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1
Liu, Di, Jingjing Tian, Guangxing Liu, and Huancai Yin. "Development of Influenza H7N9 Virus Like Particle and Its Application in the Delivery of Fluorescent Quantum Dots." Nanoscience and Nanotechnology Letters 11, no. 12 (December 1, 2019): 1750–55. http://dx.doi.org/10.1166/nnl.2019.3066.
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Quantum dots are widely used in biomedical investigation, but the application is often limited by their systemic toxicity. This paper aimed to investigate the effects of virus like particles coating on the toxicity and cellular accumulation of quantum dots, providing a new paradigm for the design of intracellular microscopic probes. For this purpose, an H7N9 virus like particle composed of unmodified hemagglutinin, neuraminidase and the matrix 1 protein from the A/Shanghai/02/2013 strain were produced in Spodoptera frugiperda insect cells. After then, quantum dots successfully self-assembled into viral like particles with an incorporation efficiency of about 80%, exhibiting enhanced accumulation and minimal toxicity in HepG2 cells. Together, the data demonstrated that recombinant H7N9 virus like particle could be developed as a promising carrier for the delivery of nanoparticles and other relating drugs. And future work would be carried out on the development of incorporation efficiency of quantum dots.
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Rehman, Mubashar. "Nano-Technological Approach towards Anti-Viral Therapy." Global Immunological & Infectious Diseases Review I, no. I (December 30, 2016): 12–20. http://dx.doi.org/10.31703/giidr.2016(i-i).02.
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With time viral infections are increasing day by day due to various reasons like new viruses, the resistance of viruses to antiviral therapy, and mutation of one form of the virus to another form; these types of problems create many challenges in the field of research. Furthermore, a lot of challenges are encountered in the treatment of antiviral therapy, like interaction with other medication and use of increased frequency and a high dose of antiviral due to infection in CNS or synovial fluid where drug permeation is less. Consequently, toxicity and other side effect chances will be more. Nano-technological approaches are used to overcome these challenges. The beneficial properties come from such engineering, including stimuli sensitivity, targetability, and longevity; these are all combined to give multifunctional nano-carriers that concurrently execute different beneficial tasks
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Hamid, Oday, Mary L. Varterasian, Scott Wadler, J. Randolph Hecht, Al Benson, Evanthia Galanis, Margaret Uprichard, et al. "Phase II Trial of Intravenous CI-1042 in Patients With Metastatic Colorectal Cancer." Journal of Clinical Oncology 21, no. 8 (April 15, 2003): 1498–504. http://dx.doi.org/10.1200/jco.2003.09.114.
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Purpose: To evaluate the antitumor activity, safety, immune response, and replication of CI-1042 (ONYX-015), an E1B 55-kd gene-deleted replication-selective adenovirus, administered intravenously to patients with metastatic colorectal cancer Patients and Methods: Eighteen patients with metastatic colorectal cancer for whom prior chemotherapy failed were enrolled onto an open-label, multicenter, phase II study. CI-1042 was administered intravenously at a dose of 2 × 1012 viral particles every 2 weeks. Patients were evaluated for tumor response and toxicity; in addition, blood samples were taken for adenovirus DNA and neutralizing antibody analysis. Results: Common toxicities included flu-like symptoms, nausea, and emesis. All 18 patients eventually were removed from study because of progressive disease. Seven patients were assessed as having stable disease after 2 months of treatment, whereas two patients were considered to have stable disease after 4 months. Detectable circulating CI-1042 DNA was identified in 36% of patients 72 hours after last infusion, which is suggestive of ongoing viral replication. Conclusion: In this phase II study, intravenous CI-1042 was administered safely to patients with advanced colorectal cancer. Toxicity was manageable, consisting primarily of flu-like symptoms. Stable disease was experienced by seven patients for 11 to 18 weeks.
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Sohrab, Sayed Sartaj, Sherif Aly El-Kafrawy, Zeenat Mirza, Mohammad Amjad Kamal, and Esam Ibraheem Azhar. "Design and Delivery of Therapeutic siRNAs: Application to MERS-Coronavirus." Current Pharmaceutical Design 24, no. 1 (March 22, 2018): 62–77. http://dx.doi.org/10.2174/1381612823666171109112307.
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Background: The MERS-CoV is a novel human coronavirus causing respiratory syndrome since April 2012. The replication of MERS-CoV is mediated by ORF 1ab and viral gene activity can be modulated by RNAi approach. The inhibition of virus replication has been documented in cell culture against multiple viruses by RNAi approach. Currently, very few siRNA against MERS-CoV have been computationally designed and published. Methods: In this review, we have discussed the computational designing and delivery of potential siRNAs. Potential siRNA can be designed to silence a desired gene by considering many factors like target site, specificity, length and nucleotide content of siRNA, removal of potential off-target sites, toxicity and immunogenic responses. The efficient delivery of siRNAs into targeted cells faces many challenges like enzymatic degradation and quick clearance through renal system. The siRNA can be delivered using transfection, electroporation and viral gene transfer. Currently, siRNAs delivery has been improved by using advanced nanotechnology like lipid nanoparticles, inorganic nanoparticles and polymeric nanoparticles. Conclusion: The efficacy of siRNA-based therapeutics has been used not only against many viral diseases but also against non-viral diseases, cancer, dominant genetic disorders, and autoimmune disease. This innovative technology has attracted researchers, academia and pharmaceuticals industries towards designing and development of highly effective and targeted disease therapy. By using this technology, effective and potential siRNAs can be designed, delivered and their efficacy with toxic effects and immunogenic responses can be tested against MERS-CoV.
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Fang, Shangling, Li Wang, Wei Guo, Xia Zhang, Donghai Peng, Chunping Luo, Ziniu Yu, and Ming Sun. "Bacillus thuringiensis Bel Protein Enhances the Toxicity of Cry1Ac Protein to Helicoverpa armigera Larvae by Degrading Insect Intestinal Mucin." Applied and Environmental Microbiology 75, no. 16 (June 19, 2009): 5237–43. http://dx.doi.org/10.1128/aem.00532-09.
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ABSTRACT Bacillus thuringiensis has been used as a bioinsecticide to control agricultural insects. Bacillus cereus group genomes were found to have a Bacillus enhancin-like (bel) gene, encoding a peptide with 20 to 30% identity to viral enhancin protein, which can enhance viral infection by degradation of the peritrophic matrix (PM) of the insect midgut. In this study, the bel gene was found to have an activity similar to that of the viral enhancin gene. A bel knockout mutant was constructed by using a plasmid-free B. thuringiensis derivative, BMB171. The 50% lethal concentrations of this mutant plus the cry1Ac insecticidal protein gene were about 5.8-fold higher than those of the BMB171 strain. When purified Bel was mixed with the Cry1Ac protein and fed to Helicoverpa armigera larvae, 3 μg/ml Cry1Ac alone induced 34.2% mortality. Meanwhile, the mortality rate rose to 74.4% when the same amount of Cry1Ac was mixed with 0.8 μg/ml of Bel. Microscopic observation showed a significant disruption detected on the midgut PM of H. armigera larvae after they were fed Bel. In vitro degradation assays showed that Bel digested the intestinal mucin (IIM) of Trichoplusia ni and H. armigera larvae to various degrading products, similar to findings for viral enhancin. These results imply Bel toxicity enhancement depends on the destruction of midgut PM and IIM, similar to the case with viral enhancin. This discovery showed that Bel has the potential to enhance insecticidal activity of B. thuringiensis-based biopesticides and transgenic crops.
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León-Gutiérrez, Gabriela, Carlos Cabello-Gutiérrez, Mario Héctor Martínez-Gómez, Pedro Azuara, Brian Madden, Jaime Shalkow, and Armando Mejía. "Secondary Metabolites in Functionalized Titanium Dioxide (TIO<sub>2</sub>) Nanoparticles: A Novel and Safe Virucide against SARS-CoV-2." Journal of Nano Research 70 (October 25, 2021): 137–45. http://dx.doi.org/10.4028/www.scientific.net/jnanor.70.137.
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Nanotechnology and nanomedicine have been shown to provide a novel and safe platform to combat a variety of viruses like SARS-CoV-2. Secondary metabolites implanted into a carrier of functionalized titanium dioxide (TiO2) nanoparticles (SMNP) were tested for efficacy versus SARS-CoV-2 infectivity, and cytotoxicity on healthy cells. Viral load; from a clinical point of view, it is not as important as the number of infective viral particles, which relates to the viral particles capable of causing the disease. To measure viral infectivity SARS-CoV-2 was placed into cell cultures and evaluating the destructive effect on cultured cells. In this system, SMNP demonstrated significant reduction of viral infectivity in vitro. Lytic plaques of viral infectivity were observed at a dilution of 4x10-8 in VERO E6 cells, while SARS-CoV-2 preincubated with the SMNP compound, tissue damage was observed only up to the 3x10-5 dilution. SMNP reduced the number of infective viral particles by 3 orders of magnitude. Surprising minimal toxicity to healthy cells was observed when compared to other commercially available antiseptics (glutaraldehyde, chlorine, chlorhexidine, ethanol and Lysol™), cell viability decreased only by 5.5%. SMNP is a safe and effective antiviral against SARS-CoV-2, and further studies are warranted to explore this compound further.
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Ennishi, Daisuke, Yoshinobu Maeda, Nozomi Niitsu, Minoru Kojima, Koji Izutsu, Jun Takizawa, Shigeru Kusumoto, et al. "Hepatic toxicity and prognosis in hepatitis C virus–infected patients with diffuse large B-cell lymphoma treated with rituximab-containing chemotherapy regimens: a Japanese multicenter analysis." Blood 116, no. 24 (December 9, 2010): 5119–25. http://dx.doi.org/10.1182/blood-2010-06-289231.
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Abstract The influence of hepatitis C virus (HCV) infection on prognosis and hepatic toxicity in patients with diffuse large B-cell lymphoma in the rituximab era is unclear. Thus, we analyzed 553 patients, 131 of whom were HCV-positive and 422 of whom were HCV-negative, with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP)–like chemotherapy. Survival outcomes and hepatic toxicity were compared according to HCV infection. The median follow-up was 31 and 32 months for patients who were HCV-positive and HCV-negative, respectively. HCV infection was not a significant risk factor for prognosis (3-year progression-free survival, 69% vs 77%, P = .22; overall survival, 75% vs 84%, P = .07). Of 131 patients who were HCV-positive, 36 (27%) had severe hepatic toxicity (grade 3-4), compared with 13 of 422 (3%) patients who were HCV-negative. Multivariate analysis revealed that HCV infection was a significant risk factor for severe hepatic toxicity (hazard ratio: 14.72; 95% confidence interval, 6.37-34.03; P < .001). An exploratory analysis revealed that pretreatment transaminase was predictive of severe hepatic toxicity. HCV-RNA levels significantly increased during immunochemotherapy (P = .006). These results suggest that careful monitoring of hepatic function and viral load is indicated during immunochemotherapy for HCV-positive patients.
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Goldenberg, Seth J., Jeffrey L. McDermott, Tauseef R. Butt, Michael R. Mattern, and Benjamin Nicholson. "Strategies for the identification of novel inhibitors of deubiquitinating enzymes." Biochemical Society Transactions 36, no. 5 (September 19, 2008): 828–32. http://dx.doi.org/10.1042/bst0360828.
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Dysregulation of the UPS (ubiquitin–proteasome system) has been implicated in a wide range of pathologies including cancer, neurodegeneration and viral infection. Inhibiting the proteasome has been shown to be an effective therapeutic strategy in humans; yet toxicity with this target remains high. DUBs (deubiquitinating enzymes) represent an alternative target in the UPS with low predicted toxicity. Currently, there are no DUB inhibitors that have been used clinically. To address this situation, Progenra has developed a novel assay to measure the proteolytic cleavage of Ub (ubiquitin) or UBL (Ub-like protein) conjugates such as SUMO (small Ub-related modifier), NEDD8 (neural-precursor-cell-expressed, developmentally down-regulated 8) or ISG15 (interferon-stimulated gene 15) by isopeptidases. In this review, current platforms for detecting DUB inhibitors are discussed and the advantages and disadvantages of the approaches are underlined.
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Obermann, Wiebke, Alexandra Friedrich, Ramakanth Madhugiri, Paul Klemm, Jan Philipp Mengel, Torsten Hain, Stephan Pleschka, et al. "Rocaglates as Antivirals: Comparing the Effects on Viral Resistance, Anti-Coronaviral Activity, RNA-Clamping on eIF4A and Immune Cell Toxicity." Viruses 14, no. 3 (March 3, 2022): 519. http://dx.doi.org/10.3390/v14030519.
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Rocaglates are potent broad-spectrum antiviral compounds with a promising safety profile. They inhibit viral protein synthesis for different RNA viruses by clamping the 5′-UTRs of mRNAs onto the surface of the RNA helicase eIF4A. Apart from the natural rocaglate silvestrol, synthetic rocaglates like zotatifin or CR-1-31-B have been developed. Here, we compared the effects of rocaglates on viral 5′-UTR-mediated reporter gene expression and binding to an eIF4A-polypurine complex. Furthermore, we analyzed the cytotoxicity of rocaglates on several human immune cells and compared their antiviral activities in coronavirus-infected cells. Finally, the potential for developing viral resistance was evaluated by passaging human coronavirus 229E (HCoV-229E) in the presence of increasing concentrations of rocaglates in MRC-5 cells. Importantly, no decrease in rocaglate-sensitivity was observed, suggesting that virus escape mutants are unlikely to emerge if the host factor eIF4A is targeted. In summary, all three rocaglates are promising antivirals with differences in cytotoxicity against human immune cells, RNA-clamping efficiency, and antiviral activity. In detail, zotatifin showed reduced RNA-clamping efficiency and antiviral activity compared to silvestrol and CR-1-31-B, but was less cytotoxic for immune cells. Our results underline the potential of rocaglates as broad-spectrum antivirals with no indications for the emergence of escape mutations in HCoV-229E.
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Firdayani, A. Riswoko, and I. Helianti. "Inhibition of SARS-Cov-2 proteases by medicinal plant bioactive constituents: Molecular docking simulation." IOP Conference Series: Earth and Environmental Science 976, no. 1 (February 1, 2022): 012054. http://dx.doi.org/10.1088/1755-1315/976/1/012054.
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Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a virus that has caused the corona pandemic since 2019 or known as Covid-19. The cleavage of its polyprotein started this viral replication into functional viral proteins by two proteases: 3-chymotrypsin-like protease (3CL protease), also known as main protease (Mpro), and Papain-like protease (PLpro). Medicinal plant bioactive constituents could potentially become protease inhibitor agents of this virus and prevent viral replication. Thus, further might be developed into drug candidates for diseases with no specific drug currently available. The first step of discovering the medicine is virtual screening with a molecular docking simulation approach. The stable conformation structure of the bioactive compounds was docked into the enzymes SARS-CoV-2 Main Protease (PDB ID: 6XMK) and SARS-CoV-2 Papain-Like Protease (PDB ID: 7CMD). Molecular docking simulations were operated using Molegro Virtual Docker (MVD) program after the validation process. In this study, analysis of the docking simulation was carried out of compounds in Andrographis paniculata, Phyllanthus niruri L., Aloe vera, and Sonchus arvensis. They are medicinal plants that have been used as a medicine for generations and may have potential as antivirals. A docking score with a more negative presentation binding energy value has a more significant potential to be a lead compound. Several potential compounds were evaluated for their absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. This method can reduce the trial and error factor in the drug discovery stage, although it needs further proof by experimentation in a wet laboratory.
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Bhole, R. P., Yogita Shinde, C. G. Bonde, and R. D. Wavhale. "Vitamin Drug conjugate: a systematic review of pharmacological potential." Bulletin of the Karaganda University. "Chemistry" series 101, no. 1 (March 30, 2021): 27–52. http://dx.doi.org/10.31489/2021ch1/27-52.
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Cancer is a chronic disease which can cause death. In traditional chemotherapycytotoxic drugs are used to kill proliferating cancer cells. The cytotoxic agent exhibits less specificity, less biological activity, causes sys-temic toxicity and undesirable side effects. Each year, about 1.8 million of the population are infected and die due to tuberculosis infection. An increase of drug resistance during the tuberculosis treatment is a significant concern. So, it is necessary to develop a new approach or therapies to resolve drug resistance, drug selectivity in tuberculosis infection and the reduction of the side effects of cytotoxic agents and anti-tubercular drugs. This review describes the newly emerging concept of «vitamin drug conjugate». Vitamin-drug conjugate is a specifically carried drug toward the target site, is one of the promising ways to treat chronic diseases like can-cer and tuberculosis and enhance the therapeutic outcome. The purpose of this review is to explore vitamin as a targeting moiety for new anticancer and anti-tubercular drug to overcome challenges, such as non-selectivity, systemic toxicity and multidrug resistance. This approach is beneficial in the treatment of life-threatening disease like cancer, tuberculosis and also in many viral infections.
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Smith, Tiffany, Prashika Singh, Kay Ole Chmielewski, Kristie Bloom, Toni Cathomen, Patrick Arbuthnot, and Abdullah Ely. "Improved Specificity and Safety of Anti-Hepatitis B Virus TALENs Using Obligate Heterodimeric FokI Nuclease Domains." Viruses 13, no. 7 (July 12, 2021): 1344. http://dx.doi.org/10.3390/v13071344.
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Persistent hepatitis B virus (HBV) infection remains a serious medical problem worldwide, with an estimated global burden of 257 million carriers. Prophylactic and therapeutic interventions, in the form of a vaccine, immunomodulators, and nucleotide and nucleoside analogs, are available. Vaccination, however, offers no therapeutic benefit to chronic sufferers and has had a limited impact on infection rates. Although immunomodulators and nucleotide and nucleoside analogs have been licensed for treatment of chronic HBV, cure rates remain low. Transcription activator-like effector nucleases (TALENs) designed to bind and cleave viral DNA offer a novel therapeutic approach. Importantly, TALENs can target covalently closed circular DNA (cccDNA) directly with the potential of permanently disabling this important viral replicative intermediate. Potential off-target cleavage by engineered nucleases leading to toxicity presents a limitation of this technology. To address this, in the context of HBV gene therapy, existing TALENs targeting the viral core and surface open reading frames were modified with second- and third-generation FokI nuclease domains. As obligate heterodimers these TALENs prevent target cleavage as a result of FokI homodimerization. Second-generation obligate heterodimeric TALENs were as effective at silencing viral gene expression as first-generation counterparts and demonstrated an improved specificity in a mouse model of HBV replication.
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Savva, Renos. "The Essential Co-Option of Uracil-DNA Glycosylases by Herpesviruses Invites Novel Antiviral Design." Microorganisms 8, no. 3 (March 24, 2020): 461. http://dx.doi.org/10.3390/microorganisms8030461.
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Vast evolutionary distances separate the known herpesviruses, adapted to colonise specialised cells in predominantly vertebrate hosts. Nevertheless, the distinct herpesvirus families share recognisably related genomic attributes. The taxonomic Family Herpesviridae includes many important human and animal pathogens. Successful antiviral drugs targeting Herpesviridae are available, but the need for reduced toxicity and improved efficacy in critical healthcare interventions invites novel solutions: immunocompromised patients presenting particular challenges. A conserved enzyme required for viral fitness is Ung, a uracil-DNA glycosylase, which is encoded ubiquitously in Herpesviridae genomes and also host cells. Research investigating Ung in Herpesviridae dynamics has uncovered an unexpected combination of viral co-option of host Ung, along with remarkable Subfamily-specific exaptation of the virus-encoded Ung. These enzymes apparently play essential roles, both in the maintenance of viral latency and during initiation of lytic replication. The ubiquitously conserved Ung active site has previously been explored as a therapeutic target. However, exquisite selectivity and better drug-like characteristics might instead be obtained via targeting structural variations within another motif of catalytic importance in Ung. The motif structure is unique within each Subfamily and essential for viral survival. This unique signature in highly conserved Ung constitutes an attractive exploratory target for the development of novel beneficial therapeutics.
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Rudd, Harrison, and Michal Toborek. "Pitfalls of Antiretroviral Therapy: Current Status and Long-Term CNS Toxicity." Biomolecules 12, no. 7 (June 26, 2022): 894. http://dx.doi.org/10.3390/biom12070894.
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HIV can traverse the BBB using a Trojan horse-like mechanism. Hidden within infected immune cells, HIV can infiltrate the highly safeguarded CNS and propagate disease. Once integrated within the host genome, HIV becomes a stable provirus, which can remain dormant, evade detection by the immune system or antiretroviral therapy (ART), and result in rebound viraemia. As ART targets actively replicating HIV, has low BBB penetrance, and exposes patients to long-term toxicity, further investigation into novel therapeutic approaches is required. Viral proteins can be produced by latent HIV, which may play a synergistic role alongside ART in promoting neuroinflammatory pathophysiology. It is believed that the ability to specifically target these proviral reservoirs would be a vital driving force towards a cure for HIV infection. A novel drug design platform, using the in-tandem administration of several therapeutic approaches, can be used to precisely target the various components of HIV infection, ultimately leading to the eradication of active and latent HIV and a functional cure for HIV. The aim of this review is to explore the pitfalls of ART and potential novel therapeutic alternatives.
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Brown, Ronald B. "Sodium Toxicity in the Nutritional Epidemiology and Nutritional Immunology of COVID-19." Medicina 57, no. 8 (July 22, 2021): 739. http://dx.doi.org/10.3390/medicina57080739.
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Dietary factors in the etiology of COVID-19 are understudied. High dietary sodium intake leading to sodium toxicity is associated with comorbid conditions of COVID-19 such as hypertension, kidney disease, stroke, pneumonia, obesity, diabetes, hepatic disease, cardiac arrhythmias, thrombosis, migraine, tinnitus, Bell’s palsy, multiple sclerosis, systemic sclerosis, and polycystic ovary syndrome. This article synthesizes evidence from epidemiology, pathophysiology, immunology, and virology literature linking sodium toxicological mechanisms to COVID-19 and SARS-CoV-2 infection. Sodium toxicity is a modifiable disease determinant that impairs the mucociliary clearance of virion aggregates in nasal sinuses of the mucosal immune system, which may lead to SARS-CoV-2 infection and viral sepsis. In addition, sodium toxicity causes pulmonary edema associated with severe acute respiratory syndrome, as well as inflammatory immune responses and other symptoms of COVID-19 such as fever and nasal sinus congestion. Consequently, sodium toxicity potentially mediates the association of COVID-19 pathophysiology with SARS-CoV-2 infection. Sodium dietary intake also increases in the winter, when sodium losses through sweating are reduced, correlating with influenza-like illness outbreaks. Increased SARS-CoV-2 infections in lower socioeconomic classes and among people in government institutions are linked to the consumption of foods highly processed with sodium. Interventions to reduce COVID-19 morbidity and mortality through reduced-sodium diets should be explored further.
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Haxhinasto, Kari, Anant Kamath, Ken Blackwell, James Bodmer, Jon Van Heukelom, Anthony English, Er-Wei Bai, and Alan B. Moy. "Gene delivery of l-caldesmon protects cytoskeletal cell membrane integrity against adenovirus infection independently of myosin ATPase and actin assembly." American Journal of Physiology-Cell Physiology 287, no. 4 (October 2004): C1125—C1138. http://dx.doi.org/10.1152/ajpcell.00530.2003.
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The cytoskeleton is critical to the viral life cycle. Agents like cytochalasin inhibit viral infections but cannot be used for antiviral therapy because of their toxicity. We report the efficacy, safety, and mechanisms by which gene delivery of human wild-type low-molecular-weight caldesmon (l-CaD) protects cell membrane integrity from adenovirus infection in a DF-1 cell line, an immortalized avian fibroblast that is null for l-CaD. Transfection with an adenovirus (Ad)-controlled construct mediated a dose-dependent decline in transcellular resistance. In accordance with a computational model of cytoskeletal membrane properties, Ad disturbed cell-cell and cell-matrix adhesion and membrane capacitance. Transfection with the Ad-l-CaD construct attenuated adenovirus-mediated loss in transcellular resistance. Quantitation of vinculin-stained plaques revealed an increase in total focal contact mass in monolayers transfected with the Ad-l-CaD construct. Expression of l-CaD protected transcellular resistance through primary effects on membrane capacitance and independently of actin solubility and effects on prestress, as measured by the decline in isometric tension in response to cytochalasin D. Expression of l-CaD exhibited less Trypan blue cell toxicity than cytochalasin, and, unlike cytochalasin, it did not interfere with wound closure or adversely effect transcellular resistance. These findings demonstrate the gene delivery of wild-type human l-CaD as a potentially efficacious and safe agent that inhibits some of the cytopathic effects of adenovirus.
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Kurnia, Ryan, Rahajeng Setiawaty, Ketut Natih, Christian Nugroho, Otto Silaen, Silvia Widyaningtyas, Simson Tarigan, Fera Ibrahim, and Pratiwi Sudarmono. "Evaluation of inhibitor activity of bacterial sialidase from Clostridium perfringens against Newcastle disease virus in the cell culture model using chicken embryo fibroblast." Journal of Advanced Veterinary and Animal Research 9, no. 2 (2022): 335. http://dx.doi.org/10.5455/javar.2022.i600.
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Objective: The Newcastle disease virus (NDV) is an infectious disease that causes very high eco¬nomic losses due to decreased livestock production and poultry deaths. The vaccine’s ineffec¬tiveness due to mutation of the genetic structure of the virus impacts obstacles in controlling the disease, especially in some endemic areas. This study aimed to provide an alternative treatment for NDV infection by observing the viral replication inhibitor activity of Clostridium perfringens sialidase in primary chicken embryo fibroblast (CEF) cells. Materials and Methods: The virus was adapted in CEF monolayer cells, then collected thrice using the freeze–thaw method and stored at −20°C for the next step in the challenge procedure. C. perfringens crude sialidase was obtained, but it was further purified via stepwise elution in ion exchange using Q Sepharose® Fast Flow and affinity chromatography with oxamic acid agarose. The purified sialidase was tested for its toxicity, ability to breakdown sialic acid, stopping viral replication, and how treated cells expressed their genes. Results: According to this study, purified C. perfringens sialidase at dosages of 187.5, 93.75, and 46.87 mU effectively hydrolyzes CEF cells’ sialic acid and significantly inhibits viral replication on the treated cells. However, sialidase dosages of 375 and 750 mU affected the viability of mono¬layer CEF cells. Interestingly, downregulation of toll-like receptor (TLR)3 and TLR7 (p < 0.05) in the sialidase-treated group indicates viral endocytosis failure. Conclusions: By stopping endocytosis and viral replication in host cells, sialidase from C. perfrin¬gens can be used as an alternative preventive treatment for NDV infection.
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Rodgers, Corica Marie, Aditi Shastri, and Ramakrishna Battini. "Outcomes of HCV-Positive Patients with Lymphoma Treated with Rituximab-Containing Therapies." Blood 124, no. 21 (December 6, 2014): 1713. http://dx.doi.org/10.1182/blood.v124.21.1713.1713.
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Abstract Introduction: The impact that hepatitis C virus (HCV) infection has on the clinical outcome of patients with lymphoma treated with rituximab-containing therapies is uncertain. Rituximab has improved outcomes in patients with aggressive lymphomas however the prognostic value of rituximab in HCV infected patients has not been well established. It has been shown that reactivation is a common complication in patients with hepatitis B treated with rituximab. It is possible that patients with hepatitis C also develop reactivation with rituximab resulting in worsening liver function and a poor clinical outcome. A prior Japanese study showed that HCV-positive patients with diffuse large B-cell lymphoma have a high incidence of severe hepatic toxicity (Ennishi, D., Maeda, Y., et al. 2010). In this study we wanted to further analyze this idea and see if it is applicable to American population with hepatitis C and lymphoma receiving rituximab-containing therapies. Methods: We collected data from patients who were HCV-positive with lymphoma treated with rituximab between 2003 and 2014 at Montefiore Medical Center. Patients were included who were over 18 years old with a positive HCV test prior to treatment. Data was analyzed using statistical software Stata (version 12.0, StataCorp LP, College Station, TX, USA). Results: A total of 33 HCV-positive patients with lymphoma were included. Most of these patients (82%) had diffuse large B-cell lymphoma (DLBCL). Of the 33 patients, 24 (73%) showed worsening liver function after starting Rituximab containing therapy. Hepatitis C viral load before and after the treatment was documented for 8 patients. 5 of these 8 patients had clear reactivation of hepatitis C with rising hepatitis C viral load. All of these 5 patients noted with worsening of liver function tests. These patients received an average of 2 doses of Rituximab before having the rise in liver function tests (LFTs). Also, the median duration to see a rise in liver transaminases was at 2.5 months with the peak level in liver enzymes observed at 4 months after starting rituximab. Conclusion: These results show that patients with HCV infection have a high incidence of hepatic toxicity with rituximab. Some of these patients also showed evidence of reactivation with increased hepatitis C viral load. Further studies need to be done to determine if addition of new oral hepatitis C treatments like Sofosbuvir to the chemotherapy would change the course of viral reactivation and hepatic toxicity. These patients may need closer hepatic monitoring during and after treatment with rituximab. References: Ennishi, D., Maeda, Y., et al. (2010). “Hepatic toxicity and prognosis in hepatitis C virus-infected patients with diffuse large B-cell lymphoma treated with rituximab-containing chemotherapy regimens: a Japanese multicenter analysis.” Blood 116(24): 5119-25 Disclosures No relevant conflicts of interest to declare.
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Damen, Mark, Mario Izidoro, Debora Okamoto, Lilian Oliveira, Helene Amatdjais-Groenen, Stijn van Dongen, Koen van Cleef, et al. "Cationic Geminoid Peptide Amphiphiles Inhibit DENV2 Protease, Furin, and Viral Replication." Molecules 27, no. 10 (May 17, 2022): 3217. http://dx.doi.org/10.3390/molecules27103217.
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Dengue is an important arboviral infectious disease for which there is currently no specific cure. We report gemini-like (geminoid) alkylated amphiphilic peptides containing lysines in combination with glycines or alanines (C15H31C(O)-Lys-(Gly or Ala)nLys-NHC16H33, shorthand notation C16-KXnK-C16 with X = A or G, and n = 0–2). The representatives with 1 or 2 Ala inhibit dengue protease and human furin, two serine proteases involved in dengue virus infection that have peptides with cationic amino acids as their preferred substrates, with IC50 values in the lower µM range. The geminoid C16-KAK-C16 combined inhibition of DENV2 protease (IC50 2.3 µM) with efficacy against replication of wildtype DENV2 in LLC-MK2 cells (EC50 4.1 µM) and an absence of toxicity. We conclude that the lysine-based geminoids have activity against dengue virus infection, which is based on their inhibition of the proteases involved in viral replication and are therefore promising leads to further developing antiviral therapeutics, not limited to dengue.
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Mills, Anne M., Megan E. Ward, Taylor P. Heyl, and Cindy L. Van Dover. "Parasitism as a potential contributor to massive clam mortality at the Blake Ridge Diapir methane-hydrate seep." Journal of the Marine Biological Association of the United Kingdom 85, no. 6 (November 9, 2005): 1489–97. http://dx.doi.org/10.1017/s0025315405012683.
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Vesicomyid clam species are abundant in many deep-sea chemosynthetic communities, including cold seeps. They rely primarily on thiotrophic (sulphide-oxidizing) gill symbionts for nutrition and thus require sulphide-rich environments. Submersible surveys of megafaunal distributions at the Blake Ridge Diapir, a deep-sea methane-hydrate seep located ∼200 miles off the coast of Charleston, South Carolina, documented massive mortalities of vesicomyid clams. The cause of these mortalities is unknown, but sulphide deprivation, sulphide toxicity, and disease are possible agents of mortality in this system. Similar redox profiles in sediment cores from live and dead clam beds do not support the hypothesis that there has been a transient shift in the flux of sulphide. To address the potential for disease as a cause of mortality, we undertook a histological survey of microparasites and other indications of disease in clam tissues. Six morphological types of parasites were identified using light microscopy, including two viral-like inclusions, Rickettsia-like gill inclusions, possible bacterial gut inclusions, bacterial gill infections, and a protistan inclusion. Of these parasites, two were pathogenic: viral-like inclusions in mantle tissues caused tissue degradation; bacterial gill infections resulted in localized disruption and degradation of gill filaments. Infection prevalence and densities were low for all parasites observed. The majority of clams examined showed intense haemocytic responses in the absence of any obvious etiologic agent, suggesting the presence of parasites not detectable by our methods. Our findings indicate that the clam population at the Blake Ridge seep was in relatively good health at the time of sampling.
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Syahputra, Gita, Nunik Gustini, Bustanussalam Bustanussalam, Yatri Hapsari, Martha Sari, Ardi Ardiansyah, Asep Bayu, and Masteria Yunovilsa Putra. "Molecular docking of secondary metabolites from Indonesian marine and terrestrial organisms targeting SARS-CoV-2 ACE-2, M pro, and PL pro receptors." Pharmacia 68, no. 3 (July 23, 2021): 533–60. http://dx.doi.org/10.3897/pharmacia.68.e68432.
Full textAbstract:
With the uncontrolled spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), development and distribution of antiviral drugs and vaccines have gained tremendous importance. This study focused on two viral proteases namely main protease (Mpro) and papain-like protease (PLpro) and human angiotensin-converting enzyme (ACE-2) to identify which of these are essential for viral replication. We screened 102 secondary metabolites against SARS-CoV-2 isolated from 36 terrestrial plants and 36 marine organisms from Indonesian biodiversity. These organisms are typically presumed to have antiviral effects, and some of them have been used as an immunomodulatory activity in traditional medicine. For the molecular docking procedure to obtain Gibbs free energy value (∆G), toxicity, ADME and Lipinski, AutoDock Vina was used. In this study, five secondary metabolites, namely corilagin, dieckol, phlorofucofuroeckol A, proanthocyanidins, and isovitexin, were found to inhibit ACE-2, Mpro, and PLpro receptors in SARS-CoV-2, with a high affinity to the same sites of ptilidepsin, remdesivir, and chloroquine as the control molecules. This study was delimited to molecular docking without any validation by simulations concerned with molecular dynamics. The interactions with two viral proteases and human ACE-2 may play a key role in developing antiviral drugs for five active compounds. In future, we intend to investigate antiviral drugs and the mechanisms of action by in vitro study.
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Kishore, Abhinoy, Anurag Kanaujia, Soma Nag, A. M. Rostami, Lawrence C. Kenyon, Kenneth S. Shindler, and Jayasri Das Sarma. "Different Mechanisms of Inflammation Induced in Virus and Autoimmune-Mediated Models of Multiple Sclerosis in C57BL6 Mice." BioMed Research International 2013 (2013): 1–9. http://dx.doi.org/10.1155/2013/589048.
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Multiple sclerosis (MS) is an inflammatory demyelinating disease of the human central nervous system (CNS). Neurotropic demyelinating strain of MHV (MHV-A59 or its isogenic recombinant strain RSA59) induces MS-like disease in mice mediated by microglia, along with a small population of T cells. The mechanism of demyelination is at least in part due to microglia-mediated myelin stripping, with some direct axonal injury. Immunization with myelin oligodendrocyte glycoprotein (MOG) induces experimental autoimmune encephalomyelitis (EAE), a mainly CD4+T-cell-mediated disease, although CD8+T cells may play a significant role in demyelination. It is possible that both autoimmune and nonimmune mechanisms such as direct viral toxicity may induce MS. Our study directly compares CNS pathology in autoimmune and viral-induced MS models. Mice with viral-induced and EAE demyelinating diseases demonstrated similar patterns and distributions of demyelination that accumulated over the course of the disease. However, significant differences in acute inflammation were noted. Inflammation was restricted mainly to white matter at all times in EAE, whereas inflammation initially largely involved gray matter in acute MHV-induced disease and then is subsequently localized only in white matter in the chronic disease phase. The presence of dual mechanisms of demyelination may be responsible for the failure of immunosuppression to promote long-term remission in many MS patients.
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Yosri, Nermeen, Aida A. Abd El-Wahed, Reem Ghonaim, Omar M. Khattab, Aya Sabry, Mahmoud A. A. Ibrahim, Mahmoud F. Moustafa, et al. "Anti-Viral and Immunomodulatory Properties of Propolis: Chemical Diversity, Pharmacological Properties, Preclinical and Clinical Applications, and In Silico Potential against SARS-CoV-2." Foods 10, no. 8 (July 31, 2021): 1776. http://dx.doi.org/10.3390/foods10081776.
Full textAbstract:
Propolis, a resin produced by honeybees, has long been used as a dietary supplement and folk remedy, and more recent preclinical investigations have demonstrated a large spectrum of potential therapeutic bioactivities, including antioxidant, antibacterial, anti-inflammatory, neuroprotective, immunomodulatory, anticancer, and antiviral properties. As an antiviral agent, propolis and various constituents have shown promising preclinical efficacy against adenoviruses, influenza viruses, respiratory tract viruses, herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), human immunodeficiency virus (HIV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Over 300 chemical components have been identified in propolis, including terpenes, flavonoids, and phenolic acids, with the specific constituent profile varying widely according to geographic origin and regional flora. Propolis and its constituents have demonstrated potential efficacy against SARS-CoV-2 by modulating multiple pathogenic and antiviral pathways. Molecular docking studies have demonstrated high binding affinities of propolis derivatives to multiple SARS-CoV-2 proteins, including 3C-like protease (3CLpro), papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp), the receptor-binding domain (RBD) of the spike protein (S-protein), and helicase (NSP13), as well as to the viral target angiotensin-converting enzyme 2 (ACE2). Among these compounds, retusapurpurin A has shown high affinity to 3CLpro (ΔG = −9.4 kcal/mol), RdRp (−7.5), RBD (−7.2), NSP13 (−9.4), and ACE2 (−10.4) and potent inhibition of viral entry by forming hydrogen bonds with amino acid residues within viral and human target proteins. In addition, propolis-derived baccharin demonstrated even higher binding affinity towards PLpro (−8.2 kcal/mol). Measures of drug-likeness parameters, including metabolism, distribution, absorption, excretion, and toxicity (ADMET) characteristics, also support the potential of propolis as an effective agent to combat COVID-19.
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Ion, Daniel, Adelina-Gabriela Niculescu, Dan Nicolae Păduraru, Octavian Andronic, Florentina Mușat, Alexandru Mihai Grumezescu, and Alexandra Bolocan. "An Up-to-Date Review of Natural Nanoparticles for Cancer Management." Pharmaceutics 14, no. 1 (December 22, 2021): 18. http://dx.doi.org/10.3390/pharmaceutics14010018.
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Cancer represents one of the leading causes of morbidity and mortality worldwide, imposing an urgent need to develop more efficient treatment alternatives. In this respect, much attention has been drawn from conventional cancer treatments to more modern approaches, such as the use of nanotechnology. Extensive research has been done for designing innovative nanoparticles able to specifically target tumor cells and ensure the controlled release of anticancer agents. To avoid the potential toxicity of synthetic materials, natural nanoparticles started to attract increasing scientific interest. In this context, this paper aims to review the most important natural nanoparticles used as active ingredients (e.g., polyphenols, polysaccharides, proteins, and sterol-like compounds) or as carriers (e.g., proteins, polysaccharides, viral nanoparticles, and exosomes) of various anticancer moieties, focusing on their recent applications in treating diverse malignancies.
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Asghar, Naveed, Wessam Melik, Katrine M. Paulsen, Bendikte N. Pedersen, Erik G. Bø-Granquist, Rose Vikse, Snorre Stuen, et al. "Transient Expression of Flavivirus Structural Proteins in Nicotiana benthamiana." Vaccines 10, no. 10 (October 6, 2022): 1667. http://dx.doi.org/10.3390/vaccines10101667.
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Flaviviruses are a threat to public health and can cause major disease outbreaks. Tick-borne encephalitis (TBE) is caused by a flavivirus, and it is one of the most important causes of viral encephalitis in Europe and is on the rise in Sweden. As there is no antiviral treatment available, vaccination remains the best protective measure against TBE. Currently available TBE vaccines are based on formalin-inactivated virus produced in cell culture. These vaccines must be delivered by intramuscular injection, have a burdensome immunization schedule, and may exhibit vaccine failure in certain populations. This project aimed to develop an edible TBE vaccine to trigger a stronger immune response through oral delivery of viral antigens to mucosal surfaces. We demonstrated successful expression and post-translational processing of flavivirus structural proteins which then self-assembled to form virus-like particles in Nicotiana benthamiana. We performed oral toxicity tests in mice using various plant species as potential bioreactors and evaluated the immunogenicity of the resulting edible vaccine candidate. Mice immunized with the edible vaccine candidate did not survive challenge with TBE virus. Interestingly, immunization of female mice with a commercial TBE vaccine can protect their offspring against TBE virus infection.
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Rodríguez-Valentín, Madeline, Sheila López, Mariela Rivera, Eddy Ríos-Olivares, Luis Cubano, and Nawal M. Boukli. "Naturally Derived Anti-HIV Polysaccharide Peptide (PSP) Triggers a Toll-Like Receptor 4-Dependent Antiviral Immune Response." Journal of Immunology Research 2018 (July 15, 2018): 1–14. http://dx.doi.org/10.1155/2018/8741698.
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Aim. Intense interest remains in the identification of compounds to reduce human immunodeficiency virus type 1 (HIV-1) replication. Coriolus versicolor’s polysaccharide peptide (PSP) has been demonstrated to possess immunomodulatory properties with the ability to activate an innate immune response through Toll-like receptor 4 (TLR4) showing insignificant toxicity. This study sought to determine the potential use of PSP as an anti-HIV agent and whether its antiviral immune response was TLR4 dependent. Materials and Methods. HIV-1 p24 and anti-HIV chemokine release was assessed in HIV-positive (HIV+) THP1 cells and validated in HIV+ peripheral blood mononuclear cells (PBMCs), to determine PSP antiviral activity. The involvement of TLR4 activation in PSP anti-HIV activity was evaluated by inhibition. Results. PSP showed a promising potential as an anti-HIV agent, by downregulating viral replication and promoting the upregulation of specific antiviral chemokines (RANTES, MIP-1α/β, and SDF-1α) known to block HIV-1 coreceptors in THP1 cells and human PBMCs. PSP produced a 61% viral inhibition after PSP treatment in HIV-1-infected THP1 cells. Additionally, PSP upregulated the expression of TLR4 and TLR4 inhibition led to countereffects in chemokine expression and HIV-1 replication. Conclusion. Taken together, these findings put forward the first evidence that PSP exerts an anti-HIV activity mediated by TLR4 and key antiviral chemokines. Elucidating these new molecular mediators may reveal additional drug targets and open novel therapeutic avenues for HIV-1 infection.
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K. Khatab, Tamer, and Ashraf S. Hassan. "Computational molecular docking and in silico ADMET prediction studies of pyrazole derivatives as Covid-19 main protease (MPRO) and papain-like protease (PLPRO) inhibitors." Bulletin of the Chemical Society of Ethiopia 37, no. 2 (December 14, 2022): 449–61. http://dx.doi.org/10.4314/bcse.v37i2.14.
Full textAbstract:
ABSTRACT. The inhibition of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) and papain-like protease (PLpro) prevents viral multiplications. Molecular docking, absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies of pyrazole-indole molecules 6a, b, Schiff bases 8a, b, and pyrazolo[1,5-a]pyrimidines 10a, b were performed and done. Based on the molecular docking study verified that the presented structures (6a, 6b, 8a, 8b, 10a, and 10b) give promised attached bonds with the active site in the COVID-19 main protease (Mpro). The results of in silico ADMET prediction study revealed that these compounds may be considered candidates for the discovery or development of new series of COVID-19 drugs.
KEY WORDS: Pyrazole, Fused pyrazole, Schiff bases, COVID-19, Molecular docking, Computational studies
Bull. Chem. Soc. Ethiop. 2023, 37(2), 449-461.
DOI: https://dx.doi.org/10.4314/bcse.v37i2.14
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Satpathy, R., and S. Acharya. "Development of a database of RNA helicase inhibitors (VHIMDB) of pathogenic viruses and in silico screening for the potential drug molecules." EuroBiotech Journal 6, no. 3 (July 1, 2022): 116–25. http://dx.doi.org/10.2478/ebtj-2022-0012.
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Abstract The pathogenic RNA virus that infects human beings contains the RNA helicase enzyme, responsible for the replication of the viral genome. The enzyme is used as a suitable target against which the drug molecule acts. Therefore, the identification and proposal the novel compounds that can be targeted toward the helicase enzymes to stop the functioning of the enzyme is desirable. Although many viral helicase inhibitor molecules have been identified, still yet no unique database is available for these compounds. This research work envisages developing a curated database of RNA helicase inhibitors. The database contains in total of 353 entries that are computationally predicted and experimentally verified RNA helicase inhibitors. The database contains information like compound name, chemical properties, chemical format, and name of the target virus to which it acts against it with a user-friendly menu-driven search engine. Presently, the database is freely available at: https://vhimdb.rsatpathy.in/. Further, in silico screening of the whole database by drug-likeness and toxicity resulted in 14 potential drug molecules. The selected molecules were analyzed for their effectiveness in binding by using molecular docking score and interaction with the helicase enzymes of three categories of pathogenic viruses (SARS-CoV-2, SARS-CoV, and MERS-CoV).
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Dwivedi, L. K., and Mansi Shrivastava. "Antiâ€ÂHIV Therapy: Pipeline Approaches and Future Directions." South Asian Journal of Experimental Biology 1, no. 1 (February 1, 2011): 1–8. http://dx.doi.org/10.38150/sajeb.1(1).p1-8.
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Human Immunodeficiency Virus (HIV), with about 30 million deaths and double infections in developing countries, is an open challenge today for global scientists. Developing safe and effective measurements against it has become the prime need of hour. Though, putting it at health priority, various efforts like chemotherapy, immune activation through vaccine development and others are made globally over the last decade. Consequently, Highly Active Antiretroviral Therapy (HAART) was introduced but fails to completely block the viral replication due to drug resistance and various other severe side effects. Moreover, the antigenic variability and lack of appropriate experimental models has backed it to be a great puzzle. However, to overcome the present hurdles and to emerge a preventive HIV vaccine, efforts at various platforms are continued. A renewed, coordinated research, preclinical studies, clinical trials together with sufficient long term scientific and commercial commitments are made. Few of the therapeutic efforts viz. RNA interference (RNAi) and nanotechnology based approaches to control the HIV, viral enzymes’ inhibitors and various preclinically trialed vaccines are reviewed in this paper. Also, the observed toxicity of existing therapeutic regimen, key challenges and future prospects for the development of better tolerated prophylactic HIVâ€Â1 vaccine are discussed.
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Chable-Bessia, Christine, Charlotte Boullé, Aymeric Neyret, Jitendriya Swain, Mathilde Hénaut, Peggy Merida, Nathalie Gros, et al. "Low Selectivity Indices of Ivermectin and Macrocyclic Lactones on SARS-CoV-2 Replication In Vitro." COVID 2, no. 1 (January 12, 2022): 60–75. http://dx.doi.org/10.3390/covid2010005.
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Ivermectin was first approved for human use as an endectocide in the 1980s. It remains one of the most important global health medicines in history and has recently been shown to exert in vitro activity against SARS-CoV-2. However, the macrocyclic lactone family of compounds has not previously been evaluated for activity against SARS-CoV-2. The present study aims at comparing their anti-viral activity in relevant human pulmonary cell lines in vitro. Here, in vitro antiviral activity of the avermectins (ivermectin and selamectin) and milbemycins (moxidectin and milbemycin oxime) were assessed against a clinical isolate from a CHU Montpellier patient infected with SARS-CoV-2 in 2020. Ivermectin, like the other macrocyclic lactones moxidectin, milbemycin oxime and selamectin, reduced SARS-CoV-2 replication in vitro (EC50 of 2–5 μM). Immunofluorescence assays with ivermectin and moxidectin showed a reduction in the number of infected and polynuclear cells, suggesting a drug action on viral cell fusion. However, cellular toxicity of the avermectins and milbemycins during infection showed a very low selectivity index of <10. Thus, none of these agents appears suitable for human use for its anti-SARS-CoV-2 activity per se, due to low selectivity index.
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Ji, Y., L. A. Ward, and C. J. Hawkins. "Reconstitution of Human Necrosome Interactions in Saccharomyces cerevisiae." Biomolecules 11, no. 2 (January 25, 2021): 153. http://dx.doi.org/10.3390/biom11020153.
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The necrosome is a large-molecular-weight complex in which the terminal effector of the necroptotic pathway, Mixed Lineage Kinase Domain-Like protein (MLKL), is activated to induce necroptotic cell death. The precise mechanism of MLKL activation by the upstream kinase, Receptor Interacting Serine/Threonine Protein Kinase 3 (RIPK3) and the role of Receptor Interacting Serine/Threonine Protein Kinase 1 (RIPK1) in mediating MLKL activation remain incompletely understood. Here, we reconstituted human necrosome interactions in yeast by inducible expression of these necrosome effectors. Functional interactions were reflected by the detection of phosphorylated MLKL, plasma membrane permeabilization, and reduced proliferative potential. Following overexpression of human necrosome effectors in yeast, MLKL aggregated in the periphery of the cell, permeabilized the plasma membrane and compromised clonogenic potential. RIPK1 had little impact on RIPK3/MLKL-mediated yeast lethality; however, it exacerbated the toxicity provoked by co-expression of MLKL with a RIPK3 variant bearing a mutated RHIM-domain. Small molecule necroptotic inhibitors necrostatin-1 and TC13172, and viral inhibitors M45 (residues 1–90) and BAV_Rmil, abated the yeast toxicity triggered by the reconstituted necrosome. This yeast model provides a convenient tool to study necrosome protein interactions and to screen for and characterize potential necroptotic inhibitors.
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Alam, Zenifer, Md Nazmul Islam Bappy, Abida Sultana, Fayeza Sadia Laskar, Kawsar Miah, Kazi Md Ali Zinnah, and Sudeb Saha. "In-Silico Exploration of Plant Metabolites as Potential Remedies of Norovirus." Advances in Virology 2022 (October 20, 2022): 1–13. http://dx.doi.org/10.1155/2022/8905962.
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Research is still being carried out to develop specific medications or vaccinations to fight norovirus, a key contributor to foodborne illness. This study evaluated certain plant-based active chemicals as prospective candidates for such treatments using virtual screening techniques and other computer assessments. Twenty (20) plant metabolites were tested against the norovirus VP1, VP2, P48, and P22 protein domains using the molecular docking method. In terms of the lowest global binding energy, Asiatic acid, avicularin, guaijaverin, and curcumin exhibited the highest binding affinity with all selected proteins. Each viral protein’s essential binding sites with the potential drugs and drug surface hotspots were uncovered. The ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis was used to further analyze the pharmacological profiles of the top candidates. According to the results, none of the substances showed any adverse consequences that would reduce their drug-like properties. According to the analysis of the toxicity pattern, no detectable tumorigenic, mutagenic, irritating, or reproductive effects of the compounds were discovered. However, among the top four alternatives, curcumin exhibited the highest levels of cytotoxicity and immunotoxicity. These discoveries may open the way for the development of effective norovirus therapies and safety measures. Due to the positive outcomes, we strongly propose more in vivo experiments for the experimental validation of our findings.
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Asseri, Amer H., Md Jahidul Alam, Faisal Alzahrani, Ahmed Khames, Mohammad Turhan Pathan, Mohammed A. S. Abourehab, Salman Hosawi, et al. "Toward the Identification of Natural Antiviral Drug Candidates against Merkel Cell Polyomavirus: Computational Drug Design Approaches." Pharmaceuticals 15, no. 5 (April 20, 2022): 501. http://dx.doi.org/10.3390/ph15050501.
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Merkel cell carcinoma (MCC) is a rare form of aggressive skin cancer mainly caused by Merkel cell polyomavirus (MCPyV). Most MCC tumors express MCPyV large T (LT) antigens and play an important role in the growth-promoting activities of oncoproteins. Truncated LT promotes tumorigenicity as well as host cell proliferation by activating the viral replication machinery, and inhibition of this protein in humans drastically lowers cellular growth linked to the corresponding cancer. Our study was designed with the aim of identifying small molecular-like natural antiviral candidates that are able to inhibit the proliferation of malignant tumors, especially those that are aggressive, by blocking the activity of viral LT protein. To identify potential compounds against the target protein, a computational drug design including molecular docking, ADME (absorption, distribution, metabolism, and excretion), toxicity, molecular dynamics (MD) simulation, and molecular mechanics generalized Born surface area (MM-GBSA) approaches were applied in this study. Initially, a total of 2190 phytochemicals isolated from 104 medicinal plants were screened using the molecular docking simulation method, resulting in the identification of the top five compounds having the highest binding energy, ranging between −6.5 and −7.6 kcal/mol. The effectiveness and safety of the selected compounds were evaluated based on ADME and toxicity features. A 250 ns MD simulation confirmed the stability of the selected compounds bind to the active site (AS) of the target protein. Additionally, MM-GBSA analysis was used to determine the high values of binding free energy (ΔG bind) of the compounds binding to the target protein. The five compounds identified by computational approaches, Paulownin (CID: 3084131), Actaealactone (CID: 11537736), Epigallocatechin 3-O-cinnamate (CID: 21629801), Cirsilineol (CID: 162464), and Lycoricidine (CID: 73065), can be used in therapy as lead compounds to combat MCPyV-related cancer. However, further wet laboratory investigations are required to evaluate the activity of the drugs against the virus.
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Kučera, Otto, Halka Lotková, Roman Kanďár, Renata Héžová, Vladimíra Mužáková, and Zuzana Červinková. "The Model of D-Galactosamine-Induced Injury of Rat Hepatocytes in Primary Culture." Acta Medica (Hradec Kralove, Czech Republic) 49, no. 1 (2006): 59–65. http://dx.doi.org/10.14712/18059694.2017.111.
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D-galactosamine (GalN) is a highly selective hepatotoxin that causes liver damage similar to human viral hepatitis via depletion of uridine nucleotides, which subsequently diminishes synthesis of RNA and proteins. Model of galactosamine hepatotoxicity is frequently used in animal experiments in vitro. The purpose of our study was to establish the model of GalN-induced hepatocyte injury in in vitro conditions using primocultures of rat hepatocytes as an important prerequisite for further experiments in which we would like to study potential hepatoprotective effect of various substances. Rate of hepatocyte injury was evaluated by morphological changes, changes in cell viability, albumin production, mitochondrial membrane potential, activity of mitochondrial dehydrogenases and glutathione content. Marked dose dependent hepatocyte injury was found after 24-hour incubation with GalN. Based on the results we suggest as an optimal model for short-term toxicity test exposure to GalN for 24 hours in dose of 40 mM.
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Vázquez, Nancy, Hana Schmeisser, Michael A. Dolan, Joseph Bekisz, Kathryn C. Zoon, and Sharon M. Wahl. "Structural variants of IFNα preferentially promote antiviral functions." Blood 118, no. 9 (September 1, 2011): 2567–77. http://dx.doi.org/10.1182/blood-2010-12-325027.
Full textAbstract:
AbstractIFNα, a cytokine with multiple functions in innate and adaptive immunity and a potent inhibitor of HIV, exerts antiviral activity, in part, by enhancing apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3 (APOBEC3) family members. Although IFNα therapy is associated with reduced viral burden, this cytokine also mediates immune dysfunction and toxicities. Through detailed mapping of IFNα receptor binding sites, we generated IFNα hybrids and mutants and determined that structural changes in the C-helix alter the ability of IFN to limit retroviral activity. Selective IFNα constructs differentially block HIV replication and their directional magnitude of inhibition correlates with APOBEC3 levels. Importantly, certain mutants exhibited reduced toxicity as reflected by induced indoleamine 2,3-dioxygenase (IDO), suggesting discreet and shared intracellular signaling pathways. Defining IFN structure and function relative to APOBEC and other antiviral genes may enable design of novel IFN-related molecules preserving beneficial antiviral roles while minimizing negative effects.
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Ahmed, Sherif G., Casey A. Maguire, Shiliang Alice Cao, and Gary J. Brenner. "Schwannoma Gene Therapy via Adeno-Associated Viral Vector Delivery of Apoptosis-Associated Speck-like Protein Containing CARD (ASC): Preclinical Efficacy and Safety." International Journal of Molecular Sciences 23, no. 2 (January 13, 2022): 819. http://dx.doi.org/10.3390/ijms23020819.
Full textAbstract:
Schwannomas are tumors derived from Schwann-lineage cells, cells that protect and support myelinated nerves in the peripheral nervous system. They are typically slow-growing, encapsulated and benign. These tumors develop along peripheral, spinal and cranial nerves causing pain, sensory-motor dysfunction and death. Primary treatment for schwannoma is operative resection which can be associated with significant morbidity. Pharmacotherapy is largely restricted to bevacizumab, which has minimal or no efficacy for many patients and can be associated with treatment-limiting adverse effects. Given the suffering and morbidity associated with schwannoma and the paucity of therapeutic options, there is an urgent need for safe and effective therapies for schwannomas. We previously demonstrated that adeno-associated virus serotype 1 (AAV1) vector mediated delivery of the inflammasome adaptor protein, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) under the control of the P0 promoter, produced a prolonged reduction in tumor volume and tumor-associated pain in human xenograft and mouse syngeneic schwannoma models. Here, we present data essential for the translation of our AAV1-P0-ASC schwannoma gene therapy to clinical trials. We determine the minimum effective dose of AAV1-P0-hASC required to induce an anti-tumor effect in the xenograft human-schwannoma model. We also show that the presence of preexisting AAV1 immunity does not alter the antitumor efficacy of AAV-P0-mASC in a syngeneic mouse schwannoma model. Furthermore, the maximum deliverable intratumoral dose of AAV1-P0-ASC was not associated with neuronal toxicity in immunocompetent mice. Taken together, these safety and efficacy data support the translation of the AAV1-P0-ASC schwannoma gene therapy strategy to clinical trials.
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Chahal, Kavita, and Renu Mishra. "Challenges and Future Prospects of Nanotechnology for Antiviral Drugs." INTERNATIONAL JOURNAL OF APPLIED PHARMACEUTICAL SCIENCES AND RESEARCH 6, no. 02 (April 1, 2021): 22–26. http://dx.doi.org/10.21477/ijapsr.6.2.2.
Full textAbstract:
The emergence and re-emergence of pathogenic viruses during the last few decades are causing several pandemics. This has become a serious public health concern. The major causes could be resistance, latency, and toxicity of the virus. Also, there are other factors like improper diagnosis and immunosuppression caused by antivirals. Hence, the rapid development of antivirals following a conventional protocol of drug development is challenging. However, there is a ray of hope reflected from some alternative approaches such as gene inhibition by RNA interference (RNAi), regulation of gene expression by aptamers, ribozymes, novel drug delivery systems, in silico resources recent advances in nanomedicines. Nanotechnology-based strategies show pinkiepromise to the therapeutic management (diagnosis, treatment, and prevention) of life-threatening viral infections. The basis for the potential pharmaceutical use of nanoparticles includes their interactions with biological interfaces, their particle size, good electrical conductivity, and the Localized Surface Plasmon Resonance effect. This review discusses the strategies, challenges, drawbacks, and prospects of nanotechnology for making effective and safe antiviral drugs.
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Nie, Chuanxiong, Marlena Stadtmüller, Badri Parshad, Matthias Wallert, Vahid Ahmadi, Yannic Kerkhoff, Sumati Bhatia, et al. "Heteromultivalent topology-matched nanostructures as potent and broad-spectrum influenza A virus inhibitors." Science Advances 7, no. 1 (January 2021): eabd3803. http://dx.doi.org/10.1126/sciadv.abd3803.
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Here, we report the topology-matched design of heteromultivalent nanostructures as potent and broad-spectrum virus entry inhibitors based on the host cell membrane. Initially, we investigate the virus binding dynamics to validate the better binding performance of the heteromultivalent moieties as compared to homomultivalent ones. The heteromultivalent binding moieties are transferred to nanostructures with a bowl-like shape matching the viral spherical surface. Unlike the conventional homomultivalent inhibitors, the heteromultivalent ones exhibit a half maximal inhibitory concentration of 32.4 ± 13.7 μg/ml due to the synergistic multivalent effects and the topology-matched shape. At a dose without causing cellular toxicity, >99.99% reduction of virus propagation has been achieved. Since multiple binding sites have also been identified on the S protein of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), we envision that the use of heteromultivalent nanostructures may also be applied to develop a potent inhibitor to prevent coronavirus infection.
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Jahangir, Mohammed Asadullah. "Phytonutrients and Technological Development in Formulations." Journal of Pharmaceutical Research Science & Technology 6, no. 1 (February 7, 2022): 38–66. http://dx.doi.org/10.31531/jprst.1000159.
Full textAbstract:
Phytomedicines are used by humans since ancient civilizations and is now considered as an important part of traditional and alternative system of medicine. In recent time, phytomedicines have gained special attention based on the fact that a number of current medicines are derived from plant source. Phytochemicals exhibits lesser side effects and are potentially strong therapeutic agents. The global market for herbal drugs is increasing day by day. It has gained widespread acceptance due to its efficacy, accessibility, minimum toxicity, and cost effectiveness. However, solubility, stability and bioavailability are some of the major hindrances in the commercialization process of phytomedicines. Nanotechnology have been potentially productive in improving the solubility, stability, bioavailability, and bioactivity of phytomedicines. Development of nano-phytomedicines or attaching phytomedicines with polymers and modifying their surface properties and permeability have altogether influenced the bioavailability of phytochemicals. Novel formulations like solid lipid nanoparticles, micelles, niosomes, dendrimers, nanotube, liposomes, nano-emulsions nanospheres, phytosomes etc. Have been developed loaded with phytomedicines and have shown extraordinary result. This chapter extensively reviews phytomedicines based novel drug delivery systems having potential activity in different diseases like metabolic disorders, cardiovascular disorders, neurological disorders, viral diseases, cancers, inflammatory diseases and wound healing and lastly future prospect is discussed.
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Chang, J. Y., R. Komaki, X. Zhang, L. Wang, and B. Fang. "Oncolytic adenovirus expressing apoptotic genes targets radiation resistant (RR) esophageal cancer." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 21043. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.21043.
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21043 Background: Only 25% of esophageal cancer patients achieve pathological complete response after standard chemoradiotherapy. Radiation dose escalation is associated with higher toxicity but no therapeutic improvement. In addition, esophageal cancer cells may develop radiation resistance (RR) after fractionated radiation exposure. Therefore, molecular targeting therapy for RR esophageal cancer is urgently needed. Methods: Six pairs of RR esophageal cancer cell lines were established by applying continuous 2 Gy fractionated irradiation. Ad/TRAIL-E1, an oncolytic adenoviral vector expressing both apoptotic TRAIL and viral E1A genes under the control of tumor specific human telomerase reverse transcriptase promoter, was constructed. Phosphate buffer solution and vectors expressing the TRAIL gene only, the GFP marker protein only, or the E1A gene only served as controls. Trans-gene expression, apoptosis activation, and the RR esophageal cancer cells targeted were evaluated in vitro and in vivo. A human esophageal RR cancer model was established and locally treated with Ad/TRAIL-E1 or controls. Results: After fractionated radiation exposure, esophageal cancer cell lines developed RR (up to 25-fold) that was associated with activation of the anti-apoptotic pathway. Ad/TRAIL-E1 activated an apoptotic cascade of caspases and selectively killed esophageal cancer cells but not normal cells. Ad/TRAIL-E1 preferentially targeted RR stem-like cancer cells with higher trans-gene expression and cell killing compared with parental cells. Overexpression (3 times) of Coxsackie's and adenoviral receptors in RR esophageal cancer cells compared with parental cells was noted. Ad/TRAIL-E1 therapy resulted in 40% tumor-free survival without the treatment- related toxicity found in human RR esophageal adenocarcinoma mouse models (p<0.05 as compared with controls). Conclusions: Esophageal cancer cells develop RR after fractionated radiation exposure. Ad/TRAIL-E1 preferentially targeted RR stem-like esophageal cancer cells, which resulted in a 40% cure rate. No significant financial relationships to disclose.
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Kluin-Nelemans, J. C., Marinus Van Marwijk Kooij, P. J. Lugtenburg, Pierre W. Wijermans, Willem JL Van Putten, and Gustaaf W. van Imhoff. "Alemtuzumab-CHOP for Aggressive T Cell Lymphoma. A Phase II HOVON 69 Trial." Blood 112, no. 11 (November 16, 2008): 1999. http://dx.doi.org/10.1182/blood.v112.11.1999.1999.
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Abstract The prognosis of patients with aggressive mature T cell lymphoma is very poor. We wondered whether the addition of the anti-CD52 monoclonal antibody alemtuzumab to 2-weekly CHOP chemotherapy as 1st line treatment would result in acceptable toxicity, improved response, and outcome. In a multicenter phase II design, 20 patients were to receive 8 cycles of CHOP14 (d 1: cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2, 2 mg max, and day 1–5 prednisone 100 mg; repeat at day 15). Alemtuzumab 30 mg subcutaneously was added at day 1, 5 and 10 of each cycle (total of 24 administrations). Valaciclovir, cotrimoxazol and fluconazol were given as prophylaxis for herpes viral, PCP and fungal infections, respectively; G-CSF was given to enhance neutrophil recovery. Blood products were irradiated. Monitoring for CMV (re)activation by PCR or pp65 antigenemia was mandatory. Between Nov 2005 and Oct 2007, 20 patients with newly diagnosed T-NHL were included by 10 different centers (55% male; median age 50, range 20 to 65 years; 19 stage III/IV; 11 IPI high/high-intermediate). T-NHL histologies were: peripheral T cell lymphoma NOS (n=10), angioimmunoblastic lymphoma (n=6), subcutaneous panniculitis-like lymphoma (n=3), enteropathy-associated T cell lymphoma (n=1). Patients received a median of 8 CHOP cycles, 85% received 6 or more. Response to treatment was: 12 CR, 6 PR (ORR 85%) and 2 NR. At a median follow-up of 18 months, 11 patients are still alive, 9 patients have relapsed; the median FFS is 20 months (range 2–25) and median OS is 23 months (5–29). Toxicity was considerable, with CMV reactivation in 7/20 patients; one patient developed CMV disease; hospital admissions because of (mostly neutropenic) fever occurred in 8 patients. However, none of these patients died from these adverse events. One patient died in CR, 5 months after treatment due to sepsis complicating an extensive varicella zoster infection. Three patients (two with peripheral T cell lymphoma, one with angioimmunoblastic lymphoma without initial EBV activity) developed an EBV-related lymphoproliferative disorder. These patients ultimately died of relapse T-NHL. In conclusion, an intensive alemtuzumab-CHOP14 regimen is feasible and effective in aggressive T-NHL as far as response and early outcome are concerned. Toxicity, especially the high percentage of herpes viral reactivation including EBV-related lymphoproliferation requires careful monitoring.
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Akbay, Burkitkan, Syed Hani Abidi, Mahmoud A. A. Ibrahim, Zhussipbek Mukhatayev, and Syed Ali. "Multi-Subunit SARS-CoV-2 Vaccine Design Using Evolutionarily Conserved T- and B- Cell Epitopes." Vaccines 9, no. 7 (June 26, 2021): 702. http://dx.doi.org/10.3390/vaccines9070702.
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The SARS-CoV-2 pandemic has created a public health crisis worldwide. Although vaccines against the virus are efficiently being rolled out, they are proving to be ineffective against certain emerging SARS-CoV-2 variants. The high degree of sequence similarity between SARS-CoV-2 and other human coronaviruses (HCoV) presents the opportunity for designing vaccines that may offer protection against SARS-CoV-2 and its emerging variants, with cross-protection against other HCoVs. In this study, we performed bioinformatics analyses to identify T and B cell epitopes originating from spike, membrane, nucleocapsid, and envelope protein sequences found to be evolutionarily conserved among seven major HCoVs. Evolutionary conservation of these epitopes indicates that they may have critical roles in viral fitness and are, therefore, unlikely to mutate during viral replication thus making such epitopes attractive candidates for a vaccine. Our designed vaccine construct comprises of twelve T and six B cell epitopes that are conserved among HCoVs. The vaccine is predicted to be soluble in water, stable, have a relatively long half-life, and exhibit low allergenicity and toxicity. Our docking results showed that the vaccine forms stable complex with toll-like receptor 4, while the immune simulations predicted that the vaccine may elicit strong IgG, IgM, and cytotoxic T cell responses. Therefore, from multiple perspectives, our multi-subunit vaccine design shows the potential to elicit a strong immune-protective response against SARS-CoV-2 and its emerging variants while carrying minimal risk for causing adverse effects.
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Vasey, P. A., L. N. Shulman, S. Campos, J. Davis, M. Gore, S. Johnston, D. H. Kirn, et al. "Phase I Trial of Intraperitoneal Injection of the E1B-55-kd-Gene–Deleted Adenovirus ONYX-015 (dl1520) Given on Days 1 Through 5 Every 3 Weeks in Patients With Recurrent/Refractory Epithelial Ovarian Cancer." Journal of Clinical Oncology 20, no. 6 (March 15, 2002): 1562–69. http://dx.doi.org/10.1200/jco.2002.20.6.1562.
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PURPOSE: Resistance to chemotherapy in ovarian cancer is frequently associated with mutations in the p53 gene. The adenovirus dl1520 (ONYX-015) with the E1B 55-kd gene deleted, allowing selective replication in and lysis of p53-deficient tumor cells, has shown preclinical efficacy against p53-deficient nude mouse-human ovarian carcinomatosis xenografts. PATIENTS AND METHODS: We undertook a phase I trial of intraperitoneal dl1520 in patients with recurrent ovarian cancer. Sixteen women with recurrent/refractory ovarian cancer received 35 cycles (median, two cycles) of dl1520 delivered on days 1 through 5 in four dose cohorts: 1 × 109 plaque forming units (pfu), 1 × 1010 pfu, 3 × 1010 pfu, and 1 × 1011 pfu. RESULTS: The most common significant toxicities related to virus administration were flu-like symptoms, emesis, and abdominal pain. One patient receiving 1 × 1010 pfu developed common toxicity criteria grade 3 abdominal pain and diarrhea, which was dose-limiting. The maximum-tolerated dose was not reached at 1011 pfu, and at this dose level patients did not experience significant toxicity. There was no clear-cut evidence of clinical or radiologic response in any patient. Blood samples were taken for adenovirus DNA and neutralizing antibodies. Polymerase chain reaction data indicating presence of virus up to 10 days after the final (day 5) infusion of dl1520 are suggestive of continuing viral replication. CONCLUSION: This article therefore describes the first clinical experience with the intraperitoneal delivery of any replication-competent/-selective virus in cancer patients.
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Choy, Jin Ho, Jae Min Oh, and Soo Jin Choi. "Nanoceramics-Biomolecular Conjugates for Gene and Drug Delivery." Advances in Science and Technology 45 (October 2006): 769–78. http://dx.doi.org/10.4028/www.scientific.net/ast.45.769.
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We were quite successful in demonstrating that two-dimensional inorganic compounds like anionic and cationic clays can be used as gene or drug delivery carriers, those which are completely different from conventional ones such as viral-based, naked, and cationic liposomes, those which are limited in certain cases of applications due to their toxicity, immunogenecity, poor integration, and etc. Since LDHs with positive layer charge have an anion exchange capacity, functional biomolecules with a negative charge can be intercalated into hydroxide layers of LDH by a simple ion-exchange reaction to form a bio-LDH nanohybrid. On the contrary, clays can uptake biofuctional molecules or drugs with positive charge in the interlayer space by cation exchange reaction. The possible roles of inorganic lattice as the gene and drug delivery carrier will be shown by demonstrating the cellular uptake experiments of FITC-LDH, with laser scanning confocal fluorescence microscopy as well as of radioactive isotope-labeled ATP-LDH hybrid. As the typical examples for gene and drug delivery systems, As-myc-LDH, MTX-LDH, and Itraconazol-clay nanohybrids will be demonstrated in detail.
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Shagyrova, Zhadyra Sagykyzy, Yerzhan Yersaiynuly Zhienbay, Mikhail Seregeyevich Voikov, and Alexander Vyacheslavovich Shustov. "PREPARATION OF CHEMICAL AND PHYSICAL CONJUGATES OF SELF-ASSEMBLING NANOPARTICLES WITH CELL-PENETRATING PEPTIDE AND DOXORUBICIN." CBU International Conference Proceedings 3 (September 19, 2015): 405–11. http://dx.doi.org/10.12955/cbup.v3.630.
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Abstract: Nano-sized carriers can help to reduce toxicity and improve clinical efficacy of drugs. Virus-like particles (VLPs) are biocompatible and biodegradable self-assembling nanoparticles, which show great promise as carriers for substances for targeted delivery and controlled release. Either chemical conjugation of physical incorporation without formation of covalent bonds is possible to load substances of interest into VLPs.Objectives: To produce VLPs from recombinant viral capsid protein (HBcAg) and test feasibility of methods of formation of chemical and physical conjugates of VLPs with substances of pharmacological interest.Methods: Virus-like particles composed from recombinant hepatitis B core antigen (HBcAg) were produced by recombinant expression in E.coli and purified by successive centrifugation through sucrose gradients. Peptide transportan 10 was synthesized and used for carbodiimide (EDC)-mediated conjugation to VLPs. Doxorubicin (DOX) was loaded into the nucleic acid-containing VLPs to form physical conjugate.Results: VLPs with chemically attached moieties of cell-penetrating peptide transportan 10 were produced. The conjugate was examined in SDS-PAGE to confirm presence of conjugation products. Conjugation efficiency (molar ration peptide/protein in the conjugate) reaches 0.5:1 (i.e. 50% of protein chains have one attached peptide moiety). The nucleic acid-containing VLPs can be loaded with the DOX forming stable non-covalent physical conjugate.Conclusion: Recombinantly expressed VLPs allow easy attaching of small molecules making them a convenient platform to develop drug carriers.
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Sargis, Timothy, Seock-Won Youn, Hyun Lee, L. A. Naiche, and Jan Kitajewski. "Abstract 3207: Notch decoys as potential anti-angiogenic biotherapeutics." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3207. http://dx.doi.org/10.1158/1538-7445.am2022-3207.
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Abstract Notch signaling is activated by ligands Delta-like 4 (Dll4) and Jagged1 in the tumor microenvironment to promote tumor angiogenesis and perfusion. Notch activation is associated with poor outcomes in several cancers, particularly triple negative breast cancer (TNBC), and affects both tumor angiogenesis and metastasis. The development of therapeutics targeting angiogenesis, such as the Notch pathway, has again attracted attention. Previous approaches to globally inhibit the Notch pathway or block Dll4/Notch1 activation, such as γ-secretase inhibitors (GSI), have raised safety concerns due to gastrointestinal toxicity due to accumulation of secretory goblet cells in the intestine. Similarly, anti-Dll4 therapy resulted in pathological changes in the liver as well as severe vascular neoplasms when evaluated using preclinical animal models. Development of new approaches for targeting the Notch pathway remains a critical clinical problem currently unaddressed. Our lab has previously developed ligand-specific inhibitors of Notch signaling, called Notch decoys, which are comprised of Fc fusions to specific EGF-like repeats of the Notch1 extracellular domain. These Notch decoys bind ligand non-productively and interfere with ligand function. Jagged-specific Notch1 decoys inhibit angiogenesis in vitro and significantly impair tumor growth, tumor angiogenesis, and perfusion without apparent toxicity in mouse models of TNBC. However, this previous work utilized Notch decoys produced via viral expression vectors, which preclude dosage control and limit clinical applicability. We have developed a new generation of Notch “mini” decoys that contain fewer EGF-like repeats. These mini decoys show improved secretion characteristics and can be purified as active proteins in clinically relevant quantities. Using a variety of binding assays, we observed that these Notch mini decoys demonstrate strong but distinct binding to Notch ligands Dll4 and Jagged1 and block Notch signaling when evaluated in cultured cells. Our newly generated Notch decoys can now be sufficiently purified for use in a dose-dependent manner to test the therapeutic role of Notch inhibition on tumor angiogenesis using preclinical animal models. Citation Format: Timothy Sargis, Seock-Won Youn, Hyun Lee, L.A. Naiche, Jan Kitajewski. Notch decoys as potential anti-angiogenic biotherapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3207.
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Lischka, Peter, Guy Hewlett, Tobias Wunberg, Judith Baumeister, Daniela Paulsen, Thomas Goldner, Helga Ruebsamen-Schaeff, and Holger Zimmermann. "InVitro and In Vivo Activities of the Novel Anticytomegalovirus Compound AIC246." Antimicrobial Agents and Chemotherapy 54, no. 3 (January 4, 2010): 1290–97. http://dx.doi.org/10.1128/aac.01596-09.
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ABSTRACT Human cytomegalovirus (HCMV) remains a serious threat for immunocompromised individuals, including transplant recipients and newborns. To date, all drugs licensed for the treatment of HCMV infection and disease target the viral DNA polymerase. Although these drugs are effective, several drawbacks are associated with their use, including toxicity and emergence of drug resistance. Hence, new and improved antivirals with novel molecular targets are urgently needed. Here we report on the antiviral properties of AIC246, a representative of a novel class of low-molecular-weight compounds that is currently undergoing clinical phase II studies. The anti-HCMV activity of AIC246 was evaluated in vitro and in vivo using various cell culture assays and an engineered mouse xenograft model. In addition, antiviral properties of the drug were characterized in comparison to the current gold standard ganciclovir. We demonstrate that AIC246 exhibits excellent in vitro inhibitory activity against HCMV laboratory strains and clinical isolates, retains activity against ganciclovir-resistant viruses, is well tolerated in different cell types (median selectivity index, 18,000), and exerts a potent in vivo efficacy in a mouse xenograft model. Moreover, we show that the antiviral block induced by AIC246 is reversible and the efficacy of the drug is not significantly affected by cell culture variations such as cell type or multiplicity of infection. Finally, initial mode-of-action analyses reveal that AIC246 targets a process in the viral replication cycle that occurs later than DNA synthesis. Thus, AIC246 acts via a mode of action that differs from that of polymerase inhibitors like ganciclovir.
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Zampieri, Carisa A., Jean-Francois Fortin, Garry P. Nolan, and Gary J. Nabel. "The ERK Mitogen-Activated Protein Kinase Pathway Contributes to Ebola Virus Glycoprotein-Induced Cytotoxicity." Journal of Virology 81, no. 3 (November 15, 2006): 1230–40. http://dx.doi.org/10.1128/jvi.01586-06.
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ABSTRACT Ebola virus is a highly lethal pathogen that causes hemorrhagic fever in humans and nonhuman primates. Among the seven known viral gene products, the envelope glycoprotein (GP) alone induces cell rounding and detachment that ultimately leads to cell death. Cellular cytoxicity is not seen with comparable levels of expression of a mutant form of GP lacking a mucin-like domain (GPΔmuc). GP-induced cell death is nonapoptotic and is preceded by downmodulation of cell surface molecules involved in signaling pathways, including certain integrins and epidermal growth factor receptor. To investigate the mechanism of GP-induced cellular toxicity, we analyzed the activation of several signal transduction pathways involved in cell growth and survival. The active form of extracellular signal-regulated kinases types 1 and 2 (ERK1/2), phospho-ERK1/2, was reduced in cells expressing GP compared to those expressing GPΔmuc as determined by flow cytometry, in contrast to the case for several other signaling proteins. Subsequent analysis of the activation states and kinase activities of related kinases revealed a more pronounced effect on the ERK2 kinase isoform. Disruption of ERK2 activity by a dominant negative ERK or by small interfering RNA-mediated ERK2 knockdown potentiated the decrease in αV integrin expression associated with toxicity. Conversely, activation of the pathway through the expression of a constitutively active form of ERK2 significantly protected against this effect. These results indicate that the ERK signaling cascade mediates GP-mediated cytotoxicity and plays a role in pathogenicity induced by this gene product.
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Rai, Raj, Saniya Alwani, and Ildiko Badea. "Polymeric Nanoparticles in Gene Therapy: New Avenues of Design and Optimization for Delivery Applications." Polymers 11, no. 4 (April 25, 2019): 745. http://dx.doi.org/10.3390/polym11040745.
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The field of polymeric nanoparticles is quickly expanding and playing a pivotal role in a wide spectrum of areas ranging from electronics, photonics, conducting materials, and sensors to medicine, pollution control, and environmental technology. Among the applications of polymers in medicine, gene therapy has emerged as one of the most advanced, with the capability to tackle disorders from the modern era. However, there are several barriers associated with the delivery of genes in the living system that need to be mitigated by polymer engineering. One of the most crucial challenges is the effectiveness of the delivery vehicle or vector. In last few decades, non-viral delivery systems have gained attention because of their low toxicity, potential for targeted delivery, long-term stability, lack of immunogenicity, and relatively low production cost. In 1987, Felgner et al. used the cationic lipid based non-viral gene delivery system for the very first time. This breakthrough opened the opportunity for other non-viral vectors, such as polymers. Cationic polymers have emerged as promising candidates for non-viral gene delivery systems because of their facile synthesis and flexible properties. These polymers can be conjugated with genetic material via electrostatic attraction at physiological pH, thereby facilitating gene delivery. Many factors influence the gene transfection efficiency of cationic polymers, including their structure, molecular weight, and surface charge. Outstanding representatives of polymers that have emerged over the last decade to be used in gene therapy are synthetic polymers such as poly(l-lysine), poly(l-ornithine), linear and branched polyethyleneimine, diethylaminoethyl-dextran, poly(amidoamine) dendrimers, and poly(dimethylaminoethyl methacrylate). Natural polymers, such as chitosan, dextran, gelatin, pullulan, and synthetic analogs, with sophisticated features like guanidinylated bio-reducible polymers were also explored. This review outlines the introduction of polymers in medicine, discusses the methods of polymer synthesis, addressing top down and bottom up techniques. Evaluation of functionalization strategies for therapeutic and formulation stability are also highlighted. The overview of the properties, challenges, and functionalization approaches and, finally, the applications of the polymeric delivery systems in gene therapy marks this review as a unique one-stop summary of developments in this field.
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Davidson, Robert M., and Timothy R. Winey. "Vitamin C Mitigating and Rescuing from Synergistic Toxicity: Sodium Fluoride, Silicofluorides, Aluminum Salts, Electromagnetic Pollution, and SARS-CoV-2." International Journal of Vaccine Theory, Practice, and Research 1, no. 2 (January 5, 2021): 243–82. http://dx.doi.org/10.56098/ijvtpr.v1i2.12.
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A supramolecular paradigm for mitigation and rescue from SARS-COV2 infection is proposed. Similarities between the Sanarelli-Shwartzman phenomenon and biological responses to viral pathogens are considered. Non-enzymatic group transfer catalysis (NGTC) by L-ascorbic acid, the L-ascorbic acid free radical and the 2-O-phosphate substituted L-ascorbic acid derivative are proposed under the ascorbolysis hypothesis to provide a supramolecular basis for mitigating the synergistic toxicity and catalytic mimicry by the environmental toxicants, sodium fluoride, aluminum salts, and silicofluorides in public water supplies. Ascorbolysis is the term we adopt to describe a redox active, hyperconjugated, vinylogous variant of acidolysis. The objective of this paper is to provide a plausible supramolecular basis for mitigation and rescue from well-known environmental toxicity represented by the presence of sodium fluoride, aluminum salts, and silicofluoride species in public water supplies. An overview of the conceptual basis for NGTC by vitamin C during inflammatory states is provided. Controversies concerning the initial oxidation steps and pH-dependent speciation of L-ascorbic acid are addressed. Non-skeletal fluorosis is a serious systemic malady which we propose arises from disruption of hydrogen bond networks and hydrogen bond cooperativity resulting from the marked electronegativity and hydrogen bond accepting ability of fluoride atoms found in NaF and AlFx species. AlFx species have been previously shown to arise in situ spontaneously from NaF, aluminum salts, and silicofluorides often found in toothpastes and “fluoridated” drinking water. AlFx species are thought to act as isosteric mimics of biophosphates during group transfers of phosphoryl moieties. We propose that catalytic mimicry by AlFx species inhibits postulated non-enzymatic kinase-like and RNA polymerase-like function of the AA-2P derivative during inflammatory states. We describe how NGTC by L-ascorbic acid is likely to be disrupted by AlFx and sodium fluoride of a specific H3-O2 intramolecular hydrogen bond in L-ascorbic acid, the L-ascorbic acid free radical, and their 2-O-substituted derivatives, which are necessary for NGTC in the moderately acidic, mildly oxidative, relatively hydrophobic microenvironment which typify inflammatory states. Suggestions are made to achieve less variation in results of large randomized clinical trials (RCTs) seeking to validate use of high-dose intravenous vitamin C in critical care and cancer settings.