Omentin-1 attenuates adipose tissue inflammation via restoration of TXNIP/NLRP3 signaling in high-fat diet-induced obese mice

Omentin-1 is an adipokine expressed by the adipose tissue and is reduced in obesity. This study was designed to calculate the protective efficiency and mechanism of omentin-1 against inflammation of the adipose tissue in obese mice. A transgenic mouse model with omentin-1 protein overexpression was established by crossing omentin-1 transgenic mice with Fabp4-Cre mice. Obesity was induced in the mice by feeding them a high-fat diet for 10 weeks. Fabp4-Cre-mediated overexpression of omentin-1 significantly increased serum omentin-1 level, serum anti-inflammatory factor levels, and expression of M2-specific mRNAs; inhibited body weight and adipose tissue weight gain; improved glucose tolerance, insulin tolerance, and insulin sensitivity; decreased serum levels of insulin and proinflammatory factors, adipocyte size, and expression of M1-specific mRNAs; suppressed macrophage infiltration; downregulated expression of proinflammatory factors; upregulated expression of anti-inflammatory factors; and inhibited thioredoxin-interacting protein (TXNIP)/NOD-like receptor 3 (NLRP3) signaling in the adipose tissue of obese mice. An NLRP3 inhibitor (20 mg/kg MCC950) exhibited the same effects as overexpression of omentin-1. Pretreatment with omentin-1 inhibited lipopolysaccharide-induced inflammation via TXNIP/NLRP3 signaling in RAW 264.7 macrophages. These findings suggest that omentin-1 suppresses adipose tissue inflammation in obese mice, at least partly, via inhibiting the TXNIP/NLRP3 signaling pathway.     

Deletion of thioredoxin-interacting protein preserves retinal neuronal function by preventing inflammation and vascular injury

BACKGROUND AND PURPOSE

Retinal neurodegeneration is an early and critical event in several diseases associated with blindness. Clinically, therapies that target neurodegeneration fail. We aimed to elucidate the multiple roles by which thioredoxin-interacting protein (TXNIP) contributes to initial and sustained retinal neurodegeneration.

EXPERIMENTAL APPROACH

Neurotoxicity was induced by intravitreal injection of NMDA into wild-type (WT) and TXNIP-knockout (TKO) mice. The expression of apoptotic and inflammatory markers was assessed by immunohistochemistry, elisa and Western blot. Microvascular degeneration was assessed by periodic acid-Schiff and haematoxylin staining and retinal function by electroretinogram.

KEY RESULTS

NMDA induced early (1 day) and significant retinal PARP activation, a threefold increase in TUNEL-positive nuclei and 40% neuronal loss in ganglion cell layer (GCL); and vascular permeability in WT but not TKO mice. NMDA induced glial activation, expression of TNF-α and IL-1β that co-localized with Müller cells in WT but not TKO mice. In parallel, NMDA triggered the expression of NOD-like receptor protein (NLRP3), activation of caspase-1, and release of IL-1β and TNF-α in primary WT but not TKO Müller cultures. After 14 days, NMDA induced 1.9-fold microvascular degeneration, 60% neuronal loss in GCL and increased TUNEL-labelled cells in the GCL and inner nuclear layer in WT but not TKO mice. Electroretinogram analysis showed more significant reductions in b-wave amplitudes in WT than in TKO mice.

CONCLUSION AND IMPLICATIONS

Targeting TXNIP expression prevented early retinal ganglion cell death, glial activation, retinal inflammation and secondary neuro/microvascular degeneration and preserved retinal function. TXNIP is a promising new therapeutic target for retinal neurodegenerative diseases.     

涤痰活血舒痹汤上调microRNA-148a表达减轻心肌缺血再灌注损伤的分子机制研究

目的 探究涤痰活血舒痹汤（DHS）与microRNA-148a(miR-148a)的调控关系以及其在心肌缺血再灌注损伤中的分子作用机制。方法 将H9c2细胞培养后分为对照组、缺氧/复氧（H/R）组、H/R+空白血清组、H/R+DHS含药血清组、H/R+DHS含药血清+miR-148a拮抗剂组、H/R+DHS含药血清+OE-NC组和H/R+DHS含药血清+硫氧还蛋白互作蛋白（TXNIP）过表达质粒组。采用CCK-8检测H9c2细胞增殖,TUNEL染色检测H9c2细胞凋亡,Western blot检测H9c2细胞凋亡和自噬相关蛋白及靶蛋白TXNIP的表达,qRT-PCR检测miR-148a的表达。结果 与对照组比较,H/R组H9c2细胞活力下降[（69.72±8.80）%比（97.75±5.58）%,P<0.01]、细胞凋亡和自噬水平上升。与H/R+空白血清组比较,H/R+DHS含药血清组miR-148a表达上调[（2.45±0.39）比（1.04±0.25）,P<0.01],H9c2细胞活力增加[（135.98±10.45）%比（97.75±7.94）%,P<0.01]...     

Ischemic Cardiomyopathy Affects the Thioredoxin System in the Human Myocardium

Background

Oxidative stress due to reactive oxygen species (ROS) production is a key factor in the development of heart failure (HF). This study investigated the thioredoxin (Trx) system, which plays a major role in antioxidant defense, in patients suffering from ischemic (ICM) or dilated (DCM) cardiomyopathy.

硫氧还原蛋白结合蛋白基因多态性与精神分裂症的关联分析

目的探索硫氧还原蛋白结合蛋白（TXNIP）基因与精神分裂症的关联关系。方法以182个精神分裂症核心家系为研究对象，应用聚合酶链反应和限制性片段长度多态性技术（PCR-RFLP）对TXNIP基因标签单核苷酸多态性（htSNP）rs9245进行基因分型；使用传递不平衡（TDT）、基于单体型的单体型相对危险度分析（HHRR）检测TXNIP基因与精神分裂症之间的关联关系。结果①患者组、父母组htSNP rs9245位点各基因型的分布均符合Hardy-Weinberg平衡法则（矿值分别为0．68，0．02，df=1，P〉0．05）；②单体型相对风险分析（HHRR）显示htSNP rs9245位点等位基因在患者组和父母组的频数分布为χ^2=3．42，P=0．064；③传递不平衡检验（TDT）分析显示，杂合子父母传递给受累子女与非传递等位基因频率分布为χ^2=3．40，P=0．065，虽然差异未达到显著性，但接近边缘显著性。结论本研究虽未发现TXNIP基因htSNP rs9245与精神分裂症的发生存在关联，但不能排除两者的阳性关联，尚需选择更多SNP及扩大样本量进一步分析。     

TXNIP interaction with the Her-1/2 pathway contributes to overall survival in breast cancer

Previous studies have indicated that Her-2 induction causes a strong decrease in thioredoxin interaction protein (TXNIP) in breast cancer cells. However, little is known regarding the prognostic value of TXNIP in clinical breast cancer patients with anti-Her-2 treatment. Using a tissue microarray, we detected TXNIP and p27 expression in breast cancer tissue, as well as corresponding noncancerous tissues. We found that TXNIP expression was associated with better overall survival (OS) in these 150 breast cancer patients and that TXNIP and Her-2 expression status were significantly inversely correlated (r=-0.334, P<0.001). These results were validated in another 101 breast cancer tissue samples (r=-0.422, P<0.001). Moreover, TXNIP expression increased significantly following treatment of the human breast cancer cell lines BT474 and SK-BR-3 with a Her-1/2 inhibitor. Furthermore, TXNIP transfection induced p27 expression and G₁ cell cycle arrest and apoptosis. Taken together, our findings suggest that TXNIP plays a critical role in anti-Her-1/Her-2 treatment and may be a potential prognostic marker in breast cancer.