Objective:Obesity-induced kidney injury contributes to the development of diabetic nephropathy(DN).Here,we identified the functions of ubiquitin-specific peptidase 19(USP19)in HK-2 cells exposed to a combination of high glucose(HG)and free fatty acid(FFA)and determined its association with TGF-beta-activated kinase 1(TAK1).Methods:HK-2 cells were exposed to a combination of HG and FFA.USP19 mRNA expression was detected by quantitative RT-PCR(qRT-PCR),and protein analysis was performed by immunoblotting(IB).Cell growth was assessed by Cell Counting Kit-8(CCK-8)viability and 5-ethynyl-2'-deoxyuridine(EdU)proliferation assays.Cell cycle distribution and apoptosis were detected by flow cytometry.The USP19/TAK1 interaction and ubiquitinated TAK1 levels were assayed by coimmunoprecipitation(Co-IP)assays and IB.Results:In HG+FFA-challenged HK-2 cells,USP19 was highly expressed.USP19 knockdown attenuated HG+FFA-triggered growth inhibition and apoptosis promotion in HK-2 cells.Moreover,USP19 knockdown alleviated HG+FFA-mediated PTEN-induced putative kinase 1(PINK1)/Parkin pathway inactivation and increased mitochondrial reactive oxygen species(ROS)generation in HK-2 cells.Mechanistically,USP19 stabilized the TAK1 protein through deubiquitination.Importantly,increased TAK1 expression reversed the USP19 knockdown-mediated phenotypic changes and PINKl/Parkin pathway activation in HG+FFA-challenged HK-2 cells.Conclusion:The findings revealed that USP19 plays a crucial role in promoting HK-2 cell dysfunction induced by combined stimulation with HG and FFAs by stabilizing TAK1,providing a potential therapeutic strategy for combating DN.

Objective:Colorectal cancer(CRC),a prevalent malignancy worldwide,has prompted extensive research into anticanccr drugs.Traditional Chinese medicinal materials offer promising avenues for cancer management due to their diverse pharmacological activities.This study investigated the effects of Notopterygium incisum,a traditional Chinese medicine named Qianghuo(QH),on CRC cells and the underlying mechanism.Methods:The sulforhodamine B assay and colony formation assay were employed to assess the effect of QH extract on the proliferation of CRC cell lines HCT116 and Caco-2.Propidium iodide(PI)staining was utilized to detect cell cycle progression,and PE Annexin V staining to detect apoptosis.Western blotting was conducted to examine the levels of apoptotic proteins,including B-cell lymphoma 2-interacting mediator of cell death(BIM),B-cell lymphoma 2(Bcl-2),Bcl-2-associated X protein(BAX)and cleaved caspase-3,as well as BIM stability after treatment with the protein synthesis inhibitor cycloheximide.The expression of BAX was suppressed using lentivirus-mediated shRNA to validate the involvement of the BIM/BAX axis in QH-induced apoptosis.The in vivo effects of QH extract on tumor growth were observed using a xenograft model.Lastly,APCMin+mice were used to study the effects of QH extract on primary intestinal tumors.Results:QH extract exhibited significant in vitro anti-CRC activities evidenced by the inhibition of cell proliferation,perturbation of cell cycle progression,and induction of apoptosis.Mechanistically,QH extract significantly increased the stability of BIM proteins,which undergo rapid degradation under unstressed conditions.Knockdown of BAX,the downstream effector of BIM,significantly rescued QH-induced apoptosis.Furthermore,the in vitro effect of QH extract was recapitulated in vivo.QH extract significantly inhibited the tumor growth of HCT116 xenografts in nude mice and decreased the number of intestinal polyps in the APCMin+mice.Conclusion:QH extract promotes the apoptosis of CRC cells by preventing the degradation of BIM.

目的:探究汉黄芩素调节Hippo/Yes相关蛋白(YAP)信号通路对慢性心力衰竭(CHF)大鼠心肌纤维化的影响.方法:采用腹腔注射阿霉素的方式构建大鼠CHF模型,成功造模36只大鼠,将其随机分为模型组、汉黄芩素组(汉黄芩素100 mg/kg)、汉黄芩素+维替泊芬组(100 mg/kg汉黄芩素+100 mg/kg维替泊芬),每组12只.剩余12只大鼠作为对照组.采用彩色多普勒超声系统检测各组大鼠心功能参数:左室射血分数(LVEF)、左室短轴缩短率(LVFS)、左室舒张末期内径(LVEDD)、左室收缩末期内径(LVESD);称重并计算各组大鼠心脏质量指数(HMI)和左心室质量指数(LVMI);酶联免疫吸附法(ELISA)检测心肌组织超氧化物歧化酶(SOD)、丙二醛(MDA)水平;Masson染色法检测大鼠心肌胶原容积分数(CVF)和血管周围纤维面积和血管管腔面积比值(PVCA/LA);苏木精-伊红(HE)染色观察大鼠心肌组织病理学变化;蛋白免疫印迹(Western Blot)法检测大鼠心肌组织Hippo/YAP信号通路相关蛋白、基质金属蛋白酶(MMP)-2、MMP-9、结缔组织生长因子(CTGF)表达.结果:与对照组相比,模型组大鼠LVEF、LVFS、心肌组织SOD水平及哺乳动物ste-20样激酶(MST)1/2、大型肿瘤抑制因子(LATS)1/2磷酸化水平明显降低(P＜0.05),LVEDD、LVESD、HMI、LVMI、心肌组织MDA水平、CVF、PVCA/LA、心肌组织YAP、MMP-2、MMP-9、CTGF蛋白表达明 显升高(P＜0.05),心肌组织出现大量胶原纤维沉积和损伤.与模型组相比,汉黄芩素组LVEF、LVFS、心肌组织SOD水平、MST1/2、LATS1/2磷酸化水平明显升高(P＜0.05),LVEDD、LVESD、HMI、LVMI、心肌组织 MDA 水平、CVF、PVCA/LA、心肌组织 YAP、MMP-2、MMP-9、CTGF 蛋白表达明显降低(P＜0.05),心肌组织胶原纤维沉积和损伤减少.维替泊芬增强了汉黄芩素对CHF大鼠心肌纤维化的改善作用.结论:汉黄芩素可能通过激活Hippo/YAP信号通路、抑制YAP表达来减轻CHF大鼠心肌纤维化.

背景 先天性心脏病(CHD)青少年在成长过程中面临身心挑战,赋能水平是衡量其自我管理能力和生存质量的重要指标.目前中国缺乏相应的评估工具.目的 对哥德堡CHD青少年赋能量表(GYPES-CHD)进行汉化,并检验其信、效度,以便在中国的CHD青少年群体中推广应用.设计 信、效度分析.方法 运用Brislin翻译模型经直译、回译和对比回译进行量表翻译,邀请 7 名相关领域专家,抽取 15 名不同年龄段和学业程度的CHD青少年行认知性访谈.纳入在复旦大学附属儿科医院(我院)确诊为CHD并处于我院长期随访队列,具有一定的读写能力,能够理解问卷的 10～18 岁青少年.排除合并影响智力发育、需多次手术的其他系统疾病及导致精神异常的疾病的患儿.通过问卷星由患儿或家长填写一般资料调查表、中文版GYPES-CHD和中文版一般自我效能感量表(GSES).校标关联效度以中文版GSES为校标量表,信度采用内部一致性信度和重测信度评价.主要结局指标 中文版GYPES-CHD信度和效度.结果 共发放 166 份问卷,回收 153 份(92.2%),153 例进入本文分析.中文版GYPES-CHD分为 5 个维度,共 15 个条目;量表各条目及维度得分与量表总分的Pearson相关系数为 0.210～0.538(P＜0.001);15 个条目的决断值为 4.218～12.358(P＜0.001).量表的Cronbach's α系数为 0.905,5 个分维度的Cronbach's α系数为 0.740～0.851.重测信度为 0.869,5 个维度的Cronbach's α系数 0.783～0.837,两次量表总分相关系数 0.841.中文版GSES总分与中文版GYPES-CHD总分之间的相关系数为 0.52(P＜0.01),与 5 个维度的效标关联效度为 0.375～0.495(P均＜0.01).结论 中文版GYPES-CHD量表具有较好的信效度,可用于评估中国文化背景下CHD青少年的赋能程度.

Objective:Lindqvist-type polyoxometalates(POMs)exhibit potential antitumor activities.This study aimed to examine the effects of Lindqvist-type POMs against breast cancer and the underlying mechanism.Methods:Using different cancer cell lines,the present study evaluated the antitumor activities of POM analogues that were modified at the body skeleton based on molybdenum-vanadium-centered negative oxygen ion polycondensations with different side strains.Cell colony formation assay,autophagy detection,mitochondrial observation,qRT-PCR,Western blotting,and animal model were used to evaluate the antitumor activities of POMs against breast cancer cells and the related mechanism.Results:MO-4,a Lindqvist-type POM linking a proline at its side strain,was selected for subsequent experiments due to its low half maximal inhibitory concentration in the inhibition of proliferation of breast cancer cells.It was found that MO-4 induced the apoptosis of multiple types of breast cancer cells.Mechanistically,MO-4 activated intracellular mitophagy by elevating mitochondrial reactive oxygen species(ROS)levels and resulting in apoptosis.In vivo,breast tumor growth and distant metastasis were significantly reduced following MO-4 treatment.Conclusion:Collectively,the results of the present study demonstrated that the novel Lindqvist-type POM MO-4 may exhibit potential in the treatment of breast cancer.

Objective:The Vickers ligament is thought to hinder the growth of palmar ulnar radius by tethering the lunate to the radius,leading to Madelung deformity.The purpose of this study was to clarify the nature of the Vickers ligament and investigate its pathogenesis in Madelung deformities based on our observation of the Vickers ligament.Methods:All 22 patients(33 wrists)with Madelung deformities treated surgically between 2018 and 2022 were included.The diagnosis was confirmed radiographically in all patients.The three-dimensional computed tomography(3D-CT)data of 16 patients(19 wrists)were available.Magnetic resonance imaging(MRI)data were available for 9 patients(14 wrists).Wrist arthroscopy was used in 4 patients.The Vickers ligament was resected and submitted for histopathological examination in 8 patients.Radiographic outcomes,3D-CT,MRI,arthroscopy,surgical findings,and histopathology of the Vickers ligament were evaluated.Results:The 3D-CT revealed that the Vickers ligament originated in the metaphysis and formed a metaphyseal defect at the palmar ulnar radius.In the sequential MR coronal images,the Vickers ligament could be divided into 3 branches,extending to the lunate,triquetrum and ulnar styloid.Arthroscopy and surgical findings revealed that the nature of the Vickers ligament was the stretched palmar ligament of the wrist.The histopathology results revealed ligamentous tissue and fibrocartilaginous metaplasia with a structure similar to that of the triangular fibrocartilage complex(TFCC).Conclusions:The Vickers ligament is not a separate aberrant ligament.The nature of the Vickers ligament is a combination of the stretched TFCC ligament(palmar radioulnar ligament,ulnotriquetral ligament and ulnolunate ligament)and radiolunate ligament.The possible pathogenesis of Madelung deformity might be focal early epiphyseal closure at the middle part of the sigmoid notch,which leads to focal growth retardation of the radius and pulls palmar ligaments proximally to form the Vickers ligament.

目的:探讨血清骨形态发生蛋白9(BMP9)与生长分化因子15(GDF15)表达在脓毒症诊断和预后评估中的价值.方法:收集脓毒症患者30例作为脓毒症组,非脓毒症重症患者31例为非脓毒症组,同期体检的健康成人23例为对照组.追踪随访脓毒症组患者28d转归,分为存活组16例和死亡组14例.分析比较3组一般资料、临床指标及血清BMP9与GDF15水平.采用Logistic回归分析脓毒症发病及预后的危险因素.通过受试者工作特征曲线(ROC)的曲线下面积(AUC)评估血BMP9及GDF15在脓毒症诊断及预后预测中的价值.结果:与非脓毒症组和对照组比较,脓毒症组血清BMP9表达明显增高(P均＜0.05).与对照组比较,脓毒症组血清GDF15表达明显增高(P＜0.05).脓毒症死亡组患者血清BMP9、GDF15水平显著高于存活组(P均＜0.05).Logistic回归示血BMP9、C反应蛋白(CRP)、序贯器官衰竭评分(SOFA)是脓毒症发病的独立危险因素,GDF15是脓毒症患者死亡的独立影响因素.BMP9联合CRP诊断脓毒症的AUC为0.845,特异性83.9％,灵敏度73.3％,诊断效能与序贯器官衰竭评分相当(AUC 0.809,特异性83.9％,灵敏度70.0％).GDF15联合中性粒细胞与淋巴细胞的比值(NLR)对脓毒症患者预后预测的AUC为0.898,特异性80％,灵敏度100％,预测效能与急性生理与慢性健康状况评估(APACHE Ⅱ)评分相当(AUC 0.687,特异性93.9％,灵敏度53.3％).结论:脓毒症患者BMP9和GDF15表达明显增高,BMP9联合CRP对脓毒症诊断价值较高.GDF15联合NLR对脓毒症患者预后预测效能较高.

目的 了解我国心脑血管疾病(cardiovascular diseases,CVD)与空气污染的相关研究状况、关注热点、发展趋势与前沿,为我国研究发展提供参考.方法 检索中国知识资源总库(CNKI)、中文科技期刊数据库(VIP)、中国学术期刊数据库(万方)中的相关研究文献.对检索结果进行去重、无关文献剔除、缺失信息(发表时间、作者、关键词、机构等)详细补充、同一机构和同义词的识别替换等处理.统计发文量分布并绘制知识图谱.结果 使用有效中文文献556篇,发文数量整体呈波动上升趋势,近10年增幅扩大明显.主要作者团队和机构内的合作较为密切,但之间合作较为缺乏.研究呈现出污染物、疾病、其他结局或指标、研究方法、动物模型、机制等研究热点.发展趋势与前沿方面,PM2.5的研究热度可能持续,而近年突现明显的臭氧、气温、健康风险等方面也可能是未来相关研究的部分热点.随着时间发展,相关研究内容逐渐具体化、细化和全面化.结论 基于本研究文献,我国CVD与空气污染相关研究可能正处于并将继续处于快速发展的初期阶段,将持续受到关注.建议进一步加强跨区域、跨机构、跨团队的多元研究合作,持续关注该领域的热点和发展趋势变化,推动我国CVD与空气污染相关研究的进一步发展.

背景 PI3Kδ 过度活化综合征(APDS)采用传统治疗方案预防感染的疗效欠佳,近年来雷帕霉素被用于PIK3CD基因突变所致的APDS1 患儿的临床治疗.目的 探讨雷帕霉素治疗APDS1 的疗效和安全性.设计 病例系列报告.方法 纳入2017 年6 月至2023 年6 月在浙江大学医学院附属儿童医院经基因检测确诊为APDS1 且口服雷帕霉素治疗的连续病例.国内儿童雷帕霉素治疗APDS引起的非肿瘤性淋巴细胞增生,仍属于超说明书用药,用药前家长均充分了解用药风险并签署了知情同意书.雷帕霉素口服剂量为 1 mg·m-2·d-1.主要结局指标 ①12 个月内发生肺炎的次数;②B超评估肝、脾、淋巴结肿大情况.结果 4 例使用雷帕霉素治疗的 APDS1 患儿中,男 3 例、女 1 例,发病年龄为(35.5±17.9)月龄,确诊年龄(56.5±35.0)月龄;全外显子组测序均显示PIK3CD基因c.3061G＞A(p.E1021K)新发杂合突变;均因"反复咳嗽"就诊,均有肝、脾、淋巴结肿大;均有肺炎,反复腮腺炎 2 例,伴特异性皮炎、炎症性肠病和韦格纳肉芽肿病各1 例,生长迟缓 2 例;4 例均行支气管镜检查,3 例有支气管内膜鹅卵石样凸起;均有CD19+B细胞比例下降、CD4+/CD8+倒置,3 例 IgM升高,1 例 IgG下降.在雷帕霉素治疗前均予IVIG、抗感染、糖皮质激素等治疗,治疗后仍有反复呼吸道感染、肝脾肿大,且 3 例出现PLT减少,2 例出现贫血.4 例患儿确诊后 1～44 个月起口服雷帕霉素,疗程 12～58 个月.雷帕霉素治疗后 12 个月肺炎年均次数由 5.3 次降至 1.0 次,肝、脾和浅表淋巴结肿大均明显改善,Hb和PLT均恢复至正常水平,但免疫学指标在治疗前后比较差异均无统计学意义.随访期间未发现雷帕霉素相关不良反应,无发生肿瘤及死亡病例.结论 雷帕霉素对APSD1 有一定疗效且相对安全.

目的 观察骨质疏松性椎体压缩性骨折(osteoporotic vertebral compression fracture,OVCF)患者在经皮椎体成形术后使用特立帕肽序贯地舒单抗对比序贯唑来膦酸治疗绝经后骨质疏松症的疗效.方法 回顾性选择 2020 年 12 月至 2023 年 12月在南京市第一医院行经皮椎体成形术且术后使用特立帕肽治疗 12 个月的绝经后骨质疏松症患者 60 例,根据序贯用药情况将纳入患者分为特立帕肽序贯地舒单抗组和特立帕肽序贯唑来膦酸组,每组 30 例.比较两组治疗前、治疗 6 个月、治疗 12 个月的血清P1NP、血清β-CTX、腰椎及髋部骨密度(bone mineral density,BMD)变化情况和再骨折的发生情况,评估两组的疗效差异.结果 地舒单抗组治疗 12 个月的髋部BMD增长率高于唑来膦酸组(P=0.001).两组治疗 12 个月后的腰椎和髋部BMD均高于治疗前(P＜0.05),地舒单抗组和唑来膦酸组治疗 12 个月的腰椎BMD较治疗前分别提升 8.7%和 6.7%,髋部BMD较治疗前分别提升 6.6%和 2.9%.地舒单抗组治疗 6 个月、12 个月的血清P1NP和血清β-CTX水平均低于唑来膦酸组(P＜0.05).两组治疗期间再骨折发生率无统计学差异(P＞0.05).结论 合并OVCF的绝经后骨质疏松症患者,特立帕肽序贯地舒单抗较序贯唑来膦酸对提高髋部骨密度和降低骨代谢标志物的作用更明显,两种治疗方案对再骨折的发生率无明显影响.