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Journal: Clinical science (London, England : 1979)


Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) (ME/CFS) is a disabling and debilitating disease of unknown aetiology. It is a heterogeneous disease characterized by various inflammatory, immune, viral, neurological and endocrine symptoms. Several microbiome studies have described alterations in the bacterial component of the microbiome (dysbiosis) consistent with a possible role in disease development. However, in focusing on the bacterial components of the microbiome, these studies have neglected the viral constituent known as the virome. Viruses, particularly those infecting bacteria (bacteriophages), have the potential to alter the function and structure of the microbiome via gene transfer and host lysis. Viral-induced microbiome changes can directly and indirectly influence host health and disease. The contribution of viruses towards disease pathogenesis is therefore an important area for research in ME/CFS. Recent advancements in sequencing technology and bioinformatics now allow more comprehensive and inclusive investigations of human microbiomes. However, as the number of microbiome studies increases, the need for greater consistency in study design and analysis also increases. Comparisons between different ME/CFS microbiome studies are difficult because of differences in patient selection and diagnosis criteria, sample processing, genome sequencing and downstream bioinformatics analysis. It is therefore important that microbiome studies adopt robust, reproducible and consistent study design to enable more reliable and valid comparisons and conclusions to be made between studies. This article provides a comprehensive review of the current evidence supporting microbiome alterations in ME/CFS patients. Additionally, the pitfalls and challenges associated with microbiome studies are discussed.

Concepts: DNA, Gene, Bacteria, Molecular biology, Virus, Genome, Infection, Chronic fatigue syndrome


Human endometrium is a highly dynamic tissue, undergoing periodic growth and regression at each menstrual cycle. Endometriosis is a frequent chronic pathological status characterized by endometrial tissue with an ectopic localization, causing pelvic pain and infertility and a variable clinical presentation. In addition, there is well-established evidence that, although endometriosis is considered benign, it is associated with an increased risk of malignant transformation in approximately 1.0% of affected women, with the involvement of multiple pathways of development. Increasing evidence supports a key contribution of different stem/progenitor cell populations not only in the cyclic regeneration of eutopic endometrium, but also in the pathogenesis of at least some types of endometriosis. Evidence has arisen from experiments in animal models of disease through different kinds of assays (including clonogenicity, the label-retaining cell approach, the analysis of undifferentiation markers), as well as from descriptive studies on ectopic and eutopic tissue samples harvested from affected women. Changes in stem cell populations in endometriotic lesions are associated with genetic and epigenetic alterations, including imbalance of miRNA expression, histone and DNA modifications and chromosomal aberrations. The present short review mainly summarizes the latest observations contributing to the current knowledge regarding the presence and the potential contribution of stem/progenitor cells in eutopic endometrium and the aetiology of endometriosis, together with a report of the most recently identified genetic and epigenetic alterations in endometriosis. We also describe the potential advantages of single cell molecular profiling in endometrium and in endometriotic lesions. All these data can have clinical implications and provide a basis for new potential therapeutic applications.

Concepts: DNA, Gene, Cell, Histone, Chromosome, Menstrual cycle, Endometrium, Endometriosis


Diabetic mice are characterized by a disrupted expression pattern of vascular-endothelial-growth-factor (VEGF), and impaired vasculogenesis during healing. Experimental evidence suggest that relaxin (RLX) can improve several parameters associated with wound healing. Therefore, we investigated the effects of porcine derived relaxin in diabetes-related wound healing defects in genetically diabetic mice. An incisional wound model was produced on the back of female diabetic C57BL/KsJ-m+/+Leptdb (db+/db+) mice and their normal littermates (db+/+m). Animals were treated daily with porcine RLX (25µg mouse/day/s.c.) or its vehicle. Mice were killed on 3, 6 and 12 days after skin injury for measurements of VEGF mRNA and protein synthesis, stromal cell-derived factor-1α (SDF-1α) mRNA and endothelial nitric oxide synthase (eNOS) expression. Furthermore, we evaluated wound-breaking strength, histological changes, angiogenesis and vasculogenesis at day 12. Diabetic animals showed a reduced expression of VEGF, eNOS and SDF-1α compared to nondiabetic animals. At day 6, RLX administration resulted in an increase in VEGF mRNA expression and protein wound content, in eNOS expression and in SDF-1α mRNA. Furthermore the histological evaluation indicated that RLX improved the impaired wound healing, enhanced the staining of matrix metalloproteinase-11 (MMP-11) and increased wound breaking strength at day 12 in diabetic mice. Immunohistochemistry showed that RLX in diabetic animals augmented new vessel formation by stimulating both angiogenesis and vasculogenesis. RLX significantly reduced the time to complete skin normalization and this effect was abrogated by a concomitant treatment with antibodies against VEGF and CXCR4, the SDF-1α receptor. These data strongly suggest that RLX may have a potential application in diabetes-related wound disorders.

Concepts: DNA, Protein, Wound healing, Angiogenesis, Messenger RNA, Endothelium, Nitric oxide, Nitric oxide synthase


Real-word evaluation studies have shown that many patients with asthma remain symptomatic despite treatment with inhaled corticosteroids (ICS). As conventional ICS have poor access to the peripheral airways, the aim of present study was to study the relationship between peripheral airway inflammation and clinical control in allergic asthma. Consequently, bronchial and transbronchial biopsies were obtained from poorly controlled asthmatics (n=12, Asthma Control Test (ACT) score <20), well-controlled asthmatics (n=12, ACT score ≥20) and healthy controls (n=8). Tissue sections were immunostained to assess multiple leukocyte populations. To determine the degree of T helper type 2 (Th2) immunity, the logarithmic value of the ratio between Th2 cells/mm2 and Th1 cells/mm2 was used as a surrogate score for Th2 skewed immunity. In the bronchi, the leukocyte infiltration pattern and the Th2-score were similar between well-controlled and poorly controlled asthmatics. In contrast, in the alveolar parenchyma the expression of T helper cells was significant higher in poorly controlled asthmatics compared to well-controlled asthmatics (p<0.01). Furthermore, the alveolar Th2-score was significantly higher in poorly controlled asthma (median 0.4) compared to the controlled patients (median -0.10, p<0.05). Additionally, in contrast to bronchial Th2-score, the alveolar Th2-score correlated significantly with ACT score (rs=-0.56, p<0.01) in the pooled asthma group. Collectively, our data reveal an alveolar Th2-skewed inflammation specifically in asthma patients that are poorly controlled with ICS and suggest that pharmacological targeting of the peripheral airways may be beneficial in this large patient category.

Concepts: AIDS, Immune system, White blood cell, Asthma, Immunology, Allergy, T helper cell, Bronchiole


Abdominal aortic aneurysm (AAA) evolution is unpredictable. Moreover, no specific treatment exists for AAA, except surgery to prevent aortic rupture. Galectin-3 has been previously associated with CVD, but its potential role in AAA have not been addressed. Galectin-3 levels were increased in plasma of AAA patients (n=225) compared to controls (n=100). Moreover, galectin-3 concentrations were associated with need for surgical repair, independently of potential confounding factors. Galectin-3 mRNA and protein expression were increased in human AAA samples compared to healthy aortas. Experimental AAA in mice was induced by aortic elastase perfusion. Mice were treated i.v. with the galectin-3 inhibitor modified citrus pectin (MCP, 10mg/kg, every other day) or saline. Similar to humans, galectin-3 serum and aortic mRNA levels were also increased in elastase-induced AAA mice compared to control mice. Mice treated with MCP showed decreased aortic dilation, as well as elastin degradation, VSMC loss and macrophage content at day 14 post-elastase perfusion compared with control mice. The underlying mechanism(s) of the protective effect of MCP was associated to a decrease in galectin-3 and cytokine (mainly CCL5) mRNA and protein expression. Interestingly, galectin-3 induced CCL5 expression by a mechanism involving STAT3 activation in VSMC. Accordingly, MCP treatment decreased STAT3 phosphorylation in elastase-induced AAA. In conclusion, increased galectin-3 levels are associated with AAA progression, while galectin-3 inhibition decreased experimental AAA development. Our data suggest the potential role of galectin-3 as a therapeutic target in AAA.

Concepts: Protein, Gene expression, Aortic aneurysm, Aneurysm, Aortic dissection, Aorta, Abdominal aortic aneurysm, Aneurysm of sinus of Valsalva


The pathogenesis of asthma is complex and multi-faceted. Asthma patients have a diverse range of underlying dominant disease processes and pathways despite apparent similarities in clinical expression. Here, we present the current understanding of asthma pathogenesis. We discuss airway inflammation (both T2(HIGH) and T2(LOW)), airway hyperresponsiveness (AHR) and airways remodelling as four key factors in asthma pathogenesis, and also outline other contributory factors such as genetics and co-morbidities. Response to current asthma therapies also varies greatly, which is probably related to the inter-patient differences in pathogenesis. Here, we also summarize how our developing understanding of detailed pathological processes potentially translates into the targeted treatment options we require for optimal asthma management in the future.

Concepts: Immune system, Inflammation, Medicine, Gene expression, Asthma, Pathology, Future, Futures contract


Mechanistic target of rapamycin complex 1 (mTORC1) signaling is active in inflammation, but its involvement in septic acute kidney injury (AKI) has not been shown. mTORC1 activation (p-S6) in renal fibroblasts was increased in a mouse AKI model induced by 1.5 mg/kg lipopolysaccharide (LPS). Deletion of TSC1, an mTORC1 negative regulator, in fibroblasts (Fibro-TSC1-/-) inhibited the elevation of serum creatinine and blood urea nitrogen in AKI compared with that in TSC1fl/fl control mice. Endothelin-1 and p-JNK were upregulated in Fibro-TSC1-/- renal fibroblasts after LPS challenge. Rapamycin, an mTORC1 inhibitor, and bosentan, an endothelin-1 antagonist, eliminated the difference in renal function between TSC1fl/fl and Fibro-TSC1-/- mice after LPS injection. Rapamycin restored LPS-induced upregulation of endothelin-1, endothelin converting enzyme-1 (ECE1), and p-JNK in TSC1-knockdown mouse embryonic fibroblasts (MEFs). SP600125, a JNK inhibitor, attenuated LPS-induced enhancement of endothelin-1 and ECE1 in TSC1-knockdown MEFs without a change in p-S6 level. The results indicate that mTORC1-JNK-dependent upregulation of ECE1 elevated endothelin-1 in TSC1-knockout renal fibroblasts and contributed to improvement of renal function in Fibro-TSC1-/- mice with LPS-induced AKI. Renal fibroblast mTORC1 plays an important role in septic AKI.


Elevated expression of the multifunctional cytokine transforming growth factor β1 (TGF-β1) is causatively linked to kidney fibrosis progression initiated by diabetic, hypertensive, obstructive, ischemic and toxin-induced injury. Therapeutically relevant approaches to directly target the TGF-β1 pathway (e.g., neutralizing antibodies against TGF-β1), however, remain elusive in humans. TGF-β1 signaling is subjected to extensive negative control at the level of TGF-β1 receptor, SMAD2/3 activation, complex assembly and promoter engagement due to its critical role in tissue homeostasis and numerous pathologies. Progressive kidney injury is accompanied by the deregulation (loss or gain of expression) of several negative regulators of the TGF-β1 signaling cascade by mechanisms involving protein and mRNA stability or epigenetic silencing, further amplifying TGF-β1/SMAD3 signaling and fibrosis. Expression of bone morphogenetic proteins 6 and 7 (BMP6/7), SMAD7, Sloan-Kettering Institute proto-oncogene (Ski) and Ski-related novel gene (SnoN), phosphate tensin homolog on chromosome 10 (PTEN), protein phosphatase magnesium/manganese dependent 1A (PPM1A) and Klotho are dramatically decreased in various nephropathies in animals and humans albeit with different kinetics while the expression of Smurf1/2 E3 ligases are increased. Such deregulations frequently initiate maladaptive renal repair including renal epithelial cell dedifferentiation and growth arrest, fibrotic factor (connective tissue growth factor (CTGF/CCN2), plasminogen activator inhibitor type-1 (PAI-1), TGF-β1) synthesis/secretion, fibroproliferative responses and inflammation. This review addresses how loss of these negative regulators of TGF-β1 pathway exacerbates renal lesion formation and discusses the therapeutic value in restoring the expression of these molecules in ameliorating fibrosis, thus, presenting novel approaches to suppress TGF-β1 hyperactivation during chronic kidney disease (CKD) progression.


Dietary sugars are linked to the development of non-alcoholic fatty liver disease (NAFLD) and dyslipidaemia, but it is unknown if NAFLD itself influences the effects of sugars on plasma lipoproteins. To study this further, men with NAFLD (n=11) and low liver fat ‘controls’ (n= 14) were fed two iso-energetic diets, high or low in sugars (26% or 6% total energy) for 12 weeks, in a randomised, cross-over design. Fasting plasma lipid and lipoprotein kinetics were measured after each diet by stable isotope trace-labelling. There were significant differences in the production and catabolic rates of VLDL subclasses between men with NAFLD and controls, in response to the high and low sugar diets. Men with NAFLD had higher plasma concentrations of VLDL1-triacylglycerol (TAG) after the high ( P <0.02) and low sugar ( P <0.0002) diets, a lower VLDL1-TAG fractional catabolic rate after the high sugar diet ( P <0.01), and a higher VLDL1-TAG production rate after the low sugar diet ( P <0.01), relative to controls. An effect of the high sugar diet, was to channel hepatic TAG into a higher production of VLDL1-TAG ( P <0.02) in the controls, but in contrast, a higher production of VLDL2-TAG ( P <0.05) in NAFLD. These dietary effects on VLDL subclass kinetics could be explained, in part, by differences in the contribution of fatty acids from intra-hepatic stores, and de novo lipogenesis. This study provides new evidence that liver fat accumulation leads to a differential partitioning of hepatic TAG into large and small VLDL subclasses, in response to high and low intakes of sugars.

Concepts: Cholesterol, Metabolism, Nutrition, Obesity, Fat, Lipid, Non-alcoholic fatty liver disease, Fatty liver


Third-hand smoke (THS) is a newly discovered environmental health hazard that results from accumulation and aging of second-hand smoke (SHS) toxins on surfaces where smoking has occurred. Our objective was to determine whether there is a time-dependent effect of THS exposure on health. Using an in vivo exposure mouse system that mimics exposure of humans to THS, we investigated its effects on biomarkers found in serum, and in liver and brain tissues. Mice were exposed to THS for 1, 2, 4, or 6 months and brain, liver, and serum were collected. We found that THS exposure, as early as 1 month, resulted in increased circulating inflammatory cytokines, tumor necrosis factor by an order of magnitude of 2 and granulocyte macrophage colony-stimulating factor by an order of magnitude of 1.5 and in increases in the stress hormone epinephrine and the liver damage biomarker aspartate aminotransferase (AST), increased in magnitude 1.5 and 2.5 times compared with controls, respectively. THS exposure for 2 months resulted in further damage and at 4 and 6 months, many factors related to oxidative stress were altered and caused molecular damage. We also found that the mice became hyperglycemic and hyperinsulinimic suggesting that insulin resistance (IR) may be a significant consequence of long-term exposure to THS. In conclusion, time-dependent THS exposure has a significant effect on health as early as 1 month after initiation of exposure and these alterations progressively worsen with time. Our studies are important because virtually nothing is known about the effects of increased THS exposure time, they can serve to educate the public on the dangers of THS, and the biomarkers we identified can be used in the clinic, once verified in exposed humans.

Concepts: Health, Asthma, Insulin, Liver, Smoking, Aspartate transaminase, Tumor necrosis factor-alpha, Norepinephrine