White Button Mushroom (Agaricus bisporus) Interrupts Tissue AR-TMPRSS2 Expression and Attenuates Pro-inflammatory Cytokines in C57BL/6 Mice: Implication for COVID-19 Dietary Intervention

Abstract Transmembrane protease serine 2 (TMPRSS2), an androgen-induced protease associated with prostate cancer, is one putative receptor for coronavirus entry into host cells, where triggering aggressive inflammatory cytokine storm and possibly death in COVID-19 patients. We previously reported that dietary white button mushroom (WBM) antagonized dihydrotestosterone (DHT)-induced androgen receptor (AR) activation and reduced myeloid-derived suppressor cells (MDSCs) in prostate cancer animal models and patients. The present study on C57BL/6 mice revealed that WBM is a unique food that A) interrupts DHT induced AR-TMPRSS2 expression in putative COVID-19 targeted organs through its AR antagonistic activity and B) attenuates serum pro-inflammatory cytokines which have been implicated in COVID-19 pathogenesis. We hereby propose WBM intake as a potentially low-cost, efficient, and safe dietary intervention to mitigate COVID-19.

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White button mushroom interrupts tissue AR-mediated TMPRSS2 expression and attenuates pro-inflammatory cytokines in C57BL/6 mice

npj Science of Food ◽

10.1038/s41538-021-00102-6 ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

Xiaoqiang Wang ◽

Desiree Ha ◽

Ryohei Yoshitake ◽

Shiuan Chen

Keyword(s):

Prostate Cancer ◽

Inflammatory Cytokines ◽

Suppressor Cells ◽

Edible Mushroom ◽

The United States ◽

Scientific Basis ◽

Asia Pacific ◽

Button Mushroom ◽

White Button Mushroom ◽

Pro Inflammatory Cytokines

AbstractWhite button mushroom (WBM) is a common edible mushroom consumed in the United States and many European and Asia-Pacific countries. We previously reported that dietary WBM antagonized dihydrotestosterone (DHT)-induced androgen receptor (AR) activation and reduced myeloid-derived suppressor cells (MDSCs) in prostate cancer animal models and patients. Transmembrane protease serine 2 (TMPRSS2), an androgen-induced protease in prostate cancer, has been implicated in influenza and coronavirus entry into the host cell, triggering host immune response. The present study on C57BL/6 mice revealed that WBM is a unique functional food that (A) interrupts AR-mediated TMPRSS2 expression in prostate, lungs, small intestine, and kidneys through its AR antagonistic activity and (B) attenuates serum pro-inflammatory cytokines and reduces MDSC counts through its immunoregulatory activity. These findings provide a scientific basis for translational studies toward clinical applications of WBM in diseases related to TMPRSS2 expression and immune dysregulation.

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Abstract 162: Reduced pro-inflammatory cytokines and immunosuppressive cells in patients with prostate cancer following consumption of soy isoflavone enriched bread.

10.1158/1538-7445.am2013-162 ◽

2013 ◽

Author(s):

Gregory Brian Lesinski ◽

Thomas A. Mace ◽

Patrick Reville ◽

Jennifer Ahn-Jarvis ◽

Matthew Bill ◽

...

Keyword(s):

Prostate Cancer ◽

Inflammatory Cytokines ◽

Soy Isoflavone ◽

Immunosuppressive Cells ◽

Pro Inflammatory Cytokines

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White Button Mushroom Disrupts AR Signaling in Prostate Cancer: The Scientific Basis for a Diet-Based Chemoprevention

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1672 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A820-A821

Author(s):

Xiaoqiang Wang ◽

Desiree Ha ◽

Hitomi Mori ◽

Shiuan Chen

Keyword(s):

Prostate Cancer ◽

Prostate Specific Antigen ◽

Agaricus Bisporus ◽

Specific Antigen ◽

Scientific Basis ◽

Luciferase Assay ◽

Dependent Manner ◽

Button Mushroom ◽

Western Blots ◽

White Button Mushroom

Abstract White button mushroom (WBM) (Agaricus bisporus) is a potential prostate cancer (PCa) chemo-preventive and therapeutic agent. Our clinical phase trial of WBM powder in patients with biochemically recurrent PCa indicated that WBM intake reduced the circulating levels of prostate-specific antigen (PSA), with minimal side effects [1]. We hypothesized that WBM exerts its effects on PCa through the androgen receptor (AR) signaling axis. We thus conducted the reverse translational study. Androgen-sensitive PCa cell lines (LNCaP and VCaP) and patient-derived-xenografts (PDX), of a prostate tumor (TM00298) were used. In both LNCaP and VCaP cells, western blots and qRT-PCR assays indicated that WBM extract (6~30 mg/mL) suppressed DHT-induced PSA expression and cell proliferation in a dose-dependent manner. Immunofluorescence on AR revealed that the nuclear localization of AR was reduced upon WBM extract treatment, which agreed with the results of a PSA promotor-luciferase assay, suggesting that WBM extract inhibited DHT-induced luciferase activity. RNA-Seq on WBM-treated LNCaP cells confirmed that WBM treatment suppressed androgen response pathways and cell-cycle control pathways. Our prostate cancer PDX showed that oral intake of WBM extract (200 mg/kg/day) significantly suppressed tumor growth, as well as decreased PSA levels in both tumors and serum. Both in vitro and in vivo studies suggested that chemical(s) in WBM extract behave as AR antagonist(s). We previously identified a conjugated linoleic acid isomer (CLA-9Z11E) as an active component in WBM extract. In the present study, we extended these findings by performing LanthaScreen™ TR-FRET AR Coactivator Interaction Assays for a direct interaction of CLA-9Z11E with AR. We report here that CLA-9Z11E exerts a strong antagonist potency against the recruitment of an AR coactivator peptide towards AR. The inhibitory effect of CLA-9Z11E (IC50: 350 nM) was nearly two times stronger than the known AR antagonist, cyproterone acetate (IC50: 672 nM). The information gained from this study improves the overall understanding of how WBM may contribute to the prevention and treatment of PCa. It also serves as an important, scientific basis for developing diet-based chemoprevention and integrative therapeutic strategies for prostate cancer (supported by NIH R01 CA227230). Reference: [1] Twardowski P, et al. A phase I trial of mushroom powder in patients with biochemically recurrent prostate cancer: Roles of cytokines and myeloid-derived suppressor cells for Agaricus bisporus-induced prostate-specific antigen responses. Cancer. 2015.121(17):2942-50.

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Prostate cancer cells undergoing ER stress in vitro and in vivo activate transcription of pro-inflammatory cytokines

Journal of Inflammation Research ◽

10.2147/jir.s11190 ◽

2010 ◽

pp. 99 ◽

Cited By ~ 4

Author(s):

Zanetti

Keyword(s):

Prostate Cancer ◽

Er Stress ◽

Cancer Cells ◽

Inflammatory Cytokines ◽

Prostate Cancer Cells ◽

Pro Inflammatory Cytokines

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Human herpesvirus 6A tegument protein U14 induces NF-κB signaling by interacting with p65

Journal of Virology ◽

10.1128/jvi.01269-21 ◽

2021 ◽

Author(s):

Salma Aktar ◽

Jun Arii ◽

Lidya Handayani Tjan ◽

Mitsuhiro Nishimura ◽

Yasuko Mori

Keyword(s):

Transcription Factor ◽

Inflammatory Cytokines ◽

Virus Replication ◽

Nuclear Translocation ◽

Human Herpesvirus ◽

Host Cells ◽

Viral Gene ◽

Virus Protein ◽

Protein Accumulation ◽

Pro Inflammatory Cytokines

Viral infection induces host cells to mount a variety of immune responses, which may either limit viral propagation or create conditions conducive to virus replication in some instances. In this regard, activation of the NF-κB transcription factor is known to modulate virus replication. Human herpesvirus 6A (HHV-6A), which belongs to the Betaherpesvirinae subfamily, is frequently found in patients with neuro-inflammatory diseases, although its role in disease pathogenesis has not been elucidated. In this study, we found that the HHV-6A-encoded U14 protein activates NF-κB signaling following interaction with the NF-κB complex protein, p65. Through induction of nuclear translocation of p65, U14 increases the expression of IL-6, IL-8 and MCP-1 transcripts. We also demonstrated that activation of NF-κB signaling is important for HHV-6A replication, as inhibition of this pathway reduced virus protein accumulation and viral genome copy number. Taken together, our results suggest that HHV-6A infection activates the NF-κB pathway and promotes viral gene expression via late gene products including U14. IMPORTANCE Human herpesvirus 6A (HHV-6A) is frequently found in patients with neuro-inflammation, although its role in the pathogenesis of this disease has not been elucidated. Most viral infections activate the NF-κB pathway, which causes the transactivation of various genes, including those encoding pro-inflammatory cytokines. Our results indicate that HHV-6A U14 activates the NF-κB pathway, leading to upregulation of pro-inflammatory cytokines. We also found that activation of the NF-κB transcription factor is important for efficient viral replication. This study provides new insight into HHV-6A U14 function in host cell signaling, and identifies potential cellular targets involved in HHV-6A pathogenesis and replication.

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