Repurposing Ivermectin for COVID-19: Molecular Aspects and Therapeutic Possibilities

As of January 2021, SARS-CoV-2 has killed over 2 million individuals across the world. As such, there is an urgent need for vaccines and therapeutics to reduce the burden of COVID-19. Several vaccines, including mRNA, vector-based vaccines, and inactivated vaccines, have been approved for emergency use in various countries. However, the slow roll-out of vaccines and insufficient global supply remains a challenge to turn the tide of the pandemic. Moreover, vaccines are important tools for preventing the disease but therapeutic tools to treat patients are also needed. As such, since the beginning of the pandemic, repurposed FDA-approved drugs have been sought as potential therapeutic options for COVID-19 due to their known safety profiles and potential anti-viral effects. One of these drugs is ivermectin (IVM), an antiparasitic drug created in the 1970s. IVM later exerted antiviral activity against various viruses including SARS-CoV-2. In this review, we delineate the story of how this antiparasitic drug was eventually identified as a potential treatment option for COVID-19. We review SARS-CoV-2 lifecycle, the role of the nucleocapsid protein, the turning points in past research that provided initial ‘hints’ for IVM’s antiviral activity and its molecular mechanism of action- and finally, we culminate with the current clinical findings.

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MOLECULAR ASPECTS OF SARCOPENIA PATHOGENESIS IN CHRONOC KIDNEY DISEASE: INTEGRATED ROLE OF mTOR

Nephrology (Saint-Petersburg) ◽

10.24884/1561-6274-2018-22-5-9-16 ◽

2018 ◽

Vol 22 (5) ◽

pp. 9-16 ◽

Cited By ~ 3

Author(s):

M. Z. Gasanov

Keyword(s):

Kidney Disease ◽

Muscle Mass ◽

Protein Metabolism ◽

Mammalian Target Of Rapamycin ◽

Healthy Person ◽

Scientific Review ◽

Cytoskeleton Organization ◽

Molecular Aspects ◽

End Stage

In recent decades, the main pathogenetic mechanisms for maintaining muscle mass and strength have been discovered. Most of the scientific papers on the molecular aspects of the pathogenesis of sarcopenia were focused on the Akt-signaling pathway. The subject of the study were people of elderly and senile age, immobilized patients, patients with CKD 1-4 stages, animals. However, recently more attention has been paid to the role of protein – the mammalian target of rapamycin mTOR. It seems to be a key link in the control of muscle mass and is a promising marker in understanding the mechanisms of the pathogenesis of sarcopenia. Its importance in protein metabolism in patients with end stage kidney disease is not studied and requires further research. The presented scientific review contains information on the role of mTOR and its components – mTORC1 and mTORC2 in maintaining muscle mass and strength in a healthy person and in the formation of sarcopenia in patients with CKD. The general aid of mTORC1 complex is regulation of protein production which is necessary for cell growth and differentiation. mTORC2 complex functions are not enough studied. It is established that it plays important role in such biological processes as cytoskeleton organization, intracellular homeostasis maintaining, so it provides cell resistance and cell survivability in negative external and internal impulses. mTOR protein can be considered as promising molecular marker in diagnostics of protein metabolism early disturbances in patients with CKD and also as additory factor of sarcopenia severity assessment.

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Autophagy Modulators and Neuroinflammation

Current Medicinal Chemistry ◽

10.2174/0929867325666181031144605 ◽

2020 ◽

Vol 27 (6) ◽

pp. 955-982 ◽

Cited By ~ 4

Author(s):

Kyoung Sang Cho ◽

Jang Ho Lee ◽

Jeiwon Cho ◽

Guang-Ho Cha ◽

Gyun Jee Song

Keyword(s):

Neurodegenerative Disorders ◽

Neurological Disorders ◽

Mammalian Cells ◽

Critical Role ◽

Therapeutic Agents ◽

Mechanisms Of Action ◽

Scientific Interest ◽

Therapeutic Tools ◽

Underlying Mechanisms

Background: Neuroinflammation plays a critical role in the development and progression of various neurological disorders. Therefore, various studies have focused on the development of neuroinflammation inhibitors as potential therapeutic tools. Recently, the involvement of autophagy in the regulation of neuroinflammation has drawn substantial scientific interest, and a growing number of studies support the role of impaired autophagy in the pathogenesis of common neurodegenerative disorders. Objective: The purpose of this article is to review recent research on the role of autophagy in controlling neuroinflammation. We focus on studies employing both mammalian cells and animal models to evaluate the ability of different autophagic modulators to regulate neuroinflammation. Methods: We have mostly reviewed recent studies reporting anti-neuroinflammatory properties of autophagy. We also briefly discussed a few studies showing that autophagy modulators activate neuroinflammation in certain conditions. Results: Recent studies report neuroprotective as well as anti-neuroinflammatory effects of autophagic modulators. We discuss the possible underlying mechanisms of action of these drugs and their potential limitations as therapeutic agents against neurological disorders. Conclusion: Autophagy activators are promising compounds for the treatment of neurological disorders involving neuroinflammation.

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Importance of Apolipoprotein A-I and A-II Composition in HDL and Its Potential for Studying COVID-19 and SARS-CoV-2

Medicines ◽

10.3390/medicines8070038 ◽

2021 ◽

Vol 8 (7) ◽

pp. 38

Author(s):

Kyung-Hyun Cho

Keyword(s):

Antiviral Activity ◽

High Density ◽

High Density Lipoproteins ◽

Potent Antiviral Activity ◽

Apolipoprotein A ◽

Putative Role

The composition and properties of apolipoprotein (apo) A-I and apoA-II in high-density lipoproteins (HDL) might be critical to SARS-CoV-2 infection via SR-BI and antiviral activity against COVID-19. HDL containing native apoA-I showed potent antiviral activity, while HDL containing glycated apoA-I or other apolipoproteins did not. However, there has been no report to elucidate the putative role of apoA-II in the antiviral activity of HDL.

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O-GlcNAcylation protein disruption by Thiamet G promotes changes on the GBM U87-MG cells secretome molecular signature

Clinical Proteomics ◽

10.1186/s12014-021-09317-x ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Maria Cecilia Oliveira-Nunes ◽

Glaucia Julião ◽

Aline Menezes ◽

Fernanda Mariath ◽

John A. Hanover ◽

...

Keyword(s):

Experimental Evidence ◽

Critical Role ◽

Molecular Signature ◽

Label Free ◽

Intercellular Signaling ◽

Tumor Aggressiveness ◽

Signaling Axis ◽

Literature Evidence ◽

Therapeutic Tools

AbstractGlioblastoma (GBM) is a grade IV glioma highly aggressive and refractory to the therapeutic approaches currently in use. O-GlcNAcylation plays a key role for tumor aggressiveness and progression in different types of cancer; however, experimental evidence of its involvement in GBM are still lacking. Here, we show that O-GlcNAcylation plays a critical role in maintaining the composition of the GBM secretome, whereas inhibition of OGA activity disrupts the intercellular signaling via microvesicles. Using a label-free quantitative proteomics methodology, we identified 51 proteins in the GBM secretome whose abundance was significantly altered by activity inhibition of O-GlcNAcase (iOGA). Among these proteins, we observed that proteins related to proteasome activity and to regulation of immune response in the tumor microenvironment were consistently downregulated in GBM cells upon iOGA. While the proteins IGFBP3, IL-6 and HSPA5 were downregulated in GBM iOGA cells, the protein SQSTM1/p62 was exclusively found in GBM cells under iOGA. These findings were in line with literature evidence on the role of p62/IL-6 signaling axis in suppressing tumor aggressiveness and our experimental evidence showing a decrease in radioresistance potential of these cells. Taken together, our findings provide evidence that OGA activity may regulate the p62 and IL-6 abundance in the GBM secretome. We propose that the assessment of tumor status from the main proteins present in its secretome may contribute to the advancement of diagnostic, prognostic and even therapeutic tools to approach this relevant malignancy.

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Sialic Acid—Modified Nanoparticles—New Approaches in the Glioma Management—Perspective Review

International Journal of Molecular Sciences ◽

10.3390/ijms22147494 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7494

Author(s):

Przemyslaw Wielgat ◽

Katarzyna Niemirowicz-Laskowska ◽

Agnieszka Z. Wilczewska ◽

Halina Car

Keyword(s):

Sialic Acid ◽

Clinical Observation ◽

Malignant Cell ◽

Cellular Heterogeneity ◽

Molecular Processes ◽

Management Perspective ◽

Therapeutic Tools ◽

And Function ◽

Worse Prognosis

The cell surface is covered by a dense and complex network of glycans attached to the membrane proteins and lipids. In gliomas, the aberrant sialylation, as the final stage of glycosylation, is an important regulatory mechanism of malignant cell behavior and correlates with worse prognosis. Better understanding of the role of sialylation in cellular and molecular processes opens a new way in the development of therapeutic tools for human brain tumors. According to the recent clinical observation, the cellular heterogeneity, activity of brain cancer stem cells (BCSCs), immune evasion, and function of the blood–brain barrier (BBB) are attractive targets for new therapeutic strategies. In this review, we summarize the importance of sialic acid-modified nanoparticles in brain tumor progression.

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Possible role of tocopherols in the modulation of host microRNA with potential antiviral activity in patients with hepatitis B virus-related persistent infection: a systematic review

British Journal Of Nutrition ◽

10.1017/s0007114514002839 ◽

2014 ◽

Vol 112 (11) ◽

pp. 1751-1768 ◽

Cited By ~ 10

Author(s):

S. Fiorino ◽

L. Bacchi-Reggiani ◽

S. Sabbatani ◽

F. Grizzi ◽

L. di Tommaso ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Antiviral Activity ◽

Hbv Infection ◽

Cochrane Library ◽

Viral Pathogen ◽

Increased Risk ◽

B Virus ◽

Chronic Hbv

Hepatitis B virus (HBV) infection represents a serious global health problem and persistent HBV infection is associated with an increased risk of cirrhosis, hepatocellular carcinoma and liver failure. Recently, the study of the role of microRNA (miRNA) in the pathogenesis of HBV has gained considerable interest as well as new treatments against this pathogen have been approved. A few studies have investigated the antiviral activity of vitamin E (VE) in chronic HBV carriers. Herein, we review the possible role of tocopherols in the modulation of host miRNA with potential anti-HBV activity. A systematic research of the scientific literature was performed by searching the MEDLINE, Cochrane Library and EMBASE databases. The keywords used were ‘HBV therapy’, ‘HBV treatment’, ‘VE antiviral effects’, ‘tocopherol antiviral activity’, ‘miRNA antiviral activity’ and ‘VE microRNA’. Reports describing the role of miRNA in the regulation of HBV life cycle,in vitroandin vivoavailable studies reporting the effects of VE on miRNA expression profiles and epigenetic networks, and clinical trials reporting the use of VE in patients with HBV-related chronic hepatitis were identified and examined. Based on the clinical results obtained in VE-treated chronic HBV carriers, we provide a reliable hypothesis for the possible role of this vitamin in the modulation of host miRNA profiles perturbed by this viral pathogen and in the regulation of some cellular miRNA with a suggested potential anti-HBV activity. This approach may contribute to the improvement of our understanding of pathogenetic mechanisms involved in HBV infection and increase the possibility of its management and treatment.

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Immune-Mediated Drug-Induced Liver Injury: Immunogenetics and Experimental Models

International Journal of Molecular Sciences ◽

10.3390/ijms22094557 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4557

Author(s):

Alessio Gerussi ◽

Ambra Natalini ◽

Fabrizio Antonangeli ◽

Clara Mancuso ◽

Elisa Agostinetto ◽

...

Keyword(s):

Liver Injury ◽

Experimental Models ◽

Clinical Event ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Immune Mediated ◽

Liver Injuries ◽

Immunological Mechanisms ◽

Molecular Aspects ◽

Therapeutic Tools

Drug-induced liver injury (DILI) is a challenging clinical event in medicine, particularly because of its ability to present with a variety of phenotypes including that of autoimmune hepatitis or other immune mediated liver injuries. Limited diagnostic and therapeutic tools are available, mostly because its pathogenesis has remained poorly understood for decades. The recent scientific and technological advancements in genomics and immunology are paving the way for a better understanding of the molecular aspects of DILI. This review provides an updated overview of the genetic predisposition and immunological mechanisms behind the pathogenesis of DILI and presents the state-of-the-art experimental models to study DILI at the pre-clinical level.

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“When” Does It Pay to Be Good? Attributions Mediate the Way CSR Elements Impact on Consumer Responses, and Are Controllable

Sustainability ◽

10.3390/su13115869 ◽

2021 ◽

Vol 13 (11) ◽

pp. 5869

Author(s):

Athanasios Krystallis ◽

Vlad Zaharia ◽

Antonis Zairis

Keyword(s):

Past Research ◽

Consumer Response ◽

Multiple Mediation ◽

Consumer Responses ◽

Mediating Role ◽

Consumer Attributions ◽

The Right ◽

The Relationship ◽

Experimental Survey

Responding to the appeal for more research on the contingencies that shape the relationship between CSR and corporate performance, this paper incorporates environmental CSR, sets up an experimental survey and employs multiple mediation analysis with the aim to test the mediating role of consumer attributions on the CSR elements–consumer responses relationship; and further to examine the degree to which attributions are controllable, i.e., specific CSR elements activate specific type of attributions. Results support that attributions have a strong predicting power on consumer outcomes. The right time of appearance and the appropriate amount of resources committed to a CSR campaign, through the dual type of attributions they activate (more positive, i.e., values-driven and less negative, i.e., egoistic), impact positively on consumer reactions. In this respect, the study adds to past research showing that attributions are controllable, i.e., specific CSR initiative characteristics of a impact on the dimensionality of attributions and, through that, on specific target-types of consumer responses. This study thus shows that the activation of a dual-level attributions’ system is ambivalent, dependent on the character of the CSR campaign. The fact that specific CSR elements (i.e., CSR Timing) activate dual-level CSR motives that act complementarily indicates that managers should be clear about the capabilities of the elements of their CSR initiatives and how much impact they expect those elements to have on consumer response.

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Data Integration Reveals the Potential Biomarkers of Circulating MicroRNAs in Osteoarthritis

Diagnostics ◽

10.3390/diagnostics11030412 ◽

2021 ◽

Vol 11 (3) ◽

pp. 412

Author(s):

Thuan Duc Lao ◽

Thuy Ai Huyen Le

Keyword(s):

Target Genes ◽

Potential Implication ◽

Circulating Micrornas ◽

Abnormal Expression ◽

Online Databases ◽

Socioeconomic Burden ◽

Therapeutic Tools ◽

Potential Use ◽

Potential Biomarkers

The abnormal expression of circulating miRNAs (c-miRNAs) has become an emerging field in the development of miRNAs-based diagnostic and therapeutic tools for human diseases, including osteoarthritis (OA). OA is the most common form of arthritis leading to disability and a major socioeconomic burden. The abnormal expression of miRNAs plays important roles in the pathogenesis of OA. Unraveling the role of miRNAs in the pathogenesis of OA will throw light on the potential for the development of miRNAs-based diagnostic and therapeutic tools for OA. This article reviews and highlights recent advances in the study of miRNAs in OA, with specific demonstration of the functions of miRNA, especially c-miRNA, in OA pathogenesis as well as its potential implication in the treatment of OA. Based on a systematic literature search using online databases, we figured out the following main points: (1) the integrative systematic review of c-mRNAs and its target genes related to OA pathogenesis; (2) the potential use of c-miRNAs for OA diagnosis purposes as potential biomarkers; and (3) for therapeutic purposes, and we also highlight certain remedies that regulate microRNA expression based on its target genes.

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Racial/Ethnic Differences in Alcohol and Drug Misuse Among IPV-Victimized Women: Exploring the Role of Difficulties Regulating Positive Emotions

Journal of Interpersonal Violence ◽

10.1177/0886260520943735 ◽

2020 ◽

pp. 088626052094373

Author(s):

Nicole H. Weiss ◽

Melissa R. Schick ◽

Ateka A. Contractor ◽

Miranda E. Reyes ◽

Nazaret C. Suazo ◽

...

Keyword(s):

African American ◽

Partner Violence ◽

Positive Emotions ◽

Past Research ◽

Drug Misuse ◽

Emotional Dysfunction ◽

Culturally Sensitive Interventions ◽

Race Ethnicity ◽

Racial Ethnic

Alcohol and drug misuse is prevalent and problematic among women who experience intimate partner violence (IPV). Emotional dysfunction has been identified as a key mechanism in the etiology, maintenance, and treatment of alcohol and drug misuse. However, existing research has not considered the role of race/ethnicity in the relations between emotional dysfunction and alcohol and drug misuse. Furthermore, past research in this area has focused almost exclusively on emotional dysfunction stemming from negative (vs. positive) emotions. The goals of the current study were as follows: (a) to explore whether levels of difficulties regulating positive emotions differ among Latina, African American, and White IPV-victimized women, and (b) to examine the moderating role of race/ethnicity in the relations between difficulties regulating positive emotions and alcohol and drug misuse. Participants were 197 IPV-victimized women recruited through the criminal justice system ( Mage = 36.14; 51.8% African American, 31.5% White, and 16.8% Latina). Difficulties regulating positive emotions did not differ as a function of race/ethnicity. However, relations among difficulties regulating positive emotions and alcohol and drug misuse were significant for Latina and White but not African American IPV-victimized women. Moreover, race/ethnicity moderated an association between difficulties regulating positive emotions and drug misuse; this relation was significant and positive for White (compared with African American) IPV-victimized women. While preliminary, these results may inform culturally sensitive interventions for alcohol and drug misuse that are tailored to the unique needs of Latina, African American, and White IPV-victimized women.

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