Long Noncoding RNA: Regulatory Mechanisms and Therapeutic Potential in Sepsis

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection and is characterized by a hyperinflammatory state accompanied by immunosuppression. Long noncoding RNAs (lncRNAs) are noncoding RNAs longer than 200 nucleotides and have important roles in mediating various biological processes. Recently, lncRNAs were found to exert both promotive and inhibitory immune functions in sepsis, thus participating in sepsis regulation. Additionally, several studies have revealed that lncRNAs are involved in sepsis-induced organ dysfunctions, including cardiovascular dysfunction, acute lung injury, and acute kidney injury. Considering the lack of effective biomarkers for early identification and specific treatment for sepsis, lncRNAs may be promising biomarkers and even targets for sepsis therapies. This review systematically highlights the recent advances regarding the roles of lncRNAs in sepsis and sheds light on their use as potential biomarkers and treatment targets for sepsis.

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Acute kidney injury

Oxford Textbook of Medicine ◽

10.1093/med/9780198746690.003.0477 ◽

2020 ◽

pp. 4807-4829

Author(s):

John D. Firth

Keyword(s):

Acute Kidney Injury ◽

Specific Treatment ◽

Kidney Injury ◽

Initial Assessment ◽

Volume Depletion ◽

Excretory Function ◽

Tubular Necrosis ◽

Life Threatening ◽

Common Precipitant ◽

General Aspects

Definition—for practical clinical purposes, acute kidney injury (AKI) is defined as a significant decline in renal excretory function occurring over hours or days, detected by either a fall in urinary output or a rise in the serum concentration of creatinine. Oliguria—defined (arbitrarily) as a urinary volume of less than 400 ml/day—is usually present, but not always. Clinical approach: diagnosis—all patients admitted to hospital with acute illness, but particularly older people and those with pre-existing chronic kidney disease, should be considered at risk of developing AKI. The most common precipitant is volume depletion. Serum creatinine and electrolytes should be measured on admission in all acutely ill patients, and repeated daily or on alternate days in those who remain so. Assessment—after treatment of life-threatening complications, the initial assessment of a patient who appears to have AKI must answer three questions: (1) is the kidney injury really acute? (2) Is urinary obstruction a possibility? And (3) is there a renal inflammatory cause? General aspects of management—the immediate management of a patient with renal impairment is directed towards three goals: (1) recognition and treatment of any life-threatening complications of AKI, (2) prompt diagnosis and treatment of hypovolaemia, and (3) specific treatment of the underlying condition—if this persists untreated then renal function will not improve. Specific causes of acute kidney injury—there are many possible causes of AKI, but in any given clinical context few of these are likely to require consideration. By far the most frequent are prerenal failure and acute tubular necrosis, which together account for 80 to 90% of cases of AKI seen by physicians.

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Mrhl Long Noncoding RNA Mediates Meiotic Commitment of Mouse Spermatogonial Cells by Regulating Sox8 Expression

Molecular and Cellular Biology ◽

10.1128/mcb.00632-16 ◽

2017 ◽

Vol 37 (14) ◽

Cited By ~ 12

Author(s):

Shubhangini Kataruka ◽

Vijay Suresh Akhade ◽

Bhavana Kayyar ◽

Manchanahalli R. Satyanarayana Rao

Keyword(s):

Wnt Signaling ◽

Germ Cells ◽

Noncoding Rna ◽

Noncoding Rnas ◽

Stem Cell Markers ◽

Biological Processes ◽

Meiotic Progression ◽

Regulatory Link ◽

Regulatory Loop ◽

Signaling Activation

ABSTRACT Long noncoding RNAs (lncRNAs) are important regulators of various biological processes, including spermatogenesis. Our previous studies have revealed the regulatory loop of mrhl RNA and Wnt signaling, where mrhl RNA negatively regulates Wnt signaling and gets downregulated upon Wnt signaling activation. This downregulation of mrhl RNA is important for the meiotic progression of spermatogonial cells. In our present study, we identified the transcription factor Sox8 as the regulatory link between mrhl RNA expression, Wnt signaling activation, and meiotic progression. In contrast to reports from other groups, we report the expression of Sox8 in germ cells and describe the molecular mechanism of Sox8 regulation by mrhl RNA during differentiation of spermatogonial cells. Binding of mrhl RNA to the Sox8 promoter is accompanied by the assembly of other regulatory factors involving Myc-Max-Mad transcription factors, corepressor Sin3a, and coactivator Pcaf. In the context of Wnt signaling, Sox8 directly regulates the expression of premeiotic and meiotic markers. Prolonged Wnt signaling activation in spermatogonial cells leads to changes in global chromatin architecture and a decrease in levels of stem cell markers.

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c-MYC-induced long noncoding RNA MEG3 aggravates kidney ischemia–reperfusion injury through activating mitophagy by upregulation of RTKN to trigger the Wnt/β-catenin pathway

Cell Death and Disease ◽

10.1038/s41419-021-03466-5 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Dajun Liu ◽

Ying Liu ◽

Xiaotong Zheng ◽

Naiquan Liu

Keyword(s):

Reperfusion Injury ◽

Noncoding Rna ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

In Vitro Models ◽

Downstream Effector ◽

Life Threatening

AbstractIschemia–reperfusion injury (IRI)-induced acute kidney injury (AKI) is a life-threatening disease. The activation of mitophagy was previously identified to play an important role in IRI. Maternally expressed 3 (MEG3) can promote cerebral IRI and hepatic IRI. The present study was designed to study the role of MEG3 in renal IRI. Renal IRI mice models were established, and HK-2 cells were used to construct the in vitro models of IRI. Hematoxylin–eosin staining assay was applied to reveal IRI-triggered tubular injury. MitoTracker Green FM staining and an ALP kit were employed for detection of mitophagy. TdT-mediated dUTP-biotin nick-end labeling assay was used to reveal cell apoptosis. The results showed that renal cortex of IRI mice contained higher expression of MEG3 than that of sham mice. MEG3 expression was also elevated in HK-2 cells following IRI, suggesting that MEG3 might participate in the development of IRI. Moreover, downregulation of MEG3 inhibited the apoptosis of HK-2 cells after IRI. Mitophagy was activated by IRI, and the inhibition of MEG3 can restore mitophagy activity in IRI-treated HK-2 cells. Mechanistically, we found that MEG3 can bind with miR-145-5p in IRI-treated cells. In addition, rhotekin (RTKN) was verified to serve as a target of miR-145-5p. MEG3 upregulated RTKN expression by binding with miR-145-5p. Further, MEG3 activated the Wnt/β-catenin pathway by upregulation of RTKN. The downstream effector of Wnt/β-catenin pathway, c-MYC, served as the transcription factor to activate MEG3. In conclusion, the positive feedback loop of MEG3/miR-145-5p/RTKN/Wnt/β-catenin/c-MYC promotes renal IRI by activating mitophagy and inducing apoptosis, which might offer a new insight into the therapeutic methods for renal IRI in the future.

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Biomarkers of inflammation and the etiology of sepsis

Biochemical Society Transactions ◽

10.1042/bst20190029 ◽

2020 ◽

Vol 48 (1) ◽

pp. 1-14 ◽

Cited By ~ 5

Author(s):

Inge Grondman ◽

Andrei Pirvu ◽

Anca Riza ◽

Mihai Ioana ◽

Mihai G. Netea

Keyword(s):

Host Response ◽

Viral Infections ◽

Immune Cell ◽

Inflammatory Responses ◽

Treatment Options ◽

Specific Treatment ◽

Adverse Outcomes ◽

Preclinical Research ◽

Related Factors ◽

Life Threatening

Sepsis is characterized as a life-threatening organ dysfunction syndrome that is caused by a dysregulated host response to infection. The main etiological causes of sepsis are bacterial, fungal, and viral infections. Last decades clinical and preclinical research contributed to a better understanding of pathophysiology of sepsis. The dysregulated host response in sepsis is complex, with both pathogen-related factors contributing to disease, as well as immune-cell mediated inflammatory responses that can lead to adverse outcomes in early or advanced stages of disease. Due to its heterogenous nature, clinical diagnosis remains challenging and sepsis-specific treatment options are still lacking. Classification and early identification of patient subgroups may aid clinical decisions and improve outcome in sepsis patients. The initial clinical presentation is rather similar in sepsis of different etiologies, however, inflammatory profiles may be able to distinguish between different etiologies of infections. In this review, we summarize the role and the discriminating potency of host-derived inflammatory biomarkers in the context of the main etiological types of sepsis.

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The mechanistic, diagnostic and therapeutic novel nucleic acids for hepatocellular carcinoma emerging in past score years

Briefings in Bioinformatics ◽

10.1093/bib/bbaa023 ◽

2020 ◽

Cited By ~ 2

Author(s):

Song Zhang ◽

Ying Zhou ◽

Yanan Wang ◽

Zhengwen Wang ◽

Qitao Xiao ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Nucleic Acids ◽

Noncoding Rna ◽

Noncoding Rnas ◽

Circular Rna ◽

Circulating Tumor Dna ◽

Clinical Applications ◽

Biological Processes ◽

Diagnosis And Therapy ◽

Tumor Dna

Abstract Despite The Central Dogma states the destiny of gene as ‘DNA makes RNA and RNA makes protein’, the nucleic acids not only store and transmit genetic information but also, surprisingly, join in intracellular vital movement as a regulator of gene expression. Bioinformatics has contributed to knowledge for a series of emerging novel nucleic acids molecules. For typical cases, microRNA (miRNA), long noncoding RNA (lncRNA) and circular RNA (circRNA) exert crucial role in regulating vital biological processes, especially in malignant diseases. Due to extraordinarily heterogeneity among all malignancies, hepatocellular carcinoma (HCC) has emerged enormous limitation in diagnosis and therapy. Mechanistic, diagnostic and therapeutic nucleic acids for HCC emerging in past score years have been systematically reviewed. Particularly, we have organized recent advances on nucleic acids of HCC into three facets: (i) summarizing diverse nucleic acids and their modification (miRNA, lncRNA, circRNA, circulating tumor DNA and DNA methylation) acting as potential biomarkers in HCC diagnosis; (ii) concluding different patterns of three key noncoding RNAs (miRNA, lncRNA and circRNA) in gene regulation and (iii) outlining the progress of these novel nucleic acids for HCC diagnosis and therapy in clinical trials, and discuss their possibility for clinical applications. All in all, this review takes a detailed look at the advances of novel nucleic acids from potential of biomarkers and elaboration of mechanism to early clinical application in past 20 years.

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Long Noncoding RNA LIFR-AS1: A New Player in Human Cancers

BioMed Research International ◽

10.1155/2022/1590815 ◽

2022 ◽

Vol 2022 ◽

pp. 1-11

Author(s):

Zhiqun Bai ◽

Xuemei Wang ◽

Zhen Zhang

Keyword(s):

Leukemia Inhibitory Factor ◽

Noncoding Rna ◽

Noncoding Rnas ◽

Clinicopathological Characteristics ◽

Vital Role ◽

Tumor Proliferation ◽

Biological Processes ◽

Leukemia Inhibitory Factor Receptor ◽

Human Cancers

Emerging evidence has indicated that aberrantly expressed long noncoding RNAs (lncRNAs) play a vital role in various biological processes associated with tumorigenesis. Leukemia inhibitory factor receptor antisense RNA1 (LIFR-AS1) is a recently identified lncRNA transcribed in an antisense manner from the LIFR gene located on human chromosome 5p13.1. LIFR-AS1 regulates tumor proliferation, migration, invasion, apoptosis, and drug resistance through different mechanisms. Its expression level is related to the clinicopathological characteristics of tumors and plays a key role in tumor occurrence and development. In this review, we summarize the role of LIFR-AS1 in the development and progression of different cancers and highlight the potential for LIFR-AS1 to serve as a biomarker and therapeutic target for a variety of human cancers.

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The Roles of Host Noncoding RNAs in Mycobacterium tuberculosis Infection

Frontiers in Immunology ◽

10.3389/fimmu.2021.664787 ◽

2021 ◽

Vol 12 ◽

Author(s):

Li Wei ◽

Kai Liu ◽

Qingzhi Jia ◽

Hui Zhang ◽

Qingli Bie ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Host Response ◽

Noncoding Rnas ◽

Host Cells ◽

Regulatory Mechanisms ◽

Biological Processes ◽

Mycobacterium Tuberculosis Infection ◽

Major Health Problem ◽

Major Health ◽

Tuberculosis Diagnosis

Tuberculosis remains a major health problem. Mycobacterium tuberculosis, the causative agent of tuberculosis, can replicate and persist in host cells. Noncoding RNAs (ncRNAs) widely participate in various biological processes, including Mycobacterium tuberculosis infection, and play critical roles in gene regulation. In this review, we summarize the latest reports on ncRNAs (microRNAs, piRNAs, circRNAs and lncRNAs) that regulate the host response against Mycobacterium tuberculosis infection. In the context of host-Mycobacterium tuberculosis interactions, a broad and in-depth understanding of host ncRNA regulatory mechanisms may lead to potential clinical prospects for tuberculosis diagnosis and the development of new anti-tuberculosis therapies.

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Biological relevance and therapeutic potential of G-quadruplex structures in the human noncoding transcriptome

Nucleic Acids Research ◽

10.1093/nar/gkab127 ◽

2021 ◽

Vol 49 (7) ◽

pp. 3617-3633

Author(s):

Martina Tassinari ◽

Sara N Richter ◽

Paolo Gandellini

Keyword(s):

Gene Expression ◽

Protein Interactions ◽

Noncoding Rna ◽

Therapeutic Potential ◽

Functional Characterization ◽

Noncoding Rnas ◽

Tertiary Structures ◽

Form Complex ◽

G Quadruplex ◽

Rna Interaction

Abstract Noncoding RNAs are functional transcripts that are not translated into proteins. They represent the largest portion of the human transcriptome and have been shown to regulate gene expression networks in both physiological and pathological cell conditions. Research in this field has made remarkable progress in the comprehension of how aberrations in noncoding RNA drive relevant disease-associated phenotypes; however, the biological role and mechanism of action of several noncoding RNAs still need full understanding. Besides fulfilling its function through sequence-based mechanisms, RNA can form complex secondary and tertiary structures which allow non-canonical interactions with proteins and/or other nucleic acids. In this context, the presence of G-quadruplexes in microRNAs and long noncoding RNAs is increasingly being reported. This evidence suggests a role for RNA G-quadruplexes in controlling microRNA biogenesis and mediating noncoding RNA interaction with biological partners, thus ultimately regulating gene expression. Here, we review the state of the art of G-quadruplexes in the noncoding transcriptome, with their structural and functional characterization. In light of the existence and further possible development of G-quadruplex binders that modulate G-quadruplex conformation and protein interactions, we also discuss the therapeutic potential of G-quadruplexes as targets to interfere with disease-associated noncoding RNAs.

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Noncoding Rnas Emerging as Novel Biomarkers in Pancreatic Cancer

Current Pharmaceutical Design ◽

10.2174/1381612825666190119125804 ◽

2019 ◽

Vol 24 (39) ◽

pp. 4601-4604 ◽

Cited By ~ 2

Author(s):

Ingrid Garajová ◽

Rita Balsano ◽

Chiara Tommasi ◽

Elisa Giovannetti

Keyword(s):

Pancreatic Cancer ◽

Noncoding Rna ◽

Noncoding Rnas ◽

Predictive Biomarkers ◽

Chemotherapy Response ◽

Biological Processes ◽

Metastatic Behavior ◽

Novel Biomarkers ◽

Non Coding Rnas

Noncoding RNAs play important regulatory roles in diverse biological processes and their misregulation might lead to different diseases, including cancer. Previous studies have reported the evolving role of miRNAs as new potential biomarkers in cancer diagnosis, prognosis, as well as predictive biomarkers of chemotherapy response or therapeutic targets. In this review, we outline the involvement of noncoding RNA in pancreatic cancer, providing an overview of known miRNAs in its diagnosis, prognosis and chemoresistance. In addition, we discuss the influence of non-coding RNAs in the metastatic behavior of pancreatic cancer, as well as the role of diet in epigenetic regulation of non-coding RNAs in cancer, which can, in turn, lead the development of new prevention’s techniques or novel targets for cancer therapy.

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Differential long noncoding RNA profiling of BMI in twins

Epigenomics ◽

10.2217/epi-2020-0033 ◽

2020 ◽

Vol 12 (17) ◽

pp. 1531-1541

Author(s):

Weilong Li ◽

Jan Baumbach ◽

Martin J Larsen ◽

Afsaneh Mohammadnejad ◽

Jesper Lund ◽

...

Keyword(s):

Whole Blood ◽

Generalized Estimating Equations ◽

Noncoding Rna ◽

Kidney Development ◽

Noncoding Rnas ◽

Monozygotic Twin ◽

Causal Effects ◽

Biological Processes ◽

Rna Profiling ◽

False Discovery

Aim: Many efforts have been deployed to identify genetic variants associated with BMI. Alternatively, we explore epigenetic contribution to BMI variation by focusing on long noncoding RNAs (lncRNAs) which represents a key layer of epigenetic control. Materials & methods: We analyzed lncRNA expression in whole blood of 229 monozygotic twin pairs in association with BMI using generalized estimating equations. Results & conclusion: Six lncRNA probes were identified as significant (false discovery rate <0.05), with BMI showing causal effects on the expression of the significant lncRNAs. Functional annotation of differential profiles identified Gene ontology biological processes including kidney development, regulations of lipid biosynthetic process, circadian rhythm, notch signaling, etc. Whole blood lncRNAs are significantly expressed in response to BMI variation.

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