{"title":"抑制 RIP1/RIP3 坏死通路可促进冷应激大鼠模型的勃起功能","authors":"Pei Yang, Lipan Niu, Bingbing Zhu, Siyiti Amuti, Adilijiang Yiming, Fengxia Liu","doi":"10.1155/2024/9483858","DOIUrl":null,"url":null,"abstract":"<p>Cold stimulation is the most common stressor in cold regions. Continuous cold stimulation can cause a series of pathophysiological changes in the body, such as aggregated neutrophils, macrophage activation, and increased inflammatory factors, which is also a risk factor for erectile function impairment. In addition, necroptosis is an important form of programmed cell death. However, the mechanisms of necroptosis in erectile function impairment due to cold stimulation have been very poorly studied. Therefore, we explored the mechanism of tumor necrosis factor-<i>α</i> (TNF-<i>α</i>)-mediated receptor interacting protein kinase 1 (RIP1)/receptor interacting protein kinase 3 (RIP3) necroptosis pathway on erectile function among cold-stressed rats. First, we established a cold-stressed rat model using cold stimulation and selected those rats that had developed erectile function impairment. Then, we used Necrostatin-1 (RIP1 specific inhibitor, Nec-1), Etanercept (TNF-<i>α</i> inhibitor, Ent), and Sildenafil (Sil) to intervene for 14 days and subsequently assessed their erectile function by apomorphine test and sexual behavioural test. Lastly, we performed various molecular studies and histopathological analyses of penile tissues collected from these rats after the experiments. We found that erectile function was impaired in cold-stressed rats, with increased penile tissue fibrosis and elevated levels of TNF-<i>α</i> and necroptosis. Contrastingly, intervention with Nec-1 and Ent restored erectile function, reduced penile tissue fibrosis, and decreased TNF-<i>α</i> and necroptosis levels, consistent with the results of intervention with Sil. Based on these results, we confirmed that the TNF-<i>α</i>-mediated RIP1/RIP3 necroptosis pathway was significantly altered in cold-stressed rats. In conclusion, inhibition of the TNF-<i>α</i>-mediated RIP1/RIP3 necroptosis pathway improved erectile function, suggesting that the specific downstream mechanisms need to be further explored.</p>","PeriodicalId":7817,"journal":{"name":"Andrologia","volume":"2024 1","pages":""},"PeriodicalIF":2.1000,"publicationDate":"2024-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Inhibition of RIP1/RIP3 Necroptosis Pathway Promote Erectile Function in Cold-Stressed Rat Model\",\"authors\":\"Pei Yang, Lipan Niu, Bingbing Zhu, Siyiti Amuti, Adilijiang Yiming, Fengxia Liu\",\"doi\":\"10.1155/2024/9483858\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Cold stimulation is the most common stressor in cold regions. Continuous cold stimulation can cause a series of pathophysiological changes in the body, such as aggregated neutrophils, macrophage activation, and increased inflammatory factors, which is also a risk factor for erectile function impairment. In addition, necroptosis is an important form of programmed cell death. However, the mechanisms of necroptosis in erectile function impairment due to cold stimulation have been very poorly studied. Therefore, we explored the mechanism of tumor necrosis factor-<i>α</i> (TNF-<i>α</i>)-mediated receptor interacting protein kinase 1 (RIP1)/receptor interacting protein kinase 3 (RIP3) necroptosis pathway on erectile function among cold-stressed rats. First, we established a cold-stressed rat model using cold stimulation and selected those rats that had developed erectile function impairment. Then, we used Necrostatin-1 (RIP1 specific inhibitor, Nec-1), Etanercept (TNF-<i>α</i> inhibitor, Ent), and Sildenafil (Sil) to intervene for 14 days and subsequently assessed their erectile function by apomorphine test and sexual behavioural test. Lastly, we performed various molecular studies and histopathological analyses of penile tissues collected from these rats after the experiments. We found that erectile function was impaired in cold-stressed rats, with increased penile tissue fibrosis and elevated levels of TNF-<i>α</i> and necroptosis. Contrastingly, intervention with Nec-1 and Ent restored erectile function, reduced penile tissue fibrosis, and decreased TNF-<i>α</i> and necroptosis levels, consistent with the results of intervention with Sil. Based on these results, we confirmed that the TNF-<i>α</i>-mediated RIP1/RIP3 necroptosis pathway was significantly altered in cold-stressed rats. In conclusion, inhibition of the TNF-<i>α</i>-mediated RIP1/RIP3 necroptosis pathway improved erectile function, suggesting that the specific downstream mechanisms need to be further explored.</p>\",\"PeriodicalId\":7817,\"journal\":{\"name\":\"Andrologia\",\"volume\":\"2024 1\",\"pages\":\"\"},\"PeriodicalIF\":2.1000,\"publicationDate\":\"2024-03-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Andrologia\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1155/2024/9483858\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"ANDROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Andrologia","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1155/2024/9483858","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"ANDROLOGY","Score":null,"Total":0}
引用次数: 0
摘要
寒冷刺激是寒冷地区最常见的应激源。持续的寒冷刺激会引起机体一系列病理生理变化,如中性粒细胞聚集、巨噬细胞活化、炎症因子增多等,这也是导致勃起功能障碍的危险因素。此外,坏死也是细胞程序性死亡的一种重要形式。然而,关于寒冷刺激导致勃起功能受损的坏死机制的研究还非常少。因此,我们探讨了肿瘤坏死因子-α(TNF-α)介导的受体互作蛋白激酶1(RIP1)/受体互作蛋白激酶3(RIP3)坏死途径对冷应激大鼠勃起功能的影响机制。首先,我们利用冷刺激建立了冷应激大鼠模型,并筛选出出现勃起功能障碍的大鼠。然后,我们使用Necrostatin-1(RIP1特异性抑制剂,Nec-1)、Etanercept(TNF-α抑制剂,Ent)和Sildenafil(Sil)进行为期14天的干预,随后通过阿朴吗啡试验和性行为试验评估其勃起功能。最后,我们对实验后收集的大鼠阴茎组织进行了各种分子研究和组织病理学分析。我们发现,冷应激大鼠的勃起功能受损,阴茎组织纤维化加重,TNF-α和坏死因子水平升高。相反,使用 Nec-1 和 Ent 进行干预后,大鼠的勃起功能得到恢复,阴茎组织纤维化程度降低,TNF-α 和坏死蛋白水平下降,这与使用 Sil 进行干预的结果一致。基于这些结果,我们证实 TNF-α 介导的 RIP1/RIP3 坏死通路在冷应激大鼠中发生了显著改变。总之,抑制TNF-α介导的RIP1/RIP3坏死途径可改善勃起功能,这表明具体的下游机制还需要进一步探索。
Inhibition of RIP1/RIP3 Necroptosis Pathway Promote Erectile Function in Cold-Stressed Rat Model
Cold stimulation is the most common stressor in cold regions. Continuous cold stimulation can cause a series of pathophysiological changes in the body, such as aggregated neutrophils, macrophage activation, and increased inflammatory factors, which is also a risk factor for erectile function impairment. In addition, necroptosis is an important form of programmed cell death. However, the mechanisms of necroptosis in erectile function impairment due to cold stimulation have been very poorly studied. Therefore, we explored the mechanism of tumor necrosis factor-α (TNF-α)-mediated receptor interacting protein kinase 1 (RIP1)/receptor interacting protein kinase 3 (RIP3) necroptosis pathway on erectile function among cold-stressed rats. First, we established a cold-stressed rat model using cold stimulation and selected those rats that had developed erectile function impairment. Then, we used Necrostatin-1 (RIP1 specific inhibitor, Nec-1), Etanercept (TNF-α inhibitor, Ent), and Sildenafil (Sil) to intervene for 14 days and subsequently assessed their erectile function by apomorphine test and sexual behavioural test. Lastly, we performed various molecular studies and histopathological analyses of penile tissues collected from these rats after the experiments. We found that erectile function was impaired in cold-stressed rats, with increased penile tissue fibrosis and elevated levels of TNF-α and necroptosis. Contrastingly, intervention with Nec-1 and Ent restored erectile function, reduced penile tissue fibrosis, and decreased TNF-α and necroptosis levels, consistent with the results of intervention with Sil. Based on these results, we confirmed that the TNF-α-mediated RIP1/RIP3 necroptosis pathway was significantly altered in cold-stressed rats. In conclusion, inhibition of the TNF-α-mediated RIP1/RIP3 necroptosis pathway improved erectile function, suggesting that the specific downstream mechanisms need to be further explored.
期刊介绍:
Andrologia provides an international forum for original papers on the current clinical, morphological, biochemical, and experimental status of organic male infertility and sexual disorders in men. The articles inform on the whole process of advances in andrology (including the aging male), from fundamental research to therapeutic developments worldwide. First published in 1969 and the first international journal of andrology, it is a well established journal in this expanding area of reproductive medicine.