Publications by authors named "Murat Oz"

117 Publications

The prognostic value of squamous differentiation in endometrioid type endometrial cancer: a matched analysis.

J Obstet Gynaecol 2021 Jun 22:1-7. Epub 2021 Jun 22.

Department of Gynecologic Oncology, Ankara City Hospital, Ankara, Turkey.

We aimed to examine the effect of the squamous differentiation on survival outcomes of women with endometrioid adenocarcinoma. We retrospectively reviewed the patients with endometrioid adenocarcinoma who underwent primary surgical treatment in a tertiary referral hospital. Sixty-nine patients having squamous differentiation constituted the case group. Each woman in the case group was matched with two patients in the control group based on age, disease stage, tumour grade, lymphovascular space invasion, tumour size, myometrial invasion, type of surgery and adjuvant therapy. During the follow-up, the recurrence rates were similar between the case (5/69, 7.2%) and control (10/138, 7.2%) groups ( = 1.0). The 5-year disease-free survival rate was 90.2% for the case group and 88.6% for the control group ( = .51). The 5-year overall survival rate was 94.6% for the case group and 91.8% for the control group ( = .12). Squamous differentiation seems to have no impact on the prognosis of patients with endometrioid adenocarcinoma.IMPACT STATEMENT A focus of squamous differentiation is recognised in 12.8-25% of women with endometrioid adenocarcinoma. The prognostic value of the squamous differentiation was evaluated in several previous studies. However, it could not be clarified due to the conflicting results of these studies. The probable confounding effects of well-known prognostic factors including age at diagnosis, International Federation of Gynaecology and Obstetrics stage, tumour grade, lymphovascular space invasion, tumour size, myometrial invasion, type of surgery and adjuvant therapy were eliminated with the case-control study design in the current study. Our findings indicate that the presence of squamous differentiation does not have any prognostic effect in endometrioid type endometrial cancer. The molecular prognosticators of endometrial cancer were extensively studied in recent years. It is likely that clinicopathological and molecular prognostic factors will be integrated for predicting prognosis as a part of routine clinical practice soon. In this context, the prognostic value of the squamous differentiation in endometrioid adenocarcinomas may further be clarified by larger and multicentric studies that utilise central pathology review.
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http://dx.doi.org/10.1080/01443615.2021.1916809DOI Listing
June 2021

Apigenin and Structurally Related Flavonoids Allosterically Potentiate the Function of Human α7-Nicotinic Acetylcholine Receptors Expressed in SH-EP1 Cells.

Cells 2021 May 5;10(5). Epub 2021 May 5.

Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Kuwait University, Safat 13110, Kuwait.

Phytochemicals, such as monoterpenes, polyphenols, curcuminoids, and flavonoids, are known to have anti-inflammatory, antioxidant, neuroprotective, and procognitive effects. In this study, the effects of several polyhydroxy flavonoids, as derivatives of differently substituted 5,7-dihydroxy-4-chromen-4-one including apigenin, genistein, luteolin, kaempferol, quercetin, gossypetin, and phloretin with different lipophilicities (cLogP), as well as topological polar surface area (TPSA), were tested for induction of Ca transients by α7 human nicotinic acetylcholine (α7 nACh) receptors expressed in SH-EP1 cells. Apigenin (10 μM) caused a significant potentiation of ACh (30 μM)-induced Ca transients, but did not affect Ca transients induced by high K (60 mM) containing solutions. Co-application of apigenin with ACh was equally effective as apigenin preincubation. However, the effect of apigenin significantly diminished by increasing ACh concentrations. The flavonoids tested also potentiated α nACh mediated Ca transients with descending potency (highest to lowest) by genistein, gossypetin, kaempferol, luteolin, phloretin, quercetin, and apigenin. The specific binding of α7 nACh receptor antagonist [I]-bungarotoxin remained unchanged in the presence of any of the tested polyhydroxy flavonoids, suggesting that these compounds act as positive allosteric modulators of the α7-nACh receptor in SH-EP1 cells. These findings suggest a clinical potential for these phytochemicals in the treatment of various human diseases from pain to inflammation and neural disease.
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http://dx.doi.org/10.3390/cells10051110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147998PMC
May 2021

Mecamylamine inhibits seizure-like activity in CA1-CA3 hippocampus through antagonism to nicotinic receptors.

PLoS One 2021 12;16(3):e0240074. Epub 2021 Mar 12.

Department of Cellular Membranology, Bogomoletz Institute of Physiology, Kiev, Ukraine.

Cholinergic modulation of hippocampal network function is implicated in multiple behavioral and cognitive states. Activation of nicotinic and muscarinic acetylcholine receptors affects neuronal excitability, synaptic transmission and rhythmic oscillations in the hippocampus. In this work, we studied the ability of the cholinergic system to sustain hippocampal epileptiform activity independently from glutamate and GABA transmission. Simultaneous CA3 and CA1 field potential recordings were obtained during the perfusion of hippocampal slices with the aCSF containing AMPA, NMDA and GABA receptor antagonists. Under these conditions, spontaneous epileptiform discharges synchronous between CA3 and CA1 were recorded. Epileptiform discharges were blocked by addition of the calcium-channel blocker Cd2+ and disappeared in CA1 after a surgical cut between CA3 and CA1. Cholinergic antagonist mecamylamine abolished CA3-CA1 synchronous epileptiform discharges, while antagonists of α7 and α4β2 nAChRs, MLA and DhβE, had no effect. Our results suggest that activation of nicotinic acetylcholine receptors can sustain CA3-CA1 synchronous epileptiform activity independently from AMPA, NMDA and GABA transmission. In addition, mecamylamine, but not α7 and α4β2 nAChRs antagonists, reduced bicuculline-induced seizure-like activity. The ability of mecamylamine to decrease hippocampal network synchronization might be associated with its therapeutic effects in a wide variety of CNS disorders including addiction, depression and anxiety.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240074PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954330PMC
March 2021

CRISPR/Cas9 Mediated Knock Down of δ-ENaC Blunted the TNF-Induced Activation of ENaC in A549 Cells.

Int J Mol Sci 2021 Feb 12;22(4). Epub 2021 Feb 12.

Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Kuwait University, Safat, Kuwait City 13110, Kuwait.

Tumor necrosis factor (TNF) is known to activate the epithelial Na channel (ENaC) in A549 cells. A549 cells are widely used model for ENaC research. The role of δ-ENaC subunit in TNF-induced activation has not been studied. In this study we hypothesized that δ-ENaC plays a major role in TNF-induced activation of ENaC channel in A549 cells which are widely used model for ENaC research. We used CRISPR/Cas 9 approach to knock down (KD) the δ-ENaC in A549 cells. Western blot and immunofluorescence assays were performed to analyze efficacy of δ-ENaC protein KD. Whole-cell patch clamp technique was used to analyze the TNF-induced activation of ENaC. Overexpression of wild type δ-ENaC in the δ-ENaC KD of A549 cells restored the TNF-induced activation of whole-cell Na current. Neither N-linked glycosylation sites nor carboxyl terminus domain of δ-ENaC was necessary for the TNF-induced activation of whole-cell Na current in δ-ENaC KD of A549 cells. Our data demonstrated that in A549 cells the δ-ENaC plays a major role in TNF-induced activation of ENaC.
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http://dx.doi.org/10.3390/ijms22041858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917654PMC
February 2021

Multifunctional angiotensin converting enzyme 2, the SARS-CoV-2 entry receptor, and critical appraisal of its role in acute lung injury.

Biomed Pharmacother 2021 Apr 5;136:111193. Epub 2021 Jan 5.

Department of Anatomy and Cellular Biology, Khalifa University, Abu Dhabi, United Arab Emirates; Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates.

The recent emergence of coronavirus disease-2019 (COVID-19) as a pandemic affecting millions of individuals has raised great concern throughout the world, and the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was identified as the causative agent for COVID-19. The multifunctional protein angiotensin converting enzyme 2 (ACE2) is accepted as its primary target for entry into host cells. In its enzymatic function, ACE2, like its homologue ACE, regulates the renin-angiotensin system (RAS) critical for cardiovascular and renal homeostasis in mammals. Unlike ACE, however, ACE2 drives an alternative RAS pathway by degrading Ang-II and thus operates to balance RAS homeostasis in the context of hypertension, heart failure, and cardiovascular as well as renal complications of diabetes. Outside the RAS, ACE2 hydrolyzes key peptides, such as amyloid-β, apelin, and [des-Arg9]-bradykinin. In addition to its enzymatic functions, ACE2 is found to regulate intestinal amino acid homeostasis and the gut microbiome. Although the non-enzymatic function of ACE2 as the entry receptor for SARS-CoV-2 has been well established, the contribution of enzymatic functions of ACE2 to the pathogenesis of COVID-19-related lung injury has been a matter of debate. A complete understanding of this central enzyme may begin to explain the various symptoms and pathologies seen in SARS-CoV-2 infected individuals, and may aid in the development of novel treatments for COVID-19.
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http://dx.doi.org/10.1016/j.biopha.2020.111193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836742PMC
April 2021

Is the extent of lymphadenectomy a prognostic factor in International Federation of Gynecology and Obstetrics stage II endometrioid endometrial cancer?

J Obstet Gynaecol Res 2021 Mar 10;47(3):1134-1144. Epub 2021 Jan 10.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Faculty of Medicine, Baskent University, Ankara, Turkey.

Aim: This study aimed to evaluate the prognostic significance of adequate lymph node dissection (LND) (≥10 pelvic lymph nodes (LNs) and ≥ 5 paraaortic LNs removed) in patients with International Federation of Gynecology and Obstetrics (FIGO) stage II endometrioid endometrial cancer (EEC).

Methods: A multicenter department database review was performed to identify patients who had been operated and diagnosed with stage II EEC at seven centers in Turkey retrospectively. Demographic, clinicopathological, and survival data were collected and analyzed.

Results: We identified 284 women with stage II EEC. There were 170 (59.9%) patients in the adequate lymph node dissection (LND) group and 114 (40.1%) in the inadequate LND group. The 5-year overall survival (OS) rate of the inadequate LND group was significantly lower than that of the adequate LND group (84.1% vs. 89.1%, respectively; p = 0.028). In multivariate analysis, presence of lymphovascular space invasion (LVSI) (hazard ratio [HR]: 2.39, 95% confidence interval [CI]: 1.23-4.63; p = 0.009), age ≥ 60 (HR: 3.30, 95% CI: 1.65-6.57; p = 0.001], and absence of adjuvant therapy (HR: 2.74, 95% CI: 1.40-5.35; p = 0.003) remained as independent risk factors for decreased 5-year disease-free survival (DFS). Inadequate LND (HR: 2.34, 95% CI: 1.18-4.63; p < 0.001), age ≥ 60 (HR: 2.67, 95% CI: 1.25-5.72; p = 0.011), and absence of adjuvant therapy (HR: 4.95, 95% CI: 2.28-10.73; p < 0.001) were independent prognostic factors for decreased 5-year OS in multivariate analysis.

Conclusion: Adequate LND and adjuvant therapy were significant for the improvement of outcomes in FIGO stage II EEC patients. Furthermore, LVSI was associated with worse 5-year DFS rate in stage II EEC.
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http://dx.doi.org/10.1111/jog.14648DOI Listing
March 2021

Low-grade endometrial stromal sarcoma: A Turkish uterine sarcoma group study analyzing prognostic factors and disease outcomes.

Gynecol Oncol 2021 03 27;160(3):674-680. Epub 2020 Dec 27.

Department of Gynecologic Oncology, Saglik Bilimleri University Ankara City Hospital, Ankara, Turkey.

Objective: To investigate factors associated with refractory disease, recurrence, or death as well as disease-free survival (DFS) and overall survival (OS) in low-grade endometrial sarcoma (LGESS).

Methods: A multi-institutional, retrospective study was conducted in a total of 124 patients, who received a curative-intent surgery. The exclusion criteria were as follows: i) history of any other invasive disease; ii) neoadjuvant therapy; iii) fertility sparing surgery; iv) a different diagnosis after review of the slides.

Results: All patients underwent hysterectomy, 96% had bilateral salpingo-oophorectomy, and 65% had lymphadenectomy. Twelve (14.8%) of 81 patients undergoing lymphadenectomy had lymph node (LN) metastasis. Of those, 8 (9.8%) had pelvic LN metastasis whereas 4 (5.6%) had isolated paraaortic LN metastasis. Six of 8 (75%) patients with positive pelvic LNs had concurrent paraaortic LN metastasis. Among 124 patients, 3 patients (2.4%) had refractory disease following primary therapy. During a median follow-up of 45.5 months, 27 (22.3%) of 121 patients who achieved complete remission after primary therapy developed recurrence, and 10 patients (8.1%) died of disease. The 3-year DFS and OS were 76.9% and 93.8%, respectively. Stage was the sole independent prognostic factor in the whole cohort. When analyzing factors within subgroups of stage I and stage ≥II, there was no significant prognostic factor for stage I; however, lymphadenectomy and adjuvant chemotherapy were significantly associated with disease outcomes for stage ≥II. While lymphadenectomy was related with improved DFS, chemotherapy was associated with poor DFS and OS.

Conclusion: The risk of LN metastasis at pelvic as well as paraaortic lymphatic basins is not negligible to omit lymphadenectomy in stage ≥II LGESS. Moreover, lymphadenectomy provides significant DFS advantage in patients with extrauterine disease.
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http://dx.doi.org/10.1016/j.ygyno.2020.12.017DOI Listing
March 2021

A comprehensive guide to the pharmacologic regulation of angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 entry receptor.

Pharmacol Ther 2021 05 1;221:107750. Epub 2020 Dec 1.

School of Systems Biology, George Mason University, Fairfax, VA 22030, USA.

The recent emergence of coronavirus disease-2019 (COVID-19) as a global pandemic has prompted scientists to address an urgent need for defining mechanisms of disease pathology and treatment. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent for COVID-19, employs angiotensin converting enzyme 2 (ACE2) as its primary target for cell surface attachment and likely entry into the host cell. Thus, understanding factors that may regulate the expression and function of ACE2 in the healthy and diseased body is critical for clinical intervention. Over 66% of all adults in the United States are currently using a prescription drug and while earlier findings have focused on possible upregulation of ACE2 expression through the use of renin angiotensin system (RAS) inhibitors, mounting evidence suggests that various other widely administered drugs used in the treatment of hypertension, heart failure, diabetes mellitus, hyperlipidemias, coagulation disorders, and pulmonary disease may also present a varied risk for COVID-19. Specifically, we summarize mechanisms on how heparin, statins, steroids and phytochemicals, besides their established therapeutic effects, may also interfere with SARS-CoV-2 viral entry into cells. We also describe evidence on the effect of several vitamins, phytochemicals, and naturally occurring compounds on ACE2 expression and activity in various tissues and disease models. This comprehensive review aims to provide a timely compendium on the potential impact of commonly prescribed drugs and pharmacologically active compounds on COVID-19 pathology and risk through regulation of ACE2 and RAS signaling.
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http://dx.doi.org/10.1016/j.pharmthera.2020.107750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854082PMC
May 2021

Perioperative SARS-CoV-2 infection among women undergoing major gynecologic cancer surgery in the COVID-19 era: A nationwide, cohort study from Turkey.

Gynecol Oncol 2021 02 17;160(2):499-505. Epub 2020 Nov 17.

Department of Gynecologic Oncology, Ankara City Hospital, Faculty of Medicine, University of Health Sciences, Ankara, Turkey.

Objective: The objective of this study was to determine the rate of perioperative SARS-CoV-2 infection among gynecologic cancer patients undergoing major surgery.

Methods: The database of the Turkish Ministry of Health was searched in order to identify all consecutive gynecologic cancer patients undergoing major surgery between March 11, 2020 and April 30, 2020 for this retrospective, nationwide, cohort study. The inclusion criteria were strictly founded on a final histopathological diagnosis of a malignant gynecologic tumor. COVID-19 cases were diagnosed by reverse transcriptase- polymerase chain reaction testing for SARS-CoV-2. The rate of perioperative SARS-CoV-2 infection and the 30-day mortality rate of COVID-19 patients were investigated.

Results: During the study period, 688 women with gynecologic cancer undergoing major surgery were identified nationwide. The median age of the patients was 59 years. Most of the surgeries were open (634/688, 92.2%). There were 410 (59.6%) women with endometrial cancer, 195 (28.3%) with ovarian cancer, 66 (9.6%) with cervical cancer, 14 (2.0%) with vulvar cancer and 3 (0.4%) with uterine sarcoma. The rate of SARS-CoV-2 infections confirmed within 7 days before or 30 days after surgery was 46/688 (6.7%). All but one woman was diagnosed postoperatively (45/46, 97.8%). The rates of intensive care unit admission and invasive mechanical ventilation were 4/46 (8.7%) and 2/46 (4.3%), respectively. The 30-day mortality rate was 0%.

Conclusion: In the COVID-19 era, gynecologic cancer surgery may be performed with an acceptable rate of perioperative SARS-CoV-2 infection if the staff and the patients strictly adhere to the established infection control measures.
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http://dx.doi.org/10.1016/j.ygyno.2020.11.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670981PMC
February 2021

Neuroprotective Effect of Curcumin on the Nigrostriatal Pathway in a 6-Hydroxydopmine-Induced Rat Model of Parkinson's Disease is Mediated by α7-Nicotinic Receptors.

Int J Mol Sci 2020 Oct 3;21(19). Epub 2020 Oct 3.

Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain PO BOX 17666, UAE.

Parkinson's disease (PD) is a common neurodegenerative disorder, characterized by selective degeneration of dopaminergic nigrostriatal neurons. Most of the existing pharmacological approaches in PD consider replenishing striatal dopamine. It has been reported that activation of the cholinergic system has neuroprotective effects on dopaminergic neurons, and human α7-nicotinic acetylcholine receptor (α7-nAChR) stimulation may offer a potential therapeutic approach in PD. Our recent in-vitro studies demonstrated that curcumin causes significant potentiation of the function of α7-nAChRs expressed in oocytes. In this study, we conducted in vivo experiments to assess the role of the α7-nAChR on the protective effects of curcumin in an animal model of PD. Intra-striatal injection of 6-hydroxydopmine (6-OHDA) was used to induce Parkinsonism in rats. Our results demonstrated that intragastric curcumin treatment (200 mg/kg) significantly improved the abnormal motor behavior and offered neuroprotection against the reduction of dopaminergic neurons, as determined by tyrosine hydroxylase (TH) immunoreactivity in the substantia nigra and caudoputamen. The intraperitoneal administration of the α7-nAChR-selective antagonist methyllycaconitine (1 µg/kg) reversed the neuroprotective effects of curcumin in terms of both animal behavior and TH immunoreactivity. In conclusion, this study demonstrates that curcumin has a neuroprotective effect in a 6-hydroxydopmine (6-OHDA) rat model of PD via an α7-nAChR-mediated mechanism.
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http://dx.doi.org/10.3390/ijms21197329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583812PMC
October 2020

Capsaicin Is a Negative Allosteric Modulator of the 5-HT Receptor.

Front Pharmacol 2020 31;11:1274. Epub 2020 Aug 31.

Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Kuwait University, Safat, Kuwait.

In this study, effects of capsaicin, an active ingredient of the capsicum plant, were investigated on human 5-hydroxytryptamine type 3 (5-HT) receptors. Capsaicin reversibly inhibited serotonin (5-HT)-induced currents recorded by two-electrode voltage clamp method in oocytes. The inhibition was time- and concentration-dependent with an IC = 62 μM. The effect of capsaicin was not altered in the presence of capsazepine, and by intracellular BAPTA injections or trans-membrane potential changes. In radio-ligand binding studies, capsaicin did not change the specific binding of the 5-HT antagonist [H]GR65630, indicating that it is a noncompetitive inhibitor of 5-HT receptor. In HEK-293 cells, capsaicin inhibited 5-HT receptor induced aequorin luminescence with an IC of 54 µM and inhibition was not reversed by increasing concentrations of 5-HT. In conclusion, the results indicate that capsaicin acts as a negative allosteric modulator of human 5-HT receptors.
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http://dx.doi.org/10.3389/fphar.2020.01274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490547PMC
August 2020

The prognostic value of lymph node ratio in stage IIIC cervical cancer patients triaged to primary treatment by radical hysterectomy with systematic pelvic and para-aortic lymphadenectomy.

J Gynecol Oncol 2020 Jan 24;31(1):e1. Epub 2019 Jun 24.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Faculty of Medicine, Baskent University, Ankara, Turkey.

Objective: The aim of this study was to determine the prognostic value of lymph node ratio (LNR) in women with 2018 International Federation of Gynecology and Obstetrics stage IIIC cervical cancer.

Methods: In this retrospective dual-institutional study, a total of 185 node-positive cervical cancer patients who had undergone radical hysterectomy with systematic pelvic and para-aortic lymphadenectomy were included. All of the patients received adjuvant chemoradiation after surgery. LNR was defined as the ratio of positive lymph nodes (LNs) to the total number of LNs removed. The patients were categorized into 2 groups according to LNR; LNR <0.05 and LNR ≥0.05. The prognostic value of LNR was evaluated with univariate log-rank tests and multivariate Cox regression models.

Results: A total of 138 patients (74.6%) had stage IIIC1 disease and 47 (25.4%) patients had stage IIIC2 disease. With a median follow-up period of 45.5 months (range 3-135 months), the 5-year disease-free survival (DFS) rate was 62.5% whereas the 5-year overall survival (OS) rate was 70.4% for the entire study population. The 5-year DFS rates for LNR <0.05 and LNR ≥0.05 were 78.2%, and 48.4%, respectively (p<0.001). Additionally, the 5-year OS rates for LNR <0.05 and LNR ≥0.05 were 80.6%, and 61.2%, respectively (p=0.007). On multivariate analysis, LNR ≥0.05 was associated with a worse DFS (hazard ratio [HR]=2.12; 95% confidence interval [CI]=1.15-3.90; p=0.015) and OS (HR=1.95; 95% CI=1.01-3.77; p=0.046) in women with stage IIIC cervical cancer.

Conclusions: LNR ≥0.05 seems to be an independent prognostic factor for decreased DFS and OS in stage IIIC cervical carcinoma.
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http://dx.doi.org/10.3802/jgo.2020.31.e1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918892PMC
January 2020

Paraaortic lymphadenectomy: Step by step surgical education video

J Turk Ger Gynecol Assoc 2019 Aug 9. Epub 2019 Aug 9.

Department of Anatomy, Hacettepe University Faculty of Medicine, Ankara, Turkey

Paraaortic lymph nodes are exclusively important in staging of gynecologic malignancies. This surgical education video describes the step by step technique of paraaortic lymphadenectomy with anatomic landmarks on a cadaver.
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http://dx.doi.org/10.4274/jtgga.galenos.2019.2019.0117DOI Listing
August 2019

A novel multivariable prediction model for lymphatic dissemination in endometrioid endometrial cancer: The lymph node Metastasis Risk Index.

Eur J Obstet Gynecol Reprod Biol 2019 Sep 25;240:310-315. Epub 2019 Jul 25.

Zekai Tahir Burak Women's Health Hospital, Talatpasa Blv, Ankara, Turkey.

Objective: The purpose of this study was to develop a risk assessment index that could determine which endometrioid endometrial cancer (EC) patients would benefit from a lymphadenectomy.

Methods: The final pathology reports of 353 women who underwent complete surgical staging, including pelvic and para-aortic lymphadenectomy, for endometrioid EC between January 2008 and June 2018 were retrospectively reviewed. A logistic regression was used to investigate the clinicopathological factors associated with a positive nodal status. The independent risk factors for lymphatic dissemination were used to build a risk model and a "Lymph Node (LN) Metastasis Risk Index" was defined as follows: (tumor grade) × (primary tumor diameter) × (percentage of myometrial invasion) × (preoperative serum CA 125 level). The scores used in the LN Metastasis Risk Index were weighted according to the odds ratios assigned for each variable. The diagnostic performance of the model was expressed as the sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio.

Results: The LN Metastasis Risk Index correctly identified 35 of 40 LN-positive women at a cutoff point of 981.0 (sensitivity: 87.5%, specificity: 86.3%, negative predictive value: 98.2%, positive predictive value: 44.9%, positive likelihood ratio: 6.37, and negative likelihood ratio: 0.14). The area under the receiver operating characteristic curve was 0.90 (95% confidence interval = 0.858-0.947) at this cutoff. The clinical accuracy of the model was 86.4%. When a cutoff point of <981.0 was selected in order to define those women at low-risk for lymphatic dissemination, our prediction model classified 275 women (77.9%) as being at low-risk for nodal involvement. Among these 275 women, 5 actually had positive LNs, which indicated a 1.8% false-negative rate.

Conclusion: After external validation, the LN Metastasis Risk Index may be a valuable tool for the surgical management of endometrioid EC.
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http://dx.doi.org/10.1016/j.ejogrb.2019.07.015DOI Listing
September 2019

Is the revised 2018 FIGO staging system for cervical cancer more prognostic than the 2009 FIGO staging system for women previously staged as IB disease?

Eur J Obstet Gynecol Reprod Biol 2019 Sep 6;240:209-214. Epub 2019 Jul 6.

Department of Gynecologic Oncology, Zekai Tahir Burak Women's Health Training and Research Hospital, Faculty of Medicine, University of Health Sciences, Ankara, Turkey.

Objective: The purpose of this study was to compare the prognostic value of the revised FIGO staging system with that of the 2009 FIGO staging system for women previously staged as IB disease.

Methods: Institutional cervical cancer databases of two high-volume gynecologic cancer centers in Ankara, Turkey, were retrospectively analyzed. Only women with 2009 FIGO stage IB1 or IB2 disease who underwent primary surgery were included. Survival curves were generated using Kaplan-Meier plots, and the log-rank test was used for survival comparisons. The Cox proportional hazards regression model was used to obtain hazard ratios (HRs) and 95% confidence interval (CI).

Results: Data from 425 women were analyzed. The 2009 FIGO stage IB2 (n = 131) disease was associated with a nearly three-fold increased risk of mortality when compared to the 2009 FIGO stage IB1 (n = 294) disease (HR: 2.72, 95% CI: 1.69-4.37; p < 0.001). Stage migration was observed in 372 (87.5%) patients, according to the revised FIGO staging system, leading to no significant difference in five-year overall survival rates between stage IB1 (n=53) and IB2 (n=127) disease (95.2% vs. 89.3%, respectively; p = 0.23),or between stage IB2 (n=127) and IB3 (n=95) disease (89.3% vs. 84.2%, respectively; p = 0.12). Similarly, there was no significant difference in five-year overall survival rates between stage IIIC1 (n=114) and IIIC2 (n=36) disease (79.0% vs. 67.2%, respectively; p = 0.34).

Conclusion: When compared to the 2009 FIGO staging system, the revised staging system has more sub-stages, which leads to fewer patients in each sub-stage, resulting in diminished statistical power.
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http://dx.doi.org/10.1016/j.ejogrb.2019.07.002DOI Listing
September 2019

Para-aortic lymph node involvement revisited in the light of the revised 2018 FIGO staging system for cervical cancer.

Arch Gynecol Obstet 2019 09 1;300(3):675-682. Epub 2019 Jul 1.

Department of Gynecologic Oncology, Zekai Tahir Burak Women's Health Training and Research Hospital, Faculty of Medicine, University of Health Sciences, Talatpaşa Bulvarı, 06230, Ankara, Turkey.

Objective: This dual-institutional, retrospective study aimed to determine the clinicopathological risk factors for para-aortic lymph node (LN) metastasis among women who underwent radical hysterectomy with systematic pelvic and para-aortic lymphadenectomy for 2009 FIGO stage IB1-IIA2 cervical cancer.

Methods: Institutional cervical cancer databases of two high-volume gynecologic cancer centers in Ankara, Turkey were retrospectively analyzed. Women with 2009 FIGO stage IB1-IIA2 cervical cancer that had undergone radical hysterectomy with pelvic and para-aortic lymphadenectomy between January 2006 and December 2018 were included in the study. Patient data were analyzed with respect to para-aortic LN involvement and all potential clinicopathological risk factors for para-aortic LN metastasis were investigated.

Results: A total of 522 women met the inclusion criteria. Pelvic LN metastasis was detected in 190 patients (36.4%), para-aortic LN metastasis in 48 patients (9.2%), isolated para-aortic LN metastasis in 4 (0.8%), and both pelvic and para-aortic LN metastasis in 44 (8.4%) women, respectively. The independent risk factors identified for para-aortic LN involvement included parametrial invasion (odds ratio [OR]: 3.57, 95% confidence interval [CI]: 1.65-7.72; p = 0.001), metastasized pelvic LN size > 1 cm (OR: 4.51, 95% CI: 1.75-11.64; p = 0.002), multiple pelvic LN metastases (OR: 3.83, 95% CI: 1.46-10.01; p = 0.006), and common iliac LN metastasis (OR: 2.97, 95% CI: 1.01-8.68; p = 0.04). A total of 196 (37.5%) patients exhibited at least one risk factor for para-aortic nodal disease.

Conclusion: Parametrial invasion, metastasized pelvic LN size > 1 cm, multiple pelvic LN metastases, and common iliac LN metastasis seem to be independent predictors of para-aortic LN involvement.
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http://dx.doi.org/10.1007/s00404-019-05232-7DOI Listing
September 2019

Capsaicin inhibits the function of α-nicotinic acetylcholine receptors expressed in Xenopus oocytes and rat hippocampal neurons.

Eur J Pharmacol 2019 Aug 30;857:172411. Epub 2019 May 30.

Departments of Pharmacology, College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates; Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Kuwait University, Safat, Kuwait. Electronic address:

Capsaicin is a naturally occurring alkaloid derived from Chili peppers fruits. Using the two-electrode voltage-clamp technique in Xenopus oocyte expression system, actions of capsaicin on the functional properties of α subunit of the human nicotinic acetylcholine (α nACh) receptor were investigated. Ion currents activated by ACh (100 μM) were reversibly inhibited with an IC value of 8.6 μM. Inhibitory actions of capsaicin was independent of membrane potential. Furthermore, Ca-dependent Cl channels expressed endogenously in oocytes were not involved in inhibitory actions of capsaicin. In addition, increasing the ACh concentrations could not reverse the inhibitory effects of capsaicin. Importantly, specific binding of [I] α-bungarotoxin remained unaltered by capsaicin suggesting that its effect is noncompetitive. Whole cell patch-clamp technique was performed in CA1 stratum radiatum interneurons of rat hippocampal slices. Ion currents induced by choline, a selective-agonist of α-receptor, were reversibly inhibited by 10 min bath application of capsaicin (10 μM). Collectively, results of our investigation indicate that the function of the α7-nACh receptor expressed in Xenopus oocytes and in hippocampal interneurons are inhibited by capsaicin.
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http://dx.doi.org/10.1016/j.ejphar.2019.172411DOI Listing
August 2019

Is It Possible to Develop a Prediction Model for Lymphovascular Space Invasion in Endometrioid Endometrial Cancer?

Int J Gynecol Pathol 2020 May;39(3):213-220

Department of Gynecologic Oncology, Zekai Tahir Burak Women's Health Training and Research Hospital, Faculty of Medicine, University of Health Sciences.

Objective: The purpose of this retrospective study was to define a risk index that would serve as a surrogate marker of lymphovascular space invasion (LVSI) in women with endometrioid endometrial cancer (EC).

Materials And Methods: Final pathology reports of 498 women who underwent surgery with curative intent for endometrioid EC between January 2008 and June 2018 were retrospectively reviewed. Logistic regression was used to investigate clinicopathologic factors associated with positive LVSI status. Independent risk factors for LVSI were used to build a risk model and "risk of LVSI index" was defined as "tumor grade×primary tumor diameter×percentage of myometrium involved." The scores used in the "risk of LVSI index" were weighted according to the odds ratios assigned for each variable. The risk of LVSI index was noted for each patient. The diagnostic performance of the model was expressed as sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio.

Results: According to the "risk of LVSI index," presence of LVSI was correctly estimated in 89 of 104 LVSI-positive women at a cutoff of 161.0 (sensitivity 85.5%, specificity 79.4%, negative predictive value 95.4%, positive predictive value 52.3%, positive likelihood ratio 4.15, negative likelihood ratio 0.18). The area under curve of the receiver-operating characteristics was 0.90 (95% confidence interval, 0.87-0.93) at this cutoff.

Conclusions: It seems possible to predict the presence of LVSI in women with endometrioid EC when the "risk of LVSI index" is calculated. However, external validation of this model is warranted.
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http://dx.doi.org/10.1097/PGP.0000000000000596DOI Listing
May 2020

Menthol inhibits oxidative stress and inflammation in acetic acid-induced colitis in rat colonic mucosa.

Am J Transl Res 2018 15;10(12):4210-4222. Epub 2018 Dec 15.

Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, PO Box-17666, United Arab Emirates University Al Ain, Abu Dhabi, UAE.

Inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease are characterized by chronic inflammation of the gastrointestinal system. There is no permanent cure from IBD except constant medication or surgery to keep the disease in remission. In the present study, the effect of menthol, a major ingredient of peppermint has been investigated in acetic acid-induced colitis model in Wistar rats. Menthol (50 mg/kg/day) was orally administered for either 3 days before or 30 min after IBD induction for 7 days. The changes in body weight, macroscopic and microscopic analysis of the colon of rats of different experimental groups were observed on day 0, 2, 4 and 7. Acetic acid caused a significant reduction in mean body weight and induced macroscopic and microscopic ulceration along with a significant decline of glutathione (GSH) levels, an antioxidant substrate concomitant to increased malondialdehyde (MDA) level, a marker of lipid peroxidation and raised myeloperoxidase (MPO) activity, itself a marker for neutrophil activation. Acetic acid also induced the release of pro-inflammatory cytokines. Furthermore, acetic acid also raised the levels of calprotectin, a protein released by neutrophils under inflammatory conditions of the gastrointestinal tract. Treatment with menthol significantly improved IBD-induced reduction in mean body weight and mean macroscopic and microscopic ulcer scores and reduced activities of MPO and levels of MDA with concomitant increase in GSH level. Additionally, menthol treatment significantly reduced the levels of pro-inflammatory cytokines such as interleukin-1, interleukin-23 and tumor necrosis factor-α with no significant change in interleukin-6 levels. The data indicate that menthol improved body weight gain, mean macroscopic and microscopic ulcer scores, attenuated lipid peroxidation, oxidative stress and inflammation in the IBD rat mucosa.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325525PMC
December 2018

Pure large cell neuroendocrine carcinoma of ovary: A rare clinical entity.

J Exp Ther Oncol 2019 Jan;13(1):55-58

Zekai Tahir Burak Woman's Health Education And Research Hospital, Ankara, Turkey.

Objective: Large cell neuroendocrine carcinoma (LCNEC) of the ovary is a rare tumour. Its pure form without any associated surface epithelial stromal or germ cell component is more rarely seen. Its prognosis is generally very poor even when the diagnosis is made at an early stage. We report a case of pure large cell neuroendocrine tumour of ovary. The patient was a 73-year-old woman with symptom of pelvic pain. Ultrasonography detected an abdominal tumour larger than 10 cm. She underwent an exploratory laparotomy with resection of the pelvic mass. After the surgery six cycles of chemotherapy (Etoposide and Cisplatin) were administered to the woman. She is still healthy after the last chemotherapy. Due to the rarity of the disease, few number of reported cases and the lack of systematic population based studies or registry data, we reported this case.
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January 2019

Natural Negative Allosteric Modulators of 5-HT₃ Receptors.

Molecules 2018 Dec 3;23(12). Epub 2018 Dec 3.

Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Kuwait University, 13060 Kuwait.

Chemotherapy-induced nausea and vomiting (CINV) remain the most common and devastating side-effects associated with cancer chemotherapy. In recent decades, several lines of research emphasize the importance of 5-hydroxytryptamine3 (5-HT serotonin) receptors in the pathogenesis and treatment of CINV. 5-HT₃ receptors are members of ligand-gated ion channels that mediate the rapid and transient membrane-depolarizing effect of 5-HT in the central and peripheral nervous system. These receptors play important roles in nausea and vomiting, as well as regulation of peristalsis and pain transmission. The development of antagonists for 5-HT₃ receptor dramatically improved the treatment of CINV in cancer patients. In fact, the most common use of 5-HT₃ receptor antagonists to date is the treatment of nausea and vomiting. In recent years, there has been an increasing tendency to use natural plant products as important therapeutic entities in the treatment of various diseases. In this article, we examined the results of earlier studies on the actions of natural compounds on the functional properties of 5-HT₃ receptors. It is likely that these natural modulators of 5-HT₃ receptors can be employed as lead structures for the synthesis of therapeutic agents for treating CINV in future clinical studies.
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http://dx.doi.org/10.3390/molecules23123186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321066PMC
December 2018

Comparison of stage III mucinous and serous ovarian cancer: a case-control study.

J Ovarian Res 2018 Oct 30;11(1):91. Epub 2018 Oct 30.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Faculty of Medicine, BaskentUniversity, Ankara, Turkey.

Background: The purpose of this case-control study was to compare the prognoses of women with stage III mucinous ovarian carcinoma (MOC) who received maximal or optimal cytoreduction followed by paclitaxel plus carboplatin chemotherapy to those of women with stage III serous epithelial ovarian cancer (EOC) treated in the similar manner.

Methods: We performed a multicenter, retrospective review to identify patients with stage III MOC at seven gynecologic oncology departments in Turkey. Eighty-one women with MOC were included. Each case was matched to two women with stage III serous EOC in terms of age, tumor grade, substage of disease, and extent of residual disease. Survival estimates were measured using Kaplan-Meier plots. Variables predictive of outcome were analyzed using Cox regression models.

Results: With a median follow-up of 54 months, the median progression-free survival (PFS) for women with stage III MOC was 18.0 months (95% CI; 13.8-22.1, SE: 2.13) compared to 29.0 months (95% CI; 24.04-33.95, SE: 2.52) in the serous group (p = 0.19). The 5-year overall survival rate of the MOC group was significantly lower than that of the serous EOC group (44.9% vs. 66.3%, respectively; p < 0.001). For the entire cohort, presence of multiple peritoneal implants (Hazard ratio [HR] 2.39; 95% confidence interval [CI], 1.38-4.14, p = 0.002) and mucinous histology (HR 2.28; 95% CI, 1.53-3.40, p < 0.001) were identified as independent predictors of decreased OS.

Conclusion: Patients with MOC seem to be 2.3 times more likely to die of their tumors when compared to women with serous EOC.
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http://dx.doi.org/10.1186/s13048-018-0464-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208168PMC
October 2018

Impact of lymph node ratio on survival in stage IIIC endometrioid endometrial cancer: a Turkish Gynecologic Oncology Group study.

J Gynecol Oncol 2018 Jul 13;29(4):e48. Epub 2018 Mar 13.

Department of Gynecologic Oncology, Zekai Tahir Burak Women's Health Training and Research Hospital, Faculty of Medicine, University of Health Sciences, Ankara, Turkey.

Objective: The purpose of this study was to investigate the prognostic value of lymph node ratio (LNR) in women with stage IIIC endometrioid endometrial cancer (EC).

Methods: A multicenter, retrospective department database review was performed to identify patients with stage IIIC pure endometrioid EC at 6 gynecologic oncology centers in Turkey. A total of 207 women were included. LNR, defined as the percentage of positive lymph nodes (LNs) to total nodes recovered, was stratified into 2 groups: LNR1 (≤0.15), and LNR2 (>0.15). Kaplan-Meier method was used to generate survival data. Factors predictive of outcome were analyzed using Cox proportional hazards models.

Results: One hundred and one (48.8%) were classified as stage IIIC1 and 106 (51.2%) as stage IIIC2. The median age at diagnosis was 58 (range, 30-82) and the median duration of follow-up was 40 months (range, 1-228 months). There were 167 (80.7%) women with LNR ≤0.15, and 40 (19.3%) women with LNR >0.15. The 5-year progression-free survival (PFS) rates for LNR ≤0.15 and LNR >0.15 were 76.1%, and 58.5%, respectively (p=0.045). An increased LNR was associated with a decrease in 5-year overall survival (OS) from 87.0% for LNR ≤0.15 to 62.3% for LNR >0.15 (p=0.005). LNR >0.15 was found to be an independent prognostic factor for both PFS (hazard ratio [HR]=2.05; 95% confidence interval [CI]=1.07-3.93; p=0.03) and OS (HR=3.35; 95% CI=1.57-7.19; p=0.002).

Conclusion: LNR seems to be an independent prognostic factor for decreased PFS and OS in stage IIIC pure endometrioid EC.
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http://dx.doi.org/10.3802/jgo.2018.29.e48DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5981100PMC
July 2018

Prognostic factors and patterns of recurrence in lymphovascular space invasion positive women with stage IIIC endometriod endometrial cancer.

J Obstet Gynaecol Res 2018 Jun 8;44(6):1140-1149. Epub 2018 Mar 8.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Faculty of Medicine, Baskent University, Ankara, Turkey.

Aim: The purpose of this study was to determine the prognostic factors and patterns of failure in lymphovascular space invasion (LVSI)-positive women with stage IIIC endometrioid endometrial cancer (EC).

Methods: A multicenter, retrospective, department database review was performed to identify LVSI-positive patients with stage IIIC endometrioid EC at five gynecological oncology centers in Turkey. Demographic, clinicopathological and survival data were collected.

Results: We identified 172 LVSI-positive women with stage IIIC endometrioid EC during the study period; 75 (43.6%) were classified as Stage IIIC and 97 (56.4%) as Stage IIIC . The median age at diagnosis was 59 years, and the median duration of follow up was 34.5 months. The total number of recurrences was 46 (26.7%). We observed 14 (8.1%) locoregional recurrences, 12 (7.0%) retroperitoneal failures and 20 (11.6%) distant relapses. For the entire study cohort, 5-year progression-free survival (PFS) was 67.4%, while the 5-year overall survival (OS) rate was 75.1%. Grade 3 histology (hazard ratio [HR] 2.62, 95% confidence interval [CI] 1.34-5.12; P = 0.005), cervical stromal invasion (HR 2.33, 95% CI 1.09-4.99; P = 0.028) and myometrial invasion (MMI) ≥50% (HR 4.0, 95% CI 1.16-13.69; P = 0.028) were found to be independent prognostic factors for decreased OS.

Conclusion: Uterine factors such as grade 3 disease, cervical stromal invasion and deep MMI seem to be independently associated with decreased OS in LVSI-positive women with stage IIIC endometrioid EC. The high distant recurrence rate in this subgroup of patients warrants further studies in order to identify the most effective treatment strategy for those patients.
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http://dx.doi.org/10.1111/jog.13615DOI Listing
June 2018

Cell shortening and calcium dynamics in epicardial and endocardial myocytes from the left ventricle of Goto-Kakizaki type 2 diabetic rats.

Exp Physiol 2018 04 25;103(4):502-511. Epub 2018 Feb 25.

Department of Physiology, College of Medicine & Health Sciences, UAE University, Al Ain, United Arab Emirates.

New Findings: What is the central question of this study? To investigate haemodynamic dysfunction in the type 2 diabetic Goto-Kakizaki (GK) rat, we measured shortening and Ca transport in ventricular myocytes from epicardial (EPI) and endocardial (ENDO) regions. What is the main finding and its importance? EPI and ENDO GK myocytes displayed similar hypertrophy. Time to peak (TPK) and time to half (THALF) relaxation were prolonged in EPI GK myocytes. TPK Ca transient was prolonged and THALF decay of the Ca transient was shortened in EPI GK myocytes. Amplitude of shortening, Ca transient and sarcoplasmic reticulum Ca were unaltered in EPI and ENDO myocytes from Goto-Kakizaki compared with control rats. We demostrated regional differences in shortening and Ca transport in Goto-Kakizaki rats.

Abstract: Diabetic cardiomyopathy is considered to be one of the major diabetes-associated complications, and the pathogenesis of cardiac dysfunction is not well understood. The electromechanical properties of cardiac myocytes vary across the walls of the chambers. The aim of this study was to investigate shortening and Ca transport in epicardial (EPI) and endocardial (ENDO) left ventricular myocytes in the Goto-Kakizaki (GK) type 2 diabetic rat heart. Shortening and intracellular Ca transients were measured by video edge detection and fluorescence photometry. Myocyte surface area was increased in EPI-GK and ENDO-GK compared with control EPI-CON and ENDO-CON myocytes. Time to peak shortening was prolonged in EPI-GK compared with EPI-CON and in ENDO-CON compared with EPI-CON myocytes. Time to half-relaxation of shortening and time to peak Ca transient were prolonged in EPI-GK compared with EPI-CON myocytes. Time to half-decay of the Ca transient was prolonged in EPI-CON compared with EPI-GK and in EPI-CON compared with ENDO-CON myocytes. The amplitude of shortening and the Ca transient were unaltered in EPI-GK and ENDO-GK compared with their respective controls. Sarcoplasmic reticulum Ca and myofilament sensitivity to Ca were unaltered in EPI-GK and ENDO-GK compared with their respective controls. Regional differences in Ca signalling in healthy and diabetic myocytes might account for variation in the dynamics of myocyte shortening. Further studies will be required to clarify the mechanisms underlying regional differences in the time course of shortening and the Ca transient in EPI and ENDO myocytes from diabetic and control hearts.
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http://dx.doi.org/10.1113/EP086542DOI Listing
April 2018

Curcumin potentiates the function of human α-nicotinic acetylcholine receptors expressed in SH-EP1 cells.

Neurochem Int 2018 03 16;114:80-84. Epub 2018 Jan 16.

Department of Pharmacology, College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates; Department of Basic Medical Sciences, College of Medicine, Qatar University, Doha, Qatar. Electronic address:

Effects of curcumin, a biologically active ingredient of turmeric, were tested on the Ca transients induced by the activation of α subunit of the human nicotinic acetylcholine (α nACh) receptor expressed in SH-EP1 cells. Curcumin caused a significant potentiation of choline (1 mM)-induced Ca transients with an EC value of 133 nM. The potentiating effect of curcumin was not observed in Ca transients induced by high K (60 mM) containing solutions or activation of αβ nACh receptors and the extent of curcumin potentiation was not altered in the presence of Ca channel antagonists nifedipine (1 μM), verapamil (1 μM), ω-conotoxin (1 μM), and bepridil (10 μM). Noticeably the effect of curcumin was not observed when curcumin and choline were co-applied without curcumin pre-incubation. The effect of curcumin on choline-induced Ca transients was not reversed by pre-incubation with inhibitors of protein C, A, and CaM kinases. Metabolites of curcumin such as tetrahydrocurcumin, demethylcurcumin, and didemethylcurcumin also caused potentiation of choline-induced Ca transients. Notably, specific binding of [I]-bungarotoxin was not altered in the presence of curcumin. Collectively, our results indicate that curcumin allosterically potentiate the function of the α7-nACh receptor expressed in SH-EP1 cells.
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http://dx.doi.org/10.1016/j.neuint.2017.12.010DOI Listing
March 2018

Curcumin Acts as a Positive Allosteric Modulator of -Nicotinic Acetylcholine Receptors and Reverses Nociception in Mouse Models of Inflammatory Pain.

J Pharmacol Exp Ther 2018 04 16;365(1):190-200. Epub 2018 Jan 16.

Departments of Pharmacology (E.G.E.N., H.A.S., M.O.) and Physiology (F.C.H.), College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates; Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia (D.B., W.T., A.B., Y.A., I.M.D.); Experimental Animals Breeding and Research Center, Faculty of Medicine, Uludag University, Bursa, Turkey (D.B.); Department of Biological Sciences, Schmid College of Science and Technology, Chapman University, One University Drive, Orange, California (K.-H.S.Y.); and Department of Basic Medical Sciences, College of Medicine, Qatar University, Doha, Qatar (M.O.)

Effects of curcumin, a major ingredient of turmeric, were tested on the function of the -subunit of the human nicotinic acetylcholine (-nACh) receptor expressed in oocytes and on nociception in mouse models of tonic and visceral pain. Curcumin caused a significant potentiation of currents induced by acetylcholine (ACh; 100 M) with an EC value of 0.2 M. The effect of curcumin was not dependent on the activation of G-proteins and protein kinases and did not involve Ca-dependent Cl channels expressed endogenously in oocytes. Importantly, the extent of curcumin potentiation was enhanced significantly by decreasing ACh concentrations. Curcumin did not alter specific binding of [I]-bungarotoxin. In addition, curcumin attenuated nociceptive behavior in both tonic and visceral pain models without affecting motor and locomotor activity and without producing tolerance. Pharmacological and genetic approaches revealed that the antinociceptive effect of curcumin was mediated by -nACh receptors. Curcumin potentiated the antinociceptive effects of the -nACh receptor agonist -(3R)-1-azabicyclo[2.2.2]oct-3-yl-4-chlorobenzamide (PNU282987). Collectively, our results indicate that curcumin is a positive allosteric modulator of -nACh receptor and reverses nociception in mouse models of tonic and visceral pain.
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http://dx.doi.org/10.1124/jpet.117.245068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947331PMC
April 2018

Voltage dependence of the Ca transient in endocardial and epicardial myocytes from the left ventricle of Goto-Kakizaki type 2 diabetic rats.

Mol Cell Biochem 2018 Sep 9;446(1-2):25-33. Epub 2018 Jan 9.

Department of Physiology, College of Medicine & Health Sciences, UAE University, P.O. Box 17666, Al Ain, UAE.

Diabetes mellitus is a major global health disorder and, currently, over 450 million people have diabetes with 90% suffering from type 2 diabetes. Left untreated, diabetes may lead to cardiovascular diseases which are a leading cause of death in diabetic patients. Calcium is the trigger and regulator of cardiac muscle contraction and derangement in cellular Ca homeostasis, which can result in heart failure and sudden cardiac death. It is of paramount importance to investigate the regional involvement of Ca in diabetes-induced cardiomyopathy. Therefore, the aim of this study was to investigate the voltage dependence of the Ca transients in endocardial (ENDO) and epicardial (EPI) myocytes from the left ventricle of the Goto-Kakizaki (GK) rats, an experimental model of type 2 diabetes mellitus. Simultaneous measurement of L-type Ca currents and Ca transients was performed by whole-cell patch clamp techniques. GK rats displayed significantly increased heart weight, heart weight/body weight ratio, and non-fasting and fasting blood glucose compared to controls (CON). Although the voltage dependence of L-type Ca current was unaltered, the voltage dependence of the Ca transients was reduced to similar extents in EPI-GK and ENDO-GK compared to EPI-CON and ENDO-CON myocytes. TPK L-type Ca current and Ca transient were unaltered. THALF decay of L-type Ca current was unaltered; however, THALF decay of the Ca transient was shortened in ENDO and EPI myocytes from GK compared to CON rat hearts. In conclusion, the amplitude of L-type Ca current was unaltered; however, the voltage dependence of the Ca transient was reduced to similar extents in EPI and ENDO myocytes from GK rats compared to their respective controls, suggesting the possibility of dysfunctional sarcoplasmic reticulum Ca transport in the GK diabetic rat hearts.
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http://dx.doi.org/10.1007/s11010-018-3269-0DOI Listing
September 2018

Vanishing endometrial carcinoma in hysterectomy specimens: probable implications for fertility sparing management

Turk J Med Sci 2017 Dec 19;47(6):1744-1750. Epub 2017 Dec 19.

Background/aim: The vanishing cancer phenomenon was first reported in radical prostatectomy specimens in the absence of neo-adjuvant treatment. Reported cases are mostly well-differentiated and low-volume tumors. A similar entity was described for hysterectomy specimens of patients with biopsy proven endometrial cancer (EC). In this study, we discuss the probable reasons for vanishing EC and long-term follow-up results of EC patients without residual tumors in hysterectomy specimens. Materials and methods: This study was carried at two institutions in Ankara, Turkey, in a retrospective design. The computerized databases of both institutions were searched for endometrioid type EC patients whose final pathological specimens failed to show any residual tumor. Results: We evaluated 38 endometrial biopsy confirmed EC patients with no residual tumor detected in the hysterectomy specimens among a total of 224 women (17%) with the disease confined to the endometrium. During the follow-up period, no recurrences were noted among the patients. Conclusion: It can be suggested that premenopausal women with FIGO grade 1 endometrioid type EC with MRI proven "absent myometrial invasion" would have a significant probability of having no residual tumor after endometrial biopsy without any further medical treatment.
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http://dx.doi.org/10.3906/sag-1607-93DOI Listing
December 2017

Cellular and Molecular Targets of Menthol Actions.

Front Pharmacol 2017 18;8:472. Epub 2017 Jul 18.

Department of Health Sciences, College of Natural and Health Sciences, Zayed UniversityAbu Dhabi, United Arab Emirates.

Menthol belongs to monoterpene class of a structurally diverse group of phytochemicals found in plant-derived essential oils. Menthol is widely used in pharmaceuticals, confectionary, oral hygiene products, pesticides, cosmetics, and as a flavoring agent. In addition, menthol is known to have antioxidant, anti-inflammatory, and analgesic effects. Recently, there has been renewed awareness in comprehending the biological and pharmacological effects of menthol. TRP channels have been demonstrated to mediate the cooling actions of menthol. There has been new evidence demonstrating that menthol can significantly influence the functional characteristics of a number of different kinds of ligand and voltage-gated ion channels, indicating that at least some of the biological and pharmacological effects of menthol can be mediated by alterations in cellular excitability. In this article, we examine the results of earlier studies on the actions of menthol with voltage and ligand-gated ion channels.
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http://dx.doi.org/10.3389/fphar.2017.00472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513973PMC
July 2017