Significance and nature of bystander responses induced by various agents

Verma, Neha; Tiku, Ashu Bhan

doi:10.1016/j.mrrev.2017.05.003

Cited by 50 publications

(21 citation statements)

References 190 publications

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“…The number of molecules, including TNF-α, TGF-β1, IL-6, IL-8, and nitric oxide are involved in cellcell communications. 303,304 Earlier studies showed that the overexpression of Cx32 reduces HCC growth. 305 Cx32 knockout mice show increased susceptibility to chemical hepatocarcinogenesis.…”

Section: Bystander Hcc Mechanisms Through Nonsterile Inflammationmentioning

confidence: 99%

<p>Hepatocellular Carcinoma Mechanisms Associated with Chronic HCV Infection and the Impact of Direct-Acting Antiviral Treatment</p>

Dash¹,

Aydın²,

Widmer³

et al. 2020

JHC

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Hepatitis C virus (HCV) infection is the major risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). The mechanisms of HCC initiation, growth, and metastasis appear to be highly complex due to the decade-long interactions between the virus, immune system, and overlapping bystander effects of host metabolic liver disease. The lack of a readily accessible animal model system for HCV is a significant obstacle to understand the mechanisms of viral carcinogenesis. Traditionally, the primary prevention strategy of HCC has been to eliminate infection by antiviral therapy. The success of virus elimination by antiviral treatment is determined by the SVR when the HCV is no longer detectable in serum. Interferon-alpha (IFNα) and its analogs, pegylated IFN-α (PEG-IFN-α) alone with ribavirin (RBV), have been the primary antiviral treatment of HCV for many years with a low cure rate. The cloning and sequencing of HCV have allowed the development of cell culture models, which accelerated antiviral drug discovery. It resulted in the selection of highly effective direct-acting antiviral (DAA)-based combination therapy that now offers incredible success in curing HCV infection in more than 95% of all patients, including those with cirrhosis. However, several emerging recent publications claim that patients who have liver cirrhosis at the time of DAAs treatment face the risk of HCC occurrence and recurrence after viral cure. This remains a substantial challenge while addressing the long-term benefit of antiviral medicine. The host-related mechanisms that drive the risk of HCC in the absence of the virus are unknown. This review describes the multifaceted mechanisms that create a tumorigenic environment during chronic HCV infection. In addition to the potential oncogenic programming that drives HCC after viral clearance by DAAs, the current status of a biomarker development for early prediction of cirrhosis regression and HCC detection post viral treatment is discussed. Since DAAs treatment does not provide full protection against reinfection or viral transmission to other individuals, the recent studies for a vaccine development are also reviewed.

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Section: Bystander Hcc Mechanisms Through Nonsterile Inflammationmentioning

confidence: 99%

<p>Hepatocellular Carcinoma Mechanisms Associated with Chronic HCV Infection and the Impact of Direct-Acting Antiviral Treatment</p>

Dash¹,

Aydın²,

Widmer³

et al. 2020

JHC

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“…The medium transfer assay is another important method to further study bystander responses [2], as shown in Fig. 1b.…”

Section: Characteristics Of Ws 2 Nanosheetsmentioning

confidence: 99%

“…The bystander effect in a biological system refers to a unique process in which factors released by cells or tissues exposed to stressors exert effects on other parts of the cells or tissues not exposed to stressors, causing stress responses, genomic instability and altered apoptosis or cell proliferation [1,2]. To date, bystander effect studies have focused on post-irradiation effects [1,2], but there is growing evidence that other environmental stressors also induce damage in bystander populations, including heat stresses, photodynamic therapy, genotoxic chemicals, heavy metals, and other multiple stressors [3,4,5,6,7]. The use of nanoparticles in biology continues to increase and release to the environment are inevitable [8,9,10].…”

Section: Introductionmentioning

confidence: 99%

“…Coculture method in vitro has been frequently used in many experiments to study bystander responses. In this approach, both targeted and non-targeted cells are either physically connected or are separated by a physical barrier [2,3,15]. Transwell insert coculture system is a widely used no-physical contact coculture system to study bystander effects and its mediators in vitro [13,15,16].…”

Section: Introductionmentioning

confidence: 99%

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The Nanomaterial-Induced Bystander Effects Reprogrammed Macrophage Immune Function

Yuan¹,

Ban²,

Hu³

et al. 2020

Preprint

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Background: In the case of most popularly engineered nanomaterials (e.g., transition-metal dichalcogenide (TMDCs) nanosheets), direct exposure toxicities are investigated extensively to understand the effect on specific cells and organs; however, there has been limited focus on their potential bystander effects. Bystander effects in biological systems are the responses shown by nontargeted neighboring cells or tissues, and critical to the bio-nano interface interactions. In addition to direct effects, bystander effects also determine the design, applications and safety of nanomaterials, although the related information of bystander effects remain largely unknown.Results: A coculture system of A549 and THP-1 was established to mimic the lung microenvironment to study the bystander effects of WS2 nanosheets (representative TMDCs nanosheets) on microenvironment macrophages during the inhalation exposure or the nanomaterial biomedical application in the lung. Lung cells exposed to WS2 nanosheet resulted in an increase in reactive oxygen species and the depolarization of mitochondrial membrane potential in neighboring macrophages. Bystander exposure also induced macrophage polarization toward the anti-inflammatory M2 phenotype, which is adverse to disease therapy. Metabolomics showed that WS2 nanosheets disturbed the energy metabolism and amino acid metabolism of macrophages, consistent with the metabolic characteristics of M2 macrophages. Nitric oxide-transforming growth factor-β1 played an important mediator in the bystander effects. Importantly, WS2 nanosheet bystander exposure affected macrophage phagocytosis and migration and altered the macrophage immune response to environmental endotoxin.Conclusion: This study demonstrated that WS2 exposed lung cells would elicit bystander effects on surrounding macrophage cells, which weaken the immune response of surrounding macrophage cells. This study improves the current understanding of bio-nano interactions and highlights the importance of bystander effects and neighboring cell responses, allowing us to use the maximum benefits of nanomaterials while limiting their adverse bystander effects.

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“…Microvascular endothelial cells respond with early production of reactive oxygen species (ROS) and DNA damage, including DNA double strand breaks (DSB), and late responses leading to apoptosis and senescence, resulting in ischemia, necrosis, and tissue fibrosis in normal surrounding tissues 2 . The damage inflicted to directly irradiated cells can be propagated to unexposed surrounding cells, known as the radiationinduced bystander effect, and mimics the direct effects of ionizing radiation encompassing induction of apoptosis, micronucleus formation, DSBs, and mutations 3,4 . Among the different effects of ionizing radiation exposure, DSBs are the most deleterious because of the high risk of misrepair 5,6 and their potential to induce early and late radiation-induced effects 7 .…”

Section: Introductionmentioning

confidence: 99%

Cx43 channels and signaling via IP3/Ca2+, ATP, and ROS/NO propagate radiation-induced DNA damage to non-irradiated brain microvascular endothelial cells

et al. 2020

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Radiotherapeutic treatment consists of targeted application of radiation beams to a tumor but exposure of surrounding healthy tissue is inevitable. In the brain, ionizing radiation induces breakdown of the blood-brain barrier by effects on brain microvascular endothelial cells. Damage from directly irradiated cells can be transferred to surrounding non-exposed bystander cells, known as the radiation-induced bystander effect. We investigated involvement of connexin channels and paracrine signaling in radiation-induced bystander DNA damage in brain microvascular endothelial cells exposed to focused X-rays. Irradiation caused DNA damage in the directly exposed area, which propagated over several millimeters in the bystander area. DNA damage was significantly reduced by the connexin channel-targeting peptide Gap26 and the Cx43 hemichannel blocker TAT-Gap19. ATP release, dye uptake, and patch clamp experiments showed that hemichannels opened within 5 min post irradiation in both irradiated and bystander areas. Bystander signaling involved cellular Ca 2+ dynamics and IP 3 , ATP, ROS, and NO signaling, with Ca 2+ , IP 3 , and ROS as crucial propagators of DNA damage. We conclude that bystander effects are communicated by a concerted cascade involving connexin channels, and IP 3 /Ca 2+ , ATP, ROS, and NO as major contributors of regenerative signal expansion.

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Significance and nature of bystander responses induced by various agents

Cited by 50 publications

References 190 publications

<p>Hepatocellular Carcinoma Mechanisms Associated with Chronic HCV Infection and the Impact of Direct-Acting Antiviral Treatment</p>

<p>Hepatocellular Carcinoma Mechanisms Associated with Chronic HCV Infection and the Impact of Direct-Acting Antiviral Treatment</p>

The Nanomaterial-Induced Bystander Effects Reprogrammed Macrophage Immune Function

Cx43 channels and signaling via IP3/Ca2+, ATP, and ROS/NO propagate radiation-induced DNA damage to non-irradiated brain microvascular endothelial cells

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