Summary
The intrauterine environment is critical for the development of the foetus. Barker and colleagues were the first to identify that adverse perturbations during foetal development are ...associated with an increased risk of developing diseases in adulthood, including cardiorenal disease. Specifically for the kidney, perturbations in utero can lead to nephron deficits and renal dysfunction by a number of mechanisms. Altered programming of nephron number is associated with an increased risk of developing kidney disease via glomerular hypertrophy and reduced vasodilative capacity of the renal blood vessels; both of which would contribute to hypertension in adulthood, with males being more susceptible to disease outcomes. Additionally, alterations in the renin‐angiotensin system (RAS) such as an upregulation or downregulation of specific receptors, depending on the nature of the insult, have also been implicated in the development of renal dysfunction. Sex‐specific differences in the expression of the RAS during late gestation and in the early postnatal environment have also been identified. Extensive research has demonstrated that both uteroplacental insufficiency and maternal malnutrition alter renal development in utero. Equally, exposure to maternal diabetes and maternal obesity during development are also associated with an increased risk of developing renal disease, however, the mechanism behind this association is poorly understood. Therefore, identifying the link between an adverse intrauterine environment and the programmed kidney disease risk in adulthood may facilitate the development of strategies to alleviate the epidemics of cardiorenal disease worldwide, in addition to understanding why males are more susceptible to adult‐onset cardiovascular diseases.
Apoptosis plays a crucial role in chemotherapy-induced cell death. The conventional theory holding that apoptosis needs to be immunologically silent has recently been revised, and the concept of ...immunogenic cell death (ICD) has been proposed. This review describes the main features of ICD induction. These ICD markers are important for the effectiveness of anticancer therapy, as well as for basic research into cell death regulation. The mechanism of the "vaccination effect" of dying cancer cells undergoing ICD has been fully described, including the activation of specific antitumor response after re-challenge by the same living tumor cells. This review also discusses the whole set of molecular events attributing cell death to immunogenic type: the exposure of calreticulin and the heat shock protein HSP70 to the outer surface of the cell membrane and the release of the nuclear protein HMGB1 and ATP into the extracellular space. ICD inducers of various nature (chemotherapy drugs, cytotoxic proteins, and oncolytic viruses), as well as physical methods, are classified in the current review.
The airway and alveolar surface is exposed daily to 8,000 L of air containing oxygen, particles, bacteria, allergens and pollutants, all of which have the potential to induce oxidative stress within ...cells. If one is also a cigarette smoker, then the exposure to reactive oxidants increases exponentially. More than any other tissue, the lung is at risk of undergoing oxidative changes in protein expression, structure and function. The oxidant burden of chronic cigarette smoke exposure can overwhelm the lung cells' capacity to maintain proteostasis, a process of regulated protein synthesis, folding and turnover. Somewhat surprisingly, most chronic cigarette smokers do not develop chronic obstructive pulmonary disease (COPD), likely because cells initiate a highly effective unfolded protein response (UPR) in the presence of oxidant-derived endoplasmic reticulum (ER) stress that allows cells to survive. The UPR initiates several signaling pathways that decrease protein translation, limit cell cycle progression, increase protein degradation and chaperone-mediated protein folding, and activate the transcription factor Nrf2 that induces antioxidant gene expression. Each of these actions decreases ER stress in a process of "healthy proteostasis". If these responses are insufficient, apoptosis ensues. In this article, we review the mechanisms of healthy and dysfunctional proteostasis related to cigarette smoke exposure and COPD.
Esophageal ulcers are a rare cause of upper gastrointestinal morbidity and may be due to different etiologies. We sought to systematically evaluate patients with esophageal ulcers and describe their ...presentations, endoscopic findings, etiologies, treatments, and outcomes.
Patients diagnosed with esophageal ulcers over an 11-year period were retrospectively identified from our institution's electronic medical records.
We identified 100 patients with esophageal ulcers (0.49% of patients undergoing upper endoscopy). Half of them presented due to gastrointestinal bleeding and three-quarters were admitted to the hospital. The majority were in the lower esophagus. Twenty-two unique etiologies, including multiple iatrogenic causes, were diagnosed in 91 of the cases. The most common etiology was gastroesophageal reflux disease (57%), followed by non-steroidal anti-inflammatory drug use (7%), malignancies (3%), vomiting (3%), caustic ingestion (2%), pill esophagitis (2%) and radiation (2%). Many etiologies showed a predilection for specific segments of the esophagus. Nine ulcers required endoscopic intervention and all were treated successfully. Repeat endoscopies were performed 5 times for diagnostic or "second look" reasons, none of which changed the patients' diagnosis or treatment. No patients required surgery or stricture dilation. One patient's ulcer was complicated by perforation and he subsequently died. Four other patients died from non-ulcer related causes.
While the majority of ulcers were due to gastroesophageal reflux disease, 22 different etiologies were identified. Many were due to medication or iatrogenic causes. Repeat endoscopy did not appear to be helpful. While the incidence was low, they were frequently associated with significant morbidity.
Marine chlorophytes of the genus Chlorella are unicellular algae capable of accumulating a high proportion of cellular lipids that can be used for biodiesel production. In this study, we examined the ...broad physiological capabilities of a subtropical strain (C596) of Chlorella sp. "SAG-211-18" including its heterotrophic growth and tolerance to low salt. We found that the alga replicates more slowly at diluted salt concentrations and can grow on a wide range of carbon substrates in the dark. We then sequenced the RNA of Chlorella strain C596 to elucidate key metabolic genes and investigate the transcriptomic response of the organism when transitioning from a nutrient-replete to a nutrient-deficient condition when neutral lipids accumulate. Specific transcripts encoding for enzymes involved in both starch and lipid biosynthesis, among others, were up-regulated as the cultures transitioned into a lipid-accumulating state whereas photosynthesis-related genes were down-regulated. Transcripts encoding for two of the up-regulated enzymes-a galactoglycerolipid lipase and a diacylglyceride acyltransferase-were also monitored by reverse transcription quantitative polymerase chain reaction assays. The results of these assays confirmed the transcriptome-sequencing data. The present transcriptomic study will assist in the greater understanding, more effective application, and efficient design of Chlorella-based biofuel production systems.
•A cost-benefit analysis of the Styrian bovine viral diarrhoea virus (BVDV) control and eradication programme was conducted.•The voluntary programme had a higher cost:benefit ratio than the ...compulsory programme.•Alternative surveillance strategies would have led to a reduced total cost compared to the current testing strategy.•A positive impact on the cattle export market was observed.
This study evaluated the voluntary and compulsory implementation of a bovine viral diarrhoea virus (BVDV) eradication programme in the Austrian Federal State of Styria, Austria, from an economic point of view using ex-post assessment of costs and benefits (disease losses avoided). An economic net benefit (benefit:cost ratio, BCR=1.18) of the programme was demonstrated during the voluntary programme phase (January 1998–July 2004). The break-even point was reached in 2003. If investments in the compulsory programme (August 2004–December 2016) were taken into account, a net economic loss (BCR=0.16) was demonstrated. In contrast to on-going annual testing of all cattle herds, annual testing in accordance with a revised sampling scheme could reduce total surveillance costs by more than 77%. A Bayesian structural time series model was applied to analyse a hypothesised positive impact of the compulsory BVDV programme on the Styrian cattle export market. The average number of exported cows and bulls increased significantly by 42% (P=0.03) and 47% (P=0.01), respectively, and the producer price increased by 14% (P=0.00) and 5% (P=0.16), respectively, during the compulsory programme period compared with the period prior to intervention. This equates to an average revenue increase of €29,754 for cows and €137,563 for bulls per month. These results justify the implementation of eradication programmes, which initially may not appear to be economically viable, particularly if trade effects are not included in the calculations.
The synthesis of ionically functionalized branched polythiophenes with either carboxylic acid (anionic, P3T-COOH) or methylimidazolium (cationic, P3T-MIM) end groups is presented. Due to the large ...number of end groups present in the polymer, the functionalization has a major impact on the solubility of the polymers. In the case of P3T-COOH, the polymer shows a fully reversible phase transfer between organic solvents and water, depending on the pH. Remarkably, the ionic-liquid-modified polymer P3T-MIM is soluble in a room-temperature ionic liquid. The absorption properties are unaffected by the functional end groups.
The stromal elements of a malignant tumor can promote cancer progression and metastasis. The structure of the tumor stroma includes connective tissue elements, blood vessels, nerves, and ...extracellular matrix (ECM). Some of the cellular elements of the tumor stroma are cancer-associated f ibroblasts (CAFs). The origin and function of CAFs have been actively studied over the past thirty years. CAFs produce collagen, the main scaffold protein of the extracellular matrix. Collagen in the tumor stroma stimulates f ibrosis, enhances the rigidity of tumor tissue, and disrupts the transmission of proliferation and differentiation signaling pathways. CAFs control tumor angiogenesis, cell motility, tumor immunogenic properties, and the development of resistance to chemo- and immunotherapy. As a result of metabolic adaptation of rapidly growing tumor tissue to the nutrients and oxygen deprivation, the main type of energy production in cells changes from oxidative phosphorylation to anaerobic glycolysis. These changes lead to sequential molecular alterations, including the induction of specif ied transcriptional factors that result in the CAFs activation. The molecular phenotype of activated CAFs is similar to f ibroblasts activated during inf lammation. In activated CAFs, alpha-smooth muscle actin (α-SMA) is synthetized de novo and various proteases and f ibronectin are produced. Since CAFs are found in all types of carcinomas, these cells are potential targets for the development of new approaches for anticancer therapy. Some CAFs originate from resident f ibroblasts of the organs invaded by the tumor, while others originate from epithelial tumor cells, which are undergoing an epithelial-mesenchymal transition (EMT). To date, many molecular and metabolic inducers of the EMT have been discovered including the transforming growth factor-beta (TGF-β), hypoxia, and inf lammation. This review classif ies modern concepts of molecular markers of CAFs, their functional features, and discusses the stages of epithelial- mesenchymal transition, and the potential of CAFs as a target for antitumor therapy.
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