Key point• Fibroblasts play a major role in heart physiology. In pathological conditions, they can lead to cardiac fibrosis when they differentiate into myofibroblasts.• This differentiated status is associated with changes in expression profile leading to neo-expression of proteins such as ionic channels.• The present study investigates electrophysiological changes associated with fibroblast differentiation focusing on voltage-gated sodium channels in human atrial fibroblasts and myofibroblasts.• We show that human atrial fibroblast differentiation in myofibroblasts is associated with de novo expression of voltage gated sodium current. Multiple arguments support that this current is predominantly supported by the Na v 1.5 α-subunit which may generate a persistent sodium entry into myofibroblasts.• Our data revealed that Na v 1.5 α-subunit expression is not restricted to cardiac myocytes within the atrium. Since fibrosis is one of the fundamental mechanisms implicated in atrial fibrillation, it is of great interest to investigate how this channel could influence myofibroblasts function.Abstract Fibroblasts play a major role in heart physiology. They are at the origin of the extracellular matrix renewal and production of various paracrine and autocrine factors. In pathological conditions, fibroblasts proliferate, migrate and differentiate into myofibroblasts leading to cardiac fibrosis. This differentiated status is associated with changes in expression profile leading to neo-expression of proteins such as ionic channels. The present study investigates further electrophysiological changes associated with fibroblast differentiation focusing on the activity of voltage-gated sodium channels in human atrial fibroblasts and myofibroblasts. Using the patch clamp technique we show that human atrial myofibroblasts display a fast inward voltage gated sodium current with a density of 13.28 ± 2.88 pA pF −1 whereas no current was detectable in non-differentiated fibroblasts. Quantitative RT-PCR reveals a large amount of transcripts encoding the Na v 1.5 α-subunit with a fourfold increased expression level in myofibroblasts when compared to fibroblasts. Accordingly, half of the current was blocked by 1 μM of tetrodotoxin and immunocytochemistry experiments reveal the presence of Na v 1.5 proteins. Overall, this current exhibits similar biophysical characteristics to sodium currents found in cardiac myocytes except for the window current that is enlarged for potentials between −100 and −20 mV. Since fibrosis is one of the fundamental mechanisms implicated in atrial fibrillation, it is of great interest to investigate how this current could influence myofibroblast properties. Moreover, since several Na v 1.5 mutations are related to cardiac pathologies, this study offers a new avenue on the fibroblasts involvement of these mutations.
The cardiovascular effects of mild and overt thyroid disease include a vast array of pathological changes. As well, thyroid replacement therapy has been suggested for preserving cardiac function. However, the influence of thyroid hormones on cardiac remodeling has not been thoroughly investigated at the molecular and cellular levels. The purpose of this paper is to study the effect of hypothyroidism and thyroid replacement therapy on cardiac alterations. Thirty Wistar rats were divided into 2 groups: a control (n = 10) group and a group treated with 6-propyl-2-thiouracil (PTU) (n = 20) to induce hypothyroidism. Ten of the 20 rats in the PTU group were then treated with L-thyroxine to quickly re-establish euthyroidism. The serum levels of inflammatory markers, such as C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL6) and pro-fibrotic transforming growth factor beta 1 (TGF-β1), were significantly increased in hypothyroid rats; elevations in cardiac stress markers, brain natriuretic peptide (BNP) and cardiac troponin T (cTnT) were also noted. The expressions of cardiac remodeling genes were induced in hypothyroid rats in parallel with the development of fibrosis, and a decline in cardiac function with chamber dilation was measured by echocardiography. Rapidly reversing the hypothyroidism and restoring the euthyroid state improved cardiac function with a decrease in the levels of cardiac remodeling markers. However, this change further increased the levels of inflammatory and fibrotic markers in the plasma and heart and led to myocardial cellular infiltration. In conclusion, we showed that hypothyroidism is related to cardiac function decline, fibrosis and inflammation; most importantly, the rapid correction of hypothyroidism led to cardiac injuries. Our results might offer new insights for the management of hypothyroidism-induced heart disease.
Purpose To study the distribution of breast mammogram density in Lebanese women and correlate it with breast cancer (BC) incidence. Methods Data from 1,049 women who had screening or diagnostic mammography were retrospectively reviewed. Age, menopausal status, contraceptives or hormonal replacement therapy (HRT), parity, breastfeeding, history of BC, breast mammogram density, and final BI-RADS assessment were collected. Breast density was analyzed in each age category and compared according to factors that could influence breast density and BC incidence. Results 120 (11.4%) patients had BC personal history with radiation and/or chemotherapy; 66 patients were postmenopausal under HRT. Mean age was 52.58 ± 11.90 years. 76.4% of the patients (30–39 years) had dense breasts. Parity, age, and menopausal status were correlated to breast density whereas breastfeeding and personal/family history of BC and HRT were not. In multivariate analysis, it was shown that the risk of breast cancer significantly increases 3.3% with age (P = 0.005), 2.5 times in case of menopause (P = 0.004), and 1.4 times when breast density increases (P = 0.014). Conclusion Breast density distribution in Lebanon is similar to the western society. Similarly to other studies, it was shown that high breast density was statistically related to breast cancer, especially in older and menopausal women.
Backgroundp53 is a tumor suppressor and key regulator of glycolysis in cancer cells, however highly mutated in tumors. In ovarian cancer, studies concerning p53 mutations focus on the DNA binding domain since the majority of hotspot mutations affects this region. Yet, mutations in other regions such as the proline rich domain may also affect the protein’s expression and activity. The aim of this study is to investigate the effect of various positions of mutations in TP53 gene on glycolysis, apoptosis and transcription of p53 target genes.MethodsMutations frequency and their effect on p53 expression were assessed by PCR-SSCP, sequencing and immunohistochemistry on 30 ovarian cancer biopsies. Six tumors were cultured, as well as SK-OV-3, OVCAR-3 and Igrov-1. SK-OV-3 cells were transfected with 2 TP53 mutants. p53 transcriptional activity was assayed by qPCR, apoptosis by flow cytometry and glycolysis by glucose and lactate measurements, with quantification of glycolytic enzymes expression.ResultsOur results showed a high frequency of the P72R mutant, associated with p53 overexpression in the ovarian biopsies. However, P72R mutant cells showed similar apoptosis and glycolysis as WT cells. DNA binding domain mutations decreased the transcriptional activity of the protein and increased glucose consumption and lactate production.ConclusionDespite the overexpression of the P72R mutated protein in the biopsies, it showed a similar apoptotic activity and glucose regulation ability as WT p53. Knowing that p53 expression status is used for chemotherapeutic approaches and prognosis in ovarian cancer, the results obtained highlight the importance of locating TP53 mutations.Electronic supplementary materialThe online version of this article (10.1186/s12935-018-0514-2) contains supplementary material, which is available to authorized users.
Aim: To describe the activity in the ‘breast unit’ at the department of radiology during the coronavirus disease 19 lockdown in a university hospital treating coronovirus disease 19 patients in a Middle-Eastern developing country. Materials: This was a retrospective study conducted from March 9 until 11 May 2020, in the breast unit at the department of radiology of a central university hospital in a Middle-Eastern developing country. Data were collected from 205 patients visiting the breast unit during the lockdown period and compared with the activity in the same period in the previous year. Results: Reduction of the breast unit activity was estimated at 73%. In addition, 153 mammograms, 205 ultrasounds, and 16 breast MRIs were done. Indications for mammogram were screening (41.5%), follow-up (22%), clinical symptoms (20%) and breast cancer surveillance (16.5%). MRI was performed mostly for preoperative surgical management. The rate of positive biopsies was 41%. All staff members and patients have accommodated to new adjustments. Conclusion: Activity in the breast unit dropped during the lockdown period. Staff should continue to seek their own and their patient’s safety without diminishing the quality of healthcare.
BackgroundClinical trials conducted in Lebanon are increasing. However, little is known about the performance of research ethics committees (RECs) in charge of reviewing the research protocols. This study aimed to assess the level of adherence to the ethics surrounding the conduct of clinical trials and perceptions of team members regarding roles of the RECs during the conduct of clinical trials in Lebanon. The research question was: Are RECs adherent to the ethics surrounding the conduct of clinical trials (chapters II and IV in ‘Standards and Operational Guidance for Ethics Review of Health-related Research with Human Participants’ in Lebanon?’MethodsThis was a quantitative and descriptive questionnaire-based study conducted among RECs of university hospitals in Lebanon. The questionnaire had to be completed online and included general questions in addition to items reflecting the different aspects of a REC performance and effectiveness. All the questionnaire was assigned a total score of 175 points. General information and questions assigned point values/scores were analysed using descriptive statistics: frequency and percentage, mean score ± standard deviation.ResultsTen RECs participated in the study (52 persons: four chairs, one vice-president, 47 ordinary members). Forty-seven (90.4%) had previous experience with clinical research and 30 (57.7%) had a diploma or had done a training in research ethics. Forty-one percent confirmed that they were required to have a training in research ethics. All RECs had a policy for disclosing and managing potential conflicts of interest for its members, but 71.8% of participants reported the existence of such a policy for researchers. Thirty-three point three percent reported that the RECs had an anti-bribery policy. The questionnaire mean score was 129.6 ± 22.3/175 points reflecting thus an excellent adherence to international standards.ConclusionInadequate training of REC members and the lack of anti-bribery policies should be resolved to improve their performance.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-017-2397-2) contains supplementary material, which is available to authorized users.
Atrial natriuretic peptide antifibrotic properties are mainly described in cardiac myocytes or in induced cardiac myofibroblasts (Angiotensin II or TGF-β induced differentiation).In the present work, we investigate the effects of ANP/NPRA/cGMP system in modulating rat cardiac fibroblasts function. Cardiac fibroblasts were isolated from adult Wistar male rats and cultured in the presence of serum in order to induce fibroblasts differentiation. Cultures were then treated with ANP (1 µM), 8-Br-cGMP (100 µM) or IBMX (100 µM), a non-specific phosphodiesterases inhibitor. ANP significantly decreased proliferation rate and collagen secretion. Its effect was mimicked by the cGMP analog, while combining ANP with 8-Br-cGMP did not lead to additional effects. Moreover intracellular cGMP levels were elevated when cells were incubated with ANP confirming that ANP intracellular pathway is mediated by cGMP. Additionally, immunoblotting and immunofluorescence were used to confirm the presence of guanylyl cyclase specific natriuretic peptide receptors A and B. Finally we scanned specific cGMP dependent PDEs via RT-qPCR, and noticed that inhibiting all PDEs led to an important decrease in proliferation rate. Effect of ANP became more prominent after 10 culture days, confirming the importance of ANP in fibroblasts to myofibroblasts differentiation. Uncovering cellular aspects of ANP/NPRA/cGMP signaling system provided more elements to help understand cardiac fibrotic process.
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