The polypeptide antibiotic polymyxin B acts as a pro-inflammatory irritant by preferentially targeting macrophages

Kagi, Tomohiro; Naganuma, Rio; Inoue, Aya; Noguchi, Takuya; Hamano, Shuhei; Sekiguchi, Yuto; Hwang, Gi-Wook; Hirata, Yusuke; Matsuzawa, Atsushi

doi:10.1038/s41429-021-00490-7

Cited by 14 publications

(5 citation statements)

References 48 publications

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“…However, it is hard to say there is not any off-target effects of Polymyxin B in vivo. The systemic treatment of Polymyxin B killed bacteria 48 , induced necrosis of macrophages 49 , and decreased the regulatory T cells (Treg) population 50 , which may contribute to the anti-tumor activities of Polymyxin B in vivo. In summary, our study indicates that SCARB2, particularly in the context of the SCARB2-MYC PPI, is a potential therapeutic target for HCC.…”

Section: Discussionmentioning

confidence: 99%

SCARB2 drives hepatocellular carcinoma tumor initiating cells via enhanced MYC transcriptional activity

Wang,

Gao,

Xue

et al. 2023

Nat Commun

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CSCs (Cancer stem cells) with distinct metabolic features are considered to cause HCC (hepatocellular carcinoma) initiation, metastasis and therapeutic resistance. Here, we perform a metabolic gene CRISPR/Cas9 knockout library screen in tumorspheres derived from HCC cells and find that deletion of SCARB2 suppresses the cancer stem cell-like properties of HCC cells. Knockout of Scarb2 in hepatocytes attenuates HCC initiation and progression in both MYC-driven and DEN (diethylnitrosamine)-induced HCC mouse models. Mechanistically, binding of SCARB2 with MYC promotes MYC acetylation by interfering with HDCA3-mediated MYC deacetylation on lysine 148 and subsequently enhances MYC transcriptional activity. Screening of a database of FDA (Food and Drug Administration)-approved drugs shows Polymyxin B displays high binding affinity for SCARB2 protein, disrupts the SCARB2-MYC interaction, decreases MYC activity, and reduces the tumor burden. Our study identifies SCARB2 as a functional driver of HCC and suggests Polymyxin B-based treatment as a targeted therapeutic option for HCC.

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Section: Discussionmentioning

confidence: 99%

SCARB2 drives hepatocellular carcinoma tumor initiating cells via enhanced MYC transcriptional activity

Wang,

Gao,

Xue

et al. 2023

Nat Commun

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“…However, the drugs also produced marked nephrotoxicity, illustrating the second point that the change of bacterial communities results in the formation of toxic compounds, causing harm to the host. The mode of action of polymixins is thought to be by interaction with phospholipids, causing membrane disruption including macrophages, and stimulating the production of IL-1β ( 50 ). An alternative theory suggests that polymixins induce oxidative stress caused by the formation of reactive oxygen species ( 51 ), which resonates with altered oxidative resistance in RPE.…”

Section: Discussionmentioning

confidence: 99%

Chinese medicine, Qijudihuang pill, mediates cholesterol metabolism and regulates gut microbiota in high-fat diet-fed mice, implications for age-related macular degeneration

Cao,

Ibrahim,

et al. 2023

Front. Immunol.

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BackgroundTraditional Chinese Medicines have been used for thousands of years but without any sound empirical basis. One such preparation is the Qijudihuang pill (QP), a mixture of eight herbs, that has been used in China for the treatment of various conditions including age-related macular degeneration (AMD), the most common cause of blindness in the aged population. In order to explain the mechanism behind the effect of QP, we used an AMD model of high-fat diet (HFD) fed mice to investigate cholesterol homeostasis, oxidative stress, inflammation and gut microbiota.MethodsMice were randomly divided into three groups, one group was fed with control diet (CD), the other two groups were fed with high-fat-diet (HFD). One HFD group was treated with QP, both CD and the other HFD groups were treated with vehicles. Tissue samples were collected after the treatment. Cholesterol levels in retina, retinal pigment epithelium (RPE), liver and serum were determined using a commercial kit. The expression of enzymes involved in cholesterol metabolism, inflammation and oxidative stress was measured with qRT-PCR. Gut microbiota was analyzed using 16S rRNA sequencing.ResultsIn the majority of the lipid determinations, analytes were elevated by HFD but this was reversed by QP. Cholesterol metabolism including the enzymes of bile acid (BA) formation was suppressed by HFD but again this was reversed by QP. BAs play a major role in signaling between host and microbiome and this is disrupted by HFD resulting in major changes in the composition of colonic bacterial communities. Associated with these changes are predictions of the metabolic pathway complexity and abundance of individual pathways. These concerned substrate breakdowns, energy production and the biosynthesis of pro-inflammatory factors but were changed back to control characteristics by QP.ConclusionWe propose that the ability of QP to reverse these HFD-induced effects is related to mechanisms acting to lower cholesterol level, oxidative stress and inflammation, and to modulate gut microbiota.

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“…HT1080 cells were from JCRB Cell Bank (Japanese Collection of Research Bioresources Cell Bank) [ 49 ]. PC12 and SH-SY5Y cells were provided by RIKEN BRC (Tsukuba, Japan) [ 50 , 51 ].…”

Section: Methodsmentioning

confidence: 99%

Aggregability of the SQSTM1/p62-based aggresome-like induced structures determines the sensitivity to parthanatos

Hamano,

Noguchi,

Asai

et al. 2024

Cell Death Discov.

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Overactivation of poly (ADP-ribose) polymerase-1 (PARP-1) triggers a noncanonical form of programmed cell death (PCD) called parthanatos, yet the mechanisms of its induction are not fully understood. We have recently demonstrated that the aggresome-like induced structures (ALIS) composed of the autophagy receptor SQSTM1/p62 and K48-linked polyubiquitinated proteins (p62-based ALIS) mediate parthanatos. In this study, we identified the D1 dopamine receptor agonist YM435 as a unique parthanatos inhibitor that acts as the disaggregating agent for the p62-based ALIS. We found that YM435 structurally reduces aggregability of the ALIS, and then increases its hydrophilicity and liquidity, which prevents parthanatos. Moreover, dopamine and L-DOPA, a dopamine precursor, also prevented parthanatos by reducing the aggregability of the ALIS. Together, these observations suggest that aggregability of the p62-based ALIS determines the sensitivity to parthanatos, and the pharmacological properties of YM435 that reduces the aggregability may be suitable for therapeutic drugs for parthanatos-related diseases such as neurodegenerative diseases.

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The polypeptide antibiotic polymyxin B acts as a pro-inflammatory irritant by preferentially targeting macrophages

Cited by 14 publications

References 48 publications

SCARB2 drives hepatocellular carcinoma tumor initiating cells via enhanced MYC transcriptional activity

SCARB2 drives hepatocellular carcinoma tumor initiating cells via enhanced MYC transcriptional activity

Chinese medicine, Qijudihuang pill, mediates cholesterol metabolism and regulates gut microbiota in high-fat diet-fed mice, implications for age-related macular degeneration

Aggregability of the SQSTM1/p62-based aggresome-like induced structures determines the sensitivity to parthanatos

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