Study of kaempferol in the treatment of COVID-19 combined with Chikungunya co-infection by network pharmacology and molecular docking technology.

Chikungunya (CHIK) patients may be vulnerable to coronavirus disease (COVID-19). However, presently there are no anti-COVID-19/CHIK therapeutic alternatives available. The purpose of this research was to determine the pharmacological mechanism through which kaempferol functions in the treatment of COVID-19-associated CHIK co-infection. We have used a series of network pharmacology and computational analysis-based techniques to decipher and define the binding capacity, biological functions, pharmacological targets, and treatment processes in COVID-19-mediated CHIK co-infection. We identified key therapeutic targets for COVID-19/CHIK, including TP53, MAPK1, MAPK3, MAPK8, TNF, IL6 and NFKB1. Gene ontology, molecular and upstream pathway analysis of kaempferol against COVID-19 and CHIK showed that DEGs were confined mainly to the cytokine-mediated signalling pathway, MAP kinase activity, negative regulation of the apoptotic process, lipid and atherosclerosis, TNF signalling pathway, hepatitis B, toll-like receptor signaling, IL-17 and IL-18 signaling pathways. The study of the gene regulatory network revealed several significant TFs including KLF16, GATA2, YY1 and FOXC1 and miRNAs such as let-7b-5p, mir-16-5p, mir-34a-5p, and mir-155-5p that target differential-expressed genes (DEG). According to the molecular coupling results, kaempferol exhibited a high affinity for 5 receptor proteins (TP53, MAPK1, MAPK3, MAPK8, and TNF) compared to control inhibitors. In combination, our results identified significant targets and pharmacological mechanisms of kaempferol in the treatment of COVID-19/CHIK and recommended that core targets be used as potential biomarkers against COVID-19/CHIK viruses. Before conducting clinical studies for the intervention of COVID-19 and CHIK, kaempferol might be evaluated in wet lab tests at the molecular level.

The TP53 Gene and COVID-19 Virus: A Correlation Analysis

Aim: This study aimed to discover the most effective anti-cancer medicine for cancer patients infected with SARS-CoV-2. Background: The correlation between TP53 and SARS-CoV-2 was examined using biomolecular networking analysis. Objective: Cancer patients with TP53 gene mutations are more likely to be infected with the SARS-CoV-2 virus since it is the most frequently mutated tumor suppressor gene in human cancer. The main goal of this study is to discover the most effective and efficient anti-cancer therapy for patients with SARS-CoV-2 infection. Materials and Methods: Topp gene analysis was used to prioritize candidate genes based on molecular function, biological process, and pathway analysis. Biomolecular networking was carried out using Cytoscape 2.8.2. The protein-protein interaction network was used to identify the functionally associated proteins. The protein-drug interaction network was used to observe the molecular therapeutic efficiency of drugs. The network was further analyzed using CytoHubba to find the hub nodes. The molecular docking was used to study the protein-ligand interaction, and the protein-ligand complex was further evaluated through molecular dynamic simulation to determine its stability. Results: Functionally relevant genes were prioritized through Toppgene analysis. Using Cytohabba, it was found that the genes UBE2N, BRCA1, BARD1, TP53, and DPP4 had a high degree and centrality score. The drugs 5-fluorouracil, Methotrexate, Temozolomide, Favipiravir, and Levofloxacin have a substantial association with the hub protein, according to protein-drug interaction analysis. Finally, a docking study revealed that 5-fluorouracil has the highest connection value and stability compared to Methotrexate, Favipiravir, and Levofloxacin. Conclusion: The biomolecular networking study was used to discover the link between TP53 and SARS-CoV-2, and it was found that 5-fluorouracil had a higher affinity for binding to TP53 and its related genes, such as UBE2N, BRCA1, RARD1, and SARS-CoV-2 specific DPP4. For cancer patients with TP53 gene mutations and Covid-19 infection, this treatment is determined to be the most effective. © 2022 Bentham Science Publishers.

Diagnostic Efficacy of CT Examination on Early Detection of Lung Cancer during Pandemic of COVID-19.

BACKGROUND: Since the outbreak of COVID-19 in 2020, routine CT examination was recommended to hospitalized patients at some hospitals and discovered lung cancer patients at an early stage. This study aimed to investigate the detection efficacy of routine CT examination on early diagnosis of lung cancer, especially on pathological characteristics. METHODS: The epidemic of COVID-19 outbreak in January 2020 in China, and routine CT examination was recommended to hospitalized patients in June 2020 and ended in July 2021. Based on the time points, we compared the diagnosis efficacy between three periods: pre-period, peri-period, and the period of routine CT examination. RESULTS: During the period of routine CT examination, more early stages of lung cancer were detected and the tumor size was reduced to 2.14 cm from 3.21 cm at pre-period (p = 0.03). The proportion of lung adenocarcinoma and early stage adenocarcinoma was increased by 12% and 30% in the period of routine CT examination, with referral to the pre-period of CT examination (p < 0.05). A total of 61% of diagnosed patients had the wild type of TP53 gene during the period of routine CT examination, compared to 45% of patients at the pre-period of CT examination (p = 0.001). The median Ki-67 index was 15% among patients diagnosed at the period of routine CT examination and increased to 35% at the pre-period of CT examination (p < 0.001). The period of routine CT examination was associated with a 78% higher probability of detecting an early stage of adenocarcinoma (OR = 1.78, 95%CI 1.03, 3.08) but no significant association was observed for squamous cell carcinoma. From the pre-period to the period of routine CT examination, the proportion of female patients and non-smoking patients increased by 57% and 44%, respectively (p < 0.001). CONCLUSION: Routine CT examination could detect more lung cancer at an early stage, especially for adenocarcinoma, and detect patients with less aggressive features. Further studies were warranted to confirm the findings.

TP53 Gene Therapy as a Potential Treatment for Patients with COVID-19.

SGT-53 is a novel investigational agent that comprises an immunoliposome carrying a plasmid vector driving expression of the human TP53 gene that encodes wild-type human p53. SGT-53 is currently in phase II human trials for advanced pancreatic cancer. Although p53 is best known as a tumor suppressor, its participation in both innate and adaptive immune responses is well documented. It is now clear that p53 is an important component of the host response to various viral infections. To facilitate their viral life cycles, viruses have developed a diverse repertoire of strategies for counteracting the antiviral activities of host immune system by manipulating p53-dependent pathways in host cells. Coronaviruses reduce endogenous p53 levels in the cells they infect by enhancing the degradation of p53 in proteasomes. Thus, interference with p53 function is an important component in viral pathogenesis. Transfection of cells by SGT-53 has been shown to transiently produce exogenous p53 that is active as a pleiotropic transcription factor. We herein summarize the rationale for repurposing SGT-53 as a therapy for infection by SARS-CoV-2, the pathogen responsible for the COVID-19 pandemic. Because p53 regulation was found to play a crucial role in different infection stages of a wide variety of viruses, it is rational to believe that restoring p53 function based on SGT-53 treatment may lead to beneficial therapeutic outcomes for infectious disease at large including heretofore unknown viral pathogens that may emerge in the future.

MYC Expression Is Associated With p53 Expression and TP53 Aberration and Predicts Poor Overall Survival in Acute Lymphoblastic Leukemia/Lymphoma.

OBJECTIVES: We evaluated MYC and p53 expression, TP53 aberration, their relationship, and their impact on overall survival (OS) in acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL). METHODS: We identified 173 patients with ALL and LBL, including 12 cases of mixed-phenotype acute leukemia, 8 cases of therapy-related B-cell ALL (B-ALL), 119 cases of B-ALL, and 34 cases of T-cell ALL/LBL diagnosed from 2003 to 2019. We retrospectively assessed p53 and MYC expression by immunohistochemistry of bone marrow and correlated MYC expression with p53 expression and TP53 aberration. RESULTS: Expression of p53 and MYC was present in 11.5% and 27.7% of ALL/LBL cases (n = 20 and n = 48), respectively. MYC expression was significantly correlated with p53 expression and TP53 aberration (P = .002 and P = .03), and p53 expression and MYC expression had an adverse impact on OS in patients with ALL/LBL (P < .05). MYC and p53 dual expression as well as combined MYC expression and TP53 aberration had a negative impact on OS in patients with ALL/LBL. CONCLUSIONS: MYC expression is correlated with p53 overexpression, TP53 aberration, and poor OS in patients with ALL/LBL.

Analysis of SARS-CoV-2 infection associated cell entry proteins ACE2, CD147, PPIA, and PPIB in datasets from non SARS-CoV-2 infected neuroblastoma patients, as potential prognostic and infection biomarkers in neuroblastoma.

SARS-CoV-2 viral contagion has given rise to a worldwide pandemic. Although most children experience minor symptoms from SARS-CoV-2 infection, some have severe complications including Multisystem Inflammatory Syndrome in Children. Neuroblastoma patients may be at higher risk of severe infection as treatment requires immunocompromising chemotherapy and SARS-CoV-2 has demonstrated tropism for nervous cells. To date, there is no sufficient epidemiological data on neuroblastoma patients with SARS-CoV-2. Therefore, we evaluated datasets of non-SARS-CoV-2 infected neuroblastoma patients to assess for key genes involved with SARS-CoV-2 infection as possible neuroblastoma prognostic and infection biomarkers. We hypothesized that ACE2, CD147, PPIA and PPIB, which are associated with viral-cell entry, are potential biomarkers for poor prognosis neuroblastoma and SARS-CoV-2 infection. We have analysed three publicly available neuroblastoma gene expression datasets to understand the specific molecular susceptibilities that high-risk neuroblastoma patients have to the virus. Gene Expression Omnibus (GEO) GSE49711 and GEO GSE62564 are the microarray and RNA-Seq data, respectively, from 498 neuroblastoma samples published as part of the Sequencing Quality Control initiative. TARGET, contains microarray data from 249 samples and is part of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. ACE2, CD147, PPIA and PPIB were identified through their involvement in both SARS-CoV-2 infection and cancer pathogenesis. In-depth statistical analysis using Kaplan-Meier, differential gene expression, and Cox multivariate regression analysis, demonstrated that overexpression of ACE2, CD147, PPIA and PPIB is significantly associated with poor-prognosis neuroblastoma samples. These results were seen in the presence of amplified MYCN, unfavourable tumour histology and in patients older than 18 months of age. Previously, we have shown that high levels of the nerve growth factor receptor NTRK1 together with low levels of the phosphatase PTPN6 and TP53 are associated with increased relapse-free survival of neuroblastoma patients. Interestingly, low levels of expression of ACE2, CD147, PPIA and PPIB are associated with this NTRK1-PTPN6-TP53 module, suggesting that low expression levels of these genes are associated with good prognosis. These findings have implications for clinical care and therapeutic treatment. The upregulation of ACE2, CD147, PPIA and PPIB in poor-prognosis neuroblastoma samples suggests that these patients may be at higher risk of severe SARS-CoV-2 infection. Importantly, our findings reveal ACE2, CD147, PPIA and PPIB as potential biomarkers and therapeutic targets for neuroblastoma.

Structural similarity-based prediction of host factors associated with SARS-CoV-2 infection and pathogenesis.

The current pandemic resulted from SARS-CoV-2 still remains as the major public health concern globally. The precise mechanism of viral pathogenesis is not fully understood, which remains a major hurdle for medical intervention. Here we generated an interactome profile of protein-protein interactions based on host and viral protein structural similarities information. Further computational biological study combined with Gene enrichment analysis predicted key enriched pathways associated with viral pathogenesis. The results show that axon guidance, membrane trafficking, vesicle-mediated transport, apoptosis, clathrin-mediated endocytosis, Vpu mediated degradation of CD4 T cell, and interferon-gamma signaling are key events associated in SARS-CoV-2 life cycle. Further, degree centrality analysis reveals that IRF1/9/7, TP53, and CASP3, UBA52, and UBC are vital proteins for IFN-γ-mediated signaling, apoptosis, and proteasomal degradation of CD4, respectively. We crafted chronological events of the virus life cycle. The SARS-CoV-2 enters through clathrin-mediated endocytosis, and the genome is trafficked to the early endosomes in a RAB5-dependent manner. It is predicted to replicate in a double-membrane vesicle (DMV) composed of the endoplasmic reticulum, autophagosome, and ERAD machinery. The SARS-CoV-2 down-regulates host translational machinery by interacting with protein kinase R, PKR-like endoplasmic reticulum kinase, and heme-regulated inhibitor and can phosphorylate eIF2a. The virion assembly occurs in the ER-Golgi intermediate compartment (ERGIC) organized by the spike and matrix protein. Collectively, we have established a spatial link between viral entry, RNA synthesis, assembly, pathogenesis, and their associated diverse host factors, those could pave the way for therapeutic intervention.

TMPRSS2, a SARS-CoV-2 internalization protease is downregulated in head and neck cancer patients.

BACKGROUND: SARS-coronavirus-2 enters host cells through binding of the Spike protein to ACE2 receptor and subsequent S priming by the TMPRSS2 protease. We aim to assess differences in both ACE2 and TMPRSS2 expression in normal tissues from oral cavity, pharynx, larynx and lung tissues as well as neoplastic tissues from the same areas. METHODS: The study has been conducted using the TCGA and the Regina Elena Institute databases and validated by experimental model in HNSCC cells. We also included data from one COVID19 patient who went under surgery for HNSCC. RESULTS: TMPRSS2 expression in HNSCC was significantly reduced compared to the normal tissues. It was more evident in women than in men, in TP53 mutated versus wild TP53 tumors, in HPV negative patients compared to HPV positive counterparts. Functionally, we modeled the multivariate effect of TP53, HPV, and other inherent variables on TMPRSS2. All variables had a statistically significant independent effect on TMPRSS2. In particular, in tumor tissues, HPV negative, TP53 mutated status and elevated TP53-dependent Myc-target genes were associated with low TMPRSS2 expression. The further analysis of both TCGA and our institutional HNSCC datasets identified a signature anti-correlated to TMPRSS2. As proof-of-principle we also validated the anti-correlation between microRNAs and TMPRSS2 expression in a SARS-CoV-2 positive HNSCC patient tissues Finally, we did not find TMPRSS2 promoter methylation. CONCLUSIONS: Collectively, these findings suggest that tumoral tissues, herein exemplified by HNSCC and lung cancers might be more resistant to SARS-CoV-2 infection due to reduced expression of TMPRSS2. These observations may help to better assess the frailty of SARS-CoV-2 positive cancer patients.