利拉鲁肽联合二甲双胍对2型糖尿病伴肥胖患者血清NLRP3炎症小体水平、心肌损伤标志物和胰岛素抵抗的影响

目的 探究2型糖尿病伴肥胖患者采用利拉鲁肽联合二甲双胍治疗对患者血清NLRP3炎症小体水平、心肌损伤标志物和胰岛素抵抗的影响.方法 以我院2017年6月至2019年6月期间收治的80例2型糖尿病伴肥胖患者为研究对象,按照随机奇偶数分组方法将患者分为联合组与对照组,各40例,分别采用利拉鲁肽联合二甲双胍、单纯二甲双胍进行...     

Annexin A1 inhibition facilitates NLRP3 inflammasome activation in arsenic-induced insulin resistance in rat liver

Hepatic insulin resistance (IR) is the primary pathology of type 2 diabetes (T2D). The role of the NOD-like receptor protein 3 (NLRP3) inflammasome in arsenic-induced hepatic IR has been previously demonstrated. However, the mechanism of the arsenic-induced activation of the NLRP3 inflammasome is still unclear. Here, we demonstrate that NaAsO₂ downregulated the mRNA and protein level of Annexin A1 (AnxA1), an anti-inflammatory factor, in rat livers and L-02 cells. Moreover, AnxA1 overexpression significantly alleviated arsenic-induced NLRP3 inflammasome activation and IR in L-02 cells. Importantly, Co-immunoprecipitation (Co-IP) results showed that AnxA1 1–190 peptide could bind to the domain encompassing amino acids 1–210 and 211–550 of NLRP3. In conclusion, our experiments demonstrated that arsenic exposure could activate the NLRP3 inflammasome and IR by inhibiting the AnxA1 activity. These findings suggest that AnxA1 may be a promising therapeutic target of arsenicosis.     

绞股蓝总皂苷对2型糖尿病大鼠游离脂肪酸代谢的影响及改善胰岛素抵抗相关机制研究

目的 探讨绞股蓝总皂苷(GPS)对2型糖尿病(T2DM)大鼠游离脂肪酸代谢的影响并初步探讨其改善胰岛素抵抗的作用机制.方法 80只大鼠腹腔注射40 mg·kg-1链脲佐菌素,并加高脂饲料喂养构建T2DM脂代谢紊乱模型,选取50只成模大鼠随机分为模型组(n=10)、二甲双胍组(n=10)、GPS低剂量组(n=10)、GPS中剂量组(n=10)和GPS高剂量组(n=10).二甲双胍和不同GPS剂量干预4周后,测定空腹血糖(FPG)、糖化血红蛋白(HbA1 C)、游离脂肪酸(FFA)、三酰甘油(TG)、总胆固醇(TC)、低密度脂蛋白(LDL-C)、高密度脂蛋白(HDL-C)、胰岛素(INS)、胰岛素抵抗指数(HOMA-IR)、胰岛β细胞功能指数(HOMA-β)和定量胰岛素敏感性检测指数(QUIC-KI).结果 模型组与GPS低剂量组细胞凋亡指数(AI)较正常组显著升高(P<0.05);各治疗组AI较模型组显著降低(P<0.05);GPS高剂量组和二甲双胍组AI较中剂量组显著降低(P<0.05);GPS高剂量组AI和二甲双胍组AI差异无统计学意义(P>0.05).模型组FPG、HbA1C、FFA、TG、TC、LDL-C、INS和HOMA-IR均高于正常组水平,而HDL-C、QUICKI和HOMA-β均低于正常组,均差异有统计学意义(P<0.05).经二甲双胍和GPS干预后,各模型组FPG、HbA1 C、FFA、TG、TC、LDL-C、INS和HOMA-IR较干预前均明显降低,而HDL-C、QUICKI和HOMA-β较干预前均明显升高(P<0.05).相关性分析结果显示,HOMA-IR与FPG、HbA1 C、FFA、TG、TC和LDL-C呈明显的正相关,与HDL-C和体质量呈明显的负相关(P<0.05).结论 GPS可明显改善T2DM中出现的胰岛素抵抗,其机制与绞股蓝总皂苷改善脂代谢紊乱和降血糖的作用有关.     

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.     

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。     

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.     

2型糖尿病脂肪肝与胰岛素抵抗的关系

目的：探讨2型糖尿病脂肪肝与胰岛素抵抗的关系。方法：对81例糖尿病并脂肪肝患者与80例未合并脂肪肝患者的血糖， 脂，胰岛素进行测定，计算胰岛素敏感指数（IAI），体重指数（BMI）并进行分析比较，结果：2型尿病并脂肪肝时IAI显著降低，而餐后2小时血糖，甘油三酯，空腹胰岛素，体重指数均显著高于对照组。结论：2型糖尿病人脂肪肝的发生与胰岛素抵抗关系密切，提示改善胰岛素抵抗对糖尿病脂肪肝病人具有重要意义。     

2型糖尿病并发脂肪肝临床分析

目的分析2型糖尿病(T2DM)合并脂肪肝(FLD)的相关因素。方法采用对照研究的方法,观察156例T2DM伴有脂肪肝和不伴脂肪肝患者的体质指数(BMI)、空腹血糖(FBS)、餐后2小时血糖(PG2h)、糖化血红蛋白(HbA1C)、空腹胰岛素(FINS)、C-肽(C-P)、胰岛素敏感指数(ISI)、胰岛素抵抗指数(HOMA-IR)、甘油三酯(TG)、胆固醇(TC)、高密度胆固醇(HDL)、低密度胆固醇(LDL)、载脂蛋白(Apo)、转氨酶(ALT)等指标,同时检查是否合并糖尿病的慢性并发症。结果与非脂肪肝组相比,T2DM合并脂肪肝组FBS、PG2h、HbA1C无差别(P>0.05);BMI、FINS、C-P、LDLTG、TC、ALT、HOMA-IR明显升高,HDL、ISI明显降低(P<0.05或P<0.01);大血管的并发症较多(P<0.05)。结论T2DM脂肪肝伴有较明显脂代谢紊乱及胰岛素抵抗,且大血管的并发症发生较多。     

益母草碱抑制NLRP3炎症小体过度激活调控巨噬细胞M1/M2表型分化

目的 研究益母草碱对脂多糖(LPS)诱导小鼠腹腔巨噬细胞免疫应答影响及相关机制.方法 分离小鼠腹腔巨噬细胞,用脂多糖和益母草碱预处理24 h,MMT法检测巨噬细胞活性;Griess法检测NO释放量;ELISA法检测IL-1β、IL-18、IL-6、TNF-α的释放量;RT-PCR法检测NLRP3、ASC、caspase...     

2型糖尿病患者合并脂肪肝的临床分析

目的探讨2型糖尿病患者脂肪肝和胰岛素抵抗、体重指数、血糖、血脂、血压的关系。方法采用病例对照研究,分两组,①2型糖尿病合并脂肪肝组;②2型糖尿病不伴脂肪肝组做对照。进行体重指数(BMI)、血脂、空腹和餐后2小时血糖(2hPBG)、胰岛素抵抗指数(HOMA-IR)的比较。结果2型糖尿病合并脂肪肝组的体重、BMI,舒张压、餐后2小时血糖、总胆固醇、甘油三酯、HOMA-IR明显高于2型糖尿病对照组(P<0.05)。结论TC,TG,HOMA-IR,BMI,LDL和糖尿病脂肪肝的形成有关。脂肪肝形成危险因素的Logistic回归分析,体重、2hPBG是2型糖尿病脂脂肝形成的最主要的危险因素。     

利拉鲁肽治疗2型糖尿病合并代谢相关脂肪性肝病的研究进展

随着肥胖、糖尿病及其代谢综合征的全球化,代谢相关脂肪性肝病（MAFLD）逐渐成为全球最普遍的肝脏疾病。据报道,50%～75%的糖尿病患者患有MAFLD。由于没有药物可用,目前通过调整健康的生活方式,如恰当的运动及合理的饮食习惯,仍然是MAFLD的主要管理策略。近几年,利拉鲁肽被越来越多的学者发现,它不仅可以降低血糖血脂、改善胰岛素抵抗,还拥有减少肝脏脂肪堆积,减缓代谢相关脂肪性肝炎（MASH）和显著降低肝纤维化程度等诸多疗效。在本篇综述文章中,我们回顾并总结了利拉鲁肽在治疗2型糖尿病（T2DM）合并MAFLD中的诸多作用和最新的研究进展。     

2型糖尿病并高血压与胰岛素抵抗的关系

目的　探讨高血压与胰岛素抵抗之间的关系。方法　2型糖尿病高血压组110例，正常血压组112例。测定FPG、FINS、TC、MAU、血压、计算BMI，并评价胰岛素抵抗和β细胞功能采用稳态模式评估法及改良胰岛素敏感性指数公式计算。结果　高血压组ISI显著低于正常血压组，HOMA－βcell、HOMA—IR显著高于正常血压组(P＜0.005)，正常体重者也有相同的结果(P＜0．05)。两组ISI与FPG、FINS、BMI均呈显著负相关(P＜0．05)，高血压组ISI与TC、TG呈弱负相关(P＜0．5)。结论　2型搪尿病伴高血压病人无论是否肥胖都存在胰岛素抵抗。肥胖病人胰岛素抵抗更为严重。     

胰高血糖素与2型糖尿病病人胰岛素抵抗关系研究

目的　探讨胰高血糖素 (Glu)与 2型糖尿病 (DM)病人胰岛素抵抗 (IR)的关系。方法　对 1 0 0例 2型DM病人分别检测空腹及 75g葡萄糖粉负荷 2h血糖 (BG)、胰岛素 (Ins)、C肽、Glu。并以空腹血糖 /空腹胰岛素 (G/I) <6作为IR指标。将G/I<6 ,G/I≥ 6两组的Glu进行统计学的比较。结果　G/I <6组较G/I≥ 6组Glu空腹及糖负荷后均明显升高 (P <0 0 5 ,P <0 0 1 )。结论　Glu可能参与了 2型糖尿病IR的形成     

胰岛素联合吡格列酮治疗2型糖尿病的疗效观察

目的评价胰岛素联合吡格列酮对2型糖尿病患者降血糖的协同作用。方法将60例2型糖尿病患者随机分为2组,治疗组（n=31）;胰岛素联合吡格列酮15mg.d-1;对照组（n=29）;只应用胰岛素,疗程均为12周。观察两组患者的空腹血糖（FBG）、餐后2h血糖（2hBG）、糖化血红蛋白（HbA1C）和胰岛素用量。结果两组患者的FBG,2hBG和HbA1C均得到良好控制;治疗组胰岛素用量明显低于对照组（P〈0.05）。结论胰岛素联合吡格列酮治疗2型糖尿病,可更有效控制血糖,减少胰岛素剂量,改善胰岛素抵抗。     

Costunolide covalently targets NACHT domain of NLRP3 to inhibit inflammasome activation and alleviate NLRP3-driven inflammatory diseases

The NLRP3 inflammasome’s core and most specific protein, NLRP3, has a variety of functions in inflammation-driven diseases. Costunolide (COS) is the major active ingredient of the traditional Chinese medicinal herb Saussurea lappa and has anti-inflammatory activity, but the principal mechanism and molecular target of COS remain unclear. Here, we show that COS covalently binds to cysteine 598 in NACHT domain of NLRP3, altering the ATPase activity and assembly of NLRP3 inflammasome. We declare COS’s great anti-inflammasome efficacy in macrophages and disease models of gouty arthritis and ulcerative colitis via inhibiting NLRP3 inflammasome activation. We also reveal that the α-methylene-γ-butyrolactone motif in sesquiterpene lactone is the certain active group in inhibiting NLRP3 activation. Taken together, NLRP3 is identified as a direct target of COS for its anti-inflammasome activity. COS, especially the α-methylene-γ-butyrolactone motif in COS structure, might be used to design and produce novel NLRP3 inhibitors as a lead compound.     

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.     

Enalapril inhibits tubulointerstitial inflammation and NLRP3 inflammasome expression in BSA-overload nephropathy of rats

Aim:

Proteinuria is not only a common marker of renal disease, but also involved in renal tubulointerstitial inflammation and fibrosis. The aim of this study was to investigate the mechanisms underlying the protective effects of enalapril, an ACEI, against nephropathy in rats.

Methods:

Wistar rats underwent unilateral right nephrectomy, and then were treated with BSA (5 g·kg⁻¹·d⁻¹, ip), or BSA plus enalapril (0.5 g·kg⁻¹·d⁻¹, po) for 9 weeks. The renal lesions were evaluated using histology and immunohistochemistry. The expression of NLRP3, caspase-1, IL-1β and IL-18 was analyzed using immunohistochemistry, RT-PCR and Western blot.

Results:

BSA-overload resulted in severe proteinuria, which peaked at week 7, and interstitial inflammation with prominent infiltration of CD68⁺ cells (macrophages) and CD3⁺ cells (T lymphocytes), particularly of CD20⁺ cells (B lymphocytes). BSA-overload markedly increased the expression of NLRP3, caspase-1, IL-1β and IL-18 in the proximal tubular epithelial cells, and in inflammatory cells as well. Furthermore, the expression of IL-1β or IL-18 was significantly correlated with proteinuria (IL-1β: r=0.757; IL-18: r=0.834). These abnormalities in BSA-overload rats were significantly attenuated by concurrent administration of enalapril.

Conclusion:

Enalapril exerts protective effects against BSA-overload nephropathy in rats via suppressing NLRP3 inflammasome expression and tubulointerstitial inflammation.     

细胞因子与2型糖尿病胰岛素抵抗的相关性研究

目的研究2型糖尿病及胰岛素抵抗患者白细胞介素6（IL-6）、IL-8、肿瘤坏死因子仪（TNF—α）及C反应蛋白（CRP）的变化,分析细胞因子与糖尿病及胰岛素抵抗的相关性。方法125例2型糖尿病患者其中胰岛素抵抗者80例为胰岛素抵抗组,非胰岛素抵抗者45例为非胰岛素抵抗组,40例健康体检者为对照组,采用酶联免疫吸附法测定3组的IL-6、IL-8、TNF-α,并同时测定空腹血糖、糖化血红蛋白、空腹胰岛素及空腹C肽水平,分析各指标与细胞因子的相关性。结果与正常对照组比较;2型糖尿病组血清细胞因子的含量均明显增高（P〈0．05）;胰岛素抵抗组的IL-6、TNF-α、CRP分别为（91．09±22．25）ng／L、（69．51±32．37）ng／L、（0．75±0．11）ng／L与非胰岛素抵抗组[分别为（77．09±22．20）ng/L、（54．87±13．23）ng/L、（0．43±0．09）ng／L]比较差异有统计学意义（P〈0．05）。结论2型糖尿病患者存在着细胞因子的过度激活,并与胰岛素抵抗密切相关,细胞因子在2型糖尿病及胰岛素抵抗的发生发展中起着重要的作用。     

血清抵抗素与2型糖尿病胰岛素抵抗关系的研究

目的探讨抵抗素在2型糖尿病胰岛素抵抗发生中的作用。方法测量42例2型糖尿病患者及40例健康对照者的身高、体重、腰围,计算体重指数,酶联免疫吸附法测空腹血清抵抗素浓度。同时测定空腹胰岛素、空腹血糖、血脂的水平,根据Homa模型提出的公式,计算出胰岛素抵抗指数并分析各指标间的关系。结果2型糖尿病组抵抗素的水平显著高于对照组(P<0.01);血清抵抗素水平与胰岛素抵抗指数(IR)、空腹血糖、腰围呈显著正相关。结论抵抗素参与了胰岛素抵抗的发生,与糖尿病的发生、发展密切相关,可作为评价胰岛素抵抗程度的一项指标。