β-Sitosterol Alters the Inflammatory Response in CLP Rat Model of Sepsis by Modulation of NFκB Signaling

Kasirzadeh, Sara; Ghahremani, Mohammad Hossein; Setayesh, Neda; Jeivad, Fereshteh; Shadboorestan, Amir; Taheri, Ramezan Ali; Beh-Pajooh, Abbas; Shalmani, Armin Azadkhah; Ebadollahi-Natanzi, Alireza; Khan, Alamgir; Sabzevari, Samin; Sabzevari, Omid

doi:10.1155/2021/5535562

Cited by 28 publications

(22 citation statements)

References 43 publications

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“…Besides CS, DG, and HH, beta-sitosterol was also found to exist in Hechtia glomerata Zucc., which was used as a source in ethnomedicine to treat various diseases derived from bacterial infections, such as sepsis, bronchitis, and laryngitis ( Stefani et al, 2019 ). Beta-sitosterol was predicted to mediate NF-κB signaling pathway ( Kasirzadeh et al, 2021 ) and was found to significantly reduce the pro-inflammatory cytokines in the sera of cecal ligation and puncture-induced septic rats, such as TNF-α and NF-κB mRNA expressions. In addition, stigmasterol was proved to decrease the levels of cyclooxygenase-2 (Cox-2) and NF-κB (p65) in the brain of rats, thereby attenuating inflammation and improving antioxidant defenses ( Liang et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

“…The level of TNF-α was reported to be increased significantly in LPS-stimulated BMDMs ( Liu et al, 2020 ). Comparatively, TNF-α could be reduced by baicalin (MOL002776) in the blood of sepsis mice ( Chen et al, 2016 ) and was reduced by beta-sitosterol [MOL000358 (CS, DG, and HH)] ( Kasirzadeh et al, 2021 ), caffeic acid [MOL000223 (CX, DS, and HH)] ( Chen et al, 2019 ). A Chinese formula, RDN, had been proved to ameliorate LPS-induced acute lung injury by downregulating TNF-α ( Yang et al, 2021 ).…”

Section: Resultsmentioning

confidence: 99%

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Detecting Critical Functional Ingredients Group and Mechanism of Xuebijing Injection in Treating Sepsis

Yin

et al. 2021

Front. Pharmacol.

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Sepsis is a systemic inflammatory reaction caused by various infectious or noninfectious factors, which can lead to shock, multiple organ dysfunction syndrome, and death. It is one of the common complications and a main cause of death in critically ill patients. At present, the treatments of sepsis are mainly focused on the controlling of inflammatory response and reduction of various organ function damage, including anti-infection, hormones, mechanical ventilation, nutritional support, and traditional Chinese medicine (TCM). Among them, Xuebijing injection (XBJI) is an important derivative of TCM, which is widely used in clinical research. However, the molecular mechanism of XBJI on sepsis is still not clear. The mechanism of treatment of “bacteria, poison and inflammation” and the effects of multi-ingredient, multi-target, and multi-pathway have still not been clarified. For solving this issue, we designed a new systems pharmacology strategy which combines target genes of XBJI and the pathogenetic genes of sepsis to construct functional response space (FRS). The key response proteins in the FRS were determined by using a novel node importance calculation method and were condensed by a dynamic programming strategy to conduct the critical functional ingredients group (CFIG). The results showed that enriched pathways of key response proteins selected from FRS could cover 95.83% of the enriched pathways of reference targets, which were defined as the intersections of ingredient targets and pathogenetic genes. The targets of the optimized CFIG with 60 ingredients could be enriched into 182 pathways which covered 81.58% of 152 pathways of 1,606 pathogenetic genes. The prediction of CFIG targets showed that the CFIG of XBJI could affect sepsis synergistically through genes such as TAK1, TNF-α, IL-1β, and MEK1 in the pathways of MAPK, NF-κB, PI3K-AKT, Toll-like receptor, and tumor necrosis factor signaling. Finally, the effects of apigenin, baicalein, and luteolin were evaluated by in vitro experiments and were proved to be effective in reducing the production of intracellular reactive oxygen species in lipopolysaccharide-stimulated RAW264.7 cells, significantly. These results indicate that the novel integrative model can promote reliability and accuracy on depicting the CFIGs in XBJI and figure out a methodological coordinate for simplicity, mechanism analysis, and secondary development of formulas in TCM.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Detecting Critical Functional Ingredients Group and Mechanism of Xuebijing Injection in Treating Sepsis

Yin

et al. 2021

Front. Pharmacol.

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“…Later, Lee et al found that Candida albicans -infected mice treated with plant-derived β-sitosterol glucosides (daucosterol) survived longer than untreated mice and had greater numbers of activated splenic lymphocytes compared to untreated mice 38 . β-sitosterol glucosides may also play a protective role in the septic process by mitigating inflammation in a rat model of sepsis 39 . Lastly, the effect of β-sitosterol glucosides on the immune response was also observed in a human study 40 .…”

Section: Introductionmentioning

confidence: 99%

Vaccine protection by Cryptococcus neoformans Δsgl1 is mediated by γδ T cells via TLR2 signaling

et al. 2022

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We previously reported that administration of Cryptococcus neoformans Δsgl1 mutant vaccine, accumulating sterylglucosides (SGs) and having normal capsule (GXM), protects mice from a subsequent infection even during CD4+ T cells deficiency, a condition commonly associated with cryptococcosis. Here, we studied the immune mechanism that confers host protection during CD4+T deficiency. Mice receiving Δsgl1 vaccine produce IFNγ and IL-17A during CD4+ T (or CD8+ T) deficiency, and protection was lost when either cytokine was neutralized. IFNγ and/or IL-17A are produced by γδ T cells, and mice lacking these cells are no longer protected. Interestingly, ex vivo γδ T cells are highly stimulated in producing IFNγ and/or IL-17A by Δsgl1 vaccine, but this production was significantly decreased when cells were incubated with C. neoformans Δcap59/Δsgl1 mutant, accumulating SGs but lacking GXM. GXM modulates toll-like receptors (TLRs), including TLR2. Importantly, neither Δsgl1 nor Δcap59/Δsgl1 stimulate IFNγ or IL-17A production by ex vivo γδ T cells from TLR2−/− mice. Finally, TLR2−/− animals do not produce IL-17A in response to Δsgl1 vaccine and were no longer protected from WT challenge. Our results suggest that SGs may act as adjuvants for GXM to stimulate γδ T cells in producing IFNγ and IL-17A via TLR2, a mechanism that is still preserved upon CD4+ T deficiency.

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“…2,4,6-Trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice could be suppressed by SITO through downregulating the expression of NF-κB-modulated proinflammatory cytokines, including TNF-α, IL-1β, and IL-6 [11]. It could also alleviate the sepsis process by inhibiting the NF-κB signaling pathway in a cecal ligation and puncture (CLP)-induced septic rat model [12]. SITO has also been shown to mitigate the proinflammatory responses caused by influenza A by inhibiting both RIG-1 and STAT1 pathways other than the NF-κB signaling pathway [13].…”

Section: Introductionmentioning

confidence: 99%

Liposomal β-Sitosterol Suppresses Metastasis of CT26/luc Colon Carcinoma via Inhibition of MMP-9 and Evoke of Immune System

et al. 2022

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β-sitosterol (SITO) has been reported with anticancer effects; however, with poor bioavailability. The current study aimed to investigate whether liposomal encapsulated β-sitosterol (LS) has a better inhibition effect on tumor metastasis than β-sitosterol in a CT26/luc lung metastasis mouse model and the possible underlying mechanism. LS was liposomal-encapsulated SITO and was delivered to mice by oral gavage. The cell viability was determined by the MTT assay, and invasiveness of the tumor cells and related protein expression were evaluated with the invasion assay and Western blotting. For therapeutic efficacy evaluation, male BALB/c mice were treated with PBS, SITO, and LS once a day for 7 days prior to intravenous injections of CT26/luc cells; treatments were continued twice a week post-cell inoculation throughout the entire experiment. Tumor growth inhibition was monitored by bioluminescent imaging (BLI). IL-12, IL-18, and IFN-γ in the intestinal epithelium were determined by ELISA. The results show that LS treatment had a better invasion inhibition with lower cytotoxicity than SITO when the same dose was utilized. Notably, mice treated with LS significantly exhibited fewer metastases to the lungs and other tissues/organs compared with the Control and SITO groups. Additionally, the IL-12, IL-18, and IFN-γ levels were significantly increased in the LS-treated mice compared with the Control and SITO groups. The underlying mechanism may be through the inhibition of MMP-9 and elicitation of the antitumoral Th1 immune response, such as increasing CD4+ and CD8+ T cells, IL-12, IL-18, and IFN-γ.

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β-Sitosterol Alters the Inflammatory Response in CLP Rat Model of Sepsis by Modulation of NFκB Signaling

Cited by 28 publications

References 43 publications

Detecting Critical Functional Ingredients Group and Mechanism of Xuebijing Injection in Treating Sepsis

Detecting Critical Functional Ingredients Group and Mechanism of Xuebijing Injection in Treating Sepsis

Vaccine protection by Cryptococcus neoformans Δsgl1 is mediated by γδ T cells via TLR2 signaling

Liposomal β-Sitosterol Suppresses Metastasis of CT26/luc Colon Carcinoma via Inhibition of MMP-9 and Evoke of Immune System

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