NLRP3炎症小体激活及调节机制的研究进展

炎症小体是一种由Nod样受体(NLR)家族成员与PYHIN (pyrin and HIN domain)家族成员组成的胞浆多蛋白复合物,能被多种病原相关分子模式或损伤相关分子模式激活。炎症小体的功能是激活半胱天冬酶1(Caspase-1),进而引起促炎细胞因子白细胞介素(IL)-1β和IL-18的成熟和分泌,并诱导细胞焦亡。NLR家族蛋白3(NLRP3)炎症小体是由NLRP3、接头蛋白ASC和效应蛋白Caspase-1组成的大分子多蛋白复合体。与其他炎症小体不同,NLRP3炎症小体可以被多种刺激物活化,包括微生物组分和内源性分子。NLRP3炎症小体在免疫系统和人类疾病中的重要性显而易见,但其激活及调节的机制仍不清楚。在此,主要对NLRP3炎症小体活化和调节的机制进行综述。

     

NLRP3炎症小体在动脉粥样硬化相关细胞中作用的研究进展

炎症小体是一种调控IL-1β产生的大分子多蛋白复合体,在动脉粥样硬化(atherosclerosis,As)病变发生发展中发挥重要作用。NLRP3炎症小体是目前研究最为深入和广泛的炎症小体类型。该文主要通过总结AS相关细胞(内皮细胞、巨噬细胞、血管平滑肌细胞)与NLRP3炎症小体之间的关系来探讨NLRP3炎症小体在AS病变发生发展中的作用。     

EGCG通过调控胱天蛋白酶介导的NLRP3炎症小体激活抑制LPS+Aβ诱导BV2细胞的炎症反应

目的从离体水平研究胱天蛋白酶11介导的NLRP3炎症小体激活在表没食子儿茶素没食子酸酯(EGCG)对LPS+Aβ诱导的BV2细胞炎症反应的抑制作用及其可能机制。方法应用LPS+Aβ诱导的BV2细胞建立MG活化模型,建立空白对照组,LPS+Aβ组,LPS+Aβ+EGCG组。实时PCR、Western印迹和ELISA检测EGCG对BV2细胞Iba-1表达及相关炎性因子IL-1β,IL-18的转录、表达和分泌水平。与SH-SY5Y进行条件培养,流式细胞术和CCK8检测SH-SY5Y细胞的存活率。Western印迹、免疫荧光等检测EGCG对BV2细胞胱天蛋白酶1与Iba-1的共定位、胱天蛋白酶1活性、胱天蛋白酶1 P20和胱天蛋白酶11 P26的蛋白表达水平。应用胱天蛋白酶11抑制剂wedelolactone处理LPS+Aβ诱导的BV2细胞。结果 (1) EGCG在降低LPS+Aβ诱导的BV2细胞Iba-1表达,抑制炎性因子IL-1β,IL-18的转录、表达和分泌水平,提示EGCG可抑制MG活化及其介导的炎症反应。(2) EGCG显著增加与LPS+Aβ诱导的BV2条件培养的SH-SY5Y细胞的存活率,提示EGCG可通过抑制MG内炎症反应改善神经元存活,发挥神经保护作用。(3) EGCG可显著降低LPS+Aβ诱导的胱天蛋白酶1与Iba-1共定位,胱天蛋白酶1活性及胱天蛋白酶1 P20、胱天蛋白酶11 P26蛋白的表达水平,提示EGCG抑制MG活化与其抑制胱天蛋白酶11表达和NLRP3炎症小体介导的炎症反应有关。(4)与EGCG处理一致,wedelolactone可降低LPS+Aβ诱导的胱天蛋白酶11 P26及胱天蛋白酶1 P20,IL-1β,IL-18和Iba-1的蛋白表达水平,提示胱天蛋白酶11可促进LPS+Aβ诱导的NLRP3炎症小体激活,而EGCG可抑制胱天蛋白酶11介导的NLRP3炎症小体激活。结论 EGCG通过抑制胱天蛋白酶11介导的NLRP3炎症小体激活抑制LPS+Aβ诱导BV2细胞的炎症反应,发挥神经保护作用。     

小檗碱调控NLRP3炎症小体对TGF-β1诱导HK-2细胞转分化的影响

摘要：目的:探讨小檗碱（BBR）调控NLRP3炎症小体对转化生长因子-β1（TGF-β1）诱导人肾小管上皮细胞（HK-2）转分化的影响。方法:计算机分子对接预测BBR与NLRP3炎症小体的结合情况;采用CCK8法检测不同浓度的BBR对HK-2细胞增殖的影响;将HK-2细胞分为正常组、模型组和小檗碱低、中、高剂量组(10,25,50μmol·L-1),小檗碱预孵18 h后加入TGF-β1刺激48 h,镜下观察各组细胞形态;采用Western blotting法检测E-钙粘蛋白（E-cadherin）、α-平滑肌肌动蛋白（α-SMA）、NOD样受体蛋白3（NLRP3）及半胱氨酸天冬氨酸蛋白酶-1（caspase-1）的表达; caspase-1活性检测试剂盒检测caspase-1的酶活力;采用酶联免疫吸附测定法（ELISA）检测细胞上清液中白细胞介素-1β（IL-1β）的含量。结果:分子对接显示BBR与NLRP3、pro-caspase-1存在结合,可靠性较高。与正常组比较,BBR对HK-2细胞的增殖呈浓度和时间依赖性抑制（P<0.05）。与模型组比较,BBR(10,25,50μmol·L-1)可改善HK-2细胞形态,使其趋向椭圆形;上调E-cadherin蛋白和下调α-SMA、NLRP3及caspase-1蛋白的表达（P<0.05）;并可降低caspase-1的酶活力、减少IL-1β的分泌（P<0.05）。结论:BBR能改善TGF-β1诱导HK-2细胞的转分化,可能与抑制NLRP3炎症小体活化有关。     

星形胶质细胞Drd2受体通过β-arrestin2抑制NLRP3炎症小体活化

帕金森病(PD)的主要病理特征为黑质致密部多巴胺(DA)能神经元进行性丢失,并伴有α-突触核蛋白(α-syn)沉积和神经炎症。前期研究发现,星形胶质细胞多巴胺D_2受体(D_2R)具有抑制神经炎症作用,近年来又发现D_2R可以通过激活接头蛋白β-arrestin2(arrb2)相关而非cAMP依赖的非经典通路调控细胞功能。因此,揭示D_2R对α-syn诱导的神经炎症的影响及其arrb2在星形胶质细胞D_2R抗炎效应中的作用具有重要的科学意义。应用Drd2敲除(Drd2~(-/-))、arrb2敲除(arrb2b2~(-/-))和突变型α-syn转基因(A53Ttg/tg)小鼠的研究发现,不同D_2R激动剂(quinpirole,quinelorane,bromocriptine)均可浓度依赖性地抑制LPS+ATP,LPS+MSU和LPS+Nigericin等方式诱导的星形胶质细胞NLRP3炎症小体的激活,但对α-syn诱导的炎症则无效。进一步研究发现,D_2R激动剂促进arrb2与NLRP3分子直接结合,减少ASC与NLRP3的结合,进而抑制NLRP3炎症小体激活;arrb2敲除则取消了D_2R激动剂抑制NLRP3炎症小体活化和保护DA神经元的作用。研究表明,α-Syn通过干扰星形胶质细胞arrb2与炎性分子的相互作用,从而取消了D_2R激动剂的抑炎效应。上述结果从全新的角度阐明了α-syn干扰β-arrestin 2分子的抑炎功能、阻断D_2R激动剂的作用通路,为诠释晚期PD患者应用D_2R激动剂无效提供了直接的理论依据。此外,本研究揭示了选择性激活arrb2偏爱的信号转导在PD抗炎治疗和神经保护中的重要意义,为PD临床治疗学的突破提供了新的思路。     

NLRP3炎症小体在器官纤维化中的作用及研究进展

<正>纤维化(fibrosis)可发生于多种器官,主要由外界因素或内源性免疫因素刺激下引起的,表现为器官组织内纤维结缔组织增多,实质细胞减少,可破坏器官的结构和功能。感染、自身免疫反应、毒素、辐射和机械损伤等损伤组织后,组织会进行自我修复。如果修复异常,正常组织发生不可逆的纤维化改变,影响器官的结构和功能,使患者致残甚至死亡。     

线粒体自噬与NLRP3炎症小体调控通路及中医药干预的关系研究进展

线粒体能通过自噬选择性地去除损伤的线粒体,以控制线粒体的质量并确保线粒体的功能,从而实现微调线粒体的数量来维持能量代谢。NLRP3炎性小体是机体固有免疫重要成分,可由多种类型病原体或危险信号启动激活,对许多疾病的发生与发展起着至关重要的作用。而线粒体自噬在NLRP3炎症小体激活过程中,通过作用于诸多环节发挥负调节作用。近年来,中医药在线粒体代谢与调控通路方面的研究发展迅速,线粒体自噬和NLRP3炎症小体调控通路被认为是潜在的强有力的中医药干预疾病靶点。本文通过对线粒体自噬的主要通路与NLRP3炎症小体的调控通路及中医药对线粒体自噬和NLRP3炎症小体的影响在疾病中的作用进行综述,以期为中医药通过线粒体自噬和NLRP3炎症小体途径防治疾病尤其是代谢性与心脑血管疾病的研究提供借鉴和新的思路。     

萝卜硫素抑制幽门螺杆菌诱导胃黏膜上皮细胞NLRP3炎症小体活化的研究

目的 研究萝卜硫素（sulforaphane,SFP）对幽门螺杆菌感染的胃黏膜上皮GES-1细胞线粒体和氧化应激损伤及NLRP3炎症小体活化的影响。方法 SFP （100 ng·mL^-1）预处理GES-1细胞12 h,然后10⁹CFU·mL^-1的幽门螺杆菌感染细胞6 h;CCK8检测细胞活力,qRT-PCR分析PGC1α、COX-4、NRF1、TFAM、SOD1和HO-1 mRNA表达水平,Western blotting检测NLRP3、CASP1 p20、CASP1 p10、pro-IL-1β和IL-1β蛋白表达水平,并对GES-1细胞线粒体膜电位、氧耗量和ROS水平进行检测。结果 幽门螺杆菌感染可明显诱导NLRP3、CASP1 p20、CASP1 p10、IL-1β蛋白和PGC1α、COX-4、NRF1 mRNA表达,促使氧消耗量和ROS水平增高,而细胞活力、SOD1、HO-1、TFAM mRNA表达和线粒体膜电位降低（P<0.05）;SFP处理后能明显抑制NLRP3、IL-1β蛋白和PGC1α、COX-4、NRF1 mRNA表达,降低氧消耗量和ROS水平,而细胞活力、SOD1、HO-1、TFAM mRNA表达和线粒体膜电位增高（P<0.05）;另外,ROS抑制剂NAC也能显著抑制NLRP3炎症小体和IL-1β表达水平。结论 SFP可通过降低线粒体损伤和ROS水平改善幽门螺杆菌感染诱导GES-1细胞炎症反应。     

雷公藤红素调控NLRP3炎症小体改善大鼠代谢相关脂肪性肝病研究

目的 评价雷公藤红素对高脂饮食诱导的代谢相关脂肪性肝病（MAFLD）大鼠的保护作用,并探讨其可能的作用机制。方法 60只健康雄性Wistar大鼠,随机分为6组：对照组、模型组、水飞蓟素胶囊组（阳性对照,100 mg·kg⁻¹）和雷公藤红素低、中、高剂量（125、250、500 μg·kg⁻¹）组,每组10只。对照组给予普通饲料喂养,其余5组给予高脂饲料喂养建立MAFLD模型,造模4周后,从第5周开始给药,ig给予相应剂量的药物至第8周。记录大鼠体质量和肝脏湿质量,计算肝脏系数;腹主动脉取血,检测大鼠血清中丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、三酰甘油（TG）、总胆固醇（TC）、低密度脂蛋白-胆固醇（LDL-C）、高密度脂蛋白-胆固醇（HDL-C）、肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）水平;HE染色观察肝脏病理变化;Western blotting法检测肝脏中NOD样受体热蛋白结构域相关蛋白3（NLRP3）和半胱氨酸蛋白酶-1（Caspase-1）蛋白表达水平。结果 与模型组比较,雷公藤红素各剂量组的肝脏病理学表现均有所改善,肝脏系数均显著降低（P＜0.05、0.01）;中、高剂量组大鼠血清中TC、TG、LDL-C、AST、ALT、TNF_-α和IL-1β水平均显著降低（P＜0.05、0.01）;肝脏中NLRP3和Caspase-1的蛋白表达显著减少（P＜0.05、0.01）。结论 雷公藤红素可明显减轻MAFLD大鼠的肝脏病理学损伤,改善血脂水平,其机制可能与调控NLRP3通路密切相关。     

肠道疾病中胆汁酸及其受体对NLRP3炎症小体调控作用的研究进展

胆汁酸作为一种重要的内源性信号分子,参与机体代谢、免疫和炎症等多种生理病理过程,对维持肠道的正常生理功能具有重要作用。核苷酸结合寡聚结构域样受体蛋白3（NLRP3）炎症小体是一种模式识别受体,可通过识别病原体相关分子模式或危险相关分子模式,感知外源性微生物或来自损伤、死亡细胞的内源性危险信号,从而调节肠道免疫进程。研究表明,胆汁酸与NLRP3炎症小体之间存在多种调控模式,共同参与肠道稳态维持和疾病调节。基于国内外现有相关研究综述了肠道疾病中胆汁酸及其受体对NLRP3炎症小体调控作用的研究进展。     

Acetylase inhibitor SI-2 is a potent anti-inflammatory agent by inhibiting NLRP3 inflammasome activation

Aberrant activation of Nod-like receptor family pyrin domain-containing-3 (NLRP3) inflammasome is implicated in a variety of inflammatory diseases. Targeting NLRP3 inflammasome represents a promising therapy to cure such diseases. We and others recently demonstrated that acetylation of NLRP3 promotes the inflammasome activity and also suggested lysine acetyltransferases inhibitors could be a kind of promising agents for treating NLRP3 associated disorders. In this study, by searching for kinds of lysine acetyltransferases inhibitors, we showed that SI-2 hydrochloride (SI-2), a specific inhibitor of lysine acetyltransferase KAT13B (lysine acetyltransferases 13B), specifically blocks NLRP3 inflammasome activation both in mice in vivo and in human cells ex vivo. Intriguingly, SI-2 does not affect the acetylation of NLRP3. Instead, it disrupts the interaction between NLRP3 and adaptor apoptosis-associated speck-like protein containing CARD (ASC), then blocks the formation of ASC speck. Thus, our study identified a specific inhibitor for NLRP3 inflammasome and suggested SI-2 as a potential inhibitory agent for the therapy of NLRP3-driven diseases.     

Dexamethasone alleviate allergic airway inflammation in mice by inhibiting the activation of NLRP3 inflammasome

Dexamethasone (DEX) is the mainstay treatment for asthma, which is a common chronic airway inflammation disease. However, the mechanism of DEX resolute symptoms of asthma is not completely clear. Here, we aimed to analyze the effect of DEX on airway inflammation in OVA-induced mice and whether this effect is related to the inhibition of the activation of NLRP3 inflammasome. Female (C57BL/6) mice were used to establish the allergic airway inflammation model by inhalation OVA. The number of inflammatory cells in the bronchi alveolar lavage fluid (BALF) was counted by Swiss-Giemsa staining, and the contents of IL-1β, IL-18, IL-5 and IL-17 were detected by ELISA. The degree of inflammatory cells infiltration and mucous cells proliferation in lung tissue were separately observed by H&E and PAS staining. The proteins expression of NLRP3, pro-caspase-1, caspase-1, IL-1β, IL-6 and IL-17 in lung tissue were detected by Western blotting. We found that DEX significantly inhibited OVA-induced inflammatory cells infiltration, airway mucus secretion and goblet cell proliferation in mice. The total and classified numbers of inflammatory cells and the levels of IL-1β, IL-18, IL-5 and IL-17 in the BALF of the experimental group were significantly lower than those of the model group after DEX treatment. DEX also significantly inhibited the activity of NLRP3 inflammasome and reduced the protein contents of Pro-Caspase-1, Caspase-1, Capase-1/Pro-Caspase-1, IL-1β, IL-6 and IL-17 in lung tissues. Our study suggested that DEX alleviates allergic airway inflammation by inhibiting the activity of NLRP3 inflammasome and the levels of IL-1β and IL-18.     

Adenovirus-delivered angiopoietin-1 ameliorates phosgene-induced acute lung injury via inhibition of NLRP3 inflammasome activation

Objective: Angiopoietin-1 (Ang1) is reported to have the ability to attenuate endothelial permeability and inflammation during the stress condition and is considered to play a critical role in vascular stabilization. The aim of this study was to investigate the mechanisms involved in the protective effects of adenovirus-delivered Ang1 in phosgene-induced acute lung injury (ALI).

Methods: ALI was induced in rats by phosgene exposure at 8.33?g/m³ for 5?min, followed by an intravenous injection of adenovirus-Ang1 (Ad/Ang1). The histologic changes of the lung were evaluated with H&;E staining. The levels of cytokines in the serum and bronchoalveolar lavage fluid (BALF) were determined by ELISA. NLRP3 inflammasome activation was assessed with immunohistochemistry, RT-PCR, Western blotting and TUNEL staining.

Results: Histologic analyses suggested that reduced severity in phosgene-induced ALI with Ad/Ang1 treatment. Reduced levels of IL-1β, IL-18 and IL-33 were found in both serum and BALF samples from Ad/Ang1-treated ALI rats induced by phosgene. Moreover, immunohistochemistry analysis revealed that Ad/Ang1 treatment inhibited the NLRP3 inflammasome activation. Decreased mRNA and protein levels of NLRP3 and caspase-1 were found in phosgene-exposed rats treated with Ad/Ang1. In addition, TUNEL staining indicated a decrease in pyroptosis in phosgene-exposed rats treated with Ad/Ang1.

Conclusions: Ang1 exerts beneficial effects on phosgene-induced lung injury via inhibition of NLRP3 inflammasome activation. Disruption of NLRP3 inflammasome activation might be served as therapeutic modality for the treatment of phosgene-induced ALI.     

Ghrelin attenuates secondary brain injury following intracerebral hemorrhage by inhibiting NLRP3 inflammasome activation and promoting Nrf2/ARE signaling pathway in mice

Ghrelin, a brain-gut peptide, has been proven to exert neuroprotection in different kinds of neurological diseases; however, its role and the potential molecular mechanisms in secondary brain injury (SBI) after intracerebral hemorrhage (ICH) are still unknown. In this study, we investigate whether treatment with ghrelin may attenuate SBI in a murine ICH model, and if so, whether the neuroprotective effects are due to the inhibition of nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation and promotion of nuclear factor-E2-related factor 2 (Nrf2)/antioxidative response element (ARE) signaling pathway. Stereotactically intrastriatal infusion of autologous blood was performed to mimic ICH. Ghrelin was given intraperitoneally immediately following ICH and again 1 h later. Results showed that ghrelin attenuated neurobehavioral deficits, brain edema, hematoma volume, and perihematomal cell death post-ICH. Ghrelin inhibited the NLRP3 inflammasome activation and subsequently suppressed the neuroinflammatory response as evidenced by reduced microglia activation, neutrophil infiltration, and pro-inflammatory mediators release after ICH. Additionally, ghrelin alleviated ICH-induced oxidative stress according to the chemiluminescence of luminol and lucigenin, malondialdehyde (MDA) content, and total superoxide dismutase (SOD) activity assays. These changes were accompanied by upregulation of Nrf2 expression, Nrf2 nuclear accumulation, and enhanced Nrf2 DNA binding activity, as well as by increased expressions of Nrf2 downstream target antioxidative genes, including NAD(P)H quinine oxidoreductase-1 (NQO1), glutathione cysteine ligase regulatory subunit (GCLC), and glutathione cysteine ligase modulatory subunit (GCLM). Together, our data suggested that ghrelin protected against ICH-induced SBI by inhibiting NLRP3 inflammasome activation and promoting Nrf2/ARE signaling pathway.     

Hydroxysafflor yellow A inhibits hypoxia/reoxygenation-induced cardiomyocyte injury via regulating the AMPK/NLRP3 inflammasome pathway

Hydroxysafflor yellow A (HSYA) is an effective therapeutic agent that alleviates myocardial ischaemia/reperfusion injury (MIRI), but the exact mechanisms remain elusive. The aim of this study was to investigate the potential protective effect of HSYA against MIRI through mechanisms related to NLRP3 inflammasome regulation. In this study, hypoxia/reoxygenation (H/R)-induced H9c2 cardiomyocytes were treated with HSYA or the AMPK inhibitor, compound C (CC). Our results showed that HSYA pretreatment improved cardiomyocyte viability, maintained mitochondrial membrane potential, reduced apoptotic cardiomyocytes, decreased caspase-3 activity, and inhibited NOD-like receptor 3 (NLRP3) inflammasome activation during H/R injury. Moreover, the inhibition of AMPK activation by the CC inhibitor partially abolished the effects of HSYA treatment, including suppressing the upregulation of NLRP3 inflammasome components (NLRP3, caspase-1 and interleukin-1β) and promoting autophagy (LC3-II/LC3-I and p62). In conclusion, the protective mechanism of HSYA in H/R-induced cardiomyocyte injury is associated with inhibiting NLRP3 inflammasome activation through the AMPK signalling pathway.     

GPR84 signaling promotes intestinal mucosal inflammation via enhancing NLRP3 inflammasome activation in macrophages

The putative medium-chain free fatty acid receptor GPR84 is a G protein-coupled receptor primarily expressed in myeloid cells that constitute the innate immune system, including neutrophils, monocytes, and macrophages in the periphery and microglia in the brain. The fact that GPR84 expression in leukocytes is remarkably increased under acute inflammatory stimuli such as lipopolysaccharide (LPS) and TNFα suggests that it may play a role in the development of inflammatory and fibrotic diseases. Here we demonstrate that GPR84 is highly upregulated in inflamed colon tissues of active ulcerative colitis (UC) patients and dextran sulfate sodium (DSS)-induced colitis mice. Infiltrating GPR84⁺ macrophages are significantly increased in the colonic mucosa of both the UC patients and the mice with colitis. Consistently, GPR84^−/− mice are resistant to the development of colitis induced by DSS. GPR84 activation imposes pro-inflammatory properties in colonic macrophages through enhancing NLRP3 inflammasome activation, while the loss of GPR84 prevents the M1 polarization and properties of proinflammatory macrophages. CLH536, a novel GPR84 antagonist discovered by us, suppresses colitis by reducing the polarization and function of pro-inflammatory macrophages. These results define a unique role of GPR84 in innate immune cells and intestinal inflammation, and suggest that GPR84 may serve as a potential drug target for the treatment of UC.     

Astragaloside IV attenuates sepsis-induced intestinal barrier dysfunction via suppressing RhoA/NLRP3 inflammasome signaling

Intestinal barrier dysfunction is a trigger for sepsis progression. NLRP3 inflammasome and RhoA contribute to sepsis and intestinal inflammation. The current study aimed to explore the effects of Astragaloside IV (AS-IV), a bioactive compound from Astragalus membranaceus, on sepsis-caused intestinal barrier dysfunction and whether NLRP3 inflammasome and RhoA are involved. Septic mice modeled by cecal ligation and puncture (CLP) operation were administered with 3 mg/kg AS-IV intravenously. AS-IV decreased mortality, cytokines release, I-FABP secretion, intestinal histological score and barrier permeability, and increased tight junction (TJ) expression in intestine in CLP model. Also, in Caco-2 cells subjected to lipopolysaccharide (LPS), 200 μg/mL AS-IV co-incubation reduced cytokines levels and enhanced in vitro gut barrier function without cytotoxicity. Subsequently, NLRP3 inflammasome and RhoA were highly activated both in intestinal tissue in vivo and in Caco-2 cells in vitro, both of which were significantly suppressed by AS-IV treatment. In addition, the benefits of AS-IV on Caco-2 monolayer barrier were largely counteracted by RhoA agonist CN03 and NLRP3 gene overexpression, respectively. Furthermore, LPS-induced NLRP3 inflammasome activation was abrogated by RhoA inhibitor C3 exoenzyme. However, NLRP3 knockdown by siRNA hardly affected RhoA activation in Caco-2 cells. These data suggest that AS-IV protects intestinal epithelium from sepsis-induced barrier dysfunction via inhibiting RhoA/NLRP3 inflammasome signal pathway.     

Salidroside protects mice against CCl4-induced acute liver injury via down-regulating CYP2E1 expression and inhibiting NLRP3 inflammasome activation

Salidroside (Sal), a natural phenolic compound isolated from Rhodiola sachalinensis, has been utilized as anti-inflammatory and antioxidant for centuries, however, its effects against liver injury and the underlying mechanisms are unclear. This study was designed to evaluate the protective effects and underlying mechanisms of Sal on carbon tetrachloride (CCl4)-induced acute liver injury (ALI) in mice. C57BL/6 mice were pretreated with Sal before CCl4 injection, the serum and liver tissue were collected to evaluate liver damage and molecular indices. The results showed that Sal pretreatment dose-dependently attenuated CCl4-induced acute liver injury, as indicated by lowering the activities of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and inhibiting hepatic pathological damage and apoptosis. In addition, Sal alleviated CCl4-primed oxidative stress and inflammatory response by restoring hepatic glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), and inhibiting cytokines. Finally, Sal also down-regulated the expression of cytochrome P4502E1 (CYP2E1), and Nod-like receptor protein 3 (NLRP3) inflammasome activation in the liver of mice by CCl4. Our study demonstrates that Sal exerts its hepatoprotective effects on ALI through its antioxidant and anti-inflammatory effects, which might be mediated by down-regulating CYP2E1 expression and inhibiting NLRP3 inflammasome activation.     

Free fatty acids as modulators of the NLRP3 inflammasome in obesity/type 2 diabetes

Free fatty acids (FFAs) are metabolic intermediates that may be obtained through the diet or synthesized endogenously. In addition to serving as an important source of energy, they produce a variety of both beneficial and detrimental effects. They play essential roles as structural components of all cell membranes and as signaling molecules regulating metabolic pathways through binding to nuclear or membrane receptors. However, under conditions of FFAs overload, they become toxic, inducing ROS production, ER stress, apoptosis and inflammation. SFAs (saturated fatty acids), unlike UFAs (unsaturated fatty acids), have recently been proposed as triggers of the NLRP3 inflammasome, a molecular platform mediating the processing of IL-1β in response to infection and stress conditions. Interestingly, UFAs, especially ω-3 FAs, inhibit NLRP3 inflammasome activation in various settings. We focus on emerging models of NLRP3 inflammasome activation with a special emphasis on the molecular mechanisms by which FFAs modulate the activation of this complex. Taking into consideration the current literature and FFA properties, we discuss the putative involvement of mitochondria and the role of cardiolipin, a mitochondrial phospholipid, proposed to be sensed by NLRP3 after release, exposure and/or oxidation. Finally, we review how this SFA-mediated NLRP3 inflammasome activation contributes to the development of both insulin resistance and deficiency associated with obesity/type 2 diabetes. In this context, we highlight the potential clinical use of ω-3 FAs as anti-inflammatory compounds.