FASEB Journal最新文献_第8页

Correction to “Exosomes derived from umbilical cord-derived mesenchymal stem cells exposed to diabetic microenvironment enhance M2 macrophage polarisation and protect against diabetic nephropathy” 对 "暴露于糖尿病微环境中的脐带间充质干细胞产生的外泌体可增强 M2 巨噬细胞极化并防止糖尿病肾病 "的更正。

IF 4.4 2区生物学

FASEB Journal Pub Date : 2024-08-16 DOI: 10.1096/fj.202401836

引用次数: 0

Diverse biophysical mechanisms in voltage-gated sodium channel Nav1.4 variants associated with myotonia 与肌张力障碍有关的电压门控钠通道 Nav1.4 变体的生物物理机制多种多样。

IF 4.4 2区生物学

FASEB Journal Pub Date : 2024-08-16 DOI: 10.1096/fj.202400867R

Tatiana B. Tikhonova, Artem A. Sharkov, Boris S. Zhorov, Alexander A. Vassilevski

{"title":"Diverse biophysical mechanisms in voltage-gated sodium channel Nav1.4 variants associated with myotonia","authors":"Tatiana B. Tikhonova, Artem A. Sharkov, Boris S. Zhorov, Alexander A. Vassilevski","doi":"10.1096/fj.202400867R","DOIUrl":"10.1096/fj.202400867R","url":null,"abstract":"Mutations in SCN4A gene encoding Nav1.4 channel α-subunit, are known to cause neuromuscular disorders such as myotonia or paralysis. Here, we study the effect of two amino acid replacements, K1302Q and G1306E, in the DIII–IV loop of the channel, corresponding to mutations found in patients with myotonia. We combine clinical, electrophysiological, and molecular modeling data to provide a holistic picture of the molecular mechanisms operating in mutant channels and eventually leading to pathology. We analyze the existing clinical data for patients with the K1302Q substitution, which was reported for adults with or without myotonia phenotypes, and report two new unrelated patients with the G1306E substitution, who presented with severe neonatal episodic laryngospasm and childhood-onset myotonia. We provide a functional analysis of the mutant channels by expressing Nav1.4 α-subunit in Xenopus oocytes in combination with β1 subunit and recording sodium currents using two-electrode voltage clamp. The K1302Q variant exhibits abnormal voltage dependence of steady-state fast inactivation, being the likely cause of pathology. K1302Q does not lead to decelerated fast inactivation, unlike several other myotonic mutations such as G1306E. For both mutants, we observe increased window currents corresponding to a larger population of channels available for activation. To elaborate the structural rationale for our experimental data, we explore the contacts involving K/Q1302 and E1306 in the AlphaFold2 model of wild-type Nav1.4 and Monte Carlo-minimized models of mutant channels. Our data provide the missing evidence to support the classification of K1302Q variant as likely pathogenic and may be used by clinicians.","PeriodicalId":50455,"journal":{"name":"FASEB Journal","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141992560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Interferon-gamma signaling drives epithelial TNF-alpha receptor-2 expression during colonic tissue repair 干扰素-γ 信号在结肠组织修复过程中驱动上皮 TNF-α 受体-2 的表达。

IF 4.4 2区生物学

FASEB Journal Pub Date : 2024-08-14 DOI: 10.1096/fj.202401695

Sean Watson, Rodolfo I. Cabrera-Silva, Charles A. Parkos, Asma Nusrat, Miguel Quiros

{"title":"Interferon-gamma signaling drives epithelial TNF-alpha receptor-2 expression during colonic tissue repair","authors":"Sean Watson, Rodolfo I. Cabrera-Silva, Charles A. Parkos, Asma Nusrat, Miguel Quiros","doi":"10.1096/fj.202401695","DOIUrl":"10.1096/fj.202401695","url":null,"abstract":"Interferon-gamma (IFNγ) is traditionally recognized for its pro-inflammatory role during intestinal inflammation. Here, we demonstrate that IFNγ also functions as a pro-repair molecule by increasing TNFα receptor 2 (TNFR2 protein/TNFRSF1B gene) expression on intestinal epithelial cells (IEC) following injury in vitro and in vivo. In silico analyses identified binding sites for the IFNγ signaling transcription factor STAT1 in the promoter region of TNFRSF1B. Scratch-wounded IEC exposed to IFNγ exhibited a STAT1-dependent increase in TNFR2 expression. In situ hybridization revealed elevated Tnfrsf1b mRNA levels in biopsy-induced colonic mucosal wounds, while intraperitoneal administration of IFNγ neutralizing antibodies following mucosal injury resulted in impaired IEC Tnfrsf1b mRNA and inhibited colonic mucosal repair. These findings challenge conventional notions that “pro-inflammatory” mediators solely exacerbate damage by highlighting latent pro-repair functions. Moreover, these results emphasize the critical importance of timing and amount in the synthesis and release of IFNγ and TNFα during the inflammatory process, as they are pivotal in restoring tissue homeostasis.","PeriodicalId":50455,"journal":{"name":"FASEB Journal","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202401695","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141977113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Interstitial cells of the sip syncytium regulate basal membrane potential in murine gastric corpus 胃窦间质细胞调节小鼠胃窦的基础膜电位

IF 4.4 2区生物学

FASEB Journal Pub Date : 2024-08-14 DOI: 10.1096/fj.202400982R

Sung Jin Hwang, MinKyung Kim, Amanda Jones, Naseer Basma, Salah A. Baker, Kenton M. Sanders, Sean M. Ward

{"title":"Interstitial cells of the sip syncytium regulate basal membrane potential in murine gastric corpus","authors":"Sung Jin Hwang, MinKyung Kim, Amanda Jones, Naseer Basma, Salah A. Baker, Kenton M. Sanders, Sean M. Ward","doi":"10.1096/fj.202400982R","DOIUrl":"10.1096/fj.202400982R","url":null,"abstract":"Smooth muscle cells (SMCs), Interstitial cells of Cajal (ICC) and Platelet-derived growth factor receptor α positive (PDGFRα+) cells form an integrated, electrical syncytium within the gastrointestinal (GI) muscular tissues known as the SIP syncytium. Immunohistochemical analysis of gastric corpus muscles showed that c-KIT+/ANO1+ ICC-IM and PDGFRα+ cells were closely apposed to one another in the same anatomical niches. We used intracellular microelectrode recording from corpus muscle bundles to characterize the roles of intramuscular ICC and PDGFRα+ cells in conditioning membrane potentials of gastric muscles. In muscle bundles, that have a relatively higher input impedance than larger muscle strips or sheets, we recorded an ongoing discharge of stochastic fluctuations in membrane potential, previously called unitary potentials or spontaneous transient depolarizations (STDs) and spontaneous transient hyperpolarizations (STHs). We reasoned that STDs should be blocked by antagonists of ANO1, the signature conductance of ICC. Activation of ANO1 has been shown to generate spontaneous transient inward currents (STICs), which are the basis for STDs. Ani9 reduced membrane noise and caused hyperpolarization, but this agent did not block the fluctuations in membrane potential quantitatively. Apamin, an antagonist of small conductance Ca2+-activated K+ channels (SK3), the signature conductance in PDGFRα+ cells, further reduced membrane noise and caused depolarization. Reversing the order of channel antagonists reversed the sequence of depolarization and hyperpolarization. These experiments show that the ongoing discharge of STDs and STHs by ICC and PDGFRα+ cells, respectively, exerts conditioning effects on membrane potentials in the SIP syncytium that would effectively regulate the excitability of SMCs.","PeriodicalId":50455,"journal":{"name":"FASEB Journal","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141983778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Platelets at the intersection of inflammation and coagulation in the APC-mediated response to myocardial ischemia/reperfusion injury 在 APC 介导的心肌缺血/再灌注损伤反应中，血小板处于炎症和凝血的交汇点。

IF 4.4 2区生物学

FASEB Journal Pub Date : 2024-08-14 DOI: 10.1096/fj.202401128R

Lily Slotabec, Blaise Seale, Hao Wang, Changhong Wen, Fernanda Filho, Nadiyeh Rouhi, Michael I. Adenawoola, Ji Li

{"title":"Platelets at the intersection of inflammation and coagulation in the APC-mediated response to myocardial ischemia/reperfusion injury","authors":"Lily Slotabec, Blaise Seale, Hao Wang, Changhong Wen, Fernanda Filho, Nadiyeh Rouhi, Michael I. Adenawoola, Ji Li","doi":"10.1096/fj.202401128R","DOIUrl":"10.1096/fj.202401128R","url":null,"abstract":"Thromboinflammation is a complex pathology associated with inflammation and coagulation. In cases of cardiovascular disease, in particular ischemia–reperfusion injury, thromboinflammation is a common complication. Increased understanding of thromboinflammation depends on an improved concept of the mechanisms of cells and proteins at the axis of coagulation and inflammation. Among these elements are activated protein C and platelets. This review summarizes the complex interactions of activated protein C and platelets regulating thromboinflammation in cardiovascular disease. By unraveling the pathways of platelets and APC in the inflammatory and coagulation cascades, this review summarizes the role of these vital mediators in the development and perpetuation of heart disease and the thromboinflammation-driven complications of cardiovascular disease. Furthermore, this review emphasizes the significance of the counteracting effects of platelets and APC and their combined role in disease states.","PeriodicalId":50455,"journal":{"name":"FASEB Journal","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202401128R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141983779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Liver kinase B1 (LKB1) regulates the epigenetic landscape of mouse pancreatic beta cells 肝激酶 B1 (LKB1) 调控小鼠胰腺β细胞的表观遗传结构。

IF 4.4 2区生物学

FASEB Journal Pub Date : 2024-08-14 DOI: 10.1096/fj.202401078R

Nejc Haberman, Rebecca Cheung, Grazia Pizza, Nevena Cvetesic, Dorka Nagy, Hannah Maude, Lorea Blazquez, Boris Lenhard, Inês Cebola, Guy A. Rutter, Aida Martinez-Sanchez

{"title":"Liver kinase B1 (LKB1) regulates the epigenetic landscape of mouse pancreatic beta cells","authors":"Nejc Haberman, Rebecca Cheung, Grazia Pizza, Nevena Cvetesic, Dorka Nagy, Hannah Maude, Lorea Blazquez, Boris Lenhard, Inês Cebola, Guy A. Rutter, Aida Martinez-Sanchez","doi":"10.1096/fj.202401078R","DOIUrl":"10.1096/fj.202401078R","url":null,"abstract":"Liver kinase B1 (LKB1/STK11) is an important regulator of pancreatic β-cell identity and function. Elimination of Lkb1 from the β-cell results in improved glucose-stimulated insulin secretion and is accompanied by profound changes in gene expression, including the upregulation of several neuronal genes. The mechanisms through which LKB1 controls gene expression are, at present, poorly understood. Here, we explore the impact of β cell-selective deletion of Lkb1 on chromatin accessibility in mouse pancreatic islets. To characterize the role of LKB1 in the regulation of gene expression at the transcriptional level, we combine these data with a map of islet active transcription start sites and histone marks. We demonstrate that LKB1 elimination from β-cells results in widespread changes in chromatin accessibility, correlating with changes in transcript levels. Changes occurred in hundreds of promoter and enhancer regions, many of which were close to neuronal genes. We reveal that dysregulated enhancers are enriched in binding motifs for transcription factors (TFs) important for β-cell identity, such as FOXA, MAFA or RFX6, and we identify microRNAs (miRNAs) that are regulated by LKB1 at the transcriptional level. Overall, our study provides important new insights into the epigenetic mechanisms by which LKB1 regulates β-cell identity and function.","PeriodicalId":50455,"journal":{"name":"FASEB Journal","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202401078R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141977069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The alleviating effect of Phillygenin on the regulation of respiratory microbiota and its metabolites in IBV-infected broilers by inhibiting the TLR7/MyD88/NF-κB axis 菲利根因通过抑制 TLR7/MyD88/NF-κB 轴对 IBV 感染肉鸡呼吸道微生物群及其代谢物的调节作用。

IF 4.4 2区生物学

FASEB Journal Pub Date : 2024-08-14 DOI: 10.1096/fj.202400168RR

Haipeng Feng, Kang Zhang, Jingyan Zhang, Xuezhi Wang, Zhiting Guo, Lei Wang, Fubing Chen, Songwei Han, Jianxi Li

{"title":"The alleviating effect of Phillygenin on the regulation of respiratory microbiota and its metabolites in IBV-infected broilers by inhibiting the TLR7/MyD88/NF-κB axis","authors":"Haipeng Feng, Kang Zhang, Jingyan Zhang, Xuezhi Wang, Zhiting Guo, Lei Wang, Fubing Chen, Songwei Han, Jianxi Li","doi":"10.1096/fj.202400168RR","DOIUrl":"10.1096/fj.202400168RR","url":null,"abstract":"Phillygenin (PHI) is an active ingredient derived from the leaf of Forsythia suspensa that has been found to alleviate inflammation and peroxidation response. Avian infectious bronchitis (IB) is a major threat to poultry industry viral respiratory tract disease that infected with infectious bronchitis virus (IBV). This study investigated the protection of PHI to CEK cell and broiler's tracheal injury triggered by avian infectious bronchitis virus (IBV). The results showed that IBV infection did not cause serious clinical symptoms and slowing-body weight in PHI-treated broilers. The expression of virus loads, pro-inflammation factors (IL-6, TNF-α, and IL-1β) in CEK cell, and tracheas were decreased compared to the IBV group, exhibiting its potent anti-inflammation. Mechanistically, the study demonstrated that the inhibition of TLR7/MyD88/NF-κB pathway was mainly involved in the protection effect of PHI to inflammation injury. Interestingly, a higher abundance of Firmicutes and Lactobacillus in respiratory tract was observed in PHI-treated broilers than in the IBV group. Significant differences were observed between the IBV group and PHI-treated group in the Ferroptosis, Tryptophan metabolism, and Glutathione metabolism pathways. PHI exhibited potent protection effect on IBV infection and alleviated inflammation injury, mainly through inhibiting TLR7/MyD88/NF-κB pathway. The study encourages further development of PHI, paving the way to its clinical use as a new candidate drug to relieve IBV-induced respiratory symptoms.","PeriodicalId":50455,"journal":{"name":"FASEB Journal","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141983780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inhibition of TFEB deacetylation in proximal tubular epithelial cells (TECs) promotes TFEB activation and alleviates TEC damage in diabetic kidney disease 抑制近端肾小管上皮细胞（TEC）中的 TFEB 去乙酰化可促进 TFEB 的活化，减轻糖尿病肾病对 TEC 的损伤。

IF 4.4 2区生物学

FASEB Journal Pub Date : 2024-08-13 DOI: 10.1096/fj.202302634R

Xiaoyu Li, Yaozhi Zhang, Huixia Chen, Yang Wu, Yongming Chen, Siqiao Gong, Yonghan Liu, Huafeng Liu

{"title":"Inhibition of TFEB deacetylation in proximal tubular epithelial cells (TECs) promotes TFEB activation and alleviates TEC damage in diabetic kidney disease","authors":"Xiaoyu Li, Yaozhi Zhang, Huixia Chen, Yang Wu, Yongming Chen, Siqiao Gong, Yonghan Liu, Huafeng Liu","doi":"10.1096/fj.202302634R","DOIUrl":"10.1096/fj.202302634R","url":null,"abstract":"The inhibition of the autophagolysosomal pathway mediated by transcription factor EB (TFEB) inactivation in proximal tubular epithelial cells (TECs) is a key mechanism of TEC injury in diabetic kidney disease (DKD). Acetylation is a novel mechanism that regulates TFEB activity. However, there are currently no studies on whether the adjustment of the acetylation level of TFEB can reduce the damage of diabetic TECs. In this study, we investigated the effect of Trichostatin A (TSA), a typical deacetylase inhibitor, on TFEB activity and damage to TECs in both in vivo and in vitro models of DKD. Here, we show that TSA treatment can alleviate the pathological damage of glomeruli and renal tubules and delay the DKD progression in db/db mice, which is associated with the increased expression of TFEB and its downstream genes. In vitro studies further confirmed that TSA treatment can upregulate the acetylation level of TFEB, promote its nuclear translocation, and activate the expression of its downstream genes, thereby reducing the apoptosis level of TECs. TFEB deletion or HDAC6 knockdown in TECs can counteract the activation effect of TSA on autophagolysosomal pathway. We also found that TFEB enhances the transcription of Tfeb through binding to its promoter and promotes its own expression. Our results, thus, provide a novel therapeutic mechanism for DKD that the alleviation of TEC damage by activating the autophagic lysosomal pathway through upregulating TFEB acetylation can, thus, delay DKD progression.","PeriodicalId":50455,"journal":{"name":"FASEB Journal","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202302634R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141972256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

LncRNA-Snhg3 regulates mouse hepatic glycogenesis under normal chow diet LncRNA-Snhg3调控正常进食条件下的小鼠肝糖生成

IF 4.4 2区生物学

FASEB Journal Pub Date : 2024-08-12 DOI: 10.1096/fj.202401064R

Xianghong Xie, Mingyue Gao, Heping Wang, Minglong Zhang, Wei Zhao, Chunmei Li, Weihong Zhang, Jiahui Yang, Yinliang Zhang, Enhui Chen, Yanfang Guo, Zeyu Guo, Ebenezeri Erasto Ngowi, Xiaoman Wang, Yinghan Zhu, Yiting Wang, Xiaolu Li, Hong Yao, Li Yan, Fude Fang, Meixia Li, Aijun Qiao, Xiaojun Liu

{"title":"LncRNA-Snhg3 regulates mouse hepatic glycogenesis under normal chow diet","authors":"Xianghong Xie, Mingyue Gao, Heping Wang, Minglong Zhang, Wei Zhao, Chunmei Li, Weihong Zhang, Jiahui Yang, Yinliang Zhang, Enhui Chen, Yanfang Guo, Zeyu Guo, Ebenezeri Erasto Ngowi, Xiaoman Wang, Yinghan Zhu, Yiting Wang, Xiaolu Li, Hong Yao, Li Yan, Fude Fang, Meixia Li, Aijun Qiao, Xiaojun Liu","doi":"10.1096/fj.202401064R","DOIUrl":"10.1096/fj.202401064R","url":null,"abstract":"Long noncoding RNAs (lncRNAs) are strongly associated with glucose homeostasis, but their roles remain largely unknown. In this study, the potential role of lncRNA-Snhg3 in glucose metabolism was evaluated both in vitro and in vivo. Here, we found a positive relationship between Snhg3 and hepatic glycogenesis. Glucose tolerance improved in hepatocyte-specific Snhg3 knock-in (Snhg3-HKI) mice, while it worsened in hepatocyte-specific Snhg3 knockout (Snhg3-HKO) mice. Furthermore, hepatic glycogenesis had shown remarkable increase in Snhg3-HKI mice and reduction in Snhg3-HKO mice, respectively. Mechanistically, Snhg3 increased mRNA and protein expression levels of PPP1R3B through inducing chromatin remodeling and promoting the phosphorylation of protein kinase B. Collectively, these results suggested that lncRNA-Snhg3 plays a critical role in hepatic glycogenesis.","PeriodicalId":50455,"journal":{"name":"FASEB Journal","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141917927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

FTY720/Fingolimod mitigates paclitaxel-induced Sparcl1-driven neuropathic pain and breast cancer progression FTY720/芬戈莫德可减轻紫杉醇诱导的Sparcl1驱动的神经病理性疼痛和乳腺癌进展。

IF 4.4 2区生物学

FASEB Journal Pub Date : 2024-08-10 DOI: 10.1096/fj.202401277R

Sandeep K. Singh, Cynthia Weigel, Ryan D. R. Brown, Christopher D. Green, Connor Tuck, Daniela Salvemini, Sarah Spiegel

{"title":"FTY720/Fingolimod mitigates paclitaxel-induced Sparcl1-driven neuropathic pain and breast cancer progression","authors":"Sandeep K. Singh, Cynthia Weigel, Ryan D. R. Brown, Christopher D. Green, Connor Tuck, Daniela Salvemini, Sarah Spiegel","doi":"10.1096/fj.202401277R","DOIUrl":"10.1096/fj.202401277R","url":null,"abstract":"Paclitaxel is among the most active chemotherapy drugs for the aggressive triple negative breast cancer (TNBC). Unfortunately, it often induces painful peripheral neuropathy (CIPN), a major debilitating side effect. Here we demonstrate that in naive and breast tumor-bearing immunocompetent mice, a clinically relevant dose of FTY720/Fingolimod that targets sphingosine-1-phosphate receptor 1 (S1PR1), alleviated paclitaxel-induced neuropathic pain. FTY720 also significantly attenuated paclitaxel-stimulated glial fibrillary acidic protein (GFAP), a marker for activated astrocytes, and expression of the astrocyte-secreted synaptogenic protein Sparcl1/Hevin, a key regulator of synapse formation. Notably, the formation of excitatory synapses containing VGluT2 in the spinal cord dorsal horn induced by paclitaxel was also inhibited by FTY720 treatment, supporting the involvement of astrocytes and Sparcl1 in CIPN. Furthermore, in this TNBC mouse model that mimics human breast cancer, FTY720 administration also enhanced the anti-tumor effects of paclitaxel, leading to reduced tumor progression and lung metastasis. Taken together, our findings suggest that targeting the S1P/S1PR1 axis with FTY720 is a multipronged approach that holds promise as a therapeutic strategy for alleviating both CIPN and enhancing the efficacy of chemotherapy in TNBC treatment.","PeriodicalId":50455,"journal":{"name":"FASEB Journal","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202401277R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141914426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0