ADAR1p150 Forms a Complex with Dicer to Promote miRNA-222 Activity and Regulate PTEN Expression in CVB3-Induced Viral Myocarditis

Adenosine deaminases acting on RNA (ADAR) are enzymes that regulate RNA metabolism through post-transcriptional mechanisms. ADAR1 is involved in a variety of pathological conditions including inflammation, cancer, and the host defense against viral infections. However, the role of ADAR1p150 in vascular disease remains unclear. In this study, we examined the expression of ADAR1p150 and its role in viral myocarditis (VMC) in a mouse model. VMC mouse cardiomyocytes showed significantly higher expression of ADAR1p150 compared to the control samples. Coimmunoprecipitation verified that ADAR1p150 forms a complex with Dicer in VMC. miRNA-222, which is involved in many cardiac diseases, is highly expressed in cardiomyocytes in VMC. In addition, the expression of miRNA-222 was promoted by ADAR1p150/Dicer. Among the target genes of miRNA-222, the expression of phosphatase-and-tensin (PTEN) protein was significantly reduced in VMC. By using a bioinformatics tool, we found a potential binding site of miRNA-222 on the PTEN gene’s 3′-UTR, suggesting that miRNA-222 might play a regulatory role. In cultured cells, miR-222 suppressed PTEN expression. Our findings suggest that ADAR1p150 plays a key role in complexing with Dicer and promoting the expression of miRNA-222, the latter of which suppresses the expression of the target gene PTEN during VMC. Our work reveals a previously unknown role of ADAR1p150 in gene expression in VMC.

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MicroRNA 130a Regulates both Hepatitis C Virus and Hepatitis B Virus Replication through a Central Metabolic Pathway

Journal of Virology ◽

10.1128/jvi.02009-17 ◽

2018 ◽

Vol 92 (7) ◽

Cited By ~ 8

Author(s):

Xiaoqiong Duan ◽

Shilin Li ◽

Jacinta A. Holmes ◽

Zeng Tu ◽

Yujia Li ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Target Genes ◽

Viral Infections ◽

Cultured Cells ◽

Guide Rna ◽

Hbv Replication ◽

B Virus

ABSTRACTHepatitis C virus (HCV) infection has been shown to regulate microRNA 130a (miR-130a) in patient biopsy specimens and in cultured cells. We sought to identify miR-130a target genes and to explore the mechanisms by which miR-130a regulates HCV and hepatitis B virus (HBV) replication. We used bioinformatics software, including miRanda, TargetScan, PITA, and RNAhybrid, to predict potential miR-130a target genes. miR-130a and its target genes were overexpressed or were knocked down by use of small interfering RNA (siRNA) or clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 guide RNA (gRNA). Selected gene mRNAs and their proteins, together with HCV replication in OR6 cells, HCV JFH1-infected Huh7.5.1 cells, and HCV JFH1-infected primary human hepatocytes (PHHs) and HBV replication in HepAD38 cells, HBV-infected NTCP-Huh7.5.1 cells, and HBV-infected PHHs, were measured by quantitative reverse transcription-PCR (qRT-PCR) and Western blotting, respectively. We selected 116 predicted target genes whose expression was related to viral pathogenesis or immunity for qPCR validation. Of these, the gene encoding pyruvate kinase in liver and red blood cell (PKLR) was confirmed to be regulated by miR-130a overexpression. miR-130a overexpression (via a mimic) knocked down PKLR mRNA and protein levels. A miR-130a inhibitor and gRNA increased PKLR expression, HCV replication, and HBV replication, while miR-130a gRNA and PKLR overexpression increased HCV and HBV replication. Supplemental pyruvate increased HCV and HBV replication and rescued the inhibition of HCV and HBV replication by the miR-130a mimic and PKLR knockdown. We concluded that miR-130a regulates HCV and HBV replication through its targeting of PKLR and subsequent pyruvate production. Our data provide novel insights into key metabolic enzymatic pathway steps regulated by miR-130a, including the steps involving PKLR and pyruvate, which are subverted by HCV and HBV replication.IMPORTANCEWe identified that miR-130a regulates the target genePKLRand its subsequent effect on pyruvate production. Pyruvate is a key intermediate in several metabolic pathways, and we identified that pyruvate plays a key role in regulation of HCV and HBV replication. This previously unrecognized, miRNA-regulated antiviral mechanism has implications for the development of host-directed strategies to interrupt the viral life cycle and prevent establishment of persistent infection for HCV, HBV, and potentially other viral infections.

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Comparison and Analysis on the Existing Single-Herbal Strategies against Viral Myocarditis

Genetics Research ◽

10.1155/2021/9952620 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Yu Cao ◽

Yang Liu ◽

Tian Zhang ◽

Jing Pan ◽

Wei Lei ◽

...

Keyword(s):

Cardiac Troponin ◽

Target Genes ◽

Viral Myocarditis ◽

Herbal Medicines ◽

Heart Tissue ◽

Discovery Studio ◽

Radix Bupleuri ◽

Natural Components ◽

Spatholobus Suberectus

Purpose. Herbal medicine is one of crucial symbols of Chinese national medicine. Investigation on molecular responses of different herbal strategies against viral myocarditis is immeasurably conducive to targeting drug development in the current international absence of miracle treatment. Methods. Literature retrieval platforms were applied in the collection of existing empirical evidences for viral myocarditis-related single-herbal strategies. SwissTargetPrediction, Metascape, and Discovery Studio coordinating with multidatabases investigated underlying target genes, interactive proteins, and docking molecules in turn. Results. Six single-herbal medicines consisting of Huangqi (Hedysarum Multijugum Maxim), Yuganzi (Phyllanthi Fructus), Kushen (Sophorae Flavescentis Radix), Jianghuang (Curcumaelongae Rhizoma), Chaihu (Radix Bupleuri), and Jixueteng (Spatholobus Suberectus Dunn) meet the requirement. There were 11 overlapped and 73 unique natural components detected in these herbs. SLC6A2, SLC6A4, NOS2, PPARA, PPARG, ACHE, CYP2C19, CYP51A1, and CHRM2 were equally targeted by six herbs and identified as viral myocarditis-associated symbols. MCODE algorithm exposed the hub role of SRC and EGFR in strategies without Jianghuang. Subsequently, we learned intermolecular interactions of herbal components and their targeting heart-tissue-specific CHRM2, FABP3, TNNC1, TNNI3, TNNT2, and SCN5A and cardiac-myocytes-specific IL6, MMP1, and PLAT coupled with viral myocarditis. Ten interactive characteristics such as π-alkyl and van der Waals were modeled in which ARG111, LYS253, ILE114, and VAL11 on cardiac troponin (TNNC1-TNNI3-TNNT2) and ARG208, ASN106, and ALA258 on MMP1 fulfilled potential communicating anchor with ellagic acid, 5α, 9α-dihydroxymatrine, and leachianone g via hydrogen bond and hydrophobic interaction, respectively. Conclusions. The comprehensive outcomes uncover differences and linkages between six herbs against viral myocarditis through component and target analysis, fostering development of drugs.

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Th2 Regulation of Viral Myocarditis in Mice: Different Roles for TLR3 versus TRIF in Progression to Chronic Disease

Clinical and Developmental Immunology ◽

10.1155/2012/129486 ◽

2012 ◽

Vol 2012 ◽

pp. 1-12 ◽

Cited By ~ 45

Author(s):

Eric D. Abston ◽

Michael J. Coronado ◽

Adriana Bucek ◽

Djahida Bedja ◽

Jaewook Shin ◽

...

Keyword(s):

Viral Infections ◽

Heart Function ◽

Viral Myocarditis ◽

Alternative Activation ◽

Toll Like Receptor ◽

T Helper ◽

Chronic Myocarditis ◽

First Time ◽

Deficient Mice

Viral infections are able to induce autoimmune inflammation in the heart. Here, we investigated the role of virus-activated Toll-like receptor (TLR)3 and its adaptor TRIF on the development of autoimmune coxsackievirus B3 (CVB3) myocarditis in mice. Although TLR3- or TRIF-deficient mice developed similarly worse acute CVB3 myocarditis and viral replication compared to control mice, disease was significantly worse in TRIF compared to TLR3-deficient mice. Interestingly, TLR3-deficient mice developed an interleukin (IL)-4-dominant T helper (Th)2 response during acute CVB3 myocarditis with elevated markers of alternative activation, while TRIF-deficient mice elevated the Th2-associated cytokine IL-33. Treatment of TLR3-deficient mice with recombinant IL-33 improved heart function indicating that elevated IL-33 in the context of a classic Th2-driven response protects against autoimmune heart disease. We show for the first time that TLR3 versus TRIF deficiency results in different Th2 responses that uniquely influence the progression to chronic myocarditis.

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Toll-Like Receptors: Are They Taking a Toll on the Heart in Viral Myocarditis?

Viruses ◽

10.3390/v13061003 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1003

Author(s):

Kasper Favere ◽

Matthias Bosman ◽

Karin Klingel ◽

Stephane Heymans ◽

Sophie Van Linthout ◽

...

Keyword(s):

Immune Responses ◽

Viral Infections ◽

Viral Myocarditis ◽

Disease Process ◽

Future Research ◽

Toll Like Receptors ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

Evolutionarily Conserved

Myocarditis is an inflammatory disease of the heart with viral infections being the most common aetiology. Its complex biology remains poorly understood and its clinical management is one of the most challenging in the field of cardiology. Toll-like receptors (TLRs), a family of evolutionarily conserved pattern recognition receptors, are increasingly known to be implicated in the pathophysiology of viral myocarditis. Their central role in innate and adaptive immune responses, and in the inflammatory reaction that ensues, indeed makes them prime candidates to profoundly affect every stage of the disease process. This review describes the pathogenesis and pathophysiology of viral myocarditis and scrutinises the role of TLRs in every phase. We conclude with directions for future research in this field.

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Viruses in the Heart: Direct and Indirect Routes to Myocarditis and Heart Failure

Viruses ◽

10.3390/v13101924 ◽

2021 ◽

Vol 13 (10) ◽

pp. 1924

Author(s):

Colton R. Martens ◽

Federica Accornero

Keyword(s):

Heart Failure ◽

Cardiac Dysfunction ◽

Viral Infections ◽

Heart Function ◽

Viral Myocarditis ◽

Therapeutic Interventions ◽

Cardiovascular Risks ◽

Immune Systems

Viruses are an underappreciated cause of heart failure. Indeed, several types of viral infections carry cardiovascular risks. Understanding shared and unique mechanisms by which each virus compromises heart function is critical to inform on therapeutic interventions. This review describes how the key viruses known to lead to cardiac dysfunction operate. Both direct host-damaging mechanisms and indirect actions on the immune systems are discussed. As viral myocarditis is a key pathologic driver of heart failure in infected individuals, this review also highlights the role of cytokine storms and inflammation in virus-induced cardiomyopathy.

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Erratum

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics ◽

10.3727/096504020x16032056440094 ◽

2020 ◽

Vol 28 (5) ◽

pp. 553-557

Author(s):

Fen Liu ◽

Shaojun Liu ◽

Feiyan Ai ◽

Decai Zhang ◽

Zhiming Xiao ◽

...

Keyword(s):

Negative Control ◽

Luciferase Reporter ◽

Positive Role ◽

Tumor Tissues ◽

Potential Binding ◽

Lovo Cells ◽

Proliferation And Apoptosis ◽

High Incidence ◽

Potential Binding Site

Colorectal cancer (CRC) is one of the most common malignancies in the world, with a high incidence and a high mortality. However, the pathogenesis of CRC carcinogenesis is still unexplored. In this study, we investigated the role of miR-107 in the regulation of CRC cell proliferation and apoptosis. First, the expression of miR-107 was observed to be aberrantly increased in human CRC tumor tissues and cell lines when compared to the colonic control tissues and colon epithelial cells. Further study showed that the proliferative and apoptotic capacities of human CRC SW480 and LoVo cells were aberrantly regulated by miR-107. The proliferation of SW480 and LoVo cells was remarkably enhanced by the miR-107 mimic but suppressed by the miR-107 inhibitor when compared to the negative control. On the contrary, the apoptotic rate of both SW480 and LoVo cells was significantly inhibited by miR-107 overexpression but increased by miR-107 inhibition. In addition, we identified prostate apoptosis response-4 (Par4) as a direct target of miR-107 with a potential binding site on the 3-UTR of mRNA, as evaluated by bioinformatics prediction and luciferase reporter assay. Par4 expression levels were significantly inhibited by the miR-107 mimic but upregulated by the miR-107 inhibitor in both SW480 and LoVo cells. Compared to the control, the increase in Par4 expression significantly inhibited the induction role of miR-107 in the proliferation of SW480 and LoVo cells, and the apoptotic rate of cells repressed by the miR-107 mimic was also reversed by Par4 overexpression. In summary, our results demonstrated that miR-107 exerts a positive role in the survival of CRC cells by directly targeting Par4. This might reveal a novel understanding about human CRC pathogenesis.

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Human Herpesvirus 6A (HHV-6A) and HHV-6B Alter E2F1/Rb Pathways and E2F1 Localization and Cause Cell Cycle Arrest in Infected T Cells

Journal of Virology ◽

10.1128/jvi.01496-07 ◽

2007 ◽

Vol 81 (24) ◽

pp. 13499-13508 ◽

Cited By ~ 16

Author(s):

Guy Mlechkovich ◽

Niza Frenkel

Keyword(s):

Cell Cycle ◽

T Cells ◽

Cell Cycle Arrest ◽

Cellular Localization ◽

Target Genes ◽

Viral Infections ◽

Human Herpesvirus ◽

Cycle Arrest ◽

E2f Transcription Factors

ABSTRACT E2F transcription factors play pivotal roles in controlling the expression of genes involved in cell viability as well as genes involved in cell death. E2F1 is an important constituent of this protein family, which thus far contains eight members. The interaction of E2F1 with its major regulator, retinoblastoma protein (Rb), has been studied extensively in the past two decades, concentrating on the role of E2F1 in transcriptional regulation and the role of Rb in cell replication and cancer formation. Additionally, the effect of viral infections on E2F1/Rb interactions has been analyzed for different viruses, concentrating on cell division, which is essential for viral replication. In the present study, we monitored E2F1-Rb interactions during human herpesvirus 6A (HHV-6A) and HHV-6B infections of SupT1 T cells. The results have shown the following dramatic alterations in E2F1-Rb pathways compared to the pathways of parallel mock-infected control cultures. (i) The E2F1 levels were elevated during viral infections. (ii) The cellular localization of E2F1 was dramatically altered, and it was found to accumulate both in the cytoplasmic and nuclear fractions, as opposed to the strict nuclear localization seen in the mock-infected cells. (iii) Although E2F1 expression was elevated, two exemplary target genes, cyclin E and MCM5, were not upregulated. (iv) The Rb protein was dephosphorylated early postinfection, a trait that also occurred with UV-inactivated virus. (v) Infection was associated with significant reduction of E2F1/Rb complexing. (vi) HHV-6 infections were accompanied by cell cycle arrest. The altered E2F1-Rb interactions and functions might contribute to the observed cell cycle arrest.

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Possible Role of PTEN expression in discriminating Benign Endometrial hyperplasia from Atypical Hyperplasia/Endometrial Intraepithelial Neoplasia in a series of Egyptian Patients

Current Women s Health Reviews ◽

10.2174/1573404817666210811125751 ◽

2021 ◽

Vol 17 ◽

Author(s):

Nevine I. Ramzy ◽

Wael S. Ibrahiam ◽

Hanan H.M. Ali ◽

Mona M.A. Akle ◽

Sara E. Khalifa

Keyword(s):

Endometrial Hyperplasia ◽

Intraepithelial Neoplasia ◽

Atypical Hyperplasia ◽

Pten Expression ◽

Histological Evaluation ◽

Type I ◽

Pten Protein ◽

Endometrial Intraepithelial Neoplasia ◽

Egyptian Patients

Background: Endometrial hyperplasia represents a heterogeneous group of lesions in response to the unopposed growth-promoting action of estrogen. WHO classified endometrial hyperplastic lesions into Benign Hyperplasia (BH) and atypical hyperplasia/ endometrial intraepithelial neoplasia AH/EIN. Phosphatase and tensin homolog (PTEN) is one of the earliest and most common genetic abnormalities detected in endometrioid adenocarcinoma (type I) and even in its precursors. This study aimed at histological evaluation of hyperplastic endometrial lesions according to WHO 2014 and investigating the role of PTEN expression in highlighting the precancerous group (AH/EIN). Patient and Method: This study included a series of 70 Egyptian patients suffered from hyperplastic endometrial lesions. They were previously diagnosed according to WHO1994 schema simple endometrial hyperplasia without atypia (n=18), simple endometrial hyperplasia with atypia (n=2), complex hyperplasia without atypia (n=25), complex hyperplasia with atypia (n=5) and hyperplastic endometrial polyps (n=20). Results: Cases were histologically re-evaluated according to WHO 2014 classification; BH (62 cases) and eight cases of AH/EIN. A significant difference in PTEN expression (regarding percentage and intensity of staining) in relation to histopathological diagnosis was detected (P-value 0.02 and <0.05, respectively). The sensitivity and specificity of the absence of diffuse PTEN protein expression (>50%) to detect AH/EIN were 100% and 77.4%, respectively. Conclusion: Diffuse, dim or loss of immunohistochemical expression of PTEN protein is significantly correlated with the new WHO classification segregation of AH/EIN as precancerous lesions. However, further studies are recommended to confirm this association.

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Treatment of ebola and other infectious diseases: melatonin “goes viral”

Melatonin Research ◽

10.32794/mr11250047 ◽

2020 ◽

Vol 3 (1) ◽

pp. 43-57 ◽

Cited By ~ 21

Author(s):

Russel J Reiter ◽

Qiang Ma ◽

Ramaswamy Sharma

Keyword(s):

Mortality Rate ◽

Infectious Diseases ◽

Hemorrhagic Shock ◽

Safety Profile ◽

Ebola Virus ◽

Viral Infections ◽

Virus Disease ◽

Attractive Potential ◽

Potential Treatment

This review summarizes published reports on the utility of melatonin as a treatment for virus-mediated diseases. Of special note are the data related to the role of melatonin in influencing Ebola virus disease. This infection and deadly condition has no effective treatment and the published works documenting the ability of melatonin to attenuate the severity of viral infections generally and Ebola infection specifically are considered. The capacity of melatonin to prevent one of the major complications of an Ebola infection, i.e., the hemorrhagic shock syndrome, which often contributes to the high mortality rate, is noteworthy. Considering the high safety profile of melatonin, the fact that it is easily produced, inexpensive and can be self-administered makes it an attractive potential treatment for Ebola virus pathology.

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Role of Rasayana in Prevention of COVID-19 - A Review

International Journal of Research in Pharmaceutical Sciences ◽

10.26452/ijrps.v11ispl1.3072 ◽

2020 ◽

Vol 11 (SPL1) ◽

pp. 716-722

Author(s):

Sneha Dhakite ◽

Sadhana Misar Wajpeyi

Keyword(s):

Immune System ◽

Respiratory System ◽

Viral Infections ◽

Cost Effective ◽

The Body ◽

Healthy Life ◽

Vital Functions ◽

Healthy Life Style ◽

And Control

The “Coronavirus disease 19 (COVID-19)” is caused by “Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)”, a newly discovered member of the Coronaviridae family of viruses which is a highly communicable. There is no effective medical treatment till date for Coronavirus disease hence prevention is the best way to keep disease away. Rasayana proved to be highly efficacious and cost effective for the Prevention and Control of viral infections when vaccines and standard therapies are lacking. Rasayana Chikitsa is one of the eight branches of Ashtanga Ayurveda which helps to maintain healthy life style. Rasayana improves immunity and performs many vital functions of human body. Vyadhikshamatva that is immune mechanism of the body is involved in Prevention of the occurrence of a new disease and it also decreases the virulence and progression of an existing disease. In COVID-19 the Respiratory system mainly get affected which is evident from its symptoms like cold, cough and breathlessness. Here the drugs help in enhancing immune system and strengthening functions of Respiratory system can be useful. For this purpose, the Rasayana like Chyavanprasha, Agastya Haritaki, Pippali Rasayana, Guduchi, Yashtimadhu, Haridra, Ashwagandha, Tulsi are used. Rasayana working on Respiratory system are best for Prevention of Coronavirus and boosting immune system. Rasayana Chikitsa can be effective in the Prevention as well as reducing symptoms of COVID-19.

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