Phytochemical alkaloids orchestrate immunometabolism against viral infections.

The role of cholesterol metabolism in antiviral immunity has been established, but if and how this cholesterol-mediated immunometabolism can be regulated by specific small molecules is of particular interest in the quest for novel antiviral therapeutics. Here, we first demonstrate that NPC1 is the key cholesterol transporter for suppressing viral replication by changing cholesterol metabolism and triggering the innate immune response via systemic analyses of all possible cholesterol transporters. We then use the Connectivity Map (CMap), a systematic methodology for identifying functional connections between genetic perturbations and drug actions, to screen NPC1 inhibitors, and found that bis-benzylisoquinoline alkaloids (BBAs) exhibit high efficacy in the inhibition of viral infections.

The human disease-associated gene ZNFX1 controls inflammation through inhibition of the NLRP3 inflammasome.

Inherited deficiency of zinc finger NFX1-type containing 1 (ZNFX1), a dsRNA virus sensor, is associated with severe familial immunodeficiency, multisystem inflammatory disease, increased susceptibility to viruses, and early mortality. However, limited treatments for patients with pathological variants of ZNFX1 exist due to an incomplete understanding of the diseases resulting from ZNFX1 mutations. Here, we demonstrate that ZNFX1 specifically inhibits the activation of the NLR family pyrin domain-containing protein 3 (NLRP3) inflammasome in response to NLRP3 activators both in vitro and in vivo.

A Alcohol Extract Exerts Bidirectional Immunoregulatory Effects by Regulating Macrophage Polarization.

For background, , the only anamorphic fungus considered an effective substitute for , possesses immunoregulatory properties. However, the specific mechanism underlying the immunoregulatory function of remains unclear. The purpose is to investigate the therapeutic effects of alcohol extract (HSAE) on immune dysregulation and elucidate the underlying mechanisms involved.

Suppressing FXR promotes antiviral effects of bile acids enhancing the interferon transcription.

Bile acids (BAs) are natural metabolites in mammals and have the potential to function as drugs against viral infection. However, the limited understanding of chenodeoxycholic acid (CDCA) receptors and downstream signaling, along with its lower suppression efficiency in inhibiting virus infection limits its clinical application. In this study, we demonstrate that farnesoid X receptor (FXR), the receptor of CDCA, negatively regulates interferon signaling, thereby contributing to the reduced effectiveness of CDCA against virus replication.

Capsaicin functions as a selective degrader of STAT3 to enhance host resistance to viral infection.

Although STAT3 has been reported as a negative regulator of type I interferon (IFN) signaling, the effects of pharmacologically inhibiting STAT3 on innate antiviral immunity are not well known. Capsaicin, approved for the treatment of postherpetic neuralgia and diabetic peripheral nerve pain, is an agonist of transient receptor potential vanilloid subtype 1 (TRPV1), with additional recognized potencies in anticancer, anti-inflammatory, and metabolic diseases. We investigated the effects of capsaicin on viral replication and innate antiviral immune response and discovered that capsaicin dose-dependently inhibited the replication of VSV, EMCV, and H1N1.

Isoliquiritigenin inhibits virus replication and virus-mediated inflammation via NRF2 signaling.

Background: The transcription factor NRF2 is a master redox switch that regulates the cellular antioxidant response. However, recent advances have revealed new roles for NRF2, including the regulation of antiviral responses to various viruses, suggesting that pharmacological NRF2-activating agents may be a promising therapeutic drug for viral diseases. Isoliquiritigenin (ISL), a chalcone isolated from liquorice (Glycyrrhizae Radix) root, is reported to be a natural NRF2 agonist and has has antiviral activities against HCV (hepatitis C virus) and IAV (influenza A virus).

ZNFX1 antisense RNA1 promotes antiviral innate immune responses via modulating ZNFX1 function.

Increasing evidence suggests that natural antisense transcriptional lncRNAs regulate their adjacent coding genes to mediate diverse aspects of biology. Bioinformatics analysis of the previously identified antiviral gene ZNFX1 revealed neighboring lncRNA ZFAS1 transcribed on the opposite strand from ZNFX1. Whether ZFAS1 exerts antiviral function via regulating the dsRNA sensor ZNFX1 is unknown.

Scoparone suppresses mitophagy-mediated NLRP3 inflammasome activation in inflammatory diseases.

Recent evidence shows that targeting NLRP3 inflammasome activation is an important means to treat inflammasome-driven diseases. Scoparone, a natural compound isolated from the Chinese herb Artemisia capillaris Thunb, has anti-inflammatory activity. In this study we investigated the effect of scoparone on NLRP3 inflammasome activation in inflammatory diseases.