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1.
Steroids ; 199: 109299, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37619674

ABSTRACT

The kidney is considered to be one of the most estrogen-responsive, not reproductive organs in the body. Different estrogen receptors (ERs) show sex-specific differences in expression along the nephron and the expression of different ERs also changes with the estrous cycle of the female. The kidney becomes more estrogen-sensitive when estradiol levels are at their highest, just prior to ovulation. This review discusses the different mechanisms by which estradiol can modify the salt and water conservation processes of the kidney through transporter regulation to support the fluid and electrolyte homeostasis changes required in mammalian reproduction. The kidney plays a critical role in regulating blood pressure by controlling fluid homeostasis, and so protects the female cardiovascular system from dramatic changes in whole body fluid volume that occur at critical points in the human menstrual cycle and in pregnancy. This is augmented by the direct actions of estradiol on the cardiovascular system, for example through the direct stimulation of endothelial nitric oxide (NO) synthase, which releases NO to promote vasodilation. This and other mechanisms are less evident in the male and give women a degree of cardiovascular protection up until menopause, when the risks of cardiovascular disease and chronic kidney disease begin to match the risks experienced by males.

2.
Stud Health Technol Inform ; 294: 614-618, 2022 May 25.
Article in English | MEDLINE | ID: mdl-35612162

ABSTRACT

Many patients with Type 2 Diabetes (T2D) have difficulty in controlling their disease despite wide-spread availability of high-quality guidelines, T2D education programs and primary care follow-up programs. Current diabetes education and treatment programs translate knowledge from bench to bedside well, but underperform on the 'last-mile' of converting that knowledge into action (KTA). Two innovations to the last-mile problem in management of patients with T2D are introduced. 1) Design of a platform for peer-to-peer groups where patients can solve KTA problems together in a structured and psychologically safe environment using all the elements of the Action Cycle phase of the KTA framework. The platform uses Self-Determination Theory as the behavior change theory. 2) A novel patient segmentation method to enable the formation of groups of patients who have similar behavioral characteristics and therefore who are more likely to find common cause in the fight against diabetes.


Subject(s)
Diabetes Mellitus, Type 2 , Diabetes Mellitus, Type 2/therapy , Health Education , Humans , Knowledge , Peer Group
3.
J Community Health ; 46(4): 645-652, 2021 08.
Article in English | MEDLINE | ID: mdl-32778989

ABSTRACT

The choice to take-up specific complimentary and alternative medicine (CAM) modalities is influenced by many factors including cultural background, experience and peer-participation. In this study we investigated the beliefs and attitudes that contributed to CAM choices in a non-urban Malaysian population (N = 700). We found significant differences in the beliefs held by men and women in this population. Specifically, women believed more strongly than men that CAM providers offered healthy lifestyle advice (p = 0.042) and that those who were averse to discomfort from conventional treatments were more likely to take up CAM (p = 0.016). In addition, those individuals who chose to use CAM more strongly believed that CAM products were more healthy than conventional treatments (p = 0.002), that their effects were well understood (p = 0.002) and that CAM products worked with the body (p = 0.017). The data obtained in this study emphasize the lessons that can be learned by conventional healthcare providers in communicating the benefits of treatments to their patients. CAM users also believed that CAM products never caused harm (p = 0.007), which is a concern given that the modes of action of some CAM modalities and their interaction with prescribed treatments are not always well understood.


Subject(s)
Complementary Therapies , Health Knowledge, Attitudes, Practice , Female , Health Personnel , Humans , Male , Peer Group , Sex Factors
4.
J Community Health ; 46(3): 515-521, 2021 06.
Article in English | MEDLINE | ID: mdl-32710232

ABSTRACT

Complementary and alternative medicine (CAM) therapies have been an integral part of Malaysia culture for many centuries. In recent years influences from other parts of the world have gained a foot-hold in Malaysian popular culture. We investigated the engagement with CAM in a non-urban, Malaysian population. We investigated the association of CAM use with cultural influence, perceived health status, gender and age. We recruited 700 adult participants to this study across three sites in central Malaysia. We found massage, Vitamin supplements, Herbal medicine and traditional Chinese medicine to be the most popular CAM modalities with participation at 67.7%, 55.7%, 55.5% and 26.3% respectively. CAM use was equally high at 67% among those people who claimed a predominantly Malay or Chinese cultural influence. The use of vitamins and participation in yoga were at higher prevalence among female participants compared to males. There was no gender difference for other CAM modalities. There were differences between age groups for most CAM modalities, and those over 50 years tended to be the highest frequency users for most modalities. There is a high rate of CAM use in non-urban Malaysia with younger people being more engaged with less traditional modalities such as aromatherapy, yoga and music therapy.


Subject(s)
Complementary Therapies , Adult , Cross-Sectional Studies , Female , Herbal Medicine , Humans , Male , Middle Aged , Phytotherapy , Prevalence
5.
J Steroid Biochem Mol Biol ; 208: 105786, 2021 04.
Article in English | MEDLINE | ID: mdl-33189851

ABSTRACT

Lung cancer is increasing in incidence particularly among women, associated with a global change in smoking habits. Steroid hormones, particularly oestrogen exert an influence on tumour progression in tissues where their target receptor is expressed. Oestrogen receptor, particularly ERß is highly expressed in the lung and becomes more highly expressed in lung carcinogenesis. Genes involved in the process of lung carcinoma progression and signalling cascades linked to invasion and angiogenesis are modulated by oestrogen receptors. This review intends to collate recently published evidence identifying a role for oestrogen in the initiation and progression of lung carcinoma and how these two processes are differentially affected by circulating oestrogens both in women and in men. Circulating oestrogens may be a significant risk factor in women's susceptibility to lung carcinoma and also provide an additional approach for more targeted therapy.


Subject(s)
Carcinoma/blood , Estrogen Receptor alpha/blood , Estrogen Receptor beta/blood , Estrogens/blood , Lung Neoplasms/blood , Carcinoma/epidemiology , Carcinoma/pathology , Female , Humans , Lung/pathology , Lung Neoplasms/epidemiology , Lung Neoplasms/pathology , Male , Risk Factors , Sex Characteristics , Signal Transduction/genetics , Smoking/adverse effects
6.
Sci Rep ; 10(1): 819, 2020 01 21.
Article in English | MEDLINE | ID: mdl-31964900

ABSTRACT

Misuse of antibiotics in the clinical and agricultural sectors has caused the emergence of multidrug-resistant (MDR) Klebsiella pneumoniae which contributes a threat to human health. In this study, we assessed the feasibility of lavender essential oil (LVO) as an antimicrobial agent in combinatory therapy with meropenem in suppressing the growth of carbapenemase-producing K. pneumoniae (KPC-KP). Synergistic interactions between LVO and meropenem were detected, which significantly reduce the inhibitory concentration of both LVO and meropenem by 15 and 4-fold respectively. Comparative proteomic profiling identified a disruption in the bacterial membrane via oxidative stress that was indicated by loss of membrane and cytoplasmic proteins and the upregulation of oxidative regulators. As a proof of concept, zeta potential measurements showed a change in cell surface charge while outer membrane permeability measurement indicated an increase in membrane permeability following exposure to LVO. This was indicative of a disrupted outer membrane. Ethidium bromide influx/efflux assays demonstrated no significant efflux pump inhibition by LVO, and scanning electron microscopy revealed irregularities on the cell surface after exposure to LVO. Oxidative stress was also detected with increased level of ROS and lipid peroxidation in LVO-treated cells. In conclusion, our data suggest that LVO induced oxidative stress in K. pneumoniae which oxidizes the outer membrane, enabling the influx of generated ROS, LVO and meropenem into the bacterial cells, causing damage to the cells and eventually death.


Subject(s)
Anti-Bacterial Agents , Cell Membrane Permeability/drug effects , Klebsiella pneumoniae/drug effects , Oils, Volatile/pharmacology , Oxidative Stress/drug effects , Plant Oils/pharmacology , Bacterial Proteins/metabolism , Drug Resistance, Bacterial , Drug Synergism , Feasibility Studies , Klebsiella pneumoniae/cytology , Klebsiella pneumoniae/growth & development , Klebsiella pneumoniae/metabolism , Lavandula , Meropenem/pharmacology , Microbial Sensitivity Tests , Reactive Oxygen Species/metabolism , beta-Lactamases/metabolism
7.
Curr Drug Discov Technol ; 17(4): 430-447, 2020.
Article in English | MEDLINE | ID: mdl-30836923

ABSTRACT

Antimicrobials are useful compounds intended to eradicate or stop the growth of harmful microorganisms. The sustained increase in the rates of antimicrobial resistance (AMR) worldwide is worrying and poses a major public health threat. The development of new antimicrobial agents is one of the critical approaches to overcome AMR. However, in the race towards developing alternative approaches to combat AMR, it appears that the scientific community is falling behind when pitched against the evolutionary capacity of multi-drug resistant (MDR) bacteria. Although the "pioneering strategy" of discovering completely new drugs is a rational approach, the time and effort taken are considerable, the process of drug development could instead be expedited if efforts were concentrated on enhancing the efficacy of existing antimicrobials through: combination therapies; bacteriophage therapy; antimicrobial adjuvants therapy or the application of nanotechnology. This review will briefly detail the causes and mechanisms of AMR as background, and then provide insights into a novel, future emerging or evolving strategies that are currently being evaluated and which may be developed in the future to tackle the progression of AMR.


Subject(s)
Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Bacterial Infections/therapy , Drug Resistance, Multiple, Bacterial/physiology , Phage Therapy/methods , Anti-Bacterial Agents/therapeutic use , Bacteria/virology , Bacterial Infections/microbiology , Bacterial Proteins/antagonists & inhibitors , Bacterial Proteins/metabolism , Biofilms/drug effects , Combined Modality Therapy/methods , Drug Carriers/chemistry , Drug Discovery , Drug Resistance, Multiple, Bacterial/drug effects , Drug Therapy, Combination/methods , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Humans , Nanoparticles/chemistry
8.
Med Teach ; 42(1): 36-38, 2020 01.
Article in English | MEDLINE | ID: mdl-31411913

ABSTRACT

The Royal College of Surgeons in Ireland (RCSI) was among the first medical institutions to establish a global education community which now provides high-quality transnational health professions education aligned across three locations: Europe, the Middle East and South-East Asia. The successful implementation of a shared modularized curriculum in this context can be complex and challenging. Here we describe our insights, gained from a decade of working together as shared module Academic Leads to deliver a system-based medical module to an international student cohort. The themes covered are some of the areas where we consider our joint deliberations have led to improved outcomes for the delivery and assessment of the module, which may be helpful to academic staff embarking on similar module sharing experiences.


Subject(s)
Education, Medical, Undergraduate/methods , International Cooperation , Asia , Curriculum , Education, Medical, Undergraduate/standards , Humans , Ireland , Malaysia , Middle East , Students, Medical
9.
Steroids ; 155: 108553, 2020 03.
Article in English | MEDLINE | ID: mdl-31836481

ABSTRACT

Protein kinase D2 (PKD2) is a serine/threonine protein kinase which plays an important role in vesicle fission at the trans-Golgi network (TGN) to coordinate subcellular trafficking with gene expression. We found that in the rat kidney, PKD2 is specifically expressed in collecting duct principal cells predominantly at the apical membrane and with lower basal expression in cytosolic compartments. When rats were maintained on a Na+ depleted diet (<0.87 mmol Na+/kg) to increase plasma aldosterone levels, PKD2 became internalized to a cytoplasmic compartment. Treatment of murine M1 cortical collecting duct (M1-CCD) cells with aldosterone (10 nM) promoted PKD2 co-localization with the trans-Golgi network within 30 min. PKD2 underwent autophosphorylation at Ser876 within 10 min of aldosterone treatment and remained phosphorylated (active) for at least 24 h. A stable PKD2 shRNA knock-down (PKD2 KD) M1-CCD cell line was developed to study the role of PKD2 in epithelial Na+ channel (ENaC) trafficking and transepithelial Na+ transport (SCC) in epithelial monolayers grown in Ussing chambers. The PKD2 KD cells developed transepithelial resistance with kinetics equivalent to wild-type cells, however the transepithelial voltage and Na+ current were significantly elevated in PKD2 knock-down CCD epithelia. The higher basal SCC was due to increased ENaC activity. Aldosterone treatment for 24 h resulted in a decline in ENaC activity in the PKD2 KD cells as opposed to the increase observed in the wild-type cells. The paradoxical inhibition of SCC by aldosterone in PKD2 KD epithelium was attributed to a reduction in ENaC current and lower membrane abundance of ENaC, demonstrating that PKD2 plays a critical tonic role in ENaC trafficking and channel subunit stability. The rapid activation of PKD2 by aldosterone is synergistic with the transcriptional activity of MR and contributes to increased ENaC activity.


Subject(s)
Aldosterone/pharmacology , Epithelial Sodium Channels/metabolism , Kidney Tubules, Collecting/drug effects , Protein Kinases/metabolism , Aldosterone/blood , Animals , Cells, Cultured , Disease Models, Animal , Kidney Tubules, Collecting/metabolism , Male , Mice , Mice, Transgenic , Phosphorylation , Protein Kinase D2 , Protein Kinase Inhibitors/pharmacology , RNA, Small Interfering/pharmacology , Rats , Rats, Sprague-Dawley
10.
Cancer Invest ; 37(8): 393-414, 2019.
Article in English | MEDLINE | ID: mdl-31502477

ABSTRACT

Colorectal cancer (CRC) is one of the most common malignancies. In recent decades, early diagnosis and conventional therapies have resulted in a significant reduction in mortality. However, late stage metastatic disease still has very limited effective treatment options. There is a growing interest in using viruses to help target therapies to tumour sites. In recent years the evolution of immunotherapy has emphasised the importance of directing the immune system to eliminate tumour cells; we aim to give a state-of-the-art over-view of the diverse viruses that have been investigated as potential oncolytic agents for the treatment of CRC.


Subject(s)
Colonic Neoplasms/therapy , Oncolytic Virotherapy/trends , Oncolytic Viruses/pathogenicity , Rectal Neoplasms/therapy , Animals , Colonic Neoplasms/mortality , Colonic Neoplasms/pathology , Colonic Neoplasms/virology , Diffusion of Innovation , Forecasting , Host-Pathogen Interactions , Humans , Oncolytic Virotherapy/adverse effects , Rectal Neoplasms/mortality , Rectal Neoplasms/pathology , Rectal Neoplasms/virology , Treatment Outcome
11.
PLoS One ; 14(4): e0214326, 2019.
Article in English | MEDLINE | ID: mdl-30939149

ABSTRACT

Klebsiella pneumoniae (KP) remains the most prevalent nosocomial pathogen and carries the carbapenemase (KPC) gene which confers resistance towards carbapenem. Thus, it is necessary to discover novel antimicrobials to address the issue of antimicrobial resistance in such pathogens. Natural products such as essential oils are a promising source due to their complex composition. Essential oils have been shown to be effective against pathogens, but the overall mechanisms have yet to be fully explained. Understanding the molecular mechanisms of essential oil towards KPC-KP cells would provide a deeper understanding of their potential use in clinical settings. Therefore, we aimed to investigate the mode of action of essential oil against KPC-KP cells from a proteomic perspective by comparing the overall proteome profile of KPC-KP cells treated with cinnamon bark (Cinnamomum verum J. Presl) essential oil (CBO) at their sub-inhibitory concentration of 0.08% (v/v). A total of 384 proteins were successfully identified from the non-treated cells, whereas only 242 proteins were identified from the CBO-treated cells. Proteins were then categorized based on their biological processes, cellular components and molecular function prior to pathway analysis. Pathway analysis showed that CBO induced oxidative stress in the KPC-KP cells as indicated by the abundance of oxidative stress regulator proteins such as glycyl radical cofactor, catalase peroxidase and DNA mismatch repair protein. Oxidative stress is likely to oxidize and disrupt the bacterial membrane as shown by the loss of major membrane proteins. Several genes selected for qRT-PCR analysis validated the proteomic profile and were congruent with the proteomic abundance profiles. In conclusion, KPC-KP cells exposed to CBO undergo oxidative stress that eventually disrupts the bacterial membrane possibly via interaction with the phospholipid bilayer. Interestingly, several pathways involved in the bacterial membrane repair system were also affected by oxidative stress, contributing to the loss of cells viability.


Subject(s)
Klebsiella Infections/drug therapy , Klebsiella pneumoniae/drug effects , Oils, Volatile/pharmacology , Oxidative Stress/drug effects , Bacterial Proteins/genetics , Carbapenems/adverse effects , Cinnamomum zeylanicum/chemistry , Drug Resistance, Bacterial/genetics , Humans , Klebsiella Infections/genetics , Klebsiella Infections/microbiology , Klebsiella pneumoniae/pathogenicity , Oils, Volatile/chemistry , Plant Bark/chemistry , beta-Lactamases/genetics
12.
Ir J Med Sci ; 188(2): 389-395, 2019 May.
Article in English | MEDLINE | ID: mdl-30014247

ABSTRACT

Colorectal cancer (CRC) is a malignancy whose incidence is increasing globally, and there is a gender difference in the increasing risk. Evidence from hormone replacement therapy studies points to a role for circulating estrogens in suppressing the development of CRC. Estrogen receptor-ß has been identified as a tumor suppressor, but other actions of estrogen may also contribute to the difference in CRC incidence between men and women. The KCNQ1/KCNE3 potassium channel is regulated by estrogen in order to modulate chloride secretion during the menstrual cycle; the effect of estrogen on the colon is to promote fluid conservation during the implantation window. KCNQ1 is also a tumor suppressor in CRC, and its sustained expression has been linked to suppression of the Wnt/ß-catenin signaling pathway that contributes to CRC tumor progression. KCNQ1 regulation may represent a link between the normal physiological actions of estrogen in the colon and the hormone's apparent tumor-suppressive effects in CRC development.


Subject(s)
Colorectal Neoplasms/metabolism , Estrogens/metabolism , Colorectal Neoplasms/pathology , Female , Gender Identity , Humans , Male , Signal Transduction
13.
Steroids ; 133: 67-74, 2018 05.
Article in English | MEDLINE | ID: mdl-29079406

ABSTRACT

Aldosterone acts through the mineralocorticoid receptor (MR) to modulate gene expression in target tissues. In the kidney, the principal action of aldosterone is to promote sodium conservation in the distal nephron and so indirectly enhance water conservation under conditions of hypotension. Over the last twenty years the rapid activation of protein kinase signalling cascades by aldosterone has been described in various tissues. This review describes the integration of rapid protein kinase D signalling responses with the non-genomic actions of aldosterone and transcriptional effects of MR activation.


Subject(s)
Aldosterone/metabolism , Electrolytes/metabolism , Protein Kinases/metabolism , Signal Transduction , Animals , Humans , Receptors, Mineralocorticoid/metabolism , Sodium/metabolism
14.
Oncotarget ; 8(48): 84258-84275, 2017 Oct 13.
Article in English | MEDLINE | ID: mdl-29137421

ABSTRACT

The estrogen receptor ERß is the predominant ER subtype expressed in normal well-differentiated colonic epithelium. However, ERß expression is lost under the hypoxic microenvironment as colorectal cancer (CRC) malignancy progresses. This raises questions about the role of signalling through other estrogen receptors such as ERα or G-protein coupled estrogen receptor (GPER, GPR30) by the estrogen 17ß-estradiol (E2) under hypoxic conditions after ERß is lost in CRC progression. We tested the hypothesis that E2 or hypoxia can act via GPER to contribute to the altered phenotype of CRC cells. GPER expression was found to be up-regulated by hypoxia and E2 in a panel of CRC cell lines. The E2-modulated gene, Ataxia telangiectasia mutated (ATM), was repressed in hypoxia via GPER signalling. E2 treatment enhanced hypoxia-induced expression of HIF1-α and VEGFA, but repressed HIF1-α and VEGFA expression under normoxic conditions. The expression and repression of VEGFA by E2 were mediated by a GPER-dependent mechanism. E2 treatment potentiated hypoxia-induced CRC cell migration and proliferation, whereas in normoxia, cell migration and proliferation were suppressed by E2 treatment. The effects of E2 on these cellular responses in normoxia and hypoxia were mediated by GPER. In a cohort of 566 CRC patient tumor samples, GPER expression significantly associated with poor survival in CRC Stages 3-4 females but not in the stage-matched male population. Our findings support a potentially pro-tumorigenic role for E2 in ERß-negative CRC under hypoxic conditions transduced via GPER and suggest a novel route of therapeutic intervention through GPER antagonism.

15.
Proc Natl Acad Sci U S A ; 114(16): 4159-4164, 2017 04 18.
Article in English | MEDLINE | ID: mdl-28373572

ABSTRACT

The K+ channel KCNQ1 has been proposed as a tumor suppressor in colorectal cancer (CRC). We investigated the molecular mechanisms regulating KCNQ1:ß-catenin bidirectional interactions and their effects on CRC differentiation, proliferation, and invasion. Molecular and pharmacologic approaches were used to determine the influence of KCNQ1 expression on the Wnt/ß-catenin signaling and epithelial-to-mesenchymal transition (EMT) in human CRC cell lines of varying stages of differentiation. The expression of KCNQ1 was lost with increasing mesenchymal phenotype in poorly differentiated CRC cell lines as a consequence of repression of the KCNQ1 promoter by ß-catenin:T-cell factor (TCF)-4. In well-differentiated epithelial CRC cell lines, KCNQ1 was localized to the plasma membrane in a complex with ß-catenin and E-cadherin. The colocalization of KCNQ1 with adherens junction proteins was lost with increasing EMT phenotype. ShRNA knock-down of KCNQ1 caused a relocalization of ß-catenin from the plasma membrane and a loss of epithelial phenotype in CRC spheroids. Overexpression of KCNQ1 trapped ß-catenin at the plasma membrane, induced a patent lumen in CRC spheroids, and slowed CRC cell invasion. The KCNQ1 ion channel inhibitor chromanol 293B caused membrane depolarization, redistribution of ß-catenin into the cytosol, and a reduced transepithelial electrical resistance, and stimulated CRC cell proliferation. Analysis of human primary CRC tumor patient databases showed a positive correlation between KCNQ1:KCNE3 channel complex expression and disease-free survival. We conclude that the KCNQ1 ion channel is a target gene and regulator of the Wnt/ß-catenin pathway, and its repression leads to CRC cell proliferation, EMT, and tumorigenesis.


Subject(s)
Cell Differentiation , Cell Movement , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Gene Expression Regulation, Neoplastic , KCNQ1 Potassium Channel/metabolism , beta Catenin/metabolism , Animals , Apoptosis , Carcinogenesis , Cell Proliferation , Colorectal Neoplasms/genetics , Epithelial-Mesenchymal Transition , Humans , KCNQ1 Potassium Channel/genetics , Male , Neoplasm Invasiveness , Prognosis , Promoter Regions, Genetic , Rats, Sprague-Dawley , Survival Rate , Tumor Cells, Cultured , Xenograft Model Antitumor Assays , beta Catenin/genetics
16.
Anticancer Res ; 36(11): 5905-5913, 2016 11.
Article in English | MEDLINE | ID: mdl-27793915

ABSTRACT

INTRODUCTION: Malignant pleural mesothelioma (MPM) is a rare but highly aggressive malignancy most often associated with exposure to asbestos. Recent evidence points to oestrogen receptor (ER)-ß having a tumour-suppressor role in MPM progression, and this raises the question of whether selective modulators of ERs could play a role in augmenting MPM therapy. MATERIALS AND METHODS: We investigated the action of tamoxifen in inhibiting the growth and modulating the cisplatin sensitivity of four MPM cell lines. RESULTS: Tamoxifen inhibited the growth of MPM cells and also modulated their sensitivity to cisplatin. The MPM cell lines expressed ERß, but the actions of tamoxifen were not blocked by antagonism of nuclear ERs. Tamoxifen treatment repressed the expression of cyclins by MPM cells, resulting in cell-cycle arrest and caspase-3-coupled apoptosis signaling. CONCLUSION: The ER-independent actions of tamoxifen on MPM cell proliferation and cell-cycle progression may have clinical benefits for a subset of patients with MPM.


Subject(s)
Antineoplastic Agents, Hormonal/pharmacology , Cell Proliferation/drug effects , Mesothelioma/pathology , Pleural Neoplasms/pathology , Tamoxifen/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Cisplatin/administration & dosage , Cyclin-Dependent Kinases/antagonists & inhibitors , Humans , Tamoxifen/administration & dosage
17.
Nephron ; 134(2): 59-63, 2016.
Article in English | MEDLINE | ID: mdl-27476173

ABSTRACT

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a systemic disease characterised by the formation of multiple renal cysts that adversely affect renal function. ADPKD shows significant progression with age when complications due to hypertension are most significant. The activation of the renin-angiotensin-aldosterone system (RAAS) occurs in progressive kidney disease leading to hypertension. The RAAS system may also contribute to ADPKD progression by stimulating signalling pathways in the renal cyst cells to promote growth and deregulate epithelial transport. This mini review focuses on the contribution of the RAAS system to renal cyst enlargement and the potential for antagonists of the RAAS system to suppress cyst enlargement as well as control ADPKD-associated hypertension.


Subject(s)
Polycystic Kidney, Autosomal Dominant/drug therapy , Renin-Angiotensin System/drug effects , TRPP Cation Channels/genetics , Disease Progression , Humans , Hypertension/etiology , Mutation , Polycystic Kidney, Autosomal Dominant/complications , Polycystic Kidney, Autosomal Dominant/pathology
18.
Methods Mol Biol ; 1204: 219-31, 2014.
Article in English | MEDLINE | ID: mdl-25182774

ABSTRACT

Molecular imaging and electrophysiological techniques are powerful tools to analyze the responses stimulated by aldosterone and other hormones in target tissues. Studies with Ussing-type chambers can be used to measure and characterize changes in transepithelial currents resulting from hormone treatment. Confocal imaging techniques can be used in real time or in fixed preparations to evaluate the localization of receptors, signalling intermediates, and transporters.


Subject(s)
Aldosterone/metabolism , Epithelial Cells/cytology , Epithelium/physiology , Patch-Clamp Techniques/methods , Aldosterone/analysis , Animals , Cell Culture Techniques/methods , Cell Line , Electric Conductivity , Equipment Design , Fluorescent Antibody Technique/methods , Mice , Microscopy, Confocal/methods , Patch-Clamp Techniques/instrumentation , Staining and Labeling/methods
19.
Physiol Rep ; 2(5)2014 May 01.
Article in English | MEDLINE | ID: mdl-24872356

ABSTRACT

The most active estrogen, 17ß-estradiol (E2), has previously been shown to stimulate a female sex-specific antisecretory response in the intestine. This effect is thought to contribute to the increase in whole body extracellular fluid (ECF) volume which occurs in high estrogen states, such as in the implantation window during estrous cycle. The increased ECF volume may be short-circuited by a renal compensation unless estrogen exerts a proabsorptive effect in the nephron. Thus, the effect of E2 on ENaC in kidney cortical collecting duct (CCD) cells is of interest to understand estrogen regulation of ECF volume. Previous studies showed a rapid stimulatory effect of estrogen on ENaC in bronchial epithelium. In this study we examined if such a rapid effect on Na(+) absorption could occur in the kidney. Experiments were carried out on murine M1-CCD cell cultures. E2 (25 nmol/L) treatment caused a rapid-onset (<15 min) and sustained increase in the amiloride-sensitive Na(+) current (INa) in CCD monolayers mounted in Ussing chambers (control, 1.9 ± 0.2 µA/cm(2); E2, 4.7 ± 0.3 µA/cm(2); n = 43, P < 0.001), without affecting the ouabain-sensitive Na(+)/K(+) pump current. The INa response to E2 was inhibited by PKCδ activity antagonism with rottlerin (5 µmol/L), inhibition of matrix metalloproteinases activity with GM6001 (1 µmol/L), inhibition of EGFR activity with AG1478 (10 µmol/L), inhibition of PLC activity with U-73122 (10 µmol/L), and inhibition of estrogen receptors with the general ER antagonist ICI-182780 (100 nmol/L). The estrogen activation of INa could be mimicked by the ERα agonist PPT (1 nmol/L). The nuclear excluded estrogen dendrimer conjugate (EDC) induced similar stimulatory effects on INa comparable to free E2. The end target for E2 stimulation of PKCδ was shown to be an increased abundance of the γ-ENaC subunit in the apical plasma membrane of CCD cells. We have demonstrated a novel rapid "nongenomic" function of estrogen to stimulate ENaC via ERα-EGFR transactivation in kidney CCD cells. We propose that the salt-retaining effect of estrogen in the kidney together with its antisecretory action in the intestine are the molecular mechanisms causing the expanded ECF volume in high-estrogen states.

20.
Cancer Epidemiol ; 38(1): 35-41, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24394956

ABSTRACT

OBJECTIVE: Malignant pleural mesothelioma (MPM) is a rare malignancy associated with exposure to asbestos. The protracted latent period of MPM means that its incidence has continued to rise across Europe after the introduction of restrictions on asbestos use. In order to obtain a clearer indication of trends in the Republic of Ireland (ROI), incidence and survival were assessed based on all MPM cases reported since the establishment of the National Cancer Registry of Ireland (NCR). METHODS: NCR recorded 337 MPM diagnoses in the ROI during 1994-2009. Survival was assessed for all cases diagnosed with adequate follow-up (n=330). Crude and European age-standardized incidence rates were calculated for all cases and for 4-year periods. A Cox model of observed (all-cause) survival was used to generate hazard ratios for the effect of: gender; age at diagnosis; diagnosis cohort; region of residence; histological type; and tumour stage. Single P-values for the variables indicated were calculated using either a stratified log-rank test or stratified trend test. RESULTS: Over the study period the age-standardized MPM incidence in the ROI rose from 4.98cases per million (cpm) to 7.24cpm. The 1-year survival rate for all MPM cases was 29.6% (CI 24.7-34.6%). Excess mortality risk was associated with age at diagnosis (75-89 yrs vs. 55-64 yrs, HR 1.88, 95% CI 1.35-2.63, P<0.001) and tumour stage (III vs. I HR 1.57, 95% CI 1.00-2.48, P<0.05; IV vs. I HR 1.55, 95% CI 1.08-2.21, P<0.05). Age showed a significant survival trend (P<0.001) but tumour stage did not (P=0.150). There was significant heterogeneity between the survival of patients resident in different regions (P=0.027). CONCLUSION: MPM incidence and mortality continued to rise in the ROI after the restrictions on asbestos use and the predictors of survival detected in this study are broadly consistent with those identified for other countries.


Subject(s)
Asbestos/toxicity , Lung Neoplasms/epidemiology , Mesothelioma/epidemiology , Pleural Neoplasms/epidemiology , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Environmental Exposure , Female , Follow-Up Studies , Humans , Incidence , Ireland/epidemiology , Lung Neoplasms/etiology , Lung Neoplasms/pathology , Male , Mesothelioma/etiology , Mesothelioma/pathology , Mesothelioma, Malignant , Middle Aged , Neoplasm Staging , Pleural Neoplasms/etiology , Pleural Neoplasms/pathology , Proportional Hazards Models , Registries , Risk Factors , Survival Rate , Young Adult
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