Berberine suppresses influenza virus-triggered NLRP3 inflammasome activation in macrophages by inducing mitophagy and decreasing mitochondrial ROS

Liu, Hui; You, Leiming; Wu, Jun; Zhao, Mengfan; Guo, Rui; Zhang, Haili; Su, Rina; Mao, Qin; Deng, Di; Yu, Hui

doi:10.1002/jlb.3ma0320-358rr

Cited by 84 publications

(55 citation statements)

References 56 publications

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“…It has also been reported to contribute to the pathology of paralysis agitans, diabetes and kidney disease [68][69][70]. Importantly, mitophagy is also linked to cellular antiviral responses [71,72]. It is worth noting that HCV and CSFV induce mitophagy to attenuate the IFN response.…”

Section: Discussionmentioning

confidence: 99%

LDHB inhibition induces mitophagy and facilitates the progression of CSFV infection

Fan

Zhao

et al. 2020

Autophagy

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Cellular metabolism caters to the energy and metabolite needs of cells. Although the role of the terminal metabolic enzyme LDHB (lactate dehydrogenase B) in the glycolysis pathway has been widely studied in cancer cells, its role in viral infection is relatively unknown. In this study, we found that CSFV (classical swine fever virus) infection reduces pyruvate levels while promotes lactate release in pigs and in PK-15 cells. Moreover, using a yeast two-hybrid screening system, we identified LDHB as a novel interacting partner of CSFV non-structural protein NS3. These results were confirmed via co-immunoprecipitation, glutathione S-transferase and confocal assays. Furthermore, knockdown of LDHB via interfering RNA induced mitochondrial fission and mitophagy, as detected reduced mitochondrial mass. Upon inhibition of LDHB, expression of the mitophagy proteins TOMM20 and VDAC1 decreased and the ubiquitination of MFN2, a mitochondrial fusion mediator, was promoted. In addition, a sensitive dual fluorescence reporter (mito-mRFP-EGFP) was utilized to analyze the delivery of autophagosomes to lysosomes in LDHB inhibition cells. Furthermore, LDHB inhibition promoted NFKB signaling, which was regulated by mitophagy; meanwhile, infection with CSFV negated these NFKB anti-viral responses. Inhibition of LDHB also inhibited apoptosis, providing an environment conducive to persistent viral infection. Finally, we demonstrated that LDHB inhibition promoted CSFV growth via mitophagy, whereas its overexpression decreased CSFV replication. Our data revealed a novel mechanism through which LDHB, a metabolic enzyme, mediates CSFV infection, and provides new avenues for the development of anti-viral strategies.

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Section: Discussionmentioning

confidence: 99%

LDHB inhibition induces mitophagy and facilitates the progression of CSFV infection

Fan

Zhao

et al. 2020

Autophagy

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“…Biological targets of berberine were identified from literature reports 51,52 and published databases including Similarity Ensemble Approach, 56,57 PubChem, 58,59 and DrugBank 60,61 . The relevant human genes associated with COVID‐19 and SARS were selected as drug targets from various databases including Therapeutic Target Database, 62,63 Genetic Association Database, 64,65 GeneCards, 66,67 Open Targets Platform, 68,69 and Comparative Toxicogenomics Database 70,71 .…”

Section: Methodsmentioning

confidence: 99%

A small molecule compound berberine as an orally active therapeutic candidate against COVID‐19 and SARS: A computational and mechanistic study

Wang

Maskey

et al. 2021

The FASEB Journal

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The novel coronavirus disease, COVID-19, has grown into a global pandemic and a major public health threat since its breakout in December 2019. To date, no specific therapeutic drug or vaccine for treating COVID-19 and SARS has been FDA approved. Previous studies suggest that berberine, an isoquinoline alkaloid, has shown various biological activities that may help against COVID-19 and SARS, including antiviral, anti-allergy and inflammation, hepatoprotection against drug-and infectioninduced liver injury, as well as reducing oxidative stress. In particular, berberine has a wide range of antiviral activities such as anti-influenza, anti-hepatitis C, anticytomegalovirus, and anti-alphavirus. As an ingredient recommended in guidelines issued by the China National Health Commission for COVID-19 to be combined with other therapy, berberine is a promising orally administered therapeutic candidate against SARS-CoV and SARS-CoV-2. The current study comprehensively evaluates the potential therapeutic mechanisms of berberine in preventing and treating COVID-19 and SARS using computational modeling, including target mining, gene ontology enrichment, pathway analyses, protein-protein interaction analysis, and 2 of 19 | WANG et Al. 1 | INTRODUCTION Coronavirus disease-19 (COVID-19) is an infectious disease caused by a newly discovered coronavirus SARS-CoV2 that has reached global pandemic status and become a major global health threat. As of December 1 2020, there have been 63,751,931 confirmed cases and 1,477,976 deaths worldwide. 1 The United States hit record-high daily COVID-19 cases in November, 2020. Since the pandemic started in March, 2020, the nation has surpassed 12 million cases and more than 266,000 Americans have died. United States could see "a surge upon a surge" of COVID-19 cases this winter. 2 During just two full days at the end of November, 2020, the country saw over 360,000 new COVID-19 cases nationwide, in addition to over 2,700 new deaths. In 2003, a zoonotic coronavirus outbreak of SARS-CoV had resulted in severe SARS with fatality rates of 10%. 3-6 The SARS-CoV-2 genome shares approximately 70%-80% sequence similarity to SARS-CoV, and causes similar clinical symptoms. 7,8 Key clinical features of COVID-19 and SARS include fever, chills, muscle pain, headache, sore throat, new loss of taste or smell, cough, shortness of breath, gastrointestinal problems in mild to moderate cases, and more serious disease involving pneumonia, acute respiratory distress syndrome, cardiovascular and hepatic failure with high morbidity. 7,8 Individuals with pre-existing conditions like cardiovascular disease, hypertension, asthma, and diabetes, 9 and elderly patients are at a higher risk to become infected with severe symptoms. 10 To date, no specific therapeutic drug or vaccine COVID-19 and SARS is available, resulting in an urgent need for broad-spectrum therapeutics for COVID-19 and other CoV infections.

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“…In addition, itaconate was investigated for its role as an anti-inflammatory and antioxidant metabolite of the TCA cycle [124]. NLRP3 inflammasome activation by decreased ROS through mitophagy might play a crucial role in berberine (BBR)-mediated alleviation of IV-induced inflammatory lesions [125].…”

Section: Potential Interaction With Inflammasomesmentioning

confidence: 99%

Redox control in the pathophysiology of influenza virus infection

et al. 2020

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Triggered in response to external and internal ligands in cells and animals, redox homeostasis is transmitted via signal molecules involved in defense redox mechanisms through networks of cell proliferation, differentiation, intracellular detoxification, bacterial infection, and immune reactions. Cellular oxidation is not necessarily harmful per se, but its effects depend on the balance between the peroxidation and antioxidation cascades, which can vary according to the stimulus and serve to maintain oxygen homeostasis. The reactive oxygen species (ROS) that are generated during influenza virus (IV) infection have critical effects on both the virus and host cells. In this review, we outline the link between viral infection and redox control using IV infection as an example. We discuss the current state of knowledge on the molecular relationship between cellular oxidation mediated by ROS accumulation and the diversity of IV infection. We also summarize the potential anti-IV agents available currently that act by targeting redox biology/pathophysiology.

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Berberine suppresses influenza virus-triggered NLRP3 inflammasome activation in macrophages by inducing mitophagy and decreasing mitochondrial ROS

Cited by 84 publications

References 56 publications

LDHB inhibition induces mitophagy and facilitates the progression of CSFV infection

LDHB inhibition induces mitophagy and facilitates the progression of CSFV infection

A small molecule compound berberine as an orally active therapeutic candidate against COVID‐19 and SARS: A computational and mechanistic study

Redox control in the pathophysiology of influenza virus infection

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