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Journal: Clinical science (London, England : 1979)


The physical and immunological properties of the human intestinal epithelial barrier in ageing are largely unknown. Ileal biopsies from young (7-12 years), adult (20-40y) and ageing (67-77y) individuals not showing symptoms of gastrointestinal pathologies were used to assess levels of inflammatory cytokines, barrier integrity, and cytokine production in response to microbial challenges. Increased expression of IL-6, but not IFNg, TNF-a and IL-1b was observed during ageing; further analysis showed that CD11c+ dendritic cells (DCs) are one of the major sources of IL-6 in the ageing gut and expressed higher levels of CD40. Up-regulated production of IL-6 was accompanied by increased expression of Claudin-2 leading to reduced transepithelial electric resistance (TEER); TEER could be restored in in vitro and ex-vivo cultures by neutralizing anti-IL-6 antibody. In contrast, expression of Zonula occludens-1, Occludin and Junctional-Adhesion Molecule-A1 did not vary with age and overall permeability to macromolecules was not affected. Finally, cytokine production to different microbial stimuli was assessed in a polarized in vitro organ culture. IL-8 production in response to flagellin declined progressively with age although the expression and distribution of TLR-5 on intestinal epithelial cells remained unchanged. Also, flagellin-induced production of IL-6 was less pronounced in ageing. In contrast, TNF-a production in response to probiotics (VSL#3) did not decline with age; however, in our experimental model probiotics did not down-regulate the production of IL- 6 and expression of Claudin 2. These data suggested that ageing affects properties of the intestinal barrier likely to impact on age-associated disturbances both locally and systemically.

Concepts: Digestive system, Epithelium, Antibody, Small intestine, Intestinal epithelium, Bacteria, Immune system, Cytokine


Energy balance is not a simple algebraic sum of energy expenditure and energy intake as often depicted in communications. Energy balance is a dynamic process and there exist reciprocal effects between food intake and energy expenditure. An important distinction is that of metabolic and behavioural components of energy expenditure. These components not only contribute to the energy budget directly, but also by influencing the energy intake side of the equation. It has recently been demonstrated that resting metabolic rate (RMR) is a potential driver of energy intake, and evidence is accumulating on the influence of physical activity (behavioural energy expenditure) on mechanisms of satiety and appetite control. These effects are associated with changes in leptin and insulin sensitivity, and in the plasma levels of gastrointestinal (GI) peptides such as glucagon-like peptide-1 (GLP-1), ghrelin and cholecystokinin (CCK). The influence of fat-free mass on energy expenditure and as a driver of energy intake directs attention to molecules emanating from skeletal tissue as potential appetite signals. Sedentariness (physical inactivity) is positively associated with adiposity and is proposed to be a source of overconsumption and appetite dysregulation. The molecular signals underlying these effects are not known but represent a target for research.

Concepts: Nutrition, Diabetes mellitus, Adipose tissue, Basal metabolic rate, Metabolism, Appetite, Energy, Obesity


Fully-sedated patients, being treated in the ICU, experience substantial skeletal muscle loss. Consequently, survival rate is reduced and full recovery after awakening is compromised. Neuromuscular electrical stimulation (NMES) represents an effective method to stimulate muscle protein synthesis and alleviate muscle disuse atrophy in healthy subjects. We investigated the efficacy of twice-daily NMES to alleviate muscle loss in six fully-sedated ICU patients admitted for acute critical illness (n=3 males, n=3 females; age 63±6 y; APACHE II disease severity-score: 29±2). One leg was subjected to twice-daily NMES of the quadriceps muscle for a period of 7±1 d while the other leg acted as non-stimulated control (CON). Directly before the first and on the morning after the final NMES session, quadriceps muscle biopsies were collected from both legs to assess muscle fiber-type specific cross-sectional area (CSA). Furthermore, phosphorylation status of key proteins involved in the regulation of muscle protein synthesis was assessed, and mRNA expression of selected genes was measured. In the CON leg, type I and type II muscle fiber CSA decreased by 16±9 and 24±7%, respectively (P<0.05). No muscle atrophy was observed in the stimulated leg. NMES increased mTOR phosphorylation by 19% when compared to baseline (P<0.05), with no changes in the CON leg. Furthermore, mRNA expression of key genes involved in muscle protein breakdown either declined (FOXO1; P<0.05) or remained unchanged (MAFBx and MuRF1), with no differences between legs. In conclusion, NMES represents an effective and feasible interventional strategy to prevent skeletal muscle atrophy in critically ill, comatose patients.

Concepts: Sarcopenia, Messenger RNA, DNA, Protein, Muscle atrophy, Muscle, Skeletal muscle, Atrophy


Mental clouding is an almost universal complaint among patients with postural tachycardia syndrome (POTS), but remains poorly understood. Thus, we determined whether POTS patients exhibit deficits during neuropsychological testing relative to healthy subjects. A comprehensive battery of validated neuropsychological tests was administered to 28 female POTS patients and 24 healthy subjects in a semi-recumbent position. Healthy subjects were matched to POTS patients on age and gender. Selective attention, a primary outcome measure, and cognitive processing speed were reduced in POTS patients compared to healthy subjects (Ruff 2&7 Speed t-score: 40±9 vs. 49±8; p=0.009; Symbol Digit Modalities Test t-score: 45±12 vs. 51±8; p=0.011). Measures of executive function were also lower in POTS patients (Trails B t-score: 46±8 vs. 52±8; p=0.007; Stroop Word Color t-score: 45±10 vs. 56±8; p=0.001) suggesting difficulties in tracking and mental flexibility. Measures of sustained attention, psychomotor speed, memory function or verbal fluency were not significantly different between groups. This study provides evidence for deficits in selective attention and cognitive processing in patients with POTS, in the seated position when orthostatic stress is minimized. In contrast, other measures of cognitive function including memory assessments were not impaired in these patients, suggesting selectivity in these deficits. These findings provide new insight into the profile of cognitive dysfunction in POTS, and provide the basis for further studies to identify clinical strategies to better manage the mental clouding associated with this condition.

Concepts: Stroop effect, Postural orthostatic tachycardia syndrome, Memory, Cognitive neuroscience, Neuropsychological assessment, Neurocognitive, Cognitive psychology, Psychology


Beneficial effects of physical activity on mitochondrial health are well substantiated in the scientific literature, with regular exercise improving mitochondrial quality and quantity in normal healthy population, and in cardiometabolic and neurodegenerative disorders and aging. However, several recent studies questioned this paradigm, suggesting that extremely heavy or exhaustive exercise fosters mitochondrial disturbances that could permanently damage its function in health and disease. Exercise-induced mitochondrial dysfunction (EIMD) might be a key proxy for negative outcomes of exhaustive exercise, being a pathophysiological substrate of heart abnormalities, chronic fatigue syndrome (CFS) or muscle degeneration. Here, we overview possible factors that mediate negative effects of exhaustive exercise on mitochondrial function and structure, and put forward alternative solutions for the management of EIMD.

Concepts: Exercise physiology, Weight loss, Epidemiology, Exercise, Mitochondrion, Muscle, Chronic fatigue syndrome, Medicine


Normal skeletal muscle metabolism is essential for whole body metabolic homoeostasis and disruptions in muscle metabolism are associated with a number of chronic diseases. Transcriptional control of metabolic enzyme expression is a major regulatory mechanism for muscle metabolic processes. Substantial evidence is emerging that highlights the importance of epigenetic mechanisms in this process. This review will examine the importance of epigenetics in the regulation of muscle metabolism, with a particular emphasis on DNA methylation and histone acetylation as epigenetic control points. The emerging cross-talk between metabolism and epigenetics in the context of health and disease will also be examined. The concept of inheritance of skeletal muscle metabolic phenotypes will be discussed, in addition to emerging epigenetic therapies that could be used to alter muscle metabolism in chronic disease states.

Concepts: Metabolism, Methylation, DNA methylation, DNA, Gene expression, Histone, Medicine, Epigenetics


In high-, middle- and low-income countries, the rising prevalence of obesity is the underlying cause of numerous health complications and increased mortality. Being a complex and heritable disorder, obesity results from the interplay between genetic susceptibility, epigenetics, metagenomics and the environment. Attempts at understanding the genetic basis of obesity have identified numerous genes associated with syndromic monogenic, non-syndromic monogenic, oligogenic and polygenic obesity. The genetics of leanness are also considered relevant as it mirrors some of obesity’s aetiologies. In this report, we summarize ten genetically elucidated obesity syndromes, some of which are involved in ciliary functioning. We comprehensively review 11 monogenic obesity genes identified to date and their role in energy maintenance as part of the leptin-melanocortin pathway. With the emergence of genome-wide association studies over the last decade, 227 genetic variants involved in different biological pathways (central nervous system, food sensing and digestion, adipocyte differentiation, insulin signalling, lipid metabolism, muscle and liver biology, gut microbiota) have been associated with polygenic obesity. Advances in obligatory and facilitated epigenetic variation, and gene-environment interaction studies have partly accounted for the missing heritability of obesity and provided additional insight into its aetiology. The role of gut microbiota in obesity pathophysiology, as well as the 12 genes associated with lipodystrophies is discussed. Furthermore, in an attempt to improve future studies and merge the gap between research and clinical practice, we provide suggestions on how high-throughput ‘-omic’ data can be integrated in order to get closer to the new age of personalized medicine.

Concepts: Nutrition, Gene, DNA, Nervous system, Gene expression, Bacteria, Biology, Genetics


Generating a pneumococcal vaccine that is serotype-independent and cost effective remains a global challenge. Gamma-irradiation has been used widely to sterilize biological products. It can also be utilised as an inactivation technique to generate whole cell bacterial and viral vaccines with minimal impact on pathogen structure and antigenic determinants. In the present study, we utilised gamma-irradiation to inactivate an unencapsulated Streptococcus pneumoniae strain Rx1 with an unmarked deletion of the autolysin gene lytA and with the pneumolysin gene ply replaced with an allele encoding a non-toxic pneumolysoid (PdT) (designated g-PN vaccine). Intranasal vaccination of C57BL/6 mice with g-PN was shown to elicit serotype-independent protection in lethal challenge models of pneumococcal pneumonia and sepsis. Vaccine efficacy was shown to be reliant on B cells and IL-17A responses. Interestingly, immunisation promoted IL-17 production by innate cells not Th17 cells. These data are the first to report the development of a non-adjuvanted intranasal gamma-irradiated pneumococcal vaccine that generates effective serotype-independent protection, which is mediated by both humoral and innate IL-17 responses.

Concepts: Gene, Microbiology, Vaccination, Vaccine, Bacteria, Streptococcus pneumoniae, Immune system, Pneumonia


Arthritis is a process of chronic inflammation that results in joint damage. Interleukin-1β (IL-1β) is an inflammatory cytokine that acts as a key mediator of cartilage degradation, and is abundantly expressed in arthritis. Neovascularization is one of the pathological characteristics of arthritis. However, the role of IL-1β in the angiogenesis of chondrocytes remains unknown. Here, we demonstrate that stimulating chondrocytes (ATDC5) with IL-1β increased the expression of fibroblast growth factor (FGF)-2, a potent angiogenic inducer, and then promoted endothelial progenitor cell (EPC) tube formation and migration. In addition, FGF-2 neutralizing antibody abolished ATDC5-conditional medium-mediated angiogenesis in vitro , as well as its angiogenic effects in the chick chorioallantoic membrane (CAM) assay and Matrigel plug nude mice model in vivo . Immunohistochemistry (IHC) staining from collagen-induced arthritis (CIA) mouse model also demonstrate that arthritis increased expression of IL-1β and FGF-2, as well as EPCs homing in articular cartilage. Moreover, IL-1β-induced FGF-2 expression via the type-1 interleukin-1 receptor (IL-1RI), reactive oxygen species (ROS) generation, AMP-activated protein kinase (AMPK), p38, and nuclear factor kappa B (NF-κB) pathway has been demonstrated. Based on the above findings, we conclude that IL-1β promotes FGF-2 expression in chondrocytes through the ROS/AMPK/p38/NF-κB signaling pathway and subsequently increases EPC angiogenesis. Therefore, IL-1β serves as a link between inflammation and angiogenesis during arthritis.

Concepts: Hormone, Growth factor, Fibroblast growth factor, Inflammation, Extracellular matrix, Immune system, Signal transduction, Angiogenesis


Fibroblasts derived from the lungs of patients with idiopathic pulmonary fibrosis and systemic sclerosis produce low levels of prostaglandin E2, due to a limited capacity to up-regulate cyclooxygenase-2. This deficiency contributes functionally to the fibroproliferative state, however the mechanisms responsible are incompletely understood.In the present study we examined whether the reduced level of cyclooxygenase-2 mRNA expression observed in fibrotic lung fibroblasts is regulated epigenetically. The DNA methylation inhibitor, 5 Aza-2'-deoxycytidine restored cyclooxygenase-2 mRNA expression by fibrotic lung fibroblasts dose dependently. Functionally, this resulted in normalization of fibroblast phenotype in terms of prostaglandin E2 production, collagen mRNA expression and sensitivity to apoptosis. Cyclooxygenase-2 methylation assessed by bisulphite sequencing and methylation microarrays was not different in fibrotic fibroblasts compared with controls. However, further analysis of the methylation array data identified a transcriptional regulator, c8orf4, which is hypermethylated and down-regulated in fibrotic fibroblasts compared with controls. siRNA knock-down of c8orf4 in control fibroblasts down-regulated cyclooxygenase-2 and prostaglandin E2 production generating a phenotype similar to that observed in fibrotic lung fibroblasts. Chromatin immunoprecipitation demonstrated that c8orf4 regulates cyclooxygenase-2 expression in lung fibroblasts through binding of the proximal promoter.We conclude that the decreased capacity of fibrotic lung fibroblasts to up-regulate cyclooxygenase-2 expression and cyclooxygenase-2 derived prostaglandin E2 synthesis is due to an indirect epigenetic mechanism involving hypermethylation of the transcriptional regulator, c8orf4.

Concepts: Messenger RNA, Histone, Bisulfite sequencing, DNA methylation, Methylation, Epigenetics, DNA, Gene expression