Life sciences最新文献_第10页

The effect of modulation Piezo2 by IGF-1 on tactile hypersensitivity in BTBR model mice

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-05 DOI: 10.1016/j.lfs.2025.123449

Jinhe Zhai , Haiying Hao , Zihan Xu , Akemi Tomoda , Xinyi Zhang , Xinxin Wang , Yutong Liu , Xuan Cao , Dongxin Li , Yuying Zhang , Xueke Yao , Lili Fan , Jia Wang

Aims

Autism spectrum disorder (ASD) is classified as a neurodevelopmental disorder. Individuals with ASD exhibit a higher incidence of tactile hypersensitivity. However, the underlying mechanisms remain unclear. The dorsal root ganglion (DRG) plays a crucial role in influencing tactile processing. This study aims to integrate RNA sequencing (RNA-seq) and molecular biology experiments to identify key molecules involved in tactile hypersensitivity in ASD, further investigate related mechanisms, and develop effective intervention strategy.

Main methods

Using BTBR as the ASD model mouse and wild-type C57BL/6J as the control mouse, the differences in tactile sensitivity between them was compared. DRG were collected for RNA-seq analysis. Immunofluorescence and Enzyme-linked immunosorbent assay (ELISA) techniques were employed to validate the identified key molecules. And combined western blot to investigate the associated regulatory pathways.

Key findings

BTBR mice exhibit tactile hypersensitivity, which are associated with the upregulation of IGF-1 in the DRG. IGF-1 regulates the expression of Piezo2 ion channels. Inhibition of the IGF-1/Piezo2 pathway can significantly alleviate tactile hypersensitivity and social deficits in BTBR mice. Additionally, gentle touch intervention has been shown to reduce the overexpression of IGF-1/Piezo2 in the DRG, thereby ameliorating ASD symptoms.

Significance

The upregulation of the IGF-1/Piezo2 pathway in DRG may serve as a potential mechanism for tactile hypersensitivity observed in BTBR mice. Restoring the normalization of the IGF-1/Piezo2 is crucial for alleviating tactile hypersensitivity and synergistically rescues social deficits. Gentle touch intervention has the potential to ameliorate these behaviors through regulating IGF-1/Piezo2, positioning it as a promising strategy for ASD.

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引用次数: 0

Identification of biomarkers associated with macrophage polarization in diabetic cardiomyopathy based on bioinformatics and machine learning approaches

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-04 DOI: 10.1016/j.lfs.2025.123443

Yi Liu , Juan Zhang , Quancheng Han , Yan Li , Yitao Xue , Xiujuan Liu

Background

Numerous studies have investigated the role of macrophages in the pathogenesis of diabetic cardiomyopathy (DCM); however, the underlying mechanisms remain unclear.

Methods

The DCM dataset (GSE62203) was downloaded from the GEO database. DEGs and WGCNA key module genes were identified. Macrophage polarization-associated genes were obtained from the GeneCards database. GO and KEGG functional enrichment were constructed. Two machine learning techniques, LASSO logistic regression and random forest, were further used to identify hub genes. The diagnostic efficiency was evaluated using ROC curves. Single-gene GSEA investigated the biological functions. Then, the relationship between hub genes and macrophage pathways was explored. Predicted Transcription factor (TF), miRNA, and lncRNA. Single cell sequencing analysis was performed. Finally, experimental validation of the hub genes using the DCM rat model.

Results

Three hub genes (PGK1, LDHA, EDN1) were identified through machine learning approaches. All three hub genes were found to be associated with the HIF-1 signaling pathway. Functional enrichment analysis revealed that the HIF-1 signaling pathway and Glycolysis/Gluconeogenesis are potentially linked to DCM-induced macrophage polarization. The mRNA and protein expression levels of the hub genes were consistent with the bioinformatics analysis. Furthermore, mRNA expression of the hub genes showed a positive correlation with CD80 and CD86.

Conclusion

PGK1, LDHA, and EDN1 represent potential biomarkers for M1 macrophage polarization in DCM. These genes may facilitate M1 macrophage polarization in DCM. Targeting macrophage polarization could represent a novel therapeutic strategy for DCM.

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引用次数: 0

KLK8 modulates macrophage function following myocardial infarction by promoting the paracrine of epidermal growth factor from cardiac fibroblasts

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-04 DOI: 10.1016/j.lfs.2025.123445

Jinchao Song , Jiankui Du , Qian Zhao , Yuan Gao , Xing Tan , Binhai Cong

Aims

Tissue kallikrein-related peptidase 8 (KLK8) plays a significant role in the regulation of cardiac remodeling following myocardial infarction (MI). However, the impact of KLK8 on macrophage (MΦ) function in the context of MI remains to be elucidated.

Materials and methods

MI was induced through the ligation of the left anterior descending coronary artery for a duration of 1 h, followed by reperfusion. The morphological and molecular alterations in the heart were assessed at 24 h and 14 days post-ischemic injury. Adult rat cardiac fibroblasts and bone marrow-derived macrophages were employed to explore the underlying molecular mechanisms in vitro.

Key findings

In the acute phase of MI (24 h post-MI), KLK8 was observed to diminish the inflammatory response and mitigate tissue damage within the ischemic ventricle. Conversely, during the reparative phase of MI (14 days post-MI), KLK8 was found to enhance the accumulation of the M2 MΦs, elevate pro-fibrotic factors, and intensify cardiac fibrosis. The in vitro analysis revealed that KLK8 did not exert a direct effect on MΦs; rather, it facilitated the paracrine secretion of epidermal growth factor (EGF) from the cardiac fibroblasts. This EGF may play a role in inhibiting the pro-inflammatory activation of the MΦs and promoting their polarization towards the M2 phenotype under conditions of inflammatory stress.

Significance

In summary, KLK8 modulates MΦ function through the paracrine of EGF derived from cardiac fibroblasts, which may have implications for cardiac injury and remodeling following MI.

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引用次数: 0

CRBN deletion enhances mitochondrial metabolism by stimulating mitochondrial calcium accumulation in non-small cell lung cancer

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-04 DOI: 10.1016/j.lfs.2025.123444

Seungheon Shin , Steve K. Cho

CRBN (Cereblon), a substrate receptor of the CRL4 (Cullin4-RING E3 ubiquitin ligase) complex, has emerged as a key player in cancer metabolism. While its role in influencing metabolic phenotypes has been suggested, the precise functions of CRBN in cellular metabolism and cancer progression remain underexplored. This study investigates the impact of CRBN downregulation in lung cancer, focusing on mitochondrial metabolism and cellular functions. Data from The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) revealed significant reductions in CRBN expression at both mRNA and protein levels in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). This downregulation was further confirmed in most lung cancer cell lines examined. Functional analyses of CRBN knockout (KO) cells revealed substantial alterations in mitochondrial metabolism, including enhanced oxidative phosphorylation, increased mitochondrial membrane potential (ΔΨm), and elevated production of mitochondrial reactive oxygen species (mROS). CRBN deficiency also accelerated tricarboxylic acid (TCA) cycle flux and increased mitochondrial calcium accumulation, contributing to elevated ΔΨm and potentially compromised mitochondrial integrity. Additionally, CRBN KO cells demonstrated increased cell migration, which could be mitigated by inhibiting mitochondrial calcium import. These findings suggest that CRBN plays a pivotal role in regulating mitochondrial function and metabolic activity in non-small cell lung cancer. The loss of CRBN enhances mitochondrial metabolism and contributes to increased cancer cell migration, providing new insights into the metabolic adaptations associated with CRBN deficiency in cancer progression.

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引用次数: 0

IL-4-primed human umbilical cord mesenchymal stem cells-derived extracellular vesicles facilitate recovery in spinal cord injury via the miR-21-5p/PDCD4-mediated shifting of macrophage M1/M2 polarization

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-03 DOI: 10.1016/j.lfs.2025.123441

Mi Li , Tao Zhang , Pengfei Li , Zhiwei Luan , Jingsong Liu , Yangyang Wang , Yubo Zhang , Yishu Liu , Yansong Wang

Spinal cord injury (SCI) represents a significant neurological disorder that profoundly impacts human life. Transplantation of extracellular vesicles (EVs) from human umbilical cord mesenchymal stem cells (hUC-MSCs) has emerged as a promising therapeutic strategy. microRNA (miRNA) containing EVs serve as crucial mediators of intercellular communication, playing vital roles in physiological and pathological processes. Research indicates that EVs from hUC-MSCs could attenuate inflammation and facilitate recovery from SCI. Nevertheless, their application in clinical treatment necessitates further investigation. We are actively pursuing an effective approach to modulate the intensity of the inflammatory response, thereby addressing secondary SCI. Initially, we activated hUC-MSCs with interleukin-4 (IL-4) and subsequently harvested their EVs. We investigated the influences of A-hUC-MSCs-EVs compared to routinely acquired EVs on macrophage polarization phenotypes both in vitro and in vivo. Our results show that EVs originating from A-hUC-MSCs are more effective at promoting macrophage polarization from the M1 phenotype to the M2 phenotype than those derived from hUC-MSCs. Notably, we found that A-hUC-MSCs-derived EVs had a superior impact on motor function recovery in mice with SCI. Importantly, we observed that IL-4 activation significantly upregulated the expression of miR-21-5p within these EVs. More specifically, our data demonstrate that A-hUC-MSCs-EVs depend on miR-21-5p to inhibit the effects of PDCD4 on macrophage polarization. This mechanism regulates inflammatory responses while simultaneously reducing apoptosis. In summary, EVs derived from IL-4 primed hUC-MSCs are enriched with miR-21-5p, which exerts a pivotal influence in shifting macrophage polarization, alleviating inflammatory responses following SCI, and facilitating recovery.

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引用次数: 0

Molecular pathological characteristics and mechanisms of the liver in metabolic disease-susceptible transgenic pigs 代谢性疾病易感转基因猪肝脏的分子病理特征及机制

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-01 DOI: 10.1016/j.lfs.2024.123337

Juan Du, Kaiyi Zhang, Jiakun Miao, Yu Yang, Yuying Tian, Tianwen Wu, Cong Tao, Yanfang Wang, Shulin Yang

Aims

This study aimed to explore the molecular pathological mechanisms of the liver in metabolic disease-susceptible transgenic pigs via multiomics analysis.

Materials and methods

The triple-transgenic (PNPLA3^I148M-GIPR^dn-hIAPP) pig model (TG pig) was successfully constructed in our laboratory via the CRISPR/Cas9 technique previously described. Wild-type (WT) pigs and TG pigs after 2 or 12 months of high-fat and high-sucrose diet (HFHSD) induction (WT2, TG2, WT12, and TG12 groups, respectively) were used as materials. The transcriptome, metabolome, and lipidome were used to investigate the molecular mechanisms of the liver in pigs.

Key findings

The TG2 pigs presented mild metaflammation and insulin resistance (IR) which was similar to WT12 pigs. Compared with the other three groups, the TG12 pigs presented severe hepatocyte ballooning, fat deposition, and portal area fibrosis. The transcriptome data suggested that the TG2 pigs presented upregulated gene expression in the extracellular matrix (ECM). The TG12 pigs presented more severe metaflammation and exhibited imbalanced glycolipid metabolism. Interestingly, genes such as ETNPPL, GABBR2, and BMP8B might be key regulatory targets for liver injury. The metabolome and lipidome suggested that long-chain polyunsaturated fatty acids (LCPUFAs) and phospholipids with corresponding LCPUFAs were remodelled. Importantly, bis(monoacylglycerol) phosphates (BMPs) and sulfatides (SLs) could be the key regulatory metabolites in liver injury.

Significance

ETNPPL, GABBR2, and BMP8B might be potential therapeutic targets for liver injury. BMPs and SLs might be biomarkers for the diagnosis and treatment of liver diseases.

目的：通过多组学分析，探讨代谢性疾病易感转基因猪肝脏的分子病理机制。材料与方法：本实验室利用前述CRISPR/Cas9技术成功构建了三转基因（PNPLA3I148M-GIPRdn-hIAPP）猪模型（TG猪）。以高脂高糖饲粮（HFHSD）诱导2或12 个月后的野生型（WT）猪和TG猪（WT2、TG2、WT12和TG12组）为材料。利用转录组、代谢组和脂质组研究猪肝脏的分子机制。主要发现：TG2猪表现出与WT12猪相似的轻度炎症和胰岛素抵抗（IR）。与其他三组相比，TG12猪出现严重的肝细胞球囊化、脂肪沉积和门区纤维化。转录组数据表明，TG2猪在细胞外基质（ECM）中表达上调。TG12组猪出现更严重的超炎症，糖脂代谢失衡。有趣的是，诸如ETNPPL、GABBR2和BMP8B等基因可能是肝损伤的关键调控靶点。代谢组学和脂质组学表明，长链多不饱和脂肪酸（LCPUFAs）和具有相应LCPUFAs的磷脂被重塑。重要的是，双酰基甘油磷酸（BMPs）和硫脂（SLs）可能是肝损伤的关键调节代谢物。意义：ETNPPL、GABBR2和BMP8B可能是肝损伤的潜在治疗靶点。BMPs和SLs可能是肝脏疾病诊断和治疗的生物标志物。

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引用次数: 0

AAV2-mediated ABD-FGF21 gene delivery produces a sustained anti-hyperglycemic effect in type 2 diabetic mouse aav2介导的ABD-FGF21基因传递在2型糖尿病小鼠中产生持续的降糖作用。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-01 DOI: 10.1016/j.lfs.2024.123344

Sen-lin Lu , Zhi-hao Pan , Zhi Cui , Ji-li Wang , Jian-lin Yang , Ya-feng Lv , Chun-yu Cao , Xiao-fei Huang

Background

Fibroblast Growth Factor 21 (FGF21) is a naturally occurring peptide hormone involved in the regulation of glycolipid metabolism, and it shows promise as a potential treatment for type 2 diabetes mellitus (T2DM). However, the short half-life and poor pharmacokinetics of native FGF21 limit its efficacy in reducing hyperglycemia in vivo. Therefore, maintaining stable and sustained blood concentrations of FGF21 is crucial for its role as an effective regulator of glycolipid metabolism in vivo. In this study, we developed an AAV2-mediated gene delivery system incorporating an Albumin-binding domain (ABD) fused to FGF21, and we evaluated its effects in a type 2 diabetic mouse model.

Methods

The plasmids pAAV-FGF21-Luciferase, pHelper, and the capsid plasmid were transfected into HEK293T cells to generate recombinant AAV (rAAV) virus. A type 2 diabetes mellitus (T2DM) mouse model was established for evaluation. The rAAV was administered via tail vein injection into the mice. The effects of rAAV injection on various parameters were assessed using commercial kits. Histological changes in the liver and adipose tissue of T2DM mice were examined using hematoxylin and eosin (H&E) staining.

Results

The data showed that the inclusion of ABD significantly prolonged the half-life of FGF21 in the serum of mice. Additionally, AAV2-mediated delivery of ABD-FGF21 to the liver resulted in sustained gene expression and a significant increase in circulating FGF21 levels in mice. Treatment with AAV2-ABD-FGF21 led to several benefits, including reduced fasting glucose, improved insulin sensitivity, decreased triglyceride and total cholesterol levels, and improved body weight in T2DM mice. Furthermore, serum analysis and histological examination showed no significant liver damage at the study endpoint after seven weeks.

Conclusion

In conclusion, we have developed a novel strategy for producing long-acting FGF21 using the AAV vector, and AAV2-ABD-FGF21 shows promise as a therapeutic approach for type 2 diabetes mellitus and other glycolipid metabolic disorders.

背景：成纤维细胞生长因子 21（FGF21）是一种天然存在的多肽激素，参与调节糖脂代谢，有望成为 2 型糖尿病（T2DM）的潜在治疗药物。然而，原生 FGF21 的半衰期短、药代动力学差，限制了其降低体内高血糖的疗效。因此，维持 FGF21 稳定和持续的血药浓度对其作为体内糖脂代谢的有效调节剂至关重要。在这项研究中，我们开发了一种以 AAV2 为介导的基因递送系统，该系统结合了与 FGF21 融合的白蛋白结合域（ABD），并在 2 型糖尿病小鼠模型中评估了其效果：方法：将质粒 pAAV-FGF21-荧光素酶、pHelper 和囊膜质粒转染到 HEK293T 细胞中，生成重组 AAV（rAAV）病毒。为进行评估，建立了 2 型糖尿病（T2DM）小鼠模型。小鼠通过尾静脉注射 rAAV。使用商业试剂盒评估了注射 rAAV 对各种参数的影响。使用苏木精和伊红（H&E）染色法检测 T2DM 小鼠肝脏和脂肪组织的组织学变化：数据显示，加入 ABD 能显著延长 FGF21 在小鼠血清中的半衰期。此外，以AAV2为媒介将ABD-FGF21输送到肝脏可使小鼠体内的基因持续表达，并显著提高循环中FGF21的水平。用AAV2-ABD-FGF21治疗T2DM小鼠可带来多种益处，包括降低空腹血糖、改善胰岛素敏感性、降低甘油三酯和总胆固醇水平以及改善体重。此外，血清分析和组织学检查显示，七周后的研究终点没有发现明显的肝损伤：总之，我们开发了一种利用 AAV 载体生产长效 FGF21 的新策略，AAV2-ABD-FGF21 有希望成为治疗 2 型糖尿病和其他糖脂代谢紊乱的一种方法。

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引用次数: 0

Research progress on pathogenesis and treatment of febrile seizures 热性惊厥病机及治疗研究进展。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-01 DOI: 10.1016/j.lfs.2024.123360

Chang Wu , Qingmei Wang , Wenmi Li , Mingxuan Han , Huawei Zhao , Zhenghao Xu

Febrile seizures (FSs) are the most common pediatric neurological disorder, affecting approximately 5 % of children aged 6 months to 5 years. While most FSs are self-limiting and benign, about 20–30 % present as complex FSs (CFSs), which pose a risk of acute brain injury and the development of temporal lobe epilepsy. Various factors, including age, geographical distribution, and type of infection influence the occurrence of FS. Infection is the primary external trigger for FS, while the underlying intrinsic factors are linked to the immature and incomplete myelination of the brain during specific developmental stages. Although the precise pathogenesis of FS is not yet fully understood, it is likely caused by the interaction of immature brain development, fever, neuroinflammation, and genetic susceptibility. This review discussed the pathogenesis of febrile seizures, focusing on factors such as age, fever, neuroinflammation, genetics, and intestinal microbiota, and summarized existing therapeutic approaches. Our review may facilitate the identification of new targets for mechanistic studies and clinical treatment of febrile seizures.

热性惊厥（FSs）是最常见的儿科神经系统疾病，影响约5 %的6 个月至5 岁的儿童。虽然大多数FSs是自限性和良性的，但约20- 30% %的FSs表现为复杂的FSs (CFSs)，具有急性脑损伤和颞叶癫痫发展的风险。年龄、地理分布、感染类型等因素影响FS的发生。感染是FS的主要外部触发因素，而潜在的内在因素与特定发育阶段大脑未成熟和不完整的髓鞘形成有关。虽然FS的确切发病机制尚不完全清楚，但它可能是由未成熟的大脑发育、发热、神经炎症和遗传易感性的相互作用引起的。本文从年龄、发热、神经炎症、遗传、肠道菌群等方面讨论了热性惊厥的发病机制，并对现有的治疗方法进行了总结。我们的综述可能有助于确定热性惊厥的机制研究和临床治疗的新靶点。

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引用次数: 0

Anticancer and therapeutic efficacy of XPO1 inhibition in pancreatic ductal adenocarcinoma through DNA damage and modulation of miR-193b/KRAS/LAMC2/ERK/AKT signaling cascade 通过DNA损伤和miR-193b/KRAS/LAMC2/ERK/AKT信号级联调控XPO1抑制胰腺导管腺癌的抗癌和治疗效果

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-01 DOI: 10.1016/j.lfs.2024.123364

Anuradha Kirtonia , Gouri Pandya , Aishwarya Singh , Rachana Kumari , Bhavana Singh , Sonia Kapoor , Ekta Khattar , Amit Kumar Pandey , Manoj Garg

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and grave malignancies with confined and ineffective therapeutic options. XPO1 is a critical regulator of nuclear export and activation of tumor suppressor proteins. The present study evaluated the therapeutic potential and molecular mechanisms of XPO1 inhibition against PDAC. Firstly, we observed significant overexpression of XPO1 transcript in 179 PDAC patients than 171 normal pancreatic tissues in TCGA transcriptomic dataset. Higher XPO1 transcript levels displayed worse overall and disease-free survival. Further, we confirmed significant upregulation of XPO1 in a panel of PDAC cells. Eltanexor treatment resulted in significant inhibition of cell viability, clonogenic growth, migration, and epithelial-mesenchymal transition (EMT), along with the induction of cell cycle arrest. Mechanistically, eltanexor modulated the expression of key proteins including p21, p27, p53, cyclin B1, cyclin D1, c-Myc, N-cadherin, vimentin, E-cadherin associated with the cell viability, growth, cell cycle and EMT. Additionally, the eltanexor treatment resulted in marked increase in expression of γH2AX, and cleaved PARP, cleaved caspase-9 leading to induction of DNA damage and apoptosis of PDAC cells, respectively. Moreover, eltanexor treatment regulated the expression of key non-coding RNAs including miR193b, DINO, MALAT-1, H19, and SOX21-AS1 linked with tumorigenesis. Our results revealed a correlation among miR193b/KRAS/LAMC2, XPO1/KRAS, and LAMC2/KRAS. The findings also revealed that eltanexor treatment rescued the expression of miR193b which acts as a sponge for LAMC2 and KRAS resulting in the suppression of AKT/ERK downstream signaling cascade in PDAC. Interestingly, the combination of eltanexor with gemcitabine showed significant anticancer activity in PDAC cells. Altogether, our findings revealed the crucial role of XPO1 in modulating the expression of oncogenic proteins, ncRNAs, and DNA damage during PDAC progression as well as identified novel therapeutic miR-193b/KRAS/LAMC2/ERK/AKT axis.

胰腺导管腺癌（PDAC）是最具侵袭性和严重的恶性肿瘤之一，治疗方法有限且无效。XPO1是核输出和肿瘤抑制蛋白激活的关键调节因子。本研究评估了XPO1抑制PDAC的治疗潜力和分子机制。首先，我们观察到179名PDAC患者的XPO1转录物比TCGA转录组数据集中的171名正常胰腺组织明显过表达。XPO1转录物水平越高，总体生存率和无病生存率越差。此外，我们在PDAC细胞中证实了XPO1的显著上调。Eltanexor治疗可显著抑制细胞活力、克隆生长、迁移和上皮-间质转化（EMT），并诱导细胞周期阻滞。在机制上，eltanexor调节了与细胞活力、生长、细胞周期和EMT相关的关键蛋白的表达，包括p21、p27、p53、cyclin B1、cyclin D1、c-Myc、N-cadherin、vimentin、E-cadherin。此外，eltanexor处理导致γ - h2ax、裂解PARP、裂解caspase-9的表达显著增加，分别诱导PDAC细胞DNA损伤和凋亡。此外，eltanexor治疗可调节与肿瘤发生相关的关键非编码rna的表达，包括miR193b、DINO、MALAT-1、H19和SOX21-AS1。我们的研究结果显示miR193b/KRAS/LAMC2、XPO1/KRAS和LAMC2/KRAS之间存在相关性。研究结果还显示，eltanexor治疗挽救了miR193b的表达，miR193b作为LAMC2和KRAS的海绵，导致PDAC中AKT/ERK下游信号级联的抑制。有趣的是，埃他exor与吉西他滨的组合在PDAC细胞中显示出显著的抗癌活性。总之，我们的研究结果揭示了XPO1在调节PDAC进展过程中致癌蛋白、ncRNAs和DNA损伤的表达中的关键作用，以及鉴定出的新型治疗性miR-193b/KRAS/LAMC2/ERK/AKT轴。

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引用次数: 0

Progesterone signaling in uterine fibroids: Molecular mechanisms and therapeutic opportunities 子宫肌瘤中的黄体酮信号：分子机制和治疗机会。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-01 DOI: 10.1016/j.lfs.2024.123345

Ioanna Ploumaki , Valeria I. Macri , James H. Segars , Md Soriful Islam

Progesterone (P4) is a vital female sex hormone involved in various physiological processes, including the maintenance of the endometrium, mammary gland development, and bone health. Beyond its reproductive roles, P4 is implicated in the pathogenesis of hormone-dependent conditions like uterine fibroids, the most common benign tumors in women, which can severely affect quality of life and fertility. Traditionally, estrogen was considered the primary driver of fibroid growth, but recent research highlights the significant role of P4 in fibroid growth. P4 interacts with progesterone receptors (PRs) and non-genomic membrane receptors (mPRs and PGRMCs) to activate signaling pathways that enhance tumor growth and survival. P4 promotes vascular changes that improve the blood supply to fibroids and modifies the extracellular matrix, a key component of fibroid structure. This understanding has led to the investigation of selective progesterone receptor modulators (SPRMs) as potential therapies for fibroids. Clinical trials have demonstrated the effectiveness of SPRMs like mifepristone, asoprisnil, and ulipristal acetate in reducing fibroid size and symptoms, though concerns about safety, particularly with long-term use, remain. Newer SPRMs, such as vilaprisan, show promise, but further research is necessary to assess the long-term safety and effectiveness. This review discusses the mechanisms by which progesterone contributes to fibroid growth and examines clinical effectiveness of SPRMs as potential treatments for uterine fibroids.

黄体酮（P4）是一种重要的女性性激素，参与多种生理过程，包括维持子宫内膜、乳腺发育和骨骼健康。除了生殖功能外，P4还与激素依赖性疾病如子宫肌瘤的发病机制有关，子宫肌瘤是女性中最常见的良性肿瘤，可严重影响生活质量和生育能力。传统上，雌激素被认为是肌瘤生长的主要驱动因素，但最近的研究强调了P4在肌瘤生长中的重要作用。P4与孕激素受体（PRs）和非基因组膜受体（mPRs和PGRMCs）相互作用，激活促进肿瘤生长和生存的信号通路。P4促进血管改变，改善肌瘤的血液供应，并改变细胞外基质，这是肌瘤结构的关键组成部分。这一认识导致了选择性孕激素受体调节剂（SPRMs）作为子宫肌瘤潜在治疗方法的研究。临床试验已经证明，米非司酮、阿索普利尼和醋酸乌普利司等sprm在减少肌瘤大小和症状方面是有效的，尽管对安全性的担忧，特别是长期使用，仍然存在。较新的sprm，如vilaprisan，显示出希望，但需要进一步的研究来评估长期安全性和有效性。本文讨论了孕酮促进子宫肌瘤生长的机制，并探讨了SPRMs作为子宫肌瘤潜在治疗方法的临床有效性。

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引用次数: 0