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Lucic B, Franciscato DS, Nogueira HP, Gallucci L, Silveira Junior AT, Ismail AM, Robinson M, Dallinger T, Gutfleisch C, Kurz J, Toledo M, Dias da Silva Ferraz J, Tarek M, Dias D, Diaz RS, ElHefnawi M, Forcato M, Monteiro HP, Lusic M, Shytaj IL, Savarino A. Fast pH-Driven Solubilization Method of Realgar (As 4S 4) to Reduce the Toxicity of Arsenic [As(III)] for Medicinal Purposes. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2502740. [PMID: 40271739 DOI: 10.1002/advs.202502740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Indexed: 04/25/2025]
Abstract
Acute promyelocytic leukemia (APL) accounts for 5-15% of acute myeloid leukemia cases. It is typically characterized by the (15;17) chromosomal translocation, producing the pathogenic retinoic acid receptor (RAR) alpha/promyelocytic leukemia (PML) fusion protein. Recently, remission of APL has been achieved using the first chemotherapy-independent oral drug regimen in anticancer therapy, consisting of all-trans retinoic acid (targeting RARalpha) and the arsenic sulfide realgar (targeting PML). However, clinical adoption of realgar and the characterization of its active breakdown products have been hampered by its poor solubility. Here, a scalable pH/temperature-based process is described that partially mimics gut transition, achieving fast and reproducible solubilization of realgar. Six different spectroscopic and spectrometric techniques are employed to investigate solubilized realgar. Furthermore, it is shown that solubilized realgar targets PML, displaying wider in vitro therapeutic indices and lower off-target effects than arsenic trioxide, the current APL standard of care. Moreover, in line with evidence of an interplay between PML and HIV persistence, solubilized realgar can disrupt HIV latency, the main barrier to an HIV/AIDS cure, in CD4 T cells of people living with HIV. These findings may open avenues for streamlining realgar solubilization and designing less toxic, orally administrable arsenic-based therapies.
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Affiliation(s)
- Bojana Lucic
- Department of Infectious Diseases, Integrative Virology, Heidelberg University, 69120, Heidelberg, Germany
- German Center for Infection Research, 69120, Heidelberg, Germany
| | | | | | - Lara Gallucci
- School of Cellular and Molecular Medicine, University of Bristol, Bristol, BS8 1TD, UK
| | | | - Asmaa Mohamed Ismail
- Spectroscopy Department, National Research Centre, 33 El Bohouth Street, Dokki, Giza, 12622, Egypt
| | - Millie Robinson
- School of Cellular and Molecular Medicine, University of Bristol, Bristol, BS8 1TD, UK
| | - Teresa Dallinger
- Department of Infectious Diseases, Integrative Virology, Heidelberg University, 69120, Heidelberg, Germany
| | - Claudia Gutfleisch
- Center for Infectious Diseases, Medical Microbiology und Hygiene, University Hospital Heidelberg, 69120, Heidelberg, Germany
| | - Jochen Kurz
- Center for Infectious Diseases, Medical Microbiology und Hygiene, University Hospital Heidelberg, 69120, Heidelberg, Germany
| | - Maytê Toledo
- Department of Biochemistry, Center for Cellular and Molecular Therapy, Federal University of São Paulo, São Paulo, 04021-001, Brazil
| | | | - Mohammad Tarek
- Clinical Hematology Department, Armed Forces College of Medicine (AFCM) Cairo Governatorate, Heliopolis, 11774, Egypt
| | - Danilo Dias
- Infectious Diseases Department, Federal University of São Paulo, São Paulo, 04021-001, Brazil
| | - Ricardo Sobhie Diaz
- Infectious Diseases Department, Federal University of São Paulo, São Paulo, 04021-001, Brazil
| | - Mahmoud ElHefnawi
- Informatics and Systems Department, National Research Centre, 33 El Bohouth Street, Dokki, Giza, 12622, Egypt
| | - Mattia Forcato
- Department of Molecular Medicine, University of Padova, Padova, 35122, Italy
| | - Hugo P Monteiro
- Department of Biochemistry, Center for Cellular and Molecular Therapy, Federal University of São Paulo, São Paulo, 04021-001, Brazil
| | - Marina Lusic
- Department of Infectious Diseases, Integrative Virology, Heidelberg University, 69120, Heidelberg, Germany
- German Center for Infection Research, 69120, Heidelberg, Germany
| | - Iart Luca Shytaj
- School of Cellular and Molecular Medicine, University of Bristol, Bristol, BS8 1TD, UK
- Infectious Diseases Department, Federal University of São Paulo, São Paulo, 04021-001, Brazil
| | - Andrea Savarino
- Department of Infectious Diseases, Italian Institute of Health, Rome, 00161, Italy
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Wen Z, Li P, Yuan Y, Wang C, Li M, Wang H, Shi M, He Y, Cui M, Chen L, Sun C. Purging viral latency by a bifunctional HSV-vectored therapeutic vaccine in chronically SIV-infected macaques. eLife 2025; 13:RP95964. [PMID: 40266253 PMCID: PMC12017772 DOI: 10.7554/elife.95964] [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] [Indexed: 04/24/2025] Open
Abstract
The persistence of latent viral reservoirs remains the major obstacle to eradicating human immunodeficiency virus (HIV). We herein found that ICP34.5 can act as an antagonistic factor for the reactivation of HIV latency by herpes simplex virus type I (HSV-1), and thus recombinant HSV-1 with ICP34.5 deletion could more effectively reactivate HIV latency than its wild-type counterpart. Mechanistically, HSV-ΔICP34.5 promoted the phosphorylation of HSF1 by decreasing the recruitment of protein phosphatase 1 (PP1α), thus effectively binding to the HIV LTR to reactivate the latent reservoirs. In addition, HSV-ΔICP34.5 enhanced the phosphorylation of IKKα/β through the degradation of IκBα, leading to p65 accumulation in the nucleus to elicit NF-κB pathway-dependent reactivation of HIV latency. Then, we constructed the recombinant HSV-ΔICP34.5 expressing simian immunodeficiency virus (SIV) env, gag, or the fusion antigen sPD1-SIVgag as a therapeutic vaccine, aiming to achieve a functional cure by simultaneously reactivating viral latency and eliciting antigen-specific immune responses. Results showed that these constructs effectively elicited SIV-specific immune responses, reactivated SIV latency, and delayed viral rebound after the interruption of antiretroviral therapy (ART) in chronically SIV-infected rhesus macaques. Collectively, these findings provide insights into the rational design of HSV-vectored therapeutic strategies for pursuing an HIV functional cure.
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Affiliation(s)
- Ziyu Wen
- School of Public Health (Shenzhen), Sun Yat-sen UniversityShenzhenChina
| | - Pingchao Li
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of SciencesGuangzhouChina
| | - Yue Yuan
- School of Public Health (Shenzhen), Sun Yat-sen UniversityShenzhenChina
| | - Congcong Wang
- School of Public Health (Shenzhen), Sun Yat-sen UniversityShenzhenChina
| | - Minchao Li
- School of Public Health (Shenzhen), Sun Yat-sen UniversityShenzhenChina
| | - Haohang Wang
- School of Public Health (Shenzhen), Sun Yat-sen UniversityShenzhenChina
| | - Minjuan Shi
- School of Public Health (Shenzhen), Sun Yat-sen UniversityShenzhenChina
| | - Yizi He
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of SciencesGuangzhouChina
| | - Mingting Cui
- School of Public Health (Shenzhen), Sun Yat-sen UniversityShenzhenChina
| | - Ling Chen
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of SciencesGuangzhouChina
| | - Caijun Sun
- School of Public Health (Shenzhen), Sun Yat-sen UniversityShenzhenChina
- Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of EducationGuangzhouChina
- Shenzhen Key Laboratory of Pathogenic Microbes and Biosafety, Shenzhen Campus of Sun Yat-sen UniversityShenzhenChina
- State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen UniversityGuangzhouChina
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Ahmed YM, El-Shoura EAM, Kozman MR, Abdel-Wahab BA, Abdel-Sattar AR. Combined bisoprolol and trimetazidine ameliorate arsenic trioxide -induced acute myocardial injury in rats: targeting PI3K/GSK-3β/Nrf2/HO-1 and NF-κB/iNOS signaling pathways, inflammatory mediators and apoptosis. Immunopharmacol Immunotoxicol 2024:1-17. [PMID: 39604018 DOI: 10.1080/08923973.2024.2435323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 11/24/2024] [Indexed: 11/29/2024]
Abstract
BACKGROUND Arsenic-trioxide (ATO) is an effective therapy for acute promyelocytic leukemia. Unfortunately, its utility is hindered by the risk of myocardial injury. Both bisoprolol (BIS) and trimetazidine (TMZ) have various pharmacological features, including anti-oxidant, anti-inflammatory, and anti-apoptotic properties. AIM The cardioprotective effects of BIS and TMZ were studied, and their mechanistic role in ameliorating ATO-induced myocardial injury. MATERIALS AND METHODS Forty male Wistar rats were randomly allotted into five groups as follows: normal control group (received normal saline, orally), ATO group (7.5 mg/kg, orally), BIS (8 mg/kg, orally), TMZ (60 mg/kg, orally), and finally combination group (BIS+TMZ+ATO). Following 21 days, samples of serum and cardiac tissues were obtained to perform biochemical, molecular, and histopathological investigations. RESULTS The present study showed that ATO caused myocardial injury evidenced by changes in serum biomarkers (Aspatate aminotransferase, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase, creatine kinase-MB, and cardiac troponin-1), electrolyte imbalance, and lipid profiles alongside histopathologic changes. In addition, ATO administration significantly elevated malondialdehyde, nicotinamide adenine dinucleotide phosphate hydrogen oxidase, myloperoxidase, total nitrite, inducible nitric oxide synthase, tumor necrosis factor-alpha, interleukin-1β, interleukin-6, 8-Hydroxy-2'-deoxyguanosine, nuclear factor NF-kappa-B p65 subunit, glycogen synthase kinase-3 beta, and caspase-3 expression contemporaneously with down-regulation of reduced glutathione, glutathione peroxidase, superoxide dismutase, catalase, heme oxygenase 1, nuclear factor erythroid 2-related factor 2, phosphatidylinositol-3 kinase, p-PI3K, and Bcl-2 expression. Interestingly, pretreatment with BIS and TMZ significantly reversed the detrimental effects of ATO-induced myocardial injury at both cellular and molecular levels. Otherwise, combining the two drugs displayed more enhancement than each drug alone. CONCLUSION The present research depicted that BIS and TMZ have the potential to protect the heart and provide therapeutic benefits by preventing acute heart injury induced by ATO. This is achieved by reversing the redox-sensitive pathway, reducing inflammation, and inhibiting apoptosis.
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Affiliation(s)
- Yasmin M Ahmed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Nile Valley (NVU) University, Fayoum, Egypt
| | - Ehab A M El-Shoura
- Clinical Pharmacy Department, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt
| | - Magy R Kozman
- Clinical Pharmacy Department, Faculty of Pharmacy, Misr University for Science and Technology, Giza, Egypt
| | - Basel A Abdel-Wahab
- Department of Pharmacology, College of Pharmacy, Najran University, Najran, Saudi Arabia
| | - Asmaa Ramadan Abdel-Sattar
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Nile Valley (NVU) University, Fayoum, Egypt
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Komorowicz I, Hanć A. Can arsenic do anything good? Arsenic nanodrugs in the fight against cancer - last decade review. Talanta 2024; 276:126240. [PMID: 38754186 DOI: 10.1016/j.talanta.2024.126240] [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: 02/03/2024] [Revised: 05/07/2024] [Accepted: 05/09/2024] [Indexed: 05/18/2024]
Abstract
Arsenic has been an element of great interest among scientists for many years as it is a widespread metalloid in our ecosystem. Arsenic is mostly recognized with negative connotations due to its toxicity. Surely, most of us know that a long time ago, arsenic trioxide was used in medicine to treat, mainly, skin diseases. However, not everyone knows about its very wide and promising use in the treatment of cancer. Initially, in the seventies, it was used to treat leukemia, but new technological possibilities and the development of nanotechnology have made it possible to use arsenic trioxide for the treatment of solid tumours. The most toxic arsenic compound - arsenic trioxide - as the basis of anticancer drugs in which they function as a component of nanoparticles is used in the fight against various types of cancer. This review aims to present the current solutions in various cancer treatment using arsenic compounds with different binding motifs and methods of preparation to create targeted nanoparticles, nanodiamonds, nanohybrids, nanodrugs, or nanovehicles.
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Affiliation(s)
- Izabela Komorowicz
- Department of Trace Analysis, Faculty of Chemistry, Adam Mickiewicz University in Poznań, 8 Uniwersytetu Poznańskiego Street, 61-614, Poznań, Poland.
| | - Anetta Hanć
- Department of Trace Analysis, Faculty of Chemistry, Adam Mickiewicz University in Poznań, 8 Uniwersytetu Poznańskiego Street, 61-614, Poznań, Poland
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Yan M, Wang H, Wei R, Li W. Arsenic trioxide: applications, mechanisms of action, toxicity and rescue strategies to date. Arch Pharm Res 2024; 47:249-271. [PMID: 38147202 DOI: 10.1007/s12272-023-01481-y] [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: 03/11/2023] [Accepted: 12/15/2023] [Indexed: 12/27/2023]
Abstract
Arsenical medicine has obtained its status in traditional Chinese medicine for more than 2,000 years. In the 1970s, arsenic trioxide was identified to have high efficacy and potency for the treatment of acute promyelocytic leukemia, which promoted many studies on the therapeutic effects of arsenic trioxide. Currently, arsenic trioxide is widely used to treat acute promyelocytic leukemia and various solid tumors through various mechanisms of action in clinical practice; however, it is accompanied by a series of adverse reactions, especially cardiac toxicity. This review presents a comprehensive overview of arsenic trioxide from preclinical and clinical efficacy, potential mechanisms of action, toxicities, and rescue strategies for toxicities to provide guidance or assistance for the clinical application of arsenic trioxide.
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Affiliation(s)
- Meng Yan
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China.
| | - Hao Wang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Rui Wei
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
- Pharmacy Department, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Wenwen Li
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
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He Y, Wu C, Liu Z, Zhang Y, Feng F, Lin Z, Wang C, Yang Q, Wen Z, Liu Y, Zhang F, Lin Y, Zhang H, Qu L, Li L, Cai W, Sun C, Chen L, Li P. Arsenic trioxide-induced apoptosis contributes to suppression of viral reservoir in SIV-infected rhesus macaques. Microbiol Spectr 2023; 11:e0052523. [PMID: 37695104 PMCID: PMC10581169 DOI: 10.1128/spectrum.00525-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 07/07/2023] [Indexed: 09/12/2023] Open
Abstract
Latent viral reservoir is recognized as the major obstacle to achieving a functional cure for HIV infection. We previously reported that arsenic trioxide (As2O3) combined with antiretroviral therapy (ART) can reactivate the viral reservoir and delay viral rebound after ART interruption in chronically simian immunodeficiency virus (SIV)-infected macaques. In this study, we further investigated the effect of As2O3 independent of ART in chronically SIV-infected macaques. We found that As2O3-only treatment significantly increased the CD4/CD8 ratio, improved SIV-specific T cell responses, and reactivated viral latency in chronically SIVmac239-infected macaques. RNA-sequencing analysis revealed that As2O3 treatment downregulated the expression levels of genes related to HIV entry and infection, while the expression levels of genes related to transcription initiation, cell apoptosis, and host restriction factors were significantly upregulated. Importantly, we found that As2O3 treatment specifically induced apoptosis of SIV-infected CD4+ T cells. These findings revealed that As2O3 might not only impact viral latency, but also induce the apoptosis of HIV-infected cells and thus block the secondary infection of bystanders. Moreover, we investigated the therapeutic potential of this regimen in acutely SIVmac239-infected macaques and found that As2O3 + ART treatment effectively restored the CD4+ T cell count, delayed disease progression, and improved survival in acutely SIV-infected macaques. In sum, this work provides new insights to develop As2O3 as a component of the "shock-and-kill" strategy toward HIV functional cure. IMPORTANCE Although antiretroviral therapy (ART) can effectively suppress the viral load of AIDS patients, it cannot functionally cure HIV infection due to the existence of HIV reservoir. Strategies toward HIV functional cure are still highly anticipated to ultimately end the pandemic of AIDS. Herein, we investigated the direct role of As2O3 independent of ART in chronically SIV-infected macaques and explored the underlying mechanisms of the potential of As2O3 in the treatment of HIV/SIV infection. Meanwhile, we investigated the therapeutic effects of ART+As2O3 in acutely SIVmac239-infected macaques. This study showed that As2O3 has the potential to be launched into the "shock-and-kill" strategy to suppress HIV/SIV reservoir due to its latency-reversing and apoptosis-inducing properties.
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Affiliation(s)
- Yizi He
- Guangdong Laboratory of Computational Biomedicine, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Chunxiu Wu
- Guangdong Laboratory of Computational Biomedicine, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Zijian Liu
- Guangdong Laboratory of Computational Biomedicine, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yudi Zhang
- Guangdong Laboratory of Computational Biomedicine, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Fengling Feng
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, China
| | - Zihan Lin
- Guangdong Laboratory of Computational Biomedicine, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Congcong Wang
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, China
| | - Qing Yang
- Guangdong Laboratory of Computational Biomedicine, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Ziyu Wen
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, China
| | - Yichu Liu
- Guangdong Laboratory of Computational Biomedicine, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Fan Zhang
- Guangdong Laboratory of Computational Biomedicine, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Yanqin Lin
- Guangdong Laboratory of Computational Biomedicine, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Hao Zhang
- Guangdong Laboratory of Computational Biomedicine, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Linbing Qu
- Guangdong Laboratory of Computational Biomedicine, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Linghua Li
- Guangzhou Eighth People’s Hospital, Guangzhou Medical University, Guangzhou, China
| | - Weiping Cai
- Guangzhou Eighth People’s Hospital, Guangzhou Medical University, Guangzhou, China
| | - Caijun Sun
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, China
| | - Ling Chen
- Guangdong Laboratory of Computational Biomedicine, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- Guangzhou Eighth People’s Hospital, Guangzhou Medical University, Guangzhou, China
| | - Pingchao Li
- Guangdong Laboratory of Computational Biomedicine, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
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Paul NP, Galván AE, Yoshinaga-Sakurai K, Rosen BP, Yoshinaga M. Arsenic in medicine: past, present and future. Biometals 2023; 36:283-301. [PMID: 35190937 PMCID: PMC8860286 DOI: 10.1007/s10534-022-00371-y] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 02/05/2022] [Indexed: 12/17/2022]
Abstract
Arsenicals are one of the oldest treatments for a variety of human disorders. Although infamous for its toxicity, arsenic is paradoxically a therapeutic agent that has been used since ancient times for the treatment of multiple diseases. The use of most arsenic-based drugs was abandoned with the discovery of antibiotics in the 1940s, but a few remained in use such as those for the treatment of trypanosomiasis. In the 1970s, arsenic trioxide, the active ingredient in a traditional Chinese medicine, was shown to produce dramatic remission of acute promyelocytic leukemia similar to the effect of all-trans retinoic acid. Since then, there has been a renewed interest in the clinical use of arsenicals. Here the ancient and modern medicinal uses of inorganic and organic arsenicals are reviewed. Included are antimicrobial, antiviral, antiparasitic and anticancer applications. In the face of increasing antibiotic resistance and the emergence of deadly pathogens such as the severe acute respiratory syndrome coronavirus 2, we propose revisiting arsenicals with proven efficacy to combat emerging pathogens. Current advances in science and technology can be employed to design newer arsenical drugs with high therapeutic index. These novel arsenicals can be used in combination with existing drugs or serve as valuable alternatives in the fight against cancer and emerging pathogens. The discovery of the pentavalent arsenic-containing antibiotic arsinothricin, which is effective against multidrug-resistant pathogens, illustrates the future potential of this new class of organoarsenical antibiotics.
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Affiliation(s)
- Ngozi P Paul
- Department of Cellular Biology and Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, 33199, USA
| | - Adriana E Galván
- Department of Cellular Biology and Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, 33199, USA
| | - Kunie Yoshinaga-Sakurai
- Department of Cellular Biology and Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, 33199, USA
| | - Barry P Rosen
- Department of Cellular Biology and Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, 33199, USA.
| | - Masafumi Yoshinaga
- Department of Cellular Biology and Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, 33199, USA
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Lv T, Cao W, Xue J, Wei Q, Qiu Z, Han Y, Li T. Therapeutic effect of (5R)-5-hydroxytriptolide (LLDT-8) in SIV infected rhesus monkeys. Int Immunopharmacol 2022; 110:108932. [PMID: 35716483 DOI: 10.1016/j.intimp.2022.108932] [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: 04/05/2022] [Revised: 06/04/2022] [Accepted: 06/06/2022] [Indexed: 11/18/2022]
Abstract
BACKGROUNDS Human immunodeficiency virus (HIV) infections induce robust, generalized inflammatory responses and lead to pathological systemic immune activation. This abnormal immune status persists despite successful antiretroviral therapy (ART). Immune modulating strategies in conjunction with ART were tried to reduce abnormal immune activation. Previously, we demonstrated that Tripterygium Wilfordii Hook F has been shown immunosuppressive activity in HIV patients. (5R)-5-hydroxytriptolide (LLDT-8), a new analog of triptolide, and the most active ingredient of Tripterygium Wilfordii Hook F, has been shown to have lower cytotoxicity. However, the role of LLDT-8 in HIV or simian immunodeficiency virus (SIV) needs to be explored. METHODS Six male adult Chinese rhesus monkeys were enrolled in our study. All of them were healthy and negative for SIV, and chronically SIVmac239 infected macaques were treated with LLDT-8 combined with ART (n = 4) or ART only (n = 2) after 14 weeks of infection. ART was determined at week 33, and LLDT-8 was continued until week 48. T cell immune activation and inflammation were compared during the period, and viral rebound time and reservoir were supervised after stopping ART. RESULTS The RNA level of the two groups continued to decline after initiating ART, RNA of 4 rhesus monkeys declined to the lower limit of detection at week 20. LLDT-8 administration combined with ART did not affect T cell activation and plasma levels of IL-6 and CRP. The viral load of all the macaques in both groups was rebounded 2 weeks after ART discontinuation. Furthermore, no significant decrease of SIV DNA was observed in the LLDT-8 treatment group. CONCLUSIONS LLDT-8 administration during chronic SIV infection had no effect on T cell activation and plasma levels; Furthermore, LLDT-8 may not contribute to suppression of viral rebound and reservoir. These results suggest that LLDT-8 is unlikely to reduce immune activation and viral persistence without additional interventions.
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Affiliation(s)
- Tingxia Lv
- Department of Infectious Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China; Department of Infectious Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Wei Cao
- Department of Infectious Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jing Xue
- Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, NHC Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China
| | - Qiang Wei
- Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, NHC Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China
| | - Zhifeng Qiu
- Department of Infectious Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yang Han
- Department of Infectious Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Taisheng Li
- Department of Infectious Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China; Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China; Tsinghua-Peking Center for Life Sciences, Beijing, China.
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Li M, Yuan Y, Li P, Deng Z, Wen Z, Wang H, Feng F, Zou H, Chen L, Tang S, Sun C. Comparison of the Immunogenicity of HIV-1 CRF07_BC Gag Antigen With or Without a Seven Amino Acid Deletion in p6 Region. Front Immunol 2022; 13:850719. [PMID: 35450078 PMCID: PMC9017423 DOI: 10.3389/fimmu.2022.850719] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Accepted: 03/03/2022] [Indexed: 11/23/2022] Open
Abstract
HIV-1 CRF07_BC-p6Δ7, a strain with a seven amino acid deletion in the p6 region of the Gag protein, is becoming the dominant strain of HIV transmission among men who have sex with men (MSM) in China. Previous studies demonstrated that HIV-1 patients infected by CRF07_BC-p6Δ7 strain had lower viral load and slower disease progression than those patients infected with CRF07_BC wild-type strain. However, the underlying mechanism for this observation is not fully clarified yet. In this study, we constructed the recombinant DNA plasmid and adenovirus type 2 (Ad2) vector-based constructs to express the HIV-1 CRF07_BC Gag antigen with or without p6Δ7 mutation and then investigated their immunogenicity in mice. Our results showed that HIV-1 CRF07_BC Gag antigen with p6Δ7 mutation induced a comparable level of Gag-specific antibodies but stronger CD4+ and CD8+ T-cell immune responses than that of CRF07_BC Gag (07_BC-wt). Furthermore, we identified a series of T-cell epitopes, which induced strong T-cell immune response and cross-immunity with CRF01_AE Gag. These findings implied that the p6Gag protein with a seven amino acid deletion might enhance the Gag immunogenicity in particular cellular immunity, which provides valuable information to clarify the pathogenic mechanism of HIV-1 CRF07_BC-p6Δ7 and to develop precise vaccine strategies against HIV-1 infection.
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Affiliation(s)
- Minchao Li
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, China
| | - Yue Yuan
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, China
| | - Pingchao Li
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences, Guangzhou, China
| | - Zhaomin Deng
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, China
| | - Ziyu Wen
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, China
| | - Haiying Wang
- Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Fengling Feng
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, China
| | - Huachun Zou
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, China
| | - Ling Chen
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences, Guangzhou, China
| | - Shixing Tang
- Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Caijun Sun
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, China.,Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, China
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10
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Wen J, Li X, Zhao QX, Yang XF, Wu ML, Yan Q, Chang J, Wang H, Jin X, Su X, Deng K, Chen L, Wang JH. Pharmacological suppression of glycogen synthase kinase-3 reactivates HIV-1 from latency via activating Wnt/β-catenin/TCF1 axis in CD4 + T cells. Emerg Microbes Infect 2022; 11:391-405. [PMID: 34985411 PMCID: PMC8812804 DOI: 10.1080/22221751.2022.2026198] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
ABSTRACTHIV-1 latency posts a major obstacle for HIV-1 eradication. Currently, no desirable latency reversing agents (LRAs) have been implicated in the "Shock and Kill" strategy to mobilize the latently infected cells to be susceptible for clearance by immune responses. Identification of key cellular pathways that modulate HIV-1 latency helps to develop efficient LRAs. In this study, we demonstrate that the Wnt downstream β-catenin/TCF1 pathway is a crucial modulator for HIV-1 latency. The pharmacological activation of the β-catenin/TCF1 pathway with glycogen synthase kinase-3 (GSK3) inhibitors promoted transcription of HIV-1 proviral DNA and reactivated latency in CD4+ T cells; the GSK3 kinase inhibitor 6-bromoindirubin-3'-oxime (6-BIO)-induced HIV-1 reactivation was subsequently confirmed in resting CD4+ T cells from cART-suppressed patients and SIV-infected rhesus macaques. These findings advance our understanding of the mechanisms responsible for viral latency, and provide the potent LRA that can be further used in conjunction of immunotherapies to eradicate viral reservoirs.
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Affiliation(s)
- Jing Wen
- Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, People's Republic of China.,University of Chinese Academy of Sciences, Beijing, People's Republic of China
| | - Xin Li
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, People's Republic of China
| | - Qing-Xia Zhao
- Department of Infection, Zhengzhou Sixth People's Hospital, Zhengzhou, People's Republic of China
| | - Xiao-Fan Yang
- Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Meng-Li Wu
- College of Life Science, Henan Normal University, Xinxiang, People's Republic of China
| | - Qihong Yan
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, People's Republic of China
| | - Junbiao Chang
- College of Life Science, Henan Normal University, Xinxiang, People's Republic of China
| | - Haikun Wang
- Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, People's Republic of China
| | - Xia Jin
- College of Life Science, Henan Normal University, Xinxiang, People's Republic of China
| | - Xiao Su
- Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, People's Republic of China
| | - Kai Deng
- Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Ling Chen
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, People's Republic of China
| | - Jian-Hua Wang
- University of Chinese Academy of Sciences, Beijing, People's Republic of China.,Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, People's Republic of China
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11
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Exacerbated AIDS progression by PD-1 blockade during therapeutic vaccination in chronically SIV-infected rhesus macaques after ART treatment interruption. J Virol 2021; 96:e0178521. [PMID: 34818070 DOI: 10.1128/jvi.01785-21] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The persistence of latent HIV-1-infected cells, named the latent reservoir, is the major barrier to HIV-1 eradication, and the formation and maintenance of latent reservoir might be exacerbated by activation of the immunoinhibitory pathway and dysfunction of CD8+ T cells during HIV-1 infection. Our previous findings demonstrated that prophylactic vaccination combined with PD-1 blockade generated distinct immune response profiles and conferred effective control of highly pathogenic SIVmac239 infection in rhesus macaques. However, to our surprise, herein we found that a therapeutic vaccination in combination with PD-1 blockade resulted in activation of the viral reservoir, faster viral rebound after treatment interruption, accelerated acquired immune deficiency syndrome (AIDS) progression and ultimately death in chronically SIV-infected macaques after ART treatment interruption. Our study further demonstrated that the SIV provirus was preferentially enriched in PD-1+CD4+ T cells due to their susceptibility to viral entry, potent proliferation ability and inability to perform viral transcription. In addition, the viral latency was effectively reactivated upon PD-1 blockade. Together, these results suggest that PD-1 blockade may be a double-edged sword for HIV-1 immunotherapy, and they provide important insight for the rational design of immunotherapy strategies toward an HIV-1 cure. Importance As one of the most challenging public health problems, there is no clinically effective cure strategies against HIV-1 infection yet. We have demonstrated that prophylactic vaccination combined with PD-1 blockade generated distinct immune response profiles and conferred better control of highly pathogenic SIVmac239 infection in rhesus macaques. In the present study, to our surprise, PD-1 blockade during therapeutic vaccination accelerated the reactivation of latent reservoir and then AIDS progression in chronically SIV-infected macaques after ART treatment interruption. Our further study demonstrated that the latent SIV provirus was preferentially enriched in PD-1+CD4+ T cells because of its susceptibility of viral entry, inhibition of SIV transcription and potent ability of proliferation, and the viral latency was effectively reactivated by PD-1 blockade. Therefore, PD-1 blockade might be a double-edged sword for AIDS therapy. These findings provoke extensive interests to further exploit novel therapeutic treatment against HIV-1 infection and other emerging infectious diseases.
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12
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Ghildiyal R, Gabrani R. Computational analysis of human host binding partners of chikungunya and dengue viruses during coinfection. Pathog Dis 2021; 79:6373922. [PMID: 34550340 DOI: 10.1093/femspd/ftab046] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 09/20/2021] [Indexed: 12/31/2022] Open
Abstract
Mosquito-borne viral diseases like chikungunya and dengue infections can cause severe illness and have become major public health concerns. Chikungunya virus (CHIKV) and dengue virus (DENV) infections share similar primary clinical manifestations and are transmitted by the same vector. Thus, the probability of their coinfection gets increased with more severe clinical complications in the patients. The present study was undertaken to elucidate the common human interacting partners of CHIKV and DENV proteins during coinfection. The viral-host protein-protein interactome was constructed using Cytoscape. Subsequently, significant host interactors were identified during coinfection. The network analysis elucidated 57 human proteins interacting with both CHIKV and DENV, represented as hub-bottlenecks. The functional and biological analyses of the 40 hub-bottlenecks revealed that they are associated with phosphoinositide 3-kinases (PI3K)/AKT, p53 signaling pathways, regulation of cell cycle and apoptosis during coinfection. Moreover, the molecular docking analysis uncovered the tight and robust binding of selected hub-bottlenecks with CHIKV/DENV proteins. Additionally, 23 hub-bottlenecks were predicted as druggable candidates that could be targeted to eradicate the host-viral interactions. The elucidated common host binding partners during DENV and CHIKV coinfection as well as indicated approved drugs can support the therapeutics development.
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Affiliation(s)
- Ritu Ghildiyal
- Center for Emerging Diseases, Department of Biotechnology, Jaypee Institute of Information Technology, Noida, UP 201309, India
| | - Reema Gabrani
- Center for Emerging Diseases, Department of Biotechnology, Jaypee Institute of Information Technology, Noida, UP 201309, India
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13
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Shytaj IL, Procopio FA, Tarek M, Carlon‐Andres I, Tang H, Goldman AR, Munshi M, Kumar Pal V, Forcato M, Sreeram S, Leskov K, Ye F, Lucic B, Cruz N, Ndhlovu LC, Bicciato S, Padilla‐Parra S, Diaz RS, Singh A, Lusic M, Karn J, Alvarez‐Carbonell D, Savarino A. Glycolysis downregulation is a hallmark of HIV-1 latency and sensitizes infected cells to oxidative stress. EMBO Mol Med 2021; 13:e13901. [PMID: 34289240 PMCID: PMC8350904 DOI: 10.15252/emmm.202013901] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 06/25/2021] [Accepted: 06/28/2021] [Indexed: 12/12/2022] Open
Abstract
HIV-1 infects lymphoid and myeloid cells, which can harbor a latent proviral reservoir responsible for maintaining lifelong infection. Glycolytic metabolism has been identified as a determinant of susceptibility to HIV-1 infection, but its role in the development and maintenance of HIV-1 latency has not been elucidated. By combining transcriptomic, proteomic, and metabolomic analyses, we here show that transition to latent HIV-1 infection downregulates glycolysis, while viral reactivation by conventional stimuli reverts this effect. Decreased glycolytic output in latently infected cells is associated with downregulation of NAD+ /NADH. Consequently, infected cells rely on the parallel pentose phosphate pathway and its main product, NADPH, fueling antioxidant pathways maintaining HIV-1 latency. Of note, blocking NADPH downstream effectors, thioredoxin and glutathione, favors HIV-1 reactivation from latency in lymphoid and myeloid cellular models. This provides a "shock and kill effect" decreasing proviral DNA in cells from people living with HIV/AIDS. Overall, our data show that downmodulation of glycolysis is a metabolic signature of HIV-1 latency that can be exploited to target latently infected cells with eradication strategies.
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Affiliation(s)
- Iart Luca Shytaj
- Department of Infectious DiseasesItalian Institute of HealthRomeItaly
- Department of Infectious DiseasesHeidelberg University HospitalHeidelbergGermany
- Infectious Diseases DepartmentFederal University of São PauloSão PauloBrazil
| | - Francesco Andrea Procopio
- Service of Immunology and AllergyLausanne University HospitalUniversity of LausanneLausanneSwitzerland
| | - Mohammad Tarek
- Bioinformatics DepartmentArmed Forces College of Medicine (AFCM)CairoEgypt
| | - Irene Carlon‐Andres
- Division of Structural BiologyWellcome Centre for Human GeneticsUniversity of OxfordOxfordUK
- Department of Infectious DiseasesFaculty of Life Sciences & MedicineKing’s College LondonLondonUK
- Randall Division of Cell and Molecular BiophysicsKing’s College LondonLondonUK
| | | | | | | | | | - Mattia Forcato
- Department of Life SciencesUniversity of Modena and Reggio EmiliaModenaItaly
| | - Sheetal Sreeram
- Department of Molecular Biology and MicrobiologyCase Western Reserve UniversityClevelandOHUSA
| | - Konstantin Leskov
- Department of Molecular Biology and MicrobiologyCase Western Reserve UniversityClevelandOHUSA
| | - Fengchun Ye
- Department of Molecular Biology and MicrobiologyCase Western Reserve UniversityClevelandOHUSA
| | - Bojana Lucic
- Department of Infectious DiseasesHeidelberg University HospitalHeidelbergGermany
- German Center for Infection ResearchHeidelbergGermany
| | - Nicolly Cruz
- Infectious Diseases DepartmentFederal University of São PauloSão PauloBrazil
| | - Lishomwa C Ndhlovu
- Division of Infectious DiseasesDepartment of MedicineWeill Cornell MedicineNew YorkNYUSA
| | - Silvio Bicciato
- Department of Life SciencesUniversity of Modena and Reggio EmiliaModenaItaly
| | - Sergi Padilla‐Parra
- Division of Structural BiologyWellcome Centre for Human GeneticsUniversity of OxfordOxfordUK
- Department of Infectious DiseasesFaculty of Life Sciences & MedicineKing’s College LondonLondonUK
- Randall Division of Cell and Molecular BiophysicsKing’s College LondonLondonUK
| | - Ricardo Sobhie Diaz
- Infectious Diseases DepartmentFederal University of São PauloSão PauloBrazil
| | - Amit Singh
- Indian Institute of ScienceBangaloreIndia
| | - Marina Lusic
- Department of Infectious DiseasesHeidelberg University HospitalHeidelbergGermany
- German Center for Infection ResearchHeidelbergGermany
| | - Jonathan Karn
- Department of Molecular Biology and MicrobiologyCase Western Reserve UniversityClevelandOHUSA
| | - David Alvarez‐Carbonell
- Department of Molecular Biology and MicrobiologyCase Western Reserve UniversityClevelandOHUSA
| | - Andrea Savarino
- Department of Infectious DiseasesItalian Institute of HealthRomeItaly
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14
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Neerukonda SN. Interplay between RNA Viruses and Promyelocytic Leukemia Nuclear Bodies. Vet Sci 2021; 8:vetsci8040057. [PMID: 33807177 PMCID: PMC8065607 DOI: 10.3390/vetsci8040057] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/17/2021] [Accepted: 03/30/2021] [Indexed: 11/16/2022] Open
Abstract
Promyelocytic leukemia nuclear bodies (PML NBs) are nuclear membrane-less sub structures that play a critical role in diverse cellular pathways including cell proliferation, DNA damage, apoptosis, transcriptional regulation, stem cell renewal, alternative lengthening of telomeres, chromatin organization, epigenetic regulation, protein turnover, autophagy, intrinsic and innate antiviral immunity. While intrinsic and innate immune functions of PML NBs or PML NB core proteins are well defined in the context of nuclear replicating DNA viruses, several studies also confirm their substantial roles in the context of RNA viruses. In the present review, antiviral activities of PML NBs or its core proteins on diverse RNA viruses that replicate in cytoplasm or the nucleus were discussed. In addition, viral counter mechanisms that reorganize PML NBs, and specifically how viruses usurp PML NB functions in order to create a cellular environment favorable for replication and pathogenesis, are also discussed.
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Affiliation(s)
- Sabari Nath Neerukonda
- Department of Animal and Food and Sciences, University of Delaware, Newark, DE 19716, USA
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15
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Arsenic hexoxide has differential effects on cell proliferation and genome-wide gene expression in human primary mammary epithelial and MCF7 cells. Sci Rep 2021; 11:3761. [PMID: 33580144 PMCID: PMC7881197 DOI: 10.1038/s41598-021-82551-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 01/21/2021] [Indexed: 02/06/2023] Open
Abstract
Arsenic is reportedly a biphasic inorganic compound for its toxicity and anticancer effects in humans. Recent studies have shown that certain arsenic compounds including arsenic hexoxide (AS4O6; hereafter, AS6) induce programmed cell death and cell cycle arrest in human cancer cells and murine cancer models. However, the mechanisms by which AS6 suppresses cancer cells are incompletely understood. In this study, we report the mechanisms of AS6 through transcriptome analyses. In particular, the cytotoxicity and global gene expression regulation by AS6 were compared in human normal and cancer breast epithelial cells. Using RNA-sequencing and bioinformatics analyses, differentially expressed genes in significantly affected biological pathways in these cell types were validated by real-time quantitative polymerase chain reaction and immunoblotting assays. Our data show markedly differential effects of AS6 on cytotoxicity and gene expression in human mammary epithelial normal cells (HUMEC) and Michigan Cancer Foundation 7 (MCF7), a human mammary epithelial cancer cell line. AS6 selectively arrests cell growth and induces cell death in MCF7 cells without affecting the growth of HUMEC in a dose-dependent manner. AS6 alters the transcription of a large number of genes in MCF7 cells, but much fewer genes in HUMEC. Importantly, we found that the cell proliferation, cell cycle, and DNA repair pathways are significantly suppressed whereas cellular stress response and apoptotic pathways increase in AS6-treated MCF7 cells. Together, we provide the first evidence of differential effects of AS6 on normal and cancerous breast epithelial cells, suggesting that AS6 at moderate concentrations induces cell cycle arrest and apoptosis through modulating genome-wide gene expression, leading to compromised DNA repair and increased genome instability selectively in human breast cancer cells.
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16
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Skalny AV, Lima TRR, Ke T, Zhou JC, Bornhorst J, Alekseenko SI, Aaseth J, Anesti O, Sarigiannis DA, Tsatsakis A, Aschner M, Tinkov AA. Toxic metal exposure as a possible risk factor for COVID-19 and other respiratory infectious diseases. Food Chem Toxicol 2020; 146:111809. [PMID: 33069759 PMCID: PMC7563920 DOI: 10.1016/j.fct.2020.111809] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 09/25/2020] [Accepted: 10/01/2020] [Indexed: 01/08/2023]
Abstract
Multiple medical, lifestyle, and environmental conditions, including smoking and particulate pollution, have been considered as risk factors for COronaVIrus Disease 2019 (COVID-19) susceptibility and severity. Taking into account the high level of toxic metals in both particulate matter (PM2.5) and tobacco smoke, the objective of this review is to discuss recent data on the role of heavy metal exposure in development of respiratory dysfunction, immunotoxicity, and severity of viral diseases in epidemiological and experimental studies, as to demonstrate the potential crossroads between heavy metal exposure and COVID-19 severity risk. The existing data demonstrate that As, Cd, Hg, and Pb exposure is associated with respiratory dysfunction and respiratory diseases (COPD, bronchitis). These observations corroborate laboratory findings on the role of heavy metal exposure in impaired mucociliary clearance, reduced barrier function, airway inflammation, oxidative stress, and apoptosis. The association between heavy metal exposure and severity of viral diseases, including influenza and respiratory syncytial virus has been also demonstrated. The latter may be considered a consequence of adverse effects of metal exposure on adaptive immunity. Therefore, reduction of toxic metal exposure may be considered as a potential tool for reducing susceptibility and severity of viral diseases affecting the respiratory system, including COVID-19.
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Affiliation(s)
- Anatoly V Skalny
- IM Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia; Federal Research Centre of Biological Systems and Agro-technologies of the Russian Academy of Sciences, Orenburg, Russia.
| | - Thania Rios Rossi Lima
- São Paulo State University - UNESP, Center for Evaluation of Environmental Impact on Human Health (TOXICAM), Botucatu, SP, Brazil; Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Tao Ke
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Ji-Chang Zhou
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, Guangdong Province, China
| | - Julia Bornhorst
- Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Wuppertal, Germany
| | - Svetlana I Alekseenko
- I.I. Mechnikov North-Western State Medical University, St. Petersburg, Russia; K.A. Rauhfus Children's City Multidisciplinary Clinical Center for High Medical Technologies, St. Petersburg, Russia
| | - Jan Aaseth
- IM Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia; Research Department, Innlandet Hospital Trust, Brumunddal, Norway
| | - Ourania Anesti
- Laboratory of Toxicology, Medical School, University of Crete, Voutes, Heraklion, Crete, Greece; HERACLES Research Center on the Exposome and Health, Center for Interdisciplinary Research and Innovation, Aristotle University of Thessaloniki, Thermi, Greece
| | - Dimosthenis A Sarigiannis
- HERACLES Research Center on the Exposome and Health, Center for Interdisciplinary Research and Innovation, Aristotle University of Thessaloniki, Thermi, Greece; University School of Advanced Studies IUSS, Pavia, Italy
| | - Aristides Tsatsakis
- IM Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia; Laboratory of Toxicology, Medical School, University of Crete, Voutes, Heraklion, Crete, Greece
| | - Michael Aschner
- IM Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia; Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
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17
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Dong Z, Gao M, Li C, Xu M, Liu S. LncRNA UCA1 Antagonizes Arsenic-Induced Cell Cycle Arrest through Destabilizing EZH2 and Facilitating NFATc2 Expression. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2020; 7:1903630. [PMID: 32537408 PMCID: PMC7284218 DOI: 10.1002/advs.201903630] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 02/17/2020] [Accepted: 03/08/2020] [Indexed: 05/17/2023]
Abstract
Arsenic (As) is a widespread metalloid contaminant, and its internal exposure is demonstrated to cause serious detrimental health problems. Albeit considerable studies are performed to interrogate the molecular mechanisms responsible for As-induced toxicities, the exact mechanisms are not fully understood yet, especially at the epigenetic regulation level. In the present study, it is identified that long non-coding RNA (lncRNA) urothelial cancer associated 1 (UCA1) alleviates As-induced G2/M phase arrest in human liver cells. Intensive mechanistic investigations illustrate that UCA1 interacts with enhancer of zeste homolog 2 (EZH2) and accelerates the latter's protein turnover rate under normal and As-exposure conditions. The phosphorylation of EZH2 at the Thr-487 site by cyclin dependent kinase 1 (CDK1) is responsible for As-induced EZH2 protein degradation, and UCA1 enhances this process through increasing the interaction between CDK1 and EZH2. As a consequence, the cell cycle regulator nuclear factor of activated T cells 2 (NFATc2), a downstream target of EZH2, is upregulated to resist As-blocked cell cycle progress and cytotoxicity. In conclusion, the findings decipher a novel prosurvival signaling pathway underlying As toxicity from the perspective of epigenetic regulation: UCA1 facilitates the ubiquitination of EZH2 to upregulate NFATc2 and further antagonizes As-induced cell cycle arrest.
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Affiliation(s)
- Zheng Dong
- State Key Laboratory of Environmental Chemistry and EcotoxicologyResearch Center for Eco‐Environmental SciencesChinese Academy of SciencesBeijing100085China
- College of Resources and EnvironmentUniversity of Chinese Academy of SciencesBeijing100049China
| | - Ming Gao
- State Key Laboratory of Environmental Chemistry and EcotoxicologyResearch Center for Eco‐Environmental SciencesChinese Academy of SciencesBeijing100085China
- College of Resources and EnvironmentUniversity of Chinese Academy of SciencesBeijing100049China
| | - Changying Li
- Liver Research CenterBeijing Friendship HospitalCapital Medical UniversityBeijing100050China
| | - Ming Xu
- State Key Laboratory of Environmental Chemistry and EcotoxicologyResearch Center for Eco‐Environmental SciencesChinese Academy of SciencesBeijing100085China
- College of Resources and EnvironmentUniversity of Chinese Academy of SciencesBeijing100049China
| | - Sijin Liu
- State Key Laboratory of Environmental Chemistry and EcotoxicologyResearch Center for Eco‐Environmental SciencesChinese Academy of SciencesBeijing100085China
- College of Resources and EnvironmentUniversity of Chinese Academy of SciencesBeijing100049China
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18
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Shytaj IL, Lucic B, Forcato M, Penzo C, Billingsley J, Laketa V, Bosinger S, Stanic M, Gregoretti F, Antonelli L, Oliva G, Frese CK, Trifunovic A, Galy B, Eibl C, Silvestri G, Bicciato S, Savarino A, Lusic M. Alterations of redox and iron metabolism accompany the development of HIV latency. EMBO J 2020; 39:e102209. [PMID: 32157726 PMCID: PMC7196916 DOI: 10.15252/embj.2019102209] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 02/11/2020] [Accepted: 02/14/2020] [Indexed: 12/19/2022] Open
Abstract
HIV-1 persists in a latent form during antiretroviral therapy, mainly in CD4+ T cells, thus hampering efforts for a cure. HIV-1 infection is accompanied by metabolic alterations, such as oxidative stress, but the effect of cellular antioxidant responses on viral replication and latency is unknown. Here, we show that cells survive retroviral replication, both in vitro and in vivo in SIVmac-infected macaques, by upregulating antioxidant pathways and the intertwined iron import pathway. These changes are associated with remodeling of promyelocytic leukemia protein nuclear bodies (PML NBs), an important constituent of nuclear architecture and a marker of HIV-1 latency. We found that PML NBs are hyper-SUMOylated and that PML protein is degraded via the ubiquitin-proteasome pathway in productively infected cells, before latency establishment and after reactivation. Conversely, normal numbers of PML NBs were restored upon transition to latency or by decreasing oxidative stress or iron content. Our results highlight antioxidant and iron import pathways as determinants of HIV-1 latency and support their pharmacologic inhibition as tools to regulate PML stability and impair latency establishment.
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Affiliation(s)
- Iart Luca Shytaj
- Heidelberg University HospitalHeidelbergGermany
- German Center for Infection ResearchHeidelbergGermany
| | - Bojana Lucic
- Heidelberg University HospitalHeidelbergGermany
- German Center for Infection ResearchHeidelbergGermany
| | - Mattia Forcato
- Department of Life SciencesUniversity of Modena and Reggio EmiliaModenaItaly
| | | | - James Billingsley
- Division of Microbiology and ImmunologyYerkes National Primate Research CenterEmory UniversityAtlantaGAUSA
| | - Vibor Laketa
- Heidelberg University HospitalHeidelbergGermany
- German Center for Infection ResearchHeidelbergGermany
| | - Steven Bosinger
- Division of Microbiology and ImmunologyYerkes National Primate Research CenterEmory UniversityAtlantaGAUSA
- Department of Pathology and Laboratory MedicineEmory UniversityAtlantaGAUSA
| | - Mia Stanic
- Heidelberg University HospitalHeidelbergGermany
| | | | - Laura Antonelli
- Institute for High Performance Computing and NetworkingICAR‐CNRNaplesItaly
| | - Gennaro Oliva
- Institute for High Performance Computing and NetworkingICAR‐CNRNaplesItaly
| | | | | | - Bruno Galy
- Division of Virus‐Associated CarcinogenesisGerman Cancer Research CentreHeidelbergGermany
| | - Clarissa Eibl
- Leibniz‐Forschungsinstitut für Molekulare PharmakologieBerlinGermany
- Institute of BiologyCellular BiophysicsHumboldt Universität zu BerlinBerlinGermany
| | - Guido Silvestri
- Division of Microbiology and ImmunologyYerkes National Primate Research CenterEmory UniversityAtlantaGAUSA
- Department of Pathology and Laboratory MedicineEmory UniversityAtlantaGAUSA
| | - Silvio Bicciato
- Department of Life SciencesUniversity of Modena and Reggio EmiliaModenaItaly
| | | | - Marina Lusic
- Heidelberg University HospitalHeidelbergGermany
- German Center for Infection ResearchHeidelbergGermany
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Wang QQ, Jiang Y, Naranmandura H. Therapeutic strategy of arsenic trioxide in the fight against cancers and other diseases. Metallomics 2020; 12:326-336. [PMID: 32163072 DOI: 10.1039/c9mt00308h] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Arsenic trioxide (ATO) has been recognized as a drug for the treatment of various diseases in traditional medicine for more than two thousand years. Although ATO has recently shown excellent efficacy for the treatment of acute promyelocytic leukemia (APL), it could not provide satisfactory outcomes as a single-agent for the management of non-APL leukemia or different solid tumors. Nevertheless, combination treatment strategies, e.g., ATO with other agents, have shown promising results against different diseases. Here, we introduce in depth the latest evidence and detailed insights into ATO-mediated cures for APL by targeting PML/RARα chimeric protein, followed by the preclinical and clinical efficacy of ATO on various non-APL malignancies and solid tumors. Likewise, the antiviral activity of ATO against human immunodeficiency virus (HIV) and hepatitis C virus (HCV) was also discussed briefly. Our review would provide a clear prospect for the combination of ATO with other agents for treatment of numerous neoplastic diseases, and open a new era in the clinically applicable range of arsenicals.
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Affiliation(s)
- Qian Qian Wang
- Department of Hematology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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20
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Gavegnano C, Savarino A, Owanikoko T, Marconi VC. Crossroads of Cancer and HIV-1: Pathways to a Cure for HIV. Front Immunol 2019; 10:2267. [PMID: 31636630 PMCID: PMC6788429 DOI: 10.3389/fimmu.2019.02267] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Accepted: 09/09/2019] [Indexed: 12/12/2022] Open
Abstract
Recently, a second individual (the “London patient”) with HIV-1 infection and concomitant leukemia was cured of both diseases by a conditioning myeloablative regimen followed by transplantation of stem cells bearing the homozygous CCR5 Δ32 mutation. The substantial risks and cost associated with this procedure render it unfeasible on a large scale. This strategy also indicates that a common pathway toward a cure for both HIV and cancer may exist. Successful approaches to curing both diseases should ideally possess three components, i.e., (1) direct targeting of pathological cells (neoplastic cells in cancer and the HIV-infected reservoir cells), (2) subsequent impediment to reconstitution of the pool of pathological cells and (3) sustained, immunologic control of the disease (both diseases are characterized by detrimental immune hyper-activation that hinders successful establishment of immunity). In this review, we explore medications that are either investigational or FDA-approved anticancer treatments that may be employed to achieve the goal of curing HIV-1. These include: thioredoxin reductase inhibitors (phases 1–3), immune checkpoint inhibitors (phases 1, 3), Jak inhibitors (FDA approved for arthritis and multiple cancer indications, summarized in Table 1). Of note, some of these medications such as arsenic trioxide and Jak inhibitors may also reversibly down regulate CCR5 expression on CD4+ T-cells, thus escaping the ethical issues of inducing or transferring mutations in CCR5 that are presently the subject of interest as it relates to HIV-1 cure strategies.
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Affiliation(s)
- Christina Gavegnano
- Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United States
| | | | - Taofeek Owanikoko
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, United States
| | - Vincent C Marconi
- Emory Vaccine Center, Rollins School of Public Health, Emory University School of Medicine, Atlanta, GA, United States.,Atlanta Veterans Affairs Medical Center, Atlanta, GA, United States
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