Roles for lncRNAs in brain development and pathogenesis: emerging therapeutic opportunities.

Long noncoding RNAs (lncRNAs) are recently discovered genetic regulatory molecules that regulate immune responses and are closely associated with the occurrence and development of various diseases, including inflammation, in humans and animals. Under specific physiological conditions, lncRNA expression varies at the cell or tissue level, and lncRNAs can bind to specific miRNAs, target mRNAs, and target proteins to participate in certain processes, such as cell differentiation and inflammatory responses, via the corresponding signaling pathways. This review article summarizes the regulatory role of lncRNAs in macrophage polarization, dendritic cell differentiation, T cell differentiation, and endothelial and epithelial inflammation. In addition, it describes the molecular mechanism of lncRNAs in acute kidney injury, hepatitis, inflammatory injury of the lung, osteoarthritis, mastitis, and neuroinflammation to provide a reference for the molecular regulatory network as well as the genetic diagnosis and treatment of inflammatory diseases in humans and animals.

/pdf/role-of-long-noncoding-rnas-in-the-regulation-of-cellular-kckj6irq.pdf

Role of Long Noncoding RNAs in the Regulation of Cellular Immune Response and Inflammatory Diseases

IL-22 has emerged as a crucial cytokine mediating protective response against pathogens and tissue regeneration. Dysregulated production of IL-22 has been shown to play a pivotal role in the pathogenesis of various diseases like malignant tumours, viral, cardiovascular, allergic and autoimmune disorders. Interleukin 22 belongs to IFN-IL-10 cytokine family. It is a major proinflammatory cytokine secreted by activated Th1 cells (Th22), though can also be secreted by many other immune cells like group 3 innate lymphocytes, γδ T cells, NK cells, NK T cells, and mucosal associated invariant T cells. Th22 cells exclusively release IL-22 but not IL-17 or IFN-γ (as Th1 cells releases IFN-γ along with IL-22 and Th17 cells releases IL-17 along with IL-22) and also express aryl hydrocarbon receptor as the key transcription factor. Th22 cells also exhibit expression of chemokine receptor CCR6 and skin-homing receptors CCR4 and CCR10 indicating the involvement of this subset in bolstering epithelial barrier immunity and promoting secretion of antimicrobial peptides (AMPs) from intestinal epithelial cells. The function of IL-22 is modulated by IL-22 binding protein (binds to IL-22 and inhibits it binding to its cell surface receptor); which serves as a competitor for IL-22R1 chain of IL-22 receptor. The pathogenic and protective nature of the Th22 cells is modulated both by the site of infected tissue and the type of disease pathology. This review aims to discuss key features of IL-22 biology, comparisons between IL and 22 and IFN-γ and its role as a potential immune therapy target in different maladies.

IL-22 as a target for therapeutic intervention: Current knowledge on its role in various diseases.

Abstract Emerging evidence shows that targeting ferroptosis may be a potential therapeutic strategy for treating traumatic brain injury (TBI). Hydrogen sulfide (H 2 S) has been proven to play a neuroprotective role in TBI, but little is known about the effects of H 2 S on TBI-induced ferroptosis. In addition, it is reported that the Wnt signaling pathway can also actively regulate ferroptosis. However, whether H 2 S inhibits ferroptosis via the Wnt signaling pathway after TBI remains unclear. In this study, we first found that in addition to alleviating neuronal damage and cognitive impairments, H 2 S remarkably attenuated abnormal iron accumulation, decreased lipid peroxidation, and improved the expression of glutathione peroxidase 4, demonstrating the potent anti-ferroptosis action of H 2 S after TBI. Moreover, Wnt3a or liproxstatin-1 treatment obtained similar results, suggesting that activation of the Wnt signaling pathway can render the cells less susceptible to ferroptosis post-TBI. More importantly, XAV939, an inhibitor of the Wnt signaling pathway, almost inversed ferroptosis inactivation and reduction of neuronal loss caused by H 2 S treatment, substantiating the involvement of the Wnt signaling pathway in anti-ferroptosis effects of H 2 S. In conclusion, the Wnt signaling pathway might be the critical mechanism in realizing the anti-ferroptosis effects of H 2 S against TBI. Graphical Abstract TBI induces ferroptosis-related changes characterized by iron overload, impaired antioxidant system, and lipid peroxidation at the chronic phase after TBI. However, NaHS subchronic treatment reduces the susceptibility to TBI-induced ferroptosis, at least partly by activating the Wnt signaling pathway. 

Neuroprotective Effect of Hydrogen Sulfide Subchronic Treatment Against TBI-Induced Ferroptosis and Cognitive Deficits Mediated Through Wnt Signaling Pathway

Abstract Neurological disorders such as stroke, multiple sclerosis, as well as the neurodegenerative diseases Parkinson's or Alzheimer's disease are accompanied or even powered by danger associated molecular patterns (DAMPs), defined as endogenous molecules released from stressed or damaged tissue. Besides protein-related DAMPs or “alarmins”, numerous nucleic acid DAMPs exist in body fluids, such as cell-free nuclear and mitochondrial DNA as well as different species of extracellular RNA, collectively termed as self-extracellular nucleic acids (SENAs). Among these, microRNA, long non-coding RNAs, circular RNAs and extracellular ribosomal RNA constitute the majority of RNA-based DAMPs. Upon tissue injury, necrosis or apoptosis, such SENAs are released from neuronal, immune and other cells predominantly in association with extracellular vesicles and may be translocated to target cells where they can induce intracellular regulatory pathways in gene transcription and translation. The majority of SENA-induced signaling reactions in the brain appear to be related to neuroinflammatory processes, often causally associated with the onset or progression of the respective disease. In this review, the impact of the diverse types of SENAs on neuroinflammatory and neurodegenerative diseases will be discussed. Based on the accumulating knowledge in this field, several specific antagonistic approaches are presented that could serve as therapeutic interventions to lower the pathological outcome of the indicated brain disorders. 

Brain alarm by self-extracellular nucleic acids: from neuroinflammation to neurodegeneration

Healthy mammary gland is essential for milk performance in dairy cows. MicroRNAs (miRNAs) are the key molecules to regulate the steady state of mammary gland in dairy cows. This study investigated the potential role of miR-29c in bovine mammary epithelial cells (bMECs). RNA sequencing (RNA-seq) was used to measure the transcriptome profile of bovine mammary epithelial cells line (MAC-T) transfected with miR-29c inhibitor or negative control (NC) inhibitor, and then differentially expressed genes (DEGs) were screened. The results showed that a total of 42 up-regulated and 27 down-regulated genes were found in the miR-29c inhibitor group compared with the NC inhibitor group. The functional enrichment of the above DEGs indicates that miR-29c is a potential regulator of oxidative stress and inflammatory response in bMECs through multiple genes, such as forkhead box O1 (FOXO1), tumor necrosis factor-alpha (TNF-α), and major histocompatibility complex, class II, DQ alpha 5 (BoLA-DQA5) in the various biological process and signaling pathways of stress-activated mitogen-activated protein kinase (MAPK) cascade, Epstein-Barr virus infection, inflammatory bowel disease, etc. The results imply that miR-29c plays an important role in a steady state of bMECs or cow mammary gland and may be a potential therapeutic target for mastitis in dairy cows.

/pdf/rna-seq-reveals-the-role-of-mir-29c-in-regulating-266obb7f.pdf

RNA-Seq Reveals the Role of miR-29c in Regulating Inflammation and Oxidative Stress of Bovine Mammary Epithelial Cells

Simple Summary Bovine mastitis is an inflammatory disease of the mammary glands that causes serious harm to cow health and huge economic losses. Susceptibility or resistance to mastitis in individual cows is mainly determined by genetic factors, including coding genes and non-coding genes. Long non-coding RNAs (lncRNAs) are non-coding RNA molecules with a length of more than 200 nucleotides (nt) that have recently been discovered. They can regulate a variety of diseases of humans and animals, especially the immune response and inflammatory disease process. This paper reviews the role of long non-coding RNA (lncRNA) in inflammatory diseases, emphasizes on the latest research progress of lncRNA expression and the molecular regulatory mechanism in bovine mastitis, and looks forward to the research and application prospect of lncRNA in bovine mastitis, intending to provide a reference for scientific researchers to systematically understand this research field. Abstract Bovine mastitis is an inflammatory disease caused by pathogenic microbial infection, trauma, or other factors. Its morbidity is high, and it is difficult to cure, causing great harm to the health of cows and the safety of dairy products. Susceptibility or resistance to mastitis in individual cows is mainly determined by genetic factors, including coding genes and non-coding genes. Long non-coding RNAs (lncRNAs) are a class of endogenous non-coding RNA molecules with a length of more than 200 nucleotides (nt) that have recently been discovered. They can regulate the immune response of humans and animals on three levels (transcription, epigenetic modification, and post-transcription), and are widely involved in the pathological process of inflammatory diseases. Over the past few years, extensive findings revealed basic roles of lncRNAs in inflammation, especially bovine mastitis. This paper reviews the expression pattern and mechanism of long non-coding RNA (lncRNA) in inflammatory diseases, emphasizes on the latest research progress of the lncRNA expression pattern and molecular regulatory mechanism in bovine mastitis, analyzes the molecular regulatory network of differentially expressed lncRNAs, and looks forward to the research and application prospect of lncRNA in bovine mastitis, laying a foundation for molecular breeding and the biological therapy of bovine mastitis.

/pdf/progress-in-expression-pattern-and-molecular-regulation-3gaguij9.pdf

Progress in Expression Pattern and Molecular Regulation Mechanism of LncRNA in Bovine Mastitis

Bovine mammary epithelial cells (bMECs) are part of the first line of defense against pathogens. In recent studies, bta-miR-223 has been reported to activate congenital and innate immunity against inflammatory damage during the pathogenesis of mastitis in dairy cows. The purpose of this study was to identify the regulatory mechanism of bta-miR-223 and its downstream target genes in inflammatory bMECs. A double luciferase reporter gene assay demonstrated that ras homolog family member B (RHOB) was the target gene of bta-miR-223. To further elucidate the role of bta-miR-223 in congenital immune responses, bta-miR-223 mimics (mimic/inhibitor) were transfected into bMECs stimulated with lipopolysaccharide (LPS), which activates the Toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) signaling pathway. Real-time quantitative PCR (qPCR) and Western blot were used to detect the expression of related genes and proteins, and enzyme-linked immunosorbent assay (ELISA) was used to detect secreted inflammatory factors. Results showed that bta-miR-223 expression during inflammation in bMECs reduced the secretion of inflammatory factors by targeting RHOB and deactivation of NF-κB gene activity. Silencing RHOB inhibited LPS-induced inflammatory response in bMECs. Overall, bta-miR-223 attenuated LPS-induced inflammatory response, and acted as a negative feedback regulator via targeting RHOB, providing a novel avenue for mastitis treatment.

/pdf/bta-mir-223-targeting-the-rhob-gene-in-dairy-cows-attenuates-24y2gmil.pdf

Bta-miR-223 Targeting the RHOB Gene in Dairy Cows Attenuates LPS-Induced Inflammatory Responses in Mammary Epithelial Cells

RNA-seq reveals the role of miR-223 in alleviating inflammation of bovine mammary epithelial cells.

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