Notch信号通路对脑缺血大鼠神经干细胞移植后神经再生的影响

目的 探讨抑制Notch信号通路促进脑缺血大鼠神经干细胞（NSCs）移植后神经再生的机制。方法 采用大脑中动脉阻塞MCAO）方法构建局灶性脑缺血模型,体外培养NSCs,移植入纹状体缺血区。将40只SD大鼠随机分为假手术组、模型组、移植组（移植神经干细胞）、氮-［氮-(3,5-二氟苯乙酰)-L-丙氨酰］-S-苯基甘氨酸丁酯］（DAPT）+移植组。采用HE染色观察各组大鼠神经元损伤程度,利用免疫组织化学、Western blotting检测各组大鼠脑组织中Notch1、Hes1及Hes5的表达情况。结果 与假手术组相比,模型组神经元损伤严重,出现核固缩和核溶解,Notch1、Hes1及Hes5阳性细胞表达明显增多,Notch1、Hes1及Hes5蛋白表达显著上调（P＜0.05）。与模型组相比,移植组和DAPT+移植组神经元损伤均不同程度缓解,Notch1、Hes1及Hes5阳性细胞均有部分表达,各项蛋白表达均有所降低（P＜0.05）;DAPT+移植组神经元损伤明显恢复,较移植组各项蛋白阳性细胞和蛋白表达进一步降低(P＜0.05)。结论 抑制Notch信号通路可促进脑缺血大鼠神经干细胞移植后的神经再生,其机制主要与下调Notch1、Hes1及Hes5的表达有关。     

“They are interrelated,one feeds off the other”: A taxonomy of perceived disease interactions derived from patients with multiple chronic conditions

ObjectiveTo understand patients’ experiences with condition interactions and develop a taxonomy to inform care for patients with multiple chronic conditions.MethodsWe conducted qualitative and quantitative analysis of free-text data from patient surveys in which respondents were asked to indicate their most bothersome chronic condition and describe how their other conditions affect their self-care for that condition. Using standard content analysis, we developed a taxonomy comprising how patients perceive interactions among their conditions, and examined cross-cutting themes that reflect qualities of these interactions.ResultsAmong 383 eligible survey respondents, the mean (SD) number of chronic conditions was 4 (2); common conditions included hypertension (60%), chronic pain (49%), arthritis (41%), depression (32%), diabetes (29%), and post-traumatic stress disorder (26%). Patients’ perceived condition interactions took four broad forms: 1) unidirectional interactions among conditions and/or treatments, 2) cyclical or multidimensional interactions, 3) uncertain or indistinct interactions, and 4) no perceived interaction. Cross-cutting themes included beliefs about causal relationships between conditions, identification of interactions as negative vs. positive, and interactions between physical and mental health.ConclusionThis study presents a novel taxonomy of condition interactions from the patient perspective.Practice ImplicationsUnderstanding perceived condition interactions may support patient self-management and shared decision-making efforts.     

Epigenetic alterations in Sjögren’s syndrome patient saliva

Epigenetic mechanisms have been implicated in the pathogenesis of Sjögren’s syndrome (SS). Extensive alterations in DNA methylation have been described in minor salivary gland (MSG) epithelial cells and lymphocytes derived from SS patients compared to sicca controls. In an effort to identify novel potential epigenetic markers that could prove useful in diagnosis and disease monitoring, we explored whether DNA methylation differences can also be detected in saliva from SS patients compared to sicca controls. We performed DNA methylation analysis by methylation-sensitive restriction digestion followed by quantitative real-time polymerase chain reaction of selected genomic loci in saliva samples of 16 SS patients and 10 sicca controls with negative MSG biopsy. We identified reduced DNA methylation of the imprinting control region (ICR) of the H19 locus in SS patient saliva compared to sicca controls. Levels of saliva H19 ICR methylation were negatively correlated with C4 serum complement levels. Consistent with the reduced methylation of the ICR, H19 RNA levels were increased in SS patient peripheral blood mononuclear cells (PBMCs), while no significant change was observed in MSG H19 RNA levels compared to sicca controls. Our findings support that H19 ICR methylation could be a useful molecular epigenetic marker in monitoring patients with SS, highlighting saliva as a valuable biological sample in SS research and clinical practice. The role of H19 in SS pathogenesis remains to be addressed.     

EAACI position paper on diet diversity in pregnancy,infancy and childhood: Novel concepts and implications for studies in allergy and asthma

To fully understand the role of diet diversity on allergy outcomes and to set standards for conducting research in this field, the European Academy of Allergy and Clinical Immunology Task Force on Diet and Immunomodulation has systematically explored the association between diet diversity and allergy outcomes. In addition, a detailed narrative review of information on diet quality and diet patterns as they pertain to allergic outcomes is presented. Overall, we recommend that infants of any risk category for allergic disease should have a diverse diet, given no evidence of harm and some potential association of benefit in the prevention of particular allergic outcomes. In order to harmonize methods for future data collection and reporting, the task force members propose relevant definitions and important factors for consideration, when measuring diet diversity in the context of allergy. Consensus was achieved on practice points through the Delphi method. It is hoped that the definitions and considerations described herein will also enable better comparison of future studies and improve mechanistic studies and pathway analysis to understand how diet diversity modulates allergic outcomes.     

Preoperative TruCulture® whole blood cytokine response predicts post-operative inflammation in pancreaticoduodenectomy patients—A pilot cohort study

Major surgery is associated with substantial morbidity and mortality with early post-operative adverse events (POAE) occurring in 30% of patients within the first 30 days. The underlying pathogenesis is multifactorial, including immune dysfunction and increased inflammatory response to surgery. We investigated preoperative immune function by the TruCulture® whole blood technique in a cohort of patients undergoing pancreaticoduodenectomy (PD), hypothesizing that patients developing inflammatory POAE defined as leucocytosis, fever or high (above median) area under the curve (AUC) C-reactive protein (CRP) the first post-operative week would display perturbed preoperative immune function. Sixty-two adult patients were screened, 30 included and 11 excluded post-inclusion due to other surgical procedures than PD and post-operative complications directly attributed to surgery, leaving 19 patients for analysis of preoperative immune function. Patients developing leucocytosis (n = 5, 26%) had lower Toll-like receptor (TLR)-3–stimulated IL-12p40 and higher Candida Albicans (TLR1/2/4/6, Dectin-1)-stimulated TNF-α, compared to patients without leucocytosis (all P < .05). Patients developing fever (n = 7, 37%) had lower TLR7/8-stimulated IFN-γ and patients with high AUC CRP (n = 9, 47%) had lower TLR3-stimulated IFN-γ and IL-6 and lower TLR7/8-stimulated IL-10 (all P < .05), compared to patients without fever or low CRP, respectively. In conclusion, patients with inflammatory POAE displayed lower preoperative stimulated IL-12p40, IFN-γ, IL-6 and IL-10 and higher TNF-α response, compared to patients without inflammatory POAE. This finding suggests that TruCulture is a feasible immunologic screening tool in surgical patients, with a potential for preoperative identification of patients at increased risk for inflammatory POAE, allowing for risk-based intervention trials.     

2019新型冠状病毒导致的致命肺渗漏的病理生理学机制和防治策略:兼论血透的应用与依据

自2019年12月爆发以来,2019新型冠状病毒已在全球造成2872人死亡(截至2020年2月28日),并且有超过8000名患者仍处于严重状况。该病毒和由该病毒引起的医疗状况被分别命名为SARS-CoV-2(severe acute respiratory syndrome coronavirus-2)和COVID-19(coronavirus disease 2019)。虽然已经广泛应用了抗病毒、对症和功能支持性疗法,每天仍有大量患者死于该病毒感染。SARS-CoV-2主要通过2型肺泡上皮细胞上的血管紧张素转化酶2(angiotensin-converting enzyme 2,ACE2)首先感染肺,其最常见的致命并发症是急性呼吸窘迫综合征(acute respiratory distress syndrome,ARDS)[1]。     

CHOP在索拉菲尼联合辛二酰苯胺异羟肟酸诱导人肝癌细胞MHCC97L凋亡中的作用

目的:探讨CCAAT/增强子结合蛋白同源蛋白(CHOP)在索拉菲尼联合辛二酰苯胺异羟肟酸(SAHA)诱导人肝癌细胞MHCC97L凋亡中的作用。方法:采用CCK-8法检测索拉菲尼联合SAHA对MHCC97L细胞活力的影响;采用流式细胞术检测索拉菲尼联合SAHA对细胞周期及细胞凋亡的影响;应用Western blot法检测索拉菲尼联合SAHA对MHCC97L细胞中内质网应激相关分子葡萄糖调节蛋白78(GRP78)、蛋白激酶R样内质网激酶(PERK)、p-PERK、活化转录因子4(ATF4)及CHOP蛋白表达的影响。此外,应用CHOP siRNA沉默CHOP后,采用流式细胞术观察索拉菲尼联合SAHA对MHCC97L细胞凋亡的影响。结果:索拉菲尼联合SAHA可使MHCC97L细胞活力明显下降(P<0.05),细胞周期结果显示细胞生长被阻滞在G 1期;Western blot结果显示索拉菲尼联合SAHA可显著上调上述内质网应激凋亡通路中相关蛋白的表达,同时流式细胞术检测发现索拉菲尼联合SAHA可显著促进MHCC97L细胞凋亡(P<0.01);CHOP siRNA能显著抑制索拉菲尼联合SAHA诱导的细胞凋亡。结论:索拉菲尼联合SAHA可显著抑制MHCC97L细胞生长并诱导其凋亡,机制可能与上调内质网应激凋亡通路中CHOP的表达有关。     

Decreased CDKL2 expression is correlated with the progression and poor prognosis of glioma

Glioma is the most common form of malignant intracranial tumors. Cyclin-dependent kinase-like 2 (CDKL2) was observed in various regions of the brain, but the specific role of CDKL2 in glioma has not been reported yet. In the present study, the expression of CDKL2 mRNA was detected by real-time QPCR in freshly collected glioma and para-carcinoma tissues, and we collected genomic and clinical data from The Cancer Genome Atlas to determine mRNA expression levels of CDKL2 in the normal brain and glioma samples. Moreover, western blot assay and immunohistochemistry experiments were implemented to identify CDKL2 protein expression, and clinical pathology characteristics from 151 glioma cases and thirty-four para-carcinoma tissues were also examined. The relationship between the levels of CDKL2 expression and clinical data was analyzed. Low mRNA and protein expression of CDKL2 was observed in glioma tissues compared to non-cancerous tissues. In addition, low levels of CDKL2 correlated with Astrocytic type, higher clinical WHO grade, and higher Ki-67 expression in glioma. Low mRNA and protein expression of CDKL2 in glioma predicted an observably shorter overall survival time than high expression. However, as revealed by multivariate analysis, CDKL2 protein expression was not an independent prognostic biomarker for the survival of patients with glioma. Our study firstly determined that low levels of CDKL2 expression are associated with poor clinical diagnosis. Thus, CDKL2 may serve as a prognostic factor of glioma.     

Protective response of Sestrin under stressful conditions in aging

The aging at cellular level manifests itself in the form of uncontrolled formation of ROS, chronic inflammation, and increased susceptibility to cellular stress. Aging is often regarded as a risk factor for several diseases due to several age-associated pathological changes in cells. Sestrin (Sesn) is an important molecule for controlling normal cellular physiology and play a significant role in the progression of certain age-associated cellular pathologies. This review deals with the structure, function, regulation, signaling network, and the potential role of Sesn in age-associated cellular pathophysiology. The cellular response mediated by Sesn under stressful conditions and rescue mechanism is discussed. It would be interesting to find out the precise physiological role of Sesn in the regulation of cellular aging. The anti-aging activity of Sesn may benefit to prevent various age-associated diseases and have clinical utility in diagnostic and therapeutic intervention.