AimTo investigate the expression of succinate dehydrogenase B and its potential as a therapeutic target in pleural mesothelioma (PM).MethodsThe expression of succinate dehydrogenase B was examined in cell lines using PCR. The expression of succinate dehydrogenase B mRNA was subsequently examined in a series of fresh-frozen primary patient samples using reverse transcription polymerase chain reaction. The expression of succinate dehydrogenase B protein was examined by immunohistochemistry on a pleural mesothelioma tissue microarray derived from Formalin-Fixed and Paraffin-Embedded specimens to determine if succinate dehydrogenase B expression correlated with survival benefit. Using a resazurin-based assay we examined whether targeting the mitochondrial complex II (containing succinate dehydrogenase B) with a chemical inhibitor could have effects on cell proliferation.ResultsTotal ribonucleic acid was isolated from a panel of mesothelial-derived cell lines (both cancerous and non-cancerous), and expression of succinate dehydrogenase B messenger RNA was assessed by RT-PCR and found to be ubiquitously expressed. Total Ribonucleic acid was isolated from a panel of fresh-frozen surgical specimens, and succinate dehydrogenase B was significantly overexpressed in mesothelioma at the messenger RNA level. Immunohistochemical staining and analysis of a mesothelioma tissue microarray showed that expression did not correlate with any survival benefit, confirmed by in silico analyses of other datasets. However, links between DNA methylation at individual residues of the succinate dehydrogenase B gene and overall survival were identified, along with correlations to immune cell infiltrates. Targeting the mitochondrial complex II with oxaloacetic acid did not show any significant potential for higher efficacy in cell lines derived from malignant tumors compared to those derived from normal mesothelial cells.ConclusionsOur results demonstrate that succinate dehydrogenase B is overexpressed in PM but may not be a suitable candidate for therapeutic targeting in this disease.

The development of resistance to various antimicrobial agents by bacteria, fungi, viruses, and parasites poses a major challenge to the medical field in treating the infections they cause. Consequently, there is an urgent need to explore new and innovative antimicrobials. A promising solution lies in the use of natural products, such as essential oils, as antimicrobial agents. Herbs and essential oils have been used since ancient times in various aspects of life, including perfumes, cosmetics, agriculture, and industry. In medicine, these essential oils have demonstrated numerous applications, such as analgesic, anti-inflammatory, antioxidant, fungicidal, and antitumor activities. Essential oils present a viable alternative to synthetic chemicals due to the presence of biologically active compounds, such as phenols and terpenes, that inhibit or prevent pathogen growth. This review paper aims to explore the importance of essential oils, their components, and the mechanisms they use to combat pathogens. It will also highlight their role as a potential solution to multidrug resistance and discuss future prospects.

Autosomal dominant polycystic kidney disease (ADPKD) is a disease characterized by the growth of fluid filled cysts in the kidney. ADPKD arises due to a heritable mutation in the polycystic kidney disease 1 gene (PKD1) and polycystic kidney disease 2 gene (PKD2) ultimately leading to kidney failure. Incidence in males and females is equivalent, but differences arise in progression. This review brings together various studies regarding the impact of cyclic hormone changes on ADPKD progression, bringing attention to gaps in knowledge that needs to be addressed. Circulating hormones play a crucial role in the pathogenesis of the disease, particularly the renin angiotensin system. The physiological actions of estrogen tend to have a protective effect on the kidney, contributing to a slowed progression in females. The hormonal changes of the menstrual cycle and at menopause result in changes in pathology via blood pressure fluctuation, promotion of renal repair and prevention of renal scarring and damage. Signaling pathways that are involved in cyst growth such as cAMP, mTOR, MAPK/ERK, and PI3K/Akt are modulated by estrogen, providing insights into potential mechanisms. Estrogen-based hormonal therapy is being investigated for its efficacy in improving renal function post menopause.

Since ancient times, date fruit has been used as a staple food because of its high nutritional value and caloric content. With the development of food science and the application of modern instrumentation, we now know that date seeds contain large amounts of dietary fiber, phenols, polyphenols, amino acids, fatty acids, and many vitamins and minerals. Due to the presence of these functional food ingredients, date seeds are used in various applications, including foods such as bread, hot beverages, cosmetics such as hair and skin products, and as feed for culturing aquatic animals. Date seeds have been used in clinical applications, making use of their antioxidant, anti-inflammatory, anti-cancer, anti-diabetic, and antimicrobial properties. There is now growing awareness of the value of date seeds, which were considered a waste product. In this review, we focused on explaining the major biochemical constituents of date seeds and developing these constituents for various applications. We also highlight the expected developments in date seed use for the future.

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.

It has been known for some decades that the expression of phospholipase D (PLD) isoforms becomes altered in the transition from normal mammary epithelium to breast carcinoma. The products of PLD activity, choline and phosphatidic, have been implicated in the transformation process, and PLD itself has a scaffold function in the assembly of signaling complexes. PLD expression is also responsive to environmental stressors, and this has raised questions about its role in the adaptive response of malignant cells under conditions of hypoxia and nutrient depletion in the developing tumor. PLD is involved in epithelial mesenchymal transition and is particularly important in mTOR and ERBB1/EGFR and ERBB2/HER2 coupled signaling process. PLD has not only been implicated in cell survival signaling but also in the process of metastasis and critically in changes in the signaling profile that develop as breast cancer cells become more invasive.

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 ERβ 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.

Antimicrobial resistance has been reported since the discovery of antibiotics; the microorganisms which have been exposed to antibiotics are continuously and rapidly evolving to overcome the effect of antimicrobial agents. This has made antimicrobial resistance a major public health issue. In order to overcome antimicrobial resistance, various alternatives are being explored; this includes the utilization of plant essential oils, which are mixtures of secondary metabolites produced by plants that have antimicrobial activity. Essential oils have proven to be effective against various pathogens such as, Klebsiella pneumoniae, Campylobacter jejuni, Staphylococcus aureus and others. This chapter aims to briefly discuss resistance mechanisms employed by microorganisms and alternative methods used to overcome antimicrobial resistanceAntimicrobial resistance. Then, the chemistry of essential oilsEssential oils and the effects these essential oilsEssential oils have on the genomes and proteomes of the treated microorganisms has also been reviewed. These essential oilsEssential oils should be further explored in the future to examine their toxicity and side effects through in vitro and clinical studies.

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.

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.

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.

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.

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.

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.

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.

Aldosterone is the key regulating hormone of whole-body fluid and electrolyte homeostasis. Perturbations in aldosterone synthesis and over-activation of the mineralocorticoid receptor (MR) can lead to excess salt reabsorption and hypertension. The cortical collecting duct (CCD) is the main site of action in the kidney for aldosterone regulation of whole-body sodium homeostasis through actions on the epithelial sodium channel (ENaC) and the Na/K-ATPase (Na/K pump). Aldosterone stimulates ENaC trafficking into the apical cell membranes in the CCD and enhances channel stability and open probability, as well as activating the basolateral membrane Na/K pump to produce an overall increase in the transepithelial reabsorption of sodium. Aldosterone/MR regulates the activity of ENaC in the CCD through both rapid non-genomic (secs-mins) and latent genomic (hours-days) signaling pathways. These rapid and slow responses of renal Na+ transport pathways to aldosterone are often treated as distinct and separate events. However, recent evidence points to a close integration between genomic and non-genomic responses to aldosterone to regulate ENaC and Na/K pump activity via protein kinase signaling pathways. Here, we review the integration of aldosterone membrane-initiated non-genomic and nuclear genomic regulations of renal sodium transport via protein kinase signaling pathways and in particular via protein kinase D isoforms.

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.

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.

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-β 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/β-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.

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.