Nanoformulation of Glycyrrhizic acid as a potent antiviral agent against Covid-19

2022 ◽  
Vol 01 ◽  
Author(s):  
Sayani Ghosh ◽  
Prasun Patra
Keyword(s):  
Therapeutic Strategy ◽  
Glycyrrhizic Acid ◽  
Viral Infections ◽  
Antiviral Agent ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Replication Strategy ◽  
Increased Activity

Abstract: In many previous studies, it has been found that liquorice plant (Glycyrrhiza glabra) extracts contain more than 300 natural compounds, most of which are triterpenoids and flavonoids, and had shown promising results in clinical studies for treating many microbial and viral infections. Triterpenoids like glycyrrhizic acid have shown anti-SARS-CoV activity in- vitro. Experimentally, certain glycyrrhizic acid derivatives have shown increased activity by many folds against SARS-associated viruses. These compounds can potentially inhibit the replication cycle of SARS-associated viruses by interfering with the viral gene expression or by inhibiting the spike protein expression, which in turn inhibits the adhesion and entry of the virus. Although the therapeutic has shown great antiviral activity in vitro, but in vivo its efficiency deteriorates till it reaches the liver for metabolism. In the current review, we analyze the unique replication strategy of SARS-CoV-2 and glycyrrhizic acid as a potential drug against SARS-CoV-2. We also discuss possible nano-formulations of glycyrrhizic acid for efficient drug delivery in humans, as a potent therapeutic strategy for COVID-19.

Histone deacetylase–mediated transcriptional activation reduces proviral loads in HTLV-1–associated myelopathy/tropical spastic paraparesis patients

Blood ◽  
2007 ◽  
Vol 110 (10) ◽  
pp. 3722-3728 ◽  
Author(s):  
Agnès Lezin ◽  
Nicolas Gillet ◽  
Stéphane Olindo ◽  
Aïssatou Signaté ◽  
Nathalie Grandvaux ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Transcriptional Activation ◽  
Gene Activation ◽  
Spastic Paraparesis ◽  
Viral Gene Expression ◽  
Tropical Spastic Paraparesis ◽  
Viral Reservoir ◽  
Viral Gene

AbstractEpigenetic modifications of chromatin may play a role in maintaining viral latency and thus persistence of the human T-lymphotropic virus type 1 (HTLV-1), which is responsible for HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP). A major determinant of disease progression is increased peripheral blood proviral load (PVL), possibly via the accumulation of infected cells in the central nervous system (CNS) creating a damaging inflammatory response. Current therapeutic approaches that focus on reducing either cell proliferation, viral replication, or tissue invasion are still unsatisfactory. Contrasting with these inhibitory strategies, we evaluated the efficacy of a novel approach aimed, paradoxically, at activating viral gene expression to expose virus-positive cells to the host immune response. We used valproate (VPA), a histone deacetylase inhibitor that has been used for decades as a chronic, safe treatment for epileptic disorders. Based on in vitro and in vivo data, we provide evidence that transient activation of the latent viral reservoir causes its collapse, a process that may alleviate the condition of HAM/TSP. This represents the first such approach to treating HAM/TSP, using gene activation therapy to tilt the host-pathogen balance in favor of an existing antiviral response. This trial is registered at http://clinicaltrials.gov/as no. NCT00519181.

scholarly journals Cell-to-Cell Contact as an Efficient Mode of Epstein-Barr Virus Infection of Diverse Human Epithelial Cells

1998 ◽  
Vol 72 (5) ◽  
pp. 4371-4378 ◽  
Author(s):  
Shosuke Imai ◽  
Jun Nishikawa ◽  
Kenzo Takada
Keyword(s):  
Epithelial Cells ◽  
Cell Lines ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Cell Contact ◽  
Barr Virus ◽  
Epithelial Cell Lines ◽  
Epstein Barr

ABSTRACT We show clear evidence for direct infection of various human epithelial cells by Epstein-Barr virus (EBV) in vitro. The successful infection was achieved by using recombinant EBV (Akata strain) carrying a selective marker gene but without any other artificial operations, such as introduction of the known EBV receptor (CD21) gene or addition of polymeric immunoglobulin A against viral gp350 in culture. Of 21 human epithelial cell lines examined, 18 became infected by EBV, as ascertained by the detection of EBV-determined nuclear antigen (EBNA) 1 expression in the early period after virus exposure, and the following selection culture easily yielded a number of EBV-infected clones from 15 cell lines. None of the human fibroblasts and five nonhuman-derived cell lines examined was susceptible to the infection. By comparison, cocultivation with virus producers showed ≈800-fold-higher efficiency of infection than cell-free infection did, suggesting the significance of direct cell-to-cell contact as a mode of virus spread in vivo. Most of the epithelial cell lines infectable with EBV were negative for CD21 expression at the protein and mRNA levels. The majority of EBV-infected clones established from each cell line invariably expressed EBNA1, EBV-encoded small RNAs, rightward transcripts from theBamHI-A region of the virus genome, and latent membrane protein (LMP) 2A, but not the other EBNAs or LMP1. This restricted form of latent viral gene expression, which is a central issue for understanding epithelial oncogenesis by EBV, resembled that seen in EBV-associated gastric carcinoma and LMP1-negative nasopharyngeal carcinoma. The results indicate that direct infection of epithelial cells by EBV may occur naturally in vivo, and this could be mediated by an unidentified, epithelium-specific binding receptor for EBV. The EBV convertants are viewed, at least in terms of viral gene expression, as in vitro analogs of EBV-associated epithelial tumor cells, thus facilitating analysis of an oncogenic role(s) for EBV in epithelial cells.

scholarly journals HTLV-1 Rex is required for viral spread and persistence in vivo but is dispensable for cellular immortalization in vitro

Blood ◽  
2003 ◽  
Vol 102 (12) ◽  
pp. 3963-3969 ◽  
Author(s):  
Jianxin Ye ◽  
Lee Silverman ◽  
Michael D. Lairmore ◽  
Patrick L. Green
Keyword(s):  
Gene Expression ◽  
Interleukin 2 ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Viral Oncoprotein ◽  
Cell Leukemia Virus Type ◽  
Viral Spread ◽  
Human T Cell

Abstract Human T-cell leukemia virus type 1 (HTLV-1) is associated with leukemia/lymphoma and neurologic disorders. Although the viral transcriptional activator Tax is the critical viral oncoprotein, Rex, which regulates the expression of the viral structural and enzymatic genes, is essential for efficient viral replication. Herein, we investigate the contribution of Rex in HTLV-1 immortalization of primary T cells in vitro and viral survival in an infectious rabbit animal model. A Rex-deficient HTLV-1 (HTLVRex-) was constructed and characterized for viral gene expression, protein production, and immortalization capacity. Cells transiently transfected with the HTLVRex- proviral clone produced low detectable levels of p19 Gag. 729HTLVRex- stable transfectants produced functional Tax, but undetectable levels of Rex or p19 Gag. Coculture of irradiated 729HTLVRex- cells with peripheral blood mononuclear cells (PBMCs) resulted in sustained interleukin-2 (IL-2)-dependent growth of primary T lymphocytes. These cells carried the HTLVRex- genome and expressed tax/rex mRNA but produced no detectable Rex or p19 Gag. Rabbits inoculated with irradiated 729HTLVRex- cells or 729HTLVRex- cells transiently transfected with a Rex cDNA expression plasmid failed to become persistently infected or mount a detectable antibody response to the viral gene products. Together, our results provide the first direct evidence that Rex and its function to modulate viral gene expression and virion production is not required for in vitro immortalization by HTLV-1. However, Rex is critical for efficient infection of cells and persistence in vivo.

scholarly journals Rat Cytomegalovirus Gene Expression in Cardiac Allograft Recipients Is Tissue Specific and Does Not Parallel the Profiles Detected In Vitro

2007 ◽  
Vol 81 (8) ◽  
pp. 3816-3826 ◽  
Author(s):  
Daniel N. Streblow ◽  
Koen W. R. van Cleef ◽  
Craig N. Kreklywich ◽  
Christine Meyer ◽  
Patricia Smith ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rat Heart ◽  
Cultured Cells ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Viral Mrna ◽  
Tissue Specific ◽  
Viral Genes

ABSTRACT Rat cytomegalovirus (RCMV) is a β-herpesvirus with a 230-kbp genome containing over 167 open reading frames (ORFs). RCMV gene expression is tightly regulated in cultured cells, occurring in three distinct kinetic classes (immediate early, early, and late). However, the extent of viral-gene expression in vivo and its relationship to the in vitro expression are unknown. In this study, we used RCMV-specific DNA microarrays to investigate the viral transcriptional profiles in cultured, RCMV-infected endothelial cells, fibroblasts, and aortic smooth muscle cells and to compare these profiles to those found in tissues from RCMV-infected rat heart transplant recipients. In cultured cells, RCMV expresses approximately 95% of the known viral ORFs with few differences between cell types. By contrast, in vivo viral-gene expression in tissues from rat heart allograft recipients is highly restricted. In the tissues studied, a total of 80 viral genes expressing levels twice above background (5,000 to 10,000 copies per μg total RNA) were detected. In each tissue type, there were a number of genes expressed exclusively in that tissue. Although viral mRNA and genomic DNA levels were lower in the spleen than in submandibular glands, the number of individual viral genes expressed was higher in the spleen (60 versus 41). This finding suggests that the number of viral genes expressed is specific to a given tissue and is not dependent upon the viral load or viral mRNA levels. Our results demonstrate that the profiles, as well as the amplitude, of viral-gene expression are tissue specific and are dramatically different from those in infected cultured cells, indicating that RCMV gene expression in vitro does not reflect viral-gene expression in vivo.

scholarly journals Hydrotalcite–Niclosamide Nanohybrid as OralFormulation towards SARS-CoV-2 Viral Infections

2021 ◽  
Vol 14 (5) ◽  
pp. 486
Author(s):  
Goeun Choi ◽  
Huiyan Piao ◽  
N. Sanoj Rejinold ◽  
Seungjin Yu ◽  
Ki yeok Kim ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Viral Infections ◽  
Methyl Cellulose ◽  
Oral Formulation ◽  
Drug Candidates ◽  
Ic50 Value ◽  
Great Relevance ◽  
Tween 60

COVID-19 has been affecting millions of individuals worldwide and, thus far, there is no accurate therapeutic strategy. This critical situation necessitates novel formulations for already existing, FDA approved, but poorly absorbable drug candidates, such as niclosamide (NIC), which is of great relevance. In this context, we have rationally designed NIC-loaded hydrotalcite composite nanohybrids, which were further coated with Tween 60 or hydroxypropyl methyl cellulose (HPMC), and characterized them in vitro. The optimized nanohybrids showed particle sizes <300 nm and were orally administrated to rats to determine whether they could retain an optimum plasma therapeutic concentration of NIC that would be effective for treating COVID-19. The pharmacokinetic (PK) results clearly indicated that hydrotalcite-based NIC formulations could be highly potential options for treating the ongoing pandemic and we are on our way to understanding the in vivo anti-viral efficacy sooner. It is worth mentioning that hydrotalcite–NIC nanohybrids maintained a therapeutic NIC level, even above the required IC50 value, after just a single administration in 8–12 h. In conclusion, we were very successfully able to develop a NIC oral formulation by immobilizing with hydrotalcite nanoparticles, which were further coated with Tween 60 or HPMC, in order to enhance their emulsification in the gastrointestinal tract.

scholarly journals Over-representation of MEF-2 isoforms (A/C) is associated with HTLV-1-induced acute ATLL and their recruitment to 3’LTR facilitates HBZ expression from the antisense promoter via interactions with Menin and Jun D

2021 ◽  
Author(s):  
Kiran Madugula ◽  
Julie Joseph ◽  
Vanessa Teixeira ◽  
Rashida Ginwala ◽  
Catherine Demarino ◽  
...  
Keyword(s):  
T Cell ◽  
Transcriptional Control ◽  
Treatment Options ◽  
Viral Gene Expression ◽  
Etiologic Agent ◽  
Antisense Strand ◽  
Viral Gene ◽  
Adult T Cell Leukemia

Abstract Background. HTLV-1 is a complex human retrovirus and an etiologic agent causing a malignant and intractable T-cell neoplasia termed Adult T-cell leukemia and lymphoma (ATLL). Patients suffering from ATLL present with poor prognoses and a dearth of treatment options warranting a continuous need to develop novel therapeutic targets. In contrast to the HTLV-1 transactivator protein Tax, HTLV-1 bZIP protein (HBZ) maintains its expression in ATLL cells. The HBZ gene is encoded from the antisense strand of the provirus and is not under the transcriptional control of the 5’ long terminal repeat (LTR) unlike other viral genes such as Tax. Few modifications have been reported in the 3’LTR, which regulates HBZ expression. Herein, we delineate the activities of a transcription factor MEF (Myocyte enhancer factor)-2 at both 5’ and 3’LTRs in the context of ATLL progression and maintenance. Results. In this study, we report that two MEF isoforms (2A and 2C) are highly overexpressed in acute ATLL patients from North America. These isoforms are recruited to the viral promoters at both the 5’ and 3’LTRs. Their knockdown by shRNAs resulted in the downregulation of Tax and HBZ expression as well as a significant decrease in proliferation and cell cycle arrest in ATLL cells. Similarly, chemical inhibition of MEF proteins by MC1568 (a selective Class IIa HDAC inhibitor) resulted in the cytotoxicity of ATLL cells in vitro as well as reduction of proviral load and viral gene expression in vivo. At the molecular level, high enrichment of MEF-2C occurred at the 3’LTR along with cofactors Menin, Jun D, and Sp1/Sp3 thus providing a novel mechanism of regulation at the antisense promoter of HTLV-1. Conclusions. This study establishes MEF-2 as critical players in ATLL, which interacts with Tax and HBZ at their respective promoters highlighting a novel mechanism of regulation at the 3’LTR involving Jun D and Menin. MEF signaling represent a potential target for therapeutic intervention.

scholarly journals In vitro and Animal Models for Antiviral Therapy in Papillomavirus Infections

1997 ◽  
Vol 8 (5) ◽  
pp. 381-400 ◽  
Author(s):  
MA Stanley ◽  
PJ Masterson ◽  
PK Nicholls
Keyword(s):  
Animal Models ◽  
Viral Gene Expression ◽  
Chemotherapeutic Agents ◽  
Viral Gene ◽  
Published Data ◽  
Papillomavirus Infections ◽  
Culture Systems ◽  
Species Specific

The need for antiviral therapies for papillomavirus infections is well recognized but the difficulties of reproducing the infectious cycle of papillomaviruses in vitro has hindered our understanding of virus-cell interactions and the regulation of viral gene expression during permissive growth. Recent advances in understanding the temporal expression and function of papillomavirus proteins has enabled consideration of a targeted approach to papillomavirus chemotherapy and in particular the inhibition of viral replication by targeting the E1 and E2 proteins. There are in vitro culture systems available for the screening of new chemotherapeutic agents, since significant advances have been made with culture systems which promote epithelial differentiation in vitro. However, to date, there are no published data which show that virions generated in vitro can infect keratinocytes and initiate another round of replication in vitro. In vivo animal models are therefore necessary to assess the efficacy of antivirals in preventing and treating viral infection, particularly for the low-risk genital viruses which are on the whole refractory to culture in vitro. Although papillomaviruses affect a wide variety of hosts in a species-specific manner, the animals most useful for modelling papillomavirus infections include the rabbit, ox, mouse, dog, horse, primate and sheep. The ideal animal model should be widely available, easy to house and handle, be large enough to allow for adequate tissue sampling, develop lesions on anatomical sites comparable with those in human diseases and these lesions should be readily accessible for monitoring and ideally should yield large amounts of infectious virus particles for use in both in vivo and in vitro studies. The relative merits of the various papillomavirus animal models available in relation to these criteria are discussed.

scholarly journals An alternative AUG codon in segment 5 of the 2009 pandemic influenza A virus is a swine-derived virulence motif

2019 ◽  
Author(s):  
Helen M. Wise ◽  
Eleanor Gaunt ◽  
Jihui Ping ◽  
Barbara Holzer ◽  
Seema Jasim ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Untranslated Region ◽  
Influenza A ◽  
H1n1 Virus ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Genetic Features ◽  
Np Gene

AbstractThe 2009 influenza A virus (IAV) pandemic (pdm2009) was caused by a swine H1N1 virus with several atypical genetic features. Here, we investigate the origin and significance of an upstream AUG (uAUG) codon in the 5’-untranslated region of the NP gene. Phylogeny indicated that the uAUG codon arose in the classical swine IAV lineage in the mid 20th Century, and has become fixed in the current triple reassortant, variant pdm2009 swine IAV and human pdm2009 lineages. Functionally, it supports leaky ribosomal initiation in vitro and in vivo to produce two isoforms of NP: canonical, and a longer “eNP”. The uAUG codon had little effect on viral gene expression or replication in vitro. However, in both murine and porcine models of IAV infection, removing the uAUG codon gene attenuated pdm2009 virus pathogenicity. Thus, the NP uAUG codon is a virulence factor for swine IAVs with proven zoonotic ability.

scholarly journals The L4 22-Kilodalton Protein Plays a Role in Packaging of the Adenovirus Genome

2006 ◽  
Vol 80 (14) ◽  
pp. 6973-6981 ◽  
Author(s):  
Philomena Ostapchuk ◽  
Mary E. Anderson ◽  
Sharanya Chandrasekhar ◽  
Patrick Hearing
Keyword(s):  
Consensus Sequence ◽  
Critical Role ◽  
Viral Gene Expression ◽  
Specific Protein ◽  
Viral Gene ◽  
Sequence Motif ◽  
Binding Studies ◽  
Viral Dna

ABSTRACT Packaging of the adenovirus (Ad) genome into a capsid is absolutely dependent upon the presence of a cis-acting region located at the left end of the genome referred to as the packaging domain. The functionally significant sequences within this domain consist of at least seven similar repeats, referred to as the A repeats, which have the consensus sequence 5′ TTTG-N8-CG 3′. In vitro and in vivo binding studies have demonstrated that the adenovirus protein IVa2 binds to the CG motif of the packaging sequences. In conjunction with IVa2, another virus-specific protein binds to the TTTG motifs in vitro. The efficient formation of these protein-DNA complexes in vitro was precisely correlated with efficient packaging activity in vivo. We demonstrate that the binding activity to the TTTG packaging sequence motif is the product of the L4 22-kDa open reading frame. Previously, no function had been ascribed to this protein. Truncation of the L4 22-kDa protein in the context of the viral genome did not reduce viral gene expression or viral DNA replication but eliminated the production of infectious virus. We suggest that the L4 22-kDa protein, in conjunction with IVa2, plays a critical role in the recognition of the packaging domain of the Ad genome that leads to viral DNA encapsidation. The L4 22-kDa protein is also involved in recognition of transcription elements of the Ad major late promoter.

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