Metabolic syndrome (MetS) is a cluster ofassociated metabolic traits that collectively confer unsurpassed risk for development of cardiovascular disease (CVD) and type 2 diabetes compared to any ...single CVD risk factor. Truncal obesity plays an exceptionally critical role among all metabolic traits of the MetS. Consequently, the prevalence of the MetS has steadily increased with the growing epidemic of obesity. Pharmacotherapy has been available for obesity for more than one decade, but with little success in improving the metabolic profiles.
The serotonergic drugs and inhibitors of pancreatic lipases were among the few drugs that were initially approved to treat obesity. At the present time, only the pancreatic lipase inhibitor orlistat is approved for long-term treatment of obesity. New classes of anti-diabetic drugs, including glucagon-like peptide 1 receptor (GLP-1R) agonists and Dipeptidyl-peptidase IV (DPP-IV) inhibitors, are currently being evaluated for their effects on obesity and metabolic traits. The genetic studies of obesity and metabolic syndrome have identified novel molecules acting on the hunger and satiety peptidergic signaling of the gut-hypothalamus axis or the melanocortin system of the brain and are promising targets for future drug development. The goal is to develop drugs that not only treat obesity, but also favorably impact its associated traits.
Dietary behavior is closely connected to type 2 diabetes. The purpose of this meta-analysis was to identify behavior change techniques (BCTs) and specific components of dietary interventions for ...patients with type 2 diabetes associated with changes in HbA
and body weight.
The Cochrane Library, CINAHL, Embase, PubMed, PsycINFO, and Scopus databases were searched. Reports of randomized controlled trials published during 1975-2017 that focused on changing dietary behavior were selected, and methodological rigor, use of BCTs, and fidelity and intervention features were evaluated.
In total, 54 studies were included, with 42 different BCTs applied and an average of 7 BCTs used per study. Four BCTs-"problem solving," "feedback on behavior," "adding objects to the environment," and "social comparison"-and the intervention feature "use of theory" were associated with >0.3% (3.3 mmol/mol) reduction in HbA
. Meta-analysis revealed that studies that aimed to control or change the environment showed a greater reduction in HbA
of 0.5% (5.5 mmol/mol) (95% CI -0.65, -0.34), compared with 0.32% (3.5 mmol/mol) (95% CI -0.40, -0.23) for studies that aimed to change behavior. Limitations of our study were the heterogeneity of dietary interventions and poor quality of reporting of BCTs.
This study provides evidence that changing the dietary environment may have more of an effect on HbA
in adults with type 2 diabetes than changing dietary behavior. Diet interventions achieved clinically significant reductions in HbA
, although initial reductions in body weight diminished over time. If appropriate BCTs and theory are applied, dietary interventions may result in better glucose control.
The RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) framework is a useful tool for evaluating the impact of programs in community settings. RE-AIM has been applied to ...evaluate individual programs but seldom used to evaluate the collective impact of community-based, public health programming developed and delivered by multiple autonomous organizations. The purposes of this paper were to (a) demonstrate how RE-AIM can be operationalized and applied to evaluate the collective impact of similar autonomous programs that promote health and well-being and (b) provide preliminary data on the collective impact of Canadian spinal cord injury (SCI) peer mentorship programs on the delivery of peer mentorship services.
Criteria from all five RE-AIM dimensions were operationalized to evaluate multiple similar community-based programs. For this study, nine provincial organizations that serve people with SCI were recruited from across Canada. Organizations completed a structured self-report questionnaire and participated in a qualitative telephone interview to examine different elements of their peer mentorship program. Data were analyzed using summary statistics.
Having multiple indicators to assess RE-AIM dimensions provided a broad evaluation of the impact of Canadian SCI peer mentorship programs. Peer mentorship programs reached 1.63% of the estimated Canadian SCI population. The majority (67%) of organizations tracked the effectiveness of peer mentorship through testimonials and reports. Setting-level adoption rates were high with 100% of organizations offering peer mentorship in community and hospital settings. On average, organizations allocated 10.4% of their operating budget and 9.8% of their staff to implement peer mentorship and 89% had maintained their programming for over 10 years. Full interpretation of the collective impact of peer mentorship programs was limited as complete data were only collected for 52% of survey questions.
The lack of available organizational data highlights a significant challenge when using RE-AIM to evaluate the collective impact of multiple programs that promote health and well-being. Although researchers are encouraged to use RE-AIM to evaluate the collective impact of programs delivered by different organizations, documenting limitations and providing recommendations should be done to further the understanding of how best to operationalize RE-AIM in these contexts.
Diet behaviour is influenced by the interplay of the physical and social environment as well as macro-level and individual factors. In this study, we focus on diet behaviour at an individual level ...and describe the design of a behaviour change artefact to support diet behaviour change in persons with type 2 diabetes. This artefact was designed using a human-centred design methodology and the Behaviour Change Wheel framework. The designed artefact sought to support diet behaviour change through the addition of healthy foods and the reduction or removal of unhealthy foods over a 12-week period. These targeted behaviours were supported by the enabling behaviours of water consumption and mindfulness practice. The artefact created was a behaviour change planner in calendar format, that incorporated behaviour change techniques and which focused on changing diet behaviour gradually over the 12-week period. The behaviour change planner forms part of a behaviour change intervention which also includes a preparatory workbook exercise and one-to-one action planning sessions and can be customised for each participant.
Smooth muscle cells (SMCs) are remarkably plastic. Their reversible differentiation is required for growth and wound healing but also contributes to pathologies such as atherosclerosis and ...restenosis. Although key regulators of the SMC phenotype, including myocardin (MYOCD) and KLF4, have been identified, a unifying epigenetic mechanism that confers reversible SMC differentiation has not been reported.
Using human SMCs, human arterial tissue, and mouse models, we report that SMC plasticity is governed by the DNA-modifying enzyme ten-eleven translocation-2 (TET2). TET2 and its product, 5-hydroxymethylcytosine (5-hmC), are enriched in contractile SMCs but reduced in dedifferentiated SMCs. TET2 knockdown inhibits expression of key procontractile genes, including MYOCD and SRF, with concomitant transcriptional upregulation of KLF4. TET2 knockdown prevents rapamycin-induced SMC differentiation, whereas TET2 overexpression is sufficient to induce a contractile phenotype. TET2 overexpression also induces SMC gene expression in fibroblasts. Chromatin immunoprecipitation demonstrates that TET2 coordinately regulates phenotypic modulation through opposing effects on chromatin accessibility at the promoters of procontractile versus dedifferentiation-associated genes. Notably, we find that TET2 binds and 5-hmC is enriched in CArG-rich regions of active SMC contractile promoters (MYOCD, SRF, and MYH11). Loss of TET2 and 5-hmC positively correlates with the degree of injury in murine models of vascular injury and human atherosclerotic disease. Importantly, localized TET2 knockdown exacerbates injury response, and local TET2 overexpression restores the 5-hmC epigenetic landscape and contractile gene expression and greatly attenuates intimal hyperplasia in vivo.
We identify TET2 as a novel and necessary master epigenetic regulator of SMC differentiation.
Aberrant expression of circular RNA contributes to human diseases. Circular RNAs regulate gene expression by sequestering specific microRNAs. In this study, we investigated whether circMAP3K5 ...(circular mitogen-activated protein kinase 5) could act as a competing endogenous microRNA-22-3p (miR-22-3p) sponge and regulate neointimal hyperplasia.
Circular RNA profiling from genome-wide RNA sequencing data was compared between human coronary artery smooth muscle cells (SMCs) treated with or without platelet-derived growth factor. Expression levels of circMAP3K5 were assessed in human coronary arteries from autopsies on patients with dilated cardiomyopathy or coronary heart disease. The role of circMAP3K5 in intimal hyperplasia was further investigated in mice with adeno-associated virus 9-mediated circMAP3K5 transfection. SMC-specific Tet2 (ten-eleven translocation-2) knockout mice and global miR-22-3p knockout mice were used to delineate the mechanism by which circMAP3K5 attenuated neointimal hyperplasia using the femoral arterial wire injury model.
RNA sequencing demonstrated that treatment with platelet-derived growth factor-BB significantly reduced expression of circMAP3K5 in human coronary artery SMCs. Wire-injured mouse femoral arteries and diseased arteries from patients with coronary heart disease (where platelet-derived growth factor-BB is increased) confirmed in vivo downregulation of circMAP3K5 associated with injury and disease. Lentivirus-mediated overexpression of circMAP3K5 inhibited the proliferation of human coronary artery SMCs. In vivo adeno-associated virus 9-mediated transfection of circMap3k5 (mouse circular Map3k5) specifically inhibited SMC proliferation in the wire-injured mouse arteries, resulting in reduced neointima formation. Using a luciferase reporter assay and RNA pull-down, circMAP3K5 (human circular MAP3K5) was found to sequester miR-22-3p, which, in turn, inhibited the expression of TET2. Both in vitro and in vivo results demonstrate that the loss of miR-22-3p recapitulated the antiproliferative effect of circMap3k5 on vascular SMCs. In SMC-specific Tet2 knockout mice, loss of Tet2 abolished the circMap3k5-mediated antiproliferative effect on vascular SMCs.
We identify circMAP3K5 as a master regulator of TET2-mediated vascular SMC differentiation. Targeting the circMAP3K5/miR-22-3p/TET2 axis may provide a potential therapeutic strategy for diseases associated with intimal hyperplasia, including restenosis and atherosclerosis.
To describe the process and outcomes of using a new evidence base to develop scientific guidelines that specify the type and minimum dose of exercise necessary to improve fitness and cardiometabolic ...health in adults with spinal cord injury (SCI).
International.
Using Appraisal of Guidelines, Research and Evaluation (AGREE) II reporting criteria, steps included (a) determining the guidelines' scope; (b) conducting a systematic review of relevant literature; (c) holding three consensus panel meetings (European, Canadian and International) to formulate the guidelines; (d) obtaining stakeholder feedback; and (e) process evaluation by an AGREE II consultant. Stakeholders were actively involved in steps (c) and (d).
For cardiorespiratory fitness and muscle strength benefits, adults with a SCI should engage in at least 20 min of moderate to vigorous intensity aerobic exercise 2 times per week AND 3 sets of strength exercises for each major functioning muscle group, at a moderate to vigorous intensity, 2 times per week (strong recommendation). For cardiometabolic health benefits, adults with a SCI are suggested to engage in at least 30 min of moderate to vigorous intensity aerobic exercise 3 times per week (conditional recommendation).
Through a systematic, rigorous, and participatory process involving international scientists and stakeholders, a new exercise guideline was formulated for cardiometabolic health benefits. A previously published SCI guideline was endorsed for achieving fitness benefits. These guidelines represent an important step toward international harmonization of exercise guidelines for adults with SCI, and a foundation for developing exercise policies and programs for people with SCI around the world.
Promoters to Study Vascular Smooth Muscle Chakraborty, Raja; Saddouk, Fatima Zahra; Carrao, Ana Catarina ...
Arteriosclerosis, thrombosis, and vascular biology,
04/2019, Letnik:
39, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Smooth muscle cells (SMCs) are a critical component of blood vessel walls that provide structural support, regulate vascular tone, and allow for vascular remodeling. These cells also exhibit a ...remarkable plasticity that contributes to vascular growth and repair but also to cardiovascular pathologies, including atherosclerosis, intimal hyperplasia and restenosis, aneurysm, and transplant vasculopathy. Mouse models have been an important tool for the study of SMC functions. The development of smooth muscle-expressing Cre-driver lines has allowed for exciting discoveries, including recent advances revealing the diversity of phenotypes derived from mature SMC transdifferentiation in vivo using inducible CreER
lines. We review SMC-targeting Cre lines driven by the Myh11, Tagln, and Acta2 promoters, including important technical considerations associated with these models. Limitations that can complicate study of the vasculature include expression in visceral SMCs leading to confounding phenotypes, and expression in multiple nonsmooth muscle cell types, such as Acta2-Cre expression in myofibroblasts. Notably, the frequently employed Tagln/ SM22α- Cre driver expresses in the embryonic heart but can also confer expression in nonmuscular cells including perivascular adipocytes and their precursors, myeloid cells, and platelets, with important implications for interpretation of cardiovascular phenotypes. With new Cre-driver lines under development and the increasing use of fate mapping methods, we are entering an exciting new era in SMC research.
Genomics has provided a detailed structural description of the cancer genome. Identifying oncogenic drivers that work primarily through dosage changes is a current challenge. Unrestrained ...proliferation is a critical hallmark of cancer. We constructed modular, barcoded libraries of human open reading frames (ORFs) and performed screens for proliferation regulators in multiple cell types. Approximately 10% of genes regulate proliferation, with most performing in an unexpectedly highly tissue-specific manner. Proliferation drivers in a given cell type showed specific enrichment in somatic copy number changes (SCNAs) from cognate tumors and helped predict aneuploidy patterns in those tumors, implying that tissue-type-specific genetic network architectures underlie SCNA and driver selection in different cancers. In vivo screening confirmed these results. We report a substantial contribution to the catalog of SCNA-associated cancer drivers, identifying 147 amplified and 107 deleted genes as potential drivers, and derive insights about the genetic network architecture of aneuploidy in tumors.
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•Barcoded genome-scale ORF expression libraries allow gain-of-function screens•Regulators of proliferation exhibit a striking degree of tissue-specificity•Proliferation driver genes help predict focal SCNAs and cancer aneuploidy patterns•Approximately 250 candidate cancer drivers identified in recurring SCNAs
The highly tissue-specific epigenetic landscape of a given cell type establishes its responsiveness to oncogenic proliferation signals and determines which drivers, somatic copy number changes, and anueploidies are selected during tumorigenesis.
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