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Reconstruction of the Hepatic Microenvironment and Pathological Changes Underlying Type II Diabetes through Single-Cell RNA Sequencing. 通过单细胞 RNA 测序重建 II 型糖尿病的肝脏微环境和病理变化
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-14 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.99176
Chia-Yen Dai, Ying-Ming Tsai, Chao-Yuan Chang, Hung-Pei Tsai, Kuan-Li Wu, Yu-Yuan Wu, Ling-Yu Wu, Shu-Fang Jian, Pei-Hsun Tsai, Chai-Tung Ong, Chien-Hui Sun, Ya-Ling Hsu

The global prevalence of type 2 diabetes mellitus (T2DM) continues to rise. Therefore, it has become a major concern health issue worldwide. T2DM leads to various complications, including metabolic-associated fatty liver disease (MAFLD). However, comprehensive studies on MAFLD as a diabetic complication at different stages are still lacking. Using advanced single-cell RNA-seq technology, we explored changes of livers in two T2DM murine models. Our findings revealed that increase activation of hepatic stellate cells (HSCs) exacerbated the development of MAFLD to steatohepatitis by upregulating transforming growth factor β1 induced transcript 1 (Tgfb1i1). Upregulated thioredoxin-interacting protein (Txnip) contributed to hepatocyte damage by impairing reactive oxygen species clearance. Additionally, the capillarization of liver sinusoidal endothelial cells correlated with Fabp4 overexpression in endothelial cells. A novel subset of Kupffer cells (KCs) that expressed Cd36 exhibited an activated phenotype, potentially participating in inflammation in the liver of diabetic mice. Furthermore, ligand-receptor pair analysis indicated that activated HSCs interacted with hepatocytes or KCs through Thbs2 and Lamb2 in late-stage diseases. The reduction in cell-cell interactions within hepatocytes in diabetic mice, reflects that the mechanisms regulating liver homeostasis is disrupted. This research underscores the importance of dynamics in diabetic MAFLD, and provides new insights for targeted therapies.

全球 2 型糖尿病(T2DM)的发病率持续上升。因此,它已成为全球关注的主要健康问题。T2DM 会导致各种并发症,包括代谢相关性脂肪肝(MAFLD)。然而,目前还缺乏对代谢相关性脂肪肝作为糖尿病并发症在不同阶段的全面研究。我们利用先进的单细胞 RNA-seq 技术探讨了两种 T2DM 小鼠模型肝脏的变化。我们的研究结果表明,肝星状细胞(HSCs)的活化增加通过上调转化生长因子β1诱导转录本1(Tgfb1i1),加剧了MAFLD向脂肪性肝炎的发展。上调的硫氧还蛋白相互作用蛋白(Txnip)通过影响活性氧的清除而导致肝细胞损伤。此外,肝窦内皮细胞的毛细血管化与内皮细胞中Fabp4的过度表达有关。表达 Cd36 的 Kupffer 细胞(KCs)新亚群表现出活化表型,可能参与了糖尿病小鼠肝脏的炎症反应。此外,配体-受体配对分析表明,在疾病晚期,活化的造血干细胞通过 Thbs2 和 Lamb2 与肝细胞或 KCs 相互作用。糖尿病小鼠肝细胞内的细胞-细胞相互作用减少,反映出调节肝脏平衡的机制被破坏。这项研究强调了动态变化在糖尿病 MAFLD 中的重要性,并为靶向疗法提供了新的见解。
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引用次数: 0
ACAT1 Induces the Differentiation of Glioblastoma Cells by Rewiring Choline Metabolism. ACAT1 通过重构胆碱代谢诱导胶质母细胞瘤细胞分化
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-14 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.96651
Shen You, Ming-Jin Wang, Zhen-Yan Hou, Wei-Da Wang, Zhi-Hui Zhang, Ting-Ting Du, Shu-Ying Li, Yi-Chen Liu, Ni-Na Xue, Xiao-Min Hu, Xiao-Guang Chen, Ming Ji

Abnormal differentiation of cells is a hallmark of malignancy. Induction of cancer-cell differentiation is emerging as a novel therapeutic strategy with low toxicity in hematological malignances, but whether such treatment can be used in solid tumors is not known. Here, we uncovered a novel function of acetyl coenzyme A acetyltransferase (ACAT1) in regulating the differentiation of glioblastoma (GBM) cells. Inhibition of ACAT1 promoted the differentiation of GBM cells into astrocytes but also delayed tumor growth. Mechanistically, suppression of ACAT1 restored mitochondrial function and led to metabolic "reprogramming" in GBM cells: reduction of fatty-acid oxidation and acetyl-CoA, but an increase in free fatty acids. Importantly, ACAT1 negatively regulated the choline metabolic pathway, which is crucial for the differentiation of GBM cells. Finally, we demonstrated that a naturally available substance, chlorogenic acid (CHA), could inhibit phosphorylation of ACAT1 and so delay GBM progression, CHA is a promising candidate to treat GBM because it could induce the differentiation of cancer cells.

细胞异常分化是恶性肿瘤的标志。诱导癌细胞分化正在成为血液系统恶性肿瘤的一种新型低毒性治疗策略,但这种治疗方法能否用于实体瘤尚不清楚。在这里,我们发现了乙酰辅酶A乙酰转移酶(ACAT1)在调节胶质母细胞瘤(GBM)细胞分化中的新功能。抑制 ACAT1 可促进 GBM 细胞向星形胶质细胞分化,还能延缓肿瘤生长。从机理上讲,抑制 ACAT1 可恢复线粒体功能,并导致 GBM 细胞的代谢 "重编程":脂肪酸氧化和乙酰-CoA 减少,但游离脂肪酸增加。重要的是,ACAT1 对胆碱代谢途径有负面调节作用,而胆碱代谢途径对 GBM 细胞的分化至关重要。最后,我们证明了一种天然物质绿原酸(CHA)可以抑制 ACAT1 的磷酸化,从而延缓 GBM 的进展。
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引用次数: 0
OAS3 Deubiquitination Due to E3 Ligase TRIM21 Downregulation Promotes Epithelial Cell Apoptosis and Drives Sepsis-induced Acute Lung Injury. E3连接酶TRIM21下调导致的OAS3去泛素化促进上皮细胞凋亡并驱动败血症诱发的急性肺损伤
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-14 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.96089
Zhenfeng Chen, Bingqi Lin, Xiaodan Yao, Yihang Fang, Jinlian Liu, Ke Song, Lina Tuolihong, Zirui Zuo, Qi He, Xiaoxia Huang, Zhuanhua Liu, Qiaobing Huang, Qiulin Xu, Zhifeng Liu, Xiaohua Guo

Patients with sepsis-induced acute lung injury (SALI) show a high mortality rate, and there is no effective treatment in the clinic for SALI but only symptomatic treatment as an option. Therefore, searching for effective targets is critical for the management of SALI. Ubiquitination is an essential post-translational protein modification involved in most pathophysiological processes. However, the relationship between ubiquitination and SALI remains largely unclear. In this study, we examined the ubiquitination modification changes in SALI, identified oligoadenylate synthetase 3 (OAS3) as a key candidate accounting for SALI from integrative multi-omics analysis and confirmed its role in promoting SALI and cell apoptosis in an animal model of cecal ligation and puncture-treated mice and a cellular model of LPS-treated MLE12 cells. Mechanistically, downregulation of E3 ligase TRIM21 mediates the reduction of OAS3 K48-linked polyubiquitination at the K1079 site in lung epithelial cells of a septic model, which leads to the increase of OAS3 protein level in a proteasomal-dependent manner. The upregulated OAS3 promotes epithelial cell apoptosis through its downstream effector molecule, RNase L. In summary, these findings unveil a previously unappreciated role of OAS3 ubiquitination in SALI and offer a promising perspective for further understanding the development of sepsis and potential therapeutic target for the treatment of SALI.

脓毒症诱发的急性肺损伤(SALI)患者死亡率很高,目前临床上还没有有效治疗 SALI 的方法,只能选择对症治疗。因此,寻找有效的靶点对于治疗 SALI 至关重要。泛素化是一种重要的蛋白质翻译后修饰,参与了大多数病理生理过程。然而,泛素化与 SALI 之间的关系在很大程度上仍不清楚。在本研究中,我们研究了 SALI 中泛素化修饰的变化,通过多组学整合分析确定了寡腺苷酸合成酶 3(OAS3)作为 SALI 的关键候选蛋白,并在盲肠结扎和穿刺处理的小鼠动物模型和 LPS 处理的 MLE12 细胞模型中证实了其在促进 SALI 和细胞凋亡中的作用。从机理上讲,E3连接酶TRIM21的下调介导了败血症模型肺上皮细胞中OAS3 K48连接的多泛素化在K1079位点的减少,从而导致OAS3蛋白水平以蛋白酶体依赖的方式升高。总之,这些发现揭示了 OAS3 泛素化在 SALI 中以前未被认识到的作用,为进一步了解脓毒症的发展和治疗 SALI 的潜在治疗靶点提供了一个前景广阔的视角。
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引用次数: 0
NUSAP1 is Upregulated by Estrogen to Promote Lung Adenocarcinoma Growth and Serves as a Therapeutic Target. 雌激素上调 NUSAP1 促进肺腺癌生长并成为治疗靶点
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-07 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.100188
Shaoping Zhang, Xiaozhen Zhang, Wenjian Huang, Ganling Jiang, Yuanxin Mo, Liuxia Wei, Pingming Fan, Maojian Chen, Wei Jiang

Nucleolar and spindle-associated protein 1 (NUSAP1), a microtubule-associated protein, has been recently identified to exhibit aberrant expression patterns that correlate with malignant tumorigenesis and progression across various cancer types. However, the specific regulatory mechanisms and potential targeting therapies of NUSAP1 in lung adenocarcinoma (LUAD) remain largely elusive. In this study, by conducting bioinformatics analyses as well as in vitro and in vivo experiments, we identified that NUSAP1 was significantly upregulated in LUAD, with a notable correlation with poorer overall survival, higher scores for immunogenicity and immune infiltration, as well as increased sensitivity to conventional chemotherapeutic drugs such as paclitaxel, docetaxel and vinorelbine in LUAD. Functionally, NUSAP1 overexpression significantly promoted LUAD cell proliferation, while its knockdown markedly suppressed this process. Interestingly, our results revealed that NUSAP1 upregulation was mediated by estrogen via ERβ activation. Furthermore, we identified entinostat as a novel inhibitor of NUSAP1. Pharmacological targeting ERβ/NUSAP1 axis with fulvestrant (ERβ antagonist) or entinostat (novel NUSAP1 inhibitor) significantly reduced LUAD growth both in vitro and in vivo, which may represent effective alternative therapeutic strategies for patients with LUAD.

核极性和纺锤体相关蛋白 1(NUSAP1)是一种微管相关蛋白,最近发现它的异常表达模式与各种癌症类型的恶性肿瘤发生和发展相关。然而,NUSAP1 在肺腺癌(LUAD)中的具体调控机制和潜在靶向疗法在很大程度上仍是未知数。在本研究中,通过生物信息学分析以及体外和体内实验,我们发现 NUSAP1 在 LUAD 中显著上调,与 LUAD 较差的总生存期、较高的免疫原性和免疫浸润评分以及对传统化疗药物(如紫杉醇、多西他赛和长春瑞滨)敏感性的增加明显相关。在功能上,NUSAP1的过表达明显促进了LUAD细胞的增殖,而其敲除则明显抑制了这一过程。有趣的是,我们的研究结果表明,NUSAP1的上调是由雌激素通过ERβ激活介导的。此外,我们还发现恩替诺司他是一种新型的 NUSAP1 抑制剂。用氟维司群(ERβ拮抗剂)或恩替诺司他(新型NUSAP1抑制剂)药理靶向ERβ/NUSAP1轴,可显著降低LUAD在体外和体内的生长,这可能是LUAD患者的有效替代治疗策略。
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引用次数: 0
The dual functions of the pentacyclic triterpenoid madecassic acid in ameliorating doxorubicin-induced cardiotoxicity and enhancing the antitumor efficacy of doxorubicin. 五环三萜类化合物马德卡西酸在改善多柔比星诱导的心脏毒性和增强多柔比星抗肿瘤疗效方面的双重功能。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-07 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.97418
Wenlin Li, Kun Xu, Ming Lan, Junpeng Gao, Lin Dou, Yao Yang, Que Wang, Mingjing Yan, Sainan Li, Qinan Ma, Weimeng Tian, Beidong Chen, Ju Cui, Xiyue Zhang, Jianping Cai, Hua Wang, Liang Sun, Jian Li, Xiuqing Huang, Tao Shen

Doxorubicin (DOX) is an anthracycline that has excellent anticancer effects during tumor chemotherapy, but it can cause cardiotoxic effects and its clinical use has been limited. Therefore, finding new drugs or methods to prevent or reverse the cardiac damage caused by DOX therapy in cancer patients is essential. Previous studies have identified potential cardioprotective effects of Centella asiatica (C. asiatica), and madecassic acid (MA) is a pentacyclic triterpenoid derived from C. asiatica. However, the pharmacological effects of MA on the heart and tumors during tumor chemotherapy are not fully understood. The aim of this study was to investigate the pharmacological function and molecular mechanisms of MA in the heart and tumor during chemotherapy. In a DOX-induced acute heart failure mouse model and a cardiomyocyte injury model, MA reduced cardiomyocyte oxidative stress and the inflammatory response, improved mitochondrial function, and attenuated autophagic flux blockade and apoptosis. Interestingly, MA significantly increased the expression and activity of SIRT1. When SIRT1 was knocked down, the protective effect of MA on cardiomyocytes was significantly inhibited, suggesting that MA may exert cardioprotective effects through the SIRT1 pathway. Interestingly, in contrast to its cardioprotective effect, MA could synergize with DOX and significantly contribute to the anticancer chemotherapeutic effect of DOX by inhibiting proliferation, migration and invasion; promoting apoptosis; and suppressing tumor progression by inhibiting the expression of the DDX5 pathway in tumor cells. Here, we identified the pharmacological functions of the pentacyclic triterpenoid MA in ameliorating DOX-induced cardiotoxicity and enhancing the antitumor efficacy of DOX.

多柔比星(DOX)是一种蒽环类药物,在肿瘤化疗过程中具有极佳的抗癌效果,但它会引起心脏毒性反应,临床应用受到限制。因此,寻找新的药物或方法来预防或逆转 DOX 治疗对癌症患者造成的心脏损伤至关重要。之前的研究发现积雪草(Centella asiatica)具有潜在的心脏保护作用,而积雪草酸(MA)是从积雪草中提取的一种五环三萜类化合物。然而,MA 在肿瘤化疗过程中对心脏和肿瘤的药理作用还不完全清楚。本研究旨在探讨MA在化疗期间对心脏和肿瘤的药理作用和分子机制。在 DOX 诱导的急性心衰小鼠模型和心肌细胞损伤模型中,MA 可降低心肌细胞氧化应激和炎症反应,改善线粒体功能,减轻自噬通路阻断和细胞凋亡。有趣的是,MA 能明显提高 SIRT1 的表达和活性。当 SIRT1 被敲除时,MA 对心肌细胞的保护作用明显受到抑制,这表明 MA 可能通过 SIRT1 途径发挥心脏保护作用。有趣的是,与心肌保护作用不同,MA能与DOX协同作用,通过抑制肿瘤细胞的增殖、迁移和侵袭,促进细胞凋亡,以及抑制DDX5通路的表达来抑制肿瘤的进展,从而显著促进DOX的抗癌化疗作用。在此,我们确定了五环三萜类化合物 MA 在改善 DOX 诱导的心脏毒性和增强 DOX 抗肿瘤疗效方面的药理作用。
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引用次数: 0
Leveraging Patient-Derived Organoids for Personalized Liver Cancer Treatment. 利用源自患者的器官组织进行个性化肝癌治疗。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-07 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.96317
Jianhua Rao, Chao Song, Yangyang Hao, Zaozao Chen, Sidu Feng, Shihui Xu, Xiaoyue Wu, Zhengfeng Xuan, Ye Fan, Wenzhu Li, Junda Li, Yong Ren, Jian Li, Feng Cheng, Zhongze Gu

Primary liver cancer (PLC) is a primary cause of cancer-related death worldwide, and novel treatments are needed due to the limited options available for treatment and tumor heterogeneity. 66 surgically removed PLC samples were cultured using the self-developed 2:2 method, and the final success rate for organoid culture was 40.9%. Organoid performance has been evaluated using comprehensive molecular measurements, such as whole-exome and RNA sequencing, as well as anticancer drug testing. Multiple organoids and their corresponding tumor tissues contained several of the same mutations, with all pairs sharing conventional TP53 mutations. Regarding copy number variations and gene expression, significant correlations were observed between the organoids and their corresponding parental tumor tissues. Comparisons at the molecular level provided us with an assessment of organoid-to-tumor concordance, which, in combination with drug sensitivity testing provided direct guidance for treatment selection. Finally, we were able to determine an appropriate pharmacological regimen for a patient with ICC, demonstrating the clinical practicality in tailoring patient-specific drug regimens. Our study provides an organoid culture technology that can cultivate models that retain most of the molecular characteristics of tumors and can be used for drug sensitivity testing, demonstrating the broad potential application of organoid technology in precision medicine for liver cancer treatment.

原发性肝癌(PLC)是全球癌症相关死亡的主要原因之一,由于治疗方法有限和肿瘤的异质性,需要新的治疗方法。利用自主研发的 2:2 方法培养了 66 例手术切除的 PLC 样本,类器官培养的最终成功率为 40.9%。通过全外显子组和 RNA 测序等全面的分子测量以及抗癌药物测试,对类癌组织的性能进行了评估。多个类器官及其相应的肿瘤组织都含有几个相同的突变,所有配对都有传统的 TP53 突变。在拷贝数变异和基因表达方面,有机体与其相应的亲代肿瘤组织之间存在显著的相关性。通过分子水平的比较,我们评估了类器官与肿瘤的一致性,结合药物敏感性测试,为治疗选择提供了直接指导。最后,我们还能为 ICC 患者确定合适的药物治疗方案,证明了为患者量身定制药物治疗方案的临床实用性。我们的研究提供了一种类器官培养技术,它可以培养出保留了大部分肿瘤分子特征的模型,并可用于药物敏感性测试,这证明了类器官技术在肝癌精准医疗中的广泛应用潜力。
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引用次数: 0
Recent Trends in anti-tumor mechanisms and molecular targets of celastrol. 西司他醇的抗肿瘤机制和分子靶点的最新发展趋势。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-07 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.99592
Yongping Zhu, Yuqing Meng, Junzhe Zhang, Rui Liu, Shengnan Shen, Liwei Gu, Yin-Kwan Wong, Ang Ma, Xin Chai, Ying Zhang, Yanqing Liu, Jigang Wang

Celastrol, a compound derived from traditional Chinese medicine, has therapeutic effects and has been used to treat inflammation-related diseases, cancer, cardiovascular diseases, and neurodegenerative diseases. However, current reviews lack a comprehensive and systematic summary of the anti-tumor mechanisms and molecular targets of celastrol. For this reason, this paper reviews the anticancer properties of celastrol and the molecular mechanisms underlying its anticancer effects. This paper primarily focuses on the mechanism of action of celastrol in terms of inhibition of cell proliferation and regulation of the cell cycle, regulation of apoptosis and autophagy, inhibition of cell invasion and metastasis, anti-inflammation, regulation of immunotherapy, and angiogenesis. More importantly, the target proteins of celastrol identified by chemical proteomics or other methods are highlighted, providing detailed targets with novel therapeutic potential for anti-tumor treatment. In addition, we describe the side effects and strategies to improve the bioavailability of celastrol. In summary, this paper analyzes celastrol, a natural compound with therapeutic effects and clear targets, aiming to draw more attention from the scientific and pharmacological communities and accelerating its clinical application for the benefit of cancer patients.

青蒿素是一种源自传统中药的化合物,具有治疗作用,已被用于治疗炎症相关疾病、癌症、心血管疾病和神经退行性疾病。然而,目前的综述缺乏对青蒿素抗肿瘤机制和分子靶点的全面系统总结。因此,本文综述了青蒿素的抗癌特性及其抗癌作用的分子机制。本文主要从抑制细胞增殖和调控细胞周期、调控细胞凋亡和自噬、抑制细胞侵袭和转移、抗炎、调控免疫治疗和血管生成等方面阐述了青蒿素的作用机制。更重要的是,我们重点介绍了通过化学蛋白质组学或其他方法鉴定出的赛拉司特醇靶蛋白,为抗肿瘤治疗提供了具有新治疗潜力的详细靶点。此外,我们还介绍了西司替罗的副作用和提高其生物利用度的策略。总之,本文分析了具有治疗效果和明确靶点的天然化合物青霉烯醇,旨在引起科学界和药理学界的更多关注,并加快其临床应用,造福癌症患者。
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引用次数: 0
Cold Atmospheric Plasma: Possible Cure of Autoimmune Disorders and Cancer via Attenuating Inflammation. 冷大气等离子体:通过减轻炎症可能治疗自身免疫性疾病和癌症
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-07 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.102445
Xiaofeng Dai, Shuo Feng, Yan Zheng

Autoimmune diseases and cancers, two seemingly unrelated diseases, have been threatening human health, and many of them have no cure. By identifying pathological inflammation as the driving cause of uncontrolled cell proliferation in both classes of diseases, and differentiating autoimmune disorders and cancers by whether the cell death programs are under control, we propose the attenuation of prolonged inflammation via maintaining mitochondrial reduction-oxidation (redox) homeostasis being a possible cure of both diseases. Importantly, we propose the feasibility of applying cold atmospheric plasma (CAP) in treating autoimmune disorders and cancers given its redox-modulatory nature, which not only extends the medical utilities of CAP to autoimmune diseases and all other inflammation-driven disorders, but also positions the efficacy of CAP against cancer cells to its suppressive role on prolonged inflammation. Our insights may open an innovative avenue towards a unified view on the molecular mechanism driving the diversified types of medical miracles of CAP and what CAP can do in the field of plasma medicine.

自身免疫性疾病和癌症这两种看似毫不相关的疾病一直威胁着人类的健康,其中许多疾病都无法治愈。通过确定病理炎症是这两类疾病中细胞增殖失控的驱动原因,并根据细胞死亡程序是否受到控制来区分自身免疫性疾病和癌症,我们提出了通过维持线粒体还原氧化(氧化还原)平衡来减轻长期炎症,从而治愈这两种疾病的可能性。重要的是,鉴于冷大气等离子体(CAP)的氧化还原调节特性,我们提出了应用冷大气等离子体治疗自身免疫性疾病和癌症的可行性,这不仅将冷大气等离子体的医疗用途扩展到了自身免疫性疾病和所有其他炎症驱动的疾病,而且还将冷大气等离子体对癌细胞的疗效定位为其对长期炎症的抑制作用。我们的洞察力可能会开辟一条创新之路,使人们对 CAP 创造各种医学奇迹的分子机制以及 CAP 在血浆医学领域的作用有一个统一的认识。
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引用次数: 0
Targeting Neurological Disorders with Stilbenes: Bridging the Preclinical-Clinical Gap. 用二苯乙烯类药物治疗神经系统疾病:弥合临床前与临床之间的差距。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-07 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.102032
Md Zamshed Alam Begh, Jishan Khan, Mehrukh Zehravi, Sherouk Hussein Sweilam, A Dinesh Raja, A Muthukumar, M Akiful Haque, Nihar Ranjan Kar, Laliteshwar Pratap Singh, B Dharani Priya, Mohammed Ali Alshehri, Irfan Ahmad, Sojin Kang, Seungjoon Moon, Moon Nyeo Park, Talha Bin Emran, Bonglee Kim

Neurological disorders (NDs) encompass a range of debilitating conditions that affect the nervous system, including prevalent illnesses such as Alzheimer's disease, Parkinson's disease, and ischemic stroke. Despite significant ongoing studies, effective therapeutic strategies to halt or slow down the progression of these illnesses are still lacking. Stilbenes, a class of natural polyphenols, have shown potential as candidates for therapeutic strategies due to their capacity to protect the nervous system. Preclinical studies have provided strong evidence that stilbenes can regulate many cellular pathways implicated in neurodegeneration, with resveratrol being a well-studied compound that has shown the ability to reduce oxidative damage, promote neurogenesis, and enhance mitochondrial function - crucial for maintaining brain health. In preclinical animal models, initial research has also shown promise in additional substances such as piceatannol and pterostilbene. Furthermore, clinical studies have explored the therapeutic benefits of stilbenes in NDs. Despite promising results in preclinical research, the use of stilbenes in clinical trials is currently limited, with most studies focusing on resveratrol. Although several clinical studies have demonstrated the beneficial impact of resveratrol supplementation on brain health and degenerative consequences, other investigations have yielded ambiguous findings, underscoring the urgent need for more comprehensive and precisely planned clinical research. This study delves into the potential benefits of stilbenes as neuroprotective agents for NDs. It emphasizes the need for more clinical research to enhance our understanding of their therapeutic effectiveness in specific patient groups.

神经系统疾病(NDs)包括一系列影响神经系统的衰弱性疾病,其中包括阿尔茨海默病、帕金森病和缺血性中风等常见疾病。尽管目前正在进行大量研究,但仍缺乏有效的治疗策略来阻止或减缓这些疾病的发展。芪类是一类天然多酚类化合物,由于具有保护神经系统的能力,已显示出作为治疗策略候选物质的潜力。临床前研究已经提供了强有力的证据,证明二苯乙烯类化合物可以调节许多与神经退行性病变有关的细胞通路,其中白藜芦醇是一种经过充分研究的化合物,它能够减少氧化损伤、促进神经发生和增强线粒体功能--这对维持大脑健康至关重要。在临床前动物模型中,初步研究还显示了其他物质的前景,如皮脂醇和紫檀芪。此外,临床研究还探索了二苯乙烯类化合物对 NDs 的治疗效果。尽管临床前研究取得了可喜的成果,但目前在临床试验中使用的二苯乙烯类化合物还很有限,大多数研究都集中在白藜芦醇上。虽然有几项临床研究表明补充白藜芦醇对大脑健康和退行性后果有益,但其他调查的结果并不明确,这说明迫切需要进行更全面、更精确规划的临床研究。本研究探讨了二苯乙烯类化合物作为神经保护剂对 NDs 的潜在益处。它强调了进行更多临床研究的必要性,以加深我们对其在特定患者群体中治疗效果的了解。
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引用次数: 0
Heterophyllin B enhances transcription factor EB-mediated autophagy and alleviates pyroptosis and oxidative stress after spinal cord injury. 异茶碱B能增强转录因子EB介导的自噬作用,缓解脊髓损伤后的热蛋白沉积和氧化应激。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-07 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.97669
Haojie Zhang, Wei Wang, Xinli Hu, Zheng Wang, Junsheng Lou, Peng Cui, Xuan Zhao, Yu Wang, Xiaolong Chen, Shibao Lu

Traumatic spinal cord injury (SCI) has devastating physical, psychosocial, and vocational implications for patients and caregivers. Heterophyllin B (HB) is a brain-permeable cyclopeptide from Pseudostellaria heterophylla that promotes axonal regeneration and neuroinflammation. However, the efficacy of HB in improving functional recovery following SCI and the underlying mechanisms remain unclear. This study utilized a murine model for SCI assessment to evaluate the therapeutic effects of HB. following HB intervention, functional recovery post-SCI, was assessed through the Basso Mouse Scale, gait analysis, and the detection of motor-evoked potentials (MEPs). RNA sequencing was used to study the roles of pyroptosis, oxidative stress, and autophagy in HB's impact on SCI. Techniques such as Western blot, immunofluorescence, and enzyme-linked immunosorbent assay were used to evaluate pyroptosis, oxidative stress, and autophagy markers. Associated virus vectors were used to suppress transcription factor EB (TFEB), an autophagy regulator, in a living organism. HB promoted autophagy by enhancing TFEB nuclear translocation. In contrast, it inhibited pyroptosis and oxidative stress. Based on using the adenosine monophosphate-activated protein kinase (AMPK) inhibitor Compound C, the AMPK-TRPML1-calcineurin pathway was involved in HB's regulation of TFEB. In summary, this study demonstrated that HB facilitated functional recuperation by stimulating TFEB-driven autophagy while simultaneously suppressing pyroptosis and oxidative stress after SCI, indicating its potential for clinical application.

外伤性脊髓损伤(SCI)对患者和护理人员的身体、社会心理和职业生涯造成了毁灭性的影响。异叶黄素 B(HB)是从异叶黄素中提取的一种脑渗透性环肽,可促进轴突再生和神经炎症。然而,HB 在改善 SCI 后功能恢复方面的疗效及其潜在机制仍不清楚。本研究利用小鼠 SCI 评估模型来评估 HB 的治疗效果。在 HB 干预后,通过巴索小鼠量表、步态分析和运动诱发电位(MEPs)检测来评估 SCI 后的功能恢复情况。研究人员利用 RNA 测序技术研究了热蛋白变性、氧化应激和自噬在 HB 对 SCI 影响中的作用。研究人员采用了 Western 印迹、免疫荧光和酶联免疫吸附试验等技术来评估热蛋白沉积、氧化应激和自噬标记物。相关病毒载体被用来抑制活生物体中的自噬调节因子转录因子 EB(TFEB)。HB 通过增强 TFEB 的核转位来促进自噬。与此相反,它抑制了自噬和氧化应激。通过使用单磷酸腺苷激活的蛋白激酶(AMPK)抑制剂化合物 C,AMPK-TRPML1-calcineurin 通路参与了 HB 对 TFEB 的调控。 总之,本研究证明了 HB 通过刺激 TFEB 驱动的自噬,同时抑制 SCI 后的热蛋白沉积和氧化应激,促进了功能恢复,这表明它具有临床应用潜力。
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