Scientific reductionism has been the basis of disease classification and understanding for more than a century. However, the reductionist approach of characterizing diseases from a limited set of ...clinical observations and laboratory evaluations has proven insufficient in the face of an exponential growth in data generated from transcriptomics, proteomics, metabolomics and deep phenotyping. A new systematic method is necessary to organize these datasets and build new definitions of what constitutes a disease that incorporates both biological and environmental factors to more precisely describe the ever-growing complexity of phenotypes and their underlying molecular determinants. Network medicine provides such a conceptual framework to bridge these vast quantities of data while providing an individualized understanding of disease. The modern application of network medicine principles is yielding new insights into the pathobiology of chronic kidney diseases and renovascular disorders by expanding the understanding of pathogenic mediators, novel biomarkers and new options for renal therapeutics. These efforts affirm network medicine as a robust paradigm for elucidating new advances in the diagnosis and treatment of kidney disorders.
L-Cysteine functionalized magnetite nanoparticles (L-Cyst-Fe
O
NPs) were synthesized by chemical co-precipitation using Fe
and Fe
as iron precursors, sodium hydroxide as a base and L-Cysteine as ...functionalized agent. The structural and morphological studies were carried out using X-ray powder diffraction, transmission electron microscopy, dynamic light scattering, scanning electron microscopy and energy dispersive X-ray spectroscopy, Fourier transform infrared spectroscopy, and UV-Vis spectrophotometric techniques. The zeta potential of bare Fe
O
and functionalized L-Cyst-Fe
O
NPs were +28 mV and -30.2 mV (pH 7.0), respectively. The positive surface charge changes to negative imply the presence of L-Cyst monolayer at particle interface. Band gap energy of 2.12 eV bare Fe
O
NPs and 1.4 eV L-Cyst-Fe
O
NPs were obtained. Lead and chromium removal were investigated at different initial pHs, contact time, temperatures and adsorbate-adsorbent concentrations. Maximum Cr
and Pb
removal occurred at pH 2.0 and 6.0, respectively. Sorption dynamics data were best described by pseudo-second order rate equation. Pb
and Cr
sorption equilibrium data were best fitted to Langmuir equation. Langmuir adsorption capacities of 18.8 mg/g (Pb
) and 34.5 mg/g (Cr
) at 45 °C were obtained. Regeneration of exhausted L-Cyst-Fe
O
NPs and recovery of Pb
/Cr
were demonstrated using 0.01 M HNO
and NaOH. L-Cyst-Fe
O
NPs stability and reusability were also demonstrated.
Salt-sensing mechanisms in hypertension involving the kidney, vasculature, and central nervous system have been well studied; however, recent studies suggest that immune cells can sense sodium (Na). ...Antigen-presenting cells (APCs) including dendritic cells critically modulate inflammation by activating T cells and producing cytokines. We recently found that Na enters dendritic cells through amiloride-sensitive channels including the α and γ subunits of the epithelial sodium channel (ENaC) and mediates nicotinamide adenine dinucleotide phosphate oxidase-dependent formation of immunogenic IsoLG (isolevuglandin)-protein adducts leading to inflammation and hypertension. Here, we describe a novel pathway in which the salt-sensing kinase SGK1 (serum/glucocorticoid kinase 1) in APCs mediates salt-induced expression and assembly of ENaC-α and ENaC-γ and promotes salt-sensitive hypertension by activation of the nicotinamide adenine dinucleotide phosphate oxidase and formation of IsoLG-protein adducts. Mice lacking SGK1 in CD11c cells were protected from renal inflammation, endothelial dysfunction, and developed blunted hypertension during the high salt feeding phase of the N-Nitro-L-arginine methyl ester hydrochloride/high salt model of salt-sensitive hypertension. CD11c APCs treated with high salt exhibited increased expression of ENaC-γ which coimmunoprecipitated with ENaC-α. This was associated with increased activation and expression of various nicotinamide adenine dinucleotide phosphate oxidase subunits. Genetic deletion or pharmacological inhibition of SGK1 in CD11c cells prevented the high salt-induced expression of ENaC and nicotinamide adenine dinucleotide phosphate oxidase. These studies indicate that expression of SGK1 in CD11c APCs contributes to the pathogenesis of salt-sensitive hypertension.
RATIONALE:Hypertension represents a major risk factor for stroke, myocardial infarction, and heart failure and affects 30% of the adult population. Mitochondrial dysfunction contributes to ...hypertension, but specific mechanisms are unclear. The mitochondrial deacetylase Sirt3 (Sirtuin 3) is critical in the regulation of metabolic and antioxidant functions which are associated with hypertension, and cardiovascular disease risk factors diminish Sirt3 level.
OBJECTIVE:We hypothesized that reduced Sirt3 expression contributes to vascular dysfunction in hypertension, but increased Sirt3 protects vascular function and decreases hypertension.
METHODS AND RESULTS:To test the therapeutic potential of targeting Sirt3 expression, we developed new transgenic mice with global Sirt3OX (Sirt3 overexpression), which protects from endothelial dysfunction, vascular oxidative stress, and hypertrophy and attenuates Ang II (angiotensin II) and deoxycorticosterone acetate–salt induced hypertension. Global Sirt3 depletion in Sirt3 mice results in oxidative stress due to hyperacetylation of mitochondrial superoxide dismutase (SOD2), increases HIF1α (hypoxia-inducible factor-1), reduces endothelial cadherin, stimulates vascular hypertrophy, increases vascular permeability and vascular inflammation (p65, caspase 1, VCAM vascular cell adhesion molecule-1, ICAM intercellular adhesion molecule-1, and MCP1 monocyte chemoattractant protein 1), increases inflammatory cell infiltration in the kidney, reduces telomerase expression, and accelerates vascular senescence and age-dependent hypertension; conversely, increased Sirt3 expression in Sirt3OX mice prevents these deleterious effects. The clinical relevance of Sirt3 depletion was confirmed in arterioles from human mediastinal fat in patients with essential hypertension showing a 40% decrease in vascular Sirt3, coupled with Sirt3-dependent 3-fold increases in SOD2 acetylation, NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activity, VCAM, ICAM, and MCP1 levels in hypertensive subjects compared with normotensive subjects.
CONCLUSIONS:We suggest that Sirt3 depletion in hypertension promotes endothelial dysfunction, vascular hypertrophy, vascular inflammation, and end-organ damage. Our data support a therapeutic potential of targeting Sirt3 expression in vascular dysfunction and hypertension.
Network medicine in Cardiovascular Research Lee, Laurel Y; Pandey, Arvind K; Maron, Bradley A ...
Cardiovascular research,
08/2021, Letnik:
117, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Abstract
The ability to generate multi-omics data coupled with deeply characterizing the clinical phenotype of individual patients promises to improve understanding of complex cardiovascular ...pathobiology. There remains an important disconnection between the magnitude and granularity of these data and our ability to improve phenotype–genotype correlations for complex cardiovascular diseases. This shortcoming may be due to limitations associated with traditional reductionist analytical methods, which tend to emphasize a single molecular event in the pathogenesis of diseases more aptly characterized by crosstalk between overlapping molecular pathways. Network medicine is a rapidly growing discipline that considers diseases as the consequences of perturbed interactions between multiple interconnected biological components. This powerful integrative approach has enabled a number of important discoveries in complex disease mechanisms. In this review, we introduce the basic concepts of network medicine and highlight specific examples by which this approach has accelerated cardiovascular research. We also review how network medicine is well-positioned to promote rational drug design for patients with cardiovascular diseases, with particular emphasis on advancing precision medicine.
Hydrogen peroxide (H2O2) is the most abundant reactive oxygen species (ROS) within mammalian cells. At low concentrations, H2O2 serves as a versatile cell signaling molecule that mediates vital ...physiological functions. Yet at higher concentrations, H2O2 can be a toxic molecule by promoting pathological oxidative stress in cells and tissues. Within normal cells, H2O2 is differentially distributed in a variety of subcellular locales. Moreover, many redox-active enzymes and their substrates are themselves differentially distributed within cells. Numerous reports have described the biological and biochemical consequences of adding exogenous H2O2 to cultured cells and tissues, but many of these observations are difficult to interpret: the effects of exogenous H2O2 do not necessarily replicate the cellular responses to endogenous H2O2. In recent years, chemogenetic approaches have been developed to dynamically regulate the abundance of H2O2 in specific subcellular locales. Chemogenetic approaches have been applied in multiple experimental systems, ranging from in vitro studies on the intracellular transport and metabolism of H2O2, all the way to in vivo studies that generate oxidative stress in specific organs in living animals. These chemogenetic approaches have exploited a yeast-derived d-amino acid oxidase (DAAO) that synthesizes H2O2 only in the presence of its d-amino acid substrate. DAAO can be targeted to various subcellular locales, and can be dynamically activated by the addition or withdrawal of its d-amino acid substrate. In addition, recent advances in the development of highly sensitive genetically encoded H2O2 biosensors are providing a better understanding of both physiological and pathological oxidative pathways. This review highlights several applications of DAAO as a chemogenetic tool across a wide range of biological systems, from analyses of subcellular H2O2 metabolism in cells to the development of new disease models caused by oxidative stress in vivo.
Display omitted
•Hydrogen peroxide (H2O2) is a key molecule that is involved in both oxidant signaling and oxidative stress.•D-amino acid oxidase (DAAO) is a powerful chemogenetic tool to generate H2O2 and dissect intracellular oxidant pathways.•Chemogenetics can be used to study oxidant pathways in normal cells and in disease states, including cardiovascular disease.
Genome damage and their defective repair have been etiologically linked to degenerating neurons in many subtypes of amyotrophic lateral sclerosis (ALS) patients; however, the specific mechanisms ...remain enigmatic. The majority of sporadic ALS patients feature abnormalities in the transactivation response DNA-binding protein of 43 kDa (TDP-43), whose nucleo-cytoplasmic mislocalization is characteristically observed in spinal motor neurons. While emerging evidence suggests involvement of other RNA/DNA binding proteins, like FUS in DNA damage response (DDR), the role of TDP-43 in DDR has not been investigated. Here, we report that TDP-43 is a critical component of the nonhomologous end joining (NHEJ)-mediated DNA double-strand break (DSB) repair pathway. TDP-43 is rapidly recruited at DSB sites to stably interact with DDR and NHEJ factors, specifically acting as a scaffold for the recruitment of break-sealing XRCC4-DNA ligase 4 complex at DSB sites in induced pluripotent stem cell-derived motor neurons. shRNA or CRISPR/Cas9-mediated conditional depletion of TDP-43 markedly increases accumulation of genomic DSBs by impairing NHEJ repair, and thereby, sensitizing neurons to DSB stress. Finally, TDP-43 pathology strongly correlates with DSB repair defects, and damage accumulation in the neuronal genomes of sporadic ALS patients and in Caenorhabditis elegans mutant with TDP-1 loss-of-function. Our findings thus link TDP-43 pathology to impaired DSB repair and persistent DDR signaling in motor neuron disease, and suggest that DSB repair-targeted therapies may ameliorate TDP-43 toxicity-induced genome instability in motor neuron disease.
Glacier dynamics and mass balance observations in Himalayan-Karakoram (H-K) region are important to monitor the effect of climatic perturbations over the highest cryospheric region of the world. Such ...studies can be accomplished by employing satellite based remote sensing technique as field measurements are difficult to obtain in these inaccessible region. In the present study, an attempt was made to investigate the retreat/advancement along with their mass fluctuations of 13 select glaciers from different sectors of H-K region over a continuous period from year 1996 to 2020 using satellite images. Variation in areal and snout fluctuations shown different patterns pertaining to gain/advancement and loss/retreat of each select glaciers. Mass loss for glaciers in Karakoram Range (-0.217 ± 0.017 m w e) was marginal when compared with Western (-0.26 ± 0.08 m w e), Central (-0.56 ± 0.067 m w e) and Eastern Himalayas (-0.625 ± 0.13 m w e). Contrasting relationship between glacier dynamics and mass balance has been obtained in the present study. Validation of results with existing field observations depicted the utility of satellite-based observation.
PDF
