川芎嗪通过抑制内质网应激减轻小肠缺血再灌注损伤的研究

目的研究川芎嗪(TMP)对大鼠小肠缺血再灌注损伤及内质网应激通路的影响。方法将120只Wistar大鼠按照随机数字表法平均分为假手术组、模型组和TMP低、中、高(15、30、60 mg/kg)剂量组。造模前30 min腹腔注射给药,假手术组、模型组腹腔注射生理盐水。通过夹闭肠系膜上动脉60 min制备小肠缺血再灌注大鼠模型,再灌注2 h后,检测肠组织含水量;通过HE染色法行肠组织病理学检查并进行损伤评分(Chiu′s氏评分)、TUNEL法观察细胞凋亡情况并计算凋亡指数(AI);ELISA法检测肠组织CRP、TNF-α、IL-1β含量;Western blot法检测内质网应激相关蛋白(GRP78、CHOP)及Cleved Caspase-12、Cleved Caspase-3、NF-κB蛋白表达。结果与模型组比较,TMP中、高剂量组大鼠肠组织含水量显著降低(P<0.05);肠系膜病变明显改善且凋亡细胞数量明显减少,Chiu′s氏评分和AI显著降低(P<0.01);肠组织CRP、TNF-α、IL-1β含量和GRP78、CHOP、Cleved Caspase-12、Cleved Caspase-3、NF-κB蛋白表达水平均显著降低(P<0.05)。结论TMP能够通过抑制内质网应激相关炎症和细胞凋亡通路,对小肠缺血再灌注损伤起到保护作用。     

Differential Expression and Significance of Endoplasmic Reticulum Golgi Intermediate Compartment 1 in Precancerous Gastric Lesions and Gastric Cancer

Background

We investigated the expression of endoplasmic reticulum Golgi intermediate compartment 1 (ERGIC1) in precancerous gastric lesions and gastric cancer and the function of ERGIC in human gastric cancer cell lines.

PPARβ/δ attenuates palmitate-induced endoplasmic reticulum stress and induces autophagic markers in human cardiac cells

Background

Chronic endoplasmic reticulum (ER) stress contributes to the apoptotic cell death in the myocardium, thereby playing a critical role in the development of cardiomyopathy. ER stress has been reported to be induced after high-fat diet feeding in mice and also after saturated fatty acid treatment in vitro. Therefore, since several studies have shown that peroxisome proliferator-activated receptor (PPAR)β/δ inhibits ER stress, the main goal of this study consisted in investigating whether activation of this nuclear receptor was able to prevent lipid-induced ER stress in cardiac cells.

Methods and results

Wild-type and transgenic mice with reduced PPARβ/δ expression were fed a standard diet or a high-fat diet for two months. For in vitro studies, a cardiomyocyte cell line of human origin, AC16, was treated with palmitate and the PPARβ/δ agonist GW501516. Our results demonstrate that palmitate induced ER stress in AC16 cells, a fact which was prevented after PPARβ/δ activation with GW501516. Interestingly, the effect of GW501516 on ER stress occurred in an AMPK-independent manner. The most striking result of this study is that GW501516 treatment also upregulated the protein levels of beclin 1 and LC3II, two well-known markers of autophagy. In accordance with this, feeding on a high-fat diet or suppression of PPARβ/δ in knockout mice induced ER stress in the heart. Moreover, PPARβ/δ knockout mice also displayed a reduction in autophagic markers.

Conclusion

Our data indicate that PPARβ/δ activation might be useful to prevent the harmful effects of ER stress induced by saturated fatty acids in the heart by inducing autophagy.     

The onus of cannabinoids in interrupting the molecular odyssey of breast cancer: A critical perspective on UPRER and beyond

Cannabinoids, commonly used for medicinal and recreational purposes, consist of various complex hydrophobic molecules obtained from Cannabis sativa L. Acting as an inhibitory molecule; they have been investigated for their antineoplastic effect in various breast tumor models. Lately, it was found that cannabinoid treatment not only stimulates autophagy-mediated apoptotic death of tumor cells through unfolded protein response (UPR^ER) activated downstream effectors, but also imposes cell cycle arrest. The exploitation of UPR^ER tumors as such is believed to be a major molecular event and is therefore employed in understanding the development and progression of breast tumor. Simultaneously, the data on clinical trials following administration of cannabinoid is currently being explored to find its role not only in palliation but also in the treatment of breast cancer. The present study summarizes new achievements in understanding the extent of therapeutic progress and highlights recent developments in cannabinoid biology towards achieving a better cure of breast cancer through the exploitation of different cannabinoids.     

成骨细胞的功能与损伤和骨质疏松的防治

骨质疏松是一种全身性骨骼疾病,导致骨折风险增加。成人的骨量通过破骨细胞的骨吸收和成骨细胞的骨形成作用来维持动态平衡,治疗骨质疏松症的理想策略是抑制破骨细胞的骨吸收和/或增强成骨细胞的骨形成功能。目前针对保护成骨细胞及增强其功能的骨质疏松疗法相对较少。因此,本文针对成骨细胞相关功能蛋白、各种细胞损伤机制（内质网应激、氧化应激、机械过载、微小RNA和长链非编码RNA的影响等）及骨质疏松的治疗与预防作一综述,以期为针对增强成骨细胞功能的骨质疏松治疗策略提供新思路。     

3,5-Dimethoxy-4-hydroxy myricanol ameliorates photoreceptor cell degeneration in Pde6brd10 mouse model

Introduction: Retinitis pigmentosa (RP) caused by the photoreceptor cell degeneration is currently incurable and leads to partial or complete blindness eventually. 3,5-dimethoxy-4-hydroxy myricanol (DM) is a novel compound isolated from the leaves of Micromelum integerrimum, with proliferative activities on NIH3T3 cells. This study was to investigate whether DM could mitigate retinal degeneration of rd10 mice, a well-characterized mouse model of RP. Materials and method: Rd10 mice were treated with DM daily by intraperitoneal injection from postnatal day 12 (P12) to P26. Electroretinography (ERG) reflects the mass response of photoreceptor cells and was used to test the outer retinal function after DM treatment. Haematoxylin and Eosin staining was used to show the retinal morphology and evaluate the rod photoreceptor cell loss. TUNEL assay was used to detect the apoptosis-positive cells. Inflammatory factors were measured by ELISA to show the inflammatory response. Real-time PCR and western blot were applied to measure the gene and protein change to explore the underlying mechanisms. Results: Results showed that DM significantly improved the retinal function by increasing the ERG amplitude, preserving the retinal morphology, reducing photoreceptor cell apoptosis, decreasing inflammatory response, and inhibiting endoplasmic reticulum stress in rd10 mice. Conclusion: This is the first time when the protective effects of DM against photoreceptor cell degeneration of rd10 mice have been demonstrated, providing scientific rationale to develop DM as a potential agent to treat RP.     

心肌梗死后内质网应激的研究及治疗进展

心肌梗死是心力衰竭发生的主要原因之一,其发病率和病死率呈逐年上升的趋势。研究发现,心肌梗死后钙离子稳态失衡、氧自由基大量生成等均会诱导内质网应激,持续或过强的内质网应激则会诱导心肌细胞凋亡,引起心肌损伤,最终导致心力衰竭的发生。了解心肌梗死时内质网应激及其发生发展机制对改善心肌梗死预后有重要意义,现就心肌梗死后内质网应激的研究和治疗做一综述。     

Designing the epitope flanking regions for optimal generation of CTL epitopes

The flanking amino acids that surround epitopes are critical for effective antigen processing and maintenance of epitope integrity. In the present study, the frequency and characteristics of each amino acid that flanked the peptides generated from the proteasomal degradation of three different subtypes of HIV-1 Gag-p24 were determined. Synthetic flanking regions were designed based on the highest and the lowest frequencies of amino acid with the ideal characteristics at positions upstream and downstream of the proteasomal cleavage site. Peptides were synthesized that contained known CD8+ CTL-epitopes from HIV-1 Gag, CMV pp65, and vaccinia proteins HRP-2, and C16, flanked by amino acid sequences specifically designed to either generate or inhibit the known CD8+ CTL-epitopes. As predicted, the known CD8+ CTL-epitopes were effectively generated from the peptides with synthetic flanking regions specifically designed to promote epitope generation in a proteasome-dependent manner. The majority of the proteasome-generated epitopes were cleaved immediately after the C-terminal amino acid of the specific CTL-epitope. The synthetic peptide sequences containing known CD8+ CTL-epitopes with the flanking regions that promote epitope generation were effectively processed and presented to epitope specific CD8+ T-cells resulting in the production of IFN-γ. These results highlight the importance of flanking regions in promoting efficient antigen processing and presentation. This concept can have important implications in vaccine design and development strategies.