Drug repurposing of anti-infective clinical drugs: Discovery of two potential anti-cytokine storm agents

Su, Li; Tu, Ye; Kong, De-Pei; Chen, Dagui; Zhang, Chenxi; Zhang, Wannian; Zhuang, Chunlin; Wang, Zhibin

doi:10.1016/j.biopha.2020.110643

Cited by 17 publications

(11 citation statements)

References 41 publications

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“…Subsequent western blot experiments found that Trichomicin inhibited the Stat3 and NF-κB pathways and reduced the phosphorylation of Stat3 and p65 following LPS stimulation ( Figure 7 ). Through comparison, the anti-cytokine storm activity of Trichomicin was significantly stronger than that of entecavir ( Su et al, 2020 ). Trichomicin also showed good oral absorption and rapid uptake ( Zhu et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Screening of Microbial Natural Products and Biological Evaluation of Trichomicin as Potential Anti-Cytokine Storm Agents

et al. 2021

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COVID-19 has remained an uncontained, worldwide pandemic. Most of the infected people had mild symptoms in the early stage, and suddenly worsened or even died in the later stage which made the cytokine release syndrome (CRS) once again aroused people’s attention. CRS is an excessive immunity of the body to external stimuli such as viruses, bacteria, and nanomaterials, which can cause tissue damage, local necrosis or even death. Lipopolysaccharide (LPS) is one of the most effective CRS inducers, which can activate macrophages to release cytokines, including tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), IL- 6 and chemokines. We used RT-PCR to detect the expression of representative cytokines in mouse and human cells at different concentrations of Trichomicin, Ebosin, and 1487B after LPS stimulation. The results showed that the expression of TNF-α, IL-1β, IL-6, and CXCL10 all increased after LPS stimulation. Among the various drugs, Trichomicin had the most obvious inhibitory effect on cytokine expression in vitro, and it was further verified in vivo that Trichomicin can improve the survival rate of mice stimulated with LPS. Finally, it was proved that Trichomicin inhibited the Stat3 and NF-κB pathways and reduced the phosphorylation of Stat3 and p65 after LPS stimulation, thereby inhibiting the response of macrophages to pro-inflammatory stimuli. The article clarified the inhibitory activity and mechanism of action of Trichomicin on CRS, and laid the foundation for the research on the anti-cytokine storm activity of microbial natural products.

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Section: Discussionmentioning

confidence: 99%

Screening of Microbial Natural Products and Biological Evaluation of Trichomicin as Potential Anti-Cytokine Storm Agents

et al. 2021

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“…Macrophages play a vital role in both SARS-CoV-2 virus -induced lung lesions and the host cytokine-mediated response ( 8 ). In our previous study, entecavir, a hepatitis B virus (HBV) inhibitor, was demonstrated to directly inhibit the release of cytokines in lipopolysaccharide (LPS) -stimulated macrophage model ( 27 ), which is a classic in vitro model to evaluate the anti-inflammatory activity of the drugs ( 28 ). Herein, we also examined whether these three neuraminidase inhibitors could inhibit the expression of inflammatory cytokines in LPS-stimulated macrophages in the present study.…”

Section: Introductionmentioning

confidence: 99%

Peramivir, an Anti-Influenza Virus Drug, Exhibits Potential Anti-Cytokine Storm Effects

Zhang

Sun

et al. 2022

Front. Immunol.

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Coronavirus Disease 2019 (COVID-19) infected by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has been declared a public health emergency of international concerns. Cytokine storm syndrome (CSS) is a critical clinical symptom of severe COVID-19 patients, and the macrophage is recognized as the direct host cell of SARS-CoV-2 and potential drivers of CSS. In the present study, peramivir was identified to reduce TNF-α by partly intervention of NF-κB activity in LPS-induced macrophage model. In vivo, peramivir reduced the multi-cytokines in serum and bronchoalveolar lavage fluid (BALF), alleviated the acute lung injury and prolonged the survival time in mice. In human peripheral blood mononuclear cells (hPBMCs), peramivir could also inhibit the release of TNF-α. Collectively, we proposed that peramivir might be a candidate for the treatment of COVID-19 and other infections related CSS.

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“…It is activated by post-translational modificiation as phosphorylation, and the IκB protein’s proteolytic degradation via enhanced IκB kinase (IKK) and NF-κB inducing kinase (NIK) ( 6 ). Activated NF-κB translocate to the nucleus and acts as a transcription factor that binds to the promoter region of inflammatory related genes, triggering their transcription ( 7 ). Hyperactivation of NF-κB increases inflammatory diseases and anti-inflammatory drugs inhibit the expression of inflammatory cytokine by attenuating the NF-κB pathway ( 7 ).…”

Section: Introductionmentioning

confidence: 99%

“…Activated NF-κB translocate to the nucleus and acts as a transcription factor that binds to the promoter region of inflammatory related genes, triggering their transcription ( 7 ). Hyperactivation of NF-κB increases inflammatory diseases and anti-inflammatory drugs inhibit the expression of inflammatory cytokine by attenuating the NF-κB pathway ( 7 ). Thus, NF-κB inhibitors have important clues for the drug development of inflammation responses and therapeutic paradigms to inhibit pathological inflammation.…”

Section: Introductionmentioning

confidence: 99%

Anisomycin protects against sepsis by attenuating IκB kinase-dependent NF-κB activation and inflammatory gene expression

Park

Min

et al. 2021

BMB Rep

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Anisomycin is known to inhibit eukaryotic protein synthesis and has been established as an antibiotic and anticancer drug. However, the molecular targets of anisomycin and its mechanism of action have not been explained in macrophages. Here, we demonstrated the anti-inflammatory effects of anisomycin both in vivo and in vitro. We found that anisomycin decreased the mortality rate of macrophages in cecal ligation and puncture (CLP)-and lipopolysaccharide (LPS)-induced acute sepsis. It also declined the gene expression of proinflammatory mediators such as inducible nitric oxide synthase, tumor necrosis factor-α, and interleukin-1β as well as the nitric oxide and proinflammatory cytokines production in macrophages subjected to LPS-induced acute sepsis. Furthermore, anisomycin attenuated nuclear factor (NF)-κB activation in LPS-induced macrophages, which correlated with the inhibition of phosphorylation of NF-κBinducing kinase and IκB kinase, phosphorylation and IκBα proteolytic degradation, and NF-κB p65 subunit nuclear translocation. These results suggest that anisomycin prevented acute inflammation by inhibiting NF-κB-related inflammatory gene expression and could be a potential therapeutic candidate for sepsis.

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Drug repurposing of anti-infective clinical drugs: Discovery of two potential anti-cytokine storm agents

Abstract: Graphical abstract

Cited by 17 publications

References 41 publications

Screening of Microbial Natural Products and Biological Evaluation of Trichomicin as Potential Anti-Cytokine Storm Agents

Screening of Microbial Natural Products and Biological Evaluation of Trichomicin as Potential Anti-Cytokine Storm Agents

Peramivir, an Anti-Influenza Virus Drug, Exhibits Potential Anti-Cytokine Storm Effects

Anisomycin protects against sepsis by attenuating IκB kinase-dependent NF-κB activation and inflammatory gene expression

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