SciCombinator

Discover the most talked about and latest scientific content & concepts.

Journal: Clinical science (London, England : 1979)

27

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

27

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

26

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

24

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

23

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

15

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

11

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

11

β2-adrenoceptor agonists are the mainstay therapy for patients with asthma but their effectiveness in cigarette smoke (CS)-induced lung disease such as chronic obstructive pulmonary disease (COPD) is limited. In addition, bronchodilator efficacy of β2-adrenoceptor agonists is decreased during acute exacerbations of COPD (AECOPD), caused by respiratory viruses including influenza A. Therefore, the aim of the present study was to assess the effects of the β2-adrenoceptor agonist salbutamol (SALB) on small airway reactivity using mouse precision cut lung slices (PCLS) prepared from CS-exposed mice and from CS-exposed mice treated with influenza A virus (Mem71, H3N1). CS exposure alone reduced SALB potency and efficacy associated with decreased β2-adrenoceptor mRNA expression, and increased tumour necrosis factor α (TNFα) and interleukin-1β (IL-1β) expression. This impaired relaxation was restored by day 12 in the absence of further CS exposure. In PCLS prepared after Mem71 infection alone, responses to SALB were transient and were not well maintained. CS exposure prior to Mem71 infection almost completely abolished relaxation, although β2-adrenoceptor and TNFα and IL-1β expression were unaltered. The present study has shown decreased sensitivity to SALB after CS or a combination of CS and Mem71 occurs by different mechanisms. In addition, the PCLS technique and our models of CS and influenza infection provide a novel setting for assessment of alternative bronchodilators.

Concepts: Pulmonology, Asthma, Virus, Pneumonia, Tobacco smoking, Chronic obstructive pulmonary disease, Obstructive lung disease, Bronchodilator

8

In PCOS women, hyperinsulinemia stimulates ovarian cytochrome P450c17α activity that, in turn, stimulates ovarian androgen production. Our objective was to compare whether timed caloric intake differentially influences insulin resistance and hyperandrogenism in lean PCOS women. Sixty lean PCOS women (BMI 23.7±0.2kg/m2) were randomized into two isocaloric (~1800kcal) maintenance diets with different meal timing distribution: a breakfast diet (BF) (980kcal breakfast, 640kcal lunch, 190kcal dinner) or a dinner diet (D) group (190kcal breakfast, 640kcal lunch, 980kcal dinner) for 90 days. In the BF group, a significant decrease was observed in both AUCglucose and AUCinsulin, by 7 and 54%, respectively. In the BF group, free testosterone decreased by 50% and SHBG increased by 105%. GnRH-stimulated peak serum 17α hydroxyprogesterone decreased by 39%. No change in these parameters was observed in the D group. In addition, women in the BF group presented increased ovulation rate. In lean PCOS women, a high caloric intake at breakfast with reduced intake at dinner results in improved insulin sensitivity indices and reduced cytochrome P450c17α activity, which ameliorates hyperandrogenism and improves ovulation rate. Meal timing and distribution should be considered as a therapeutic option for women with PCOS.

Concepts: Estrogen, Luteinizing hormone, Metformin, Polycystic ovary syndrome

4

Quitting smoking is the most important step smokers can take to improve their health. Nonetheless, there is little information on long-term improvements in lung function and/or respiratory symptoms after smoking cessation. Here we illustrate long-term changes in spirometric indices as well as in respiratory symptoms in smokers invited to quit or reduce their cigarette consumption by switching to electronic cigarettes. Prospective evaluation of cigarette consumption, spirometry and symptoms was performed in a 1-year randomized controlled trial of smokers receiving electronic cigarette containing 2.4%, 1.8%, or 0% nicotine. Spirometric data are presented on the basis of participants' pooled continuous smoking phenotype classification (Quitters, Reducers, Failures), whereas respiratory symptoms on point prevalence-smoking phenotype. Smoking phenotype classification (Quitters, Reducers, Failures) had no significant effect on spirometric indices (FEV1, FVC, and FEV1/FVC) with the exception of FEF25-75%, which significantly (p=0.034) increased over the time among Quitters; their FEF25-75% (% predicted) improving from (means±SD) 85.7±15.6% at baseline to 100.8±14.6%. High prevalence of cough/phlegm (43.1%) and shortness of breath (34.8%) was reported at baseline with substantial reduction in their frequency at subsequent follow-up visits. These symptoms virtually disappeared very quickly in both quitters and reducers. Smokers invited to switch to electronic cigarettes who completely abstained from smoking showed steady progressive improvements in their FEF25-75% Normalization of peripheral airways function was associated with improvement in respiratory symptoms, adding to the notion that abstaining from smoking can reverse tobacco harm in the lung.

Concepts: Pulmonology, Smoking, Tobacco, Cigarette, Nicotine, Smoking cessation, Electronic cigarette, Spirometry