Damage-associated molecular pattern (DAMP) activation in melanoma: investigation of the immunogenic activity of 15-deoxy, Δ12,14 prostamide J2

Metastatic melanoma is the most deadly skin neoplasm in the United States. Outcomes for this lethal disease have improved dramatically due to the use of both targeted and immunostimulatory drugs. Immunogenic cell death (ICD) has emerged as another approach for initiating antitumor immunity. ICD is triggered by tumor cells that display damage-associated molecular patterns (DAMPs). These DAMP molecules recruit and activate dendritic cells (DCs) that present tumor-specific antigens to T cells which eliminate neoplastic cells. Interestingly, the expression of DAMP molecules occurs in an endoplasmic reticulum (ER) stress-dependent manner. We have previously shown that ER stress was required for the cytotoxic activity of the endocannabinoid metabolite, 15-deoxy, Δ^12,14 prostamide J₂ (15dPMJ₂). As such, the current study investigates whether 15dPMJ₂ induces DAMP signaling in melanoma. In B16F10 cells, 15dPMJ₂ caused a significant increase in the cell surface expression of calreticulin (CRT), the release of ATP and the secretion of high-mobility group box 1 (HMGB1), three molecules that serve as surrogate markers of ICD. 15dPMJ₂ also stimulated the cell surface expression of the DAMP molecules, heat shock protein 70 (Hsp70) and Hsp90. In addition, the display of CRT and ATP was increased by 15dPMJ₂ to a greater extent in tumorigenic compared to non-tumorigenic melanocytes. Consistent with this finding, the activation of bone marrow-derived DCs was upregulated in co-cultures with 15dPMJ₂-treated tumor compared to non-tumor melanocytes. Moreover, 15dPMJ₂-mediated DAMP exposure and DC activation required the electrophilic cyclopentenone double bond within the structure of 15dPMJ₂ and the ER stress pathway. These results demonstrate that 15dPMJ₂ is a tumor-selective inducer of DAMP signaling in melanoma.     

Anti-inflammatory and anti-oxidant effects of aloe vera in rats with non-alcoholic steatohepatitis

BACKGROUND Aloe vera exerts several biological activities, such as, anti-inflammatory, antioxidant, and antimicrobial effects. It was recently shown to reduce insulin resistance and triglyceride level. We hypothesized that aloe vera would have beneficial effects in alleviating non-alcoholic steatohepatitis(NASH) in rats.AIM To examine the therapeutic effects of aloe vera in NASH rats.METHODS All rats were randomly divided into 3 groups(n = 6 in each group). Rats in the control group were fed ad libitum with a standard diet for 8 wk. Rats in the NASH group were fed ad libitum with a high-fat high-fructose diet(HFHFD) for 8 wk. Rats in the aloe vera group were fed ad libitum with a HFHFD and aloe vera in dimethylsulfoxide(50 mg/kg) by gavage daily for 8 wk. Liver samples were collected at the end of the treatment period.RESULTS Hepatic malondialdehyde(MDA) levels increased significantly in the NASH group as compared with the control group(377 ± 77 nmol/mg vs 129 ± 51 nmol/mg protein, respectively, P 0.001). Glutathione(GSH) levels were significantly lower in the NASH group than the control group(9 ± 2 nmol/mg vs 24 ± 8 nmol/mg protein, respectively, P = 0.001). The expression of interleukin-18(IL-18), nuclear factor-kappa β, and caspase-3 increased, while peroxisome proliferator-activated receptor gamma decreased in the NASH group compared with the controls. Following aloe vera administration, MDA levels decreased(199 ± 35 nmol/mg protein) and GSH increased(18 ± 4 nmol/mg protein) markedly. Steatosis, hepatocyte ballooning, lobular inflammation and increased hepatocyte apoptosis were observed in the NASH group. Aloe vera treatment attenuated these changes in liver histology.CONCLUSION Aloe vera attenuated oxidative stress, hepatic inflammation and hepatocyte apoptosis, thus improving liver pathology in rats with NASH.     

NADPH oxidase inhibition rescues keratinocytes from elevated oxidative stress in a 2D atopic dermatitis and psoriasis model

Emerging evidence suggests oxidative stress plays a role in the pathophysiology of both atopic dermatitis (AD) and psoriasis (PSO). We established in vitro models of AD and PSO skin, and characterized these models in regard to their oxidative stress state. Both AD and PSO model keratinocytes exhibited elevated reactive oxygen species (ROS) levels and accumulated more DNA damage than control cells after oxidative stress induced by 250 µmol/L H₂O₂. Elevated ROS levels and DNA damage accumulation could be inhibited by the NADPH oxidase (NOX) inhibitor diphenyleneiodonium (DPI). Further, immunofluorescence analysis revealed the presence of both NOX1 and NOX4 in keratinocytes. By inhibiting NOX1, stress-related signalling cascades and elevated ROS levels could be abrogated, and survival of AD and PSO cells improved. Taken together, this study reveals that inhibition of NOX inhibition could abrogate elevated oxidative stress in a 2D model of AD and PSO.     

Otosclerosis surgery: Assessment of patient comfort

ObjectivesTo evaluate operative comfort and stress in patients undergoing stapedotomy for otosclerosis under local versus general anesthesia.Material and methodsConsecutive otosclerosis patients managed over a 9-month period responded to 3 validated questionnaires to assess peri- and post-operative comfort: Glasgow Benefit Inventory, Cohen's Perceived Stress Scale and the Posttraumatic Stress Disorder Checklist Scale. These results and audiometric data were compared between local and general anesthesia groups.ResultsTwenty-one patients were included in the local anesthesia group and 7 in the general anesthesia group, after exclusion of patients with history of otosclerosis surgery. There was no significant inter-group difference on Glasgow Benefit Inventory (P = 0.38) or Posttraumatic Stress Disorder Checklist Scale (P = 0.86). Perceived Stress Scale scores were higher in the general anesthesia group (P = 0.038). In total, 67% of patients reported no discomfort under local anesthesia, and 86% were ready to undergo the procedure under local anesthesia again. There were no significant differences in postoperative symptoms, or in air-bone gap ≤ 10 dB (local anesthesia 81%, general anesthesia 71%; P = 0.156).ConclusionsLocal anesthesia in otosclerosis surgery did not increase stress or postoperative symptoms compared to general anesthesia. Audiometric results were not affected by type of anesthesia.     

员工援助计划服务对心内科护士职业认同感、职业价值观、职业压力的影响

目的 探讨员工援助计划服务对心内科护士职业认同感、职业价值观、职业压力的影响。 方法 选择2018年1-3月我院心内科护理人员58名,为其实施员工援助计划服务,评价实施前后心内科护士的职业认同感、职业价值观、职业压力感知、职业压力反应。 结果 实施后,心内科护士工作压力源各维度评分、压力感知与压力反应各维度得分均较实施前下降(P＜0.05);职业价值观各维度及职业认同感各维度评分均较实施前显著提高(P＜0.001)。 结论 员工援助计划可提高心内科护士职业认同感、职业价值观,缓解其职业压力感知以及职业压力反应。     

中药治疗创伤后应激障碍的研究进展

创伤后应激障碍(PTSD)是指突发性、威胁性或灾难性生活事件导致个体延迟出现和长期持续存在的精神障碍,其临床表现以再度体验创伤为特征,并伴有情绪的易激惹和回避行为。PTSD的发生不仅伴随着行为学指标异常,机制研究表明还表现出神经生物学指标异常。PTSD的发生机制研究多集中在神经内分泌系统、中枢神经系统和免疫系统等方面,主要表现为应激激素、促炎细胞因子、神经递质、神经保护因子的水平异常。中药因其具有多靶点、多成分和多途径的特点,在治疗PTSD方面表现出了许多优势。当前研究表明,多种中药能够改善PTSD模型中动物行为异常、逆转神经生物学指标。其中很多中药复方已经应用于临床并且具有很好的疗效,因此中药治疗PTSD具有广阔的应用前景。但是,尚未有PTSD的专属治疗药物,且尚未完全厘清PTSD的机制。故本文对当前中药治疗PTSD的研究进行综述,并且从治疗的中药种类、作用机制、动物模型等角度,重点阐述PTSD的发生与治疗进展,以期为PTSD的治疗提供参考。     

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.     

Caffeic acid phenethyl ester,a propolis polyphenolic,attenuates potentially cadmium-induced testicular dysfunction in mice

Abstract

Cadmium (Cd) as environmental pollutant can induce severe damage, particularly to the testis. This study investigated the effects of Caffeic acid phenethyl ester (CAPE) on testicular dysfunction induced by Cd. Adult mice were intraperitoneally injected with cadmium chloride (CdCl₂) with different doses of CAPE pretreatment. After CdCl₂ injection, body/testis weight ratio decreased, Cd levels accumulated and zinc levels decreased in testis. Furthermore, Cd intoxication caused a significant increase of oxidative stress levels, antioxidant enzymes activities, and glutathione levels. Interestingly, significant improvements were observed after the administration of CAPE. Our results demonstrated the protective effect of CAPE, linking Cd testicular dysfunction to oxidative stress.     

Disparate exposure to physically demanding working conditions in France

BackgroundOur study was aimed at examining disparate exposure to physically demanding working conditions in France, a key objective being to identify the types of employees/jobs requiring high-priority preventive actions.MethodsWe analyzed the data from the 2017 French nationwide cross-sectional survey (SUMER) on occupational hazards to which French employees in various sectors were subjected. The prevalence of several types of physically demanding working conditions (lifting of heavy loads, awkward body postures, vibrations, noise, and extreme temperatures) was explored. Potential associations of individual and job characteristics with these factors of hardship at work were studied by multivariate logistic regression.ResultsIn total, 48% of employees were exposed to at least one physically demanding working condition and 24.8% were exposed to multiple constraints. While managers and intellectual professionals were exposed relatively infrequently to physical constraints, blue-collar workers experienced the highest frequency of exposure. On the one hand, the role of company size depended on the factor of hardship at work considered; on the other hand, employees in large-scale companies were generally less exposed. As expected, employees in the construction industry were the most exposed to physical constraints; that said, our results also show that some activities in the services sector (e.g., personal care, administrative and support services) were quite significantly affected by a wide array of physically demanding working conditions.ConclusionNotwithstanding the establishment in France of Plans de Santé au travail (preventive workplace health and safety plans), occupational risks were found to be high, and above all, they were unevenly distributed among the various socio-professional categories, and strongly contributed to social inequalities in health. Our results identify the types of publics to be designated as high-priority targets for preventive measures aimed at reducing the adverse impacts of physically demanding working conditions and the incidence of associated musculoskeletal disorders.