NELL1 variant protein (NV1) modulates hyper-inflammation, Th-1 mediated immune response, and the HIF-1α hypoxia pathway to promote healing in viral-induced lung injury.

Research underscores the urgent need for technological innovations to treat lung tissue damage from viral infections and the lasting impact of COVID-19. Our study demonstrates the effectiveness of recombinant human NV1 protein in promoting a pro-healing extracellular matrix that regulates homeostasis in response to excessive tissue reactions caused by infection and injury. NV1 achieves this by calibrating multiple biological mechanisms, including reducing hyperinflammatory cytokine levels (e.

Time- and sex-dependent delayed effects of acute radiation exposure manifest via miRNA dysregulation.

The detrimental effects of high-dose ionizing radiation on human health are well-known, but the influence of sex differences on the delayed effects of acute radiation exposure (DEARE) remains unclear. Here, we conducted six-month animal experiments using escalating radiation doses (7-9 Gy) on male and female C57BL/6 mice. The results show that female mice exhibited greater resistance to radiation, showing increased survival at six months post-total body irradiation.

Acss2 Deletion Reveals Functional Versatility via Tissue-Specific Roles in Transcriptional Regulation.

The coordination of cellular biological processes is regulated in part via metabolic enzymes acting to match cellular metabolism to current conditions. The acetate activating enzyme, acyl-coenzyme A synthetase short-chain family member 2 (Acss2), has long been considered to have a predominantly lipogenic function. More recent evidence suggests that this enzyme has regulatory functions in addition to its role in providing acetyl-CoA for lipid synthesis.

CDX-301 prevents radiation-induced dysregulation of miRNA expression and biogenesis.

Risks of radiation exposure necessitate the development of radioprophylactic drugs. We have reported the efficacy of CDX-301, a recombinantly developed human protein form of Fms-related tyrosine kinase 3 ligand (Flt3L), as a radioprophylactic and radiomitigatory agent. Here, we performed global microRNA profiling to further understand the mechanism of action of CDX-301.

Role of Non-Coding RNAs in Post-Transcriptional Regulation of Lung Diseases.

Non-coding RNAs (ncRNAs), notably microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), have recently gained increasing consideration because of their versatile role as key regulators of gene expression. They adopt diverse mechanisms to regulate transcription and translation, and thereby, the function of the protein, which is associated with several major biological processes. For example, proliferation, differentiation, apoptosis, and metabolic pathways demand fine-tuning for the precise development of a specific tissue or organ.

SFPQ rescues F508del-CFTR expression and function in cystic fibrosis bronchial epithelial cells.

Cystic fibrosis (CF) occurs as a result of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which lead to misfolding, trafficking defects, and impaired function of the CFTR protein. Splicing factor proline/glutamine-rich (SFPQ) is a multifunctional nuclear RNA-binding protein (RBP) implicated in the regulation of gene expression pathways and intracellular trafficking. Here, we investigated the role of SFPQ in the regulation of the expression and function of F508del-CFTR in CF lung epithelial cells.

NF-κB-induced R-loop accumulation and DNA damage select for nucleotide excision repair deficiencies in adult T cell leukemia.

Constitutive NF-κB activation (NF-κB) confers survival and proliferation advantages to cancer cells and frequently occurs in T/B cell malignancies including adult T cell leukemia (ATL) caused by human T-cell leukemia virus type 1 (HTLV-1). Counterintuitively, NF-κB by the HTLV-1 transactivator/oncoprotein Tax induces a senescence response, and HTLV-1 infections in culture mostly result in senescence or cell-cycle arrest due to NF-κB How NF-κB induces senescence, and how ATL cells maintain NF-κB and avert senescence, remain unclear. Here we report that NF-κB by Tax increases R-loop accumulation and DNA double-strand breaks, leading to senescence.

Nuclear-mitochondrial communication involving miR-181c plays an important role in cardiac dysfunction during obesity.

Aims: In cardiomyocytes, there is microRNA (miR) in the mitochondria that originates from the nuclear genome and matures in the cytoplasm before translocating into the mitochondria. Overexpression of one such miR, miR-181c, can lead to heart failure by stimulating reactive oxygen species (ROS) production and increasing mitochondrial calcium level ([Ca]). Mitochondrial calcium uptake 1 protein (MICU1), a regulatory protein in the mitochondrial calcium uniporter complex, plays an important role in regulating [Ca].

Comparative analyses of long non-coding RNA profiles in vivo in cystic fibrosis lung airway and parenchyma tissues.

Background: Recent advances in the functional analyses of endogenous non-coding RNA (ncRNA) molecules, including long non-coding RNAs (LncRNAs), have provided a new perspective on the crucial roles of RNA in gene regulation. Consequently, LncRNA deregulation is a key factor in various diseases, including pulmonary disorders like Cystic Fibrosis (CF). CF is the most common life limiting recessive disease in the U.

Digitoxin Inhibits Epithelial-to-Mesenchymal-Transition in Hereditary Castration Resistant Prostate Cancer.

Castration Resistant Prostate Cancer (CRPC) is thought to be driven by a collaborative mechanism between TNFα/NFκB and TGFβ signaling, leading to inflammation, Epithelial-to-Mesenchymal-Transition (EMT), and metastasis. Initially, TGFβ is a tumor suppressor, but in advanced metastatic disease it switches to being a tumor promoter. TGFBR2 may play a critical role in this collaboration, as its expression is driven by NFκB and it is the primary receptor for TGFβ.

Comparative RNA-seq analysis reveals dys-regulation of major canonical pathways in ERG-inducible LNCaP cell progression model of prostate cancer.

Prostate Cancer (CaP) is the second leading cause of cancer related death in USA. In human CaP, gene fusion between androgen responsive regulatory elements at the 5'-untranslated region of TMPRSS2 and ETS-related genes (ERG) is present in at least 50% of prostate tumors. Here we have investigated the unique cellular transcriptome associated with over-expression of ERG in ERG-inducible LNCaP cell model system of human CaP.

MicroRNA-155: A Master Regulator of Inflammation.

MicroRNAs (miRNAs) are naturally occurring, highly conserved families of transcripts (∼22 nucleotides in length) that are processed from larger hairpin precursors. miRNAs primarily regulate gene expression by promoting messenger RNA (mRNA) degradation or repressing mRNA translation. miRNAs have been shown to be important regulators of a variety of cellular processes involving development, differentiation, and signaling.

Regulation of mRNA turnover in cystic fibrosis lung disease.

Cystic fibrosis (CF) is an autosomal recessive disease due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, F508del-CFTR being the most frequent mutation. The CF lung is characterized by a hyperinflammatory phenotype and is regulated by multiple factors that coordinate its pathophysiology. In CF the expression of CFTR as well as proinflammatory genes are regulated at the level of messenger RNA (mRNA) stability, which subsequently affect translation.

RPTOR, a novel target of miR-155, elicits a fibrotic phenotype of cystic fibrosis lung epithelium by upregulating CTGF.

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, the most frequent of which is F508del-CFTR. CF is characterized by excessive secretion of pro-inflammatory mediators into the airway lumen, inducing a highly inflammatory cellular phenotype. This process triggers fibrosis, causing airway destruction and leading to high morbidity and mortality.

Gamma-Tocotrienol Modulates Radiation-Induced MicroRNA Expression in Mouse Spleen.

Ionizing radiation causes depletion of hematopoietic cells and enhances the risk of developing secondary hematopoietic malignancies. Vitamin E analog gamma-tocotrienol (GT3), which has anticancer properties, promotes postirradiation hematopoietic cell recovery by enhancing spleen colony-forming capacity, and provides protection against radiation-induced lethality in mice. However, the underlying molecular mechanism involved in GT3-mediated postirradiation survival is not clearly understood.

Loss of miR-449a in ERG-associated prostate cancer promotes the invasive phenotype by inducing SIRT1.

Epigenetic regulation by SIRT1, a multifaceted NAD+-dependent protein deacetylase, is one of the most common factors modulating cellular processes in a broad range of diseases, including prostate cancer (CaP). SIRT1 is over-expressed in CaP cells, however the associated mechanism is not well understood. To identify whether specific microRNAs might mediate this linkage, we have screened a miRNA library for differential expression in ERG-associated CaP tissues.

Regulation of miR-155 biogenesis in cystic fibrosis lung epithelial cells: antagonistic role of two mRNA-destabilizing proteins, KSRP and TTP.

Cystic fibrosis (CF) is characterized by a massive pro-inflammatory phenotype in the lung arising from profound expression of inflammatory genes, including interleukin-8 (IL-8). We have previously reported that IL-8 mRNA is stabilized in CF lung epithelial cells, resulting in concomitant hyper-expression of IL-8 protein through elevated expression of miR-155. We therefore investigated what factors promote the enhanced aberrant expression of miR-155 in CF.

Differential regulation of inflammation by inflammatory mediators in cystic fibrosis lung epithelial cells.

Cystic fibrosis (CF) is due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which cause a massively proinflammatory phenotype in the CF airway. The chemical basis of the inflammation is hyperproduction of interleukin-8 (IL-8) by CF airway epithelial cells, based on both an intrinsic mutation-dependent mechanism and by infection. In infection-free, cultured CF lung epithelial cells, high levels of the microRNA (miR), miR-155, is responsible for hyperexpression of IL-8.

Abnormal microRNA expression in Ts65Dn hippocampus and whole blood: contributions to Down syndrome phenotypes.

Down syndrome (DS; trisomy 21) is one of the most common genetic causes of intellectual disability, which is attributed to triplication of genes located on chromosome 21. Elevated levels of several microRNAs (miRNAs) located on chromosome 21 have been reported in human DS heart and brain tissues. The Ts65Dn mouse model is the most investigated DS model with a triplicated segment of mouse chromosome 16 harboring genes orthologous to those on human chromosome 21.

Elevated miR-155 promotes inflammation in cystic fibrosis by driving hyperexpression of interleukin-8.

Cystic Fibrosis (CF) is characterized by a massive proinflammatory phenotype in the lung arising from profound expression of inflammatory genes, including interleukin-8 (IL-8). We have previously reported that IL-8 mRNA is stabilized in CF lung epithelial cells, resulting in concomitant hyperexpression of IL-8 protein. However, the mechanistic link between mutations in CFTR and acquisition of the proinflammatory phenotype in the CF airway has remained elusive.

MAPK signaling pathways regulate IL-8 mRNA stability and IL-8 protein expression in cystic fibrosis lung epithelial cell lines.

Cystic fibrosis (CF) is characterized by a massive proinflammatory phenotype in the lung, caused by mutations in the CFTR gene. IL-8 and other proinflammatory mediators are elevated in the CF airway, and the immediate mechanism may depend on disease-specific stabilization of IL-8 mRNA in CF lung epithelial cells. MAPK signaling pathways impact directly on IL-8 protein expression in CF cells, and we have hypothesized that the mechanism may also involve stabilization of the IL-8 mRNA.

Analysis of microRNAs induced by Venezuelan equine encephalitis virus infection in mouse brain.

MicroRNAs (miRNA) are small RNA (approximately 22nts) molecules that are expressed endogenously in cells and play an important role in regulating gene expression. Recent studies have shown that cellular miRNA plays a very important role in the pathogenesis of viral infection. Venezuelan equine encephalitis virus (VEEV) is an RNA virus and is a member of the genus Alphavirus in the family Togaviridae.

Tristetraprolin regulates IL-8 mRNA stability in cystic fibrosis lung epithelial cells.

Cystic fibrosis (CF) is due to mutations in the CFTR gene and is characterized by hypersecretion of the proinflammatory chemokine IL-8 into the airway lumen. Consequently, this induces the highly inflammatory cellular phenotype typical of CF. Our initial studies revealed that IL-8 mRNA is relatively stable in CF cells compared with those that had been repaired with [WT]CFTR (wild-type CFTR).

Tristetraprolin regulates CXCL1 (KC) mRNA stability.

mRNAs encoding proinflammatory chemokines are regulated posttranscriptionally via adenine-uridine-rich sequences (AREs) located in the 3' untranslated region of the message, which are recognized by sequence-specific RNA-binding proteins. One ARE binding protein, tristetraprolin (TTP), has been implicated in regulating the stability of several ARE-containing mRNAs, including those encoding TNF-alpha and GM-CSF. In the present report we examined the role of TTP in regulating the decay of the mouse chemokine KC (CXCL1) mRNA.