Amentoflavone Attenuates Clostridium perfringens Gas Gangrene by Targeting Alpha-Toxin and Perfringolysin O

Shui, Lingling; Yang, Xiaofeng; Zhang, Hong; Zhang, Jian; Zhou, Yonglin; Wang, Tingting; Hu, Naiyu; Deng, Xuming; Bai, Xiaoxue

doi:10.3389/fphar.2020.00179

Cited by 21 publications

(14 citation statements)

References 34 publications

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“…To test whether the reduced virulence of the agrB-null mutant in the gas gangrene model was due to a decreased ability of this mutant to survive and reproduce in vivo, skeletal muscle from challenged mice was aseptically collected by the time of euthanasia for C. perfringens counting. The number of viable C. perfringens recovered from muscles 4 h after infection was approximately the same as the challenge dose, indicating that C. perfringens does not significantly grow in this infection model, in agreement with results of another recent study (43). Importantly, no significant differences were observed in the numbers of viable C. perfringens recovered after challenge with the wild-type, mutant, or complemented strains.…”

Section: Discussionsupporting

confidence: 90%

The Agr-Like Quorum-Sensing System Is Important for Clostridium perfringens Type A Strain ATCC 3624 To Cause Gas Gangrene in a Mouse Model

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et al. 2020

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Clostridium perfringens type A is involved in gas gangrene in humans and animals. Following a traumatic injury, rapid bacterial proliferation and exotoxin production result in severe myonecrosis. C. perfringens alpha toxin (CPA) and perfringolysin (PFO) are the main virulence factors responsible for the disease. Recent in vitro studies have identified an Agr-like quorum-sensing (QS) system in C. perfringens that regulates the production of both toxins. The system is composed of an AgrB membrane transporter and an AgrD peptide that interacts with a two-component regulatory system in response to fluctuations in the cell population density. In addition, a synthetic peptide named 6-R has been shown to interfere with this signaling mechanism, affecting the function of the Agr-like QS system in vitro. In the present study, C. perfringens type A strain ATCC 3624 and an isogenic agrB-null mutant were tested in a mouse model of gas gangrene. When mice were intramuscularly challenged with 106 CFU of wild-type ATCC 3624, severe myonecrosis and leukocyte aggregation occurred by 4 h. Similar numbers of an agrB-null mutant strain produced significantly less severe changes in the skeletal muscle of challenged mice. Complementation of the mutant to regain agrB expression restored virulence to wild-type levels. The burdens of all three C. perfringens strains in infected muscle were similar. In addition, animals injected intramuscularly with wild-type ATCC 3624 coincubated with the 6-R peptide developed less severe microscopic changes. This study provides the first in vivo evidence that the Agr-like QS system is important for C. perfringens type A-mediated gas gangrene. IMPORTANCE Clostridium perfringens type A strains produce toxins that are responsible for clostridial myonecrosis, also known as gas gangrene. Toxin production is regulated by an Agr-like quorum-sensing (QS) system that responds to changes in cell population density. In this study, we investigated the importance of this QS system in a mouse model of gas gangrene. Mice challenged with a C. perfringens strain with a nonfunctional regulatory system developed less severe changes in the injected skeletal muscle compared to animals receiving the wild-type strain. In addition, a synthetic peptide was able to decrease the effects of the QS in this disease model. These studies provide new understanding of the pathogenesis of gas gangrene and identified a potential therapeutic target to prevent the disease.

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Section: Discussionsupporting

confidence: 90%

The Agr-Like Quorum-Sensing System Is Important for Clostridium perfringens Type A Strain ATCC 3624 To Cause Gas Gangrene in a Mouse Model

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Beingesser

et al. 2020

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“…As a natural biflavonoid compound, AMF is reported to play various pharmacological effects such as anti-inflammatory ( Tordera et al, 1994 ; Kim et al, 1998 ; Woo et al, 2005 ; Huang et al, 2012 ; Jeong et al, 2012 ; Ishola et al, 2013 ; Oh et al, 2013 ; Sakthivel and Guruvayoorappan, 2013 ; An et al, 2016 ; Trang et al, 2016 ; Zong and Zhang, 2017 ; Cai et al, 2019 ; Kuo et al, 2019 ; Alkadi et al, 2021 ), anti-microorganism ( Lin et al, 1997 ; Ma et al, 2001 ; Jung et al, 2006 ; Jung et al, 2007 ; Ryu et al, 2010 ; Hwang et al, 2012 ; Wilsky et al, 2012 ; Coulerie et al, 2013 ; Hwang et al, 2013 ; Yin et al, 2014 ; Zhao et al, 2017b ; Shen et al, 2018 ; Bajpai et al, 2019 ; Liu et al, 2020a ), anti-oxidant ( Bonacorsi et al, 2012 ; Li et al, 2020 ), anti-angiogenesis ( Kang et al, 2004 ; Dell'Agli et al, 2006 ; Guruvayoorappan and Kuttan, 2008c ; Tarallo et al, 2011 ; Zhang et al, 2014 ), neuroprotective ( Kang et al, 2005 ; Shin et al, 2006 ; Zhang et al, 2015 ; Cao et al, 2017 ; Chen et al, 2018 ; Rong et al, 2019 ; Zhao et al, 2019 ; Liu et al, 2020b ; Choi et al, 2020 ; Sun et al, 2020 ; Cao et al, 2021 ), musculoskeletal protection ( Lee et al, 2006 ; Zha et al, 2016 ; Bais et al, 2017 ; Zhang et al, 2018 ; Vasconcelos et al, 2019 ), radioprotection ( Lee et al, 2008 ; Park et al, 2011 ; Lee et al, 2012 ; Xu et al, 2014 ; Qu et al, 2019 ), meta...…”

Section: The Multifunctional Biological Activities Of Amentoflavonementioning

confidence: 99%

Insights Into Amentoflavone: A Natural Multifunctional Biflavonoid

Xiong

Tang²,

Lai³

et al. 2021

Front. Pharmacol.

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Amentoflavone is an active phenolic compound isolated from Selaginella tamariscina over 40 years. Amentoflavone has been extensively recorded as a molecule which displays multifunctional biological activities. Especially, amentoflavone involves in anti-cancer activity by mediating various signaling pathways such as extracellular signal-regulated kinase (ERK), nuclear factor kappa-B (NF-κB) and phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), and emerges anti-SARS-CoV-2 effect via binding towards the main protease (Mpro/3CLpro), spike protein receptor binding domain (RBD) and RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2. Therefore, amentoflavone is considered to be a promising therapeutic agent for clinical research. Considering the multifunction of amentoflavone, the current review comprehensively discuss the chemistry, the progress in its diverse biological activities, including anti-inflammatory, anti-oxidation, anti-microorganism, metabolism regulation, neuroprotection, radioprotection, musculoskeletal protection and antidepressant, specially the fascinating role against various types of cancers. In addition, the bioavailability and drug delivery of amentoflavone, the molecular mechanisms underlying the activities of amentoflavone, the molecular docking simulation of amentoflavone through in silico approach and anti-SARS-CoV-2 effect of amentoflavone are discussed.

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“…PFO production was higher in the group H strains (Figure 2E), and the amount of PFO produced was significantly correlated with the hemolysis rate (Figure 2F). CPA also induces hemolysis alone (Kiu and Hall, 2018;Liu et al, 2020); however, CPA production and the hemolysis rate were not correlated. CPA, which hydrolyzes sphingomyelin and lecithin, can lyse erythrocyte, platelet, and endothelial cell membranes (Uzal et al, 2014;Kiu and Hall, 2018;Chinen, 2020).…”

Section: Discussionmentioning

confidence: 90%

Pathogenic Characterization of Clostridium perfringens Strains Isolated From Patients With Massive Intravascular Hemolysis

et al. 2021

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Sepsis caused by Clostridium perfringens infection is rare but often fatal. The most serious complication leading to poor prognosis is massive intravascular hemolysis (MIH). However, the molecular mechanism underlying this fulminant form of hemolysis is unclear. In the present study, we employed 11 clinical strains isolated from patients with C. perfringens septicemia and subdivided these isolates into groups H and NH: septicemia with (n = 5) or without (n = 6) MIH, respectively. To elucidate the major pathogenic factors of MIH, biological features were compared between these groups. The isolates of two groups did not differ in growth rate, virulence-related gene expression, or phospholipase C (CPA) production. Erythrocyte hemolysis was predominantly observed in culture supernatants of the strains in group H, and the human erythrocyte hemolysis rate was significantly correlated with perfringolysin O (PFO) production. Correlations were also found among PFO production, human peripheral blood mononuclear cell (PBMC) cytotoxicity, and production of interleukin-6 (IL-6) and interleukin-8 (IL-8) by human PBMCs. Analysis of proinflammatory cytokines showed that PFO induced tumor necrosis factor-α (TNF-α), IL-5, IL-6, and IL-8 production more strongly than did CPA. PFO exerted potent cytotoxic and proinflammatory cytokine induction effects on human blood cells. PFO may be a major virulence factor of sepsis with MIH, and potent proinflammatory cytokine production induced by PFO may influence the rapid progression of this fatal disease caused by C. perfringens.

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Amentoflavone Attenuates Clostridium perfringens Gas Gangrene by Targeting Alpha-Toxin and Perfringolysin O

Cited by 21 publications

References 34 publications

The Agr-Like Quorum-Sensing System Is Important for Clostridium perfringens Type A Strain ATCC 3624 To Cause Gas Gangrene in a Mouse Model

The Agr-Like Quorum-Sensing System Is Important for Clostridium perfringens Type A Strain ATCC 3624 To Cause Gas Gangrene in a Mouse Model

Insights Into Amentoflavone: A Natural Multifunctional Biflavonoid

Pathogenic Characterization of Clostridium perfringens Strains Isolated From Patients With Massive Intravascular Hemolysis

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