Possible kidney-lung cross-talk in COVID-19: in silico modeling of SARS-CoV-2 infection.

Background: Publicly available genomics datasets have grown drastically during the past decades. Although most of these datasets were initially generated to answer a pre-defined scientific question, their repurposing can be useful when new challenges such as COVID-19 arise. While the establishment and use of experimental models of COVID-19 are in progress, the potential hypotheses for mechanisms of onset and progression of COVID-19 can be generated by using in silico analysis of known molecular changes during COVID-19 and targets for SARS-CoV-2 invasion.

Novel Protective Role of Nicotinamide Phosphoribosyltransferase in Acetaminophen-Induced Acute Liver Injury in Mice.

Acetaminophen overdose is the most common cause of acute liver injury (ALI) or acute liver failure in the United States. Its pathogenetic mechanisms are incompletely understood. Additional studies are warranted to identify new genetic risk factors for more mechanistic insights and new therapeutic target discoveries.

Metabolic and molecular insights into an essential role of nicotinamide phosphoribosyltransferase.

Nicotinamide phosphoribosyltransferase (NAMPT) is a pleiotropic protein implicated in the pathogenesis of acute respiratory distress syndrome, aging, cancer, coronary heart diseases, diabetes, nonalcoholic fatty liver disease, obesity, rheumatoid arthritis, and sepsis. However, the underlying molecular mechanisms of NAMPT in these physiological and pathological processes are not fully understood. Here, we provide experimental evidence that a Nampt gene homozygous knockout (Nampt) resulted in lethality at an early stage of mouse embryonic development and death within 5-10 days in adult mice accompanied by a 25.

Intermittent Hypoxia Alters Gene Expression in Peripheral Blood Mononuclear Cells of Healthy Volunteers.

Obstructive sleep apnea is associated with high cardiovascular morbidity and mortality. Intermittent hypoxia of obstructive sleep apnea is implicated in the development and progression of insulin resistance and atherosclerosis, which have been attributed to systemic inflammation. Intermittent hypoxia leads to pro-inflammatory gene up-regulation in cell culture, but the effects of intermittent hypoxia on gene expression in humans have not been elucidated.

Identification of new biomarkers for Acute Respiratory Distress Syndrome by expression-based genome-wide association study.

Background: Accumulated to-date gene microarray data on Acute Respiratory Distress Syndrome (ARDS) in the Gene Expression Omnibus (GEO) represent a rich source for identifying new unsuspected targets and mechanisms of ARDS. The recently developed expression-based genome-wide association study (eGWAS) for analysis of GEO data was successfully used for analysis of gene expression of comparatively noncomplex adipose tissue, 75 % of which is represented by adipocytes. Although lung tissue is more heterogenic and does not possess a prevalent cell type for driving gene expression patterns, we hypothesized that eGWAS of ARDS samples will generate biologically meaningful results.

A critical role of nicotinamide phosphoribosyltransferase in human telomerase reverse transcriptase induction by resveratrol in aortic smooth muscle cells.

Aging is the predominant risk factor for cardiovascular diseases and contributes to a considerably more severe outcome in patients with acute myocardial infarction. Resveratrol, a polyphenol found in red wine, is a caloric restriction mimetic with potential anti-aging properties which has emerged as a beneficial nutraceutical for patients with cardiovascular disease. Although resveratrol is widely consumed as a nutritional supplement, its mechanism of action remains to be elucidated fully.

Combined meta-analysis of systemic effects of allogeneic stem cell transplantation and systemic sclerosis.

Background: Chronic graft-versus-host disease (cGVHD) is a major factor of morbidity and mortality for allogeneic stem cell transplantation (aSCT). The skin and internal organ involvement is the most common systemic complication of cGVHD and closely resembles systemic sclerosis (SSc). Circulating lymphocytes characterize the autoimmune nature of both conditions.

Meta-analysis of molecular response of kidney to ischemia reperfusion injury for the identification of new candidate genes.

Background: Accumulated to-date microarray data on ischemia reperfusion injury (IRI) of kidney represent a powerful source for identifying new targets and mechanisms of kidney IRI. In this study, we conducted a meta-analysis of gene expression profiles of kidney IRI in human, pig, rat, and mouse models, using a new scoring method to correct for the bias of overrepresented species. The gene expression profiles were obtained from the public repositories for 24 different models.

RNA-seq analysis of transcriptomes in thrombin-treated and control human pulmonary microvascular endothelial cells.

The characterization of gene expression in cells via measurement of mRNA levels is a useful tool in determining how the transcriptional machinery of the cell is affected by external signals (e.g. drug treatment), or how cells differ between a healthy state and a diseased state.

RNA-seq analysis of synovial fibroblasts brings new insights into rheumatoid arthritis.

Background: Rheumatoid arthritis (RA) is a chronic autoimmune-disease of unknown origin that primarily affects the joints and ultimately leads to their destruction. Growing evidence suggests that synvovial fibroblasts play important roles in the initiation and the perpetuation of RA but underlying molecular mechanisms are not understood fully. In the present study, Illumina RNA sequencing was used to profile two human normal control and two rheumatoid arthritis synvovial fibroblasts (RASFs) transcriptomes to gain insights into the roles of synvovial fibroblasts in RA.

Erythroid-specific transcriptional changes in PBMCs from pulmonary hypertension patients.

Background: Gene expression profiling of peripheral blood mononuclear cells (PBMCs) is a powerful tool for the identification of surrogate markers involved in disease processes. The hypothesis tested in this study was that chronic exposure of PBMCs to a hypertensive environment in remodeled pulmonary vessels would be reflected by specific transcriptional changes in these cells.

Methodology/principal Findings: The transcript profiles of PBMCs from 30 idiopathic pulmonary arterial hypertension patients (IPAH), 19 patients with systemic sclerosis without pulmonary hypertension (SSc), 42 scleroderma-associated pulmonary arterial hypertensio patients (SSc-PAH), and 8 patients with SSc complicated by interstitial lung disease and pulmonary hypertension (SSc-PH-ILD) were compared to the gene expression profiles of PBMCs from 41 healthy individuals.

Transcriptional analysis of infiltrating T cells in kidney ischemia-reperfusion injury reveals a pathophysiological role for CCR5.

Although T cells have been shown to play a direct role in kidney ischemia-reperfusion injury (IRI), little is known about the underlying mechanisms. We hypothesized that studying the transcriptional responses in kidney-infiltrating T cells would help elucidate novel therapeutic targets for kidney IRI. Unilateral renal pedicle clamping for 45 min was performed in male C57BL/6 mice, and CD3(+) T cells were isolated from the kidney and purified.

Human atopic dermatitis complicated by eczema herpeticum is associated with abnormalities in IFN-γ response.

Background: The basis for increased susceptibility of patients with atopic dermatitis (AD) to develop disseminated viral skin infections such as eczema herpeticum (AD with a history of eczema herpeticum, ADEH(+)) is poorly understood.

Objective: We sought to determine whether subjects with AD prone to disseminated viral skin infections have defects in their IFN responses.

Methods: GeneChip profiling was used to identify differences in gene expression of PBMCs from patients with ADEH(+) compared with patients with AD without a history of eczema herpeticum (ADEH(-)) and nonatopic controls.

Therapeutic distant organ effects of regional hypothermia during mesenteric ischemia-reperfusion injury.

Introduction: Mesenteric ischemia-reperfusion injury (IRI) leads to systemic inflammation and multiple organ failure in clinical and laboratory settings. We investigated the lung structural, functional, and genomic response to mesenteric IRI with and without regional intraischemic hypothermia (RIH) in rodents and hypothesized that RIH would protect the lung and preferentially modulate the distant organ transcriptome under these conditions.

Methods: Sprague-Dawley rats underwent sham laparotomy or superior mesenteric artery occlusion (SMAO) for 60 minutes with or without RIH.

Intermittent and sustained hypoxia induce a similar gene expression profile in human aortic endothelial cells.

Obstructive sleep apnea may cause vascular inflammation and atherosclerosis, which has been attributed to intermittent hypoxia (IH). Recent data suggest that IH, but not sustained hypoxia (SH), activates proinflammatory genes in HeLa cells. Effects of IH and SH on the gene expression profile in human aortic endothelial cells (HAEC) have not been compared.

Transcriptional analysis of kidneys during repair from AKI reveals possible roles for NGAL and KIM-1 as biomarkers of AKI-to-CKD transition.

Acute kidney injury (AKI) is being increasingly shown to be a risk factor for chronic kidney disease (CKD), but little is known about the possible mechanistic links. We hypothesized that analysis of the genomic signature in the repair stage after AKI would reveal pathways that could link AKI and CKD. Unilateral renal pedicle clamping for 45 min was performed in male C57BL/6J mice.

Vaccinia virus-specific molecular signature in atopic dermatitis skin.

Background: Eczema vaccinatum (EV), a disseminated viral skin infection, is a life-threatening complication of vaccinia virus (VV) inoculation in patients with atopic dermatitis (AD) and is thought to be associated with a defective innate immune response. However, the precise mechanism or mechanisms and key factor or factors of EV are unknown.

Objective: Given that patients with psoriasis, another inflammatory skin disorder, are not susceptible to EV, we compared the global transcriptional response of skin to VV in healthy subjects, patients with psoriasis, and patients with AD, focusing on AD-specific genes.

Regulatory T cell-mediated resolution of lung injury: identification of potential target genes via expression profiling.

In animal models of acute lung injury (ALI), gene expression studies have focused on the acute phase of illness, with little emphasis on resolution. In this study, the acute phase of intratracheal lipopolysaccharide (IT LPS)-induced lung injury was similar in wild-type (WT) and recombinase-activating gene-1-deficient (Rag-1(-/-)) lymphocyte-deficient mice, but resolution was impaired and resolution-phase lung gene expression remained different from baseline only in Rag-1(-/-) mice. By focusing on groups of genes involved in similar biological processes (gene ontologies) pertinent to inflammation and the immune response, we identified 102 genes at days 4 and 10 after IT LPS with significantly different expression between WT and Rag-1(-/-) mice.

Transcription factor Nrf2 is protective during ischemic and nephrotoxic acute kidney injury in mice.

Oxidative stress is involved in acute kidney injury due to ischemia-reperfusion and chemotherapy-induced nephrotoxicity. To investigate their basic mechanisms we studied the role of nuclear factor-erythroid 2-p45-related factor 2 (Nrf2), a redox-sensitive transcription factor that regulates expression of several antioxidant and cytoprotective genes. We compared the responses of Nrf2-knockout mice and their wild-type littermates in established mouse models of ischemia-reperfusion injury and cisplatin-induced nephrotoxicity.

Kidney ischemia-reperfusion injury induces caspase-dependent pulmonary apoptosis.

Distant organ effects of acute kidney injury (AKI) are a leading cause of morbidity and mortality. While little is known about the underlying mechanisms, limited data suggest a role for inflammation and apoptosis. Utilizing a lung candidate gene discovery approach in a mouse model of ischemic AKI-induced lung dysfunction, we identified prominent lung activation of 66 apoptosis-related genes at 6 and/or 36 h following ischemia, of which 6 genes represent the tumor necrosis factor receptor (TNFR) superfamily, and another 23 genes are associated with the TNFR pathway.

Activated protein C protects against ventilator-induced pulmonary capillary leak.

The coagulation system is central to the pathophysiology of acute lung injury. We have previously demonstrated that the anticoagulant activated protein C (APC) prevents increased endothelial permeability in response to edemagenic agonists in endothelial cells and that this protection is dependent on the endothelial protein C receptor (EPCR). We currently investigate the effect of APC in a mouse model of ventilator-induced lung injury (VILI).

Effect of T cells on vascular permeability in early ischemic acute kidney injury in mice.

Although previous studies have demonstrated that microvascular dysfunction and inflammation occur in ischemia-reperfusion injury (IRI), the underlying mechanisms are poorly understood. We hypothesized that T cells could mediate renal vascular permeability (RVP) during IRI. We evaluated renal vascular permeability by extravasation of Evans blue dye from the kidney in CD3, CD4 or CD8 T cell deficient mice as well as in TNF receptor knock out mice in our mouse model of kidney ischemia-reperfusion injury.

Identification of candidate genes in scleroderma-related pulmonary arterial hypertension.

We hypothesize that pulmonary arterial hypertension (PAH)-associated genes identified by expression profiling of peripheral blood mononuclear cells (PBMCs) from patients with idiopathic pulmonary arterial hypertension (IPAH) can also be identified in PBMCs from scleroderma patients with PAH (PAH-SSc). Gene expression profiles of PBMCs collected from IPAH (n = 9), PAH-SSc (n = 10) patients, and healthy controls (n = 5) were generated using HG_U133A_2.0 GeneChips and were processed by the RMA/GCOS_1.

The local and systemic inflammatory transcriptome after acute kidney injury.

Studies in humans and animal models have demonstrated that acute kidney injury (AKI) has a significant effect on the function of extrarenal organs. The combination of AKI and lung dysfunction is associated with 80% mortality; the lung, because of its extensive capillary network, is a prime target for AKI-induced effects. The study presented here tested the hypothesis that AKI leads to a vigorous inflammatory response and produces distinct genomic signatures in the kidney and lung.