|
1
|
Rosales JJ, Brunner MB, Rodríguez M, Marin M, Maldonado EN, Pérez S. Reactive oxygen species favors Varicellovirus bovinealpha 5 (BoAHV-5) replication in neural cells. Mitochondrion 2025; 81:102005. [PMID: 39778729 DOI: 10.1016/j.mito.2025.102005] [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: 10/09/2024] [Revised: 12/24/2024] [Accepted: 01/05/2025] [Indexed: 01/11/2025]
Abstract
Varicellovirus bovinealpha (BoAHV) 1 and 5 are closely related neurotropic alphaherpesviruses with distinct neuropathogenic potential. BoAHV-5 causes meningoencephalitis in calves whereas encephalitis by BoAHV-1 infection is sporadic. the mechanisms underlying the differences in tropism and clinical outcomes of the infections are not yet completely understood. Here, we used neuroblastoma SH-SY5Y cells as non-differentiated in comparison with the SH-SY5Y neuronal-like cells obtained after exposing SH-SY5Y undifferentiated cells to trans-retinoic acid. We aimed to establish whether there was a relationship between the production of reactive oxygen species (ROS) and the kinetics of virus replication. We demonstrated that ROS production after BoAHV infection was higher in differentiated cells. Generation of ROS was also dependent on the infecting BoAHV strain. Higher ROS levels were produced during BoAHV-5 infection concomitantly with enhanced viral replication. We propose that increased ROS production mechanistically contributes to the tissue damage and neuroinflammation induced by BoAHV-5 infection. Future studies will determine specific targets of ROS that mediate the effects on viral replication.
Collapse
Affiliation(s)
- Juan José Rosales
- Laboratorio de Virología, Centro de Investigación Veterinaria de Tandil (CIVETAN), UNCPBA-CICPBA-CONICET, Campus Universitario, Tandil, Buenos Aires, Argentina; Universidad Nacional del Centro de la Provincia de Buenos Aires (UNCPBA), Facultad de Ciencias Veterinarias, Campus Universitario, Tandil, Buenos Aires, Argentina
| | - María Belén Brunner
- Laboratorio de Virología, Centro de Investigación Veterinaria de Tandil (CIVETAN), UNCPBA-CICPBA-CONICET, Campus Universitario, Tandil, Buenos Aires, Argentina; Universidad Nacional del Centro de la Provincia de Buenos Aires (UNCPBA), Facultad de Ciencias Veterinarias, Campus Universitario, Tandil, Buenos Aires, Argentina
| | - Marcelo Rodríguez
- Universidad Nacional del Centro de la Provincia de Buenos Aires (UNCPBA), Facultad de Ciencias Veterinarias, Campus Universitario, Tandil, Buenos Aires, Argentina
| | - Maia Marin
- Instituto de Innovación para la Producción Agropecuaria y el Desarrollo Sostenible (IPADS Balcarce), INTA-CONICET, Balcarce, Buenos Aires, Argentina
| | - Eduardo Néstor Maldonado
- Department of Drug Discovery & Pharmaceutical Sciences, Medical University of South Carolina, Charleston, SC, USA
| | - Sandra Pérez
- Laboratorio de Virología, Centro de Investigación Veterinaria de Tandil (CIVETAN), UNCPBA-CICPBA-CONICET, Campus Universitario, Tandil, Buenos Aires, Argentina; Universidad Nacional del Centro de la Provincia de Buenos Aires (UNCPBA), Facultad de Ciencias Veterinarias, Campus Universitario, Tandil, Buenos Aires, Argentina.
| |
Collapse
|
|
2
|
Wang Y, Luan T, Wang L, Feng D, Dong Y, Li S, Yang H, Chen Y, Fei Y, Lin L, Pan J, Zhong Z, Zhao W. N-Acetylcysteine Inhibits Coxsackievirus B3 Replication by Downregulating Eukaryotic Translation Elongation Factor 1 Alpha 1. Viruses 2024; 16:1503. [PMID: 39339978 PMCID: PMC11437456 DOI: 10.3390/v16091503] [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: 07/26/2024] [Revised: 09/17/2024] [Accepted: 09/21/2024] [Indexed: 09/30/2024] Open
Abstract
Group B Coxsackieviruses (CVB) are one of the causative pathogens of myocarditis, which may progress to cardiomyopathy. The pathogenesis of CVB is not fully understood, and effective antiviral therapy is not available. N-acetylcysteine (NAC), the classic antioxidant, has been used in clinical practice for several decades to treat various medical conditions. In this study, the anti-CVB effect of NAC was investigated. We show that NAC dramatically suppressed viral replication and alleviated cardiac injury induced by CVB3. To further study the antiviral mechanism of NAC, RNA-sequencing was performed for CVB3-infected cells with NAC treatment. We found that eukaryotic elongation factor 1 alpha 1 (EEF1A1) is one of the most upregulated genes in CVB3-infected cells. However, EEF1A2, the highly homologous isoform of EEF1A1, remains unchanged. EEF1A1 expression was significantly suppressed by NAC treatment in CVB3-infected cells, while EEF1A2 was not affected. eEF1A1 knockdown significantly inhibited CVB3 replication, implicating that eEF1A1 facilitates viral replication. Importantly, we show that eEF1A1, which was not expressed in the myocardia of newborn mice, was significantly upregulated by CVB3 infection. NAC markedly downregulated the expression of eEF1A1 but not eEF1A2 in the myocardia of CVB3-infected mice. Furthermore, NAC accelerated eEF1A1 degradation by promoting autophagy in CVB3-infected cells. We show that p62, one of the critical adaptors of autophagic targets, interacts with eEF1A1 and was downregulated in CVB3-infected cells upon NAC treatment. Taken together, this study demonstrated that NAC shows a potent anti-CVB effect through the downregulation of eEF1A1.
Collapse
Affiliation(s)
- Yao Wang
- Department of Cell Biology, Harbin Medical University, 157 Baojian Road, Harbin 150081, China
| | - Tian Luan
- Department of Cell Biology, Harbin Medical University, 157 Baojian Road, Harbin 150081, China
| | - Lixin Wang
- Department of Cell Biology, Harbin Medical University, 157 Baojian Road, Harbin 150081, China
| | - Danxiang Feng
- Department of Cell Biology, Harbin Medical University, 157 Baojian Road, Harbin 150081, China
| | - Yanyan Dong
- Department of Cell Biology, Harbin Medical University, 157 Baojian Road, Harbin 150081, China
| | - Siwei Li
- Department of Cell Biology, Harbin Medical University, 157 Baojian Road, Harbin 150081, China
| | - Hong Yang
- Department of Cell Biology, Harbin Medical University, 157 Baojian Road, Harbin 150081, China
| | - Yang Chen
- Department of Microbiology, Harbin Medical University, 157 Baojian Road, Harbin 150081, China
| | - Yanru Fei
- Department of Microbiology, Harbin Medical University, 157 Baojian Road, Harbin 150081, China
| | - Lexun Lin
- Department of Microbiology, Harbin Medical University, 157 Baojian Road, Harbin 150081, China
| | - Jiahui Pan
- Department of Cell Biology, Harbin Medical University, 157 Baojian Road, Harbin 150081, China
| | - Zhaohua Zhong
- Department of Microbiology, Harbin Medical University, 157 Baojian Road, Harbin 150081, China
| | - Wenran Zhao
- Department of Cell Biology, Harbin Medical University, 157 Baojian Road, Harbin 150081, China
| |
Collapse
|
|
3
|
Frasson I, Diamante L, Zangrossi M, Carbognin E, Pietà AD, Penna A, Rosato A, Verin R, Torrigiani F, Salata C, Dizanzo MP, Vaccaro L, Cacchiarelli D, Richter SN, Montagner M, Martello G. Identification of druggable host dependency factors shared by multiple SARS-CoV-2 variants of concern. J Mol Cell Biol 2024; 16:mjae004. [PMID: 38305139 PMCID: PMC11411213 DOI: 10.1093/jmcb/mjae004] [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: 02/03/2023] [Revised: 06/23/2023] [Accepted: 01/31/2024] [Indexed: 02/03/2024] Open
Abstract
The high mutation rate of SARS-CoV-2 leads to the emergence of multiple variants, some of which are resistant to vaccines and drugs targeting viral elements. Targeting host dependency factors, e.g. cellular proteins required for viral replication, would help prevent the development of resistance. However, it remains unclear whether different SARS-CoV-2 variants induce conserved cellular responses and exploit the same core host factors. To this end, we compared three variants of concern and found that the host transcriptional response was conserved, differing only in kinetics and magnitude. Clustered regularly interspaced short palindromic repeats screening identified host genes required for each variant during infection. Most of the genes were shared by multiple variants. We validated our hits with small molecules and repurposed the US Food and Drug Administration-approved drugs. All the drugs were highly active against all the tested variants, including new variants that emerged during the study (Delta and Omicron). Mechanistically, we identified reactive oxygen species production as a key step in early viral replication. Antioxidants such as N-acetyl cysteine (NAC) were effective against all the variants in both human lung cells and a humanized mouse model. Our study supports the use of available antioxidant drugs, such as NAC, as a general and effective anti-COVID-19 approach.
Collapse
Affiliation(s)
- Ilaria Frasson
- Department of Molecular Medicine, University of Padua, Padua 35121, Italy
| | - Linda Diamante
- Department of Molecular Medicine, University of Padua, Padua 35121, Italy
- Department of Biology, Armenise/Harvard Pluripotent Stem Cell Biology Laboratory, University of Padua, Padua 35131, Italy
| | - Manuela Zangrossi
- Department of Molecular Medicine, University of Padua, Padua 35121, Italy
| | - Elena Carbognin
- Department of Biology, Armenise/Harvard Pluripotent Stem Cell Biology Laboratory, University of Padua, Padua 35131, Italy
| | - Anna Dalla Pietà
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua 35128, Italy
| | - Alessandro Penna
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua 35128, Italy
| | - Antonio Rosato
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua 35128, Italy
- Veneto Institute of Oncology IOV-IRCCS, Padua 35128, Italy
| | - Ranieri Verin
- Department of Comparative Biomedicine and Food Science, University of Padua, Padua 35020, Italy
| | - Filippo Torrigiani
- Department of Comparative Biomedicine and Food Science, University of Padua, Padua 35020, Italy
| | - Cristiano Salata
- Department of Molecular Medicine, University of Padua, Padua 35121, Italy
| | | | - Lorenzo Vaccaro
- Telethon Institute of Genetics and Medicine (TIGEM), Armenise/Harvard Laboratory of Integrative Genomics, Pozzuoli 80078, Italy
- Department of Translational Medicine, University of Naples Federico II, Naples 80138, Italy
| | - Davide Cacchiarelli
- Telethon Institute of Genetics and Medicine (TIGEM), Armenise/Harvard Laboratory of Integrative Genomics, Pozzuoli 80078, Italy
- Department of Translational Medicine, University of Naples Federico II, Naples 80138, Italy
- School for Advanced Studies, Genomics and Experimental Medicine Program, University of Naples Federico II, Naples 80138, Italy
| | - Sara N Richter
- Department of Molecular Medicine, University of Padua, Padua 35121, Italy
- Microbiology and Virology Unit, Padua University Hospital, Padua 35128, Italy
| | - Marco Montagner
- Department of Molecular Medicine, University of Padua, Padua 35121, Italy
| | - Graziano Martello
- Department of Biology, Armenise/Harvard Pluripotent Stem Cell Biology Laboratory, University of Padua, Padua 35131, Italy
| |
Collapse
|
|
4
|
Wei Y, Gu Y, Zhou Z, Wu C, Liu Y, Sun H. TRIM21 Promotes Oxidative Stress and Ferroptosis through the SQSTM1-NRF2-KEAP1 Axis to Increase the Titers of H5N1 Highly Pathogenic Avian Influenza Virus. Int J Mol Sci 2024; 25:3315. [PMID: 38542289 PMCID: PMC10970474 DOI: 10.3390/ijms25063315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 02/26/2024] [Accepted: 03/03/2024] [Indexed: 04/04/2024] Open
Abstract
Tripartite motif-containing protein 21 (TRIM21) is involved in signal transduction and antiviral responses through the ubiquitination of protein targets. TRIM21 was reported to be related to the imbalance of host cell homeostasis caused by viral infection. Our studies indicated that H5N1 highly pathogenic avian influenza virus (HPAIV) infection up-regulated TRIM21 expression in A549 cells. Western blot and qPCR results showed that knockdown of TRIM21 alleviated oxidative stress and ferroptosis induced by H5N1 HPAIV and promoted the activation of antioxidant pathways. Co-IP results showed that TRIM21 promoted oxidative stress and ferroptosis by regulating the SQSTM1-NRF2-KEAP1 axis by increasing SQSTM1 K63-linked polyubiquitination under the condition of HPAIV infection. In addition, TRIM21 attenuated the inhibitory effect of antioxidant NAC on HPAIV titers and enhanced the promoting effect of ferroptosis agonist Erastin on HPAIV titers. Our findings provide new insight into the role of TRIM21 in oxidative stress and ferroptosis induced by viral infection.
Collapse
Affiliation(s)
- Yifan Wei
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China; (Y.W.); (Y.G.); (Z.Z.); (C.W.); (Y.L.)
- Key Laboratory of Zoonosis Control and Prevention of Guangdong Province, South China Agricultural University, Guangzhou 510642, China
- National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control, South China Agricultural University, Guangzhou 510642, China
| | - Yongxia Gu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China; (Y.W.); (Y.G.); (Z.Z.); (C.W.); (Y.L.)
- Key Laboratory of Zoonosis Control and Prevention of Guangdong Province, South China Agricultural University, Guangzhou 510642, China
- National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control, South China Agricultural University, Guangzhou 510642, China
| | - Ziwei Zhou
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China; (Y.W.); (Y.G.); (Z.Z.); (C.W.); (Y.L.)
- Key Laboratory of Zoonosis Control and Prevention of Guangdong Province, South China Agricultural University, Guangzhou 510642, China
- National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control, South China Agricultural University, Guangzhou 510642, China
| | - Changrong Wu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China; (Y.W.); (Y.G.); (Z.Z.); (C.W.); (Y.L.)
- Key Laboratory of Zoonosis Control and Prevention of Guangdong Province, South China Agricultural University, Guangzhou 510642, China
- National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control, South China Agricultural University, Guangzhou 510642, China
| | - Yanwei Liu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China; (Y.W.); (Y.G.); (Z.Z.); (C.W.); (Y.L.)
- Key Laboratory of Zoonosis Control and Prevention of Guangdong Province, South China Agricultural University, Guangzhou 510642, China
- National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control, South China Agricultural University, Guangzhou 510642, China
| | - Hailiang Sun
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China; (Y.W.); (Y.G.); (Z.Z.); (C.W.); (Y.L.)
- Key Laboratory of Zoonosis Control and Prevention of Guangdong Province, South China Agricultural University, Guangzhou 510642, China
- National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control, South China Agricultural University, Guangzhou 510642, China
| |
Collapse
|
|
5
|
Rajewska-Tabor J, Sosińska-Zawierucha P, Pyda M, Lesiak M, Bręborowicz A. Protective role of N-acetylcysteine and Sulodexide on endothelial cells exposed on patients' serum after SARS-CoV-2 infection. Front Cell Infect Microbiol 2023; 13:1268016. [PMID: 38188630 PMCID: PMC10768024 DOI: 10.3389/fcimb.2023.1268016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 11/09/2023] [Indexed: 01/09/2024] Open
Abstract
Severe acute respiratory syndrome coronavirus-2 causes hyperinflammation and activation of coagulation cascade and, as a result, aggravates endothelial cell dysfunction. N-acetylcysteine and Sulodexide have been found to mitigate endothelial damage. The influence on coronary artery endothelial cells of serum collected after 4 ± 1 months from coronavirus infection was studied. The concentrations of serum samples of interleukin 6, von Willebrand Factor, tissue Plasminogen Activator, and Plasminogen Activator Inhibitor-1 were studied. The cultures with serum of patients after coronavirus infection were incubated with N-acetylcysteine and Sulodexide to estimate their potential protective role. The blood inflammatory parameters were increased in the group of cultures incubated with serum from patients after coronavirus infection. Supplementation of the serum from patients after coronavirus infection with N-acetylcysteine or Sulodexide reduced the synthesis of interleukin 6 and von Willebrand Factor. No changes in the synthesis of tissue Plasminogen Activator were observed. N-acetylcysteine reduced the synthesis of Plasminogen Activator Inhibitor-1. N-acetylcysteine and Sulodexide increased the tPA/PAI-1 ratio. N-acetylcysteine may have a role in reducing the myocardial injury occurring in the post-COVID-19 syndrome. Sulodexide can also play a protective role in post-COVID-19 patients.
Collapse
Affiliation(s)
- Justyna Rajewska-Tabor
- I Clinic of Cardiology, Unit of Magnetic Resonance, Poznan University of Medical Sciences, Poznan, Poland
| | | | - Malgorzata Pyda
- I Clinic of Cardiology, Unit of Magnetic Resonance, Poznan University of Medical Sciences, Poznan, Poland
| | - Maciej Lesiak
- I Clinic of Cardiology, Unit of Magnetic Resonance, Poznan University of Medical Sciences, Poznan, Poland
| | - Andrzej Bręborowicz
- Department of Pathophysiology, Poznan University of Medical Sciences, Poznan, Poland
- Collegium Medicum, Zielona Góra, Poland
| |
Collapse
|
|
6
|
Tieu S, Charchoglyan A, Paulsen L, Wagter-Lesperance LC, Shandilya UK, Bridle BW, Mallard BA, Karrow NA. N-Acetylcysteine and Its Immunomodulatory Properties in Humans and Domesticated Animals. Antioxidants (Basel) 2023; 12:1867. [PMID: 37891946 PMCID: PMC10604897 DOI: 10.3390/antiox12101867] [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: 09/08/2023] [Revised: 10/10/2023] [Accepted: 10/13/2023] [Indexed: 10/29/2023] Open
Abstract
N-acetylcysteine (NAC), an acetylated derivative of the amino acid L-cysteine, has been widely used as a mucolytic agent and antidote for acetaminophen overdose since the 1960s and the 1980s, respectively. NAC possesses antioxidant, cytoprotective, anti-inflammatory, antimicrobial, and mucolytic properties, making it a promising therapeutic agent for a wide range of diseases in both humans and domesticated animals. Oxidative stress and inflammation play a major role in the onset and progression of all these diseases. NAC's primary role is to replenish glutathione (GSH) stores, the master antioxidant in all tissues; however, it can also reduce levels of pro-inflammatory tumor necrosis factor-alpha (TNF-∝) and interleukins (IL-6 and IL-1β), inhibit the formation of microbial biofilms and destroy biofilms, and break down disulfide bonds between mucin molecules. Many experimental studies have been conducted on the use of NAC to address a wide range of pathological conditions; however, its effectiveness in clinical trials remains limited and studies often have conflicting results. The purpose of this review is to provide a concise overview of promising NAC usages for the treatment of different human and domestic animal disorders.
Collapse
Affiliation(s)
- Sophie Tieu
- Department of Animal Biosciences, University of Guelph, Guelph, ON N1G 2W1, Canada; (S.T.); (U.K.S.)
- Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada; (L.P.); (L.C.W.-L.); (B.W.B.); (B.A.M.)
| | - Armen Charchoglyan
- ImmunoCeutica Inc., Cambridge, ON N1T 1N6, Canada
- Advanced Analysis Centre, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Lauryn Paulsen
- Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada; (L.P.); (L.C.W.-L.); (B.W.B.); (B.A.M.)
| | - Lauri C. Wagter-Lesperance
- Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada; (L.P.); (L.C.W.-L.); (B.W.B.); (B.A.M.)
- ImmunoCeutica Inc., Cambridge, ON N1T 1N6, Canada
| | - Umesh K. Shandilya
- Department of Animal Biosciences, University of Guelph, Guelph, ON N1G 2W1, Canada; (S.T.); (U.K.S.)
| | - Byram W. Bridle
- Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada; (L.P.); (L.C.W.-L.); (B.W.B.); (B.A.M.)
- ImmunoCeutica Inc., Cambridge, ON N1T 1N6, Canada
| | - Bonnie A. Mallard
- Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada; (L.P.); (L.C.W.-L.); (B.W.B.); (B.A.M.)
- ImmunoCeutica Inc., Cambridge, ON N1T 1N6, Canada
| | - Niel A. Karrow
- Department of Animal Biosciences, University of Guelph, Guelph, ON N1G 2W1, Canada; (S.T.); (U.K.S.)
- ImmunoCeutica Inc., Cambridge, ON N1T 1N6, Canada
| |
Collapse
|
|
7
|
Saleha A, Shende SS, Ingle P, Rai M, Minkina TM, Gade A. Cell free extract-mediated biogenic synthesis of ZnONPs and their application with kanamycin as a bactericidal combination. World J Microbiol Biotechnol 2023; 39:334. [PMID: 37807015 DOI: 10.1007/s11274-023-03777-z] [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: 07/28/2023] [Accepted: 09/22/2023] [Indexed: 10/10/2023]
Abstract
Antimicrobial resistance (AMR) is a main public health issue and a challenge for the scientific community all over the globe. Hence, there is a burning need to build new bactericides that resist the AMR. The ZnONPs were produced by cell free extract of mint (Mentha piperita L.) leaves. Antibiotics that are ineffective against resistant bacteria like Escherichia coli and Staphylococcus aureus were treated. The antibiotics were first screened, and then antibacterial activity was checked by disk diffusion, and MIC of Mp-ZnONPs individually and using Kanamycin (KAN) were determined against these pathogens by broth microdilution method. The synergism between Mp-ZnONPs and KAN was confirmed by checkerboard assay. The MIC showed robust antibacterial activity against the tested pathogens. The combination of KAN and Mp-ZnONPs reduces the MIC of KAN as it efficiently inhibits E. coli's growth, and KAN significantly enhances the antibacterial activity of Mp-ZnONPs. Taken together, Mp-ZnONPs have strong antimicrobial activity, and KAN significantly improves it against the tested pathogens, which would offer an effective, novel, and benign therapeutic methodology to regulate the incidence. The combination of Mp-ZnONPs and KAN would lead to the development of novel bactericides, that could be used in the formulation of pharmaceutical products.
Collapse
Affiliation(s)
- Asma Saleha
- Nanobiotechnology Laboratory, Department of Biotechnology, Sant Gadge Baba Amravati University, Amravati, MS, 444 602, India
| | - Sudhir S Shende
- Nanobiotechnology Laboratory, Department of Biotechnology, Sant Gadge Baba Amravati University, Amravati, MS, 444 602, India.
- Academy of Biology and Biotechnology, Southern Federal University, Rostov-on-Don, 344090, Russia.
| | - Pramod Ingle
- Nanobiotechnology Laboratory, Department of Biotechnology, Sant Gadge Baba Amravati University, Amravati, MS, 444 602, India
| | - Mahendra Rai
- Nanobiotechnology Laboratory, Department of Biotechnology, Sant Gadge Baba Amravati University, Amravati, MS, 444 602, India
- Department of Microbiology, Nicolaus Copernicus University, 87-100, Torun, Poland
| | - Tatiana M Minkina
- Academy of Biology and Biotechnology, Southern Federal University, Rostov-on-Don, 344090, Russia
| | - Aniket Gade
- Nanobiotechnology Laboratory, Department of Biotechnology, Sant Gadge Baba Amravati University, Amravati, MS, 444 602, India.
- Department of Microbiology, Nicolaus Copernicus University, 87-100, Torun, Poland.
- Department of Biological Sciences and Biotechnology, Institute of Chemical Technology, Mumbai, Maharashtra, 400019, India.
| |
Collapse
|
|
8
|
Kobylarz D, Noga M, Frydrych A, Milan J, Morawiec A, Glaca A, Kucab E, Jastrzębska J, Jabłońska K, Łuc K, Zdeb G, Pasierb J, Toporowska-Kaźmierak J, Półchłopek S, Słoma P, Adamik M, Banasik M, Bartoszek M, Adamczyk A, Rędziniak P, Frączkiewicz P, Orczyk M, Orzechowska M, Tajchman P, Dziuba K, Pelczar R, Zima S, Nyankovska Y, Sowińska M, Pempuś W, Kubacka M, Popielska J, Brzezicki P, Jurowski K. Antidotes in Clinical Toxicology-Critical Review. TOXICS 2023; 11:723. [PMID: 37755734 PMCID: PMC10534475 DOI: 10.3390/toxics11090723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 08/11/2023] [Accepted: 08/20/2023] [Indexed: 09/28/2023]
Abstract
Poisoning and overdose are very important aspects in medicine and toxicology. Chemical weapons pose a threat to civilians, and emergency medicine principles must be followed when dealing with patients who have been poisoned or overdosed. Antidotes have been used for centuries and modern research has led to the development of new antidotes that can accelerate the elimination of toxins from the body. Although some antidotes have become less relevant due to modern intensive care techniques, they can still save lives or reduce the severity of toxicity. The availability of antidotes is crucial, especially in developing countries where intensive care facilities may be limited. This article aims to provide information on specific antidotes, their recommended uses, and potential risks and new uses. In the case of poisoning, supportive therapies are most often used; however, in many cases, the administration of an appropriate antidote saves the patient's life. In this review, we reviewed the literature on selected antidotes used in the treatment of poisonings. We also characterised the antidotes (bio)chemically. We described the cases in which they are used together with the dosage recommendations. We also analysed the mechanisms of action. In addition, we described alternative methods of using a given substance as a drug, an example of which is N-acetylcysteine, which can be used in the treatment of COVID-19. This article was written as part of the implementation of the project of the Polish Ministry of Education and Science, "Toxicovigilance, poisoning prevention, and first aid in poisoning with xenobiotics of current clinical importance in Poland", grant number SKN/SP/570184/2023.
Collapse
Affiliation(s)
- Damian Kobylarz
- Department of Regulatory and Forensic Toxicology, Institute of Medical Expertises, Łódź, ul. Aleksandrowska 67/93, 91-205 Łódź, Poland
| | - Maciej Noga
- Department of Regulatory and Forensic Toxicology, Institute of Medical Expertises, Łódź, ul. Aleksandrowska 67/93, 91-205 Łódź, Poland
| | - Adrian Frydrych
- Laboratory of Innovative Toxicological Research and Analyzes, Institute of Medical Studies, Medical College, Rzeszów University, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland
| | - Justyna Milan
- Laboratory of Innovative Toxicological Research and Analyzes, Institute of Medical Studies, Medical College, Rzeszów University, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland
| | - Adrian Morawiec
- Toxicological Science Club ‘Paracelsus’, Institute of Medical Studies, Medical College, Rzeszów University, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland (E.K.); (G.Z.); (M.B.); (M.O.)
| | - Agata Glaca
- Toxicological Science Club ‘Paracelsus’, Institute of Medical Studies, Medical College, Rzeszów University, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland (E.K.); (G.Z.); (M.B.); (M.O.)
| | - Emilia Kucab
- Toxicological Science Club ‘Paracelsus’, Institute of Medical Studies, Medical College, Rzeszów University, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland (E.K.); (G.Z.); (M.B.); (M.O.)
| | - Julia Jastrzębska
- Toxicological Science Club ‘Paracelsus’, Institute of Medical Studies, Medical College, Rzeszów University, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland (E.K.); (G.Z.); (M.B.); (M.O.)
| | - Karolina Jabłońska
- Toxicological Science Club ‘Paracelsus’, Institute of Medical Studies, Medical College, Rzeszów University, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland (E.K.); (G.Z.); (M.B.); (M.O.)
| | - Klaudia Łuc
- Toxicological Science Club ‘Paracelsus’, Institute of Medical Studies, Medical College, Rzeszów University, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland (E.K.); (G.Z.); (M.B.); (M.O.)
| | - Gabriela Zdeb
- Toxicological Science Club ‘Paracelsus’, Institute of Medical Studies, Medical College, Rzeszów University, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland (E.K.); (G.Z.); (M.B.); (M.O.)
| | - Jakub Pasierb
- Toxicological Science Club ‘Paracelsus’, Institute of Medical Studies, Medical College, Rzeszów University, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland (E.K.); (G.Z.); (M.B.); (M.O.)
| | - Joanna Toporowska-Kaźmierak
- Toxicological Science Club ‘Paracelsus’, Institute of Medical Studies, Medical College, Rzeszów University, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland (E.K.); (G.Z.); (M.B.); (M.O.)
| | - Szczepan Półchłopek
- Toxicological Science Club ‘Paracelsus’, Institute of Medical Studies, Medical College, Rzeszów University, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland (E.K.); (G.Z.); (M.B.); (M.O.)
| | - Paweł Słoma
- Toxicological Science Club ‘Paracelsus’, Institute of Medical Studies, Medical College, Rzeszów University, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland (E.K.); (G.Z.); (M.B.); (M.O.)
| | - Magdalena Adamik
- Toxicological Science Club ‘Paracelsus’, Institute of Medical Studies, Medical College, Rzeszów University, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland (E.K.); (G.Z.); (M.B.); (M.O.)
| | - Mateusz Banasik
- Toxicological Science Club ‘Paracelsus’, Institute of Medical Studies, Medical College, Rzeszów University, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland (E.K.); (G.Z.); (M.B.); (M.O.)
| | - Mateusz Bartoszek
- Toxicological Science Club ‘Paracelsus’, Institute of Medical Studies, Medical College, Rzeszów University, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland (E.K.); (G.Z.); (M.B.); (M.O.)
| | - Aleksandra Adamczyk
- Toxicological Science Club ‘Paracelsus’, Institute of Medical Studies, Medical College, Rzeszów University, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland (E.K.); (G.Z.); (M.B.); (M.O.)
| | - Patrycja Rędziniak
- Toxicological Science Club ‘Paracelsus’, Institute of Medical Studies, Medical College, Rzeszów University, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland (E.K.); (G.Z.); (M.B.); (M.O.)
| | - Paulina Frączkiewicz
- Toxicological Science Club ‘Paracelsus’, Institute of Medical Studies, Medical College, Rzeszów University, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland (E.K.); (G.Z.); (M.B.); (M.O.)
| | - Michał Orczyk
- Toxicological Science Club ‘Paracelsus’, Institute of Medical Studies, Medical College, Rzeszów University, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland (E.K.); (G.Z.); (M.B.); (M.O.)
| | - Martyna Orzechowska
- Toxicological Science Club ‘Paracelsus’, Institute of Medical Studies, Medical College, Rzeszów University, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland (E.K.); (G.Z.); (M.B.); (M.O.)
| | - Paulina Tajchman
- Toxicological Science Club ‘Paracelsus’, Institute of Medical Studies, Medical College, Rzeszów University, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland (E.K.); (G.Z.); (M.B.); (M.O.)
| | - Klaudia Dziuba
- Toxicological Science Club ‘Paracelsus’, Institute of Medical Studies, Medical College, Rzeszów University, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland (E.K.); (G.Z.); (M.B.); (M.O.)
| | - Rafał Pelczar
- Toxicological Science Club ‘Paracelsus’, Institute of Medical Studies, Medical College, Rzeszów University, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland (E.K.); (G.Z.); (M.B.); (M.O.)
| | - Sabina Zima
- Toxicological Science Club ‘Paracelsus’, Institute of Medical Studies, Medical College, Rzeszów University, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland (E.K.); (G.Z.); (M.B.); (M.O.)
| | - Yana Nyankovska
- Toxicological Science Club ‘Paracelsus’, Institute of Medical Studies, Medical College, Rzeszów University, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland (E.K.); (G.Z.); (M.B.); (M.O.)
| | - Marta Sowińska
- Toxicological Science Club ‘Paracelsus’, Institute of Medical Studies, Medical College, Rzeszów University, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland (E.K.); (G.Z.); (M.B.); (M.O.)
| | - Wiktoria Pempuś
- Toxicological Science Club ‘Paracelsus’, Institute of Medical Studies, Medical College, Rzeszów University, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland (E.K.); (G.Z.); (M.B.); (M.O.)
| | - Maria Kubacka
- Toxicological Science Club ‘Paracelsus’, Institute of Medical Studies, Medical College, Rzeszów University, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland (E.K.); (G.Z.); (M.B.); (M.O.)
| | - Julia Popielska
- Toxicological Science Club ‘Paracelsus’, Institute of Medical Studies, Medical College, Rzeszów University, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland (E.K.); (G.Z.); (M.B.); (M.O.)
| | - Patryk Brzezicki
- Toxicological Science Club ‘Paracelsus’, Institute of Medical Studies, Medical College, Rzeszów University, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland (E.K.); (G.Z.); (M.B.); (M.O.)
| | - Kamil Jurowski
- Department of Regulatory and Forensic Toxicology, Institute of Medical Expertises, Łódź, ul. Aleksandrowska 67/93, 91-205 Łódź, Poland
- Laboratory of Innovative Toxicological Research and Analyzes, Institute of Medical Studies, Medical College, Rzeszów University, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland
| |
Collapse
|
|
9
|
Eleftheriadis T, Pissas G, Golfinopoulos S, Efthymiadi M, Poulianiti C, Polyzou Konsta MA, Liakopoulos V, Stefanidis I. Routes of Albumin Overload Toxicity in Renal Tubular Epithelial Cells. Int J Mol Sci 2023; 24:ijms24119640. [PMID: 37298591 DOI: 10.3390/ijms24119640] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 05/29/2023] [Accepted: 05/31/2023] [Indexed: 06/12/2023] Open
Abstract
Besides being a marker of kidney disease severity, albuminuria exerts a toxic effect on renal proximal tubular epithelial cells (RPTECs). We evaluated whether an unfolded protein response (UPR) or DNA damage response (DDR) is elicited in RPTECs exposed to high albumin concentration. The deleterious outcomes of the above pathways, apoptosis, senescence, or epithelial-to-mesenchymal transition (EMT) were evaluated. Albumin caused reactive oxygen species (ROS) overproduction and protein modification, and a UPR assessed the level of crucial molecules involved in this pathway. ROS also induced a DDR evaluated by critical molecules involved in this pathway. Apoptosis ensued through the extrinsic pathway. Senescence also occurred, and the RPTECs acquired a senescence-associated secretory phenotype since they overproduced IL-1β and TGF-β1. The latter may contribute to the observed EMT. Agents against endoplasmic reticulum stress (ERS) only partially alleviated the above changes, while the inhibition of ROS upregulation prevented both UPR and DDR and all the subsequent harmful effects. Briefly, albumin overload causes cellular apoptosis, senescence, and EMT in RPTECs by triggering UPR and DDR. Promising anti-ERS factors are beneficial but cannot eliminate the albumin-induced deleterious effects because DDR also occurs. Factors that suppress ROS overproduction may be more effective since they could halt UPR and DDR.
Collapse
Affiliation(s)
- Theodoros Eleftheriadis
- Department of Nephrology, Faculty of Medicine, University of Thessaly, Biopolis, Mezourlo Hill, 41110 Larissa, Greece
| | - Georgios Pissas
- Department of Nephrology, Faculty of Medicine, University of Thessaly, Biopolis, Mezourlo Hill, 41110 Larissa, Greece
| | - Spyridon Golfinopoulos
- Department of Nephrology, Faculty of Medicine, University of Thessaly, Biopolis, Mezourlo Hill, 41110 Larissa, Greece
| | - Maria Efthymiadi
- Department of Nephrology, Faculty of Medicine, University of Thessaly, Biopolis, Mezourlo Hill, 41110 Larissa, Greece
| | - Christina Poulianiti
- Department of Nephrology, Faculty of Medicine, University of Thessaly, Biopolis, Mezourlo Hill, 41110 Larissa, Greece
| | - Maria Anna Polyzou Konsta
- Department of Nephrology, Faculty of Medicine, University of Thessaly, Biopolis, Mezourlo Hill, 41110 Larissa, Greece
| | - Vassilios Liakopoulos
- Department of Nephrology, Faculty of Medicine, University of Thessaly, Biopolis, Mezourlo Hill, 41110 Larissa, Greece
| | - Ioannis Stefanidis
- Department of Nephrology, Faculty of Medicine, University of Thessaly, Biopolis, Mezourlo Hill, 41110 Larissa, Greece
| |
Collapse
|
|
10
|
Gamarra-Morales Y, Herrera-Quintana L, Molina-López J, Vázquez-Lorente H, Machado-Casas JF, Castaño-Pérez J, Pérez-Villares JM, Planells E. Response to Intravenous N-Acetylcysteine Supplementation in Critically Ill Patients with COVID-19. Nutrients 2023; 15:2235. [PMID: 37405379 DOI: 10.3390/nu15092235] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 05/01/2023] [Accepted: 05/07/2023] [Indexed: 07/06/2023] Open
Abstract
Administering N-acetylcysteine (NAC) could counteract the effect of free radicals, improving the clinical evolution of patients admitted to the Intensive Care Unit (ICU). This study aimed to investigate the clinical and biochemical effects of administering NAC to critically ill patients with COVID-19. A randomized controlled clinical trial was conducted on ICU patients (n = 140) with COVID-19 and divided into two groups: patients treated with NAC (NAC-treated group) and patients without NAC treatment (control group). NAC was administered as a continuous infusion with a loading dose and a maintenance dose during the study period (from admission until the third day of ICU stay). NAC-treated patients showed higher PaO2/FiO2 (p ≤ 0.014) after 3 days in ICU than their control group counterparts. Moreover, C-reactive protein (p ≤ 0.001), D-dimer (p ≤ 0.042), and lactate dehydrogenase (p ≤ 0.001) levels decreased on the third day in NAC-treated patients. Glutathione concentrations decreased in both NAC-treated (p ≤ 0.004) and control (p ≤ 0.047) groups after 3 days in ICU; whereas glutathione peroxidase did not change during the ICU stay. The administration of NAC manages to improve the clinical and analytical response of seriously ill patients with COVID-19 compared to the control group. NAC is able to stop the decrease in glutathione concentrations.
Collapse
Affiliation(s)
| | - Lourdes Herrera-Quintana
- Department of Physiology, School of Pharmacy, Institute of Nutrition and Food Technology "José Mataix", University of Granada, 18071 Granada, Spain
| | - Jorge Molina-López
- Faculty of Education, Psychology and Sports Sciences, University of Huelva, 21007 Huelva, Spain
| | - Héctor Vázquez-Lorente
- Department of Physiology, School of Pharmacy, Institute of Nutrition and Food Technology "José Mataix", University of Granada, 18071 Granada, Spain
| | | | - José Castaño-Pérez
- Intensive Care Unit, Virgen de las Nieves Hospital, Fuerzas Armadas Avenue, 18014 Granada, Spain
| | | | - Elena Planells
- Department of Physiology, School of Pharmacy, Institute of Nutrition and Food Technology "José Mataix", University of Granada, 18071 Granada, Spain
| |
Collapse
|
|
11
|
Chen TH, Chang CJ, Hung PH. Possible Pathogenesis and Prevention of Long COVID: SARS-CoV-2-Induced Mitochondrial Disorder. Int J Mol Sci 2023; 24:8034. [PMID: 37175745 PMCID: PMC10179190 DOI: 10.3390/ijms24098034] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 04/27/2023] [Accepted: 04/27/2023] [Indexed: 05/15/2023] Open
Abstract
Patients who have recovered from coronavirus disease 2019 (COVID-19) infection may experience chronic fatigue when exercising, despite no obvious heart or lung abnormalities. The present lack of effective treatments makes managing long COVID a major challenge. One of the underlying mechanisms of long COVID may be mitochondrial dysfunction. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections can alter the mitochondria responsible for energy production in cells. This alteration leads to mitochondrial dysfunction which, in turn, increases oxidative stress. Ultimately, this results in a loss of mitochondrial integrity and cell death. Moreover, viral proteins can bind to mitochondrial complexes, disrupting mitochondrial function and causing the immune cells to over-react. This over-reaction leads to inflammation and potentially long COVID symptoms. It is important to note that the roles of mitochondrial damage and inflammatory responses caused by SARS-CoV-2 in the development of long COVID are still being elucidated. Targeting mitochondrial function may provide promising new clinical approaches for long-COVID patients; however, further studies are needed to evaluate the safety and efficacy of such approaches.
Collapse
Affiliation(s)
- Tsung-Hsien Chen
- Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi 60002, Taiwan;
| | - Chia-Jung Chang
- Division of Critical Care Medicine, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi 60002, Taiwan
| | - Peir-Haur Hung
- Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi 60002, Taiwan;
- Department of Life and Health Science, Chia-Nan University of Pharmacy and Science, Tainan 717301, Taiwan
| |
Collapse
|
|
12
|
Zuo J, Meng T, Wang Y, Tang W. A Review of the Antiviral Activities of Glycyrrhizic Acid, Glycyrrhetinic Acid and Glycyrrhetinic Acid Monoglucuronide. Pharmaceuticals (Basel) 2023; 16:ph16050641. [PMID: 37242424 DOI: 10.3390/ph16050641] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 04/17/2023] [Accepted: 04/18/2023] [Indexed: 05/28/2023] Open
Abstract
Licorice, a natural medicine derived from the roots and rhizomes of Glycyrrhiza species, possesses a wide range of therapeutic applications, including antiviral properties. Glycyrrhizic acid (GL) and glycyrrhetinic acid (GA) are the most important active ingredients in licorice. Glycyrrhetinic acid 3-O-mono-β-d-glucuronide (GAMG) is the active metabolite of GL. GL and its metabolites have a wide range of antiviral activities against viruses, such as, the hepatitis virus, herpes virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and so on. Although their antiviral activity has been widely reported, the specific mechanism of action involving multiple links such as the virus itself, cells, and immunity are not clearly established. In this review, we will give an update on the role of GL and its metabolites as antiviral agents, and detail relevant evidence on the potential use and mechanisms of actions. Analyzing antivirals, their signaling, and the impacts of tissue and autoimmune protection may provide promising new therapeutic strategies.
Collapse
Affiliation(s)
- Jiawei Zuo
- Department of Pharmacy, The Second Affiliated Hospital of Anhui Medical University, Hefei 230011, China
- School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Tao Meng
- Department of General Surgery, The Third Affiliated Hospital of Anhui Medical University, Hefei 230061, China
| | - Yuanyuan Wang
- Department of Pharmacy, The Second Affiliated Hospital of Anhui Medical University, Hefei 230011, China
| | - Wenjian Tang
- School of Pharmacy, Anhui Medical University, Hefei 230032, China
| |
Collapse
|
|
13
|
Chen CH, Hung KF, Huang CY, Leong JL, Chu YC, Chang CY, Wang ML, Chiou SH, Cheng YF. Is N -acetylcysteine effective in treating patients with coronavirus disease 2019? A meta-analysis. J Chin Med Assoc 2023; 86:274-281. [PMID: 36728396 DOI: 10.1097/jcma.0000000000000869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Coronavirus disease 2019 (COVID-19) is a global pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). It has brought tremendous challenges to public health and medical systems around the world. The current strategy for drug repurposing has accumulated some evidence on the use of N -acetylcysteine (NAC) in treating patients with COVID-19. However, the evidence remains debated. METHODS We performed the systematic review and meta-analysis that complies with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Five databases and reference lists were searched from inception to May 14, 2022. Studies evaluating the efficacy of NAC in treating patients with COVID-19 were regarded as eligible. The review was registered prospectively on PROSPERO (CRD42022332791). RESULTS Of 778 records identified from the preliminary search, four studies were enrolled in the final qualitative review and quantitative meta-analysis. A total of 355 patients were allocated into the NAC group and the control group. The evaluated outcomes included intubation rate, improvement, duration of intensive unit stay and hospital stay and mortality. The pooled results showed nonsignificant differences in intubation rate (OR, 0.55; 95% CI, 0.16-1.89; p = 0.34; I2 = 75%), improvement of oxygenation ([MD], 80.84; 95% CI, -38.16 to 199.84; p = 0.18; I2 = 98%), ICU stay (MD, -0.74; 95% CI, -3.19 to 1.71; p = 0.55; I2 = 95%), hospital stay (MD, -1.05; 95% CI, -3.02 to 0.92; p = 0.30; I2 = 90%), and mortality (OR, 0.58; 95% CI, 0.23-1.45; p = 0.24; I2 = 54%). Subsequent trial sequential analysis (TSA) showed conclusive nonsignificant results for mortality, while the TSA for the other outcomes suggested that a larger sample size is essential. CONCLUSIONS The current evidence reveals NAC is not beneficial for treating patients with COVID- 19 with regard to respiratory outcome, mortality, duration of ICU stay and hospital stay.
Collapse
Affiliation(s)
- Chih-Hao Chen
- Department of Otolaryngology-Head and Neck Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Kai-Feng Hung
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Dentistry, School of Dentistry, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Chii-Yuan Huang
- Department of Otolaryngology-Head and Neck Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Jing-Li Leong
- Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Yuan-Chia Chu
- Information Management Office, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Medical AI Development Center, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Information Management, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan, ROC
| | - Chun-Yu Chang
- Department of Anesthesiology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan, ROC
| | - Mong-Lien Wang
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Anesthesiology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan, ROC
- Institute of Pharmacology, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Institute of Food Safety and Health Risk Assessment, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Shih-Hwa Chiou
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Institute of Pharmacology, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Yen-Fu Cheng
- Department of Otolaryngology-Head and Neck Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| |
Collapse
|
|
14
|
Yamaya M, Kikuchi A, Sugawara M, Nishimura H. Anti-inflammatory effects of medications used for viral infection-induced respiratory diseases. Respir Investig 2023; 61:270-283. [PMID: 36543714 PMCID: PMC9761392 DOI: 10.1016/j.resinv.2022.11.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Revised: 10/20/2022] [Accepted: 11/08/2022] [Indexed: 12/23/2022]
Abstract
Respiratory viruses like rhinovirus, influenza virus, respiratory syncytial virus, and coronavirus cause several respiratory diseases, such as bronchitis, pneumonia, pulmonary fibrosis, and coronavirus disease 2019, and exacerbate bronchial asthma, chronic obstructive pulmonary disease, bronchiectasis, and diffuse panbronchiolitis. The production of inflammatory mediators and mucin and the accumulation of inflammatory cells have been reported in patients with viral infection-induced respiratory diseases. Interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-α, granulocyte-macrophage colony-stimulating factor, and regulated on activation normal T-cell expressed and secreted are produced in the cells, including human airway and alveolar epithelial cells, partly through the activation of toll-like receptors, nuclear factor kappa B and p44/42 mitogen-activated protein kinase. These mediators are associated with the development of viral infection-induced respiratory diseases through the induction of inflammation and injury in the airway and lung, airway remodeling and hyperresponsiveness, and mucus secretion. Medications used to treat respiratory diseases, including corticosteroids, long-acting β2-agonists, long-acting muscarinic antagonists, mucolytic agents, antiviral drugs for severe acute respiratory syndrome coronavirus 2 and influenza virus, macrolides, and Kampo medicines, reduce the production of viral infection-induced mediators, including cytokines and mucin, as determined in clinical, in vivo, or in vitro studies. These results suggest that the anti-inflammatory effects of these medications on viral infection-induced respiratory diseases may be associated with clinical benefits, such as improvements in symptoms, quality of life, and mortality rate, and can prevent hospitalization and the exacerbation of chronic obstructive pulmonary disease, bronchial asthma, bronchiectasis, and diffuse panbronchiolitis.
Collapse
Affiliation(s)
- Mutsuo Yamaya
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan; Virus Research Center, Clinical Research Division, Sendai Medical Center, Sendai 983-8520, Japan; Department of Advanced Preventive Medicine for Infectious Disease, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
| | - Akiko Kikuchi
- Department of Kampo and Integrative Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan; Department of Education and Support for Regional Medicine, Tohoku University Hospital, Sendai 980-8574, Japan
| | - Mitsuru Sugawara
- Department of Otolaryngology, Tohoku Kosai Hospital, Sendai 980-0803, Japan
| | - Hidekazu Nishimura
- Virus Research Center, Clinical Research Division, Sendai Medical Center, Sendai 983-8520, Japan
| |
Collapse
|
|
15
|
Liu Y, Wei Y, Zhou Z, Gu Y, Pang Z, Liao M, Sun H. Overexpression of TRIM16 Reduces the Titer of H5N1 Highly Pathogenic Avian Influenza Virus and Promotes the Expression of Antioxidant Genes through Regulating the SQSTM1-NRF2-KEAP1 Axis. Viruses 2023; 15:v15020391. [PMID: 36851605 PMCID: PMC9960857 DOI: 10.3390/v15020391] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Revised: 01/19/2023] [Accepted: 01/27/2023] [Indexed: 01/31/2023] Open
Abstract
Oxidative stress plays a vital role in viral replication. Tripartite motif containing 16 (TRIM16) is involved in diverse cellular processes. However, the role of TRIM16 in oxidative stress induced by infection of the highly pathogenic H5N1 avian influenza virus (HPAIV) is unclear. We found that under conditions of H5N1 HPAIV infection, reactive oxygen species (ROS) levels in A549 cells peaked at 24 h post infection (hpi), and antioxidant genes' expression levels were down-regulated. Overexpression of TRIM16 in A549 cells resulted in a decrease in the titter of H5N1 HPAIV and led to significant up-regulation of the antioxidant genes' expression levels, which indicates that TRIM16 positively regulates the sequestosome 1/Kelch-like associated enoyl-CoA hydratase 1 protein/nuclear factor erythrocyte 2-derived 2-like 2 (SQSTM1/NRF2/KEAP1) pathway. Under basal conditions, TRIM16 led to a modification of NRF2 through an increase in K63-linked poly-ubiquitination of NRF2. Collectively, our findings provide new insight into understanding TRIM16's role in anti-oxidative stress in H5N1 HPAIV infected A549 cells.
Collapse
Affiliation(s)
- Yanwei Liu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
- Key Laboratory of Zoonosis Control and Prevention of Guangdong Province, South China Agricultural University, Guangzhou 510642, China
- National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control, South China Agricultural University, Guangzhou 510642, China
| | - Yifan Wei
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
- Key Laboratory of Zoonosis Control and Prevention of Guangdong Province, South China Agricultural University, Guangzhou 510642, China
- National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control, South China Agricultural University, Guangzhou 510642, China
| | - Ziwei Zhou
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
- Key Laboratory of Zoonosis Control and Prevention of Guangdong Province, South China Agricultural University, Guangzhou 510642, China
- National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control, South China Agricultural University, Guangzhou 510642, China
| | - Yongxia Gu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
- Key Laboratory of Zoonosis Control and Prevention of Guangdong Province, South China Agricultural University, Guangzhou 510642, China
- National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control, South China Agricultural University, Guangzhou 510642, China
| | - Zifeng Pang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
- Key Laboratory of Zoonosis Control and Prevention of Guangdong Province, South China Agricultural University, Guangzhou 510642, China
- National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control, South China Agricultural University, Guangzhou 510642, China
| | - Ming Liao
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
- Key Laboratory of Zoonosis Control and Prevention of Guangdong Province, South China Agricultural University, Guangzhou 510642, China
- National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control, South China Agricultural University, Guangzhou 510642, China
- Correspondence: (M.L.); (H.S.); Tel.: +86-18675861636 (H.S.)
| | - Hailiang Sun
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
- Key Laboratory of Zoonosis Control and Prevention of Guangdong Province, South China Agricultural University, Guangzhou 510642, China
- National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control, South China Agricultural University, Guangzhou 510642, China
- Correspondence: (M.L.); (H.S.); Tel.: +86-18675861636 (H.S.)
| |
Collapse
|
|
16
|
Kwon EB, Li W, Kim YS, Kim B, Chung HS, Go Y, Ko HJ, Song JH, Kim YH, Choi CW, Choi JG. Vitisin B inhibits influenza A virus replication by multi-targeting neuraminidase and virus-induced oxidative stress. Acta Pharm Sin B 2023; 13:174-191. [PMID: 36815046 PMCID: PMC9939323 DOI: 10.1016/j.apsb.2022.07.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 03/25/2022] [Accepted: 06/16/2022] [Indexed: 11/17/2022] Open
Abstract
The development of drug-resistant influenza and new pathogenic virus strains underscores the need for antiviral therapeutics. Currently, neuraminidase (NA) inhibitors are commonly used antiviral drugs approved by the US Food and Drug Administration (FDA) for the prevention and treatment of influenza. Here, we show that vitisin B (VB) inhibits NA activity and suppresses H1N1 viral replication in MDCK and A549 cells. Reactive oxygen species (ROS), which frequently occur during viral infection, increase virus replication by activating the NF-κB signaling pathway, downmodulating glucose-6-phosphate dehydrogenase (G6PD) expression, and decreasing the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant response activity. VB decreased virus-induced ROS generation by increasing G6PD expression and Nrf2 activity, and inhibiting NF-κB translocation to the nucleus through IKK dephosphorylation. In addition, VB reduced body weight loss, increased survival, decreased viral replication and the inflammatory response in the lungs of influenza A virus (IAV)-infected mice. Taken together, our results indicate that VB is a promising therapeutic candidate against IAV infection, complements existing drug limitations targeting viral NA. It modulated the intracellular ROS by G6PD, Nrf2 antioxidant response pathway, and NF-κB signaling pathway. These results demonstrate the feasibility of a multi-targeting drug strategy, providing new approaches for drug discovery against IAV infection.
Collapse
Affiliation(s)
- Eun-Bin Kwon
- Korean Medicine (KM) Application Center, Korea Institute of Oriental Medicine, Daegu 41062, Republic of Korea
| | - Wei Li
- Korean Medicine (KM) Application Center, Korea Institute of Oriental Medicine, Daegu 41062, Republic of Korea
| | - Young Soo Kim
- Korean Medicine (KM) Application Center, Korea Institute of Oriental Medicine, Daegu 41062, Republic of Korea
| | - Buyun Kim
- Korean Medicine (KM) Application Center, Korea Institute of Oriental Medicine, Daegu 41062, Republic of Korea
| | - Hwan-Suck Chung
- Korean Medicine (KM) Application Center, Korea Institute of Oriental Medicine, Daegu 41062, Republic of Korea
| | - Younghoon Go
- Korean Medicine (KM) Application Center, Korea Institute of Oriental Medicine, Daegu 41062, Republic of Korea
| | - Hyun-Jeong Ko
- Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon 24341, Republic of Korea
| | - Jae-Hyoung Song
- Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon 24341, Republic of Korea
| | - Young Ho Kim
- College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea
- Corresponding authors. Tel./Fax.: +82 42 8215933/+82 42 8236566, +82 31 8886131/+82 31 8886139, +82 53 9403866/+82 53 9403899
| | - Chun Whan Choi
- Natural Product Research Team, Biocenter, Gyeonggido Business and Science Accelerator, Gyeonggi-Do 16229, Republic of Korea
- Corresponding authors. Tel./Fax.: +82 42 8215933/+82 42 8236566, +82 31 8886131/+82 31 8886139, +82 53 9403866/+82 53 9403899
| | - Jang-Gi Choi
- Korean Medicine (KM) Application Center, Korea Institute of Oriental Medicine, Daegu 41062, Republic of Korea
- Corresponding authors. Tel./Fax.: +82 42 8215933/+82 42 8236566, +82 31 8886131/+82 31 8886139, +82 53 9403866/+82 53 9403899
| |
Collapse
|
|
17
|
Guarnieri JW, Angelin A, Murdock DG, Schaefer P, Portluri P, Lie T, Huang J, Wallace DC. SARS-COV-2 viroporins activate the NLRP3-inflammasome by the mitochondrial permeability transition pore. Front Immunol 2023; 14:1064293. [PMID: 36891303 PMCID: PMC9986324 DOI: 10.3389/fimmu.2023.1064293] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Accepted: 01/30/2023] [Indexed: 02/22/2023] Open
Abstract
Background Compared to healthy controls, severe COVID19 patients display increased levels of activated NLRP3-inflammasome (NLRP3-I) and interleukin (IL)-1β. SARS-CoV-2 encodes viroporin proteins E and Orf3a(2-E+2-3a) with homologs to SARS-CoV-1, 1-E+1-3a, which elevate NLRP3-I activation; by an unknown mechanism. Thus, we investigated how 2-E+2-3a activates the NLRP3-I to better understand the pathophysiology of severe COVID-19. Methods We generated a polycistronic expression-vector co-expressing 2-E+2-3a from a single transcript. To elucidate how 2-E+2-3a activates the NLRP3-I, we reconstituted the NLRP3-I in 293T cells and used THP1-derived macrophages to monitor the secretion of mature IL-1β. Mitochondrial physiology was assessed using fluorescent microscopy and plate reader assays, and the release of mitochondrial DNA (mtDNA) was detected from cytosolic-enriched fractions using Real-Time PCR. Results Expression of 2-E+2-3a in 293T cells increased cytosolic Ca++ and elevated mitochondrial Ca++, taken up through the MCUi11-sensitive mitochondrial calcium uniporter. Increased mitochondrial Ca++ stimulated NADH, mitochondrial reactive oxygen species (mROS) production and the release of mtDNA into the cytosol. Expression of 2-E+2-3a in NLRP3-I reconstituted 293T cells and THP1-derived macrophages displayed increased secretion of IL-1β. Increasing mitochondrial antioxidant defenses via treatment with MnTBAP or genetic expression of mCAT abolished 2-E+2-3a elevation of mROS, cytosolic mtDNA levels, and secretion of NLRP3-activated-IL-1β. The 2-E+2-3a-induced release of mtDNA and the secretion of NLRP3-activated-IL-1β were absent in cells lacking mtDNA and blocked in cells treated with the mitochondrial-permeability-pore(mtPTP)-specific inhibitor NIM811. Conclusion Our findings revealed that mROS activates the release of mitochondrial DNA via the NIM811-sensitive mitochondrial-permeability-pore(mtPTP), activating the inflammasome. Hence, interventions targeting mROS and the mtPTP may mitigate the severity of COVID-19 cytokine storms.
Collapse
Affiliation(s)
- Joseph W Guarnieri
- Center for Mitochondrial and Epigenomic Medicine, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Alessia Angelin
- Center for Mitochondrial and Epigenomic Medicine, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Deborah G Murdock
- Center for Mitochondrial and Epigenomic Medicine, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Patrick Schaefer
- Center for Mitochondrial and Epigenomic Medicine, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Prasanth Portluri
- Center for Mitochondrial and Epigenomic Medicine, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Timothy Lie
- Center for Mitochondrial and Epigenomic Medicine, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States.,Department of biology, University of Pennsylvania, Philadelphia, PA, United States
| | - Jessica Huang
- Center for Mitochondrial and Epigenomic Medicine, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Douglas C Wallace
- Center for Mitochondrial and Epigenomic Medicine, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States.,Department of Pediatrics, Division of Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| |
Collapse
|
|
18
|
Kobatake E, Iwama Y, Arai T, Shioya N, Kise M, Kabuki T. Intake of Lactobacillus paragasseri SBT2055 improves subjective symptoms of common cold during winter season in healthy adults: A randomized, double-blind, placebo-controlled parallel-group comparative study. Front Nutr 2022; 9:1063584. [PMID: 36570128 PMCID: PMC9773393 DOI: 10.3389/fnut.2022.1063584] [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: 10/07/2022] [Accepted: 11/22/2022] [Indexed: 12/14/2022] Open
Abstract
Objective Lactobacillus paragasseri SBT2055 (LG2055) has been reported to show immunostimulating effects. This study aimed to investigate the effects of LG2055 on the subjective symptoms of the physical condition in healthy adults. Materials and methods In this randomized, double-blind, placebo-controlled, parallel-group comparative study, Japanese individuals aged 20-64 years were recruited. A total of 200 participants were randomly divided into two groups by an independent controller (LG2055 and placebo groups; 100 participants per group). Drinkable yogurts containing LG2055 or lacking LG2055 (placebo) were used as test samples. The participants ingested one bottle of the test sample once a day for 12 weeks. A daily physical health questionnaire survey (about common cold symptoms) was performed as the primary outcome, and immunological and oxidative stress markers in saliva and serum were evaluated as secondary outcomes. Results In total, 198 participants completed the scheduled intake of the test samples, and five participants were excluded from the final analysis. Consequently, 193 participants (LG2055 group, n = 97; placebo group, n = 96) in the Per-Protocol Set were included in the efficacy analysis. The cumulative days of each symptom were evaluated, and the LG2055 group showed a significantly higher ratio of "without symptom" in runny nose, plugged nose, sneezing, sore throat, hoarseness, cough, headache, feeling tired, and fever than the placebo group, indicating that the incidence rates of common cold symptoms were lower in the LG2055 group. Additionally, changes in the salivary secretory IgA levels were significantly higher, and the serum derivatives of reactive oxygen metabolites levels were significantly lower in the LG2055 group. Conclusion Our study revealed that intake of LG2055 decreased common cold symptoms and improved immune parameters in healthy adults. This suggests that LG2055 contributes to the maintenance of physical conditions by improving the host immune system. Clinical trial registration [https://www.umin.ac.jp/ctr/index.htm], identifier [UMIN000045901].
Collapse
Affiliation(s)
- Eiji Kobatake
- Milk Science Research Institute, MEGMILK SNOW BRAND Co., Ltd., Saitama, Japan
| | | | - Toshinobu Arai
- Research and Development Planning Department, MEGMILK SNOW BRAND Co., Ltd., Tokyo, Japan
| | | | - Mai Kise
- Products Development Department, MEGMILK SNOW BRAND Co., Ltd., Saitama, Japan
| | - Toshihide Kabuki
- Milk Science Research Institute, MEGMILK SNOW BRAND Co., Ltd., Saitama, Japan
| |
Collapse
|
|
19
|
Zhang Q, Li P, Li H, Yi D, Guo S, Wang L, Zhao D, Wang C, Wu T, Hou Y. Multifaceted Effects and Mechanisms of N-Acetylcysteine on Intestinal Injury in a Porcine Epidemic Diarrhea Virus-Infected Porcine Model. Mol Nutr Food Res 2022; 66:e2200369. [PMID: 36321532 DOI: 10.1002/mnfr.202200369] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 09/04/2022] [Indexed: 11/06/2022]
Abstract
SCOPE This study investigates the potential effects of N-acetylcysteine (NAC) on intestinal injury in a porcine epidemic diarrhea virus (PEDV)-infected porcine model. METHODS AND RESULTS Thirty-two piglets are randomly assigned to one of four groups: the control, PEDV, NAC, and NAC+PEDV. Piglets in the NAC+PEDV group are orally administrated with NAC (100 mg (kg·BW)-1 day-1 ) for 4 consecutive days after 2 days of PEDV infection. The results show that NAC administration decreases the diarrhea rate and improves intestinal morphology. The concentration of diamine oxidase and intestinal fatty-acid binding protein, as well as IL-1β, IL-8, and TNF-α in the plasma, is decreased by NAC. Intriguingly, NAC administration significantly increases the viral load in the jejunum and ileum and down-regulates the expression of interferon-related genes. Microarray and proteomic analyses show that the differentially expressed genes/proteins between NAC+PEDV and PEDV groups are highly enriched in substance transport. Furthermore, aquaporin 8/10 expression is significantly increased by NAC upon PEDV infection. CONCLUSION NAC administration alleviates PEDV-induced intestinal injury by inhibiting inflammatory responses and improving substance transport, but promotes viral replication by inhibiting interferon signaling. These results suggest NAC exhibits multifaceted effects upon PEDV infection, and thus caution is required when using NAC as a dietary supplement to prevent viral infection.
Collapse
Affiliation(s)
- Qian Zhang
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, 430023, P. R. China
| | - Peng Li
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, 430023, P. R. China
| | - Hanbo Li
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, 430023, P. R. China
| | - Dan Yi
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, 430023, P. R. China
| | - Shuangshuang Guo
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, 430023, P. R. China
| | - Lei Wang
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, 430023, P. R. China
| | - Di Zhao
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, 430023, P. R. China
| | - Chao Wang
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, 430023, P. R. China
| | - Tao Wu
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, 430023, P. R. China
| | - Yongqing Hou
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, 430023, P. R. China
| |
Collapse
|
|
20
|
Zakharchenko A, Rock CA, Thomas TE, Keeney S, Hall EJ, Takano H, Krieger AM, Ferrari G, Levy RJ. Inhibition of advanced glycation end product formation and serum protein infiltration in bioprosthetic heart valve leaflets: Investigations of anti-glycation agents and anticalcification interactions with ethanol pretreatment. Biomaterials 2022; 289:121782. [PMID: 36099713 PMCID: PMC10015409 DOI: 10.1016/j.biomaterials.2022.121782] [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: 05/10/2022] [Revised: 08/22/2022] [Accepted: 08/29/2022] [Indexed: 11/16/2022]
Abstract
Bioprosthetic heart valves (BHV) fabricated from heterograft tissue, such as glutaraldehyde pretreated bovine pericardium (BP), are the most frequently used heart valve replacements. BHV durability is limited by structural valve degeneration (SVD), mechanistically associated with calcification, advanced glycation end products (AGE), and serum protein infiltration. We investigated the hypothesis that anti-AGE agents, Aminoguanidine, Pyridoxamine [PYR], and N-Acetylcysteine could mitigate AGE-serum protein SVD mechanisms in vitro and in vivo, and that these agents could mitigate calcification or demonstrate anti-calcification interactions with BP pretreatment with ethanol. In vitro, each of these agents significantly inhibited AGE-serum protein infiltration in BP. However, in 28-day rat subdermal BP implants only orally administered PYR demonstrated significant inhibition of AGE and serum protein uptake. Furthermore, BP PYR preincubation of BP mitigated AGE-serum protein SVD mechanisms in vitro, and demonstrated mitigation of both AGE-serum protein uptake and reduced calcification in vivo in 28-day rat subdermal BP explants. Inhibition of BP calcification as well as inhibition of AGE-serum protein infiltration was observed in 28-day rat subdermal BP explants pretreated with ethanol followed by PYR preincubation. In conclusion, AGE-serum protein and calcification SVD pathophysiology are significantly mitigated by both PYR oral therapy and PYR and ethanol pretreatment of BP.
Collapse
Affiliation(s)
- Andrey Zakharchenko
- The Pediatric Heart Valve Center, Division of Cardiology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
| | - Christopher A Rock
- The Pediatric Heart Valve Center, Division of Cardiology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
| | - Tina E Thomas
- The Pediatric Heart Valve Center, Division of Cardiology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
| | - Samuel Keeney
- The Pediatric Heart Valve Center, Division of Cardiology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
| | - Emily J Hall
- The Pediatric Heart Valve Center, Division of Cardiology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
| | - Hajime Takano
- Division of Neurology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
| | - Abba M Krieger
- Department of Statistics, The Wharton School, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Giovanni Ferrari
- Departments of Surgery and Biomedical Engineering, Columbia University, New York, NY, 10032, USA
| | - Robert J Levy
- The Pediatric Heart Valve Center, Division of Cardiology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
| |
Collapse
|
|
21
|
Deng H, Li Y, Li J, Shen W, Chen Q, Weng S, He J, Xu X. Neomycin inhibits Megalocytivirus infection in fish by antagonizing the increase of intracellular reduced glutathione. FISH & SHELLFISH IMMUNOLOGY 2022; 127:148-154. [PMID: 35714896 DOI: 10.1016/j.fsi.2022.06.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 06/04/2022] [Accepted: 06/09/2022] [Indexed: 06/15/2023]
Abstract
Infectious spleen and kidney necrosis virus (ISKNV) is the type species of the Megalocytivirus genus that infects a number of marine and freshwater fishes, causing huge economic losses in aquaculture. The ISKNV infection leads to increase of reducing power in cells. As the antibiotic neomycin can promote the production of reactive oxygen species (ROS) in animal cells, in the current study, the potential therapeutic effect of neomycin on ISKNV infection was explored. We showed that neomycin could decrease the reducing power in cultured MFF-1 cells and inhibit ISKNV infection by antagonizing the shift of the cellular redox balance toward reduction. In vivo experiments further demonstrated that neomycin treatment significantly suppresses ISKNV infection in mandarin fish. Expression of the major capsid protein (MCP) and the proportion of infected cells in tissues were down-regulated after neomycin treatment. Furthermore, neomycin showed complex effects on expression of a set of antiviral related genes of the host. Taking together, the current study suggested that the viral-induced redox imbalance in the infected cells could be used as a target for suppressing ISKNV infection. Neomycin can be potentially utilized for therapeutic treatment of Megalocytivirus diseases by antagonizing intracellular redox changes.
Collapse
Affiliation(s)
- Hengwei Deng
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China; Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Sun Yat-sen University, Guangzhou, PR China; Institute of Aquatic Economic Animals and Guangdong Provice Key Laboratory for Aquatic Economic Animals, Sun Yat-sen University, Guangzhou, PR China; State Key Laboratory of Marine Resource Utilization in South China Sea, Hainan University, Haikou, China
| | - Yeyu Li
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China
| | - Jinling Li
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China
| | - Wenjie Shen
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China
| | - Qiankang Chen
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China
| | - Shaoping Weng
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China; Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Sun Yat-sen University, Guangzhou, PR China; Institute of Aquatic Economic Animals and Guangdong Provice Key Laboratory for Aquatic Economic Animals, Sun Yat-sen University, Guangzhou, PR China
| | - Jianguo He
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China; Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Sun Yat-sen University, Guangzhou, PR China; Institute of Aquatic Economic Animals and Guangdong Provice Key Laboratory for Aquatic Economic Animals, Sun Yat-sen University, Guangzhou, PR China
| | - Xiaopeng Xu
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China; Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Sun Yat-sen University, Guangzhou, PR China; Institute of Aquatic Economic Animals and Guangdong Provice Key Laboratory for Aquatic Economic Animals, Sun Yat-sen University, Guangzhou, PR China.
| |
Collapse
|
|
22
|
Horowitz RI, Freeman PR. Efficacy of Short-Term High Dose Pulsed Dapsone Combination Therapy in the Treatment of Chronic Lyme Disease/Post-Treatment Lyme Disease Syndrome (PTLDS) and Associated Co-Infections: A Report of Three Cases and Literature Review. Antibiotics (Basel) 2022; 11:912. [PMID: 35884166 PMCID: PMC9311795 DOI: 10.3390/antibiotics11070912] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 06/26/2022] [Accepted: 07/04/2022] [Indexed: 02/06/2023] Open
Abstract
Lyme disease and associated co-infections are increasing worldwide and approximately 20% of individuals develop chronic Lyme disease (CLD)/Post-Treatment Lyme Disease Syndrome (PTLDS) despite early antibiotics. A seven- to eight-week protocol of double dose dapsone combination therapy (DDDCT) for CLD/PTLDS results in symptom remission in approximately 50% of patients for one year or longer, with published culture studies indicating higher doses of dapsone demonstrate efficacy against resistant biofilm forms of Borrelia burgdorferi. The purpose of this study was, therefore, to evaluate higher doses of dapsone in the treatment of resistant CLD/PTLDS and associated co-infections. A total of 25 patients with a history of Lyme and associated co-infections, most of whom had ongoing symptoms despite several courses of DDDCT, took one or more courses of high dose pulsed dapsone combination therapy (200 mg dapsone × 3-4 days and/or 200 mg BID × 4 days), depending on persistent symptoms. The majority of patients noticed sustained improvement in eight major Lyme symptoms, including fatigue, pain, headaches, neuropathy, insomnia, cognition, and sweating, where dapsone dosage, not just the treatment length, positively affected outcomes. High dose pulsed dapsone combination therapy may represent a novel therapeutic approach for the treatment of resistant CLD/PTLDS, and should be confirmed in randomized, controlled clinical trials.
Collapse
|
|
23
|
Bidgood SR, Samolej J, Novy K, Collopy A, Albrecht D, Krause M, Burden JJ, Wollscheid B, Mercer J. Poxviruses package viral redox proteins in lateral bodies and modulate the host oxidative response. PLoS Pathog 2022; 18:e1010614. [PMID: 35834477 PMCID: PMC9282662 DOI: 10.1371/journal.ppat.1010614] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Accepted: 05/24/2022] [Indexed: 01/23/2023] Open
Abstract
All poxviruses contain a set of proteinaceous structures termed lateral bodies (LB) that deliver viral effector proteins into the host cytosol during virus entry. To date, the spatial proteotype of LBs remains unknown. Using the prototypic poxvirus, vaccinia virus (VACV), we employed a quantitative comparative mass spectrometry strategy to determine the poxvirus LB proteome. We identified a large population of candidate cellular proteins, the majority being mitochondrial, and 15 candidate viral LB proteins. Strikingly, one-third of these are VACV redox proteins whose LB residency could be confirmed using super-resolution microscopy. We show that VACV infection exerts an anti-oxidative effect on host cells and that artificial induction of oxidative stress impacts early and late gene expression as well as virion production. Using targeted repression and/or deletion viruses we found that deletion of individual LB-redox proteins was insufficient for host redox modulation suggesting there may be functional redundancy. In addition to defining the spatial proteotype of VACV LBs, these findings implicate poxvirus redox proteins as potential modulators of host oxidative anti-viral responses and provide a solid starting point for future investigations into the role of LB resident proteins in host immunomodulation.
Collapse
Affiliation(s)
- Susanna R. Bidgood
- MRC Laboratory for Molecular Cell Biology, University College London, London, United Kingdom
| | - Jerzy Samolej
- Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Birmingham, United Kingdom
| | - Karel Novy
- Swiss Federal Institute of Technology (ETH Zürich), Department of Health Sciences and Technology (D-HEST), Institute of Translational Medicine (ITM), Zürich, Switzerland
| | - Abigail Collopy
- MRC Laboratory for Molecular Cell Biology, University College London, London, United Kingdom
| | - David Albrecht
- MRC Laboratory for Molecular Cell Biology, University College London, London, United Kingdom
| | - Melanie Krause
- MRC Laboratory for Molecular Cell Biology, University College London, London, United Kingdom
| | - Jemima J. Burden
- MRC Laboratory for Molecular Cell Biology, University College London, London, United Kingdom
| | - Bernd Wollscheid
- Swiss Federal Institute of Technology (ETH Zürich), Department of Health Sciences and Technology (D-HEST), Institute of Translational Medicine (ITM), Zürich, Switzerland
- Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland
| | - Jason Mercer
- MRC Laboratory for Molecular Cell Biology, University College London, London, United Kingdom
- Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Birmingham, United Kingdom
| |
Collapse
|
|
24
|
Keskinidou C, Vassiliou AG, Dimopoulou I, Kotanidou A, Orfanos SE. Mechanistic Understanding of Lung Inflammation: Recent Advances and Emerging Techniques. J Inflamm Res 2022; 15:3501-3546. [PMID: 35734098 PMCID: PMC9207257 DOI: 10.2147/jir.s282695] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 05/04/2022] [Indexed: 12/12/2022] Open
Abstract
Acute respiratory distress syndrome (ARDS) is a life-threatening lung injury characterized by an acute inflammatory response in the lung parenchyma. Hence, it is considered as the most appropriate clinical syndrome to study pathogenic mechanisms of lung inflammation. ARDS is associated with increased morbidity and mortality in the intensive care unit (ICU), while no effective pharmacological treatment exists. It is very important therefore to fully characterize the underlying pathobiology and the related mechanisms, in order to develop novel therapeutic approaches. In vivo and in vitro models are important pre-clinical tools in biological and medical research in the mechanistic and pathological understanding of the majority of diseases. In this review, we will present data from selected experimental models of lung injury/acute lung inflammation, which have been based on clinical disorders that can lead to the development of ARDS and related inflammatory lung processes in humans, including ventilation-induced lung injury (VILI), sepsis, ischemia/reperfusion, smoke, acid aspiration, radiation, transfusion-related acute lung injury (TRALI), influenza, Streptococcus (S.) pneumoniae and coronaviruses infection. Data from the corresponding clinical conditions will also be presented. The mechanisms related to lung inflammation that will be covered are oxidative stress, neutrophil extracellular traps, mitogen-activated protein kinase (MAPK) pathways, surfactant, and water and ion channels. Finally, we will present a brief overview of emerging techniques in the field of omics research that have been applied to ARDS research, encompassing genomics, transcriptomics, proteomics, and metabolomics, which may recognize factors to help stratify ICU patients at risk, predict their prognosis, and possibly, serve as more specific therapeutic targets.
Collapse
Affiliation(s)
- Chrysi Keskinidou
- First Department of Critical Care Medicine and Pulmonary Services, School of Medicine, National and Kapodistrian University of Athens, "Evangelismos" Hospital, Athens, Greece
| | - Alice G Vassiliou
- First Department of Critical Care Medicine and Pulmonary Services, School of Medicine, National and Kapodistrian University of Athens, "Evangelismos" Hospital, Athens, Greece
| | - Ioanna Dimopoulou
- First Department of Critical Care Medicine and Pulmonary Services, School of Medicine, National and Kapodistrian University of Athens, "Evangelismos" Hospital, Athens, Greece
| | - Anastasia Kotanidou
- First Department of Critical Care Medicine and Pulmonary Services, School of Medicine, National and Kapodistrian University of Athens, "Evangelismos" Hospital, Athens, Greece
| | - Stylianos E Orfanos
- First Department of Critical Care Medicine and Pulmonary Services, School of Medicine, National and Kapodistrian University of Athens, "Evangelismos" Hospital, Athens, Greece
| |
Collapse
|
|
25
|
Kumova OK, Galani IE, Rao A, Johnson H, Triantafyllia V, Matt SM, Pascasio J, Gaskill PJ, Andreakos E, Katsikis PD, Carey AJ. Severity of neonatal influenza infection is driven by type I interferon and oxidative stress. Mucosal Immunol 2022; 15:1309-1320. [PMID: 36352099 PMCID: PMC9724789 DOI: 10.1038/s41385-022-00576-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 09/26/2022] [Accepted: 10/23/2022] [Indexed: 11/11/2022]
Abstract
Neonates exhibit increased susceptibility to respiratory viral infections, attributed to inflammation at the developing pulmonary air-blood interface. IFN I are antiviral cytokines critical to control viral replication, but also promote inflammation. Previously, we established a neonatal murine influenza virus (IV) model, which demonstrates increased mortality. Here, we sought to determine the role of IFN I in this increased mortality. We found that three-day-old IFNAR-deficient mice are highly protected from IV-induced mortality. In addition, exposure to IFNβ 24 h post IV infection accelerated death in WT neonatal animals but did not impact adult mortality. In contrast, IFN IIIs are protective to neonatal mice. IFNβ induced an oxidative stress imbalance specifically in primary neonatal IV-infected pulmonary type II epithelial cells (TIIEC), not in adult TIIECs. Moreover, neonates did not have an infection-induced increase in antioxidants, including a key antioxidant, superoxide dismutase 3, as compared to adults. Importantly, antioxidant treatment rescued IV-infected neonatal mice, but had no impact on adult morbidity. We propose that IFN I exacerbate an oxidative stress imbalance in the neonate because of IFN I-induced pulmonary TIIEC ROS production coupled with developmentally regulated, defective antioxidant production in response to IV infection. This age-specific imbalance contributes to mortality after respiratory infections in this vulnerable population.
Collapse
Affiliation(s)
- Ogan K. Kumova
- Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, United States
| | - Ioanna-Evdokia Galani
- Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens, Athens, Greece
| | - Abhishek Rao
- Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, United States
| | - Hannah Johnson
- Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, United States
| | - Vasiliki Triantafyllia
- Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens, Athens, Greece
| | - Stephanie M. Matt
- Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, United States
| | - Judy Pascasio
- Pathology, Drexel University College of Medicine, Philadelphia, PA, United States
| | - Peter J. Gaskill
- Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, United States
| | - Evangelos Andreakos
- Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens, Athens, Greece
| | - Peter D. Katsikis
- Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Alison J. Carey
- Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, United States.,Pediatrics, Drexel University College of Medicine, Philadelphia, PA, United States
| |
Collapse
|
|
26
|
Title-Inflammatory Signaling Pathways in Allergic and Infection-Associated Lung Diseases. ALLERGIES 2022. [DOI: 10.3390/allergies2020006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Lung inflammation can be caused by pathogen infection alone or by allergic disease, leading to pneumonitis. Most of the allergens (antigens) that cause allergic lung diseases, including asthma and hypersensitivity pneumonitis (HP), are derived from microorganisms, such as bacteria, viruses, and fungi, but some inorganic materials, such as mercury, can also cause pneumonitis. Certain allergens, including food and pollen, can also cause acute allergic reactions and lead to lung inflammation in individuals predisposed to such reactions. Pattern recognition-associated and damage-associated signaling by these allergens can be critical in determining the type of hypersensitization and allergic disease, as well as the potential for fibrosis and irreversible lung damage. This review discusses the signs, symptoms, and etiology of allergic asthma, and HP. Furthermore, we review the immune response and signaling pathways involved in pneumonitis due to both microbial infection and allergic processes. We also discuss current and potential therapeutic interventions for infection-associated and allergic lung inflammation.
Collapse
|
|
27
|
Caceres CJ, Seibert B, Cargnin Faccin F, Cardenas‐Garcia S, Rajao DS, Perez DR. Influenza antivirals and animal models. FEBS Open Bio 2022; 12:1142-1165. [PMID: 35451200 PMCID: PMC9157400 DOI: 10.1002/2211-5463.13416] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 03/04/2022] [Accepted: 04/20/2022] [Indexed: 11/29/2022] Open
Abstract
Influenza A and B viruses are among the most prominent human respiratory pathogens. About 3-5 million severe cases of influenza are associated with 300 000-650 000 deaths per year globally. Antivirals effective at reducing morbidity and mortality are part of the first line of defense against influenza. FDA-approved antiviral drugs currently include adamantanes (rimantadine and amantadine), neuraminidase inhibitors (NAI; peramivir, zanamivir, and oseltamivir), and the PA endonuclease inhibitor (baloxavir). Mutations associated with antiviral resistance are common and highlight the need for further improvement and development of novel anti-influenza drugs. A summary is provided for the current knowledge of the approved influenza antivirals and antivirals strategies under evaluation in clinical trials. Preclinical evaluations of novel compounds effective against influenza in different animal models are also discussed.
Collapse
Affiliation(s)
- C. Joaquin Caceres
- Department of Population HealthCollege of Veterinary MedicineUniversity of GeorgiaAthensGAUSA
| | - Brittany Seibert
- Department of Population HealthCollege of Veterinary MedicineUniversity of GeorgiaAthensGAUSA
| | - Flavio Cargnin Faccin
- Department of Population HealthCollege of Veterinary MedicineUniversity of GeorgiaAthensGAUSA
| | | | - Daniela S. Rajao
- Department of Population HealthCollege of Veterinary MedicineUniversity of GeorgiaAthensGAUSA
| | - Daniel R. Perez
- Department of Population HealthCollege of Veterinary MedicineUniversity of GeorgiaAthensGAUSA
| |
Collapse
|
|
28
|
Iciek M, Bilska-Wilkosz A, Kozdrowicki M, Górny M. Reactive Sulfur Compounds in the Fight against COVID-19. Antioxidants (Basel) 2022; 11:antiox11061053. [PMID: 35739949 PMCID: PMC9220020 DOI: 10.3390/antiox11061053] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 05/20/2022] [Accepted: 05/24/2022] [Indexed: 02/04/2023] Open
Abstract
The SARS-CoV-2 coronavirus pandemic outbreak in 2019 resulted in the need to search for an effective and safe strategy for treating infected patients, relieving symptoms, and preventing severe disease. SARS-CoV-2 is an RNA virus that can cause acute respiratory failure and thrombosis, as well as impair circulatory system function. Permanent damage to the heart muscle or other cardiovascular disorders may occur during or after the infection. The severe course of the disease is associated with the release of large amounts of pro-inflammatory cytokines. Due to their documented anti-inflammatory, antioxidant, and antiviral effects, reactive sulfur compounds, including hydrogen sulfide (H2S), lipoic acid (LA), N-acetylcysteine (NAC), glutathione (GSH), and some other lesser-known sulfur compounds, have attracted the interest of scientists for the treatment and prevention of the adverse effects of diseases caused by SARS-CoV-2. This article reviews current knowledge about various endogenous or exogenous reactive sulfur compounds and discusses the possibility, or in some cases the results, of their use in the treatment or prophylaxis of COVID-19.
Collapse
|
|
29
|
Chen G, Lu H. Oral high-dose acetylcysteine: Effective against the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)? Drug Discov Ther 2022; 16:139-141. [PMID: 35527020 DOI: 10.5582/ddt.2022.01032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a high rate of transmission and it exhibits immune escape characteristics. N-acetyl-L-cysteine (NAC) is a precursor of reduced glutathione (GSH), which can enter cells to play an antioxidant role, so it is better than glutathione. Patients tolerate NAC well, and adverse reactions are rare and mild, so this type of drug with multiple actions is considered to be a mucolytic agent as well as a drug for the prevention/treatment of various diseases, including COVID-19. Previous studies indicated that the clinical effectiveness of NAC is dose-dependent. Low-dose NAC (0.2 g tid for adults) is a mucolytic expectorant, high-dose NAC (0.6 g bid or tid) has expectorant action as well as antioxidant action, and extreme-dose NAC (300 mg/kg.d) is used for detoxification in cases of an acetaminophen overdose. Presumably, orally administered high-dose NAC (0.6 g tid for adults and 10 mg/kg tid for children) could be used as an adjuvant to treat an Omicron infection. It should reduce the time to negative conversion and prevent severe COVID-19, reducing the duration of hospitalization and increasing the bed turnover rate.
Collapse
Affiliation(s)
- Guangbin Chen
- Department of Pharmacy, The Third People's Hospital of Shenzhen, Shenzhen, China
| | - Hongzhou Lu
- National Center for Infectious Disease Research, The Third People's Hospital of Shenzhen, Shenzhen, China
| |
Collapse
|
|
30
|
Bakr AF, Shao P, Farag MA. Recent advances in glycyrrhizin metabolism, health benefits, clinical effects and drug delivery systems for efficacy improvement; a comprehensive review. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 99:153999. [PMID: 35220130 DOI: 10.1016/j.phymed.2022.153999] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 02/06/2022] [Accepted: 02/15/2022] [Indexed: 06/14/2023]
Abstract
BACKGROUND Glycyrrhizin (GL) is a major active constituent of licorice root (Glycyrrhiza glabra) that is considered one of the oldest and most frequently employed botanicals in Chinese medicine and worldwide, with most effects attributed to its rich GL content. Structurally, GL a triterpene saponin that is widely used as a flavoring agent in foodstuffs and cosmetics, and also proposed for various clinical applications with a myriad of health benefits. Pharmacological and biological activities of GL include antiviral, anti-inflammatory, antioxidant, and anticancer activities (in vitro and in vivo). Currently, there is no comprehensive review on GL biological effects and its action mechanisms. PURPOSE This review summarizes GL pharmacological actions from a molecular biology perception, presented on its metabolism and side effects based on in vitro, in vitro and clinical studies. Moreover, the potential of GL as a nanomedicine delivery system is also summarized. The progress in drug delivery research using GL presented herein is expected to provide a theoretical basis for developing other novel drugs formulations. METHODS A systematic review was carried out in several electronic databases (Science Direct, SpringerLink, CNKI, PubMed, Web of Science, Elsevier, and Scopus), using the following key words: glycyrrhizin "AND" bioactivity "OR" clinic "OR" therapeutic "OR" drug delivery. This search included manuscripts published between 1989 and 2021. RESULTS 126 researches were selected and summarized in this review. The analysis of these studies indicated that GL has antiviral activity against different viruses. Further, GL efficiently suppressed the respiratory manifestations associated with COVID-19 by reducing the expression of angiotensin converting enzyme 2 (ACE2) that employed by the virus as an entry point. Otherwise, GL was found to induce antioxidant, anti-inflammatory, immune-modulatory, and anticancer activity. Besides, diminution the particle size of GL to nanometer size significantly augments their action and biodistribution. CONCLUSION This article summarizes the pharmacological actions of GL. The potential of GL as a nanomedicine delivery system is also presented. Nevertheless, most studies reported provide no deep insight of GL health effects warranting for more future studies to elucidate its action mechanism and potential therapeutic benefits through preclinical and clinical trials.
Collapse
Affiliation(s)
- Alaa F Bakr
- Pathology Department, Faculty of Veterinary Medicine, Cairo University, Gamaa St., Giza 12211, Egypt
| | - Ping Shao
- Department of Food Science and Technology, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China; Key Laboratory of Food Macromolecular Resources Processing Technology Research, China National Light Industry, China.
| | - Mohamed A Farag
- Pharmacognosy Department, College of Pharmacy, Cairo University, Kasr el Aini St., P.B. 11562, Cairo, Egypt.
| |
Collapse
|
|
31
|
Balakrishna Pillai A, JeanPierre AR, Mariappan V, Ranganadin P, S R R. Neutralizing the free radicals could alleviate the disease severity following an infection by positive strand RNA viruses. Cell Stress Chaperones 2022; 27:189-195. [PMID: 35366756 PMCID: PMC8976658 DOI: 10.1007/s12192-022-01269-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 03/22/2022] [Accepted: 03/23/2022] [Indexed: 12/12/2022] Open
Abstract
Free radical release due to oxidative stress is gaining importance in the field of viral pathogenesis. Recent studies suggest the involvement of oxidative stress and ROS levels in regulating disease virulence during RNA virus infection. Most of the RNA virus infections lead to vascular dysfunction and disease severity. However, the biology of free radicals in maintaining vascular endothelium integrity is not completely understood. In the present review, we discuss some of the common features in positive-strand RNA virus infections such as dengue and SARS-CoV-2 and suggest that anti-oxidant therapy could pave the way to develop therapeutic strategies in combating emerging and re-emerging RNA viruses.
Collapse
Affiliation(s)
- Agieshkumar Balakrishna Pillai
- Central Inter-Disciplinary Research Facility (CIDRF), School of Biological Sciences, MGM Advanced Research Institute (MGMARI), Sri Balaji Vidyapeeth (Deemed To Be University), Puducherry, 607 402, India.
| | - Aashika Raagavi JeanPierre
- Central Inter-Disciplinary Research Facility (CIDRF), School of Biological Sciences, MGM Advanced Research Institute (MGMARI), Sri Balaji Vidyapeeth (Deemed To Be University), Puducherry, 607 402, India
| | - Vignesh Mariappan
- Central Inter-Disciplinary Research Facility (CIDRF), School of Biological Sciences, MGM Advanced Research Institute (MGMARI), Sri Balaji Vidyapeeth (Deemed To Be University), Puducherry, 607 402, India
| | - Pajanivel Ranganadin
- Mahatma Gandhi Medical College and Research Institute (MGMCRI), Sri Balaji Vidyapeeth (Deemed To Be University), Puducherry, 607 402, India
| | - Rao S R
- Research, Innovation & Development, Sri Balaji Vidyapeeth (Deemed To Be University), Puducherry, 607 402, India
| |
Collapse
|
|
32
|
Chen B, Raja K, Pierre-Louis F, Patel M, Patel R, Kang S, Daniel N, Attalla M, Philips M. Intravenous N-Acetylcysteine in Management of COVID-19: A Case Series. J Pharm Pract 2022:8971900221080283. [PMID: 35331045 PMCID: PMC8958286 DOI: 10.1177/08971900221080283] [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] [Indexed: 12/15/2022]
Abstract
A novel coronavirus, severe acute respiratory syndrome coronavirus-2, was isolated from patients’ lower respiratory tracts in December 2019. As of May 19, 2021, there were over 33 million reported infections and almost 600,000 deaths in the United States. The infection, coronavirus disease-19 (COVID-19), can lead to cytokine storm, with elevations in interleukin-6 (IL-6), IL-10, tumor necrosis factor-α, nuclear factor-kappaB (NF-kappaB), and glutathione reductase. NF-kappaB activation is necessary for further transcription of other pro-inflammatory markers. Glutathione may play a role in modulation of NF-kappaB activation and elevated glutathione reductase may indicate glutathione depletion. Administration of N-acetylcysteine (NAC) may replenish spent glutathione and attenuate over-activation of NF-kappaB. This retrospective case series included 10 patients who were COVID-19 positive and received intravenous NAC in an attempt to attenuate the cytokine storm. Patients’ outcomes were graded based on the World Health Organization symptom severity scale from 0, no evidence of infection, to 8, death. Overall, the median WHO Scale prior to NAC was 6.5, and increased by day seven, which indicated clinical worsening. This retrospective case series showed no benefit of NAC; however, further studies are needed to elucidate if differences in drug regimens would lead to positive results.
Collapse
Affiliation(s)
- Brandon Chen
- Pharmacy Department, 24050Clara Maass Medical Center, Belleville, NJ, USA
| | - Karan Raja
- Pharmacy Department, 24050Clara Maass Medical Center, Belleville, NJ, USA
| | | | - Mitesh Patel
- Pharmacy Department, 24050Clara Maass Medical Center, Belleville, NJ, USA
| | - Ruben Patel
- Pharmacy Department, 24050Clara Maass Medical Center, Belleville, NJ, USA
| | - Soo Kang
- Pharmacy Department, 24050Clara Maass Medical Center, Belleville, NJ, USA
| | - Nicole Daniel
- Pharmacy Department, 24050Clara Maass Medical Center, Belleville, NJ, USA
| | - Mark Attalla
- Pharmacy Department, 24050Clara Maass Medical Center, Belleville, NJ, USA
| | - Mona Philips
- Pharmacy Department, 24050Clara Maass Medical Center, Belleville, NJ, USA
| |
Collapse
|
|
33
|
Luettich K, Sharma M, Yepiskoposyan H, Breheny D, Lowe FJ. An Adverse Outcome Pathway for Decreased Lung Function Focusing on Mechanisms of Impaired Mucociliary Clearance Following Inhalation Exposure. FRONTIERS IN TOXICOLOGY 2022; 3:750254. [PMID: 35295103 PMCID: PMC8915806 DOI: 10.3389/ftox.2021.750254] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 11/11/2021] [Indexed: 01/23/2023] Open
Abstract
Adverse outcome pathways (AOPs) help to organize available mechanistic information related to an adverse outcome into key events (KEs) spanning all organizational levels of a biological system(s). AOPs, therefore, aid in the biological understanding of a particular pathogenesis and also help with linking exposures to eventual toxic effects. In the regulatory context, knowledge of disease mechanisms can help design testing strategies using in vitro methods that can measure or predict KEs relevant to the biological effect of interest. The AOP described here evaluates the major processes known to be involved in regulating efficient mucociliary clearance (MCC) following exposures causing oxidative stress. MCC is a key aspect of the innate immune defense against airborne pathogens and inhaled chemicals and is governed by the concerted action of its functional components, the cilia and airway surface liquid (ASL). The AOP network described here consists of sequences of KEs that culminate in the modulation of ciliary beat frequency and ASL height as well as mucus viscosity and hence, impairment of MCC, which in turn leads to decreased lung function.
Collapse
Affiliation(s)
- Karsta Luettich
- Philip Morris International R&D, Philip Morris Products S.A., Neuchatel, Switzerland
| | - Monita Sharma
- PETA Science Consortium International e.V., Stuttgart, Germany
| | - Hasmik Yepiskoposyan
- Philip Morris International R&D, Philip Morris Products S.A., Neuchatel, Switzerland
| | - Damien Breheny
- British American Tobacco (Investments) Ltd., Group Research and Development, Southampton, United Kingdom
| | - Frazer J Lowe
- Broughton Nicotine Services, Earby, Lancashire, United Kingdom
| |
Collapse
|
|
34
|
Dogra R, Mandal UK. Recent Applications of Derivatization Techniques for Pharmaceutical and
Bioanalytical Analysis through High-performance Liquid Chromatography. CURR ANAL CHEM 2022. [DOI: 10.2174/1573411017666211108092115] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background:
Derivatization of analytes is a quite convenient practice from an analytical perspective. Its vast prevalence is accounted by the availability of distinct reagents, primarily pragmatic for obtaining desired modifications in an analyte structure. Another reason for its handiness is typically to overcome limitations such as lack of sensitive methodology or instrumentation.The past decades have witnessed various new derivatization techniques including in-situ, enzymatic, ultrasound-assisted, microwave-assisted, and photochemical derivatization which have gain popularity recently.
Methods:
The online literature available on the utilization of derivatization as prominent analytical tools in recent years with typical advancements is reviewed. The illustrations of the analytical condition together with the structures of different derivatizing reagents (DRs) are provided to acknowledge the vast capability of derivatization to resolve analytical problems.
Results:
The derivatization techniques have enabled analytical chemists throughout the globe to develop an enhanced sensitivity method with the simplest of the instrument like High-Performance Liquid Chromatography (HPLC). The HPLC, compared to more sensitive Liquid chromatography coupled to tandem mass spectrometer, is readily available and can be readily utilized for routine analysis in fields of pharmaceuticals, bioanalysis, food safety, and environmental contamination. A troublesome aspect of these fields is the presence of a complex matrix with trace concentrations for analyses. Liquid chromatographic methods devoid of MS detectors do not have the desired sensitivity for this. A possible solution for overcoming this is to couple HPLC with derivatization to enable the possibility of detecting trace analytes with a less expensive instrument. Running cost, enhanced sensitivity, low time consumption, and overcoming the inherent problems of analyte are critical parameters for which HPLC is quite useful in high throughput analysis.
Conclusion:
The review critically highlights various kinds of derivatization applications in different fields of analytical chemistry. The information primarily focuses on pharmaceutical and bioanalytical applications in recent years. The various modes, types, and derivatizing reagents with brief mechanisms have been ascribed briefly Additionally, the importance of HPLC coupled to fluorescence and UV detection is presented as an overview through examples accompanied by their analytical conditions.
Collapse
Affiliation(s)
- Raghav Dogra
- Department of Chemical Sciences, University of Padua, Via Marzolo 1, 35131 Padova, Italy
| | - Uttam Kumar Mandal
- Department of Pharmaceutical
Sciences & Technology, Maharaja Ranjit Singh Punjab Technical University, Punjab, India
| |
Collapse
|
|
35
|
Finsterer J, Scorza FA, Scorza CA, Fiorini AC. Repurposing the antioxidant and anti-inflammatory agent N-acetyl cysteine for treating COVID-19. World J Virol 2022; 11:82-84. [PMID: 35117973 PMCID: PMC8788215 DOI: 10.5501/wjv.v11.i1.82] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 06/23/2021] [Accepted: 12/10/2021] [Indexed: 02/06/2023] Open
Abstract
Although several considerations have been raised suggesting a beneficial effect of N-acetyl cysteine (NAC) for the treatment of severe acute respiratory syndrome coronavirus 2 infection, there is currently no clinical evidence that NAC truly prevents coronavirus disease 2019 (COVID-19), reduces the severity of the disease, or improves the outcome. Appropriately designed clinical trials are warranted to prove or disprove a therapeutic effect of NAC for COVID-19 patients.
Collapse
Affiliation(s)
- Josef Finsterer
- Neurological Department, Messerli Institute, Vienna 1180, Austria
| | - Fulvio A Scorza
- Department of Neurology, University of Sao Paolo, Sao Paolo 01000-000, Brazil
| | - Carla A Scorza
- Department of Neurology, University of Sao Paolo, Sao Paolo 01000-000, Brazil
| | - Ana C Fiorini
- Department of Neurology, University of Sao Paolo, Sao Paolo 01000-000, Brazil
| |
Collapse
|
|
36
|
El Shehaby DM, Mohammed MK, Ebrahem NE, Abd El-Azim MM, Sayed IG, Eweda SA. The emerging therapeutic role of some pharmacological antidotes in management of COVID-19. THE EGYPTIAN JOURNAL OF BRONCHOLOGY 2022. [PMCID: PMC8771180 DOI: 10.1186/s43168-021-00105-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background A novel RNA coronavirus was identified in January 2020 as the cause of a pneumonia epidemic affecting the city of Wuhan; it rapidly spread across China. Aim of the review The aim is to discuss the potential efficacy of some pharmacologically known pharmacological antidotes (N-acetylcysteine; hyperbaric oxygen; deferoxamine; low-dose naloxone) for the management of COVID-19-associated symptoms and complications. Method An extensive search was accomplished in Medline, Embase, Scopus, Web of Science, and Central databases until the end of April, 2021. Four independent researchers completed the screening, and finally, the associated studies were involved. Conclusion The current proof hinders the experts for suggesting the proper pharmacological lines of treatment of COVID-19. Organizations, for example, WHO, should pursue more practical actions and design well-planned clinical trials so that their results may be used in the treatment of future outbreaks.
Collapse
|
|
37
|
Wang R, Chan JFW, Wang S, Li H, Zhao J, Ip TKY, Zuo Z, Yuen KY, Yuan S, Sun H. Orally administered bismuth drug together with N-acetyl cysteine as a broad-spectrum anti-coronavirus cocktail therapy. Chem Sci 2022; 13:2238-2248. [PMID: 35310492 PMCID: PMC8864717 DOI: 10.1039/d1sc04515f] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 11/24/2021] [Indexed: 12/20/2022] Open
Abstract
A cocktail therapy comprising bismuth drugs and N-acetyl-l-cysteine is reported to suppress the replication of SARS-CoV-2 via the oral route. The broad-spectrum inhibitory activities of the combination upon key viral cysteine enzymes are verified.
Collapse
Affiliation(s)
- Runming Wang
- Department of Chemistry, CAS-HKU Joint Laboratory of Metallomics on Health and Environment, The University of Hong Kong, Hong Kong SAR, P. R. China
| | - Jasper Fuk-Woo Chan
- State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
- Department of Clinical Microbiology and Infection Control, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, China
- Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
- Academician Workstation of Hainan Province, Hainan Medical University, Haikou, Hainan, China
- Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong SAR, China
| | - Suyu Wang
- Department of Chemistry, CAS-HKU Joint Laboratory of Metallomics on Health and Environment, The University of Hong Kong, Hong Kong SAR, P. R. China
| | - Hongyan Li
- Department of Chemistry, CAS-HKU Joint Laboratory of Metallomics on Health and Environment, The University of Hong Kong, Hong Kong SAR, P. R. China
| | - Jiajia Zhao
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China
| | - Tiffany Ka-Yan Ip
- Department of Chemistry, CAS-HKU Joint Laboratory of Metallomics on Health and Environment, The University of Hong Kong, Hong Kong SAR, P. R. China
| | - Zhong Zuo
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China
| | - Kwok-Yung Yuen
- State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
- Department of Clinical Microbiology and Infection Control, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, China
- Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
- Academician Workstation of Hainan Province, Hainan Medical University, Haikou, Hainan, China
- Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong SAR, China
| | - Shuofeng Yuan
- State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
- Department of Clinical Microbiology and Infection Control, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, China
- Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong SAR, China
| | - Hongzhe Sun
- Department of Chemistry, CAS-HKU Joint Laboratory of Metallomics on Health and Environment, The University of Hong Kong, Hong Kong SAR, P. R. China
| |
Collapse
|
|
38
|
Construction of a Recombinant Porcine Epidemic Diarrhea Virus Encoding Nanoluciferase for High-Throughput Screening of Natural Antiviral Products. Viruses 2021; 13:v13091866. [PMID: 34578449 PMCID: PMC8473292 DOI: 10.3390/v13091866] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 09/09/2021] [Accepted: 09/14/2021] [Indexed: 02/06/2023] Open
Abstract
Porcine epidemic diarrhea virus (PEDV) is the predominant cause of an acute, highly contagious enteric disease in neonatal piglets. There are currently no approved drugs against PEDV infection. Here, we report the development of a nanoluciferase (NLuc)-based high-throughput screening (HTS) platform to identify novel anti-PEDV compounds. We constructed a full-length cDNA clone for a cell-adapted PEDV strain YN150. Using reverse genetics, we replaced the open reading frame 3 (ORF3) in the viral genome with an NLuc gene to engineer a recombinant PEDV expressing NLuc (rPEDV-NLuc). rPEDV-NLuc produced similar plaque morphology and showed similar growth kinetics compared with the wild-type PEDV in vitro. Remarkably, the level of luciferase activity could be stably detected in rPEDV-NLuc-infected cells and exhibited a strong positive correlation with the viral titers. Given that NLuc expression represents a direct readout of PEDV replication, anti-PEDV compounds could be easily identified by quantifying the NLuc activity. Using this platform, we screened for the anti-PEDV compounds from a library of 803 natural products and identified 25 compounds that could significantly inhibit PEDV replication. Interestingly, 7 of the 25 identified compounds were natural antioxidants, including Betulonic acid, Ursonic acid, esculetin, lithocholic acid, nordihydroguaiaretic acid, caffeic acid phenethyl ester, and grape seed extract. As expected, all of the antioxidants could potently reduce PEDV-induced oxygen species production, which, in turn, inhibit PEDV replication in a dose-dependent manner. Collectively, our findings provide a powerful platform for the rapid screening of promising therapeutic compounds against PEDV infection.
Collapse
|
|
39
|
Abstract
Influenza viruses are one of the leading causes of respiratory tract infections in humans and their newly emerging and re-emerging virus strains are responsible for seasonal epidemics and occasional pandemics, leading to a serious threat to global public health systems. The poor clinical outcome and pathogenesis during influenza virus infection in humans and animal models are often associated with elevated proinflammatory cytokines and chemokines production, which is also known as hypercytokinemia or "cytokine storm", that precedes acute respiratory distress syndrome (ARDS) and often leads to death. Although we still do not fully understand the complex nature of cytokine storms, the use of immunomodulatory drugs is a promising approach for treating hypercytokinemia induced by an acute viral infection, including highly pathogenic avian influenza virus infection and Coronavirus Disease 2019 (COVID-19). This review aims to discuss the immune responses and cytokine storm pathology induced by influenza virus infection and also summarize alternative experimental strategies for treating hypercytokinemia caused by influenza virus.
Collapse
Affiliation(s)
- Fanhua Wei
- Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in Western China, Ningxia University, Yinchuan, China.,College of Agriculture, Ningxia University, Yinchuan, China
| | - Chengjiang Gao
- Key Laboratory of Infection and Immunity of Shandong Province & Department of Immunology, School of Biomedical Sciences, Shandong University, Jinan, China
| | - Yujiong Wang
- Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in Western China, Ningxia University, Yinchuan, China.,College of Life Science, Ningxia University, Yinchuan, China
| |
Collapse
|
|
40
|
De La Cruz JA, Ganesh T, Diebold BA, Cao W, Hofstetter A, Singh N, Kumar A, McCoy J, Ranjan P, Smith SME, Sambhara S, Lambeth JD, Gangappa S. Quinazolin-derived myeloperoxidase inhibitor suppresses influenza A virus-induced reactive oxygen species, pro-inflammatory mediators and improves cell survival. PLoS One 2021; 16:e0254632. [PMID: 34280220 PMCID: PMC8289044 DOI: 10.1371/journal.pone.0254632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 07/01/2021] [Indexed: 11/25/2022] Open
Abstract
Superoxide radicals and other reactive oxygen species (ROS) are implicated in influenza A virus-induced inflammation. In this in vitro study, we evaluated the effects of TG6-44, a novel quinazolin-derived myeloperoxidase-specific ROS inhibitor, on influenza A virus (A/X31) infection using THP-1 lung monocytic cells and freshly isolated peripheral blood mononuclear cells (PBMC). TG6-44 significantly decreased A/X31-induced ROS and virus-induced inflammatory mediators in THP-1 cells (IL-6, IFN-γ, MCP-1, TNF-α, MIP-1β) and in human PBMC (IL-6, IL-8, TNF-α, MCP-1). Interestingly, TG6-44-treated THP-1 cells showed a decrease in percent cells expressing viral nucleoprotein, as well as a delay in translocation of viral nucleoprotein into the nucleus. Furthermore, in influenza A virus-infected cells, TG6-44 treatment led to suppression of virus-induced cell death as evidenced by decreased caspase-3 activation, decreased proportion of Annexin V+PI+ cells, and increased Bcl-2 phosphorylation. Taken together, our results demonstrate the anti-inflammatory and anti-infective effects of TG6-44.
Collapse
Affiliation(s)
- Juan A. De La Cruz
- Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
| | - Thota Ganesh
- Department of Pharmacology, Emory University, Atlanta, Georgia, United States of America
| | - Becky A. Diebold
- Department of Pathology, Emory University, Atlanta, Georgia, United States of America
| | - Weiping Cao
- Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
| | - Amelia Hofstetter
- Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
| | - Neetu Singh
- Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
| | - Amrita Kumar
- Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
| | - James McCoy
- Department of Pathology, Emory University, Atlanta, Georgia, United States of America
| | - Priya Ranjan
- Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
| | - Susan M. E. Smith
- Department of Pathology, Emory University, Atlanta, Georgia, United States of America
| | - Suryaprakash Sambhara
- Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
| | - J. David Lambeth
- Department of Pathology, Emory University, Atlanta, Georgia, United States of America
- * E-mail: (SG); (JDL)
| | - Shivaprakash Gangappa
- Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
- * E-mail: (SG); (JDL)
| |
Collapse
|
|
41
|
Wong KK, Lee SWH, Kua KP. N-Acetylcysteine as Adjuvant Therapy for COVID-19 - A Perspective on the Current State of the Evidence. J Inflamm Res 2021; 14:2993-3013. [PMID: 34262324 PMCID: PMC8274825 DOI: 10.2147/jir.s306849] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 05/26/2021] [Indexed: 12/15/2022] Open
Abstract
The looming severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a long-lasting pandemic of coronavirus disease 2019 (COVID-19) around the globe with substantial morbidity and mortality. N-acetylcysteine, being a nutraceutical precursor of an important antioxidant glutathione, can perform several biological functions in mammals and microbes. It has consequently garnered a growing interest as a potential adjunctive therapy for coronavirus disease. Here, we review evidence concerning the effects of N-acetylcysteine in respiratory viral infections based on currently available in vitro, in vivo, and human clinical investigations. The repurposing of a known drug such as N-acetylcysteine may significantly hasten the deployment of a novel approach for COVID-19. Since the drug candidate has already been translated into the clinic for several decades, its established pharmacological properties and safety and side-effect profiles expedite preclinical and clinical assessment for the treatment of COVID-19. In vitro data have depicted that N-acetylcysteine increases antioxidant capacity, interferes with virus replication, and suppresses expression of pro-inflammatory cytokines in cells infected with influenza viruses or respiratory syncytial virus. Furthermore, findings from in vivo studies have displayed that, by virtue of immune modulation and anti-inflammatory mechanism, N-acetylcysteine reduces the mortality rate in influenza-infected mice animal models. The promising in vitro and in vivo results have prompted the initiation of human subject research for the treatment of COVID-19, including severe pneumonia and acute respiratory distress syndrome. Albeit some evidence of benefits has been observed in clinical outcomes of patients, precision nanoparticle design of N-acetylcysteine may allow for greater therapeutic efficacy.
Collapse
Affiliation(s)
- Kon Ken Wong
- Department of Microbiology and Immunology, Hospital Canselor Tuanku Muhriz UKM, Cheras, Kuala Lumpur, Malaysia.,Faculty of Medicine, The National University of Malaysia, Cheras, Kuala Lumpur, Malaysia
| | - Shaun Wen Huey Lee
- School of Pharmacy, Monash University, Bandar Sunway, Selangor, Malaysia.,Asian Centre for Evidence Synthesis in Population, Implementation, and Clinical Outcomes (PICO), Health and Well-being Cluster, Global Asia in the 21st Century (GA21) Platform, Monash University, Bandar Sunway, Selangor, Malaysia.,Gerontechnology Laboratory, Global Asia in the 21st Century (GA21) Platform, Monash University, Bandar Sunway, Selangor, Malaysia.,Faculty of Health and Medical Sciences, Taylor's University, Bandar Sunway, Selangor, Malaysia
| | - Kok Pim Kua
- Puchong Health Clinic, Petaling District Health Office, Ministry of Health Malaysia, Petaling, Selangor, Malaysia
| |
Collapse
|
|
42
|
Shirey KA, Blanco JCG, Vogel SN. Targeting TLR4 Signaling to Blunt Viral-Mediated Acute Lung Injury. Front Immunol 2021; 12:705080. [PMID: 34282358 PMCID: PMC8285366 DOI: 10.3389/fimmu.2021.705080] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 06/10/2021] [Indexed: 01/14/2023] Open
Abstract
Respiratory viral infections have been a long-standing global burden ranging from seasonal recurrences to the unexpected pandemics. The yearly hospitalizations from seasonal viruses such as influenza can fluctuate greatly depending on the circulating strain(s) and the congruency with the predicted strains used for the yearly vaccine formulation, which often are not predicted accurately. While antiviral agents are available against influenza, efficacy is limited due to a temporal disconnect between the time of infection and symptom development and viral resistance. Uncontrolled, influenza infections can lead to a severe inflammatory response initiated by pathogen-associated molecular patterns (PAMPs) or host-derived danger-associated molecular patterns (DAMPs) that ultimately signal through pattern recognition receptors (PRRs). Overall, these pathogen-host interactions result in a local cytokine storm leading to acute lung injury (ALI) or the more severe acute respiratory distress syndrome (ARDS) with concomitant systemic involvement and more severe, life threatening consequences. In addition to traditional antiviral treatments, blocking the host's innate immune response may provide a more viable approach to combat these infectious pathogens. The SARS-CoV-2 pandemic illustrates a critical need for novel treatments to counteract the ALI and ARDS that has caused the deaths of millions worldwide. This review will examine how antagonizing TLR4 signaling has been effective experimentally in ameliorating ALI and lethal infection in challenge models triggered not only by influenza, but also by other ALI-inducing viruses.
Collapse
Affiliation(s)
- Kari Ann Shirey
- Department of Microbiology and Immunology, School of Medicine, University of Maryland, Baltimore, MD, United States
| | | | - Stefanie N. Vogel
- Department of Microbiology and Immunology, School of Medicine, University of Maryland, Baltimore, MD, United States
| |
Collapse
|
|
43
|
Khazeei Tabari MA, Iranpanah A, Bahramsoltani R, Rahimi R. Flavonoids as Promising Antiviral Agents against SARS-CoV-2 Infection: A Mechanistic Review. Molecules 2021; 26:3900. [PMID: 34202374 PMCID: PMC8271800 DOI: 10.3390/molecules26133900] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 06/22/2021] [Accepted: 06/23/2021] [Indexed: 01/03/2023] Open
Abstract
A newly diagnosed coronavirus in 2019 (COVID-19) has affected all human activities since its discovery. Flavonoids commonly found in the human diet have attracted a lot of attention due to their remarkable biological activities. This paper provides a comprehensive review of the benefits of flavonoids in COVID-19 disease. Previously-reported effects of flavonoids on five RNA viruses with similar clinical manifestations and/or pharmacological treatments, including influenza, human immunodeficiency virus (HIV), severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and Ebola, were considered. Flavonoids act via direct antiviral properties, where they inhibit different stages of the virus infective cycle and indirect effects when they modulate host responses to viral infection and subsequent complications. Flavonoids have shown antiviral activity via inhibition of viral protease, RNA polymerase, and mRNA, virus replication, and infectivity. The compounds were also effective for the regulation of interferons, pro-inflammatory cytokines, and sub-cellular inflammatory pathways such as nuclear factor-κB and Jun N-terminal kinases. Baicalin, quercetin and its derivatives, hesperidin, and catechins are the most studied flavonoids in this regard. In conclusion, dietary flavonoids are promising treatment options against COVID-19 infection; however, future investigations are recommended to assess the antiviral properties of these compounds on this disease.
Collapse
Affiliation(s)
- Mohammad Amin Khazeei Tabari
- Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran;
- USERN Office, Mazandaran University of Medical Sciences, Sari, Iran
| | - Amin Iranpanah
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran;
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Kermanshah USERN Office, Universal Scientific Education and Research Network (USERN), Kermanshah, Iran
| | - Roodabeh Bahramsoltani
- Department of Traditional Pharmacy, School of Persian Medicine, Tehran University of Medical Sciences, Tehran P.O. Box 1417653761, Iran;
- Research Center for Clinical Virology, Tehran University of Medical Sciences, Tehran, Iran
- PhytoPharmacology Interest Group (PPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Roja Rahimi
- Department of Traditional Pharmacy, School of Persian Medicine, Tehran University of Medical Sciences, Tehran P.O. Box 1417653761, Iran;
- PhytoPharmacology Interest Group (PPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| |
Collapse
|
|
44
|
Carbone DA, Pellone P, Lubritto C, Ciniglia C. Evaluation of Microalgae Antiviral Activity and Their Bioactive Compounds. Antibiotics (Basel) 2021; 10:746. [PMID: 34202941 PMCID: PMC8234452 DOI: 10.3390/antibiotics10060746] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 06/12/2021] [Accepted: 06/14/2021] [Indexed: 01/02/2023] Open
Abstract
During the last year, science has been focusing on the research of antivirally active compounds overall after the SARS-CoV-2 pandemic, which caused a great amount of deaths and the downfall of the economy in 2020. Photosynthetic organisms such as microalgae are known to be a reservoir of bioactive secondary metabolites; this feature, coupled with the possibility of achieving very high biomass levels without excessive energetic expenses, make microalgae worthy of attention in the search for new molecules with antiviral effects. In this work, the antiviral effects of microalgae against some common human or animal viruses were considered, focusing our attention on some possible effects against SARS-CoV-2. We summed up the data from the literature on microalgae antiviral compounds, from the most common ones, such as lectins, polysaccharides and photosynthetic pigments, to the less known ones, such as unidentified proteins. We have discussed the effects of a microalgae-based genetic engineering approach against some viral diseases. We have illustrated the potential antiviral benefits of a diet enriched in microalgae.
Collapse
Affiliation(s)
- Dora Allegra Carbone
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, Via Vivaldi 43, 81100 Caserta, Italy; (C.L.); (C.C.)
| | - Paola Pellone
- Department of Marine Biotechnology, Stazione Zoologica Anton Dohrn, Villa Comunale, 80121 Naples, Italy;
| | - Carmine Lubritto
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, Via Vivaldi 43, 81100 Caserta, Italy; (C.L.); (C.C.)
- National Institute of Nuclear Physics, Complesso Universitario di Monte S, 80126 Naples, Italy
| | - Claudia Ciniglia
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, Via Vivaldi 43, 81100 Caserta, Italy; (C.L.); (C.C.)
| |
Collapse
|
|
45
|
Taher A, Lashgari M, Sedighi L, Rahimi-bashar F, Poorolajal J, Mehrpooya M. A pilot study on intravenous N-Acetylcysteine treatment in patients with mild-to-moderate COVID19-associated acute respiratory distress syndrome. Pharmacol Rep 2021; 73:1650-1659. [PMID: 34114174 PMCID: PMC8191712 DOI: 10.1007/s43440-021-00296-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 05/31/2021] [Accepted: 06/03/2021] [Indexed: 01/08/2023]
Abstract
Background We designed this single-centre clinical trial to assess the potential benefits of N-Acetylcysteine (NAC) in patients with COVID19-associated acute respiratory distress syndrome (ARDS). Methods Ninety-two patients with mild-to-moderate COVID19-associated ARDS were allocated to the placebo (45-cases) or NAC groups (47-cases). Besides standard-of-care treatment, the patients received either intravenous NAC at a dose of 40 mg/kg/day or the placebo for three consecutive days. The efficacy outcomes were overall mortality over 28-day, clinical status on day 28, based on the WHO Master Protocol, the proportion of patients requiring mechanical ventilation, changes in ARDS-severity (based on the PaO2/FiO2 ratio), and Sequential Organ Failure Assessment (SOFA) scores 48 and 96 h after intervention, Results No differences were found in the 28-day mortality rate between the two groups (25.5% vs. 31.1% in the NAC and placebo groups, respectively). Although the distribution of the clinical status at day 28 shifted towards better outcomes in the NAC-treated group, it did not reach a statistical significance level (p value = 0.83). Similar results were achieved in terms of the proportion of patients who required invasive ventilator support (38.3% vs. 44.4%), the number of ventilator-free days (17.4 vs. 16.6), and median time of ICU and hospital stay. Results regarding the change in PaO2/FiO2 ratio and SOFA scores also showed no significant differences between the groups. Conclusions Our pilot study did not support the potential benefits of intravenous NAC in treating patients with COVID-19-associated ARDS. More studies are needed to determine which COVID-19 patients benefit from the NAC administration. Trial registration The trial was registered at Clinicaltrials.gov (identifier code: IRCT20120215009014N355). Registration date: 2020-05-18.
Collapse
Affiliation(s)
- Abbas Taher
- Department of Anesthesiology and Critical Care, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Marjan Lashgari
- Department of Anesthesiology and Critical Care, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Ladan Sedighi
- Department of Medical and Surgical Nursing, School of Nursing and Midwifery, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farshid Rahimi-bashar
- Department of Anesthesiology and Critical Care, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Jalal Poorolajal
- Department of Epidemiology, School of Public Health, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Maryam Mehrpooya
- Department of Clinical Pharmacy, School of Pharmacy, Hamadan University of Medical Sciences, Shahid Fahmideh Ave, 6517838678 Hamadan, Iran
| |
Collapse
|
|
46
|
Schwalfenberg GK. N-Acetylcysteine: A Review of Clinical Usefulness (an Old Drug with New Tricks). J Nutr Metab 2021; 2021:9949453. [PMID: 34221501 PMCID: PMC8211525 DOI: 10.1155/2021/9949453] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 05/26/2021] [Indexed: 01/13/2023] Open
Abstract
OBJECTIVE To review the clinical usefulness of N-acetylcysteine (NAC) as treatment or adjunctive therapy in a number of medical conditions. Use in Tylenol overdose, cystic fibrosis, and chronic obstructive lung disease has been well documented, but there is emerging evidence many other conditions would benefit from this safe, simple, and inexpensive intervention. Quality of Evidence. PubMed, several books, and conference proceedings were searched for articles on NAC and health conditions listed above reviewing supportive evidence. This study uses a traditional integrated review format, and clinically relevant information is assessed using the American Family Physician Evidence-Based Medicine Toolkit. A table summarizing the potential mechanisms of action for N-acetylcysteine in these conditions is presented. Main Message. N-acetylcysteine may be useful as an adjuvant in treating various medical conditions, especially chronic diseases. These conditions include polycystic ovary disease, male infertility, sleep apnea, acquired immune deficiency syndrome, influenza, parkinsonism, multiple sclerosis, peripheral neuropathy, stroke outcomes, diabetic neuropathy, Crohn's disease, ulcerative colitis, schizophrenia, bipolar illness, and obsessive compulsive disorder; it can also be useful as a chelator for heavy metals and nanoparticles. There are also a number of other conditions that may show benefit; however, the evidence is not as robust. CONCLUSION The use of N-acetylcysteine should be considered in a number of conditions as our population ages and levels of glutathione drop. Supplementation may contribute to reducing morbidity and mortality in some chronic conditions as outlined in the article.
Collapse
Affiliation(s)
- Gerry K. Schwalfenberg
- Department of Family Medicine, University of Alberta, No. 301, 9509-156 Street, Edmonton T5P 4J5, AB, Canada
| |
Collapse
|
|
47
|
Rubilar T, Barbieri ES, Gazquez A, Avaro M. Sea Urchin Pigments: Echinochrome A and Its Potential Implication in the Cytokine Storm Syndrome. Mar Drugs 2021; 19:267. [PMID: 34064550 PMCID: PMC8151293 DOI: 10.3390/md19050267] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 04/14/2021] [Accepted: 04/23/2021] [Indexed: 12/14/2022] Open
Abstract
Background: Echinochrome A (EchA) is a pigment from sea urchins. EchA is a polyhydroxylated 1,4-naphthoquinone that contains several hydroxyl groups appropriate for free-radical scavenging and preventing redox imbalance. EchA is the most studied molecule of this family and is an active principle approved to be used in humans, usually for cardiopathies and glaucoma. EchA is used as a pharmaceutical drug. Methods: A comprehensive literature and patent search review was undertaken using PubMed, as well as Google Scholar and Espacenet search engines to review these areas. Conclusions: In the bloodstream, EchA can mediate cellular responses, act as a radical scavenger, and activate the glutathione pathway. It decreases ROS imbalance, prevents and limits lipid peroxidation, and enhances mitochondrial functions. Most importantly, EchA contributes to the modulation of the immune system. EchA can regulate the generation of regulatory T cells, inhibit pro-inflammatory IL-1β and IL-6 cytokine production, while slightly reducing IL-8, TNF-α, INF-α, and NKT, thus correcting immune imbalance. These characteristics suggest that EchA is a candidate drug to alleviate the cytokine storm syndrome (CSS).
Collapse
Affiliation(s)
- Tamara Rubilar
- Laboratorio de Química de Organismos Marinos, Instituto Patagónico del Mar, Universidad Nacional de la Patagonia San Juan Bosco (UNPSJB), Puerto Madryn 9120, Chubut, Argentina;
- Laboratorio de Oceanografía Biológica, Centro Para el Estudio de Sistemas Marinos (CESIMAR), CONICET, Puerto Madryn 9120, Chubut, Argentina;
| | - Elena S. Barbieri
- Laboratorio de Oceanografía Biológica, Centro Para el Estudio de Sistemas Marinos (CESIMAR), CONICET, Puerto Madryn 9120, Chubut, Argentina;
- Laboratorio de Virología, Instituto Patagónico del Mar, Universidad Nacional de la Patagonia San Juan Bosco (UNPSJB), Puerto Madryn 9120, Chubut, Argentina
| | - Ayelén Gazquez
- Instituto Tecnológico de Chascomús, The Chascomús Technological Institute (INTECH), CONICET-UNSAM, Chascomús 7130, Buenos Aires, Argentina;
| | - Marisa Avaro
- Laboratorio de Química de Organismos Marinos, Instituto Patagónico del Mar, Universidad Nacional de la Patagonia San Juan Bosco (UNPSJB), Puerto Madryn 9120, Chubut, Argentina;
| |
Collapse
|
|
48
|
Sarco/Endoplasmic Reticulum Ca 2+ Transporting ATPase (SERCA) Modulates Autophagic, Inflammatory, and Mitochondrial Responses during Influenza A Virus Infection in Human Lung Cells. J Virol 2021; 95:JVI.00217-21. [PMID: 33692207 PMCID: PMC8139658 DOI: 10.1128/jvi.00217-21] [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] [Indexed: 01/04/2023] Open
Abstract
Influenza A virus is an important human pathogen causing significant morbidity and mortality. Numerous host factors and cellular responses are dysregulated during influenza A virus infection. This includes arrest of autophagic flux dependent on the influenza M2 ion channel, but little is known which host factors participate in this autophagic dysfunction. Sarco/endoplasmic reticulum calcium ATPase (SERCA) is known to regulate transport of calcium ions between the cytoplasm and the sarco/endoplasmic reticulum, and has been positively correlated with autophagic flux. Herein, we found that SERCA activity was suppressed in influenza A virus infected human lung cells (H1395) and that CDN1163, an activator of SERCA, restored autophagic flux and thus reduced autophagosome accumulation caused by the influenza A virus. Activating SERCA activity with CDN1163 also decreased expression of inflammatory cytokines and chemokines and attenuated mitochondrial dysfunction in IAV-infected H1395 cells. Conversely, SERCA inhibition or genetic ablation aggravated the autophagy dysfunction, mitochondria, and inflammatory responses in the cells infected with influenza A virus. Further study showed that SERCA might regulate the inflammatory response by modulating phosphorylation of MAPK-JNK pathway. These findings showed that the influenza A virus induced autophagic flux blocking, inflammatory response and mitochondrial dysfunction by inhibiting SERCA activity. This study provides further understanding of the host-viral interactions between the influenza virus, SERCA activity, autophagy, inflammatory response, and mitochondrial function. SERCA may be a potential host target for decreasing inflammatory and superoxide injury during influenza A virus infection.IMPORTANCE:IAV is a major cause of infectious respiratory diseases, characterized by a marked respiratory tract inflammatory response that causes morbidity and mortality in seasonal epidemics, or pandemic outbreaks. SERCA is a critical component in maintaining cellular calcium levels, and is positively correlated with autophagic flux. Here, we discovered that SERCA is suppressed in IAV-infected human lung cells and influenza A virus induces blocking of autophagic flux, inflammatory response and mitochondrial dysfunction by inhibiting SERCA. We posit that the pharmacological activation of SERCA can be a powerful intervention strategy to prevent autophagy arrest, inflammatory response, and mitochondrial dysfunction in IAV-infected cells. Therefore, SERCA activity modulation could be a potential therapeutic strategy for managing clinical symptoms of severe influenza disease.
Collapse
|
|
49
|
Kifle ZD, Ayele AG, Enyew EF. Drug Repurposing Approach, Potential Drugs, and Novel Drug Targets for COVID-19 Treatment. JOURNAL OF ENVIRONMENTAL AND PUBLIC HEALTH 2021; 2021:6631721. [PMID: 33953756 PMCID: PMC8063850 DOI: 10.1155/2021/6631721] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 02/23/2021] [Accepted: 04/17/2021] [Indexed: 12/16/2022]
Abstract
Novel coronavirus first appeared in Wuhan, China, in December 2019, and it speedily expanded globally. Some medications which are used to treat other diseases seem to be effective in treating COVID-19 even without explicit support. The existing drugs that are summarized in this review primarily focused on therapeutic agents that possessed activity against other RNA viruses such as MERS-CoV and SARS-CoV. Drug repurposing or repositioning is a promising field in drug discovery that identifies new therapeutic opportunities for existing drugs such as corticosteroids, RNA-dependent RNA polymerase inhibitors, interferons, protease inhibitors, ivermectin, melatonin, teicoplanin, and some others. A search for new drug/drug targets is underway. Thus, blocking coronavirus structural protein, targeting viral enzyme, dipeptidyl peptidase 4, and membrane fusion blocker (angiotensin-converting enzyme 2 and CD147 inhibitor) are major sites based on molecular targets for the management of COVID-19 infection. The possible impact of biologics for the management of COVID19 is promising and includes a wide variety of options such as cytokines, nucleic acid-based therapies targeting virus gene expression, bioengineered and vectored antibodies, and various types of vaccines. This review demonstrates that the available data are not sufficient to suggest any treatment for the eradication of COVID-19 to be used at the clinical level. This article aims to review the roles of existing drugs and drug targets for COVID-19 treatment.
Collapse
Affiliation(s)
- Zemene Demelash Kifle
- Department of Pharmacology, School of Pharmacy, College of Medicine and Health Science, University of Gondar, Gondar, Ethiopia
| | - Akeberegn Gorems Ayele
- Department of Pharmacology and Clinical Pharmacy, School of Pharmacy, College of Health Science, Addis Ababa University, Addis Ababa, Ethiopia
| | - Engidaw Fentahun Enyew
- Department of Human Anatomy, School of Medicine, College of Medicine and Health Sciences, Gondar, Ethiopia
| |
Collapse
|
|
50
|
Intracellular Redox-Modulated Pathways as Targets for Effective Approaches in the Treatment of Viral Infection. Int J Mol Sci 2021; 22:ijms22073603. [PMID: 33808471 PMCID: PMC8036776 DOI: 10.3390/ijms22073603] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 03/19/2021] [Accepted: 03/25/2021] [Indexed: 02/07/2023] Open
Abstract
Host-directed therapy using drugs that target cellular pathways required for virus lifecycle or its clearance might represent an effective approach for treating infectious diseases. Changes in redox homeostasis, including intracellular glutathione (GSH) depletion, are one of the key events that favor virus replication and contribute to the pathogenesis of virus-induced disease. Redox homeostasis has an important role in maintaining an appropriate Th1/Th2 balance, which is necessary to mount an effective immune response against viral infection and to avoid excessive inflammatory responses. It is known that excessive production of reactive oxygen species (ROS) induced by viral infection activates nuclear factor (NF)-kB, which orchestrates the expression of viral and host genes involved in the viral replication and inflammatory response. Moreover, redox-regulated protein disulfide isomerase (PDI) chaperones have an essential role in catalyzing formation of disulfide bonds in viral proteins. This review aims at describing the role of GSH in modulating redox sensitive pathways, in particular that mediated by NF-kB, and PDI activity. The second part of the review discusses the effectiveness of GSH-boosting molecules as broad-spectrum antivirals acting in a multifaceted way that includes the modulation of immune and inflammatory responses.
Collapse
|