Involvement of inducible nitric oxide synthase and mitochondrial dysfunction in the pathogenesis of enterovirus 71 infection

Dang, Dejian; Zhang, Chao; Zhang, Rongguang; Wu, Weidong; Chen, Shuaiyin; Ren, Jun; Zhang, Peng; Zhou, Guangyuan; Feng, Demin; Sun, Tiantian; Li, Ying; Liu, Qiaoli; Li, Mengchen; Xi, Yang; Jin, Yuefei

doi:10.18632/oncotarget.21250

Cited by 21 publications

(26 citation statements)

References 41 publications

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“…To further confirm the involvement of RAS in the pathogenesis of HFMD, we establish an EV71-infected mouse model [14,15]. In our study, we found that EV71 infection induced Ang II and NA expression in the brains, skeletal muscle, and lungs of EV71-infected mice.…”

Section: Discussionmentioning

confidence: 62%

“…BALB/c mice (SPF degree) were purchased from the Medical Animal Center in Zhengzhou University, Henan, China, and raised in individual ventilation cage (IVC) system. As described in our previous study [14,15], 3-day-old BALB/c mice were i.p. inoculated with EV71 strain (2×10 6 pfu/mouse) and sacrificed with isoflurane anesthesia on 3, 5 and 7 days post infection (dpi).…”

Section: Animal Modelmentioning

confidence: 99%

“…CNS injury can lead to a rapid increase in intracranial pressure, increased sympathetic tone, and excessive activation of local renin-angiotensin system (RAS), further results in over-secretion of many cytokines into circulation, leading to peripheral vasoconstriction. Peripheral vasoconstriction will cause vascular endothelium injury and increased permeability, further inducing blood accumulation in the lower pulmonary region [12][13][14][15]. The RAS plays a critical action regulating the circulation in the human body in response to low blood pressure or decrease in serum sodium levels [16].A component of this system is angiotensinogen (AGT) that is synthesized and released by the liver into the general circulation.…”

Section: Introductionmentioning

confidence: 99%

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Involvement of the renin-angiotensin system in the progression of severe hand-foot-and-mouth disease

Zhang¹,

Chen²,

Zhou³

et al. 2018

PLoS ONE

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BackgroundHand-foot-and-mouth disease (HFMD) is generally considered as a mild exanthematous disease to infants and young children worldwide. HFMD cases are usually mild and self-limiting but for few cases leads to complicated severe clinical outcomes, and even death. Previous studies have indicated that serum Ang II levels in patients with H7N9 infection were related to the severity of infection. However, the mechanisms underlying the pathogenesis of severe HFMD remain unclear. This study was undertaken to clarify the role of the renin-angiotensin system (RAS) in the progression of severe HFMD.MethodsIn the present study, 162 children including HFMD patients and healthy controls were recruited. The data was analyzed by time-series fashion. Concentrations of angiotensin II (Ang II) and noradrenaline (NA) in serum of patients were measured with ELISA. We established a mouse model for enterovirus 71 (EV71) infection and determined concentrations of Ang II, NA in tissue lysates at 3, 5 and 7 days post infection (dpi).ResultsThe concentrations of Ang II and NA in serum of the HFMD patients with mild or severe symptoms were significantly higher than that in healthy controls. Additionally, the concentrations of Ang II and NA in serum of severe cases were significantly higher than those mild cases and the increased concentrations of Ang II and NA showed the same time trend during the progression of HFMD in the severe cases. Furthermore, the concentrations of Ang II and NA in target organs of EV71-infected mice including brains, skeletal muscle, and lungs were increased with the progression of EV71 infection in mice. Histopathological alterations were observed in the brains, skeletal muscle and lungs of EV71-infected mice.ConclusionOur study suggested that activation of the RAS is implicated in the pathogenesis of severe HFMD.

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Section: Discussionmentioning

confidence: 62%

Section: Animal Modelmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Involvement of the renin-angiotensin system in the progression of severe hand-foot-and-mouth disease

Zhang¹,

Chen²,

Zhou³

et al. 2018

PLoS ONE

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“…As described previously, EV71 strain (ZZ1350) was isolated from a nonfatal case with CNS involvement in Children's Hospital of Zhengzhou (Zhengzhou, Henan, China) [17]. Virus purification was conducted as previously described [18].…”

Section: Virus and Cellsmentioning

confidence: 99%

“…Toluidine blue stained lung slices were observed under optical microscope, and the number of toluidine blue-positive cells per mm 2 was quantified in a blinded fashion using ×20 magnification. The viral VP1 antigens were detected by immunohistochemical (IHC) staining as described previously [17].…”

Section: Histopathological and Immunohistochemical Analysismentioning

confidence: 99%

Mast cells contribute to Enterovirus 71 infection-induced pulmonary edema in neonatal mice

Jin

Zhang

Wang

et al. 2018

Laboratory Investigation

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Enterovirus (EV) 71 infection has been widely acknowledged as the leading cause of severe hand, foot and mouth disease (HFMD), which may rapidly lead to fatal pulmonary edema. In this study, we established a mouse model for EV71 infection exhibiting high incidence of severe symptoms with pulmonary edema. Mast cells (MCs) accumulation, activation and allergic inflammation were found in the brains, lungs and skeletal muscle of mice after EV71 infection, especially in the lungs of mice. Levels of histamine, platelet-activating factor (PAF), interleukin (IL)-4, IL-5, IL-13, tumor necrosis factor-α (TNF-α), nitric oxide (NO), endocrine gland-derived vascular endothelial growth factor (EG-VEGF) and noradrenaline (NA) were increased in EV71-infected lungs. In addition, EV71 infection reduced the number of pulmonary T cells, dendritic cells (DCs) and monocytes, and increased the number of lung eosinophils, Tregs and MCs. MCs number and tryptase expression in target organs or tissues posed a trend towards an increase from control to severe mice. There were positive correlations between MCs number in the brains (r = 0.701, P = 0.003), lungs (r = 0.802, P < 0.0001), skeletal muscles (r = 0.737, P = 0.001) and mean clinical score. Thus, our results suggested that MCs contributed to the pulmonary edema during EV71 infection.

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High mobility group box 1 knockdown inhibits EV71 replication and attenuates cell pyroptosis through TLR4/NF‐κB/NLRP3 axis

Zhang,

Li,

Deng

et al. 2024

J Biochem & Molecular Tox

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Enterovirus 71 (EV71) is a major causative agent of hand, foot, and mouth disease (HFMD) in children. Nowadays, there are still no effective antiviral drugs for EV71 infection. High mobility group box 1 (HMGB1) is reported to be highly expressed in HFMD patients. However, the role and underlying mechanism of HMGB1 in EV71‐associated HFMD are still unclear. HMGB1 expression was detected using RT‐qPCR and western blot assays. Loss‐ and gain‐function experiments were performed to evaluate the effects of HMGB1 on EV71‐infected cells. The virus titer was examined by TCID50. CCK‐8 and flow cytometry assays were applied to detect the cell viability and cell cycle. Oxidative stress was determined by relative commercial kits. HMGB1 level was elevated in the serum of EV71‐infected patients with HFMD and EV71‐induced RD cells. EV71 infection induced the transfer of HMGB1 from the nucleus into the cytoplasm. HMGB1 knockdown inhibited virus replication, viral protein (VP1) expression and promoted antiviral factor expression. In addition, the inhibition of HMGB1 improved cell viability, protected against S phase arrest, and inhibited EV71‐induced cell injury and oxidative stress, whereas HMGB1 overexpression showed the opposite effects. In terms of mechanism, HMGB1 overexpression activated the TLR4/NF‐κB/NLRP3 signaling pathway and promoted cell pyroptosis. The inhibition of TLR4 and NF‐κB reversed the effects of HMGB1 overexpression on virus replication, oxidative stress, and pyroptosis. In conclusion, HMGB1 knockdown inhibits EV71 replication and attenuates pyroptosis through TLR4/NF‐κB/NLRP3 axis.

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Involvement of inducible nitric oxide synthase and mitochondrial dysfunction in the pathogenesis of enterovirus 71 infection

Cited by 21 publications

References 41 publications

Involvement of the renin-angiotensin system in the progression of severe hand-foot-and-mouth disease

Involvement of the renin-angiotensin system in the progression of severe hand-foot-and-mouth disease

Mast cells contribute to Enterovirus 71 infection-induced pulmonary edema in neonatal mice

High mobility group box 1 knockdown inhibits EV71 replication and attenuates cell pyroptosis through TLR4/NF‐κB/NLRP3 axis

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