Endoplasmic reticulum stress is involved in ventilator-induced lung injury in mice via the IRE1α-TRAF2-NF-κB pathway

Inflammation plays a critical role in the development of ventilator-induced lung injury (VILI). Endoplasmic reticulum (ER) stress is associated with a variety of diseases through the modulation of inflammatory responses. However, little is known about how ER stress is implicated in VILI. In this study, murine mechanical ventilation models were constructed. Total protein and inflammatory cytokines were measured in bronchoalveolar lavage fluid (BALF), and lung tissue injury was assessed by histology. Our data revealed that mice subjected to high tidal ventilation (TV) for 4 h showed more severe pulmonary edema and inflammation than those of mice with spontaneous breathing and low TV-treatment. In addition, the high TV-treated animals upregulated the ER stress markers GRP78, CHOP, p-IRE1α, TRAF2, and p-NF-κB expression at both the mRNA and protein levels in lung tissue. Administration of thapsigargin exacerbated the histological changes, inflammation and expression of GRP78 and CHOP after high TV, but treatment with ER stress and IRE1α kinase inhibitors attenuated the pathological damage and downregulated the high expression of GRP78, CHOP, p-IRE1α, TRAF2, and p-NF-κB, suggesting that ER stress is involved in VILI though the IRE1α/TRAF2/NF-κB signaling pathway in mice.     

Flavocoxid is as effective as naproxen for managing the signs and symptoms of osteoarthritis of the knee in humans: a short-term randomized,double-blind pilot study

Flavocoxid (Limbrel), a proprietary mixture of flavonoid molecules (baicalin and catechin), was tested against a traditional nonsteroidal anti-inflammatory drug, naproxen, for the management of the signs and symptoms of moderate osteoarthritis (OA) in humans. Discomfort and global disease activity were used as the primary end points, and safety assessments were also taken for both treatments as a secondary endpoint. In this double-blind study, 103 subjects were randomly assigned to receive either flavocoxid [500 mg twice daily (BID)] or naproxen (500 mg BID) in a 1-month onset of action trial. Outcome measures included the short Western Ontario and McMaster University Osteoarthritis Index, subject Visual Analogue Scale for discomfort and global response, and investigator Visual Analogue Scale for global response and fecal occult blood. Both flavocoxid and naproxen showed significant reduction in the signs and symptoms of knee OA (P ≤ .001). There were no statistically detectable differences between the flavocoxid and naproxen groups with respect to any of the outcome variables. Similarly, there were no statistically detectable differences between the groups with respect to any adverse event, although there was a trend toward a higher incidence of edema and nonspecific musculoskeletal discomfort in the naproxen group. In this short-term pilot study, flavocoxid was as effective as naproxen in controlling the signs and symptoms of OA of the knee and would present a safe and effective option for those individuals on traditional nonsteroidal anti-inflammatory drugs or cyclooxygenase-2 inhibitors. A low incidence of adverse events was reported for both groups.     

早期大剂量维生素C对重症急性胰腺炎大鼠核因子-κB的影响

目的:观察早期大剂量应用抗坏血酸(维生素C)对重症急性胰腺炎(SAP)大鼠的核因子-!B(NF-!B)的影响,研究其作用机制。方法:将72只SAP模型SD大鼠随机分成3组,每组各24只。A组:由大鼠股静脉滴注生理盐水5 ml/kg。B组:大鼠股静脉滴注Vit C 15 mg/kg加生理盐水至5 ml/kg。C组:由大鼠股静脉滴注Vit C 150 mg/kg加生理盐水至5 ml/kg。另取8只SD大鼠作为正常对照组。各组分别于8 h和24 h处死8只大鼠,采血测淀粉酶、脂肪酶、维生素C(PV-C)、超氧化物歧化酶(SOD)、TNF-αI、L-6。大鼠处死时分别取胰头组织3份,一份组织HE染色,行光镜检查,按Kusske的方法,对水肿、炎症、出血和坏死分别评分;一份制成超薄切片,行电镜检查;另一份SP法进行免疫组化染色,检测NF-!B的表达。每组另外8只大鼠观察3 d内存活情况,计算3 d成活率。结果:各组大鼠3 d内的生存率为正常对照组100%(8/8),A组0%(0/8),B组12.5%(1/8),C组50%(4/8),C组的3 d生存率显著高于其他两组(P<0.05)。各组的4项病理学评分均高于正常对照组(P<0.01),C组的4项病理学评分均低于A、B组(P<0.05)。透射电镜检查示C组中分泌颗粒较少,其包膜完整、内质网轻度肿胀、线粒体清晰,未见大片坏死。SAP大鼠体内淀粉酶、脂肪酶、细胞因子TNF-α和IL-6的水平明显增高,血清SOD和P-VC降低,胰腺组织中NF-!B活化阳性胰腺细胞数明显增多。C组的血清淀粉酶和脂肪酶低于A、B组(P<0.05),SOD和P-VC水平高于A、B组(P<0.05),血清TNF-αI、L-6水平低于A、B组(P<0.05),胰腺组织NF-!B活化水平低于A、B组(P<0.05)。结论:早期大剂量应用Vit C有助于及时提高SAP大鼠的P-VC、E-SOD水平,降低体内淀粉酶、脂肪酶、TNF-αI、L-6水平,其作用机制可能与大剂量Vit C抑制SAP大鼠体内NF-!B活化、在整体水平上抑制细胞因子基因表达、有助于机体免受自由基和过量细胞因子的损伤及减轻胰腺组织的病理性改变等因素有关。     

核因子-κB与创伤的关系及其在法医病理学中的应用

损伤时间推断是法医病理学的一个研究热点和难点。核因子-κB(NF-κB)是一种核转录调节蛋白,参与多种炎性介质的转录和调控。近年来研究发现NF-κB与机体创伤后的反应密切相关,其在损伤后的时序性表达可望在法医病理学用于损伤时间推断。     

NF-κB对尿白蛋白诱导肾小管上皮细胞骨桥蛋白转录的影响

目的研究NF-κB对尿白蛋白诱导肾小管上皮细胞骨桥蛋白转录的影响。方法去脂的小牛血清白蛋白(BSA)20mg/ml分别加入到体外培养的肾小管上皮细胞和加入NF-κB抑制剂(PDTC)共同培养半小时的肾小管上皮细胞内,EMSA、RT-PCR检测不同时限NF-κB活性、骨桥蛋白mRNA表达情况。结果去脂的小牛血清白蛋白可刺激肾小管上皮细胞内NF-κB活性增加,骨桥蛋白mRNA表达上调,而提前加入NF-κB抑制剂(PDTC)共同培养半小时的肾小管上皮细胞内NF-κB活性、骨桥蛋白mRNA表达明显下降。结论尿白蛋白诱导小管上皮细胞损伤的机制与诱导肾小管上皮细胞内NF-κB活性、骨桥蛋白mRNA增加有关,而且骨桥蛋白转录由NF-κB调控。     

Single-Cell RNA Sequencing of Tumor-Infiltrating NK Cells Reveals that Inhibition of Transcription Factor HIF-1α Unleashes NK Cell Activity

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Loss of claudin-1 expression induces epithelial-mesenchymal transition through nuclear factor-κB activation in colorectal cancer

Objective

The aim of this study was to elucidate the clinicopathological significance and prognostic role of loss of claudin-1 in colorectal cancer (CRC).