关键词： 青柠提取物   2型糖尿病   网络药理学   体内实验   作用机制  

摘要： 基于网络药理学和体内实验探讨青柠提取物（Citrus aurantiifolia extract，CAE）治疗2型糖尿病（type 2 diabetes mellitus，T2DM）作用机制。采用超高效液相色谱仪对CAE中主要成分进行分析，并对橙皮苷、柚皮素、川陈皮素、橘红素等黄酮类成分的含量进行定量检测。应用网络药理学方法预测CAE治疗T2DM作用信号通路。构建高脂饲料喂养及链脲佐菌素诱发T2DM小鼠模型，并使用CAE对T2DM的治疗作用进行动物实验验证，初步验证网络药理学的预测结果。结果显示，从CAE中，检测得到主要成分橙皮苷、柚皮素、川陈皮素、橘红素的含量分别为5.791、0.112、0.523、0.498 mg/g，预测得到此4个成分在治疗T2DM作用靶点有172个，关键靶点10个。GO和KEGG富集分析结果共获得251条通路，主要涉及脂质和动脉粥样硬化、内分泌抵抗、糖尿病并发症中的高级糖基化终末产物-受体（advanced glycation end products-receptor for advanced glycation end products，AGE-RAGE）信号通路等。T2DM小鼠模型实验显示，CAE可显著降低T2DM小鼠血糖、血清低密度脂蛋白、总胆固醇、肌酐、尿素氮的水平，并显著提高血清中高密度脂蛋白的水平。RT-qPCR实验显示，与T2DM组相比，蛋白激酶B（protein kinase B，AKT）mRNA的表达显著升高，糖原合成酶激酶3β（glycogen synthase kinase-3β，GSK3β）mRNA的表达显著降低。本研究初步表明CAE可能通过橙皮苷、柚皮素、川陈皮素、橘红素等主要成分，调控AKT/GSK3β通路，发挥调节糖脂代谢紊乱、改善T2DM的作用。

关键词： aging   circadian rhythms and sleep   cyclic-AMP response element binding protein   electroencephalography   memory  

摘要： The dysregulation of sleep-wake patterns that occurs during aging is well documented and coincides with changes in intracellular signaling pathways that regulate sleep, such as the calcium/calmodulin-dependent protein kinase (CaMKII)/cyclic-AMP response element-binding protein (CREB) pathway. However, much less is known about the relationship between other CREB-activating members of the CaMK family, such as calcium/calmodulin-dependent protein kinase IV (CaMKIV), and the regulation of sleep. Using 2- to 4-month-old (young adult) and 22- to 24-month-old (aged) male and female CaMKIV-overexpressing (CaMKIV-OE) mice, we observed that overexpression of CaMKIV in the forebrain decreased wakefulness and increased the amount of non-rapid eye movement (NREM) and rapid eye movement (REM) sleep in aged male mice, but not young adult male mice, in comparison to age- and sex-matched controls. Conversely, female mice overexpressing CaMKIV displayed no significant differences in the percentage of time spent in each vigilance state compared to their wild-type counterparts, regardless of age. While CaMKIV overexpression also led to more sleep-wake fragmentation in young adult and aged male mice, aged female mice displayed more consolidated NREM sleep. Overall, our results suggest that CaMKIV overexpression enhances sleep in aged male mice, and differentially affects sleep-wake architecture based on sex and age, providing insights into the potential mechanism by which CaMKIV overexpression enhances memory.

摘要： Restoration of the tumor suppressor function of tumor-associated p53 mutants, including the Y220C substitution, has posed a significant challenge for therapeutic discovery. In this study, we describe rezatapopt (PC14586), part of a series of compounds designed to reactivate the p53 Y220C mutant. These compounds restore p53 tumor suppressor function by correcting its conformation and enabling it to bind DNA and activate downstream target genes, thus inducing antiproliferative changes in tumor cells. Our findings are supported by biochemical and structural analysis, in vitro and in vivo transcriptomics, and functional data, revealing the recovery of multiple aspects of the wild-type p53 program. These compounds demonstrate potent antitumor activity in preclinical models as single agents and in combination with immunotherapy. Currently, rezatapopt is being evaluated in a registrational phase II clinical trial for patients with advanced solid tumors harboring the TP53 Y220C ***: Rezatapopt is a clinical-stage compound that offers a promising treatment option for TP53-mutant cancers. This study details the characterization of rezatapopt and its related compounds, which can reinstate the tumor suppressor activity of the p53 Y220C mutant. These results emphasize the potential for targeting p53 mutations in cancer therapy.

关键词： 产后期   抑郁   泌乳Ⅱ期启动延迟   Meta分析   中国  

摘要： 目的 探讨中国人群产后抑郁症状与泌乳Ⅱ期启动延迟（DOL Ⅱ）的关系及危险因素。方法 通过计算机检索PubMed、Web of Science、Embase、Scopus、Cochrane Library、中国生物医学文献服务系统、中国知网、万方医学网、维普资讯中文期刊服务平台等数据库。检索时限为建库至2024年5月31日。对所有符合纳入/排除标准的研究进行文献质量评价，并提取相关资料，应用STATA15.0统计软件进行数据分析。结果 共纳入11项研究，涉及4 026例孕产妇。产后抑郁症状女性发生DOL Ⅱ的风险明显增加，差异有统计学意义（优势比=2.509，95%可信区间：1.828～3.445，P＜0.001），产后抑郁症状是DOL Ⅱ的独立影响因素。妊娠糖尿病、高龄、早产、妊娠高血压、初产妇、孕前超重是产后抑郁症状女性发生DOL Ⅱ的危险因素（优势比=2.068、2.260、1.864、2.503、2.469、2.500，95%可信区间：1.576～2.713、1.843～2.773、1.216～2.858、1.839～3.409、2.046～2.979、1.804～3.464，P＜0.001、＜0.001、0.004、＜0.001、＜0.001、＜0.001）。结论 我国产后抑郁症状人群发生DOL Ⅱ的风险明显增加，且为其独立影响因素。妊娠糖尿病、高龄、早产、妊娠高血压、初产妇、孕前超重等是产后抑郁症状女性发生DOL Ⅱ的危险因素。为降低DOL Ⅱ的发生率、促进我国新生儿6个月内纯母乳喂养率应加强对产后抑郁症状的筛查及高危群体的早期识别与科学干预。

摘要： Mutations in the TP53 tumor-suppressor gene in human cancer are unique in that 60% to 70% are of the missense variety, resulting in a full-length protein that is often highly expressed in patients' tumors. These missense mutant proteins often exhibit pro-oncogenic activities (referred to as gain of function) in mouse models and human cell lines and correlate with poor cancer prognosis in some cases.

关键词： 糖尿病视网膜病变   社会支持   心理一致感   视觉相关生活质量   中介作用  

摘要： 目的 探讨心理一致感在糖尿病视网膜病变患者社会支持和视觉相关生活质量间的中介作用，旨在为医护人员制定针对性的干预措施以提高糖尿病视网膜病变患者视觉相关生活质量提供参考。方法 采用便利抽样法，选取2024年1—6月收治于贵州省贵阳市某三甲医院的225名糖尿病视网膜病变住院患者，采用一般资料调查表、社会支持评定量表、心理一致感量表、视觉相关生活质量量表进行问卷调查。使用Amos软件建立结构方程模型并进行中介效应分析。结果 糖尿病视网膜病变患者社会支持评分（31.00±5.62）分、心理一致感（59.14±8.33）分、视觉相关生活质量（41.06±13.77）分。相关性分析显示糖尿病视网膜病变患者社会支持与心理一致感及视觉相关生活质量总分呈正相关（均P<0.001）；结构方程模型结果显示，糖尿病视网膜病变患者社会支持能够正向预测视觉相关生活质量，患者心理一致感在社会支持与视觉相关生活质量间起部分中介作用，中介效应占比为27.6%。结论 糖尿病视网膜病变患者的心理一致感在社会支持与视觉相关生活质量间起部分中介作用，需提高患者的心理一致感水平，加强社会支持力度，从而提高患者的视觉相关生活质量。

摘要： Cooperativity between mutant p53 and mutant KRAS, although recognized, is poorly understood. In pancreatic cancer, mutant p53 induces splicing factor hnRNPK, causing an isoform switch that produces overexpression of GTPase-activating protein 17 isoform 1 (GAP17-1). GAP17-1 is mislocalized in the cytosol instead of the membrane, owing to the insertion of exon 17 encoding a PPLP motif, thus allowing mutant KRAS to remain in the GTP-bound hyperactive state. However, the role of PPLP in influencing GAP17-1 mislocalization remains unclear. We show that Smad ubiquitination regulatory factor 2 (SMURF2), a known stabilizer of mutant KRAS, interacts with GAP17-1 via the PPLP motif and displaces it from the membrane, facilitating mutant p53-mediated mutant KRAS hyperactivation. We used cell lines with known KRAS and TP53 mutations, characterized SMURF2 expression in multiple pancreatic cancer mouse models (iKras*;iKras*, p53*, and p48-Cre;Kras*), and performed single-cell RNA sequencing and tissue microarray on preclinical and clinical samples. We found that SMURF2 silencing profoundly reduces the survival of mutant TP53;KRAS-driven cells. We show that a GAP17-1 AALA mutant does not bind to SMURF2, stays in the membrane, and keeps mutant KRAS in the GDP-bound state to inhibit downstream signaling. In mouse models, mutant KRAS and SMURF2 upregulation are correlated with pancreatic intraepithelial neoplasia and ductal adenocarcinoma lesions. Furthermore, patients with pancreatic ductal adenocarcinoma who received neoadjuvant therapy and express moderate-to-high SMURF2 show decreased overall survival (P = 0.04).Implications: In TP53 and KRAS double-mutated pancreatic cancer, SMURF2-driven GAP17-1 membrane expulsion facilitates mutant p53-KRAS oncogenic synergy.

关键词： 毛霉菌病   鼻窦疾病   眶内并发症   内镜手术   综合治疗  

摘要： 目的 探讨鼻眶脑型毛霉菌病的临床特征及综合治疗方法。方法 回顾性分析1例鼻眶脑型毛霉菌病患者的临床资料，并对其临床特征、诊断及治疗方法进行总结。结果 本例患者术后细菌及真菌培养提示耐甲氧西林表皮葡萄球菌及丝状真菌感染，利奈唑胺、伏立康唑抗感染治疗效果不佳，复送真菌培养考虑毛霉菌感染，给予艾沙康唑治疗，随访6个月，患者左侧眶周肿胀及疼痛消失，左眼睑上提功能完全恢复，视力仍无改善。结论 鼻腔鼻窦的丝状真菌感染有时不易明确其具体种类，需反复送检，早期明确真菌感染类型可为该类疾病的综合治疗争取宝贵时间。鼻眶脑型毛霉菌病进展迅速，及时手术及针对毛霉菌进行抗真菌治疗可有效控制病情进展。

关键词： 乌苏里拟鲿(Pseudobagrus ussuriensis)   急性高温胁迫   细胞凋亡   酶活性   基因表达  

摘要： 全球气候变暖引发水体温度波动加剧，高温天气频发，给乌苏里拟鲿(Pseudobagrus ussuriensis)的人工养殖带来了严峻挑战。为探讨急性高温胁迫对乌苏里拟鲿肝脏和鳃组织细胞凋亡的影响，揭示其潜在的生理机制，本研究设置对照组(22 ℃)、实验组(34 ℃急性高温胁迫)及恢复组(在急性高温胁迫24 h后恢复至22 ℃并持续24 h)，在急性高温胁迫下，分别于0、3、6、12、24 h进行采样，通过组织学观察、TUNEL法检测细胞凋亡、细胞凋亡相关酶活性分析及基因表达水平测定，系统评估高温胁迫及恢复过程中乌苏里拟鲿肝脏和鳃组织的生理响应机制。组织学分析显示，高温胁迫导致鳃组织上皮细胞脱落、炎性细胞浸润、鳃小片数量减少及结构损伤，温度恢复后部分病变得以修复，但仍存轻微异常。TUNEL检测显示，高温显著增加了肝脏组织的凋亡率。酶活性分析结果表明，急性高温胁迫显著提高了肝脏和鳃组织中Caspase-3和Caspase-9的酶活性，且在24 h时达到峰值，当温度恢复后，酶活性仍维持在较高水平。基因表达分析显示，肝脏中促凋亡基因TP53、Bax、Caspase-9和Caspase-3的表达呈动态变化，Apaf-1在3 h时达到峰值，而抗凋亡基因Bcl-2在胁迫初期表达下降，12 h后迅速升高并达到峰值；鳃组织中，促凋亡基因TP53、Bax和Caspase-9的表达未出现显著差异，Apaf-1和Caspase-3的表达在3 h时达到峰值，抗凋亡基因Bcl-2在3 h达到峰值，温度恢复后，各基因的表达回归至对照组水平。综上结果表明，34 ℃急性高温胁迫会造成乌苏里拟鲿组织及细胞器受损，诱导细胞凋亡发生。

关键词： ARF   p53   interferon   JAK1   STAT1  

摘要： The tumor suppressors p53 and ARF collaborate to prevent unwarranted cell proliferation and as such are two of the most frequently mutated genes in human cancer. Concomitant loss of functional p53 and ARF leads to massive gains in cell proliferation and transformation and is often observed in some of the most aggressive human cancer subtypes. These phenotypic gains are preceded by increased type I interferon (IFN) signaling that involves canonical STAT1 activation and a subsequent IFN-stimulated gene (ISG) signature. Here, we show that cells lacking p53 and ARF require active JAK1 to phosphorylate STAT1 on Y701 to maintain their high rate of proliferation. In fact, the use of selective JAK1 inhibitors ruxolitinib or baricitinib inhibited the induction of ISG's and the proliferation of p53 and ARF deleted cells. We identify a group of solid human tumors that lack functional p53 and ARF, show an expression signature of the upregulated type I IFN response genes, and are sensitive to selective JAK1 inhibitors. These data suggest that the type I IFN response acts as a positive driver of proliferation in the absence of p53 and ARF and, as such, presents itself as a potential therapeutic target in aggressive solid tumors.