Xanthohumol inhibits PRRSV proliferation and alleviates oxidative stress induced by PRRSV via the Nrf2–HMOX1 axis

Abstract

Porcine reproductive and respiratory syndrome virus (PRRSV) is a prevalent and endemic swine pathogen that causes significant economic losses in the global swine industry. Commercial vaccines provide limited protection against this virus, and no highly effective therapeutic drugs are yet available. In this study, we first screened a library of 386 natural products and found that xanthohumol (Xn), a prenylated flavonoid found in hops, displayed high anti-PRRSV activity by inhibiting PRRSV adsorption onto and internalization into cells. Transcriptome sequencing revealed that Xn treatment stimulates genes associated with the antioxidant response in the nuclear factor-erythroid 2-related factor 2 (Nrf2) signalling pathway. Xn causes increased expression of Nrf2, HMOX1, GCLC, GCLM, and NQO1 in Marc-145 cells. The action of Xn against PRRSV proliferation depends on Nrf2 in Marc-145 cells and porcine alveolar macrophages (PAMs). This finding suggests that Xn significantly inhibits PRRSV proliferation and decreases viral-induced oxidative stress by activating the Nrf2–HMOX1 pathway. This information should be helpful for developing a novel prophylactic and therapeutic strategy against PRRSV infection.

<p>The Potential Role of Xanthohumol in SARS-CoV-2 Treatment—Globally Accessible and Economically Viable</p>

“…8 Increasing numbers of studies indicate that xanthohumol can inhibit NF-κB pathway and also inhibit the NF-κB-dependent pro-inflammatory gene expressions, such as IL-6, IL-1, 1L8 and TNF-α. 4,5,9 There was also a dosedependent inhibition of lung inflammatory infiltrate by xanthohumol in PRRSV infection in pigs and significant improvement in postmortem pathology in xanthohumoltreated pigs. 4 There may be a paradigm with SARS-CoV -2-induced lung "ARDS"-type inflammation and ability for xanthohumol to potentially inhibit NF-κB-dependent inflammation in severe COVID-19 patients.…”

“…Xanthohumol has been shown to have a wide range of antiviral effects in many in vitro and in vivo studies against both DNA and RNA viruses such as bovine viral diarrhea virus (BDDV), cytomegalovirus (CMV), herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), porcine reproductive and respiratory syndrome virus (PRRSV). [3][4][5] Infection with PRRSV was first identified in the 1980s in North America and in China in 2006 resulting in a devastating epidemic in pigs. 4,5 This single-stranded RNA virus infection shares similarities with SARS-CoV -2 with high fever, significant morbidity and severe respiratory disease resulting in high mortality.…”

“…[3][4][5] Infection with PRRSV was first identified in the 1980s in North America and in China in 2006 resulting in a devastating epidemic in pigs. 4,5 This single-stranded RNA virus infection shares similarities with SARS-CoV -2 with high fever, significant morbidity and severe respiratory disease resulting in high mortality. In view of these similar clinical features with SARS-COV-2, we present a rationale related to antiviral activity, anticytokine effect and general metabolic interactions predominantly related to PRRSV infection with potentially translatable mechanisms to SARS-COV-2.…”

“…A previous study using high-throughput screening method in 386 natural compounds found that xanthohumol was the most effective in inhibiting PRRSV. 5 In vitro studies showed that xanthohumol could effectively inhibit replication of a BVDV, CMV, HSV-1, HSV-2 and PRRSV with a low inhibitory concentration required to reduce viral replication by 50% ranging from 1.7-7.0 µM and a high toxic concentration suggestive of potentially good therapeutic efficacy. [3][4][5] In vivo study also showed that xanthohumol was effective in reducing virus level in PRRSV infected pigs in a dose-dependent manner.…”

Tomatidine inhibits porcine epidemic diarrhea virus replication by targeting 3CL protease

“…The following primers were used: PEDV N (Forward-5′-TTCTTGTTTCACAGGTGGATG-3′, Reverse-5′-GCTGCTGCGTGGTTTCA-3′); EMCV VP1 (Forward-5′-CCCCACCTCTGCTAAGATACTAAC-3′, Reverse-5′-TGGGACTGGACCTATCATAGAAG); monkey GAPDH (Forward-5′-CCTTCCGTGTCCCTACTGCCAAC-3′, Reverse-5′-GACGCCTGCTTCACCACCTTCT-3′); and porcine GAPDH (Forward-5′-TGGTGAAGGTCGGAGTGAAC-3′, Reverse-5′-AGTGGAGGTCAATGAAGGGG-3′). The detection of mRNA levels of TGEV, PRRSV, and SVA was performed as described previously [ 13 , 19 , 20 ]. Quantitative RT-PCR was performed using AceQ ® qPCR SYBR ® Green Master Mix (Vazyme, China).…”