Comparing the protective effects of resveratrol, curcumin and sulforaphane against LPS/IFN-γ-mediated inflammation in doxorubicin-treated macrophages

Abstract

Doxorubicin (DOX) chemotherapy is associated with the release of inflammatory cytokines from macrophages. This has been suggested to be, in part, due to DOX-mediated leakage of endotoxins from gut microflora, which activate Toll-like receptor 4 (TLR4) signaling in macrophages, causing severe inflammation. However, the direct function of DOX on macrophages is still unknown. In the present study, we tested the hypothesis that DOX alone is incapable of stimulating inflammatory response in macrophages. Then, we compared the anti-inflammatory effects of curcumin (CUR), resveratrol (RES) and sulforaphane (SFN) against lipopolysaccharide/interferon-gamma (LPS/IFN-γ)-mediated inflammation in the absence or presence of DOX. For this purpose, RAW 264.7 cells were stimulated with LPS/IFN-γ (10 ng/mL/10 U/mL) in the absence or presence of DOX (0.1 µM). Our results showed that DOX alone is incapable of stimulating an inflammatory response in RAW 264.7 macrophages. Furthermore, after 24 h of incubation with LPS/IFN-γ, a significant increase in tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and inducible nitric oxide synthase (iNOS) mRNA levels was observed. Similarly, nitric oxide (NO) production and TNF-α and IL-6 protein levels were significantly upregulated. Moreover, in LPS/IFN-γ-treated macrophages, the microRNAs (miRNAs) miR-146a, miR-155, and miR-21 were significantly overexpressed. Interestingly, upon testing CUR, RES, and SFN against LPS/IFN-γ-mediated inflammation, only SFN was able to significantly reverse the LPS/IFN-γ-mediated induction of iNOS, TNF-α and IL-6 and attenuate miR-146a and miR-155 levels. In conclusion, SFN, at the transcriptional and posttranscriptional levels, exhibits potent immunomodulatory action against LPS/IFN-γ-stimulated macrophages, which may indicate SFN as a potential treatment for DOX-associated inflammation.

Cow's milk αS1-casein is more sensitizing than goat's milk αS1-casein in a mouse model

“…49 Previous studies have shown that the disruption of the intestinal barrier causes the leakage of endotoxin into the circulation, where it binds to the TLR4 receptor and activates the NF-κB pathway, which in turn induces the production of inflammatory cytokines and induces systemic inflammation. 50 Occludin was the first identified tight junction specific integral membrane protein. 51 The extracellular portion and transmembrane domain of Occludin regulate paracellular permeability, and the intracellular portion is linked to the actin cytoskeleton by ZO-1.…”

Carnosine Alleviates Knee Osteoarthritis and Promotes Synoviocyte Protection via Activating the Nrf2/HO-1 Signaling Pathway: An In-Vivo and In-Vitro Study

“…CA regulates the above effects by inhibiting pro-inflammatory cytokine production and reducing inflammation [ 42 ]. CA and histidine supplementation via drinking water and diet protected diabetic Balb/cA mice by significantly suppressing pro-inflammatory cytokines, such as IL-6 and TNF-α, and inhibiting diabetes-induced neuropathy [ 43 ]. CA has recently been shown to suppress and slow aging in cultured human fibroblasts [ 44 ].…”

Chemotherapy activates inflammasomes to cause inflammation-associated bone loss

“…The effects of doxorubicin on macrophages have been reported (Chen et al, 2023, Saleh et al, 2021). To test the hypothesis that these cells were implicated in the inflammatory phenotype of mice treated with doxorubicin, we treated bone marrow-derived macrophages (BMMs) with this drug for 16 hours.…”