Month: August 2020

Upon transplantation, HPDLSCs co-cultured with DFCs grew well and produced root/periodontal ligament-like and periodontal ligament/bone-like tissues. Several studies have shown that after engraftment, MSCs contribute to tissue repair secretion of trophic molecules, including soluble extracellular matrix glycoproteins, cytokines, and growth factors, and through direct cell-to-cell contact. Moreover, as a type of MSC, DFCs are also young precursor cells. Cells with a young phenotype have been confirmed to enhance the proliferation and differentiation ability of PDLSCs by providing a young microenvironment. However, the environment supplied by DFCs is complicated, which suggests that a combination of multiple factors from DFCs may influence the proliferation and differentiation of HPDLSCs and PPDLSCs, subsequently providing better periodontal regeneration in vivo. In our study, co-culture with DFCs had a greater effect on PPDLSCs than HPDLSCs. Specifically, the stemness-associated gene expression, number of colony-forming units, proliferation index, ALP activity and osteogenic gene expression were all enhanced to a greater degree. Several studies have indicated that, in addition to secreting trophic factors as mentioned above, MSCs also have immunomodulatory and anti-inflammatory properties. MSCs have been shown to modulate the microenvironment of injured tissues and protect damaged tissues by releasing LY2109761 antiinflammatory molecules. These molecules may not only reduce inflammation, apoptosis and fibrosis in damaged tissues but also enhance tissue regeneration. The PPDLSCs in this study were derived from an inflammatory microenvironment. Epigenetics studies have shown that PPDLSCs may constitutively secrete inflammatory factors, such as TNF-a and IL-1b, in vitro. Thus, PPDLSCs are distinct from HPDLSCs with regard to both the cell source and the microenvironment. For example, inflammatory factors secreted by PPDLSCs may stimulate the immunomodulatory effects of DFCs, causing the DFCs to produce more anti-inflammatory cytokines and trophic factors, thereby enhancing the biological properties of the PPDLSCs. Future studies should further explore the specific mechanism. The inactivation of tumor-suppressor genes is a characteristic step in cancer development and progression. Among the mechanisms of tumor-suppressor gene inactivation, aberrant DNA methylation of gene promoter islands and endogenous miRNA upregulation lead to the silencing of tumor-suppressor genes in multiple tissues. The four-and-a-half LIM proteins are a family of LIM-only proteins that regulate cell proliferation, differentiation, and apoptosis. Studies using clinical samples have shown that FHL1 expression is down-regulated in multiple human tumor types, including gastric cancer and hepatocarcinoma. FHL1 exerts tumor suppressor function via multiple mechanisms, including the activation of the TGF-b-like and Src-MAPK signaling pathways and protein interaction with ZO-1, HIF1a, and ERa. Although the role of FHL1 in cancer development and progression is well established.

MicroRNAs are a class of short, highly conserved, non-coding RNAs that function as negative posttranscriptional regulators of target genes. Accumulating evidence has shown that miRNAs are aberrantly expressed during the development and/or progression of a variety of human cancers. Roles for miRNAs in the regulation of tumorigenesis via the targeting of important genes within signaling pathways are evident. To date, however, miRNAs that target FHL1 have not been reported. To clarify the mechanism of FHL1 downregulation during tumorogenesis, we assessed the involvement of miRNAs that target the FHL1 promoter. We report that Torin 1 miR-410 is upregulated in colorectal cancer and hepatocarcinoma and that miR-410 can decrease FHL1 protein levels both directly by targeting the FHL1 3’UTR and indirectly by promoting the upregulation of DNA methylases. In particular, miR-410 promotes the binding of DNMT3A to the FHL1 promoter, which leads to the hypermethylation of the FHL1 promoter. The findings here could provide a mechanism for FHL1 down-regulation during tumorigenesis. Consistently, analysis of clinical hepatocarcinoma and colorectal specimens revealed a physiological association between the expression of miR-410, FHL1 and DNMT3A, which implicates miR-410 as a potential oncogenic biomarker that functions by down-regulating FHL1 in these tissues. The findings here within indicate, for the first time, that miR410 may serve as a regulator of FHL1 expression through direct targeting of its 3’UTR and indirect regulation of its methylation in human colorectal cancer and hepatocarcinoma. Recent reports have shown other possible functions of miR-410. miR410 is involved in the regulation of lipoprotein lipase levels, muscle regeneration, and idiopathic pulmonary fibrosis. Also, miR-410 is considered a diagnostic and prognostic biomarker in some diseases. In a study based on plasma samples from 122 women, tumor tissues with a combination of miR-92a/miR-410 or miR-92a/miR-205/miR-410 expression was shown to serve as a noninvasive biomarker for early cancer detection and prognosis. Therefore, there is a precedent for a possible role of miR-410 as a biomarker for malignant diseases. Our results also show that expression is elevated in clinical tissue from colorectal and liver tumors; however, based on our limited sample size, the use of a larger sample size may be required to confirm the potential utility of miR-410 as a biomarker for colorectal and liver tumors. FHL1 is a well known tumor-suppressor gene with no or relatively low expression in tumors. Methylation-silenced mutation is one of the important mechanisms contributing its low-expression. Here, we have shown another new mechanism for silencing of FHL1 expression in tumors: miR-410 not only specifically targets the 39UTR of FHL1, but also promotes DNMT3A binding to the FHL1 promoter, which leads to its hypermethylation in cancer cells, suggesting that the regulation of FHL1 by miR-410 occurs by dual mechanisms. Exogenous miR-410 expression leads to the upregulation of methylases, and both miR-410 and DNMT3A are upregulated.

Critically appraise relevant research, and to collect and analyse data from the studies that are included in the review. Statistical methods may or may not be used to analyse and summarise the results of the included studies “. Systematic reviews are increasingly accepted as important evidence-based decision-making aids. However, decision-makers cite the lack of equity considerations as barriers to using systematic reviews. The lack of analysis and lack of reporting of evidence about sex/gender in systematic reviews raise scientific and ethical concerns. Barriers to implementing sex/gender analysis in systematic reviews are manifold. Evidence suggests that there is a general lack of understanding of the concepts of sex and gender, how they are interrelated, whether and how they affect health interventions. Other barriers include: limited access to sexdisaggregated data, issues with data quality and reporting, challenges related to measuring and analysing gender and, a lack of guidance on methods.

More recently, however, because many funding agencies now have policies mandating that both men and women be included in clinical trials and that results for men and women be reported and interpreted separately, more researchers have begun to conduct sex/gender analysis. Systematic reviewers, most notably those working within the Cochrane Collaboration, are also increasingly examining the related question “To whom does this evidence apply?” in their assessment of the quality of available evidence. However, this is an emerging area of inquiry and there continues to be a lack of exemplar reviews that address sex/gender considerations. When reviewers have addressed sex/gender their conclusions have often been contingent on methodological or data limitations. For example, a systematic review of tobacco and smoking cessation interventions found some differences in intervention effects for girls and boys. The authors reported that school-based restrictions may be more effective for girls whereas increases in the price of tobacco products may have more influence on boys; however, these findings were often from single or methodologically weak studies. Further, in a systematic review on quality of life after total hip or total knee arthroplasty, men appeared to benefit more from the intervention but the authors stated that their conclusion was tempered by the few studies that addressed this issue.

A recent meta-analysis of 89 studies using clinical trials, interrupted time series and other methods assessed the effectiveness of antibiotic stewardship programs. It showed that policy interventions changed antibiotic treatment and this was associated with significant improvement in outcomes. Unfortunately, there were hardly any studies from LMIC in this metanalysis. This is an important aspect to consider since infections and irrational antibiotic use are widely prevalent in these countries. Another purpose of antibiotic stewardship is to contain antibiotic use. Containment is important as increased antibiotic use leading to environmental pressure contributes more to bacterial resistance.

DDR is stably associated with the cellular senescence condition. The biology of SAA has been investigated extensively. SAA is a key mediator in innate immune responses, stimulation of cytokines, and matrix metalloproteinases. Biological activities include regulation of cholesterol metabolism, insulin resistance and glycemic control. During acute phase, SAA displaces 80% of ApoAI from HDL. Elevated levels of SAA are down-regulated by therapy with PPARγ agonist agents, whereas glucocorticoid treatment did not Pazopanib downregulate extrahepatic expression of SAA. In chronic inflammatory diseases, such as rheumatoid arthritis, metabolic syndrome or atherosclerosis, prolonged elevation of SAA may contribute to tissue damage and degradation. Elevated SAA contributes to AA amyloidosis if abnormal cleavage and deposition occurs in genetically predisposed individuals. SAA was shown to regulate expression of TGF-β, the master regulator of connective tissue remodeling and fibrogenesis. In mice, SAA adenoviral transfer leads to increased plasma TGF-β, and increased biglycan expression. Interestingly, it has been reported that the SAA receptor FPRL-1/FPR2 was involved in TGF-β, as well as in biglycan expression. These studies implicate SAA in extracellular matrix remodeling. The role of inflammation in SSc, and biomarkers for identifying inflammation, have received scant attention to date. Previous studies showed that erythrocyte sedimentation rate is elevated in SSc and predicts mortality. ESR is one of the parameters comprising the modified Medsger SSc Disease Severity Scale. Levels of CRP are also elevated in SSc, correlate with disease activity and pulmonary function, and predict pulmonary decline and survival. In contrast to CRP and ESR, little is known to date about SAA in SSc or its role in disease pathogenesis. A small pilot study over three decades ago showed elevated SAA levels in 24% of SSc patients; marked elevations predicted poor survival. In the present study, we sought to determine circulating levels of SAA in SSc, and to correlate these levels with clinical features of the disease. Our findings indicate that SAA levels are elevated in a subset of SSc patients, and correlate with pulmonary involvement and patient-reported outcomes, in particular symptoms related to respiratory dysfunction. In vitro, recombinant SAA induced enhanced IL-6 and IL-8 production in fibroblasts explanted from normal human lungs. These findings provide evidence for the occurrence of a systemic inflammatory process in SSc, and suggest a potential for SAA as a biomarker in evaluating patients with SSc. We show here that circulating levels of the inflammatory marker SAA are elevated in patients with SSc. Elevated SAA levels are associated with signs and symptoms of pulmonary involvement, as well as health-related quality of life measures. In particular, levels of SAA were found to correlate with measures of pulmonary function and radiologic evidence of SSc-associated interstitial lung disease. Furthermore, SAA levels were significantly correlated with PA pressure, in a manner analogous to recent findings in patients with idiopathic pulmonary arterial hypertension. Exposure of healthy lung fibroblasts in culture to SAA resulted in stimulation of the expression of IL-6 and IL-8, two cytokines previously implicated in the pathogenesis of SSc. The levels of SAA were only modestly correlated with those of the inflammatory markers CRP and ESR. While levels of CRP and ESR were elevated in 29 and 37% of SSc patients, respectively, the correlation with SAA was less than 0.5, revealing unexpected differences in these three inflammatory parameters in SSc.

Chronic inflammation and fibrosis are often linked, particularly in interstitial lung disease. For instance, in patients with sarcoid lung disease, SAA correlated with collagen deposition and lung fibrosis and negative correlation of lung functions and SAA was found. Recombinant SAA potently stimulated the production of IL-6 and IL-8 in lung fibroblasts in culture. Importantly, these stimulatory effects of SAA on cytokine gene expression occurred at physiologic concentrations of SAA. We previously reported that SAA stimulated IL-6 in human endothelial cells in culture and IL-8, MMP-3 proteins and NF-ƘB DNA binding activity were up-regulated by SAA in fibroblast-like synoviocytes. In this study we report stimulation of IL-6 in lung fibroblasts at the mRNA level and secreted cytokine production. IL-6 is emerging as a potentially important mediator of fibrosis in SSc. In fibroblasts, SAA has been recently shown to trigger a TLR2-dependent innate immune pathway, contributing to induction of IL-6, and potentially linking SAA to innate immunity and fibrosis in SSc. IL-6 is implicated in the regulation of collagen gene expression and extracellular matrix production. Furthermore, levels of IL-6 are elevated in serum and lesional tissue of patients with SSc. Treatment of SSc patients with anti-IL-6 intervention was shown to have beneficial effects in a small clinical trial. IL-8 is a multifunctional chemokine produced primarily by macrophages, and exerting potent effects on chemotaxis and angiogenesis. Scleroderma fibroblasts spontaneously secrete IL-8. We and others have shown that levels of IL-8 are elevated in the serum, as well as in bronchoalveolar lavage fluid, from patients with SSc. The present results demonstrate elevated circulating SAA levels in a subset of SSc patients that are correlated with symptoms and signs of SSc-associated pulmonary involvement. The biological implications of these findings remain to be elucidated. It is noteworthy, however, that in lung fibroblasts, SAA acts as a direct stimulus for the synthesis of IL-6 and IL-8, mediators implicated in the pathogenesis of SSc and its pulmonary complications. Longitudinal studies to determine if baseline SAA levels in SSc predict disease activity or progression, and whether changes in SAA levels over time correlate with changes in measures of disease activity, seem warranted. Nearsightedness arises from a mismatch between the focal power of the optical components and the axial length. It is the most commonly found disorder in the development of the juvenile eye and steadily rises in prevalence, currently affecting 30–50% of young adults in Europe and around 80% in Asia. Recent studies have shown that Trichostatin A outdoor exposure seems to be a promising approach to reduce the development of myopia – children who spend more time outdoors appear to be less likely to become myopic. A number of possible factors can be suggested for the protective effect of outdoor exposure, such as light intensity, physical activity, viewing distance, variations in accommodative requirement, which have been systematically discussed by a recent review. Rose et al. were the first to suggest that light intensity might be an important factor and this assumption has gained accumulating experimental evidence in animals. Specifically, with the urbanization of modern world, humans tend to spend more time indoors with illuminances typically ranging from 100 lux to 500 lux. Compared with the outdoor illuminance, the indoor illuminance is very much lower. Cohen et al., observed that chickens raised at low light for extended periods developed significant myopia, as compared to those reared under standard or high light level.