Application of System Biology to Explore the Association of Neprilysin, Angiotensin-Converting Enzyme 2 (ACE2), and Carbonic Anhydrase (CA) in Pathogenesis of SARS-CoV-2

Background: Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appears with common symptoms including fever, dry cough, and fatigue, as well as some less common sysmptoms such as loss of taste and smell, diarrhea, skin rashes and discoloration of fingers. COVID-19 patients may also suffer from serious symptoms including shortness of breathing, chest pressure and pain, as well as loss of daily routine habits, pointing out to a sever reduction in the quality of life. COVID-19 has afftected almost all countries, however, the United States contains the highest number of infection (> 1,595,000 cases) and deaths cases (> 95,000 deaths) in the world until May 21, 2020. Finding an influential treatment strategy against COVID-19 can be facilitated through better understanding of the virus pathogenesis and consequently interrupting the biochemical pathways that the virus may play role in human body as the current reservoir of the virus. Results: In this study, we combined system biology and bioinformatic approaches to define the role of coexpression of angiotensin-converting enzyme 2 (ACE2), neprilysin or membrane metallo-endopeptidase (MME), and carbonic anhydrases (CAs) and their association in the pathogenesis of SARS-CoV-2. The results revealed that ACE2 as the cellular attachment site of SARS-CoV-2, neprilysin, and CAs have a great contribution together in the renin angiotensin system (RAS) and consequently in pathogenesis of SARS-CoV-2 in the vital organs such as respiratory, renal, and blood circulation systems. Any disorder in neprilysin, ACE2, and CAs can lead to increase of CO2 concentration in blood and respiratory acidosis, induction of pulmonary edema and heart and renal failures. Conclusions: Due to the presence of ACE2-Neprilysin-CA complex in most of vital organs and as a receptor of COVID-19, it is expected that most organs are affected by SARS-CoV-2 such as inflammation and fibrosis of lungs, which may conversely affect their vital functions, temporary or permanently, sometimes leading to death. Therefore, ACE2-Neprilysin-CA complex could be the key factor of pathogenesis of SARS-CoV-2 and may provide us useful information to find better provocative and therapeutic strategies against COVID-19. © 2020 The Author(s)

Identification and characterization of the first fish parvalbumin-like protein data from a pathogenic fungal species, Trichophyton violaceum

Parvalbumins are the most important fish allergens, which are heat-stable, classified in the family of calcium-binding EF-hand proteins, and contain one magnesium binding site. The functional connection between calcium and parvalbumin gives fish the high-speed swimming ability because of high concentration of Ca2+-binding parvalbumin in fish white muscles. Although parvalbumins are widely studied and conceivably play crucial roles in the physiology and swimming pattern of fishes, still no report is available about their presence in microbes, such as pathogenic fungal species. We detected a DNA sequence in the genome of Trichophyton violaceum and used in silico and polymerase chain reaction (PCR) technique with a designed pair of primers to identify it as parvalbumin-coding gene. © 2020 The Author

Ascaris lumbricoides β carbonic anhydrase: A potential target enzyme for treatment of ascariasis

BACKGROUND: A parasitic roundworm, Ascaris lumbricoides, is the causative agent of ascariasis, with approximately 760 million cases around the world. Helminthic infections occur with a high prevalence mostly in tropical and developing xcountries. Therefore, design of affordable broad-spectrum anti-helminthic agents against a variety of pathogens, including not only A. lumbricoides but also hookworms and whipworms, is desirable. Beta carbonic anhydrases (β-CAs) are considered promising targets of novel anthelminthics because these enzymes are present in various parasites, while completely absent in vertebrates. METHODS: In this study, we identified an A. lumbricoides β-CA (AIBCA) protein from protein sequence data using bioinformatics tools. We used computational biology resources and methods (including InterPro, CATH/Gene3D, KEGG, and METACYC) to analyze AlBCA and define potential roles of this enzyme in biological pathways. The AlBCA gene was cloned into pFastBac1, and recombinant AIBCA was produced in sf-9 insect cells. Kinetics of AlBCA were analyzed by a stopped-flow method. RESULTS: Multiple sequence alignment revealed that AIBCA contains the two sequence motifs, CXDXR and HXXC, typical for β-CAs. Recombinant AIBCA showed significant CA catalytic activity with k(cat) of 6.0 × 10(5) s(−1) and k(cat)/K(M) of 4.3 × 10(7) M(−1) s(−1). The classical CA inhibitor, acetazolamide, showed an inhibition constant of 84.1 nM. Computational modeling suggests that the molecular architecture of AIBCA is highly similar to several other known β-CA structures. Functional predictions suggest that AIBCA might play a role in bicarbonate-mediated metabolic pathways, such as gluconeogenesis and removal of metabolically produced cyanate. CONCLUSIONS: These results open new avenues to further investigate the precise functions of β-CAs in parasites and suggest that novel β-CA specific inhibitors should be developed and tested against helminthic diseases. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13071-015-1098-5) contains supplementary material, which is available to authorized users

Identification and characterization of a silent mutation in RNA binding domain of N protein coding gene from SARS-CoV-2

Objective: This study describes the occurrence of a silent mutation in the RNA binding domain of nucleocapsid phosphoprotein (N protein) coding gene from SARS-CoV-2 that may consequence to a missense mutation by onset of another single nucleotide mutation. Results: In the DNA sequence isolated from severe acute respiratory syndrome (SARS-CoV-2) in Iran, a coding sequence for the RNA binding domain of N protein was detected. The comparison of Chinese and Iranian DNA sequences displayed that a thymine (T) was mutated to cytosine (C), so �TTG� from China was changed to �CTG� in Iran. Both DNA sequences from Iran and China have been encoded for leucine. In addition, the second T in �CTG� in the DNA or uracil (U) in �CUG� in the RNA sequences from Iran can be mutated to another C by a missense mutation resulting from thymine DNA glycosylase (TDG) of human and base excision repair mechanism to produce �CCG� encoding for proline, which consequently may increase the affinity of the RNA binding domain of N protein to viral RNA and improve the transcription rate, pathogenicity, evasion from human immunity system, spreading in the human body, and risk of human-to-human transmission rate of SARS-CoV-2. © 2021, The Author(s)

Expansion of Single Cell Transcriptomics Data of SARS-CoV Infection in Human Bronchial Epithelial Cells to COVID-19

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 19 (COVID-19) that was emerged as a new member of coronaviruses since December 2019 in Wuhan, China and then after was spread in all continentals. Since SARS-CoV-2 has shown about 77.5 similarity to SARS-CoV, the transcriptome and immunological regulations of SARS-CoV-2 was expected to have high percentage of overlap with SARS-CoV. Results: In this study, we applied the single cell transcriptomics data of human bronchial epithelial cells (2B4 cell line) infected with SARS-CoV, which was annotated in the Expression Atlas database to expand this data to COVID-19. In addition, we employed system biology methods including gene ontology (GO) and Reactome pathway analyses to define functional genes and pathways in the infected cells with SARS-CoV. The transcriptomics analysis on the Expression Atlas database revealed that most genes from infected 2B4 cell line with SARS-CoV were downregulated leading to immune system hyperactivation, induction of signaling pathways, and consequently a cytokine storm. In addition, GO:0016192 (vesicle-mediated transport), GO:0006886 (intracellular protein transport), and GO:0006888 (ER to Golgi vesicle-mediated transport) were shown as top three GOs in the ontology network of infected cells with SARS-CoV. Meanwhile, R-HAS-6807070 (phosphatase and tensin homolog or PTEN regulation) showed the highest association with other Reactome pathways in the network of infected cells with SARS-CoV. PTEN plays a critical role in the activation of dendritic cells, B- and T-cells, and secretion of proinflammatory cytokines, which cooperates with downregulated genes in the promotion of cytokine storm in the COVID-19 patients. Conclusions: Based on the high similarity percentage of the transcriptome of SARS-CoV with SARS-CoV-2, the data of immunological regulations, signaling pathways, and proinflammatory cytokines in SARS-CoV infection can be expanded to COVID-19 to have a valid platform for future pharmaceutical and vaccine studies. © 2020 The Author(s)

Potential therapeutic agents to COVID-19: An update review on antiviral therapy, immunotherapy, and cell therapy

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China, in December 2020 and coronavirus disease 19 (COVID-19) was later announced as pandemic by the World Health Organization (WHO). Since then, several studies have been conducted on the prevention and treatment of COVID-19 by potential vaccines and drugs. Although, the governments and global population have been attracted by some vaccine production projects, the presence of SARS-CoV-2-specific antiviral drugs would be an urge necessity in parallel with the efficient preventive vaccines. Various nonspecific drugs produced previously against other bacterial, viral, and parasite infections were recently evaluated for treating patients with COVID-19. In addition to therapeutic properties of these anti-COVID-19 compounds, some adverse effects were observed in different human organs as well. Not only several attentions were paid to antiviral therapy and treatment of COVID-19, but also nanomedicine, immunotherapy, and cell therapy were conducted against this viral infection. In this review study, we planned to introduce the present and potential future treatment strategies against COVID-19 and define the advantages and disadvantages of each treatment strategy. © 2021 The Author

Comparison of the effect of argon, hydrogen, and nitrogen gases on the reduced graphene oxide-hydroxyapatite nanocomposites characteristics

In this study, the effect of the argon, nitrogen, and hydrogen gases on the final properties of the reduced graphene oxide-hydroxyapatite nanocomposites synthesized by gas injected hydrothermal method was investigated. Four samples were synthesized, which in the first sample the pressure was controlled by volume change at a constant concentration. In subsequent samples, the pressure inside the autoclave was adjusted by the injecting gases. The initial pressure of the injected gases was 10 bar and the final pressure considered was 25 bar. The synthesized powders were consolidated at 950 °C and 2 MPa by spark plasma sintering method. The final samples were subjected to Vickers indentation analysis. The findings of this study indicate that the injection of argon, hydrogen, and nitrogen gases improved the mechanical properties of the nanocomposites. Injection of gases increased the crystallinity and particle size of hydroxyapatite, and this increase was greater for nitrogen gas than for others. Injection of these gases increased the rate of graphene oxide reduction and in this case the effect of nitrogen gas was greater than the others. Figure not available: See fulltext. © 2020 The Author(s)