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Pamidimukkala JV, Parthasarathy BR, Senapati S. Decoding potential host protein targets against Flaviviridae using protein-protein interaction network. Int J Biol Macromol 2025:143217. [PMID: 40250655 DOI: 10.1016/j.ijbiomac.2025.143217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 04/07/2025] [Accepted: 04/14/2025] [Indexed: 04/20/2025]
Abstract
Flaviviridae family comprises some of the most vulnerable viruses known for causing widespread outbreaks, high mortality rates, and severe long-term health complications in humans. Viruses like Dengue (DENV), Zika (ZIKV) and Hepatitis C (HCV) are endemic across the globe, especially in tropical and subtropical regions, infecting multiple tissues and leading to significant health crises. Investigating virus-host interactions across tissues can reveal tissue-specific drug targets and aid antiviral drug repurposing. In this study, we employed a multi-step computational approach to construct a comprehensive virus-human interactome by integrating virus-host protein-protein interactions (PPIs) with tissue-specific gene expression profiles to study key protein targets associated with Flaviviridae infections. Mapping drug-target predictions revealed druggable proteins - CCNA2 in peripheral blood mononuclear cells (PBMC) and EIF2S2, CDK7 and CARS in the liver, with Tamoxifen, Sirolimus, Entrectinib and L-cysteine as potential repurposable drugs, respectively. Further protein-ligand docking and molecular dynamics (MD) simulations were conducted to assess the stability of the complexes. These findings highlight common druggable human targets exploited by DENV, ZIKV and HCV, providing a foundation for broad-spectrum antiviral therapies. By focusing on shared host pathways and targets in viral replication, we propose promising drug candidates, supporting the development of unified therapeutic strategies against Flaviviridae viruses.
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Affiliation(s)
- Jaya Vasavi Pamidimukkala
- Department of Biotechnology and BJM School of Biosciences, Indian Institute of Technology Madras, Chennai 600036, India
| | - Bharath Raj Parthasarathy
- Department of Biotechnology and BJM School of Biosciences, Indian Institute of Technology Madras, Chennai 600036, India
| | - Sanjib Senapati
- Department of Biotechnology and BJM School of Biosciences, Indian Institute of Technology Madras, Chennai 600036, India.
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Lu JL, Cheng Y, Xu ZL, Qian GX, Wei MT, Jia WD. Immune checkpoint inhibitors plus anti-angiogenesis in patients with resected high-risk hepatitis B virus-associated hepatocellular carcinoma. World J Gastrointest Oncol 2025; 17:101371. [PMID: 40235869 PMCID: PMC11995358 DOI: 10.4251/wjgo.v17.i4.101371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 01/25/2025] [Accepted: 02/13/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Currently, there is a lack of effective adjuvant therapies for patients at high-risk of recurrent hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) after radical resection. Given the efficacy of anti-programmed death 1/anti-programmed death ligand 1 plus anti-vascular endothelial growth factor receptor agents in advanced HCC, we conducted this study to investigate the efficacy of this combination regimen in the postoperative adjuvant treatment of patients with HBV-HCC. AIM To evaluate the value of postoperative combined therapy (PCT) with anti-programmed death 1/anti-programmed death ligand 1 and anti-vascular endothelial growth factor receptor agents in patients with HBV-HCC. METHODS Patients with HBV-HCC who underwent radical resection surgery at Anhui Provincial Hospital Affiliated to Anhui Medical University between July 2020 and April 2023 were included. Recurrence-free survival (RFS) and overall survival were assessed using propensity score matching and inverse probability of treatment weighting. Cox regression analysis was used to identify factors affecting recurrence, and subgroup analysis was conducted to investigate the impact of medications on different populations. Treatment-related adverse events and liver function measurements were evaluated. RESULTS A total of 150 patients were recruited, of whom 30 underwent PCT and 120 did not. After adjusting for confounders, patients who underwent PCT had better RFS at 6 and 12 months than those who did not (P > 0.05). Similar results were observed in the Kaplan-Meier curves after propensity score matching or inverse probability of treatment weighting, although the difference was not statistically significant (P > 0.05). A maximum diameter of > 5 cm, vascular invasion, satellite nodules, and high gamma-glutamyl transferase levels were independent risk factors for recurrence (P < 0.05). No significant interaction effects were observed in subgroup analyses. The most prevalent adverse event was hypertension (66.7%). PCT was associated with an increased risk of hepatic impairment which may predict RFS rates (P = 0.041). CONCLUSION The recurrence rate was not significantly reduced in patients who underwent PCT. Hepatic impairment during treatment may indicate recurrence, and close monitoring of liver function and HBV infection is recommended.
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Affiliation(s)
- Jian-Lin Lu
- Department of Hepatic Surgery, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei 230001, Anhui Province, China
| | - Yuan Cheng
- Department of Hepatic Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230001, Anhui Province, China
| | - Zi-Ling Xu
- Department of Hepatic Surgery, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei 230001, Anhui Province, China
| | - Gui-Xiang Qian
- Department of Hepatic Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230001, Anhui Province, China
| | - Ming-Tong Wei
- Department of Hepatic Surgery, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei 230001, Anhui Province, China
| | - Wei-Dong Jia
- Department of Hepatic Surgery, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei 230001, Anhui Province, China
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Toubanaki DK, Tzortzatos OP, Efstathiou A, Bakopoulos V, Karagouni E. Influence of Viral Re-Infection on Head Kidney Transcriptome of Nervous Necrosis Virus-Resistant and -Susceptible European Sea Bass ( Dicentrarchus labrax, L.). Viruses 2025; 17:230. [PMID: 40006985 PMCID: PMC11860166 DOI: 10.3390/v17020230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 02/04/2025] [Accepted: 02/05/2025] [Indexed: 02/27/2025] Open
Abstract
Fish viral infections have great environmental and economic implications in aquaculture. Nervous necrosis virus (NNV) is a pathogen affecting more than 120 different species, causing high mortality and morbidity. Herein, we study how NNV re-infection affects the European sea bass (Dicentrarchus labrax, L.) head kidney transcriptome in disease-resistant and -susceptible sea bass families. To determine how each family responds to re-infection, we performed the RNA-sequencing analysis of experimentally NNV-infected D. labrax. Fish were experimentally infected in a long-term study, and one month after the last recorded death, all surviving fish were re-infected by the same NNV strain. Fish tissues were sampled 7 days upon re-infection. The transcriptome profiles of infected vs. non-infected fish revealed 103 differentially expressed genes (DEGs) for the resistant family and 336 DEGs for the susceptible family. Only a few pathways were commonly enriched in the two families, further indicating that the resistant and susceptible families utilize completely different mechanisms to fight the NNV re-infection. Protein-protein interaction analysis identified a variety of hub genes for the resistant and the susceptible families, quite distinct in their function on NNV resistance. In conclusion, NNV-resistant and -sensitive sea bass transcriptomes were analyzed following NNV survivors' viral re-infection, offering a glimpse into how host attempts to control the infection depending on its genetic background in relation with virus resistance.
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Affiliation(s)
- Dimitra K. Toubanaki
- Immunology of Infection Group, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece; (O.-P.T.); (A.E.)
| | - Odysseas-Panagiotis Tzortzatos
- Immunology of Infection Group, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece; (O.-P.T.); (A.E.)
| | - Antonia Efstathiou
- Immunology of Infection Group, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece; (O.-P.T.); (A.E.)
| | - Vasileios Bakopoulos
- Department of Marine Sciences, School of The Environment, University of the Aegean, University Hill, Lesvos, 81100 Mytilene, Greece;
| | - Evdokia Karagouni
- Immunology of Infection Group, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece; (O.-P.T.); (A.E.)
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Datta S, Sarkar I, Goswami N, Mahanta S, Borah P, Sen A. Phytocompounds from Phyllanthus acidus (L.) Skeels in the management of Monkeypox Virus infections. J Biomol Struct Dyn 2025; 43:1083-1100. [PMID: 38079302 DOI: 10.1080/07391102.2023.2291166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 11/20/2023] [Indexed: 01/01/2025]
Abstract
Monkeypox is a communicable disease similar to smallpox, primarily occurring in African countries. However, recently it has spread to countries outside Africa and may arise as the next threat after COVID-pandemic. The causative organism, i.e. Monkeypox Virus (MPV) spreads from one individual to another primarily through inhalation of respiratory droplets or through contact with skin lesions of infected individuals. No known drugs are available specifically for MPV. Due to its similarity with smallpox, treatment of monkeypox is being attempted through the administration of the smallpox vaccine. Therefore, we evaluated the efficacy of the plant Phyllanthus acidus against MPV since it is traditionally used in the treatment of chickenpox and smallpox. Through functional annotation, PASS prediction and Network pharmacology analysis, the effectiveness of these chosen P. acidus-derived phytocompounds against MPV was confirmed. Target prediction of the phytocompounds identified in GC-MS analysis of the plant extract showed them to be associated with 76 human proteins. The compounds also show good binding affinity with selected viral proteins: DNA polymerase (DNApol), Putative Virulence Factor (vPVF) and Cytokine Binding Protein. Prediction of Activity Spectra for Substances (PASS) and functional annotation of the target proteins further support their antiviral nature through interaction with these proteins. The compounds were found to modulate pathways related to symptoms of viral infection and this may help in maintaining homeostasis. Our study demonstrates antiviral activity as well as the therapeutic potential of the plant against MPV infection.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Sutapa Datta
- Department of Botany, Molecular Genetics Laboratory, University of North Bengal, Siliguri, India
| | - Indrani Sarkar
- Bioinformatics Facility, University of North Bengal, Siliguri, India
| | - Nabajyoti Goswami
- Department of Bioengineering and Technology, Gauhati University, Guwahati, India
- National Institute of Electronics and Information Technology (NIELIT) Guwahati, Assam Financial Corporation Building (1st and 2nd Floor), Guwahati, India
| | - Saurov Mahanta
- National Institute of Electronics and Information Technology (NIELIT) Guwahati, Assam Financial Corporation Building (1st and 2nd Floor), Guwahati, India
| | - Probodh Borah
- Department of Animal Biotechnology, College of Veterinary Science, Assam Agricultural University, Guwahati, India
| | - Arnab Sen
- Department of Botany, Molecular Genetics Laboratory, University of North Bengal, Siliguri, India
- Bioinformatics Facility, University of North Bengal, Siliguri, India
- Biswa Bangla Genome Centre, University of North Bengal, Siliguri, India
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Javid N, Abdoli S, Shahbazi M. Rational strategies for designing next-generation oncolytic viruses based on transcriptome analysis of tumor cells infected with oncolytic herpes simplex virus-1. Front Oncol 2025; 14:1469511. [PMID: 39850819 PMCID: PMC11754274 DOI: 10.3389/fonc.2024.1469511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 12/09/2024] [Indexed: 01/25/2025] Open
Abstract
Introduction Oncolytic herpes simplex viruses (oHSVs) are a type of biotherapeutic utilized in cancer therapy due to their ability to selectively infect and destroy tumor cells without harming healthy cells. We sought to investigate the functional genomic response and altered metabolic pathways of human cancer cells to oHSV-1 infection and to elucidate the influence of these responses on the relationship between the virus and the cancer cells. Methods Two datasets containing gene expression profiles of tumor cells infected with oHSV-1 (G207) and non-infected cells from the Gene Expression Omnibus (GEO) database were processed and normalized using the R software. Common differentially expressed genes between datasets were selected to identify hub genes and were further analyzed. Subsequently, the expression of hub genes was verified by real-time polymerase chain reaction (qRT-PCR) in MDA-MB-231 (a breast cancer cell line) infected with oHSV-1 and non-infected cells. Results The results of our data analysis indicated notable disparities in the genes associated with the proteasome pathway between infected and non-infected cells. Our ontology analysis revealed that the proteasome-mediated ubiquitin-dependent protein catabolic process was a significant biological process, with a p-value of 5.8E-21. Additionally, extracellular exosomes and protein binding were identified as significant cellular components and molecular functions, respectively. Common hub genes with degree and maximum neighborhood component (MNC) methods, including PSMD2, PSMD4, PSMA2, PSMD14, PSMD11, PSMC3, PSMC2, PSMD8, and PSMA4, were also identified. Analysis of gene expression by qRT-PCR and differential gene expression revealed that GADD45g genes can be effective genes in the proliferation of oncolytic HSV-1 virus. Conclusion The transcriptome changes in tumor cells infected by oHSV-1 may be utilized to predict oncolytic efficacy and provide rational strategies for designing next-generation oncolytic viruses.
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Affiliation(s)
- Naeme Javid
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Shahriyar Abdoli
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Majid Shahbazi
- Medical Cellular and Molecular Research Center, Golestan University of Medical Sciences, Gorgan, Iran
- AryaTina Gene (ATG) Biopharmaceutical Company Gorgan, Gorgan, Iran
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Al-Kuraishy HM, Al-Gareeb AI, Al-Maiahy TJ, Alexiou A, Mukerjee N, Batiha GES. An insight into the placental growth factor (PlGf)/angii axis in Covid-19: a detrimental intersection. Biotechnol Genet Eng Rev 2024; 40:3326-3345. [PMID: 36096720 DOI: 10.1080/02648725.2022.2122291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 07/29/2022] [Indexed: 11/02/2022]
Abstract
Coronavirus disease 2019 (Covid-19) is a recent and current infectious pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). Covid-19 may lead to the development of acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and extrapulmonary manifestations in severe cases. Down-regulation of angiotensin-converting enzyme (ACE2) by the SARS-CoV-2 increases the production of angiotensin II (AngII), which increases the release of pro-inflammatory cytokines and placental growth factor (PlGF). PlGF is a critical molecule involved in vasculogenesis and angiogenesis. PlGF is stimulated by AngII in different inflammatory diseases through a variety of signaling pathways. PlGF and AngII are interacted in SARS-CoV-2 infection resulting in the production of pro-inflammatory cytokines and the development of Covid-19 complications. Both AngII and PlGF are interacted and are involved in the progression of inflammatory disorders; therefore, we aimed in this review to highlight the potential role of the PlGF/AngII axis in Covid-19.
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Affiliation(s)
- Hayder M Al-Kuraishy
- Department of Clinical Pharmacology and Medicine, College of Medicine, ALmustansiriyia University, Baghdad, Iraq
| | - Ali I Al-Gareeb
- Department of Clinical Pharmacology and Medicine, College of Medicine, ALmustansiriyia University, Baghdad, Iraq
| | - Thabat J Al-Maiahy
- Department Of Gynecology and Obstetrics, College of Medicine, Al-Mustansiriyah University, Baghdad, Iraq
| | - Athanasios Alexiou
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, NSW 2770, Australia
- AFNP Med, Austria, Wien, Austria
| | - Nobendu Mukerjee
- Department of Microbiology; Ramakrishna Mission Vivekananda Centenary College, Kolkata, WestBengal, India
- Department of Health Sciences, Novel Global Community Educational Foundation, Hebersham, NSW 2770, Australia
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, AlBeheira, Egypt
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Sánchez-Martínez C, Grueso E, Calvo-López T, Martinez-Ortega J, Ruiz A, Almendral JM. VEGF-Virus Interactions: Pathogenic Mechanisms and Therapeutic Applications. Cells 2024; 13:1815. [PMID: 39513922 PMCID: PMC11545703 DOI: 10.3390/cells13211815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 10/16/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024] Open
Abstract
Many types of viruses directly or indirectly target the vascular endothelial growth factor (VEGF) system, which is a central regulator of vasculogenesis and angiogenesis in physiological homeostasis, causing diverse pathologies. Other viruses have been developed into effective therapeutic tools for VEGF modulation in conditions such as cancer and eye diseases. Some viruses may alter the levels of VEGF in the pathogenesis of respiratory syndromes, or they may encode VEGF-like factors, promoting vascular disruption and angiogenesis to enable viruses' systemic spread. Oncogenic viruses may express interactive factors that perturb VEGF's functional levels or downstream signaling, which increases the neovascularization and metastasis of tumors. Furthermore, many viruses are being developed as therapeutic vectors for vascular pathologies in clinical trials. Major examples are those viral vectors that inhibit the role of VEGF in the neovascularization required for cancer progression; this is achieved through the induction of immune responses, by exposing specific peptides that block signaling or by expressing anti-VEGF and anti-VEGF receptor-neutralizing antibodies. Other viruses have been engineered into effective pro- or anti-angiogenesis multitarget vectors for neovascular eye diseases, paving the way for therapies with improved safety and minimal side effects. This article critically reviews the large body of literature on these issues, highlighting those contributions that describe the molecular mechanisms, thus expanding our understanding of the VEGF-virus interactions in disease and therapy. This could facilitate the clinical use of therapeutic virus vectors in precision medicine for the VEGF system.
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Affiliation(s)
- Cristina Sánchez-Martínez
- Biosciences Research Institute, School of Experimental Sciences, Universidad Francisco de Vitoria, Pozuelo de Alarcón, 28223 Madrid, Spain; (C.S.-M.); (E.G.)
| | - Esther Grueso
- Biosciences Research Institute, School of Experimental Sciences, Universidad Francisco de Vitoria, Pozuelo de Alarcón, 28223 Madrid, Spain; (C.S.-M.); (E.G.)
| | - Tania Calvo-López
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Cantoblanco, 28049 Madrid, Spain or (T.C.-L.); (J.M.-O.); (A.R.)
- Departamento de Biología Molecular, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
- Department of Biomedicine, Centro de Investigaciones Biológicas Margarita Salas (CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain
| | - Jorge Martinez-Ortega
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Cantoblanco, 28049 Madrid, Spain or (T.C.-L.); (J.M.-O.); (A.R.)
- Departamento de Biología Molecular, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
| | - Ana Ruiz
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Cantoblanco, 28049 Madrid, Spain or (T.C.-L.); (J.M.-O.); (A.R.)
- Departamento de Biología Molecular, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
| | - José M. Almendral
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Cantoblanco, 28049 Madrid, Spain or (T.C.-L.); (J.M.-O.); (A.R.)
- Departamento de Biología Molecular, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
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Xiao G, Huang X, Huang T, Chen Z, Huang Y, Huang R, Wang X. Hepatitis B virus X protein differentially regulates the angiogenesis of Hepatocellular Carcinoma through p53-VEGF axis according to glucose levels. Ann Hepatol 2024; 29:101543. [PMID: 39216627 DOI: 10.1016/j.aohep.2024.101543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 06/07/2024] [Accepted: 06/13/2024] [Indexed: 09/04/2024]
Abstract
INTRODUCTION AND OBJECTIVES Blood glucose fluctuates severely in the diabetes (DM) and tumor microenvironment. Our previous works have found Hepatitis B virus X protein (HBx) differentially regulated metastasis and apoptosis of hepatoma cells depending on glucose concentration. We here aimed to explore whether HBx played dual roles in the angiogenesis of hepatocellular carcinoma varying on different glucose levels. MATERIALS AND METHODS We collected conditioned medium from HBx-overexpressing cells cultured with two solubilities of glucose, and then applied to EA.hy926 cells. Alternatively, a co-culture cell system was established with hepatoma cells and EA.hy926 cells. We analyzed the angiogenesis of EA.hy926 cells with CCK8, wound-healing, transwell-migartion and tube formation experiment. ELISA was conducted to detect the secretion levels of angiogenesis-related factors. siRNAs were used to detect the P53-VEGF axis. RESULTS HBx expressed in hepatoma cells suppressed VEGF secretion, and subsequently inhibited the proliferation, migration and tube formation of EA.hy926 cells in a high glucose condition, while attenuating these in the lower glucose condition. Furthermore, the p53-VEGF axis was required for the dual role of HBx in angiogenesis. Additionally, HBx mainly regulated the nuclear p53. CONCLUSIONS These data suggest that the dual roles of HBx confer hepatoma cells to remain in a glucose-rich environment and escape from the glucose-low milieu through tumor vessels, promoting liver tumor progression overall. We exclusively revealed the dual role of HBx on the angiogenesis of liver tumors, which may shed new light on the mechanism and management strategy of HBV- and DM-related hepatocellular carcinoma.
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Affiliation(s)
- Guitao Xiao
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, 29, Xinquan Road, Gulou, Fuzhou, Fujian 350001, PR China; Department of Cardiology, Longyan First Affiliated Hospital of Fujian Medical University, 105, Jiuyibei Road, Xin Luo, Longyan, Fujian 364000, PR China
| | - Xiaoyun Huang
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, 29, Xinquan Road, Gulou, Fuzhou, Fujian 350001, PR China; Fujian Medical University Cancer Center, Fujian Medical University, 1, Xuefubei Road, Minhou, Fuzhou, Fujian 350001, PR China
| | - Tingxuan Huang
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, 29, Xinquan Road, Gulou, Fuzhou, Fujian 350001, PR China
| | - Zhixin Chen
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, 29, Xinquan Road, Gulou, Fuzhou, Fujian 350001, PR China
| | - Yuehong Huang
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, 29, Xinquan Road, Gulou, Fuzhou, Fujian 350001, PR China
| | - Rongfeng Huang
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, 29, Xinquan Road, Gulou, Fuzhou, Fujian 350001, PR China; Fujian Medical University Cancer Center, Fujian Medical University, 1, Xuefubei Road, Minhou, Fuzhou, Fujian 350001, PR China.
| | - Xiaozhong Wang
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, 29, Xinquan Road, Gulou, Fuzhou, Fujian 350001, PR China; Fujian Medical University Cancer Center, Fujian Medical University, 1, Xuefubei Road, Minhou, Fuzhou, Fujian 350001, PR China.
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Ghose S, Roy S, Ghosh V, Sharawat SK, Pramanik R, Biswas S, Biswas A. The plasma EBV DNA load with IL-6 and VEGF levels as predictive and prognostic biomarker in nasopharyngeal carcinoma. Virol J 2024; 21:224. [PMID: 39304953 PMCID: PMC11414088 DOI: 10.1186/s12985-024-02473-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Accepted: 08/15/2024] [Indexed: 09/22/2024] Open
Abstract
Nasopharyngeal carcinoma (NPC) is often diagnosed at a very advanced stage due to its location and non-specific initial symptoms. Moreover, no clinically useful serological marker has been established so far for early detection of NPC. In this study, we have investigated the clinical significance of plasma Epstein-Barr virus DNA load along with interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) levels to evaluate if these three all together can be useful as a strong serological marker for early detection and prediction of treatment response in patients with NPC. Plasma EBV DNA load, IL-6 level, VEGF expressions were measured in 24 patients with NPC at presentation and various time points during and after treatment. There was a positive correlation between high plasma EBV DNA load with higher IL-6 and VEGF expression, which was closely associated with therapeutic response as well. Persistent or recurrent plasma EBV load with higher IL-6 and VEGF levels can potentially predict disease progression and may be useful to select patients for additional therapy and longer follow-up.
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Affiliation(s)
- Sampa Ghose
- Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, 110029, India.
| | - Swarnaditya Roy
- Department of Radiotherapy and Oncology, All India Institute of Medical Sciences, New Delhi, India
| | - Vivek Ghosh
- Department of Radiotherapy and Oncology, All India Institute of Medical Sciences, New Delhi, India
| | - Surender K Sharawat
- Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Raja Pramanik
- Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Subhrajit Biswas
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida, UP, India
| | - Ahitagni Biswas
- Department of Radiotherapy and Oncology, All India Institute of Medical Sciences, New Delhi, India
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Gazzini S, Cerullo R, Soloperto D. VEGF as a Key Actor in Recurrent Respiratory Papillomatosis: A Narrative Review. Curr Issues Mol Biol 2024; 46:6757-6768. [PMID: 39057045 PMCID: PMC11275356 DOI: 10.3390/cimb46070403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 06/20/2024] [Accepted: 06/25/2024] [Indexed: 07/28/2024] Open
Abstract
Recurrent respiratory papillomatosis (RRP) is a benign disease of the upper aerodigestive tract caused by human papillomavirus (HPV) types 6 and 11. The clinical course is unpredictable and some patients, especially younger children, experience a high rate of recurrence with a significant impact on their quality of life. The molecular mechanisms of HPV infection in keratinocytes have been extensively studied throughout the years, with particular regard to its role in causing malignant tumors, like cervical cancer and head and neck carcinomas. A minor but not negligible amount of the literature has investigated the molecular landscape of RRP patients, and some papers have studied the role of angiogenesis (the growth of blood vessels from pre-existing vasculature) in this disease. A central role in this process is played by vascular endothelial growth factor (VEGF), which activates different signaling cascades on multiple levels. The increased knowledge has led to the introduction of the VEGF inhibitor bevacizumab in recent years as an adjuvant treatment in some patients, with good results. This review summarizes the current evidence about the role of VEGF in the pathophysiology of RRP, the molecular pathways activated by binding with its receptors, and the current and future roles of anti-angiogenic treatment.
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Affiliation(s)
- Sandra Gazzini
- Division of Otolaryngology, Head and Neck Surgery Department, University Hospital of Verona, 37134 Verona, Italy
| | - Raffaele Cerullo
- Division of Otolaryngology, Hospital of Treviso, 31100 Treviso, Italy
| | - Davide Soloperto
- Department of Otorhinolaryngology, University Hospital of Modena, 41125 Modena, Italy
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Smahelova J, Pokryvkova B, Stovickova E, Grega M, Vencalek O, Smahel M, Koucky V, Malerova S, Klozar J, Tachezy R. Aspartate-β-hydroxylase and hypoxia marker expression in head and neck carcinomas: implications for HPV-associated tumors. Infect Agent Cancer 2024; 19:26. [PMID: 38858774 PMCID: PMC11163809 DOI: 10.1186/s13027-024-00588-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 05/28/2024] [Indexed: 06/12/2024] Open
Abstract
BACKGROUND A proportion of head and neck carcinomas (HNSCCs) are induced by high-risk human papillomaviruses (HPVs) and are associated with better patient outcomes compared to patients with HNSCCs related to tobacco and alcohol abuse. In the microenvironment of solid tumors, including HNSCCs, oxygen levels are often reduced, and a hypoxic state is induced. This can lead to a poor treatment response and a worse patient prognosis. One of the hypoxia-responsive genes is aspartate-β-hydroxylase (ASPH), whose activity promotes the growth, invasiveness, and metastasis of many types of solid tumors. METHODS In our study, HNSCC samples were analyzed for the expression of ASPH and selected endogenous hypoxia markers by real-time PCR and/or multiplex fluorescence immunohistochemistry. RESULTS Except for the EPAS1 gene, which had higher mRNA expression in the HPV-negative group of HNSCC (p < 0.05), we found no other differences in the expression of the tested genes that were related to HPV status. On the contrary, a statistically significantly higher number of cells producing ASPH (p < 0.0001), HIF1A (p < 0.0001), GLUT1 (p < 0.0001), and MMP13 (p < 0.05) proteins were detected in the HPV-positive tumor group than in the HPV-negative sample group. All the evaluated markers, except for MMP9/13, were more abundant in the tumor parenchyma than in the tumor stroma. The Cox proportional hazard models showed that increased numbers of cells with GLUT1 and HIF1A protein expression were positive prognostic markers for overall and disease-specific survival in patients independent of HPV tumor status. CONCLUSION The study examined HNSCC samples and found that elevated ASPH and hypoxia marker proteins, typically associated with poor prognosis, may actually indicate active HPV infection, the strongest prognostic factor in HNSCC patients. In cases where HPV status is uncertain, increased expression of HIF1A and GLUT1 can serve as positive prognostic factors.
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Affiliation(s)
- Jana Smahelova
- Department of Genetics and Microbiology, Faculty of Science BIOCEV, Charles University, Prague, Czech Republic
| | - Barbora Pokryvkova
- Department of Genetics and Microbiology, Faculty of Science BIOCEV, Charles University, Prague, Czech Republic
| | - Eliska Stovickova
- Department of Genetics and Microbiology, Faculty of Science BIOCEV, Charles University, Prague, Czech Republic
| | - Marek Grega
- Department of Pathology and Molecular Medicine, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
| | - Ondrej Vencalek
- Department of Mathematical Analysis and Applications of Mathematics, Faculty of Science, Palacky University Olomouc, Olomouc, Czech Republic
| | - Michal Smahel
- Department of Genetics and Microbiology, Faculty of Science BIOCEV, Charles University, Prague, Czech Republic
| | - Vladimir Koucky
- Department of Otorhinolaryngology and Head and Neck Surgery, First Medical Faculty, Charles University and University Hospital Motol, Prague, Czech Republic
| | - Simona Malerova
- Department of Otorhinolaryngology and Head and Neck Surgery, First Medical Faculty, Charles University and University Hospital Motol, Prague, Czech Republic
| | - Jan Klozar
- Department of Otorhinolaryngology and Head and Neck Surgery, First Medical Faculty, Charles University and University Hospital Motol, Prague, Czech Republic
| | - Ruth Tachezy
- Department of Genetics and Microbiology, Faculty of Science BIOCEV, Charles University, Prague, Czech Republic.
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12
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Stakišaitis D, Kapočius L, Kilimaitė E, Gečys D, Šlekienė L, Balnytė I, Palubinskienė J, Lesauskaitė V. Preclinical Study in Mouse Thymus and Thymocytes: Effects of Treatment with a Combination of Sodium Dichloroacetate and Sodium Valproate on Infectious Inflammation Pathways. Pharmaceutics 2023; 15:2715. [PMID: 38140056 PMCID: PMC10747708 DOI: 10.3390/pharmaceutics15122715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Revised: 11/17/2023] [Accepted: 11/29/2023] [Indexed: 12/24/2023] Open
Abstract
The research presents data from a preclinical study on the anti-inflammatory effects of a sodium dichloroacetate and sodium valproate combination (DCA-VPA). The 2-week treatment with a DCA 100 mg/kg/day and VPA 150 mg/kg/day combination solution in drinking water's effects on the thymus weight, its cortex/medulla ratio, Hassall's corpuscles (HCs) number in the thymus medulla, and the expression of inflammatory and immune-response-related genes in thymocytes of male Balb/c mice were studied. Two groups of mice aged 6-7 weeks were investigated: a control (n = 12) and a DCA-VPA-treated group (n = 12). The treatment did not affect the body weight gain (p > 0.05), the thymus weight (p > 0.05), the cortical/medulla ratio (p > 0.05), or the number of HCs (p > 0.05). Treatment significantly increased the Slc5a8 gene expression by 2.1-fold (p < 0.05). Gene sequence analysis revealed a significant effect on the expression of inflammation-related genes in thymocytes by significantly altering the expression of several genes related to the cytokine activity pathway, the inflammatory response pathway, and the Il17 signaling pathway in thymocytes. Data suggest that DCA-VPA exerts an anti-inflammatory effect by inhibiting the inflammatory mechanisms in the mouse thymocytes.
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Affiliation(s)
- Donatas Stakišaitis
- Department of Histology and Embryology, Medical Academy, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania; (L.K.); (L.Š.); (I.B.); (J.P.)
- Laboratory of Molecular Oncology, National Cancer Institute, 08660 Vilnius, Lithuania
| | - Linas Kapočius
- Department of Histology and Embryology, Medical Academy, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania; (L.K.); (L.Š.); (I.B.); (J.P.)
| | - Evelina Kilimaitė
- Department of Histology and Embryology, Medical Academy, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania; (L.K.); (L.Š.); (I.B.); (J.P.)
| | - Dovydas Gečys
- Laboratory of Molecular Cardiology, Institute of Cardiology, Lithuanian University of Health Sciences, Sukileliu Ave., 50161 Kaunas, Lithuania;
| | - Lina Šlekienė
- Department of Histology and Embryology, Medical Academy, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania; (L.K.); (L.Š.); (I.B.); (J.P.)
| | - Ingrida Balnytė
- Department of Histology and Embryology, Medical Academy, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania; (L.K.); (L.Š.); (I.B.); (J.P.)
| | - Jolita Palubinskienė
- Department of Histology and Embryology, Medical Academy, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania; (L.K.); (L.Š.); (I.B.); (J.P.)
| | - Vaiva Lesauskaitė
- Laboratory of Molecular Cardiology, Institute of Cardiology, Lithuanian University of Health Sciences, Sukileliu Ave., 50161 Kaunas, Lithuania;
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13
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Zhu Y, Xiao W, Zhong W, Xi C, Ye J, Zhang Q, Wu H, Du S. Study of the skin-penetration promoting effect and mechanism of combined system of curcumin liposomes prepared by microfluidic chip and skin penetrating peptides TD-1 for topical treatment of primary melanoma. Int J Pharm 2023; 643:123256. [PMID: 37482229 DOI: 10.1016/j.ijpharm.2023.123256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 07/08/2023] [Accepted: 07/17/2023] [Indexed: 07/25/2023]
Abstract
The transdermal drug delivery system (TDDS) is an effective strategy for the treatment of melanoma with fewer side effects and good biocompatible, but the skin penetration of drugs should be further promoted. Here, we proposed a new system that combined curcumin liposomes (Cur-Lips) with skin-penetrating peptides to promote skin penetration ability. However, the preparation of Cur-Lips has drawbacks of instability and low entrapment efficiency by the traditional methods. We thus innovatively designed and applied a microfluidic chip to optimize the preparation of Cur-Lips. Cur-Lips exhibited a particle size of 106.22 ± 4.94 nm with a low polydispersity index (＜0.3) and high entrapment efficiency of 99.33 ± 1.05 %, which were prepared by the microfluidic chip. The Cur-Lips increased the skin penetration capability of Cur by 2.76 times compared to its solution in vitro skin penetration experiment. With the help of skin-penetrating peptide TD-1, the combined system further promoted the skin penetration capability by 4.48 times. The (TD-1 + Cur-Lips) system also exhibited a superior inhibition effect of the tumor to B16F10 in vitro. Furthermore, the topical application of (TD-1 + Cur-Lips) gel suppressed melanoma growth in vivo, and induced tumor cell apoptosis in tumor tissues. The skin-penetration promotion mechanism of the system was investigated. It was proved that the system could interact with the lipids and keratin on the stratum corneum to promote the Cur distribute into the stratum corneum through hair follicles and sweat glands. We proved that the microfluidic chips had unique advantages for the preparation of liposomes. The innovative combined system of liposomes and biological transdermal enhancers can effectively promote the skin penetration effect of drugs and have great potential for the prevention and treatment of melanoma.
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Affiliation(s)
- Yingyin Zhu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, People's Republic of China
| | - Wuqing Xiao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, People's Republic of China
| | - Wanling Zhong
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, People's Republic of China
| | - Cheng Xi
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, People's Republic of China
| | - Jinhong Ye
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, People's Republic of China
| | - Qing Zhang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, People's Republic of China
| | - Huichao Wu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, People's Republic of China.
| | - Shouying Du
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, People's Republic of China.
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14
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Rauniyar K, Bokharaie H, Jeltsch M. Expansion and collapse of VEGF diversity in major clades of the animal kingdom. Angiogenesis 2023; 26:437-461. [PMID: 37017884 PMCID: PMC10328876 DOI: 10.1007/s10456-023-09874-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 03/17/2023] [Indexed: 04/06/2023]
Abstract
Together with the platelet-derived growth factors (PDGFs), the vascular endothelial growth factors (VEGFs) form the PDGF/VEGF subgroup among cystine knot growth factors. The evolutionary relationships within this subgroup have not been examined thoroughly to date. Here, we comprehensively analyze the PDGF/VEGF growth factors throughout all animal phyla and propose a phylogenetic tree. Vertebrate whole-genome duplications play a role in expanding PDGF/VEGF diversity, but several limited duplications are necessary to account for the temporal pattern of emergence. The phylogenetically oldest PDGF/VEGF-like growth factor likely featured a C-terminus with a BR3P signature, a hallmark of the modern-day lymphangiogenic growth factors VEGF-C and VEGF-D. Some younger VEGF genes, such as VEGFB and PGF, appeared completely absent in important vertebrate clades such as birds and amphibia, respectively. In contrast, individual PDGF/VEGF gene duplications frequently occurred in fish on top of the known fish-specific whole-genome duplications. The lack of precise counterparts for human genes poses limitations but also offers opportunities for research using organisms that diverge considerably from humans. Sources for the graphical abstract: 326 MYA and older [1]; 72-240 MYA [2]; 235-65 MYA [3].
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Affiliation(s)
- Khushbu Rauniyar
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Biocenter 2, (Viikinkaari 5E), P.O. Box. 56, 00790, Helsinki, Finland
| | - Honey Bokharaie
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Biocenter 2, (Viikinkaari 5E), P.O. Box. 56, 00790, Helsinki, Finland
| | - Michael Jeltsch
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Biocenter 2, (Viikinkaari 5E), P.O. Box. 56, 00790, Helsinki, Finland.
- Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
- Wihuri Research Institute, Helsinki, Finland.
- Helsinki One Health, University of Helsinki, Helsinki, Finland.
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15
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Wang W, Ye W, Chen S, Tang Y, Chen D, Lu Y, Wu Z, Huang Z, Ge Y. METTL3-mediated m 6A RNA modification promotes corneal neovascularization by upregulating the canonical Wnt pathway during HSV-1 infection. Cell Signal 2023:110784. [PMID: 37356601 DOI: 10.1016/j.cellsig.2023.110784] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 06/05/2023] [Accepted: 06/22/2023] [Indexed: 06/27/2023]
Abstract
BACKGROUND Corneal neovascularization (CNV) is a symptom of herpes simplex keratitis (HSK), which can result in blindness. The corneal angiogenesis brought on by herpes simplex virus type 1 (HSV-1) is strongly affected by vascular endothelial growth factor A (VEGFA). The N6-methyladenosine (m6A) modification catalyzed by methyltransferase-like 3 (METTL3) is a crucial epigenetic regulatory process for angiogenic properties. However, the roles of METTL3 and m6A in HSK-induced CNV remain unknown. Here, we investigated these roles in vitro and in vivo. METHODS A PCR array in HSV-1-infected human umbilical vein endothelial cells (HUVECs) was used to screen for METTL3 among the epitranscriptomic genes. Tube formation and scratch assays were conducted to investigate cell migration capacity. The global mRNA m6A abundance was evaluated using a dot blot assay. Gene expression was assessed by RT-qPCR, western blotting, and fluorescence immunostaining. In addition, bioinformatic analysis was conducted to identify the downstream molecules of METTL3 in HUVECs. METTL3 knockdown and STM2457 treatment clarified the specific underlying molecular mechanisms affecting HSV-1-induced angiogenesis in vitro. An acute HSK mouse model was established to examine the effects of METTL3 knockdown or inhibition using STM2457 on pathological angiogenic development in vivo. RESULTS METTL3 was highly upregulated in HSV-1-infected HUVECs and led to increased m6A levels. METTL3 knockdown or inhibition by STM2457 further reduced m6A levels and VEGFA expression and impaired migration and tube formation capacity in HUVECs after HSV-1 infection. Mechanistically, METTL3 regulated LRP6 expression through post-transcriptional mRNA modification in an m6A-dependent manner, increasing its stability, upregulating VEGFA expression, and promoting angiogenesis in HSV-1-infected HUVECs. Furthermore, METTL3 knockdown or inhibition by STM2457 reduced CNV in vivo. CONCLUSION Our findings revealed that METTL3 promotes pathological angiogenesis through canonical Wnt and VEGF signaling in vitro and in vivo, providing potential pharmacological targets for preventing the progression of CNV in HSK.
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Affiliation(s)
- Wenzhe Wang
- Medical School, Nanjing University, Nanjing 210093, China; Department of Ophthalmology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China
| | - Wei Ye
- Department of Ophthalmology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China
| | - Si Chen
- Department of Ophthalmology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China; School of Medicine, Southeast University, 210009, China
| | - Yun Tang
- Medical School, Nanjing University, Nanjing 210093, China; Department of Ophthalmology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China
| | - Deyan Chen
- Center for Public Health Research, Nanjing University Medical School, Nanjing 210093, China
| | - Yan Lu
- Department of Ophthalmology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China
| | - Zhiwei Wu
- Center for Public Health Research, Nanjing University Medical School, Nanjing 210093, China
| | - Zhenping Huang
- Medical School, Nanjing University, Nanjing 210093, China; Department of Ophthalmology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China
| | - Yirui Ge
- Department of Ophthalmology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China.
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16
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Laatifi M, Douzi S, Ezzine H, Asry CE, Naya A, Bouklouze A, Zaid Y, Naciri M. Explanatory predictive model for COVID-19 severity risk employing machine learning, shapley addition, and LIME. Sci Rep 2023; 13:5481. [PMID: 37015978 PMCID: PMC10071246 DOI: 10.1038/s41598-023-31542-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Accepted: 03/14/2023] [Indexed: 04/06/2023] Open
Abstract
The rapid spread of SARS-CoV-2 threatens global public health and impedes the operation of healthcare systems. Several studies have been conducted to confirm SARS-CoV-2 infection and examine its risk factors. To produce more effective treatment options and vaccines, it is still necessary to investigate biomarkers and immune responses in order to gain a deeper understanding of disease pathophysiology. This study aims to determine how cytokines influence the severity of SARS-CoV-2 infection. We measured the plasma levels of 48 cytokines in the blood of 87 participants in the COVID-19 study. Several Classifiers were trained and evaluated using Machine Learning and Deep Learning to complete missing data, generate synthetic data, and fill in any gaps. To examine the relationship between cytokine storm and COVID-19 severity in patients, the Shapley additive explanation (SHAP) and the LIME (Local Interpretable Model-agnostic Explanations) model were applied. Individuals with severe SARS-CoV-2 infection had elevated plasma levels of VEGF-A, MIP-1b, and IL-17. RANTES and TNF were associated with healthy individuals, whereas IL-27, IL-9, IL-12p40, and MCP-3 were associated with non-Severity. These findings suggest that these cytokines may promote the development of novel preventive and therapeutic pathways for disease management. In this study, the use of artificial intelligence is intended to support clinical diagnoses of patients to determine how each cytokine may be responsible for the severity of COVID-19, which could lead to the identification of several cytokines that could aid in treatment decision-making and vaccine development.
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Affiliation(s)
- Mariam Laatifi
- Laboratory of Biodiversity, Ecology and Genome, Department of Biology, Faculty of Sciences, Mohammed V University, Rabat, Morocco
| | - Samira Douzi
- IPSS Laboratory, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco.
- Laboratory of Pharmacology and Toxicology, Pharmaceutical and Toxicological Analysis Research Team, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco.
| | - Hind Ezzine
- Laboratory of Biodiversity, Ecology and Genome, Department of Biology, Faculty of Sciences, Mohammed V University, Rabat, Morocco
- Public Health International Consultant, Rabat, Morocco
| | - Chadia El Asry
- Faculty of Sciences, IPSS Laboratory, Mohammed V University, Rabat, Morocco
| | - Abdellah Naya
- Department of Biology, Immunology, and Biodiversity Laboratory, Faculty of Sciences Ain Chock, Hassan II University, Casablanca, Morocco
| | - Abdelaziz Bouklouze
- Laboratory of Pharmacology and Toxicology, Pharmaceutical and Toxicological Analysis Research Team, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco
| | - Younes Zaid
- Laboratory of Biodiversity, Ecology and Genome, Department of Biology, Faculty of Sciences, Mohammed V University, Rabat, Morocco
- Department of Biology, Immunology, and Biodiversity Laboratory, Faculty of Sciences Ain Chock, Hassan II University, Casablanca, Morocco
- Research Center of Abulcasis, University of Health Sciences, Rabat, Morocco
| | - Mariam Naciri
- Laboratory of Biodiversity, Ecology and Genome, Department of Biology, Faculty of Sciences, Mohammed V University, Rabat, Morocco
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17
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COVID-19 and Pulmonary Angiogenesis: The Possible Role of Hypoxia and Hyperinflammation in the Overexpression of Proteins Involved in Alveolar Vascular Dysfunction. Viruses 2023; 15:v15030706. [PMID: 36992415 PMCID: PMC10057465 DOI: 10.3390/v15030706] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 03/03/2023] [Accepted: 03/05/2023] [Indexed: 03/11/2023] Open
Abstract
COVID-19 has been considered a vascular disease, and inflammation, intravascular coagulation, and consequent thrombosis may be associated with endothelial dysfunction. These changes, in addition to hypoxia, may be responsible for pathological angiogenesis. This research investigated the impact of COVID-19 on vascular function by analyzing post-mortem lung samples from 24 COVID-19 patients, 10 H1N1pdm09 patients, and 11 controls. We evaluated, through the immunohistochemistry technique, the tissue immunoexpressions of biomarkers involved in endothelial dysfunction, microthrombosis, and angiogenesis (ICAM-1, ANGPT-2, and IL-6, IL-1β, vWF, PAI-1, CTNNB-1, GJA-1, VEGF, VEGFR-1, NF-kB, TNF-α and HIF-1α), along with the histopathological presence of microthrombosis, endothelial activation, and vascular layer hypertrophy. Clinical data from patients were also observed. The results showed that COVID-19 was associated with increased immunoexpression of biomarkers involved in endothelial dysfunction, microthrombosis, and angiogenesis compared to the H1N1 and CONTROL groups. Microthrombosis and vascular layer hypertrophy were found to be more prevalent in COVID-19 patients. This study concluded that immunothrombosis and angiogenesis might play a key role in COVID-19 progression and outcome, particularly in patients who die from the disease.
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Petrusevska M, Zendelovska D, Atanasovska E, Spasovska K, Grozdanovski K, Stojanovska S, Panovska Stavridis I, Eftimov A. Interplay between lymphocyte subpopulation, inflammatory cytokines and their correlation with oxidative stress parameters in COVID-19. ITALIAN JOURNAL OF MEDICINE 2023. [DOI: 10.4081/itjm.2022.1543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Our objective was to investigate the inflammatory and oxidative stress markers in patients with moderate and severe form of COVID-19. In addition, we show the correlation between changes in lymphocyte subsets and markers of oxidative stress as a tool for patient classification. IL-6 and VEGF were analysed by utilizing a High Sensitivity Evidence Investigator™ Biochip Array technology. The total antioxidant capacity (PAT) and the free radical concentrations (d-ROM) were measured in serum utilizing analytical photometric system FRAS5. Peripheral blood was used to determine CD45 + mononuclear, B, T, and NK cells using a multi-parameter flow cytometric immunophenotypic test.
Statistically significant differences in IL-6 and VEGF levels were observed between the two patient groups. Decreased values of the absolute number of lymphocytes and their CD4 + and CD8 + positive T cells, NK cells, and CD8 were obtained. In the moderate group, good correlations were found between IL-6 and VEGF and NK cells (r = 0.6973, p <0.05; for IL6 and r = 0.6498, p <0, for VEGF. 05). Cytokines were correlated with CD45+ (r = 0.5610, p <0.05; for IL-6 and r = 0.5462, p <0.05 for VEGF). The oxidative stress index can be used as a cheaper alternative and as a triage tool between severe and moderate illnesses, after showing good correlation with more expensive patient classification analysis.
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19
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Talotta R. Impaired VEGF-A-Mediated Neurovascular Crosstalk Induced by SARS-CoV-2 Spike Protein: A Potential Hypothesis Explaining Long COVID-19 Symptoms and COVID-19 Vaccine Side Effects? Microorganisms 2022; 10:2452. [PMID: 36557705 PMCID: PMC9784975 DOI: 10.3390/microorganisms10122452] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 12/03/2022] [Accepted: 12/10/2022] [Indexed: 12/14/2022] Open
Abstract
Long coronavirus disease-19 (COVID-19) is a newly discovered syndrome characterized by multiple organ manifestations that persist for weeks to months, following the recovery from acute disease. Occasionally, neurological and cardiovascular side effects mimicking long COVID-19 have been reported in recipients of COVID-19 vaccines. Hypothetically, the clinical similarity could be due to a shared pathogenic role of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike (S) protein produced by the virus or used for immunization. The S protein can bind to neuropilin (NRP)-1, which normally functions as a coreceptor for the vascular endothelial growth factor (VEGF)-A. By antagonizing the docking of VEGF-A to NRP-1, the S protein could disrupt physiological pathways involved in angiogenesis and nociception. One consequence could be the increase in unbound forms of VEGF-A that could bind to other receptors. SARS-CoV-2-infected individuals may exhibit increased plasma levels of VEGF-A during both acute illness and convalescence, which could be responsible for diffuse microvascular and neurological damage. A few studies suggest that serum VEGF-A may also be a potential biomarker for long COVID-19, whereas evidence for COVID-19 vaccines is lacking and merits further investigation.
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Affiliation(s)
- Rossella Talotta
- Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Messina, University Hospital "G. Martino", 98124 Messina, Italy
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20
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Filaggrin and cytokines in respiratory samples of preterm infants at risk for respiratory viral infection. Sci Rep 2022; 12:21278. [PMID: 36482106 PMCID: PMC9731953 DOI: 10.1038/s41598-022-25897-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 12/06/2022] [Indexed: 12/13/2022] Open
Abstract
Respiratory viral infections (RVIs) are frequent in preterm infants possibly inducing long-term impact on respiratory morbidity. Immune response and respiratory barriers are key defense elements against viral insults in premature infants admitted to Neonatal Intensive Care Units (NICUs). Our main goals were to describe the local immune response in respiratory secretions of preterm infants with RVIs during NICU admission and to evaluate the expression and synthesis of lung barrier regulators, both in respiratory samples and in vitro models. Samples from preterm infants that went on to develop RVIs had lower filaggrin gene and protein levels at a cellular level were compared to never-infected neonates (controls). Filaggrin, MIP-1α/CCL3 and MCP-1 levels were higher in pre-infection supernatants compared to controls. Filaggrin, HIF-1α, VEGF, RANTES/CCL5, IL-17A, IL-1β, MIP-1α and MIP-1β/CCL5 levels were higher during and after infection. ROC curve and logistic regression analysis shows that these molecules could be used as infection risk biomarkers. Small airway epithelial cells stimulated by poly:IC presented reduced filaggrin gene expression and increased levels in supernatant. We conclude that filaggrin gene and protein dysregulation is a risk factor of RVI in newborns admitted at the NICU.
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Virus Association with Gastric Inflammation and Cancer: An Updated Overview. JOURNAL OF MEDICAL MICROBIOLOGY AND INFECTIOUS DISEASES 2022. [DOI: 10.52547/jommid.10.4.163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
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22
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Braun SA, Bauer AT, Németh C, Rózsa A, Rusch L, Erpenbeck L, Schloer S, Silling S, Metze D, Gerber PA, Schneider SW, Gyulai R, Homey B. Immunothrombotic Mechanisms Induced by Ingenol Mebutate Lead to Rapid Necrosis and Clearance of Anogenital Warts. Int J Mol Sci 2022; 23:ijms232113377. [PMID: 36362165 PMCID: PMC9656782 DOI: 10.3390/ijms232113377] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 10/20/2022] [Accepted: 10/30/2022] [Indexed: 11/06/2022] Open
Abstract
Ingenol mebutate (IM) is highly effective in the treatment of human papillomavirus (HPV)-induced anogenital warts (AGW) leading to fast ablation within hours. However, the exact mode of action is still largely unknown. We performed dermoscopy, in vivo confocal microscopy (CLM), histology, immunohistochemistry, and immunofluorescence to gain insights in mechanisms of IM treatment in AGW. In addition, we used in vitro assays (ELISA, HPV-transfection models) to further investigate in vivo findings. IM treatment leads to a strong recruitment of neutrophils with thrombosis of small skin vessels within 8 h, in a sense of immunothrombosis. In vivo and in vitro analyses showed that IM supports a prothrombotic environment by endothelial cell activation and von Willebrand factor (VWF) secretion, in addition to induction of neutrophil extracellular traps (NETosis). IM superinduces CXCL8/IL-8 expression in HPV-E6/E7 transfected HaCaT cells when compared to non-infected keratinocytes. Rapid ablation of warts after IM treatment can be well explained by the observed immunothrombosis. This new mechanism has so far only been observed in HPV-induced lesions and is completely different from the mechanisms we see in the treatment of transformed keratinocytes in actinic keratosis. Our initial findings indicate an HPV-specific effect, which could be also of interest for the treatment of other HPV-induced lesions. Larger studies are now needed to further investigate the potential of IM in different HPV tumors.
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Affiliation(s)
- Stephan A. Braun
- Department of Dermatology, University Hospital Muenster, 48149 Muenster, Germany
- Department of Dermatology, Medical Faculty, Heinrich-Heine University, 40225 Duesseldorf, Germany
- Correspondence: ; Tel.: +49-2351-83-58637
| | - Alexander T. Bauer
- Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
| | - Csongor Németh
- Department of Dermatology, Venereology and Oncodermatology, University of Pécs, Medical Center, 7632 Pécs, Hungary
| | - Annamária Rózsa
- Department of Dermatology, Venereology and Oncodermatology, University of Pécs, Medical Center, 7632 Pécs, Hungary
| | - Louisa Rusch
- Department of Dermatology, Venereology and Allergology, University Medical Center Göttingen, 37075 Göttingen, Germany
| | - Luise Erpenbeck
- Department of Dermatology, University Hospital Muenster, 48149 Muenster, Germany
| | - Sebastian Schloer
- Center for Molecular Biology of Inflammation, Institute of Medical Biochemistry, University of Muenster, 48149 Muenster, Germany
- Leibniz Institute of Virology, 20251 Hamburg, Germany
| | - Steffi Silling
- Institute of Virology, National Reference Center for Papilloma- and Polyomaviruses, Faculty of Medicine and University Hospital Cologne, 50935 Cologne, Germany
| | - Dieter Metze
- Department of Dermatology, University Hospital Muenster, 48149 Muenster, Germany
| | - Peter A. Gerber
- Department of Dermatology, Medical Faculty, Heinrich-Heine University, 40225 Duesseldorf, Germany
| | - Stefan W. Schneider
- Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
| | - Rolland Gyulai
- Department of Dermatology, Venereology and Oncodermatology, University of Pécs, Medical Center, 7632 Pécs, Hungary
| | - Bernhard Homey
- Department of Dermatology, Medical Faculty, Heinrich-Heine University, 40225 Duesseldorf, Germany
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Fiestas Solórzano VE, de Lima RC, de Azeredo EL. The Role of Growth Factors in the Pathogenesis of Dengue: A Scoping Review. Pathogens 2022; 11:1179. [PMID: 36297236 PMCID: PMC9608673 DOI: 10.3390/pathogens11101179] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 09/30/2022] [Accepted: 10/06/2022] [Indexed: 12/07/2022] Open
Abstract
Growth factors (GFs) have a role in tissue repair and in the modulation of the expression of inflammatory cells in damage caused by pathogens. This study aims to systematize the evidence on the role of GFs in the pathogenesis of dengue. This scoping review considered all published peer-reviewed studies in the MEDLINE and Embase databases. Ultimately, 58 studies that analyzed GFs in dengue patients, published between 1998 and 2021, were included. DENV-2 infection and secondary infection were more frequent in the patients studied. ELISA and multiplex immunoassay (Luminex) were the most used measurement techniques. Increased levels of vascular endothelial growth factor, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, transforming growth factor beta, and hepatocyte growth factor as well as reduced levels of platelet-derived growth factor and epidermal growth factor were observed in severe dengue in most studies. Vascular endothelial growth factor and hepatocyte growth factor were identified as biomarkers of severity. In addition, there is evidence that the dengue virus can use the growth factor pathway to facilitate its entry into the cell and promote its viral replication. The use of tyrosine kinase inhibitors is an alternative treatment for dengue that is being studied.
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Meineke R, Stelz S, Busch M, Werlein C, Kühnel M, Jonigk D, Rimmelzwaan GF, Elbahesh H. FDA-Approved Inhibitors of RTK/Raf Signaling Potently Impair Multiple Steps of In Vitro and Ex Vivo Influenza A Virus Infections. Viruses 2022; 14:2058. [PMID: 36146864 PMCID: PMC9504178 DOI: 10.3390/v14092058] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/13/2022] [Accepted: 09/13/2022] [Indexed: 11/17/2022] Open
Abstract
Influenza virus (IV) infections pose a burden on global public health with significant morbidity and mortality. The limited range of currently licensed IV antiviral drugs is susceptible to the rapid rise of resistant viruses. In contrast, FDA-approved kinase inhibitors can be repurposed as fast-tracked host-targeted antivirals with a higher barrier of resistance. Extending our recent studies, we screened 21 FDA-approved small-molecule kinase inhibitors (SMKIs) and identified seven candidates as potent inhibitors of pandemic and seasonal IV infections. These SMKIs were further validated in a biologically and clinically relevant ex vivo model of human precision-cut lung slices. We identified steps of the virus infection cycle affected by these inhibitors (entry, replication, egress) and found that most SMKIs affected both entry and egress. Based on defined and overlapping targets of these inhibitors, the candidate SMKIs target receptor tyrosine kinase (RTK)-mediated activation of Raf/MEK/ERK pathways to limit influenza A virus infection. Our data and the established safety profiles of these SMKIs support further clinical investigations and repurposing of these SMKIs as host-targeted influenza therapeutics.
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Affiliation(s)
- Robert Meineke
- Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine in Hannover (TiHo), Bünteweg 17, 30559 Hannover, Germany
| | - Sonja Stelz
- Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine in Hannover (TiHo), Bünteweg 17, 30559 Hannover, Germany
| | - Maximilian Busch
- Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine in Hannover (TiHo), Bünteweg 17, 30559 Hannover, Germany
| | - Christopher Werlein
- Institute of Pathology, Hannover Medical School (MHH), Carl-Neuberg-Straße 1, 30625 Hannover, Germany
| | - Mark Kühnel
- Institute of Pathology, Hannover Medical School (MHH), Carl-Neuberg-Straße 1, 30625 Hannover, Germany
- Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover Medical School (MHH), Carl-Neuberg-Straße 1, 30625 Hannover, Germany
| | - Danny Jonigk
- Institute of Pathology, Hannover Medical School (MHH), Carl-Neuberg-Straße 1, 30625 Hannover, Germany
- Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover Medical School (MHH), Carl-Neuberg-Straße 1, 30625 Hannover, Germany
| | - Guus F. Rimmelzwaan
- Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine in Hannover (TiHo), Bünteweg 17, 30559 Hannover, Germany
| | - Husni Elbahesh
- Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine in Hannover (TiHo), Bünteweg 17, 30559 Hannover, Germany
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Niranjan R, Murugasamy V, Sunilkumar A, Manoj H, Ganesh K, Vidhyapriya P, Sankari T, Muthukumaravel S, Kumar A. Atorvastatin attenuates NS1 (Non-structural protein-1) of dengue type-2 serotype-induced expressions of matrix metalloproteinases in HL-60 cells, differentiated to neutrophils: Implications for the immunopathogenesis of dengue viral disease. Int Immunopharmacol 2022; 112:109082. [PMID: 36108401 DOI: 10.1016/j.intimp.2022.109082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Revised: 07/17/2022] [Accepted: 07/19/2022] [Indexed: 11/19/2022]
Abstract
BACKGROUND The dengue is a vector borne viral infection in humans. Bite of mosquito infected with a dengue virus transmits the disease. The neutrophils support more to the innate immune response by switching to infected tissues and triggering immunomodulatory mechanisms including the release of proteases and host defence peptides. METHODS Cell viability by MTT and trypan blue dye exclusion assay, bright field microscopy for assessment of cell morphology, cytokines measurements by ELISA, estimation of protein by Bradford assay were done. Assessments of matrix metalloproteinase genes mRNA expressions were done using real-time PCR. RESULTS In the present study, we have for the first time unveiled that, NS1 antigen of dengue type-2 serotype, induce and stimulate the neutrophils cells to express high levels of matrix metalloproteases. NS1 exposure of HL-60 cells differentiated to neutrophils affected cell morphology and in 24 h of exposure. We have demonstrated that, the NS1 antigen has induced MMP-2, MMP-14 and MMP-9 expressions in neutrophils in a 24hrs exposure time. NS1 exposure has also further upregulated MMP-1, MMP-13, and MMP-8 expressions in neutrophils in a 24hrs exposure time. Notably, treatment with atorvastatin concentrations downregulated the expression profile of the all matrix metalloprotease significantly. Importantly, NS1 antigen has significantly increased the IL-6, IL-13 release by the HL,60 cells which was reversed by atorvastatin. On the other hand, NS1 exposure enhanced the mRNA expressions of VEGF-A and VEGF-D which was reversed by atorvastatin. However, we found that, NS1 exposure reduced the mRNA expressions profile of VEGF-C, which was reversed by atorvastatin. CONCLUSION In conclusion, we report that, neutrophils associated matrix metalloprotease are involved in the pathogenesis of dengue viral disease. VEGF growth factors may also be released by the neutrophils which may subsequently participate in the endothelial dysfunctions leading to dengue shock syndrome.
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Affiliation(s)
- Rituraj Niranjan
- Immunology Laboratory, Division of Microbiology and Immunology, ICMR-Vector Control Research Centre, Puducherry 605006, India.
| | - Vyshali Murugasamy
- Immunology Laboratory, Division of Microbiology and Immunology, ICMR-Vector Control Research Centre, Puducherry 605006, India
| | - Anupama Sunilkumar
- Immunology Laboratory, Division of Microbiology and Immunology, ICMR-Vector Control Research Centre, Puducherry 605006, India
| | - H Manoj
- Immunology Laboratory, Division of Microbiology and Immunology, ICMR-Vector Control Research Centre, Puducherry 605006, India
| | - Khashpatika Ganesh
- Immunology Laboratory, Division of Microbiology and Immunology, ICMR-Vector Control Research Centre, Puducherry 605006, India
| | - Pitchavel Vidhyapriya
- Immunology Laboratory, Division of Microbiology and Immunology, ICMR-Vector Control Research Centre, Puducherry 605006, India
| | - T Sankari
- Division of Omics, ICMR-Vector Control Research Centre, Puducherry 605006, India
| | | | - Ashwani Kumar
- ICMR-Vector Control Research Centre, Puducherry 605006, India
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Gong F, Li X, Zhang H, Wu J, Ma G, Zhang B, Gao J, Ding Y, Huang Y, Cheng S, Zhou X, Zhao F. Comparison of the Effects of Open Surgery and Minimally Invasive Surgery on the Achilles Tendon Rupture Healing Based on Angiogenesis. COMPUTATIONAL INTELLIGENCE AND NEUROSCIENCE 2022; 2022:1447129. [PMID: 36093506 PMCID: PMC9458374 DOI: 10.1155/2022/1447129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/05/2022] [Accepted: 07/08/2022] [Indexed: 11/17/2022]
Abstract
Objective To compare the effect of three different surgical methods on rabbit Achilles tendon rupture. Methods The Achilles tendon transection model was constructed by cutting off the inner half of the Achilles tendon. Rabbits were divided into 4 groups: model group, open surgery (OS) group, minimally invasive surgery (MS) group, and conservative treatment (CT) group. Biomechanical evaluation, H&E, and Picrosirius Red staining were applied to evaluate the histological changes and healing. RT-qPCR, Western blot, ELISA, and IHC staining were used to detect the expression of COLIII, IL-1β, TNF-α, IL-6, CD31, VEGF, bFGF, and TGF-β1. Results Different surgery treatments significantly alleviated the histological changes in rabbits. The tension and elasticity of the Achilles tendon were significantly increased after surgery. In addition, surgery treatments notably alleviated the inflammatory responses in vivo via downregulation of IL-1β, TNF-α, and IL-6 and promoted the tube formation in tissues through upregulating VEGF, bFGF, TGF-β1, and CD31. Furthermore, MS exhibited best therapeutic efficiency on Achilles tendon rupture healing, compared with OS or CT. Conclusions Our research revealed the superiority of MS in Achilles tendon rupture treatment at the molecular level compared with OS or CT.
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Affiliation(s)
- Fan Gong
- Hand & Foot & Reconstruction Microsurgery, People's Hospital of Ningxia Hui Autonomous Region (The First Affiliated Hospital of Northwest University for Nationalities), Yinchuan 750002, Ningxia, China
| | - Xiaoliang Li
- Hand & Foot & Reconstruction Microsurgery, People's Hospital of Ningxia Hui Autonomous Region (The First Affiliated Hospital of Northwest University for Nationalities), Yinchuan 750002, Ningxia, China
| | - Hanling Zhang
- Hand & Foot & Reconstruction Microsurgery, People's Hospital of Ningxia Hui Autonomous Region (The First Affiliated Hospital of Northwest University for Nationalities), Yinchuan 750002, Ningxia, China
| | - Jianke Wu
- Hand & Foot & Reconstruction Microsurgery, People's Hospital of Ningxia Hui Autonomous Region (The First Affiliated Hospital of Northwest University for Nationalities), Yinchuan 750002, Ningxia, China
| | - Guoxu Ma
- Hand & Foot & Reconstruction Microsurgery, People's Hospital of Ningxia Hui Autonomous Region (The First Affiliated Hospital of Northwest University for Nationalities), Yinchuan 750002, Ningxia, China
| | - Bowen Zhang
- Hand & Foot & Reconstruction Microsurgery, People's Hospital of Ningxia Hui Autonomous Region (The First Affiliated Hospital of Northwest University for Nationalities), Yinchuan 750002, Ningxia, China
| | - Jian Gao
- Hand & Foot & Reconstruction Microsurgery, People's Hospital of Ningxia Hui Autonomous Region (The First Affiliated Hospital of Northwest University for Nationalities), Yinchuan 750002, Ningxia, China
| | - Yi Ding
- Hand & Foot & Reconstruction Microsurgery, People's Hospital of Ningxia Hui Autonomous Region (The First Affiliated Hospital of Northwest University for Nationalities), Yinchuan 750002, Ningxia, China
| | - Yonglu Huang
- Hand & Foot & Reconstruction Microsurgery, People's Hospital of Ningxia Hui Autonomous Region (The First Affiliated Hospital of Northwest University for Nationalities), Yinchuan 750002, Ningxia, China
| | - Suoli Cheng
- Hand & Foot & Reconstruction Microsurgery, People's Hospital of Ningxia Hui Autonomous Region (The First Affiliated Hospital of Northwest University for Nationalities), Yinchuan 750002, Ningxia, China
| | - Xuebing Zhou
- Hand & Foot & Reconstruction Microsurgery, People's Hospital of Ningxia Hui Autonomous Region (The First Affiliated Hospital of Northwest University for Nationalities), Yinchuan 750002, Ningxia, China
| | - Fei Zhao
- Hand & Foot & Reconstruction Microsurgery, People's Hospital of Ningxia Hui Autonomous Region (The First Affiliated Hospital of Northwest University for Nationalities), Yinchuan 750002, Ningxia, China
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Bahramian E, Furr M, Wu JT, Ceballos RM. Differential Impacts of HHV-6A versus HHV-6B Infection in Differentiated Human Neural Stem Cells. Front Immunol 2022; 13:847106. [PMID: 35911725 PMCID: PMC9326508 DOI: 10.3389/fimmu.2022.847106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Accepted: 06/16/2022] [Indexed: 12/02/2022] Open
Abstract
Within the family Herpesviridae, sub-family β-herpesvirinae, and genus Roseolovirus, there are only three human herpesviruses that have been described: HHV-6A, HHV-6B, and HHV-7. Initially, HHV-6A and HHV-6B were considered as two variants of the same virus (i.e., HHV6). Despite high overall genetic sequence identity (~90%), HHV-6A and HHV-6B are now recognized as two distinct viruses. Sequence divergence (e.g., >30%) in key coding regions and significant differences in physiological and biochemical profiles (e.g., use of different receptors for viral entry) underscore the conclusion that HHV-6A and HHV-6B are distinct viruses of the β-herpesvirinae. Despite these viruses being implicated as causative agents in several nervous system disorders (e.g., multiple sclerosis, epilepsy, and chronic fatigue syndrome), the mechanisms of action and relative contributions of each virus to neurological dysfunction are unclear. Unresolved questions regarding differences in cell tropism, receptor use and binding affinity (i.e., CD46 versus CD134), host neuro-immunological responses, and relative virulence between HHV-6A versus HHV-6B prevent a complete characterization. Although it has been shown that both HHV-6A and HHV-6B can infect glia (and, recently, cerebellar Purkinje cells), cell tropism of HHV-6A versus HHV-6B for different nerve cell types remains vague. In this study, we show that both viruses can infect different nerve cell types (i.e., glia versus neurons) and different neurotransmitter phenotypes derived from differentiated human neural stem cells. As demonstrated by immunofluorescence, HHV-6A and HHV-6B productively infect VGluT1-containing cells (i.e., glutamatergic neurons) and dopamine-containing cells (i.e., dopaminergic neurons). However, neither virus appears to infect GAD67-containing cells (i.e., GABAergic neurons). As determined by qPCR, expression of immunological factors (e.g., cytokines) in cells infected with HHV-6A versus HHV6-B also differs. These data along with morphometric and image analyses of infected differentiated neural stem cell cultures indicate that while HHV-6B may have greater opportunity for transmission, HHV-6A induces more severe cytopathic effects (e.g., syncytia) at the same post-infection end points. Cumulatively, results suggest that HHV-6A is more virulent than HHV-6B in susceptible cells, while neither virus productively infects GABAergic cells. Consistency between these in vitro data and in vivo experiments would provide new insights into potential mechanisms for HHV6-induced epileptogenesis.
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Affiliation(s)
- Elham Bahramian
- Department of Biological Sciences, University of Arkansas, Fayetteville, AR, United States
- Cell and Molecular Biology Program, University of Arkansas, Fayetteville, AR, United States
| | - Mercede Furr
- Department of Biological Sciences, University of Arkansas, Fayetteville, AR, United States
| | - Jerry T. Wu
- Department of Biology, Johns Hopkins University, Baltimore, MD, United States
| | - Ruben Michael Ceballos
- Department of Biological Sciences, University of Arkansas, Fayetteville, AR, United States
- Cell and Molecular Biology Program, University of Arkansas, Fayetteville, AR, United States
- Ecology, Evolution, and Organismal Biology Group, University of Arkansas, Fayetteville, AR, United States
- Arkansas Center for Space and Planetary Sciences, University of Arkansas, Fayetteville, AR, United States
- *Correspondence: Ruben Michael Ceballos,
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Wu W, Luo H, Wu D, Shi M, Yu J, Liao H. Biological activity of a vascular endothelial cell-hydroxyapatite orbital implant complex: An experimental study. Exp Ther Med 2022; 23:227. [PMID: 35222704 PMCID: PMC8815058 DOI: 10.3892/etm.2022.11152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 12/17/2021] [Indexed: 11/06/2022] Open
Abstract
The reduction in postoperative complications is a considerable concern after orbital reparation and reconstruction. Selecting the appropriate scaffold materials to improve the survival rates of the seeded cells is a challenge in tissue engineering. The aim of the present study was to evaluate the biological activity of a vascular endothelial cell-hydroxyapatite orbital complex, which was constructed with tissue engineering and used as an implant after enucleation of the eyeNew Zealand white rabbits were randomly divided into two groups that underwent hydroxyapatite orbital implant surgery in the right eye. The primary orbital microvascular endothelial cells were collected from the microvascular tissue and subsequently cultured. Then, hydroxyapatite ocular implants were cultured with vascular endothelial cells in the endothelial cell (EC) group, and implants were cultured without vascular endothelial cells in the blank group. Characterization of the cells was performed with immunofluorescence staining and a Transwell migration and cell tube formation assay. The levels of interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF) in the rabbit conjunctiva were measured with an ELISA. The results showed that the levels of IL-8 were decreased in the EC group and increased in the blank group. The levels of VEGF were increased in the EC group when compared to the blank group with statistical significance. The average depth of the fibrovascular tissue was obviously thicker in the EC group compared with that found in the blank group. These findings suggest that the vascular endothelial cell-hydroxyapatite orbital implant complex may be an effective strategy with which to accelerate vascularization and reduce complications of infection with satisfactory biological activity.
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Affiliation(s)
- Weiqi Wu
- Department of Ocular Oncology and Ocular Trauma, Affiliated Eye Hospital of Nanchang University, Jiangxi Research Institute of Ophthalmology and Visual Sciences, Key Laboratory of Ophthalmology of Jiangxi Province, Nanchang, Jiangxi 330006, P.R. China.,Department of Ophthalmology, The Third Affiliated Hospital of Nanchang University, Jiangxi Key Laboratory of Cancer Metastasis and Precision Treatment, Nanchang, Jiangxi 330008, P.R. China
| | - Hao Luo
- Department of Ocular Oncology and Ocular Trauma, Affiliated Eye Hospital of Nanchang University, Jiangxi Research Institute of Ophthalmology and Visual Sciences, Key Laboratory of Ophthalmology of Jiangxi Province, Nanchang, Jiangxi 330006, P.R. China
| | - Dan Wu
- Department of Internal Medical, Nanchang HongDu Hospital of Traditional Chinese Medicine, Nanchang, Jiangxi 330006, P.R. China
| | - Menglin Shi
- Department of Ocular Oncology and Ocular Trauma, Affiliated Eye Hospital of Nanchang University, Jiangxi Research Institute of Ophthalmology and Visual Sciences, Key Laboratory of Ophthalmology of Jiangxi Province, Nanchang, Jiangxi 330006, P.R. China
| | - Jinhai Yu
- Department of Ocular Oncology and Ocular Trauma, Affiliated Eye Hospital of Nanchang University, Jiangxi Research Institute of Ophthalmology and Visual Sciences, Key Laboratory of Ophthalmology of Jiangxi Province, Nanchang, Jiangxi 330006, P.R. China
| | - Hongfei Liao
- Department of Ocular Oncology and Ocular Trauma, Affiliated Eye Hospital of Nanchang University, Jiangxi Research Institute of Ophthalmology and Visual Sciences, Key Laboratory of Ophthalmology of Jiangxi Province, Nanchang, Jiangxi 330006, P.R. China
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Maranini B, Ciancio G, Ferracin M, Cultrera R, Negrini M, Sabbioni S, Govoni M. microRNAs and Inflammatory Immune Response in SARS-CoV-2 Infection: A Narrative Review. Life (Basel) 2022; 12:life12020288. [PMID: 35207576 PMCID: PMC8879390 DOI: 10.3390/life12020288] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 02/07/2022] [Accepted: 02/08/2022] [Indexed: 12/15/2022] Open
Abstract
The current SARS-CoV-2 pandemic has emerged as an international challenge with strong medical and socioeconomic impact. The spectrum of clinical manifestations of SARS-CoV-2 is wide, covering asymptomatic or mild cases up to severe and life-threatening complications. Critical courses of SARS-CoV-2 infection are thought to be driven by the so-called “cytokine storm”, derived from an excessive immune response that induces the release of proinflammatory cytokines and chemokines. In recent years, non-coding RNAs (ncRNAs) emerged as potential diagnostic and therapeutic biomarkers in both inflammatory and infectious diseases. Therefore, the identification of SARS-CoV-2 miRNAs and host miRNAs is an important research topic, investigating the host–virus crosstalk in COVID-19 infection, trying to answer the pressing question of whether miRNA-based therapeutics can be employed to tackle SARS-CoV-2 complications. In this review, we aimed to directly address ncRNA role in SARS-CoV-2-immune system crosstalk upon COVID-19 infection, particularly focusing on inflammatory pathways and cytokine storm syndromes.
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Affiliation(s)
- Beatrice Maranini
- Rheumatology Unit, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (G.C.); (M.G.)
- Correspondence:
| | - Giovanni Ciancio
- Rheumatology Unit, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (G.C.); (M.G.)
| | - Manuela Ferracin
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138 Bologna, Italy;
| | - Rosario Cultrera
- Infectious Diseases, Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy;
| | - Massimo Negrini
- Laboratorio per le Tecnologie delle Terapie Avanzate (LTTA), Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy;
| | - Silvia Sabbioni
- Department of Life Sciences and Biotechnologies, University of Ferrara, 44121 Ferrara, Italy;
| | - Marcello Govoni
- Rheumatology Unit, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (G.C.); (M.G.)
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Rani A, Jakhmola S, Karnati S, Parmar HS, Chandra Jha H. Potential entry receptors for human γ-herpesvirus into epithelial cells: A plausible therapeutic target for viral infections. Tumour Virus Res 2021; 12:200227. [PMID: 34800753 PMCID: PMC8628264 DOI: 10.1016/j.tvr.2021.200227] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 10/28/2021] [Accepted: 11/15/2021] [Indexed: 12/14/2022] Open
Abstract
Herpesviruses are ubiquitous viruses, specifically the Epstein Barr virus (EBV). EBV and Kaposi's sarcoma-associated herpesvirus (KSHV) establish their latency for a long period in B-cells and their reactivation instigates dreadful diseases from cancer to neurological modalities. The envelope glycoprotein of these viruses makes an attachment with several host receptors. For instance; glycoprotein 350/220, gp42, gHgL and gB of EBV establish an attachment with CD21, HLA-DR, Ephs, and other receptor molecules to hijack the B- and epithelial cell machinery. Ephs are reported recently as potent receptors for EBV entry into epithelial cells. Eph receptors play a role in the maintenance and control of various cellular processes including morphology, adhesion, proliferation, survival and differentiation. Alterations in the structure and expression of Eph and ephrin (Eph ligands) molecules is entangled with various pathologies including tumours and neurological complications. Along with Eph, integrins, NRP, NMHC are also key players in viral infections as they are possibly involved in viral transmission, replication and persistence. Contrarily, KSHV gH is known to interact with EphA2 and -A4 molecules, whereas in the case of EBV only EphA2 receptors are being reported to date. The ELEFN region of KSHV gH was involved in the interaction with EphA2, however, the interacting region of EBV gH is elusive. Further, the gHgL of KSHV and EBV form a complex with the EphA2 ligand-binding domain (LBD). Primarily by using gL both KSHV and EBV gHgL bind to the peripheral regions of LBD. In addition to γ-herpesviruses, several other viruses like Nipah virus, Cedar virus, Hepatitis C virus and Rhesus macaque rhadinovirus (RRV) also access the host cells via Eph receptors. Therefore, we summarise the possible roles of Eph and ephrins in virus-mediated infection and these molecules could serve as potential therapeutic targets.
Crucial understanding of human γ-herpesviruses entry mechanism. Eph receptors relate to changed biomolecular profile upon EBV infection. EBV association with neurological disorders. Eph receptors could be an elegant drug for human γ-herpesviruses.
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Affiliation(s)
- Annu Rani
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, India
| | - Shweta Jakhmola
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, India
| | - Srikanth Karnati
- Department of Medical Cell Biology, Julius Maximilians University, Wuerzburg, Germany
| | - Hamendra Singh Parmar
- School of Biotechnology, Devi Ahilya University, Takshashila Campus, Khandwa Road, Indore, 452001, MP, India
| | - Hem Chandra Jha
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, India.
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Petrushevska M, Zendelovska D, Atanasovska E, Eftimov A, Spasovska K. Presentation of cytokine profile in relation to oxidative stress parameters in patients with severe COVID-19: a case-control pilot study. F1000Res 2021; 10:719. [PMID: 34868558 PMCID: PMC8603313 DOI: 10.12688/f1000research.55166.2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/11/2021] [Indexed: 01/12/2023] Open
Abstract
Introduction: COVID-19 can be worsened by hyper-production of cytokines accompanied by increased level of oxidative stress. The aim of this study was to investigate the correlation between a set of cytokines and the markers of the oxidative stress. Methods: The levels of cytokines IL-2, IL-4, IL-6, IL8, IL-10, VEGF, IFN-γ, TNF-α, IL-1α, MCP-1 and EGF were determined by using High Sensitivity Evidence Investigator™ Biochip Array technology. The oxidative stress parameters (d-ROM, PAT, OS index) were measured in serum on FRAS5 analytical photometric system. Results: IL-6, IL-8, IL-10, VEGF, MCP-1 and EGF were significantly higher (p<0.05) in the patients with severe COVID-19 with increased levels of IL-2, IFN-y, TNF-α and IL-1α. The d-ROM, OS index, and PAT were significantly higher (p<0.05) in severe COVID-19 patients. IL-6 demonstrated the strongest correlation with all of the markers of the oxidative stress, d-ROM (r=0.9725, p=0.0001), PAT (r=0.5000, p=0.0001) and OS index (r=0.9593, p=0.012). Similar behavior was evidenced between IFN-y and d-ROM (r=0.4006, p=0.0001), PAT (r=0.6030, p=0.0001) and OS index (r=0.4298, p=0.012). Conclusion: The oxidative stress markers show good correlation with the tested cytokines which can be measured at the beginning of the disease in a primary care setting to predict the course of COVID-19.
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Affiliation(s)
- Marija Petrushevska
- Institute of preclinical and clinical pharmacology and toxicology, University of Ss Cyril and Methodius, Faculty of Medicine, Skopje, Macedonia
| | - Dragica Zendelovska
- Institute of preclinical and clinical pharmacology and toxicology, University of Ss Cyril and Methodius, Faculty of Medicine, Skopje, Macedonia
| | - Emilija Atanasovska
- Institute of preclinical and clinical pharmacology and toxicology, University of Ss Cyril and Methodius, Faculty of Medicine, Skopje, Macedonia
| | - Aleksandar Eftimov
- Institute of pathology, University of Ss Cyril and Methodius, Faculty of Medicine, Skopje, Macedonia
| | - Katerina Spasovska
- University Clinic for Infectious Diseases and Febrile Conditions, Faculty of Medicine, University of Ss Cyril and Methodius, Skopje, Macedonia
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Petrushevska M, Zendelovska D, Atanasovska E, Eftimov A, Spasovska K. Presentation of cytokine profile in relation to oxidative stress parameters in patients with severe COVID-19: an observational pilot study. F1000Res 2021; 10:719. [PMID: 34868558 PMCID: PMC8603313 DOI: 10.12688/f1000research.55166.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/28/2021] [Indexed: 09/22/2023] Open
Abstract
Introduction: COVID-19 can be worsened by hyper-production of cytokines accompanied by increased level of oxidative stress. The aim of this study was to investigate the correlation between a set of cytokines and the markers of the oxidative stress. Methods: The levels of cytokines IL-2, IL-4, IL-6, IL8, IL-10, VEGF, IFN-γ, TNF-α, IL-1α, MCP-1 and EGF were determined by using High Sensitivity Evidence Investigator™ Biochip Array technology. The oxidative stress parameters (d-ROM, PAT, OS index) were measured in serum on FRAS5 analytical photometric system. Results: IL-6, IL-8, IL-10, VEGF, MCP-1 and EGF were significantly higher (p<0.05) in the patients with severe COVID-19 with increased levels of IL-2, IFN-g, TNF-a and IL-1α. The d-ROM, OS index, and PAT were significantly higher (p<0.05) in severe COVID-19 patients. IL-6 demonstrated the strongest correlation with all of the markers of the oxidative stress, d-ROM (r=0.9725, p=0.0001), PAT (r=0.5000, p=0.0001) and OS index (r=0.9593, p=0.012). Similar behavior was evidenced between IFN-g and d-ROM (r=0.4006, p=0.0001), PAT (r=0.6030, p=0.0001) and OS index (r=0.4298, p=0.012). Conclusion: The oxidative stress markers show good correlation with the tested cytokines which can be measured at the beginning of the disease in a primary care setting to predict the course of COVID-19.
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Affiliation(s)
- Marija Petrushevska
- Institute of preclinical and clinical pharmacology and toxicology, University of Ss Cyril and Methodius, Faculty of Medicine, Skopje, Macedonia
| | - Dragica Zendelovska
- Institute of preclinical and clinical pharmacology and toxicology, University of Ss Cyril and Methodius, Faculty of Medicine, Skopje, Macedonia
| | - Emilija Atanasovska
- Institute of preclinical and clinical pharmacology and toxicology, University of Ss Cyril and Methodius, Faculty of Medicine, Skopje, Macedonia
| | - Aleksandar Eftimov
- Institute of pathology, University of Ss Cyril and Methodius, Faculty of Medicine, Skopje, Macedonia
| | - Katerina Spasovska
- University Clinic for Infectious Diseases and Febrile Conditions, Faculty of Medicine, University of Ss Cyril and Methodius, Skopje, Macedonia
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Pavan Kumar N, Padmapriyadarsini C, Rajamanickam A, Marinaik SB, Nancy A, Padmanaban S, Akbar N, Murhekar M, Babu S. Effect of BCG vaccination on proinflammatory responses in elderly individuals. SCIENCE ADVANCES 2021; 7:7/32/eabg7181. [PMID: 34348897 PMCID: PMC8336950 DOI: 10.1126/sciadv.abg7181] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Accepted: 04/15/2021] [Indexed: 05/06/2023]
Abstract
We investigated the influence of Bacillus Calmette-Guérin (BCG) vaccination on the unstimulated plasma levels of a wide panel of cytokines, chemokines, acute-phase proteins (APPs), matrix metalloproteinases (MMPs), and growth factors in a group of healthy elderly individuals (age, 60 to 80 years) at baseline (before vaccination) and 1 month after vaccination as part of our clinical study to examine the effect of BCG on COVID-19. Our results demonstrated that BCG vaccination resulted in diminished plasma levels of types 1, 2, and 17 and other proinflammatory cytokines and type 1 interferons. BCG vaccination also resulted in decreased plasma levels of CC, CXC chemokines, APPs, MMPs, and growth factors. Plasma levels of the aforementioned parameters were significantly lower in vaccinated individuals when compared to unvaccinated control individuals. Thus, our study demonstrates the immunomodulatory properties of BCG vaccination and suggests its potential utility in nonspecific vaccination of COVID-19 by down-modulating pathogenic inflammatory responses.
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Affiliation(s)
| | | | - Anuradha Rajamanickam
- ICMR-National Institute for Research in Tuberculosis- International Center for Excellence in Research, Chennai, India
| | | | - Arul Nancy
- ICMR-National Institute for Research in Tuberculosis- International Center for Excellence in Research, Chennai, India
| | | | - Nabila Akbar
- ICMR-National Institute for Research in Tuberculosis, Chennai, India
| | | | - Subash Babu
- ICMR-National Institute for Research in Tuberculosis- International Center for Excellence in Research, Chennai, India.
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Elpek GO. Molecular pathways in viral hepatitis-associated liver carcinogenesis: An update. World J Clin Cases 2021; 9:4890-4917. [PMID: 34307543 PMCID: PMC8283590 DOI: 10.12998/wjcc.v9.i19.4890] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 03/14/2021] [Accepted: 05/26/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of cancer among primary malignant tumors of the liver and is a consequential cause of cancer-related deaths worldwide. In recent years, uncovering the molecular mechanisms involved in the development and behavior of this tumor has led to the identification of multiple potential treatment targets. Despite the vast amount of data on this topic, HCC remains a challenging tumor to treat due to its aggressive behavior and complex molecular profile. Therefore, the number of studies aiming to elucidate the mechanisms involved in both carcinogenesis and tumor progression in HCC continues to increase. In this context, the close association of HCC with viral hepatitis has led to numerous studies focusing on the direct or indirect involvement of viruses in the mechanisms contributing to tumor development and behavior. In line with these efforts, this review was undertaken to highlight the current understanding of the molecular mechanisms by which hepatitis B virus (HBV) and hepatitis C virus (HCV) participate in oncogenesis and tumor progression in HCC and summarize new findings. Cumulative evidence indicates that HBV DNA integration promotes genomic instability, resulting in the overexpression of genes related to cancer development, metastasis, and angiogenesis or inactivation of tumor suppressor genes. In addition, genetic variations in HBV itself, especially preS2 deletions, may play a role in malignant transformation. Epigenetic dysregulation caused by both viruses might also contribute to tumor formation and metastasis by modifying the methylation of DNA and histones or altering the expression of microRNAs. Similarly, viral proteins of both HBV and HCV can affect pathways that are important anticancer targets. The effects of these two viruses on the Hippo-Yap-Taz pathway in HCC development and behavior need to be investigated. Additional, comprehensive studies are also needed to determine these viruses' interaction with integrins, farnesoid X, and the apelin system in malignant transformation and tumor progression. Although the relationship of persistent inflammation caused by HBV and HCV hepatitis with carcinogenesis is well defined, further studies are warranted to decipher the relationship among inflammasomes and viruses in carcinogenesis and elucidate the role of virus-microbiota interactions in HCC development and progression.
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Affiliation(s)
- Gulsum Ozlem Elpek
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Turkey
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Marlina R, Hatta M, Sridiana E, Djaharuddin I, Patellongi I, Murtiani F. The Effect of Miana (Coleus Scutellariodes [L]) on Vascular Endothelial Growth Factor Expression in Balb/C Mice Infected with Mycobacterium Tuberculosis. BIOMEDICAL AND PHARMACOLOGY JOURNAL 2021; 14:525-532. [DOI: 10.13005/bpj/2154] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2023]
Abstract
Tuberculosis (TB) is still a major global health problem. The increasing prevalence of antibiotic resistance has posed a major threat towards the mission of TB eradication. Traditional medication has been a staple alternative and adjuvant to conventional treatment for Indonesians. Miana leaves (Coleus scutellariodes) is one such traditional medicine that has a potential role as immunoregulator, antiinflammation, and antimicrobial agent. Several studies have shown that Miana leaves extract can regulate TLR 4, the number of CD4 T cells, IFN-γ levels, and TNF-α.Vascular Endothelial Growth Factor (VEGF) mediates angiogenesis and vasodilatation to provide oxygenation and access for immune cells in hypoxic and inflamed site sue to infection focus. This study aims to study the effect of Miana leaves on VEGF expression. Balb/c mice were infected with Mycobacterium tuberculosis and were treated using Miana leaves extract, rifampicin, and rifampicin plus Miana. VEGF protein levels before infection, after infection, and after treatment were measured using ELISA. The results showed that there was a significant difference in VEGF level means between treatment groups. VEGF levels in rifampicin, Miana, and rifampicin plus Miana groups were significantly lower than placebo. VEGF level was significantly lower in rifampicin group compared to Miana group. VEGF level was significantly lower in rifampicin plus Miana group compared to Miana group. There was no significant difference of VEGF level between rifampicin and rifampicin plus Miana group. The results indicate that Maina leaves does have an effect on VEGF level in mice infection with Mycobacterium tuberculosis.
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Affiliation(s)
- Rosa Marlina
- 1Sulianti Saroso Infectious Diseases Hospital, Jakarta, Indonesia
| | - Mochammad Hatta
- 2Molecular Biology and Immunology Laboratory, Faculty of Medicine Hasanusdin University, Makassar, Indonesia
| | - Eva Sridiana
- 3Pasar Rebo General Hospital, Jakarta, Indonesia
| | - Irawaty Djaharuddin
- 4Department of Pulmonology and Respiratory Medicine, Faculty of Medicine Hasanuddin University,Makassar, Indonesia
| | - Ilhamjaya Patellongi
- 5Department of Physiology, Faculty of Medicine Hasanuddin University, Makassar, Indonesia
| | - Farida Murtiani
- 1Sulianti Saroso Infectious Diseases Hospital, Jakarta, Indonesia
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Patel JC, Singh A, Tulswani R, Sharma YK, Khurana P, Ragumani S. Identification of VEGFA-centric temporal hypoxia-responsive dynamic cardiopulmonary network biomarkers. Life Sci 2021; 281:119718. [PMID: 34147483 DOI: 10.1016/j.lfs.2021.119718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 05/31/2021] [Accepted: 06/08/2021] [Indexed: 10/21/2022]
Abstract
AIMS Hypoxia, a pathophysiological condition, is profound in several cardiopulmonary diseases (CPD). Every individual's lethality to a hypoxia state differs in terms of hypoxia exposure time, dosage units and dependent on the individual's genetic makeup. Most of the proposed markers for CPD were generally aim to distinguish disease samples from normal samples. Although, as per the 2018 GOLD guidelines, clinically useful biomarkers for several cardio pulmonary disease patients in stable condition have yet to be identified. We attempt to address these key issues through the identification of Dynamic Network Biomarkers (DNB) to detect hypoxia induced early warning signals of CPD before the catastrophic deterioration. MATERIALS AND METHODS The human microvascular endothelial tissues microarray datasets (GSE11341) of lung and cardiac expose to hypoxia (1% O2) for 3, 24 and 48 h were retrieved from the public repository. The time dependent differentially expressed genes were subjected to tissue specificity and promoter analysis to filtrate the noise levels in the networks and to dissect the tissue specific hypoxia induced genes. These filtered out genes were used to construct the dynamic segmentation networks. The hypoxia induced dynamic differentially expressed genes were validated in the lung and heart tissues of male rats. These rats were exposed to hypobaric hypoxia (simulated altitude of 25,000 or PO2 - 282 mm of Hg) progressively for 3, 24 and 48 h. KEY FINDINGS To identify the temporal key genes regulated in hypoxia, we ranked the dominant genes based on their consolidated topological features from tissue specific networks, time dependent networks and dynamic networks. Overall topological ranking described VEGFA as a single node dynamic hub and strongly communicated with tissue specific genes to carry forward their tissue specific information. We named this type of VEGFAcentric dynamic networks as "V-DNBs". As a proof of principle, our methodology helped us to identify the V-DNBs specific for lung and cardiac tissues namely V-DNBL and V-DNBC respectively. SIGNIFICANCE Our experimental studies identified VEGFA, SLC2A3, ADM and ENO2 as the minimum and sufficient candidates of V-DNBL. The dynamic expression patterns could be readily exploited to capture the pre disease state of hypoxia induced pulmonary vascular remodelling. Whereas in V-DNBC the minimum and sufficient candidates are VEGFA, SCL2A3, ADM, NDRG1, ENO2 and BHLHE40. The time dependent single node expansion indicates V-DNBC could also be the pre disease state pathological hallmark for hypoxia-associated cardiovascular remodelling. The network cross-talk and expression pattern between V-DNBL and V-DNBC are completely distinct. On the other hand, the great clinical advantage of V-DNBs for pre disease predictions, a set of samples during the healthy condition should suffice. Future clinical studies might further shed light on the predictive power of V-DNBs as prognostic and diagnostic biomarkers for CPD.
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Affiliation(s)
- Jai Chand Patel
- Defence Institute of Physiology and Allied Sciences, Defence Research and Development Organization, Lucknow Road, Timarpur, Delhi, India
| | - Ajeet Singh
- Defence Institute of Physiology and Allied Sciences, Defence Research and Development Organization, Lucknow Road, Timarpur, Delhi, India
| | - Rajkumar Tulswani
- Defence Institute of Physiology and Allied Sciences, Defence Research and Development Organization, Lucknow Road, Timarpur, Delhi, India
| | - Yogendra Kumar Sharma
- Defence Institute of Physiology and Allied Sciences, Defence Research and Development Organization, Lucknow Road, Timarpur, Delhi, India
| | - Pankaj Khurana
- Defence Institute of Physiology and Allied Sciences, Defence Research and Development Organization, Lucknow Road, Timarpur, Delhi, India
| | - Sugadev Ragumani
- Defence Institute of Physiology and Allied Sciences, Defence Research and Development Organization, Lucknow Road, Timarpur, Delhi, India.
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Cahyono B, Amalina ND, Suzery M, Nur Wahyu Bima D. Exploring the Capability of Indonesia Natural Medicine Secondary Metabolite as Potential Inhibitors of SARS-CoV-2 Proteins to Prevent Virulence of COVID-19: In silico and Bioinformatic Approach. Open Access Maced J Med Sci 2021. [DOI: 10.3889/oamjms.2021.5945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND: SARS-CoV-2 was causing COVID-19 disease resulting in many deaths and being a significant concern in the world today. There is an emergent need to search for possible medications for COVID-19 treatment. The key point to halt SARS-CoV-2 infection through inhibition of the virus-receptor interaction and stimulates the immune system. Utilization of the bioinformatic and in silico molecular docking a number of available medications might be proven to be effective in inhibiting SARS-CoV-2 main drug targets including the SARS-CoV2 spike glycoprotein, the 3CL protease SARS-CoV-2 active target, PD-ACE2, 2019-nCoV PLpro, and NF-kβ.
AIM: This present study was conducted to identify the potential target and molecular mechanism of the major compound on Alpinia galanga extract and Citrus sinensis (L.) extract in circumventing COVID-19 using a bioinformatics approach and in silico molecular docking.
RESULTS: Direct protein target of all secondary metabolite and the gene list from PubMed “Severe acute respiratory syndrome coronavirus 2” generated 2 genes (CCL2 and VEGFA) as potential therapeutics target genes (PTTG). The molecular docking was conducted by the Protein-Ligand Ant System (PLANTS) software. The results show that hesperidin, naringenin, and galangin have lower docking score for all five-protein target receptor compared with chloroquine and remdesivir. The lower docking score suggests a high affinity to bind the protein. Moreover, these compounds have a strong affinity in their inhibitory capacity for viral infection.
CONCLUSION: In general, this study’s findings show that the compound of Alpinia galanga extract dan Citrus sinensis (L.) extract exhibit the best potential as an inhibitor to the development of the SARS-CoV-2 and inhibited cytokine storm through inactivation NF-kβ _pathway.
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Chen A, Tang S, He J, Li X, Peng G, Zhang H, Chen J, Chen L, Chen X. Small extracellular vesicles from human adipose-derived mesenchymal stromal cells: a potential promoter of fat graft survival. Stem Cell Res Ther 2021; 12:263. [PMID: 33941279 PMCID: PMC8091529 DOI: 10.1186/s13287-021-02319-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 03/31/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Small extracellular vesicles (sEVs) with genetic information secreted by cells play a crucial role in the cellular microenvironment. In this study, our purpose is to explore the characteristics of the small extracellular vesicles of human adipose-derived mesenchymal stromal cells (hADMSC-sEVs) and studied the role of hADMSC-sEVs in improving the survival rate of grafted fat. METHODS In the present study, we used the transmission electron microscopy, nano-tracking analysis, nanoflow surface protein analysis, and zeta potential value to identify sEVs. SEVs' trajectory was traced dynamically to verify whether hADMSC-sEVs can be internalized into human umbilical vein endothelial cells (HUVECs) in vitro at different times. The angiogenic property of hADMSC-sEVs was observed by measuring the volume, weight, and histological analysis of the grafted fats in nude mouse models. RESULTS Our research showed that the hADMSC-sEVs were sEVs with double-layer membrane structure and the diameter of which is within 30-150 nm. hADMSC-sEVs exert biological influence mainly through internalization into cells. Compared with the control group, the hADMSC-sEVs group had a significantly higher survival rate of grafted fat, morphological integrity, and a lower degree of inflammation and fibrosis. And immunohistochemistry showed that hADMSC-sEVs significantly increased the neovascularisation and the expression of CD34, VEGFR2, and Ki-67 in the graft tissue. CONCLUSIONS As a potential nanomaterial, hADMSC-sEVs have been explored in the field of cell-free application of stem cell technology. hADMSC-sEVs promoted the survival of grafted fats by promoting the formation of new blood vessels, which is another promising progress in the field of regenerative medicine. We believe that hADMSC-sEVs will have a broad application prospect in the field of regenerative medicine in the future.
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Affiliation(s)
- Aizhen Chen
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, China.,Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, China.,Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, China
| | - Shijie Tang
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, China.,Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, China.,Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, China
| | - Jiawei He
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, China.,Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, China
| | - Xiangyu Li
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, China.,Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, China
| | - Guohao Peng
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, China.,Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, China.,Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, China
| | - Haoruo Zhang
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, China.,Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, China.,Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, China
| | - Jinghua Chen
- Department of Pharmaceutical Analysis, the School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Liangwan Chen
- Department of Cardiac Surgery, Fujian Medical University Union Hospital, Fuzhou, China.
| | - Xiaosong Chen
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, China. .,Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, China.
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An Integrated Approach of the Potential Underlying Molecular Mechanistic Paradigms of SARS-CoV-2-Mediated Coagulopathy. Indian J Clin Biochem 2021; 36:387-403. [PMID: 33875909 PMCID: PMC8047580 DOI: 10.1007/s12291-021-00972-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Accepted: 04/03/2021] [Indexed: 02/06/2023]
Abstract
Coronavirus disease 2019 (Covid-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a pandemic disease which has affected more than 6.2 million people globally, with numbers mounting considerably daily. However, till date, no specific treatment modalities are available for Covid-19 and also not much information is known about this disease. Recent studies have revealed that SARS-CoV-2 infection is associated with the generation of thrombosis and coagulopathy. Fundamentally, it has been believed that a diverse array of signalling pathways might be responsible for the activation of coagulation cascade during SARS-CoV-2 infection. Henceforth, a detailed understanding of these probable underlying molecular mechanistic pathways causing thrombosis in Covid-19 disease deserves an urgent exploration. Therefore, in this review, the hypothetical crosstalk between distinct signalling pathways including apoptosis, inflammation, hypoxia and angiogenesis attributable for the commencement of thrombotic events during SARS-CoV-2 infection has been addressed which might further unravel promising therapeutic targets in Covid-19 disease.
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Wang X, Zhao H, Yang N, Jin Y, Chen J. Antiangiogenic Effect of Platelet P2Y 12 Inhibitor in Ischemia-Induced Angiogenesis in Mice Hindlimb. BIOMED RESEARCH INTERNATIONAL 2021; 2021:5529431. [PMID: 33898623 PMCID: PMC8052144 DOI: 10.1155/2021/5529431] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 03/20/2021] [Accepted: 03/22/2021] [Indexed: 11/17/2022]
Abstract
PURPOSE Postischemic inflammation induces angiogenesis, while platelet P2Y12 inhibitors can alleviate this inflammation. Therefore, we studied the potential effects of P2Y12 inhibitor, ticagrelor, on angiogenesis in a mouse model of hindlimb ischemia. METHODS Laser Doppler perfusion imaging and capillary density measurement were used for angiogenesis quantified. Immunofluorescence was used to detect the level of CD31. The mice muscle was harvested for enzyme-linked immunosorbent (ELISA) assay of interleukin- (IL) 10 activity and Western blot determination of vascular endothelial growth factor (VEGF) production. RESULTS Ischemic hindlimb angiogenesis was sharply decreased in IL-10+/+ mice than IL-10-/- mice. Ticagrelor inhibited angiogenesis and blood reperfusion recovery significantly elevated the levels of IL-10 and decreased the expression of VEGF in the IL-10+/+ mouse ischemic hindlimb, which were abolished in IL-10-deficient (IL-10-/-) C57BL/6J mice. CONCLUSION The study underscores that the effect of ticagrelor antiangiogenic function is related with the higher IL-10 expression.
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Affiliation(s)
- Xiaoli Wang
- School of Medicine, Jiangsu University, Zhenjiang 212013, China
- Clinical Laboratory, Huai'an Second People's Hospital Affiliated to Xuzhou Medical University, Huai'an 223002, China
| | - Huan Zhao
- Department of Cardiology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing 211100, China
| | - Naiquan Yang
- Department of Cardiology, Huai'an Second People's Hospital Affiliated to Xuzhou Medical University, Huai'an 223002, China
| | - Yue Jin
- Clinical Laboratory, Huai'an Second People's Hospital Affiliated to Xuzhou Medical University, Huai'an 223002, China
| | - Jianguo Chen
- Clinical Laboratory, People's Hospital Affiliated to Jiangsu University, Zhenjiang 212002, China
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Elkoshi Z. The Binary Classification of Protein Kinases. J Inflamm Res 2021; 14:929-947. [PMID: 33776467 PMCID: PMC7988341 DOI: 10.2147/jir.s303750] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 02/24/2021] [Indexed: 12/14/2022] Open
Abstract
In an earlier publication a binary model for chronic diseases classification has been proposed. According to the model, chronic diseases were classified as “high Treg” or “low Treg” diseases, depending on whether the immune response is anti- or pro-inflammatory and assuming that regulatory T cells are major determinants of the response. It turned out that most cancers are “high Treg” diseases, while autoimmune diseases are “low Treg”. This paper proposes a molecular cause for this binary response. The mechanism proposed depends on the effect of protein kinases on the immune system. Thus, protein kinases are classified as anti- or pro-inflammatory kinases depending on whether they drive “high Treg” or “low Treg” diseases. Observations reported in the earlier publication can be described in terms of anti-inflammatory kinase (AIK) or pro-inflammatory kinase (PIK) activity. Analysis of literature data reveals that the two classes of kinases display distinctive properties relating to their interactions with pathogens and environmental factors. Pathogens that promote Treg activity (“high Treg” pathogens) activate AIKs, while pathogens that suppress Treg activity (“low Treg” pathogens) activate PIKs. Diseases driven by AIKs are associated with “high Treg” pathogens while those diseases driven by PIKs are associated with “low Treg” pathogens. By promoting the activity of AIKs, alcohol consumption increases the risk of “high Treg” cancers but decreases the risk of some “low Treg” autoimmune diseases. JAK1 gain-of-function mutations are observed at high frequencies in autoimmune diseases while JAK1 loss-of-function mutations are observed at high frequencies in cancers with high tumor-infiltrating Tregs. It should also be noted that the corresponding two classes of protein kinase inhibitors are mutually exclusive in terms of their approved therapeutic indications. There is no protein kinase inhibitor that is approved for the treatment of both autoimmune diseases and “high Treg” cancers. Although there are exceptions to the conclusions presented above, these conclusions are supported by the great bulk of published data. It therefore seems that the binary division of protein kinases is a useful tool for elucidating (at the molecular level) many distinctive properties of cancers and autoimmune diseases.
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Affiliation(s)
- Zeev Elkoshi
- Research and Development Department, Taro Pharmaceutical Industries Ltd, Haifa, Israel
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Ma X, Lin Y, Liu Y, Li W, He J, Fang M, Lin D. Effects of Apigenin Treatment on Random Skin Flap Survival in Rats. Front Pharmacol 2021; 12:625733. [PMID: 33716750 PMCID: PMC7944095 DOI: 10.3389/fphar.2021.625733] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 01/04/2021] [Indexed: 11/13/2022] Open
Abstract
Random skin flaps are often used in plastic surgery, but the complications of marginal flap ischemia and necrosis often limit their wider clinical application. Apigenin (Api) is a flavonoid found in various fruits and vegetables. Api has been shown to promote angiogenesis, as well as reduce oxidative stress, membrane damage, and inflammation. In this study, we assessed the effects of Api treatment on random skin flap survival. Dorsal McFarlane skin flaps were transplanted into rats, which were randomly divided into three groups: control (normal saline), low-dose Api (20 mg/kg), and high-dose Api (50 mg/kg). Seven days after the surgery, the activity of superoxide dismutase (SOD) and the level of malondialdehyde (MDA) were measured. Histological analyses were performed to determine flap survival and tissue edema. H&E staining was performed to assess the histopathological changes in skin flaps, and the levels of microvascular density (MVD) were determined. Laser doppler flowmetry was used to assess microcirculation blood flow. Flap angiography was performed by injection of lead oxide/gelatin. The expression levels of vascular endothelial growth factor (VEGF), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interlukin-1β (IL-lβ) were evaluated by immunohistochemistry. Rats in the high-dose Api group exhibited higher average flap survival area, microcirculatory flow, increased SOD activity, and higher VEGF expression levels compared with the other two groups. Furthermore, the levels of MDA and pro-inflammatory cytokines were significantly decreased in rats treated with high-dose Api. Our findings suggest the potential usefulness of Api in preventing skin flap tissue necrosis.
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Affiliation(s)
- Xinyi Ma
- Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Second College of Clinical Medical, Wenzhou Medical University, Wenzhou, China
| | - Yuting Lin
- First College of Clinical Medical, Wenzhou Medical University, Wenzhou, China
| | - Yingying Liu
- Second College of Clinical Medical, Wenzhou Medical University, Wenzhou, China
| | - Wenjie Li
- Second College of Clinical Medical, Wenzhou Medical University, Wenzhou, China
| | - Jibing He
- Second College of Clinical Medical, Wenzhou Medical University, Wenzhou, China
| | - Miaojie Fang
- Second College of Clinical Medical, Wenzhou Medical University, Wenzhou, China
| | - Dingsheng Lin
- Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
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43
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Shi ML, Chen YF, Liao HF. Effect of luteolin on apoptosis and vascular endothelial growth factor in human choroidal melanoma cells. Int J Ophthalmol 2021; 14:186-193. [PMID: 33614445 DOI: 10.18240/ijo.2021.02.02] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Accepted: 10/12/2020] [Indexed: 12/29/2022] Open
Abstract
AIM To investigate the effects of luteolin on apoptosis, the cell cycle, and the expression and secretion of vascular endothelial growth factor (VEGF) in human choroidal melanoma cells (C918 and OCM-1). METHODS C918 and OCM-1 cells cultured in vitro were treated with various concentrations of luteolin (0, 5, 10, 15 µmol/L). Cell growth was observed with an inverted microscope, and cell cycle arrest was detected by propidium iodide (PI) staining using flow cytometry. Apoptosis was detected by Hoechst33342 staining, and apoptosis rate was determined by Annexin V-FITC/PI experiments using flow cytometry. The expression of apoptosis-related proteins Bcl-2, Bax and VEGF was analyzed using Western blots. The levels of VEGF secreted by the cells into the supernatant was analyzed using ELISA. RESULTS After treating with 5 to 15 µmol/L luteolin for 48h, the fusion degree of C918 and OCM-1 cells decreased, and more floating apoptotic cells appeared. Luteolin treatment increased the G0-G1 phase ratio of the C918 and OCM-1 cells, blocked cell cycle progression, and increased the apoptosis rate of the C918 and OCM-1 cells. Western blot showed that luteolin decreased the expression of Bcl-2 and VEGF in the C918 and OCM-1 cells and increased the expression of Bax protein. The ELISA results showed that 10 to 15 µmol/L luteolin decreased the cell secretion of VEGF. CONCLUSION Luteolin may induce apoptosis by regulating the levels of apoptosis-related proteins in C918 and OCM-1 cells. Luteolin can induce cell cycle arrest, decrease the expression of VEGF.
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Affiliation(s)
- Meng-Lin Shi
- Nanchang University, Nanchang 330000, Jiangxi Province, China.,Jiangxi Province Blood Center, Nanchang 330052, Jiangxi Province, China.,Jiangxi Research Institute of Ophthalmology & Visual Sciences, Nanchang 330006, Jiangxi Province, China
| | - Yu-Fen Chen
- Nanchang University, Nanchang 330000, Jiangxi Province, China.,Jiangxi Research Institute of Ophthalmology & Visual Sciences, Nanchang 330006, Jiangxi Province, China.,Department of Ophthalmology, the Affiliated Eye Hospital of Nanchang University, Nanchang 330000, Jiangxi Province, China
| | - Hong-Fei Liao
- Nanchang University, Nanchang 330000, Jiangxi Province, China.,Jiangxi Research Institute of Ophthalmology & Visual Sciences, Nanchang 330006, Jiangxi Province, China.,Department of Ophthalmology, the Affiliated Eye Hospital of Nanchang University, Nanchang 330000, Jiangxi Province, China
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Selvaraj G, Kaliamurthi S, Peslherbe GH, Wei DQ. Identifying potential drug targets and candidate drugs for COVID-19: biological networks and structural modeling approaches. F1000Res 2021; 10:127. [PMID: 33968364 PMCID: PMC8080978 DOI: 10.12688/f1000research.50850.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/10/2021] [Indexed: 02/05/2023] Open
Abstract
Background: Coronavirus (CoV) is an emerging human pathogen causing severe acute respiratory syndrome (SARS) around the world. Earlier identification of biomarkers for SARS can facilitate detection and reduce the mortality rate of the disease. Thus, by integrated network analysis and structural modeling approach, we aimed to explore the potential drug targets and the candidate drugs for coronavirus medicated SARS. Methods: Differentially expression (DE) analysis of CoV infected host genes (HGs) expression profiles was conducted by using the Limma. Highly integrated DE-CoV-HGs were selected to construct the protein-protein interaction (PPI) network. Results: Using the Walktrap algorithm highly interconnected modules include module 1 (202 nodes); module 2 (126 nodes) and module 3 (121 nodes) modules were retrieved from the PPI network. MYC, HDAC9, NCOA3, CEBPB, VEGFA, BCL3, SMAD3, SMURF1, KLHL12, CBL, ERBB4, and CRKL were identified as potential drug targets (PDTs), which are highly expressed in the human respiratory system after CoV infection. Functional terms growth factor receptor binding, c-type lectin receptor signaling, interleukin-1 mediated signaling, TAP dependent antigen processing and presentation of peptide antigen via MHC class I, stimulatory T cell receptor signaling, and innate immune response signaling pathways, signal transduction and cytokine immune signaling pathways were enriched in the modules. Protein-protein docking results demonstrated the strong binding affinity (-314.57 kcal/mol) of the ERBB4-3cLpro complex which was selected as a drug target. In addition, molecular dynamics simulations indicated the structural stability and flexibility of the ERBB4-3cLpro complex. Further, Wortmannin was proposed as a candidate drug to ERBB4 to control SARS-CoV-2 pathogenesis through inhibit receptor tyrosine kinase-dependent macropinocytosis, MAPK signaling, and NF-kb singling pathways that regulate host cell entry, replication, and modulation of the host immune system. Conclusion: We conclude that CoV drug target "ERBB4" and candidate drug "Wortmannin" provide insights on the possible personalized therapeutics for emerging COVID-19.
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Affiliation(s)
- Gurudeeban Selvaraj
- Centre for Research in Molecular Modeling, Concordia University, Montreal, Quebec, H4B 1R6, Canada
- Centre of Interdisciplinary Science-Computational Life Sciences, College of Chemistry and Chemical Engineering,, Henan University of Technology, Zhengzhou, Henan, 450001, China
| | - Satyavani Kaliamurthi
- Centre for Research in Molecular Modeling, Concordia University, Montreal, Quebec, H4B 1R6, Canada
- Centre of Interdisciplinary Science-Computational Life Sciences, College of Chemistry and Chemical Engineering,, Henan University of Technology, Zhengzhou, Henan, 450001, China
| | - Gilles H. Peslherbe
- Centre for Research in Molecular Modeling, Concordia University, Montreal, Quebec, H4B 1R6, Canada
| | - Dong-Qing Wei
- Centre of Interdisciplinary Science-Computational Life Sciences, College of Chemistry and Chemical Engineering,, Henan University of Technology, Zhengzhou, Henan, 450001, China
- The State Key Laboratory of Microbial Metabolism, College of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, Shanghai, 200240, China
- IASIA (International Association of Scientists in the Interdisciplinary Areas), 125 Boul. de Bromont, Quebec, J2L 2K7, Canada
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Selvaraj G, Kaliamurthi S, Peslherbe GH, Wei DQ. Identifying potential drug targets and candidate drugs for COVID-19: biological networks and structural modeling approaches. F1000Res 2021; 10:127. [PMID: 33968364 PMCID: PMC8080978 DOI: 10.12688/f1000research.50850.3] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/10/2021] [Indexed: 02/05/2023] Open
Abstract
Background: Coronavirus (CoV) is an emerging human pathogen causing severe acute respiratory syndrome (SARS) around the world. Earlier identification of biomarkers for SARS can facilitate detection and reduce the mortality rate of the disease. Thus, by integrated network analysis and structural modeling approach, we aimed to explore the potential drug targets and the candidate drugs for coronavirus medicated SARS. Methods: Differentially expression (DE) analysis of CoV infected host genes (HGs) expression profiles was conducted by using the Limma. Highly integrated DE-CoV-HGs were selected to construct the protein-protein interaction (PPI) network. Results: Using the Walktrap algorithm highly interconnected modules include module 1 (202 nodes); module 2 (126 nodes) and module 3 (121 nodes) modules were retrieved from the PPI network. MYC, HDAC9, NCOA3, CEBPB, VEGFA, BCL3, SMAD3, SMURF1, KLHL12, CBL, ERBB4, and CRKL were identified as potential drug targets (PDTs), which are highly expressed in the human respiratory system after CoV infection. Functional terms growth factor receptor binding, c-type lectin receptor signaling, interleukin-1 mediated signaling, TAP dependent antigen processing and presentation of peptide antigen via MHC class I, stimulatory T cell receptor signaling, and innate immune response signaling pathways, signal transduction and cytokine immune signaling pathways were enriched in the modules. Protein-protein docking results demonstrated the strong binding affinity (-314.57 kcal/mol) of the ERBB4-3cLpro complex which was selected as a drug target. In addition, molecular dynamics simulations indicated the structural stability and flexibility of the ERBB4-3cLpro complex. Further, Wortmannin was proposed as a candidate drug to ERBB4 to control SARS-CoV-2 pathogenesis through inhibit receptor tyrosine kinase-dependent macropinocytosis, MAPK signaling, and NF-kb singling pathways that regulate host cell entry, replication, and modulation of the host immune system. Conclusion: We conclude that CoV drug target "ERBB4" and candidate drug "Wortmannin" provide insights on the possible personalized therapeutics for emerging COVID-19.
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Affiliation(s)
- Gurudeeban Selvaraj
- Centre for Research in Molecular Modeling, Concordia University, Montreal, Quebec, H4B 1R6, Canada
- Centre of Interdisciplinary Science-Computational Life Sciences, College of Chemistry and Chemical Engineering,, Henan University of Technology, Zhengzhou, Henan, 450001, China
| | - Satyavani Kaliamurthi
- Centre for Research in Molecular Modeling, Concordia University, Montreal, Quebec, H4B 1R6, Canada
- Centre of Interdisciplinary Science-Computational Life Sciences, College of Chemistry and Chemical Engineering,, Henan University of Technology, Zhengzhou, Henan, 450001, China
| | - Gilles H. Peslherbe
- Centre for Research in Molecular Modeling, Concordia University, Montreal, Quebec, H4B 1R6, Canada
| | - Dong-Qing Wei
- Centre of Interdisciplinary Science-Computational Life Sciences, College of Chemistry and Chemical Engineering,, Henan University of Technology, Zhengzhou, Henan, 450001, China
- The State Key Laboratory of Microbial Metabolism, College of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, Shanghai, 200240, China
- IASIA (International Association of Scientists in the Interdisciplinary Areas), 125 Boul. de Bromont, Quebec, J2L 2K7, Canada
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Selvaraj G, Kaliamurthi S, Peslherbe GH, Wei DQ. Identifying potential drug targets and candidate drugs for COVID-19: biological networks and structural modeling approaches. F1000Res 2021; 10:127. [PMID: 33968364 PMCID: PMC8080978 DOI: 10.12688/f1000research.50850.2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/10/2021] [Indexed: 11/08/2024] Open
Abstract
Background: Coronavirus (CoV) is an emerging human pathogen causing severe acute respiratory syndrome (SARS) around the world. Earlier identification of biomarkers for SARS can facilitate detection and reduce the mortality rate of the disease. Thus, by integrated network analysis and structural modeling approach, we aimed to explore the potential drug targets and the candidate drugs for coronavirus medicated SARS. Methods: Differentially expression (DE) analysis of CoV infected host genes (HGs) expression profiles was conducted by using the Limma. Highly integrated DE-CoV-HGs were selected to construct the protein-protein interaction (PPI) network. Results: Using the Walktrap algorithm highly interconnected modules include module 1 (202 nodes); module 2 (126 nodes) and module 3 (121 nodes) modules were retrieved from the PPI network. MYC, HDAC9, NCOA3, CEBPB, VEGFA, BCL3, SMAD3, SMURF1, KLHL12, CBL, ERBB4, and CRKL were identified as potential drug targets (PDTs), which are highly expressed in the human respiratory system after CoV infection. Functional terms growth factor receptor binding, c-type lectin receptor signaling, interleukin-1 mediated signaling, TAP dependent antigen processing and presentation of peptide antigen via MHC class I, stimulatory T cell receptor signaling, and innate immune response signaling pathways, signal transduction and cytokine immune signaling pathways were enriched in the modules. Protein-protein docking results demonstrated the strong binding affinity (-314.57 kcal/mol) of the ERBB4-3cLpro complex which was selected as a drug target. In addition, molecular dynamics simulations indicated the structural stability and flexibility of the ERBB4-3cLpro complex. Further, Wortmannin was proposed as a candidate drug to ERBB4 to control SARS-CoV-2 pathogenesis through inhibit receptor tyrosine kinase-dependent macropinocytosis, MAPK signaling, and NF-kb singling pathways that regulate host cell entry, replication, and modulation of the host immune system. Conclusion: We conclude that CoV drug target "ERBB4" and candidate drug "Wortmannin" provide insights on the possible personalized therapeutics for emerging COVID-19.
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Affiliation(s)
- Gurudeeban Selvaraj
- Centre for Research in Molecular Modeling, Concordia University, Montreal, Quebec, H4B 1R6, Canada
- Centre of Interdisciplinary Science-Computational Life Sciences, College of Chemistry and Chemical Engineering,, Henan University of Technology, Zhengzhou, Henan, 450001, China
| | - Satyavani Kaliamurthi
- Centre for Research in Molecular Modeling, Concordia University, Montreal, Quebec, H4B 1R6, Canada
- Centre of Interdisciplinary Science-Computational Life Sciences, College of Chemistry and Chemical Engineering,, Henan University of Technology, Zhengzhou, Henan, 450001, China
| | - Gilles H. Peslherbe
- Centre for Research in Molecular Modeling, Concordia University, Montreal, Quebec, H4B 1R6, Canada
| | - Dong-Qing Wei
- Centre of Interdisciplinary Science-Computational Life Sciences, College of Chemistry and Chemical Engineering,, Henan University of Technology, Zhengzhou, Henan, 450001, China
- The State Key Laboratory of Microbial Metabolism, College of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, Shanghai, 200240, China
- IASIA (International Association of Scientists in the Interdisciplinary Areas), 125 Boul. de Bromont, Quebec, J2L 2K7, Canada
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Iriana S, Asha K, Repak M, Sharma-Walia N. Hedgehog Signaling: Implications in Cancers and Viral Infections. Int J Mol Sci 2021; 22:1042. [PMID: 33494284 PMCID: PMC7864517 DOI: 10.3390/ijms22031042] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/11/2021] [Accepted: 01/14/2021] [Indexed: 12/14/2022] Open
Abstract
The hedgehog (SHH) signaling pathway is primarily involved in embryonic gut development, smooth muscle differentiation, cell proliferation, adult tissue homeostasis, tissue repair following injury, and tissue polarity during the development of vertebrate and invertebrate organisms. GLIoma-associated oncogene homolog (GLI) family of zinc-finger transcription factors and smoothened (SMO) are the signal transducers of the SHH pathway. Both SHH ligand-dependent and independent mechanisms activate GLI proteins. Various transcriptional mechanisms, posttranslational modifications (phosphorylation, ubiquitination, proteolytic processing, SUMOylation, and acetylation), and nuclear-cytoplasmic shuttling control the activity of SHH signaling pathway proteins. The dysregulated SHH pathway is associated with bone and soft tissue sarcomas, GLIomas, medulloblastomas, leukemias, and tumors of breast, lung, skin, prostate, brain, gastric, and pancreas. While extensively studied in development and sarcomas, GLI family proteins play an essential role in many host-pathogen interactions, including bacterial and viral infections and their associated cancers. Viruses hijack host GLI family transcription factors and their downstream signaling cascades to enhance the viral gene transcription required for replication and pathogenesis. In this review, we discuss a distinct role(s) of GLI proteins in the process of tumorigenesis and host-pathogen interactions in the context of viral infection-associated malignancies and cancers due to other causes. Here, we emphasize the potential of the Hedgehog (HH) pathway targeting as a potential anti-cancer therapeutic approach, which in the future could also be tested in infection-associated fatalities.
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Angiogenesis in Regenerative Dentistry: Are We Far Enough for Therapy? Int J Mol Sci 2021; 22:ijms22020929. [PMID: 33477745 PMCID: PMC7832295 DOI: 10.3390/ijms22020929] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 01/14/2021] [Accepted: 01/15/2021] [Indexed: 12/14/2022] Open
Abstract
Angiogenesis is a broad spread term of high interest in regenerative medicine and tissue engineering including the dental field. In the last two decades, researchers worldwide struggled to find the best ways to accelerate healing, stimulate soft, and hard tissue remodeling. Stem cells, growth factors, pathways, signals, receptors, genetics are just a few words that describe this area in medicine. Dental implants, bone and soft tissue regeneration using autologous grafts, or xenografts, allografts, their integration and acceptance rely on their material properties. However, the host response, through its vascularization, plays a significant role. The present paper aims to analyze and organize the latest information about the available dental stem cells, the types of growth factors with pro-angiogenic effect and the possible therapeutic effect of enhanced angiogenesis in regenerative dentistry.
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Indari O, Chandramohanadas R, Jha HC. Epstein-Barr virus infection modulates blood-brain barrier cells and its co-infection with Plasmodium falciparum induces RBC adhesion. Pathog Dis 2021; 79:ftaa080. [PMID: 33355336 DOI: 10.1093/femspd/ftaa080] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 12/21/2020] [Indexed: 12/16/2022] Open
Abstract
Plasmodium falciparum infection-mediated Epstein-Barr virus (EBV) reactivation is well established in malaria-endemic countries. We hypothesize that, during malaria onset, the reactivated EBV can infect human brain microvascular endothelial cells (HBECs). This may cause severe cerebral manifestations. We infected HBECs with EBV in vitro. The subsequent gene expression pattern of EBV, inflammatory and endothelial markers was analysed using qRT-PCR. Further, a wound-healing assay for cells maintaining blood-brain barrier (BBB) integrity was performed to investigate the effect of EBV-infected HBECs secretions. The RBC adhesion assay was conducted to assess RBC attachment onto HBECs during EBV and P. falciparum mono- and co-infection. Our experiments revealed that EBV infection of HBECs significantly elevated several inflammatory (TNFα, CCL2) and endothelial (integrin β3, PECAM, VEGFA, VWF, claudin-5, cx37) markers. The EBV-infected HBECs secretion significantly reduced migration of HBECs, glial and neuronal cells. Additionally, EBV-P. falciparum co-infection significantly (P < 0.05) enhanced RBC adhesion to HBECs compared to mono-infection scenarios. Conclusively, the EBV infection of HBECs led to endothelial activation and modulated the BBB microenvironment. The EBV-P. falciparum co-infection scenario increased RBC adhesion on ECs which is a hallmark of cerebral malaria. Together with malaria, EBV infection can aid in exacerbation of cerebral malaria pathology.
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Affiliation(s)
- Omkar Indari
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore 453552, India
| | - Rajesh Chandramohanadas
- Department of Microbiology and Immunology, National University of Singapore, Singapore 117545, Singapore
| | - Hem Chandra Jha
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore 453552, India
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Almaeen AH, Alduraywish AA, Mobasher MA, Almadhi OIM, Nafeh HM, El-Metwally TH. Oxidative stress, immunological and cellular hypoxia biomarkers in hepatitis C treatment-naïve and cirrhotic patients. Arch Med Sci 2021; 17:368-375. [PMID: 33747272 PMCID: PMC7959056 DOI: 10.5114/aoms.2019.91451] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Accepted: 11/13/2019] [Indexed: 12/11/2022] Open
Abstract
INTRODUCTION Hepatitis C virus (HCV) is the main cause of chronic liver disease, with calamitous complications. Its highest rate is recorded in Egypt. This study investigated whether oxidative stress, immunological chaos and cellular hypoxia are implicated in the pathophysiology of the disease. MATERIAL AND METHODS This cross-sectional study aimed to evaluate the changes in blood oxidative stress, cellular hypoxia/angiogenesis and cellular immunological biomarkers in hospital-diagnosed treatment-naïve HCV-infected Upper Egyptian chronic liver disease patients vs. healthy controls (n = 40). The consecutively included patients comprised 120 with normal serum enzymes (HCV-NE) and 130 with high serum enzymes (HCV-HE), along with 120 cirrhotic patients. RESULTS Oxidative stress biomarkers - malondialdehyde (MDA), total peroxides and oxidative stress index (OSI) - were significantly lower in controls vs. each of the patient groups. Cirrhotic patients presented the highest levels. However, total antioxidants (TAO) showed non-significant differences among the four groups. The cellular hypoxia/angiogenesis biomarkers - lactate, vascular endothelial cell growth factor (VEGF) and its soluble receptor 1 (sVEGFR1) - vs. controls were massively increased in patient groups. VEGF was lowest while sVEGFR1 was highest among cirrhotic patients. Immunological biomarkers, - granulocyte/monocyte-colony stimulating factor (GM-CSF) and total immunoglobulin G (IgG) - were massively increased in patient groups vs. controls. GM-CSF was lowest in HCV-HE and IgG was highest in cirrhotic patients. sVEGFR1 correlated with the progression towards cirrhosis. CONCLUSIONS Oxidative stress is implicated in the progress of HCV infection with marked induction of cellular hypoxia and dysfunctional angiogenesis, and a futile immunological reaction. sVEGFR1 level correlated with progression towards HCV-induced liver fibrosis.
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Affiliation(s)
| | | | - Maysa Ahmed Mobasher
- Department of Pathology, Jouf University College of Medicine, Sakaka, Saudi Arabia
| | - Omar I. M. Almadhi
- College of Medicine, Jouf University College of Medicine, Sakaka, Saudi Arabia
| | - Hanan M. Nafeh
- Department of Tropical Medicine and Gastroenterology, Assiut University, Faculty of Medicine, Assiut, Egypt
| | - Tarek Hassan El-Metwally
- Department of Pathology, Jouf University College of Medicine, Sakaka, Saudi Arabia
- Department of Medical Biochemistry, Assiut University, Faculty of Medicine, Assiut, Egypt
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