Pub Date : 2024-11-09DOI: 10.1016/j.biopha.2024.117654
Sui Mao , Zhen-Yu Liu , Zhi-Yan Liu , Peng Liu , Li-Chan Lin , Ye Zhang , Jing-Jing Yang , Jian-Yuan Zhao , Hui Tao
The pathogenesis of cardiovascular diseases (CVDs) is intricate, with liquid-liquid phase separation (LLPS) considered a crucial regulatory mechanism. Epigenetics is closely intertwined with cardiovascular diseases, involving mechanisms such as DNA methylation, histone modifications, and non-coding RNAs (ncRNAs) that play pivotal roles in cardiovascular disease progression and regression. It is known that specific proteins and mRNAs associated with epigenetic modifications exhibit LLPS characteristics, influencing cardiovascular diseases. Consequently, targeting epigenetic modifications to modulate LLPS emerges as a promising strategy for cardiovascular diseases treatment. This review delves into the regulatory impact of liquid-liquid phase separation on cardiovascular diseases, with a specific focus on the epigenetic landscape. The current study sought to investigate the relationship between epigenetic landscape and phase separation in cardiovascular diseases development, as well as their therapeutic implications.
心血管疾病（CVDs）的发病机制错综复杂，其中液-液相分离（LLPS）被认为是一种关键的调控机制。表观遗传学与心血管疾病密切相关，涉及 DNA 甲基化、组蛋白修饰和非编码 RNA（ncRNA）等机制，这些机制在心血管疾病的进展和消退中发挥着关键作用。众所周知，与表观遗传修饰相关的特定蛋白质和 mRNA 具有 LLPS 特性，会对心血管疾病产生影响。因此，以表观遗传修饰为靶点调节 LLPS 成为治疗心血管疾病的一种有前景的策略。本综述深入探讨了液-液相分离对心血管疾病的调控影响，并特别关注了表观遗传学的情况。本研究试图探讨表观遗传学景观与相分离在心血管疾病发展中的关系及其治疗意义。
{"title":"Phase separation of epigenetic landscape in cardiovascular diseases","authors":"Sui Mao , Zhen-Yu Liu , Zhi-Yan Liu , Peng Liu , Li-Chan Lin , Ye Zhang , Jing-Jing Yang , Jian-Yuan Zhao , Hui Tao","doi":"10.1016/j.biopha.2024.117654","DOIUrl":"10.1016/j.biopha.2024.117654","url":null,"abstract":"<div><div>The pathogenesis of cardiovascular diseases (CVDs) is intricate, with liquid-liquid phase separation (LLPS) considered a crucial regulatory mechanism. Epigenetics is closely intertwined with cardiovascular diseases, involving mechanisms such as DNA methylation, histone modifications, and non-coding RNAs (ncRNAs) that play pivotal roles in cardiovascular disease progression and regression. It is known that specific proteins and mRNAs associated with epigenetic modifications exhibit LLPS characteristics, influencing cardiovascular diseases. Consequently, targeting epigenetic modifications to modulate LLPS emerges as a promising strategy for cardiovascular diseases treatment. This review delves into the regulatory impact of liquid-liquid phase separation on cardiovascular diseases, with a specific focus on the epigenetic landscape. The current study sought to investigate the relationship between epigenetic landscape and phase separation in cardiovascular diseases development, as well as their therapeutic implications.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"181 ","pages":"Article 117654"},"PeriodicalIF":6.9,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142632893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-09DOI: 10.1016/j.biopha.2024.117664
Kaiyue Zuo , Naiyu Liu , Peng Zhou , Mengzhu Zheng , Lingjuan Wang , Tingting Tang , Zhanqun Yang , Long Chen , Xinjie Zhu
Interleukin 2 (IL-2) is a multifunctional cytokine that is crucial for T-lymphocytes proliferation and differentiation. However, IL-2 binds to IL-2Rα (CD25) subunit preferentially and tends to stimulate regulatory T cells (Tregs), which express high-affinity trimeric receptors (IL-2Rαβγ), resulting in immunosuppressive effects. Therefore, development of methods that enhance IL-2/CD122 interactions and activate immune responses without affecting therapeutic efficacy of IL-2 may be desirable. In this work, we constructed a recombinant IL-2 fusion protein (HSA-IL-2), comprising human serum albumin (HSA) and IL-2, there was a new interaction interface between HSA domain and CD122 in HSA-IL-2 fusion protein predicted by AlphaFold2, and followed by determining binding affinity between HSA-IL-2 and CD122 through ForteBio’s Bio-Layer Interferometry technology. Strikingly, HSA did promoted interactions between HSA-IL-2 fusion protein and CD122 compared with wild-type IL-2. In vivo experiments, HSA-IL-2 fusion protein had capacity to promote CD8+ T cells infiltration while reducing Treg cells infiltration for boosting immunotherapeutic efficacy. Furthermore, it facilitated synergistic therapeutic effect with α-PD-L1 to inhibit tumor growth. Overall, our research unveiled an enhanced binding affinity method underlying interactions between IL-2 and CD122 via fusing albumin, and propose a promising therapeutic strategy to facilitate IL-2 administration and broaden its clinical use.
白细胞介素 2（IL-2）是一种多功能细胞因子，对 T 淋巴细胞的增殖和分化至关重要。然而，IL-2 优先与 IL-2Rα（CD25）亚基结合，往往会刺激表达高亲和性三聚体受体（IL-2Rαβγ）的调节性 T 细胞（Tregs），从而产生免疫抑制作用。因此，开发能增强 IL-2/CD122 相互作用并激活免疫反应而不影响 IL-2 治疗效果的方法可能是可取的。在这项工作中，我们构建了由人血清白蛋白（HSA）和IL-2组成的重组IL-2融合蛋白（HSA-IL-2），通过AlphaFold2预测了HSA-IL-2融合蛋白中HSA结构域和CD122之间新的相互作用界面，随后通过ForteBio的生物层干涉测量技术测定了HSA-IL-2和CD122之间的结合亲和力。与野生型 IL-2 相比，HSA 确实促进了 HSA-IL-2 融合蛋白与 CD122 之间的相互作用。在体内实验中，HSA-IL-2 融合蛋白有能力促进 CD8+ T 细胞浸润，同时减少 Treg 细胞浸润，从而提高免疫治疗效果。此外，它还能与α-PD-L1协同抑制肿瘤生长。总之，我们的研究揭示了一种通过融合白蛋白增强IL-2与CD122之间相互作用的结合亲和力的方法，并提出了一种很有前景的治疗策略，以促进IL-2的给药并扩大其临床应用。
{"title":"Human serum albumin promotes interactions between HSA-IL-2 fusion protein and CD122 for enhancing immunotherapy","authors":"Kaiyue Zuo , Naiyu Liu , Peng Zhou , Mengzhu Zheng , Lingjuan Wang , Tingting Tang , Zhanqun Yang , Long Chen , Xinjie Zhu","doi":"10.1016/j.biopha.2024.117664","DOIUrl":"10.1016/j.biopha.2024.117664","url":null,"abstract":"<div><div>Interleukin 2 (IL-2) is a multifunctional cytokine that is crucial for T-lymphocytes proliferation and differentiation. However, IL-2 binds to IL-2Rα (CD25) subunit preferentially and tends to stimulate regulatory T cells (Tregs), which express high-affinity trimeric receptors (IL-2Rαβγ), resulting in immunosuppressive effects. Therefore, development of methods that enhance IL-2/CD122 interactions and activate immune responses without affecting therapeutic efficacy of IL-2 may be desirable. In this work, we constructed a recombinant IL-2 fusion protein (HSA-IL-2), comprising human serum albumin (HSA) and IL-2, there was a new interaction interface between HSA domain and CD122 in HSA-IL-2 fusion protein predicted by AlphaFold2, and followed by determining binding affinity between HSA-IL-2 and CD122 through ForteBio’s Bio-Layer Interferometry technology. Strikingly, HSA did promoted interactions between HSA-IL-2 fusion protein and CD122 compared with wild-type IL-2. <em>In vivo</em> experiments, HSA-IL-2 fusion protein had capacity to promote CD8<sup>+</sup> T cells infiltration while reducing Treg cells infiltration for boosting immunotherapeutic efficacy. Furthermore, it facilitated synergistic therapeutic effect with α-PD-L1 to inhibit tumor growth. Overall, our research unveiled an enhanced binding affinity method underlying interactions between IL-2 and CD122 via fusing albumin, and propose a promising therapeutic strategy to facilitate IL-2 administration and broaden its clinical use.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"181 ","pages":"Article 117664"},"PeriodicalIF":6.9,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Opioid addiction is known as a chronic relapsing disorder associated with long-lasting molecular and cellular neuroadaptations that lead to compulsive behavior. Current pharmacotherapies target the modulation of mu-opioid receptors (MOR); however, the relapse rate remains high. In this study, we evaluated the potential effect of atorvastatin, a blood-brain barrier-permeable statin, on preventing morphine relapse through both extinction-reinstatement and abstinence-reinstatement models using conditioned place preference (CPP). Adult male Wistar rats were used to establish morphine-induced CPP (5 mg/kg), followed by extinction training and subsequent priming injection of morphine (2 mg/kg, i.p.) to induce relapse-like behavior. Extinguished rats significantly reinstated their morphine-seeking behavior. In contrast, rats that received different doses of atorvastatin (0.1, 0.5, 1 mg/kg) 1 hour before each extinction training session did not show a preference for the morphine-paired chamber. Moreover, acute atorvastatin injection (1 mg/kg, i.p.) 1 h before the reinstatement test significantly prevented reinstated morphine-seeking behavior. We found that atorvastatin 1 mg/kg attenuated morphine-seeking behaviors, and this attenuation of reinstatement was partly mediated by the upregulation of brain-derived neurotrophic factor (BDNF) in the prefrontal cortex (PFC) and hippocampus (Hipp). Furthermore, atorvastatin reversed Oprm1 upregulation (mu-opioid receptor gene) induced by relapse in the nucleus accumbens and Hipp. Moreover, treatment with atorvastatin during the extinction period alters the electrophysiological properties of the mPFC neurons following morphine priming and enhances neuronal excitability. We conclude that atorvastatin was effective in decreasing reinstatement.
{"title":"Atorvastatin facilitates extinction and prevents reinstatement of morphine-induced conditioned place preference in rats","authors":"Shiva Hashemizadeh , Elham Alaee , Niloofar Aghajani , Hossein Azizi , Saeed Semnanian","doi":"10.1016/j.biopha.2024.117639","DOIUrl":"10.1016/j.biopha.2024.117639","url":null,"abstract":"<div><div>Opioid addiction is known as a chronic relapsing disorder associated with long-lasting molecular and cellular neuroadaptations that lead to compulsive behavior. Current pharmacotherapies target the modulation of mu-opioid receptors (MOR); however, the relapse rate remains high. In this study, we evaluated the potential effect of atorvastatin, a blood-brain barrier-permeable statin, on preventing morphine relapse through both extinction-reinstatement and abstinence-reinstatement models using conditioned place preference (CPP). Adult male Wistar rats were used to establish morphine-induced CPP (5 mg/kg), followed by extinction training and subsequent priming injection of morphine (2 mg/kg, i.p.) to induce relapse-like behavior. Extinguished rats significantly reinstated their morphine-seeking behavior. In contrast, rats that received different doses of atorvastatin (0.1, 0.5, 1 mg/kg) 1 hour before each extinction training session did not show a preference for the morphine-paired chamber. Moreover, acute atorvastatin injection (1 mg/kg, i.p.) 1 h before the reinstatement test significantly prevented reinstated morphine-seeking behavior. We found that atorvastatin 1 mg/kg attenuated morphine-seeking behaviors, and this attenuation of reinstatement was partly mediated by the upregulation of brain-derived neurotrophic factor (BDNF) in the prefrontal cortex (PFC) and hippocampus (Hipp). Furthermore, atorvastatin reversed <em>Oprm1</em> upregulation (mu-opioid receptor gene) induced by relapse in the nucleus accumbens and Hipp. Moreover, treatment with atorvastatin during the extinction period alters the electrophysiological properties of the mPFC neurons following morphine priming and enhances neuronal excitability. We conclude that atorvastatin was effective in decreasing reinstatement.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"181 ","pages":"Article 117639"},"PeriodicalIF":6.9,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-08DOI: 10.1016/j.biopha.2024.117574
Lichun Zhao , Wenhao Weng , Mengyue Ni , Haoyu Shen , Shuai Zhang , Yaning Chen , Ruining Jia , Linzi Fan , Yuanhui Mao , Linyin Qin , Shengzhi Liu , Yuji Wang
Inflammatory bowel disease (IBD) is a chronic condition that afflicts individuals repeatedly and cannot be cured at present, which has seriously affected the quality of life of patients. Minerals Containing Rubidium (MCR) from Guangxi Yuechengling, which Professor Zhao Lichun purified, were explored. Against this backdrop, the present study investigates the efficacy of rubidium salt in ulcerative colitis. Rubidium salt reduced levels of inflammatory markers and improved intestinal barrier function through the Elisa kit, immunohistochemistry, and qPCR. Next, we detected the level of short-chain fatty acid and found that the content of propanoic acid, butyric acid, and n-butyric acid increased after treatment with rubidium salt. We used fecal metagenomics to explore the underlying reasons further and found that rubidium salt significantly adjusted the structure of intestinal flora, increased the abundance of beneficial bacteria such as lactobacillus and bifidobacterium, and inhibited the abundance of harmful bacteria such as Enterobacteriaceae and Escherichia coli. We also learned that rubidium salt directly weakened pathogenic bacteria’s infection and survival ability by reducing the expression of virulence factors such as fimH, invA, and hilA and virulence genes such as acrA and ompR. Overall, rubidium salt can reduce harmful bacteria and increase beneficial bacteria. The increased beneficial bacteria help enhance the gut barrier and regulate inflammatory factors by raising the levels of short-chain fatty acids. A strengthened gut barrier further stabilizes microbial homeostasis, ultimately alleviating ulcerative colitis.
{"title":"Rubidium salt can effectively relieve the symptoms of DSS-induced ulcerative colitis","authors":"Lichun Zhao , Wenhao Weng , Mengyue Ni , Haoyu Shen , Shuai Zhang , Yaning Chen , Ruining Jia , Linzi Fan , Yuanhui Mao , Linyin Qin , Shengzhi Liu , Yuji Wang","doi":"10.1016/j.biopha.2024.117574","DOIUrl":"10.1016/j.biopha.2024.117574","url":null,"abstract":"<div><div>Inflammatory bowel disease (IBD) is a chronic condition that afflicts individuals repeatedly and cannot be cured at present, which has seriously affected the quality of life of patients. Minerals Containing Rubidium (MCR) from Guangxi Yuechengling, which Professor Zhao Lichun purified, were explored. Against this backdrop, the present study investigates the efficacy of rubidium salt in ulcerative colitis. Rubidium salt reduced levels of inflammatory markers and improved intestinal barrier function through the Elisa kit, immunohistochemistry, and qPCR. Next, we detected the level of short-chain fatty acid and found that the content of propanoic acid, butyric acid, and n-butyric acid increased after treatment with rubidium salt. We used fecal metagenomics to explore the underlying reasons further and found that rubidium salt significantly adjusted the structure of intestinal flora, increased the abundance of beneficial bacteria such as lactobacillus and bifidobacterium, and inhibited the abundance of harmful bacteria such as Enterobacteriaceae and Escherichia coli. We also learned that rubidium salt directly weakened pathogenic bacteria’s infection and survival ability by reducing the expression of virulence factors such as fimH, invA, and hilA and virulence genes such as acrA and ompR. Overall, rubidium salt can reduce harmful bacteria and increase beneficial bacteria. The increased beneficial bacteria help enhance the gut barrier and regulate inflammatory factors by raising the levels of short-chain fatty acids. A strengthened gut barrier further stabilizes microbial homeostasis, ultimately alleviating ulcerative colitis.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"181 ","pages":"Article 117574"},"PeriodicalIF":6.9,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142633276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-07DOI: 10.1016/j.biopha.2024.117657
Rômulo José Soares-Bezerra , Natiele Carla da Silva Ferreira , Tânia Maria de Almeida Alves , Carlos Leomar Zani , Luiz Henrique Rosa , Andrea Surrage Calheiros , Cristiane Zanon de Souza , Julliana Alves Azeredo Miranda , Kátia Regina Ferreira Lima-Quaresma , Luiz Anastacio Alves , Válber da Silva Frutuoso
P2X7 is a purinergic receptor physiologically activated by extracellular ATP. Its activation induces proinflammatory responses, including cytokine release, reactive oxygen species formation, and cell death. Previous in vivo experimental models demonstrated that P2X7 blockade has anti-inflammatory effects; however, there are no drugs used in clinical therapy that act on the P2X7 receptor. In the context of inflammatory diseases, nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used as the first-line treatment; however, their major side effects include stomach ulcer formation, which increases patient morbidity and mortality. Here, we analyzed for the first time the analgesic and gastroprotective activities of three fungal extracts that showed antagonistic effects on P2X7 in vitro. The Antarctic fungal extracts obtained from Vishniacozyma victoriae, Metschnikowia australis, and Ascomycota sp. were tested via in vivo models of acute pain and ethanol-induced ulceration. These three extracts reduced paw licking by approximately 50 %, which is related to pain behavior, and reduced the number of stomach ulcers 3–7 times compared with the control (70 % ethanol), making them more efficient than the lansoprazole, an NSAID drug, and Brilliant Blue G (BBG), a known P2X7 antagonist, which only halves the number of ulcers. Furthermore, the extracts also protected the gastric mucosa and significantly reduced the levels of liver and renal enzymes compared with those in the ethanol group. Taken together, the fungal extracts presented both analgesic and possibly anti-inflammatory activities and had a protective effect on the gastric epithelium.
{"title":"The analgesic and gastroprotective activities of the three fungal extracts and their possible correlation with the inhibition of the P2X7 receptor","authors":"Rômulo José Soares-Bezerra , Natiele Carla da Silva Ferreira , Tânia Maria de Almeida Alves , Carlos Leomar Zani , Luiz Henrique Rosa , Andrea Surrage Calheiros , Cristiane Zanon de Souza , Julliana Alves Azeredo Miranda , Kátia Regina Ferreira Lima-Quaresma , Luiz Anastacio Alves , Válber da Silva Frutuoso","doi":"10.1016/j.biopha.2024.117657","DOIUrl":"10.1016/j.biopha.2024.117657","url":null,"abstract":"<div><div>P2X7 is a purinergic receptor physiologically activated by extracellular ATP. Its activation induces proinflammatory responses, including cytokine release, reactive oxygen species formation, and cell death. Previous <em>in vivo</em> experimental models demonstrated that P2X7 blockade has anti-inflammatory effects; however, there are no drugs used in clinical therapy that act on the P2X7 receptor. In the context of inflammatory diseases, nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used as the first-line treatment; however, their major side effects include stomach ulcer formation, which increases patient morbidity and mortality. Here, we analyzed for the first time the analgesic and gastroprotective activities of three fungal extracts that showed antagonistic effects on P2X7 <em>in vitro</em>. The Antarctic fungal extracts obtained from <em>Vishniacozyma victoriae</em>, <em>Metschnikowia australis</em>, and <em>Ascomycota</em> sp. were tested via <em>in vivo</em> models of acute pain and ethanol-induced ulceration. These three extracts reduced paw licking by approximately 50 %, which is related to pain behavior, and reduced the number of stomach ulcers 3–7 times compared with the control (70 % ethanol), making them more efficient than the lansoprazole, an NSAID drug, and Brilliant Blue G (BBG), a known P2X7 antagonist, which only halves the number of ulcers. Furthermore, the extracts also protected the gastric mucosa and significantly reduced the levels of liver and renal enzymes compared with those in the ethanol group. Taken together, the fungal extracts presented both analgesic and possibly anti-inflammatory activities and had a protective effect on the gastric epithelium.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"181 ","pages":"Article 117657"},"PeriodicalIF":6.9,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-06DOI: 10.1016/j.biopha.2024.117650
Ignacio Ortea , Lorena Rodríguez-Martínez , Mónica Carrera , Juan A. Fafián-Labora , Maria C. Arufe , Miguel González-Barcia , Anxo Fernández-Ferreiro , Jesús Mateos
Cysteamine, an aminothiol, is the only available treatment for cystinosis, an incurable metabolic recessive disease characterized by detrimental symptoms at the renal, ocular, and muscular levels. Cystinosis is due to mutations in the CTNS gene encoding for the lysosomal symporter cystinosine. Cysteamine treatment only delays the symptoms, presents undesirable side effects and the patients depend on it for life. Thus, it is of paramount importance to find new complementary therapeutic targets for the disease, as well as to understand, at the molecular level, both the beneficial and detrimental effects of cysteamine. Here, we have used ZenoSWATH DIA proteomics and clustering analysis to unravel the differences between cystinotic and non-cystinotic skin fibroblasts, and to study the effect of increasing concentrations of cysteamine. Cystinotic cells present significant differences in proteins related to extracellular matrix structure and detoxification. Only a subset of those proteins is reversed by cysteamine in a dose-dependent manner, partially providing an explanation for its therapeutic benefits. Finally, cysteamine per se alters the levels of a group of lysosomal proteins that are not modulated in basal conditions. Our results will be helpful to understand the benefits, deficiencies, and detrimental effects of the cysteamine treatment.
胱氨酸病是一种无法治愈的代谢性隐性疾病，其特征是在肾脏、眼部和肌肉层面出现有害症状。胱氨酸中毒症是由于编码溶酶体交感蛋白胱氨酸的 CTNS 基因发生突变所致。半胱胺治疗只能延缓症状的出现，并会产生不良的副作用，而且患者会终生依赖半胱胺。因此，寻找新的辅助治疗靶点，并在分子水平上了解半胱胺的有益和有害作用至关重要。在这里，我们利用 ZenoSWATH DIA 蛋白组学和聚类分析揭示了胱氨酸病性和非胱氨酸病性皮肤成纤维细胞之间的差异，并研究了增加半胱胺浓度的影响。胱氨酸细胞在与细胞外基质结构和解毒有关的蛋白质方面存在显著差异。半胱胺以剂量依赖的方式逆转了这些蛋白质中的一部分，从而部分解释了半胱胺的治疗效果。最后，半胱胺本身会改变一组溶酶体蛋白的水平，而这些蛋白在基础条件下不会受到调节。我们的研究结果将有助于了解半胱胺治疗的益处、不足和不利影响。
{"title":"ZenoSWATH DIA proteomics and clustering analysis of the effect of cysteamine at the cellular level in cystinotic fibroblasts","authors":"Ignacio Ortea , Lorena Rodríguez-Martínez , Mónica Carrera , Juan A. Fafián-Labora , Maria C. Arufe , Miguel González-Barcia , Anxo Fernández-Ferreiro , Jesús Mateos","doi":"10.1016/j.biopha.2024.117650","DOIUrl":"10.1016/j.biopha.2024.117650","url":null,"abstract":"<div><div>Cysteamine, an aminothiol, is the only available treatment for cystinosis, an incurable metabolic recessive disease characterized by detrimental symptoms at the renal, ocular, and muscular levels. Cystinosis is due to mutations in the <em>CTNS</em> gene encoding for the lysosomal symporter cystinosine. Cysteamine treatment only delays the symptoms, presents undesirable side effects and the patients depend on it for life. Thus, it is of paramount importance to find new complementary therapeutic targets for the disease, as well as to understand, at the molecular level, both the beneficial and detrimental effects of cysteamine. Here, we have used ZenoSWATH DIA proteomics and clustering analysis to unravel the differences between cystinotic and non-cystinotic skin fibroblasts, and to study the effect of increasing concentrations of cysteamine. Cystinotic cells present significant differences in proteins related to extracellular matrix structure and detoxification. Only a subset of those proteins is reversed by cysteamine in a dose-dependent manner, partially providing an explanation for its therapeutic benefits. Finally, cysteamine <em>per se</em> alters the levels of a group of lysosomal proteins that are not modulated in basal conditions. Our results will be helpful to understand the benefits, deficiencies, and detrimental effects of the cysteamine treatment.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"181 ","pages":"Article 117650"},"PeriodicalIF":6.9,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142592403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-06DOI: 10.1016/j.biopha.2024.117647
Yumei Sun , Jihong Wang , Peiyao Hu , Yi Tang , Yanwen Wang , Jianzhou Ye , Xuesong Yang , Junlin Yin
Tripterygium hypoglaucum (Lévl.) Hutch rhizome (THH) is mainly used in the clinical setting for the treatment of autoimmune diseases such as rheumatoid arthritis. In total, four active compounds were isolated from THH methanol extract （THH-MeOH）and identified. The HPLC results showed that the proportions of the active ingredients in THH-MeOH (i.e., celastrol, triptolide, and 3-O-acetyloleanolic acid) were 0.79 ‰, 0.46 ‰, and 0.76 ‰, respectively. THH-MeOH attenuated the M5-induced hyperproliferation of HaCaT cells, decreased the mRNA expression levels of inflammatory cytokines, and inhibited the phosphorylation of IκBα, NF-κB p65, MAPK, and STAT3/JAK2. Furthermore, THH-MeOH significantly reduced PASI scores in mice; reduced the level of Ki67 expression in skin tissues; decreased the expression of inflammatory cytokines in the skin lesions and serum; and ameliorated the IMQ-induced imbalance in the RORγt/Foxp3 ratio. The extract can attenuate psoriasis-like lesions by inhibiting cellular hyperproliferation, ameliorating inflammatory reactions, and modulating immune responses. Our work provides a theoretical basis to support the use of THH for treating psoriasis.
{"title":"Molecular mechanism through which Tripterygium hypoglaucum (Lévl.) Hutch alleviates psoriasis","authors":"Yumei Sun , Jihong Wang , Peiyao Hu , Yi Tang , Yanwen Wang , Jianzhou Ye , Xuesong Yang , Junlin Yin","doi":"10.1016/j.biopha.2024.117647","DOIUrl":"10.1016/j.biopha.2024.117647","url":null,"abstract":"<div><div><em>Tripterygium hypoglaucum</em> (Lévl.) Hutch rhizome (THH) is mainly used in the clinical setting for the treatment of autoimmune diseases such as rheumatoid arthritis. In total, four active compounds were isolated from THH methanol extract （THH-MeOH）and identified. The HPLC results showed that the proportions of the active ingredients in THH-MeOH (i.e., celastrol, triptolide, and 3-<em>O</em>-acetyloleanolic acid) were 0.79 ‰, 0.46 ‰, and 0.76 ‰, respectively. THH-MeOH attenuated the M5-induced hyperproliferation of HaCaT cells, decreased the mRNA expression levels of inflammatory cytokines, and inhibited the phosphorylation of I<em>κ</em>B<em>α</em>, NF-<em>κ</em>B p65, MAPK, and STAT3/JAK2. Furthermore, THH-MeOH significantly reduced PASI scores in mice; reduced the level of Ki67 expression in skin tissues; decreased the expression of inflammatory cytokines in the skin lesions and serum; and ameliorated the IMQ-induced imbalance in the ROR<em>γ</em>t<em>/</em>Foxp3 ratio. The extract can attenuate psoriasis-like lesions by inhibiting cellular hyperproliferation, ameliorating inflammatory reactions, and modulating immune responses. Our work provides a theoretical basis to support the use of THH for treating psoriasis.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"181 ","pages":"Article 117647"},"PeriodicalIF":6.9,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142592397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-06DOI: 10.1016/j.biopha.2024.117597
Changlong Fu , Yanming Lin , Qing Lin , Shujie Lan , Yanfeng Huang , Haishui Tu , Chao Li , Shiyu Lu , Xihai Li , Weihong Zhong , Dezun Ma
LncRNA XIST and Nav1.7 have been identified to be significantly associated with the onset of osteoarthritis. Prim-O-glucosylcimifugin (POG) has antiinflammatory and analgesic effects in treating osteoarthritis (OA). However, its molecular mechanism of action remains unclear. This research investigated whether POG inhibits OA cartilage degeneration by regulating Nav1.7 through lncRNA XIST. We observed the relationship between lncRNA XIST and Nav1.7 through in vivo and in vitro experiments, and utilized lentiviral plasmids for XIST overexpression to further validate the protective effect of POG against OA. In vivo experiments revealed the close association of improving OA cartilage morphological changes by POG with lncRNA XIST and Nav1.7 downregulation and related proteins expression. In vitro experiments demonstrated significantly up-regulated lncRNA XIST and Nav1.7 expression in IL1β-induced chondrocytes, and their levels and related protein expression decreased after POG intervention. FISH indicated that POG attenuated the fluorescence intensity of lncRNA XIST in chondrocytes. RT-PCR and Western blot assays revealed the positive correlation of lncRNA XIST and Nav1.7 expression in chondrocytes. Additionally, flow cytometry results revealed that POG intervention reduced OA chondrocyte apoptosis. Therefore, we conclude that POG can mediate lncRNA XIST to regulate Nav1.7 to delay cartilage degeneration, which is an effective way to treat OA. However, lncRNA XIST is not the only target for regulation, and further discussion is needed.
{"title":"Protective mechanism of Prim-O-glucosylcimifugin in the treatment of osteoarthritis: Based on lncRNA XIST regulation of Nav1.7","authors":"Changlong Fu , Yanming Lin , Qing Lin , Shujie Lan , Yanfeng Huang , Haishui Tu , Chao Li , Shiyu Lu , Xihai Li , Weihong Zhong , Dezun Ma","doi":"10.1016/j.biopha.2024.117597","DOIUrl":"10.1016/j.biopha.2024.117597","url":null,"abstract":"<div><div>LncRNA XIST and Nav1.7 have been identified to be significantly associated with the onset of osteoarthritis. Prim-O-glucosylcimifugin (POG) has antiinflammatory and analgesic effects in treating osteoarthritis (OA). However, its molecular mechanism of action remains unclear. This research investigated whether POG inhibits OA cartilage degeneration by regulating Nav1.7 through lncRNA XIST. We observed the relationship between lncRNA XIST and Nav1.7 through in vivo and in vitro experiments, and utilized lentiviral plasmids for XIST overexpression to further validate the protective effect of POG against OA. <em>In vivo</em> experiments revealed the close association of improving OA cartilage morphological changes by POG with lncRNA XIST and Nav1.7 downregulation and related proteins expression. <em>In vitro</em> experiments demonstrated significantly up-regulated lncRNA XIST and Nav1.7 expression in IL1β-induced chondrocytes, and their levels and related protein expression decreased after POG intervention. FISH indicated that POG attenuated the fluorescence intensity of lncRNA XIST in chondrocytes. RT-PCR and Western blot assays revealed the positive correlation of lncRNA XIST and Nav1.7 expression in chondrocytes. Additionally, flow cytometry results revealed that POG intervention reduced OA chondrocyte apoptosis. Therefore, we conclude that POG can mediate lncRNA XIST to regulate Nav1.7 to delay cartilage degeneration, which is an effective way to treat OA. However, lncRNA XIST is not the only target for regulation, and further discussion is needed.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"181 ","pages":"Article 117597"},"PeriodicalIF":6.9,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-04DOI: 10.1016/j.biopha.2024.117505
Liang Pei , Zhuo Yao , Dong Liang , Keda Yang , Lin Tao
Skeletal system-related diseases, such as osteoporosis, arthritis, osteosarcoma and sarcopenia, are becoming major public health concerns. These diseases are characterized by insidious progression, which seriously threatens patients’ health and quality of life. Early diagnosis and prevention in high-risk populations can effectively prevent the deterioration of these patients. Mitochondria are essential organelles for maintaining the physiological activity of the skeletal system. Mitochondrial functions include contributing to the energy supply, modulating the Ca2+ concentration, maintaining redox balance and resisting the inflammatory response. They participate in the regulation of cellular behaviors and the responses of osteoblasts, osteoclasts, chondrocytes and myocytes to external stimuli. In this review, we describe the pathogenesis of skeletal system diseases, focusing on mitochondrial function. In addition to osteosarcoma, a characteristic of which is active mitochondrial metabolism, mitochondrial damage occurs during the development of other diseases. Impairment of mitochondria leads to an imbalance in osteogenesis and osteoclastogenesis in osteoporosis, cartilage degeneration and inflammatory infiltration in arthritis, and muscle atrophy and excitationcontraction coupling blockade in sarcopenia. Overactive mitochondrial metabolism promotes the proliferation and migration of osteosarcoma cells. The copy number of mitochondrial DNA and mitochondria-derived peptides can be potential biomarkers for the diagnosis of these disorders. High-risk factor detection combined with mitochondrial component detection contributes to the early detection of these diseases. Targeted mitochondrial intervention is an effective method for treating these patients. We analyzed skeletal system-related diseases from the perspective of mitochondria and provided new insights for their diagnosis, prevention and treatment by demonstrating the relationship between mitochondria and the skeletal system.
与骨骼系统相关的疾病，如骨质疏松症、关节炎、骨肉瘤和肌肉疏松症，正在成为公众健康的主要问题。这些疾病具有隐匿性进展的特点，严重威胁患者的健康和生活质量。对高危人群进行早期诊断和预防，可以有效防止这些患者的病情恶化。线粒体是维持骨骼系统生理活动的重要细胞器。线粒体的功能包括提供能量、调节 Ca2+ 浓度、维持氧化还原平衡和抵抗炎症反应。它们参与调节细胞行为以及成骨细胞、破骨细胞、软骨细胞和肌细胞对外界刺激的反应。在这篇综述中，我们将以线粒体功能为重点，描述骨骼系统疾病的发病机理。骨肉瘤的一个特点是线粒体代谢活跃，除骨肉瘤外，线粒体损伤也发生在其他疾病的发展过程中。线粒体受损会导致骨质疏松症中的成骨和破骨细胞生成失衡、关节炎中的软骨退化和炎症浸润，以及肌肉疏松症中的肌肉萎缩和兴奋-收缩耦联阻断。过度活跃的线粒体代谢会促进骨肉瘤细胞的增殖和迁移。线粒体 DNA 的拷贝数和线粒体衍生肽可作为诊断这些疾病的潜在生物标记物。高危因素检测与线粒体成分检测相结合，有助于早期发现这些疾病。有针对性的线粒体干预是治疗这些患者的有效方法。我们从线粒体的角度分析了骨骼系统相关疾病，通过展示线粒体与骨骼系统之间的关系，为这些疾病的诊断、预防和治疗提供了新的见解。
{"title":"Mitochondria in skeletal system-related diseases","authors":"Liang Pei , Zhuo Yao , Dong Liang , Keda Yang , Lin Tao","doi":"10.1016/j.biopha.2024.117505","DOIUrl":"10.1016/j.biopha.2024.117505","url":null,"abstract":"<div><div>Skeletal system-related diseases, such as osteoporosis, arthritis, osteosarcoma and sarcopenia, are becoming major public health concerns. These diseases are characterized by insidious progression, which seriously threatens patients’ health and quality of life. Early diagnosis and prevention in high-risk populations can effectively prevent the deterioration of these patients. Mitochondria are essential organelles for maintaining the physiological activity of the skeletal system. Mitochondrial functions include contributing to the energy supply, modulating the Ca<sup>2+</sup> concentration, maintaining redox balance and resisting the inflammatory response. They participate in the regulation of cellular behaviors and the responses of osteoblasts, osteoclasts, chondrocytes and myocytes to external stimuli. In this review, we describe the pathogenesis of skeletal system diseases, focusing on mitochondrial function. In addition to osteosarcoma, a characteristic of which is active mitochondrial metabolism, mitochondrial damage occurs during the development of other diseases. Impairment of mitochondria leads to an imbalance in osteogenesis and osteoclastogenesis in osteoporosis, cartilage degeneration and inflammatory infiltration in arthritis, and muscle atrophy and excitation<img>contraction coupling blockade in sarcopenia. Overactive mitochondrial metabolism promotes the proliferation and migration of osteosarcoma cells. The copy number of mitochondrial DNA and mitochondria-derived peptides can be potential biomarkers for the diagnosis of these disorders. High-risk factor detection combined with mitochondrial component detection contributes to the early detection of these diseases. Targeted mitochondrial intervention is an effective method for treating these patients. We analyzed skeletal system-related diseases from the perspective of mitochondria and provided new insights for their diagnosis, prevention and treatment by demonstrating the relationship between mitochondria and the skeletal system.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"181 ","pages":"Article 117505"},"PeriodicalIF":6.9,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142578178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-02DOI: 10.1016/j.biopha.2024.117634
Jason Sallbach, Melanie Woods, Birgit Rasenberger, Markus Christmann , Maja T. Tomicic
Background and purpose
Standard of care for glioblastomas includes radio-chemotherapy with the monoalkylating compound temozolomide. Temozolomide induces primarily senescence, inefficiently killing glioblastoma cells. Recurrences are inevitable. Although recurrences presumably arise from cells evading/escaping TMZ-induced senescence, becoming resistant, they are often again treated with TMZ. As an alternative treatment, irinotecan could be used. Our aim was to examine to what extent and conditions the topoisomerase I inhibitor irinotecan induces senescence and to analyze the underlying mechanism.
Results
Multiple glioblastoma lines with different genetic signatures for p53, p21CIP1, p16INK4A, p14ARF, and PTEN were used. By means of LN229 glioblastoma clones which escaped from temozolomide-induced senescence, thus, being potentially recurrence-forming, we show that this escape is accompanied by increased p21CIP1 protein levels in temozolomide-unexposed senescence-evading clones and inability of temozolomide to induce p21CIP1. In contrast, irinotecan was still able to induce p21CIP1 and could elevate senescence and cell death. In combination with the senolytic drug BV6, irinotecan-induced senescence was significantly reduced. Differential response clusters were also observed in paired samples of newly diagnosed and recurrent patients’ tumors. This can partially explain a significantly prolonged progression-free time until surgery for recurrence in patients additionally treated with irinotecan after temozolomide consolidation and upon the first onset of recurrence.
Conclusions
p21CIP1 is essentially involved in induction and maintenance of irinotecan-induced senescence. Neither p16INK4A, p14ARF, nor PTEN contribute to senescence, if p21CIP1 cannot be induced. Based on the positive results of the irinotecan/BV6 treatment, combatting recurrent glioblastomas by targeting senescence cell antiapoptotic pathways (SCAPs) should be considered.
{"title":"The cell cycle inhibitor p21CIP1 is essential for irinotecan-induced senescence and plays a decisive role in re-sensitization of temozolomide-resistant glioblastoma cells to irinotecan","authors":"Jason Sallbach, Melanie Woods, Birgit Rasenberger, Markus Christmann , Maja T. Tomicic","doi":"10.1016/j.biopha.2024.117634","DOIUrl":"10.1016/j.biopha.2024.117634","url":null,"abstract":"<div><h3>Background and purpose</h3><div>Standard of care for glioblastomas includes radio-chemotherapy with the monoalkylating compound temozolomide. Temozolomide induces primarily senescence, inefficiently killing glioblastoma cells. Recurrences are inevitable. Although recurrences presumably arise from cells evading/escaping TMZ-induced senescence, becoming resistant, they are often again treated with TMZ. As an alternative treatment, irinotecan could be used. Our aim was to examine to what extent and conditions the topoisomerase I inhibitor irinotecan induces senescence and to analyze the underlying mechanism.</div></div><div><h3>Results</h3><div>Multiple glioblastoma lines with different genetic signatures for p53, p21<sup>CIP1</sup>, p16<sup>INK4A</sup>, p14<sup>ARF</sup>, and PTEN were used. By means of LN229 glioblastoma clones which escaped from temozolomide-induced senescence, thus, being potentially recurrence-forming, we show that this escape is accompanied by increased p21<sup>CIP1</sup> protein levels in temozolomide-unexposed senescence-evading clones and inability of temozolomide to induce p21<sup>CIP1</sup>. In contrast, irinotecan was still able to induce p21<sup>CIP1</sup> and could elevate senescence and cell death. In combination with the senolytic drug BV6, irinotecan-induced senescence was significantly reduced. Differential response clusters were also observed in paired samples of newly diagnosed and recurrent patients’ tumors. This can partially explain a significantly prolonged progression-free time until surgery for recurrence in patients additionally treated with irinotecan after temozolomide consolidation and upon the first onset of recurrence.</div></div><div><h3>Conclusions</h3><div>p21<sup>CIP1</sup> is essentially involved in induction and maintenance of irinotecan-induced senescence. Neither p16<sup>INK4A</sup>, p14<sup>ARF</sup>, nor PTEN contribute to senescence, if p21<sup>CIP1</sup> cannot be induced. Based on the positive results of the irinotecan/BV6 treatment, combatting recurrent glioblastomas by targeting senescence cell antiapoptotic pathways (SCAPs) should be considered.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"181 ","pages":"Article 117634"},"PeriodicalIF":6.9,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142570514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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