Endothelial progenitor cells (EPCs) play an important role in angiogenesis, which is essential for numerous physiological processes as well as tumor growth. Several microRNAs (miRNAs) have been ...reported to be involved in angiogenesis. MiR-34a, recently reported as a tumor suppressor, has been found to target silent information regulator 1 (Sirt1), leading to cell cycle arrest or apoptosis. However, the role of miR-34a in EPC-mediated angiogenesis was unknown. The present study tested the hypothesis that miR-34a inhibits EPC-mediated angiogenesis by inducing senescence via suppressing Sirt1. Bone marrow-derived EPCs from adult male Sprague-Dawley rats were used. Results of flow cytometry showed that EPCs after 7 days of culture expressed both stem cell markers CD34 and CD133 and endothelial cell markers VEGFR-2 (flk-1) and VE-cadherin. MiR-34a was expressed in normal EPCs, and overexpression of miR-34a via its mimic transfection significantly increased its expression and impaired in vitro EPC angiogenesis. MiR-34a overexpression led to a significantly increased EPC senescence, paralleled with an approximately 40% Sirt1 reduction. Furthermore, knockdown of Sirt1 by its siRNA resulted in diminished EPC angiogenesis and increased senescence. Finally, overexpression of miR-34a increased the level of Sirt1 effector-acetylated forkhead box O transcription factors 1 (FoxO1), an effect mimicked in EPCs following Sirt1 knockdown. In conclusion, miR-34a impairs EPC-mediated angiogenesis by induction of senescence via inhibiting Sirt1.
In this issue of Neuron, Uribe-Arias et al.
show that, in larval zebrafish, astrocyte-like cells exhibit calcium responses to norepinephrine during behavioral-state transitions and alter neuronal ...response properties. Thus, astroglia can sculpt neuronal dynamics in behaviorally meaningful ways.
Simultaneous recordings of large populations of neurons in behaving animals allow detailed observation of high-dimensional, complex brain activity. However, experimental approaches often focus on ...singular behavioral paradigms or brain areas. Here, we recorded whole-brain neuronal activity of larval zebrafish presented with a battery of visual stimuli while recording fictive motor output. We identified neurons tuned to each stimulus type and motor output and discovered groups of neurons in the anterior hindbrain that respond to different stimuli eliciting similar behavioral responses. These convergent sensorimotor representations were only weakly correlated to instantaneous motor activity, suggesting that they critically inform, but do not directly generate, behavioral choices. To catalog brain-wide activity beyond explicit sensorimotor processing, we developed an unsupervised clustering technique that organizes neurons into functional groups. These analyses enabled a broad overview of the functional organization of the brain and revealed numerous brain nuclei whose neurons exhibit concerted activity patterns.
•Sensory input drives behavior via distributed circuits in larval zebrafish•Activity from nearly all neurons in the brain was recorded in behaving animals•Convergent representations of diverse visual stimuli inform behavioral choices•Unsupervised clustering reveals patterns of brain-wide functional organization
Chen et al. examine brain-wide functional organization in larval zebrafish under diverse visual stimulus conditions. They systematically characterize neurons related to convergent sensorimotor processing as well as extract concerted brain-wide activity patterns beyond sensorimotor contexts.
Most cardiovascular diseases (CVDs), as well as age-related cardiovascular alterations, are accompanied by increases in oxidative stress, usually due to increased generation and/or decreased ...metabolism of ROS (reactive oxygen species; for example superoxide radicals) and RNS (reactive nitrogen species; for example peroxynitrite). The superoxide anion is generated by several enzymatic reactions, including a variety of NADPH oxidases and uncoupled eNOS (endothelial NO synthase). To relieve the burden caused by this generation of free radicals, which also occurs as part of normal physiological processes, such as mitochondrial respiratory chain activity, mammalian systems have developed endogenous antioxidant enzymes. There is an increased usage of exogenous antioxidants such as vitamins C and E by many patients and the general public, ostensibly in an attempt to supplement intrinsic antioxidant activity. Unfortunately, the results of large-scale trails do not generate much enthusiasm for the continued use of antioxidants to mitigate free-radical-induced changes in the cardiovascular system. In the present paper, we review the clinical use of antioxidants by providing the rationale for their use and describe the outcomes of several large-scale trails that largely display negative outcomes. We also describe the emerging understanding of the detailed regulation of superoxide generation by an uncoupled eNOS and efforts to reverse eNOS uncoupling. SIRT1 (sirtuin 1), which regulates the expression and activity of multiple pro- and anti-oxidant enzymes, could be considered a candidate molecule for a 'molecular switch'.
Endothelial dysfunction enhances vascular inflammation, which initiates pulmonary arterial hypertension (PAH) pathogenesis, further induces vascular remodeling and right ventricular failure. ...Activation of inflammatory caspases is an important initial event at the onset of pyroptosis. Studies have shown that caspase-1-mediated pyroptosis has played a crucial role in the pathogenesis of PAH. However, the role of caspase-11, another inflammatory caspase, remains to be elucidated. Therefore, the purpose of this study was to clarify the role of caspase-11 in the development of PAH and its mechanism on endothelial cell function.
The role of caspase-11 in the progression of PAH and vascular remodeling was assessed in vivo. In vitro, the effect of caspase-4 silencing on the human pulmonary arterial endothelial cells pyroptosis was determined.
We confirmed that caspase-11 and its human homolog caspase-4 were activated in PAH animal models and TNF (tumor necrosis factor)-α-induced human pulmonary arterial endothelial cells. Caspase-11
relieved right ventricular systolic pressure, right ventricle hypertrophy, and vascular remodeling in Sugen-5416 combined with chronic hypoxia mice model. Meanwhile, pharmacological inhibition of caspase-11 with wedelolactone exhibited alleviated development of PAH on the monocrotaline-induced rat model. Moreover, knockdown of caspase-4 repressed the onset of TNF-α-induced pyroptosis in human pulmonary arterial endothelial cells and inhibited the activation of pyroptosis effector GSDMD (gasdermin D) and GSDME (gasdermin E).
These observations identified the critical role of caspase-4/11 in the pyroptosis pathway to modulate pulmonary vascular dysfunction and accelerate the progression of PAH. Our findings provide a potential diagnostic and therapeutic target in PAH.
The goal of this study was to develop an algorithm based on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM), codes for classifying children with chronic ...disease (CD) according to level of medical complexity and to assess the algorithm's sensitivity and specificity.
A retrospective observational study was conducted among 700 children insured by Washington State Medicaid with ≥1 Seattle Children's Hospital emergency department and/or inpatient encounter in 2010. The gold standard population included 350 children with complex chronic disease (C-CD), 100 with noncomplex chronic disease (NC-CD), and 250 without CD. An existing ICD-9-CM-based algorithm called the Chronic Disability Payment System was modified to develop a new algorithm called the Pediatric Medical Complexity Algorithm (PMCA). The sensitivity and specificity of PMCA were assessed.
Using hospital discharge data, PMCA's sensitivity for correctly classifying children was 84% for C-CD, 41% for NC-CD, and 96% for those without CD. Using Medicaid claims data, PMCA's sensitivity was 89% for C-CD, 45% for NC-CD, and 80% for those without CD. Specificity was 90% to 92% in hospital discharge data and 85% to 91% in Medicaid claims data for all 3 groups.
PMCA identified children with C-CD (who have accessed tertiary hospital care) with good sensitivity and good to excellent specificity when applied to hospital discharge or Medicaid claims data. PMCA may be useful for targeting resources such as care coordination to children with C-CD.
Co‐delivery of Doxorubicin and siRNAs by mesoporous silica nanoparticles into multidrug‐resistance cancer cells with minimal premature release significantly enhances the efficacy of chemotherapy by ...conquering the nonpump resistance and possibly bypassing the efflux pump resistance (see image).
Fine ambient particle matter (PM2.5), a component of air pollution, is linked to inflammatory lung injury. PM2.5-induced diffuse intra-alveolar edema in the lungs is accompanied by polymorphonuclear ...leukocyte (PMN) activation and infiltration, as well as endothelial cell (EC) injury and VCAM-1 expression. Activated-PMNs and injured ECs exacerbate particle-induced lung injury. Through VCAM-1 upregulation, PM2.5 increases the permeability of endothelial and epithelial monolayers in vitro, and promotes PMN adhesion, chemotaxis, and migration across the monolayer. Neutropenia or soluble VCAM-1 inhibits PM2.5-induced lung injury. VCAM-1-mediated PMN infiltration is essential for a detrimental cycle of PM2.5-induced inflammation and lung injury.
Display omitted
•Short-term exposure to fine particulate matter (PM2.5) increases PMN/WBC ratio in human.•PM2.5 is deposited in alveolar space and endothelial cells, resulting in lung injury.•VCAM-1-mediated PMN infiltration was essential for a detrimental cycle of PM2.5-induced inflammation and lung injury.•PM2.5 increased VCAM-1 expression and epithelial/endothelial monolayer permeability•Neutropenia or soluble VCAM-1 inhibited PM2.5-induced lung injury.
Fine ambient particle matter (PM2.5) induces inflammatory lung injury; however, whether intratracheal administration of PM2.5 increases pulmonary polymorphonuclear leukocyte (PMN) infiltration, the mechanism of infiltration, and if these cells exacerbate PM2.5-induced lung injury are unknown.
Using 32,704 subjects, the association between blood PMNs and ambient PM2.5 levels on the previous day was retrospectively analyzed. Neutropenia was achieved by injecting mice with PMN-specific antibodies. Inhibition of PMN infiltration was achieved by pretreating PMNs with soluble vascular cell adhesion molecule-1 (sVCAM-1). The effects of PMNs on PM2.5-induced lung injury and endothelial dysfunction were observed.
Short-term PM2.5 (> 75 μg/m3 air) exposure increased the PMN/white blood cell ratio and the PMN count in human peripheral blood observed during routine examination. A significant number of PM2.5-treated PMNs was able to bind sVCAM-1. In mice, intratracheally-instilled PM2.5 deposited in the alveolar space and endothelial cells, which caused significant lung edema, morphological disorder, increased permeability of the endothelial-alveolar epithelial barrier, and PMN infiltration with increased VCAM-1 expression. Depletion of circulatory PMNs inhibited these adverse effects. Replenishment of untreated PMNs, but not those pretreated with soluble VCAM-1, restored lung injury. In vitro, PM2.5 increased VCAM-1 expression and endothelial and epithelial monolayer permeability, and promoted PMN adhesion to, chemotaxis toward, and migration across these monolayers. PMNs, but not those pretreated with soluble VCAM-1, exacerbated these effects.
VCAM-1-mediated PMN infiltration was essential for a detrimental cycle of PM2.5-induced inflammation and lung injury. Results suggest that drugs that inhibit PMN function might prevent acute deterioration of chronic pulmonary and cardiovascular diseases triggered by PM2.5.
Long non-coding RNAs (lncRNAs) are emerging regulators of pathophysiological processes including atherosclerosis. Using RNA-seq profiling of the intima of lesions, here we identify a ...macrophage-specific lncRNA MAARS (Macrophage-Associated Atherosclerosis lncRNA Sequence). Aortic intima expression of MAARS increases by 270-fold with atherosclerotic progression and decreases with regression by 60%. MAARS knockdown reduces atherosclerotic lesion formation by 52% in LDLR
mice, largely independent of effects on lipid profile and inflammation, but rather by decreasing macrophage apoptosis and increasing efferocytosis in the vessel wall. MAARS interacts with HuR/ELAVL1, an RNA-binding protein and important regulator of apoptosis. Overexpression and knockdown studies verified MAARS as a critical regulator of macrophage apoptosis and efferocytosis in vitro, in an HuR-dependent manner. Mechanistically, MAARS knockdown alters HuR cytosolic shuttling, regulating HuR targets such as p53, p27, Caspase-9, and BCL2. These findings establish a mechanism by which a macrophage-specific lncRNA interacting with HuR regulates apoptosis, with implications for a broad range of vascular disease states.
COVID-19 brought masking, a practice that was largely confined to certain technical occupational settings in the US, into the heart of a national controversy. As with prior emerging infectious ...diseases (such as HIV, SARS, and Ebola), US public health experts and governmental agencies positioned themselves as authoritative producers of emerging scientific knowledge, including best practices for public masking. US epidemiological outcomes, however, have sorely lagged behind many other countries. The US leads the world in confirmed cases of and deaths from COVID-19, undermining presumed hierarchies in global health authority today. In this essay, I compare US and Taiwanese masking policies, delineating how social relations of care in the US become sites of political conflict within a hierarchical global ecology of scientific knowledge and medical supplies. Drawing upon my experience as an MD/PhD in anthropology trainee studying emerging infectious diseases and as a Taiwanese American immigrant, I explore conflicts over mask acquisition and usage across borders and time, illuminating global inequities of scientific knowledge production and pandemic containment and underscoring racialised disavowals that persist in US public health. These racialised disavowals illustrate the structural limits that circumscribe possibilities of containment during an uncontained pandemic.
PDF
