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Background: Acute lung injury is a frequent complication after cardiopulmonary bypass (CPB). Recent studies have reported that NF-κB plays an important role in the pathogenesis of post-CPB pulmonary dysfunction. Several signaling pathways, including the TLR4 pathway, induce NF-κB leading to an inflammatory response. We designed this study to determine whether or not curcumin inhibits TLR4 and MyD88 protein levels and ameliorates lung inflammatory injury in a rat CPB model. Materials and methods: Sprague-Dawley rats were randomly divided into the following five groups (n = 12): sham; control (CPB); vehicle; low-dose curcumin (L-Cur); and high-dose curcumin (H-Cur). The percutaneous beating heart CPB model of rat was established. Animals were pretreated with a single intraperitoneal injection of vehicle, L-Cur (50 mg/kg), or H-Cur (200 mg/kg) 2 h prior to CPB. Blood were sampled at various time points, then lung tissues and bronchoalveolar lavage fluid were harvested 24 h after CPB. Results: CPB induced a marked increase in the concentrations of interleukin-8, tumor necrosis factor-α, and matrix metalloproteinase-9 in plasma, bronchoalveolar lavage fluid, and lung tissues (P < 0.05 versus sham group), whereas curcumin pretreatment reduced these inflammatory markers. Curcumin had effective inhibitory effects on the expression of TLR4, MyD88, and NF-κB in lung tissues 24 h post-CPB (P < 0.05 versus vehicle group). Administration of curcumin remarkably decreased the lung injury score (L-Cur versus vehicle group, P = 0.024; H-Cur versus vehicle group, P = 0.013). Conclusions: Curcumin may be an alternative therapy for protecting CPB-induced lung injury by suppressing the expression of inflammatory cytokines. This anti-inflammatory effect of curcumin is partly related to the inhibition of TLR4, MyD88, and NF-κB. [ABSTRACT FROM AUTHOR]

Highlights: [•] miR-93 is downregulated in the eyes of LPS-induced EIU rats. [•] miR-93 is downregulated in LPS-treated RAW 264.7 cells. [•] miR-93 inhibits LPS-induced inflammatory cytokine production. [•] miR-93 inhibits LPS-induced activation of NF-κB signaling through IRAK4. [Copyright &y& Elsevier]

Cucurbitacin IIb (CuIIb) is one of the major active compounds in Hemsleyadine tablets which have been used for clinical treatment of bacillary dysentery, enteritis and acute tonsilitis. However, its action mechanism has not been completely understood. This study aimed to explore the anti-inflammatory activity of CuIIb and its underlying mechanism in mitogen-activated lymphocytes isolated from mouse mesenteric lymph nodes. The results showed that CuIIb inhibited the proliferation of concanavalin A (Con A)-activated lymphocytes in a time- and dose-dependent manner. CuIIb treatment arrested their cell cycle in S and G2/M phases probably due to the disruption of the actin cytoskeleton and the modulation of p27Kip1 and cyclin levels. Moreover, the surface expression of activation markers CD69 and CD25 on Con A-activated CD3+ T lymphocytes was suppressed by CuIIb treatment. Both Con A- and phorbol ester plus ionomycin-induced expression of TNF-α, IFN-γ and IL-6 proteins was attenuated upon exposure to CuIIb. Mechanistically, CuIIb treatment suppressed the phosphorylation of JNK and Erk1/2 but not p38 in Con A-activated lymphocytes. Although CuIIb unexpectedly enhanced the phosphorylation of IκB and NF-κB (p65), it blocked the nuclear translocation of NF-κB (p65). In support of this, CuIIb significantly decreased the mRNA levels of IκBα and TNF-α, two target genes of NF-κB, in Con A-activated lymphocytes. In addition, CuIIb downregulated Con A-induced STAT3 phosphorylation and increased cell apoptosis. Collectively, these results suggest that CuIIb exhibits its anti-inflammatory activity through modulating multiple cellular behaviors and signaling pathways, leading to the suppression of the adaptive immune response. [ABSTRACT FROM AUTHOR]

Objective Proinflammatory cytokine TNF-α during MI/R injury has been studied extensively. However, how TNF-α induces microvascular dysfunction in MI/R is still unclear. This study investigates whether TNF-α regulates fibrinogen-like protein 2 (fgl2) expression, a procoagulant resulting in the formation of fibrin-rich microthrombus in MI/R injury. Methods and Results Microthrombosis, TNF-α and fgl2 expression were assessed in rats with MI/R injury. The effect of TNF-α on fgl2 expression and fgl2 prothrombinase activity was investigated in CMECs, then CMECs were pretreated with selective inhibitors of NF-κB and p38 MAPK pathways. TNF-α and fgl2 expression were both upregulated in MI/R group. When neutralization of TNF-α, fgl2 expression was decreased in vivo. Fgl2 expression was upregulated in CMECs exposed to TNF-α. Accordingly, the ability of thrombin generation was increased in CMECs. Besides, TNF-α-induced fgl2 expression in the cells was suppressed by NF-κB inhibitor PDTC and/or p38 MAPK inhibitor SB203580. Conclusion TNF-α upregulates fgl2 expression via activation of NF- kB and p38 MAPK in CMECs. TNF-α-induced flg2 in CMECs mediates the formation of fibrin-rich microthrombus, which may be one of the mechanisms of microvascular dysfunction or obstruction due to MI/R injury. [ABSTRACT FROM AUTHOR]