against healthy fibroblast cell lines, the 2b, 2c, 2e, 2g, 2h, and 2i are expected to be new lead compounds. In addition, molecular docking studies were performed to explore the binding interactions of silver complexes with the enzyme to explore new anticancer compounds. Furthermore, ADME properties of all complexes were predicted to explore lead-like characteristics and may be a potential drug candidate for cancer treatment.

Curcumin protects heart tissue against irinotecan-induced damage in terms of cytokine level alterations, oxidative stress, and histological damage in rats.

Irinotecan (CPT-11), commonly used in the treatment of many cancer types, may have several side effects that limit the use of CPT-11 in specific tissues such as the heart. In the current study, positive effects of curcumin (CRC) was determined in terms of antioxidant and anti-inflammatory properties against heart damage, caused by CPT-11, in rats. Rats were divided randomly into four equal groups (Control, CPT-11, CRC, and CPT-11 + CRC). CPT-11 10 mg/kg/day was administered intraperitoneally and CRC 100 mg/kg-1 was given orally. Blood and tissue samples were collected from all groups at day 30 for the detection of oxidative stress, histological changes, and cytokine levels. Results showed that CPT-11 caused dramatic changes in heart tissue for oxidative stress parameters (TBARS, SOD, CAT, GSH, and GPx levels), histological tissue damage, and cytokine levels (TNF and IL-4). CRC therapy reversed the elevated oxidative stress, histological tissue damages, and immunological changes and protected cardiac tissue against CPT-11 toxicity when given together with CPT-11.In conclusion, CPT-11 caused adverse effects on cytokine levels, histological alterations, and oxidative stress in rats. However, CRC treatment eliminated these toxic effects with its antioxidant and anti-inflammatory properties. Thus, these results suggest that CRC may play a protective role against CPT-11 toxicity in heart tissue of rats.

Schiff base-Poloxamer P85 combination demonstrates chemotherapeutic effect on prostate cancer cells in vitro.

Prostate cancer is a multistep and complicated cancer type that is regulated by androgens at the cellular level and remains the second commonest cause of death among men. Discovery and development of novel chemotherapeutic agents enabling rapid tumor cell death with minimal toxic effects to healthy tissues might greatly improve the safety of chemotherapy. The present study evaluates the anti-cancer activity of a novel heterodinuclear copper(II)Mn(II) complex (Schiff base) in combination with poly(ethylene oxide) and poly(propylene oxide) block copolymer (Pluronic) P85. We used assays for cell proliferation, apoptosis, cell migration and invasion, DNA binding and cleavage to elucidate the molecular mechanisms of action, in addition to the anti-inflammatory potency of the new combination. The combined treatment of Schiff base and P85 lead to a remarkable anti-cancer effect on prostate cancer cell lines. Cell proliferation was inhibited in Schiff base-P85 treatment. The activity of this formulation is on DNA binding and cleavage and prevents inflammation in in vitro conditions. This is the first study presenting the anti-cancer activity of the present Schiff base derivative and its combination with P85 to treat prostate cancer in vitro.

18ß-glycyrrhetinic acid attenuates global cerebral ischemia/reperfusion-induced cardiac damage in C57BL/J6 mice

Abstract The aim of the present study is to investigate the cardioprotective effects of 18ß-glycyrrhetinic acid (18ß -GA) against oxidative and histological damage caused by global cerebral ischemia/ reperfusion (I/R) in C57BL/J6 mice. All male mice (n:40) were randomly divided into four groups: (1) sham-operated (Sham), (2) I/R, (3) 18ß-GA, and (4) 18ß -GA+I/R. Ischemia was not applied to the sham and 18ß-GA groups. In the I/R group, the bilateral carotid arteries were clipped for 15 min to induce ischemia, and the mice were treated with the vehicle for 10 days. In the 18ß-GA group, the mice were given 18ß-GA (100 mg/kg) for 10 days following a median incision without carotid occlusion. In the 18ß-GA+I/R group, the ischemic procedure performed to the I/R model was applied to the animals and afterwards they were intraperitoneally (i.p.) treated with 18ß-GA (100 mg/kg) for 10 days. It was found that global cerebral I/R increased TBARS levels and decreased antioxidant parameters. The 18ß-GA treatment decreased the level of TBARS and increased GSH, GPx, CAT, SOD activities. Also, the control group cardiac tissue samples were observed to have a normal histological appearance with the Hematoxylin-Eosin staining method. Histopathological damage was observed in the heart tissue samples belonging to the I/R group. The 18ß-GA treatment ameliorates oxidative and histological injury in the heart tissue after global ischemia reperfusion, and may be a beneficial alternative treatment

Beta-glucan attenuates cerebral ischemia/reperfusion-induced neuronal injury in a C57BL/J6 mouse model

Beta-glucans (ßg), that have many useful effects on human health, are natural polysaccharides. Our aim in this study was to determine useful effect of ßg against oxidative and neuronal damage caused by global cerebral ischemia/reperfusion (IR) in stroke imitated mice via surgical operation. A total of 40 mice divided into four equal groups randomly. The group 1 (sham operated) was kept as control. Bilateral carotid arteries of subjects in group 2 (I/R) and group 4 (I/ R + ßg) were clipped for 15 min, and the mice in group 4 (I/R + ßg) were treated with ßg (50 mg/kg/day), while the mice in group 2 (I/R) were treated with only vehicle for 10 days. The mice of group 3 (ßg) were treated with ßg for 10 days without carotid occlusion. Global cerebral I/R significantly increased oxidative stress and decreased members of anti-oxidant defense system. In addition, I/R caused histopathological damage in the brain tissue. However, ßg treatment ameliorated both oxidative and histopathological effects of I/R. Our present study showed that ßg treatment significantly ameliorated oxidative and histological damage in the brain tissue caused by cerebral I/R. Therefore, ßg treatment can be used as supportive care for ischemic stroke patients

Beta-glucan prevents toxic effects of 2, 3, 7, 8-TCDD in terms of oxidative and histopathological damage in heart tissue of rats

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a widespread environmental contaminant which causes severe toxic effects. Despite there is some suggestion concerning with TCDD induced cardiotoxicity such as formation of free radicals, the main mechanism has not been entirely explained. Beta-glucan is known as strong antioxidant matter and can scavenge free radicals. Therefore this study aimed to investigate the protective effects of beta-glucan against TCDD induced cardiotoxicity in rats. In this study, 2-3 months of age and 190-250 g in weight 32 rats were randomly divided into four equal groups (n=8 for each group). Group 1 was control; Group 2 was TCDD group (2 µg/kg/week); group 3 was the beta-glucan group(50 mg/kg/day), and group 4 was TCDD and beta-glucan treatment group. The heart samples were taken from rats after 21 days treatment. The results were shown that Despite TCDD exposure visibly caused to increase (p ≤ 0.001) in TBARS levels, It caused a visible decline in the levels of GSH, CAT, GSH-Px, and SOD. However Beta glucan significantly increased GSH, CAT, GSH-Px, SOD levels and decreased generation of TBARS. Additionally, our histopathological observations were in agreement with the biochemical results. In conclusion, Beta-glucan treatment exhibited protective activity on TCDD induced cardiotoxicity