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Molecular Therapy : the Journal of the... Sep 2023Virus-induced lung injury is associated with loss of pulmonary epithelial-endothelial tight junction integrity. While the alveolar-capillary membrane may be an indirect...
Virus-induced lung injury is associated with loss of pulmonary epithelial-endothelial tight junction integrity. While the alveolar-capillary membrane may be an indirect target of injury, viruses may interact directly and/or indirectly with miRs to augment their replication potential and evade the host antiviral defense system. Here, we expose how the influenza virus (H1N1) capitalizes on host-derived interferon-induced, microRNA (miR)-193b-5p to target occludin and compromise antiviral defenses. Lung biopsies from patients infected with H1N1 revealed increased miR-193b-5p levels, marked reduction in occludin protein, and disruption of the alveolar-capillary barrier. In C57BL/6 mice, the expression of miR-193b-5p increased, and occludin decreased, 5-6 days post-infection with influenza (PR8). Inhibition of miR-193b-5p in primary human bronchial, pulmonary microvascular, and nasal epithelial cells enhanced antiviral responses. miR-193b-deficient mice were resistant to PR8. Knockdown of occludin, both in vitro and in vivo, and overexpression of miR-193b-5p reconstituted susceptibility to viral infection. miR-193b-5p inhibitor mitigated loss of occludin, improved viral clearance, reduced lung edema, and augmented survival in infected mice. Our results elucidate how the innate immune system may be exploited by the influenza virus and how strategies that prevent loss of occludin and preserve tight junction function may limit susceptibility to virus-induced lung injury.
Topics: Humans; Animals; Mice; Influenza, Human; MicroRNAs; Occludin; Lung Injury; Tight Junctions; Viral Load; Influenza A Virus, H1N1 Subtype; Mice, Inbred C57BL; Antiviral Agents
PubMed: 37340634
DOI: 10.1016/j.ymthe.2023.06.011 -
Biology of Reproduction Aug 2023Endometriosis is a chronic inflammatory disease distinguished by ectopic endometrium and fibrosis. NLRP3 inflammasome and pyroptosis are present in endometriosis....
Endometriosis is a chronic inflammatory disease distinguished by ectopic endometrium and fibrosis. NLRP3 inflammasome and pyroptosis are present in endometriosis. Aberrant increase of Long noncoding (Lnc)-metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays a vital role in endometriosis. However, the relationship between lnc-MALAT1, pyroptosis, and fibrosis is not completely known. In the present study, we found that the pyroptosis levels in ectopic endometrium of patients with endometriosis were significantly increased, consistent with fibrosis levels. Lipopolysaccharide (LPS) + ATP could induce pyroptosis of primary endometrial stromal cells (ESCs), thereby releasing interleukin (IL)-1β and stimulating transforming growth factor (TGF)-β1-mediated fibrosis. NLRP3 inhibitor MCC950 had the same effect as TGF-β1 inhibitor SB-431542 in suppressing the fibrosis-inducing effect of LPS + ATP in vivo and in vitro. The abnormal increase of lnc-MALAT1 in ectopic endometrium was connected with NLRP3-mediated pyroptosis and fibrosis. Leveraging bioinformatic prediction and luciferase assays combined with western blotting and quantitative reverse transcriptase-polymerase chain reaction, we validated that lnc-MALAT1 sponges miR-141-3p to promote NLRP3 expression. Silencing lnc-MALAT1 in HESCs ameliorated NLRP3-mediated pyroptosis and IL-1β release, thereby relieving TGF-β1-mediated fibrosis. Consequently, our findings suggest that lnc-MALAT1 is critical for NLRP3-induced pyroptosis and fibrosis in endometriosis through sponging miR-141-3p, which may indicate a new therapeutic target of endometriosis treatment.
Topics: Female; Humans; MicroRNAs; Pyroptosis; NLR Family, Pyrin Domain-Containing 3 Protein; RNA, Long Noncoding; Transforming Growth Factor beta1; Endometriosis; Lipopolysaccharides; Fibrosis; Adenosine Triphosphate
PubMed: 37233993
DOI: 10.1093/biolre/ioad057 -
Circulation Research Feb 2024Extracellular vesicles (EVs) contain bioactive cargo including miRNAs and proteins that are released by cells during cell-cell communication. Endothelial cells (ECs)...
BACKGROUND
Extracellular vesicles (EVs) contain bioactive cargo including miRNAs and proteins that are released by cells during cell-cell communication. Endothelial cells (ECs) form the innermost lining of all blood vessels, interfacing with cells in the circulation and vascular wall. It is unknown whether ECs release EVs capable of governing recipient cells within these 2 separate compartments. Given their boundary location, we propose ECs use bidirectional release of distinct EV cargo in quiescent (healthy) and activated (atheroprone) states to communicate with cells within the circulation and blood vessel wall.
METHODS
EVs were isolated from primary human aortic ECs (plate and transwell grown; ±IL [interleukin]-1β activation), quantified, visualized, and analyzed by miRNA transcriptomics and proteomics. Apical and basolateral EC-EV release was determined by miRNA transfer, total internal reflection fluorescence and electron microscopy. Vascular reprogramming (RNA sequencing) and functional assays were performed on primary human monocytes or smooth muscle cells±EC-EVs.
RESULTS
Activated ECs increased EV release, with miRNA and protein cargo related to atherosclerosis. EV-treated monocytes and smooth muscle cells revealed activated EC-EV altered pathways that were proinflammatory and atherogenic. ECs released more EVs apically, which increased with activation. Apical and basolateral EV cargo contained distinct transcriptomes and proteomes that were altered by EC activation. Notably, activated basolateral EC-EVs displayed greater changes in the EV secretome, with pathways specific to atherosclerosis. In silico analysis determined compartment-specific cargo released by the apical and basolateral surfaces of ECs can reprogram monocytes and smooth muscle cells, respectively, with functional assays and in vivo imaging supporting this concept.
CONCLUSIONS
Demonstrating that ECs are capable of polarized EV cargo loading and directional EV secretion reveals a novel paradigm for endothelial communication, which may ultimately enhance the design of endothelial-based therapeutics for cardiovascular diseases such as atherosclerosis where ECs are persistently activated.
Topics: Humans; Endothelial Cells; MicroRNAs; Extracellular Vesicles; Cell Communication; Atherosclerosis
PubMed: 38174557
DOI: 10.1161/CIRCRESAHA.123.322993 -
General and Comparative Endocrinology Sep 2024The gonadotrope cells within the pituitary control vital processes of reproduction by producing follicle stimulating hormone (FSH) and luteinizing hormone (LH). Both... (Review)
Review
The gonadotrope cells within the pituitary control vital processes of reproduction by producing follicle stimulating hormone (FSH) and luteinizing hormone (LH). Both external stimuli and internal regulatory factors contribute to the regulation of gonadotrope development and function. In recent years, growing evidences indicate that microRNAs (miRNAs), which regulate gene expression post-transcriptionally, play critical roles in multiple processes of gonadotrope development and function, including the syntheses of α or β subunits of FSH and LH, the secretion of LH, the regulation of GnRH signaling, and the maintenance of gonadotrope cell kinetics. Here, we review recent advances of miRNAs' expression, functions and mechanisms approached by using miRNA knockout mouse models, in silico analysis and the in vitro cultures of primary pituitary cells and gonadotrope-derived cell lines. By summarizing and discussing different roles of miRNAs in gonadotropes, this minireview helps to gain insights into the complex molecular network in gonadotropes and reproduction.
Topics: Animals; MicroRNAs; Gonadotrophs; Follicle Stimulating Hormone; Mice; Luteinizing Hormone; Pituitary Gland; Humans
PubMed: 38797341
DOI: 10.1016/j.ygcen.2024.114557 -
International Immunopharmacology Sep 2023Macrophages as innate immune cells with great plasticity are of great interest for cell therapy. There are two main macrophage populations - pro- and anti-inflammatory... (Review)
Review
Macrophages as innate immune cells with great plasticity are of great interest for cell therapy. There are two main macrophage populations - pro- and anti-inflammatory cells also known as M1 and M2. High potential in cancer research contributed to the in-depth study of the molecular processes leading to the polarization of macrophages into the M1 phenotype, and much less attention has been paid to anti-inflammatory M2 macrophages, which can be successfully used in cell therapy of inflammatory diseases. This review describes ontogenesis of macrophages, main functions of pro- and and-inflammatory cells and four M2 subpopulations characterized by different functionalities. Data on agents (cytokines, microRNAs, drugs, plant extracts) that may induce M2 polarization through the changes in microenvironment, metabolism, and efferocytosis are summarized. Finally, recent attempts at stable macrophage polarization using genetic modifications are described. This review may be helpful for researchers concerned with the problem of M2 macrophage polarization and potential use of these anti-inflammatory cells for the purposes of regenerative medicine.
Topics: Macrophages; Cytokines; MicroRNAs; Phagocytosis; Anti-Inflammatory Agents
PubMed: 37423155
DOI: 10.1016/j.intimp.2023.110583 -
Biology Direct Jul 2023Prostate cancer remains one of the deadliest neoplasms in developed countries. Identification of new molecular markers that predict the onset and progression of the...
BACKGROUND
Prostate cancer remains one of the deadliest neoplasms in developed countries. Identification of new molecular markers that predict the onset and progression of the disease could improve its clinical management. Low miR-145-5p expression is consistently found in primary tumors and metastases, but the regulatory mechanisms governing its functions remain largely unknown.
METHODS
Bioinformatics analysis was conducted to identify [1] a set of novel potential competing endogenous lncRNAs for sponging of miRNA-145-5p in prostate cancer and [2] miR-145-5p and other EMT-related miRNAs response elements in lnc-ZNF30-3. Quantification of miR-145-5p, lnc-ZNF30-3, and TWIST1 expression levels in tumor tissues in RNA sequencing datasets of our and TCGA PRAD cohorts revealed a correlation with clinical outcome of prostate cancer patients. Biochemical and cell biology approaches, such as RNA pull-down, western blot, immunostaining, and wound healing assays were used for evaluation of the impact of TWIST1/miR-145/ lnc-ZNF30-3 interactions in prostate cancer cells altered in miRNA and lncRNA expression.
RESULTS
We identified a few potential lncRNA sponges of miR-145-5p, including lnc-ZNF30-3. It contains five response elements for miR-145-5p, but also other miRNAs targeting EMT transcription factors. Lnc-ZNF30-3 is significantly upregulated in prostate cancer cell lines and tumor tissues, and its high expression is correlated with poor patient prognosis. We demonstrated that lnc-ZNF30-3 is associated with AGO2 and specifically interacts with the miR-145-5p seed region. Knockdown of lnc-ZNF30-3 results in decreased migration of prostate cancer cells and downregulation of EMT drivers such as TWIST1 and ZEB1 at both the RNA and protein levels. These phenotypic and molecular features of lnc-ZNF30-3-depleted cells are partially rescued by miR-145-5p inhibition.
CONCLUSIONS
Collectively, our results point to lnc-ZNF30-3 as a novel competing endogenous lncRNA for miR-145-5p and other miRNAs that target TWIST1 as well as other EMT transcription factors. Prostate cancer patients with high lncRNA expression in primary tumors show lower survival rate suggesting that lnc-ZNF30-3 may contribute to prostate cancer progression and metastasis.
Topics: Male; Humans; RNA, Long Noncoding; Prostatic Neoplasms; MicroRNAs; Carcinogenesis; Cell Line
PubMed: 37434219
DOI: 10.1186/s13062-023-00393-7 -
International Journal of Oncology Oct 2023MicroRNAs (miRNAs) are non‑coding RNAs (ncRNAs) that can post‑transcriptionally suppress targeted genes. Dysregulated miRNAs are associated with a variety of... (Review)
Review
MicroRNAs (miRNAs) are non‑coding RNAs (ncRNAs) that can post‑transcriptionally suppress targeted genes. Dysregulated miRNAs are associated with a variety of diseases. MiR‑181a‑5p is a conserved miRNA with the ability to regulate pathological processes, such as angiogenesis, inflammatory response and obesity. Numerous studies have demonstrated that miR‑181a‑5p exerts regulatory influence on cancer development and progression, acting as an oncomiR or tumor inhibitor in various cancer types by impacting multiple hallmarks of tumor. Generally, miR‑181a‑5p binds to target RNA sequences with partial complementarity, resulting in suppression of the targeted genes of miR‑181a‑5p. However, the precise role of miR‑181a‑5p in cancer remains incompletely understood. The present review aims to provide a comprehensive summary of recent research on miR‑181a‑5p, focusing on its involvement in different types of cancer and its potential as a diagnostic and prognostic biomarker, as well as its function in chemoresistance.
Topics: Humans; MicroRNAs; Neoplasms
PubMed: 37539738
DOI: 10.3892/ijo.2023.5556 -
Nature Communications Oct 2023Type 1 conventional dendritic cells (cDC1) are the most efficient cross-presenting cells that induce protective cytotoxic T cell response. However, the regulation of...
Type 1 conventional dendritic cells (cDC1) are the most efficient cross-presenting cells that induce protective cytotoxic T cell response. However, the regulation of their homeostasis and function is incompletely understood. Here we observe a selective reduction of splenic cDC1 accompanied by excessive cell death in mice with Zeb1 deficiency in dendritic cells, rendering the mice more resistant to Listeria infection. Additionally, cDC1 from other sources of Zeb1-deficient mice display impaired cross-presentation of exogenous antigens, compromising antitumor CD8 T cell responses. Mechanistically, Zeb1 represses the expression of microRNA-96/182 that target Cybb mRNA of NADPH oxidase Nox2, and consequently facilitates reactive-oxygen-species-dependent rupture of phagosomal membrane to allow antigen export to the cytosol. Cybb re-expression in Zeb1-deficient cDC1 fully restores the defective cross-presentation while microRNA-96/182 overexpression in Zeb1-sufficient cDC1 inhibits cross-presentation. Therefore, our results identify a Zeb1-microRNA-96/182-Cybb pathway that controls cross-presentation in cDC1 and uncover an essential role of Zeb1 in cDC1 homeostasis.
Topics: Animals; Mice; Antigens; CD8-Positive T-Lymphocytes; Dendritic Cells; Homeostasis; MicroRNAs; Transcription Factors
PubMed: 37863917
DOI: 10.1038/s41467-023-42428-7 -
Frontiers in Bioscience (Landmark... Nov 2023Fibrotic disorders are defined by accumulating excessive extracellular matrix (ECM) components, especially collagens, in various organs, leading to tissue scarring and... (Review)
Review
Fibrotic disorders are defined by accumulating excessive extracellular matrix (ECM) components, especially collagens, in various organs, leading to tissue scarring and organ dysfunction. These conditions are associated with significant challenges in the healthcare system because of their progressive nature and limited treatment options. MicroRNAs (miRNAs) are small non-coding RNA molecules (approximately 22 nucleotides) that modulate gene expression by selectively targeting mRNAs for degradation or translational repression. MiRNAs have recently been identified as potential targets for therapeutic developments in fibrotic disorders. They play vital roles in inducing fibrotic phenotype by regulating fibroblast activation and ECM remodeling. Multiple strategies for targeting specific miRNAs in fibrotic disorders have been explored, including antisense oligonucleotides, small molecule modulators, and natural compounds. This review discussed the role of miRNAs in different fibrotic disorders, including cardiac fibrosis, liver fibrosis, kidney fibrosis, lung fibrosis, dermal fibrosis, and primary myelofibrosis, with recent advances in developing miRNA-based therapeutics.
Topics: Humans; MicroRNAs; Fibrosis; Pulmonary Fibrosis; Liver Cirrhosis; Oligonucleotides, Antisense
PubMed: 38062842
DOI: 10.31083/j.fbl2811317 -
Current Problems in Cardiology Dec 2023Cardiovascular diseases (CVDs) encompass a range of disorders, from congenital heart malformation, cardiac valve, peripheral artery, coronary artery, cardiac muscle... (Review)
Review
Cardiovascular diseases (CVDs) encompass a range of disorders, from congenital heart malformation, cardiac valve, peripheral artery, coronary artery, cardiac muscle diseases, and arrhythmias, ultimately leading to heart failure. Despite therapeutic advancements, CVDs remain the primary cause of global mortality, highlighting the need for a thorough knowledge of CVDs at the level of molecular structure. Gene and microRNA (miRNA) expression variations significantly influence cellular pathways, impacting an organism's physiology. MiRNAs, in particular, serve as regulators of gene expression, playing critical roles in essential cellular pathways and influencing the development of various diseases, including CVD. A wealth of evidence supports the involvement of miRNAs in CVD progression. These findings highlight the potential of miRNAs as valuable diagnostic biomarkers and open new avenues for their therapeutic application in CVDs. This study focuses on the latest advancements in identifying and characterizing microRNAs, exploring their manipulation and clinical application, and discussing future perspectives.
Topics: Humans; MicroRNAs; Cardiovascular Diseases; Heart Failure
PubMed: 37544621
DOI: 10.1016/j.cpcardiol.2023.102010