Biochimica et biophysica acta. Molecular basis of disease最新文献_第10页

High MICAL-L2 promotes cancer progression and drug resistance in renal clear cell carcinoma cells through stabilization of ACTN4 following vimentin expression 高MICAL-L2通过稳定vimentin表达后的ACTN4促进肾透明细胞癌细胞的癌症进展和耐药。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-12-15 DOI: 10.1016/j.bbadis.2024.167628

Weizhen Zhao, Chenxiang Qi, Yixin Mao, Fengwen Ye, Tianxiang Xia, Mingyu Zhao, Pengxiang Min, Yujie Zhang, Jun Du

Targeted therapies persist as the conventional method of treatment of kidney clear cell carcinoma (KIRC). However, resistance to these drugs emerges as a significant impediment to the management of renal cancer. MICAL-L2 plays a pivotal role in cytoskeleton rearrangement. This study sought to elucidate the clinical relevance of MICAL-L2 in KIRC and its regulatory mechanism driving cancer progression and resistance to therapy. TCGA data mining was utilized to assess the expression of MICAL-L2 in samples from patients with KIRC. Kaplan–Meier analysis and immunohistochemistry were employed to explore the clinical significance of MICAL-L2. In vitro experiments, including assays for wound healing and Transwell migration, CCK-8, EDU staining, RT-PCR, flow cytometry, and co-immunoprecipitation analysis were conducted to investigate the effects of MICAL-L2 on the drug sensitivity of KIRC cells and to elucidate the molecular mechanisms involved. The results showed that MICAL-L2 was overexpressed in KIRC tissues. High levels of MICAL-L2 were associated with poor survival and a poor response to drug therapy among patients with KIRC. Overexpression of MICAL-L2 stimulated cell migration, proliferation, and rendered KIRC cells insensitive to sunitinib and everolimus, two traditional therapies for KIRC. Furthermore, MICAL-L2 overexpression accelerated cancer progression and resistance to therapy in KIRC cells by interacting with its downstream regulator α-actinin-4 (ACTN4) in a Rab13-dependent manner, which reduced the degradation of ACTN4, leading to increased Vimentin expression. All these findings indicate that MICAL-L2 plays a crucial role in the progression of KIRC and suggest that MICAL-L2 may serve as a potential therapeutic target for KIRC treatment.

靶向治疗仍然是治疗肾透明细胞癌（KIRC）的常规方法。然而，对这些药物的耐药性成为肾癌治疗的一个重大障碍。MICAL-L2在细胞骨架重排中起关键作用。本研究旨在阐明MICAL-L2在KIRC中的临床相关性及其驱动癌症进展和耐药的调节机制。利用TCGA数据挖掘来评估MICAL-L2在KIRC患者样本中的表达。应用Kaplan-Meier分析和免疫组织化学方法探讨MICAL-L2的临床意义。体外实验通过伤口愈合和Transwell迁移、CCK-8、EDU染色、RT-PCR、流式细胞术、共免疫沉淀分析等方法研究MICAL-L2对KIRC细胞药物敏感性的影响，并阐明其分子机制。结果显示MICAL-L2在KIRC组织中过表达。在KIRC患者中，高水平的MICAL-L2与较差的生存率和对药物治疗的不良反应相关。MICAL-L2的过度表达刺激了细胞迁移、增殖，并使KIRC细胞对舒尼替尼和依维莫司这两种传统的KIRC疗法不敏感。此外，MICAL-L2过表达通过与下游调节因子α-actin -4 （ACTN4）以rab13依赖的方式相互作用，加速了KIRC细胞的癌症进展和对治疗的耐药性，从而减少了ACTN4的降解，导致Vimentin表达增加。所有这些发现表明MICAL-L2在KIRC的进展中起着至关重要的作用，并提示MICAL-L2可能作为KIRC治疗的潜在治疗靶点。

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引用次数: 0

Synergistic anticancer activity of HSP70 and HSF1 inhibitors in colorectal cancer cells: A new strategy for combination therapy HSP70和HSF1抑制剂在结直肠癌细胞中的协同抗癌活性：一种联合治疗的新策略。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-12-14 DOI: 10.1016/j.bbadis.2024.167630

Shu-Min Xu, Xing-Zi Liu, Lu Wang, Wei-Hao Huang, Yu-Tao Hu, Shuo-Bin Chen, Zhi-Shu Huang, Shi-Liang Huang

Background

The heat shock response (HSR) is a highly conserved mechanism that maintains intracellular homeostasis in response to various environmental and physiological stresses. Heat shock proteins (HSPs), particularly HSP70, play a pivotal role in this process as molecular chaperones. Although HSP70 inhibitors have demonstrated anti-cancer activity, their therapeutic potential has been limited by the negative feedback mechanism between HSP70 and heat shock factor 1 (HSF1). The combination of HSP70 inhibitors with HSF1 inhibitors has been proposed to overcome this limitation and enhance anti-cancer effects.

Methods

We combined HSP70 inhibitors (VER-155008 and YK-5) with an HSF1 inhibitor (DTHIB) in CRC cells and evaluated their effects on cell survival, apoptosis, and protein homeostasis.

Results

Strong synergistic effects were observed (combination index <0.5, ZIP score > 10) with the combination treatment, leading to decreased cell survival and increased apoptosis in CRC cells. Mechanistic studies revealed that HSP70 inhibitors activated the phosphorylation of HSF1, inducing HSP70 expression, and that the combination therapy resulted in more pronounced HSR inhibition and protein homeostasis disturbances.

Conclusion

The combination therapy of HSP 70 and HSF 1 inhibitors showed significant synergistic antitumor activity.

General significance

Combining HSP70 and HSF1 inhibitors may be a promising anti-cancer strategy, offering a potential solution to overcome the negative feedback mechanism and enhance anti-cancer effects.

背景：热休克反应（HSR）是一种高度保守的机制，可在应对各种环境和生理压力时维持细胞内的平衡。热休克蛋白（HSPs），尤其是 HSP70，作为分子伴侣在这一过程中发挥着关键作用。尽管 HSP70 抑制剂已显示出抗癌活性，但其治疗潜力一直受到 HSP70 和热休克因子 1（HSF1）之间负反馈机制的限制。有人建议将 HSP70 抑制剂与 HSF1 抑制剂结合使用，以克服这一限制并增强抗癌效果：我们在 CRC 细胞中将 HSP70 抑制剂（VER-155008 和 YK-5）与 HSF1 抑制剂（DTHIB）联合使用，并评估了它们对细胞存活、凋亡和蛋白质平衡的影响：结果：在联合治疗中观察到了很强的协同效应（联合指数为 10），导致 CRC 细胞存活率下降，凋亡率上升。机制研究发现，HSP70抑制剂激活了HSF1的磷酸化，诱导了HSP70的表达，联合治疗导致了更明显的HSR抑制和蛋白稳态紊乱：结论：HSP70和HSF1抑制剂的联合疗法具有显著的协同抗肿瘤活性：综合意义：HSP70和HSF1抑制剂联合使用可能是一种很有前景的抗癌策略，为克服负反馈机制、增强抗癌效果提供了一种潜在的解决方案。

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引用次数: 0

Exploring the role and application of mitochondria in radiation therapy 探索线粒体在放射治疗中的作用和应用。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-12-12 DOI: 10.1016/j.bbadis.2024.167623

Yi Ding , Wang Jing , Zhichao Kang , Zhe Yang

Mitochondria are pivotal in cellular energy metabolism, the oxidative stress response and apoptosis. Recent research has focused on harnessing their functions to enhance the efficacy of radiation therapy (RT). This review focuses on the critical functions and applications of mitochondria in radiation therapy, including the targeting of mitochondrial metabolism and the modulation of mitochondria-mediated cell death and immune responses. While these strategies have demonstrated considerable potential in preclinical studies to improve radiotherapy outcomes, challenges remain, such as optimizing drug delivery systems, ensuring safety and overcoming resistance to therapy.

线粒体在细胞能量代谢、氧化应激反应和细胞凋亡中起关键作用。最近的研究集中在利用它们的功能来提高放射治疗（RT）的疗效。本文综述了线粒体在放射治疗中的重要功能和应用，包括靶向线粒体代谢和线粒体介导的细胞死亡和免疫反应的调节。虽然这些策略在临床前研究中显示出改善放射治疗结果的巨大潜力，但仍然存在挑战，例如优化药物输送系统，确保安全性和克服对治疗的耐药性。

引用次数: 0

CDK8 inhibitor KY-065 rescues skeletal abnormalities in achondroplasia model mice CDK8 抑制剂 KY-065 挽救了软骨发育不全模型小鼠的骨骼异常。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-12-12 DOI: 10.1016/j.bbadis.2024.167626

Koki Sadamori , Takuya Kubo , Tomoki Yoshida , Megumi Yamamoto , Yui Shibata , Kazuya Fukasawa , Kazuya Tokumura , Tetsuhiro Horie , Takuya Kadota , Ryotaro Yamakawa , Hironori Hojo , Nobutada Tanaka , Tatsuya Kitao , Hiroaki Shirahase , Eiichi Hinoi

Cyclin-dependent kinase 8 (CDK8) is a transcription-related CDK family member implicated in the regulation of bone homeostasis, and we recently demonstrated that our internally developed CDK8 inhibitor KY-065 can prevent postmenopausal osteoporosis in a mouse model. Achondroplasia (ACH), the most common form of genetic dwarfism in humans, is caused by a gain-of-function mutation in fibroblast growth factor receptor 3 (FGFR3), a receptor tyrosine kinase that activates downstream mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT) signaling pathways. The first precision drug approved for the treatment of ACH in children, the C-type natriuretic peptide analog vosoritide, antagonizes the MAPK pathway, while there are currently no effective and safe medications targeting the STAT1 pathway. Here, we demonstrate that KY-065 rescues impaired chondrogenesis and stunted long bone growth in the Fgfr3^Ach mouse model of ACH. KY-065 inhibited CDK8 with high affinity in vitro by competing with ATP. The CDK8 expression and STAT1^Ser727 phosphorylation were upregulated in chondrocytes isolated from ACH model mice, and KY-065 repressed its phosphorylation and restored normal chondrogenic differentiation without affecting MAPK activation. Moreover, daily administration of 10 mg/kg KY-065 to Fgfr3^Ach mice (yielding a peak concentration of 22.0 ± 1.47 μM in plasma) resulted in significant elongation of long bone and improved growth plate cytoarchitecture. Collectively, these findings identify the CDK8 in chondrocytes as a potential therapeutic target for ACH and KY-065 as a promising candidate drug treatment for this debilitating skeletal disease.

细胞周期蛋白依赖性激酶8（CDK8）是一种与转录相关的CDK家族成员，与骨稳态的调控有关。我们最近证明，我们内部开发的CDK8抑制剂KY-065可以在小鼠模型中预防绝经后骨质疏松症。软骨发育不全（ACH）是人类最常见的遗传性侏儒症，由成纤维细胞生长因子受体 3（FGFR3）的功能增益突变引起，FGFR3 是一种受体酪氨酸激酶，可激活下游的丝裂原活化蛋白激酶（MAPK）和信号转导及转录激活因子（STAT）信号通路。首个获准用于治疗儿童 ACH 的精准药物 C 型钠尿肽类似物伏索利特能拮抗 MAPK 通路，而目前还没有针对 STAT1 通路的有效而安全的药物。在这里，我们证明了 KY-065 可以挽救 Fgfr3Ach ACH 小鼠模型中受损的软骨生成和发育迟缓的长骨。KY-065 通过与 ATP 竞争，在体外高亲和力地抑制 CDK8。从 ACH 模型小鼠体内分离出的软骨细胞中，CDK8 的表达和 STAT1Ser727 的磷酸化上调，KY-065 可抑制其磷酸化并恢复正常的软骨分化，而不影响 MAPK 的激活。此外，每天给 Fgfr3Ach 小鼠注射 10 mg/kg KY-065（血浆中的峰值浓度为 22.0 ± 1.47 μM）可显著延长长骨，改善生长板细胞结构。总之，这些发现确定了软骨细胞中的 CDK8 是 ACH 的潜在治疗靶点，而 KY-065 是治疗这种使人衰弱的骨骼疾病的有希望的候选药物。

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引用次数: 0

Construction of cynomolgus monkey type 2 diabetes models by combining genetic prediction model with high-energy diet 遗传预测模型与高能饮食相结合构建食蟹猴2型糖尿病模型。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-12-11 DOI: 10.1016/j.bbadis.2024.167616

Ping Li , Huahu Ye , Feng Guo , Jianhua Zheng , Wenlong Shen , Dejian Xie , Shu Shi , Yan Zhang , Yunzhi Fa , Zhihu Zhao

Background

Type 2 diabetes mellitus (T2D) is a significant health concern. Research using non-human primates, which develop T2D with similar symptoms and pancreatic changes as humans, is crucial but limited by long timelines and low success rates.

Results

We targeted capture sequenced 61 normal and 81 T2D cynomolgus monkeys using a primer panel that captured 269 potential regulatory regions potentially associated with T2D in the cynomolgus monkey genome. 80 variants were identified to be associated with T2D and were used to construct a genetic prediction model. Among 8 machine learning algorithms tested, we found that the best prediction performance was achieve when the model using support vector machine with polynomial kernel as the machine learning algorithm (AUC = 0.933). Including age and sex in this model did not significantly improve the prediction performance. Using the genetic prediction model, we further screened 22 monkeys and found 13 were high risk while 9 were low risk. After feeding the 22 monkeys with high-energy food for 32 weeks, we found all the 9 low risk monkeys did not develop T2D while 4 out of 13 high risk monkeys (31 %) develop T2D.

Conclusions

This method greatly increased the success rate of establishing T2D monkey models while decreased the time needed compared to traditional methods. Therefore, we developed a new high-efficiency method to establish T2D monkey models by combining the genetic prediction model and high-energy diet, which will greatly contribute to the research on the clinical characteristics, pathogenesis, complications and potential new treatments.

背景：2 型糖尿病（T2D）是一个重大的健康问题。非人灵长类动物患 T2D 的症状和胰腺变化与人类相似，因此利用非人灵长类动物进行研究至关重要，但受限于时间长和成功率低：结果：我们使用一个引物面板对 61 只正常和 81 只患有 T2D 的绒猴进行了目标捕获测序，该引物面板捕获了绒猴基因组中 269 个可能与 T2D 相关的潜在调控区域。确定了 80 个与 T2D 相关的变异，并将其用于构建遗传预测模型。在测试的 8 种机器学习算法中，我们发现使用带多项式核的支持向量机作为机器学习算法的模型预测效果最好（AUC = 0.933）。在该模型中加入年龄和性别并不能显著提高预测性能。利用基因预测模型，我们进一步筛选了 22 只猴子，发现其中 13 只为高风险猴，9 只为低风险猴。在用高能量食物喂养这 22 只猴子 32 周后，我们发现所有 9 只低风险猴子都没有患上 T2D，而 13 只高风险猴子中有 4 只（31%）患上了 T2D：结论：与传统方法相比，这种方法大大提高了建立 T2D 猴模型的成功率，同时减少了所需时间。因此，我们开发了一种结合遗传预测模型和高能量饮食建立T2D猴模型的高效率新方法，这将大大有助于临床特征、发病机制、并发症和潜在新疗法的研究。

{"title":"Construction of cynomolgus monkey type 2 diabetes models by combining genetic prediction model with high-energy diet","authors":"Ping Li , Huahu Ye , Feng Guo , Jianhua Zheng , Wenlong Shen , Dejian Xie , Shu Shi , Yan Zhang , Yunzhi Fa , Zhihu Zhao","doi":"10.1016/j.bbadis.2024.167616","DOIUrl":"10.1016/j.bbadis.2024.167616","url":null,"abstract":"<div><h3>Background</h3><div>Type 2 diabetes mellitus (T2D) is a significant health concern. Research using non-human primates, which develop T2D with similar symptoms and pancreatic changes as humans, is crucial but limited by long timelines and low success rates.</div></div><div><h3>Results</h3><div>We targeted capture sequenced 61 normal and 81 T2D cynomolgus monkeys using a primer panel that captured 269 potential regulatory regions potentially associated with T2D in the cynomolgus monkey genome. 80 variants were identified to be associated with T2D and were used to construct a genetic prediction model. Among 8 machine learning algorithms tested, we found that the best prediction performance was achieve when the model using support vector machine with polynomial kernel as the machine learning algorithm (AUC = 0.933). Including age and sex in this model did not significantly improve the prediction performance. Using the genetic prediction model, we further screened 22 monkeys and found 13 were high risk while 9 were low risk. After feeding the 22 monkeys with high-energy food for 32 weeks, we found all the 9 low risk monkeys did not develop T2D while 4 out of 13 high risk monkeys (31 %) develop T2D.</div></div><div><h3>Conclusions</h3><div>This method greatly increased the success rate of establishing T2D monkey models while decreased the time needed compared to traditional methods. Therefore, we developed a new high-efficiency method to establish T2D monkey models by combining the genetic prediction model and high-energy diet, which will greatly contribute to the research on the clinical characteristics, pathogenesis, complications and potential new treatments.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167616"},"PeriodicalIF":4.2,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822978","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

Corrigendum to “A potential early-atheroprotective target: Irgm1 mediates lymphangiogenesis through LEC autophagy by Tfeb translocation” [Biochim. Biophys. Acta Mol. Basis Dis. volume 1870, issue 6, (2024) 167238] “潜在的早期动脉粥样硬化保护靶点：Irgm1通过Tfeb易位通过LEC自噬介导淋巴管生成”[biochem .]Biophys。生物学报，第1870卷，第6期，（2024）167238。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-12-11 DOI: 10.1016/j.bbadis.2024.167610

Hengxuan Cai , Guanpeng Ma , Zhenming Zhang , Guojie Liu , Rongzhe Lu , Yige Liu , Jiaxin Wang , Shanjie Wang , Song Sun , E Mingyan , Zhaoying Li , Shaohong Fang , Bo Yu

引用次数: 0

Canonical MAPK signaling in auditory neuropathy 典型MAPK信号在听神经病变中的作用。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-12-09 DOI: 10.1016/j.bbadis.2024.167619

Yueying Wang , Lusha Huang , Xiaoqing Cen , Yue Liang , Kaitian Chen

Auditory neuropathy (AN) is an under-recognized form of hearing loss characterized by lesions in inner hair cells (IHCs), ribbon synapses and spiral ganglion neurons (SGNs). The lack of a targeted therapy for AN has increased the need for a better understanding of the pathogenic mechanism of AN. As mitogen-activated protein kinase (MAPK) signaling is ubiquitous in many biological processes, its alteration may facilitate the pathogenesis of multiple sites in AN. Here, we summaries the characteristics of AN under different molecular bases and first explore the mechanism of MAPK at different lesion sites. Alterations of extracellular signal-regulated kinase (ERK)/MAPK occur in IHCs and SGNs, whereas modulations of p38 and c-Jun NH2-terminal kinase (JNK) were found in ribbon synapses and SGNs. In conclusion, inductive MAPK alterations in the pathogenesis and development of AN are likely to represent a potential therapeutic target to guide the development of treatments.

听觉神经病变（AN）是一种未被充分认识的听力损失形式，其特征是内毛细胞（IHCs）、带状突触和螺旋神经节神经元（sgn）的病变。缺乏针对AN的靶向治疗增加了对AN致病机制的更好理解的需求。由于丝裂原活化蛋白激酶（MAPK）信号在许多生物过程中普遍存在，其改变可能促进AN多个部位的发病机制。本文总结了不同分子碱基下AN的特征，并首先探讨了MAPK在不同病变部位的作用机制。细胞外信号调节激酶(ERK)/MAPK的改变发生在ihc和sgn中，而p38和c-Jun nh2末端激酶（JNK）的调节发生在带状突触和sgn中。总之，诱导MAPK改变AN的发病和发展可能代表一个潜在的治疗靶点，指导治疗的发展。

引用次数: 0

The involvement of YAP-TGFβ-SMAD-mediated fibrosis in primary inferior oblique overaction yap - tgf - β- smad介导的纤维化在原发性下斜肌过动中的作用。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-12-09 DOI: 10.1016/j.bbadis.2024.167620

Shiyu Tang , Chaojuan Wen , Tao Shen , Binbin Zhu , Xiangjun Wang , Zhonghao Wang , Licheng Fu , Yun Wen , Mengya Han , Xielan Kuang , Weixia Ma , Huangxuan Shen , Jianhua Yan

This study investigates the involvement of fibrosis in primary inferior oblique overaction (PIOOA), a strabismus characterized by excessive upward eye rotation. First, we identified extensive fibrotic changes in inferior oblique (IO) muscles in PIOOA patients compared to normal controls. A strong positive correlation was clinically established between the severity of PIOOA and the expression of collagen type I alpha 1 chain (COL1A1). COL1A1 levels correlate with preoperative and postoperative clinical grading of PIOOA and the degree of fundus deviation, as measured by disk-foveal angle (DFA). Moreover, immunofluorescence in IO muscle sections of PIOOA patients confirmed activation of fibro/adipogenic progenitors (FAPs) and suggested increased activation of YAP. Interestingly, the TGFβ signaling pathway also exhibited activation, with a notable increase observed in the expression of TGFβ2 in the PIOOA group. Subsequently, we first isolated FAPs from human IO muscles and validated these findings. In vitro, YAP overexpression promoted the differentiation of FAPs into myofibroblasts, exacerbating fibrotic changes. However, knockdown of YAP inhibited the activation of FAPs and fibrogenesis induced by TGFβ2. More importantly, we found TGFβ2 treatment promoted the activation of YAP simultaneously, and the overexpression or inhibition of YAP also affected TGFβ2 production and Smad phosphorylation, indicating a close connection between the two. Remarkably, verteporfin was observed to block both pathways effectively. Taken together, these findings suggest that the YAP-TGFβ-SMAD signaling cascade plays a key role in the pathophysiology of PIOOA through FAP-mediated fibrosis. Targeting these pathways may therefore provide a potential therapeutic strategy for managing PIOOA by alleviating muscle fibrosis.

原发性下斜肌过度活动症（PIOOA）是一种以眼球过度上转为特征的斜视，本研究探讨了纤维化对这种斜视的影响。首先，与正常对照组相比，我们发现原发性下斜肌过度活动（PIOOA）患者的下斜肌有广泛的纤维化变化。在临床上，PIOOA 的严重程度与 I 型胶原蛋白α1 链（COL1A1）的表达之间存在很强的正相关性。COL1A1 的水平与 PIOOA 的术前和术后临床分级以及眼底偏离程度（通过盘状眼窝角（DFA）测量）相关。此外，PIOOA 患者 IO 肌肉切片的免疫荧光证实了纤维/脂肪生成祖细胞（FAPs）的激活，并提示 YAP 的激活增加。有趣的是，TGFβ 信号通路也出现了激活，在 PIOOA 组中观察到 TGFβ2 的表达明显增加。随后，我们首先从人类 IO 肌肉中分离出 FAPs，并验证了这些发现。在体外，YAP 的过表达促进了 FAPs 向肌成纤维细胞的分化，加剧了纤维化变化。然而，敲除 YAP 可抑制 FAPs 的活化和 TGFβ2 诱导的纤维化。更重要的是，我们发现 TGFβ2 处理同时促进了 YAP 的活化，而过表达或抑制 YAP 也会影响 TGFβ2 的产生和 Smad 的磷酸化，这表明两者之间存在密切联系。值得注意的是，观察到 verteporfin 能有效阻断这两种途径。综上所述，这些研究结果表明，YAP-TGFβ-SMAD 信号级联通过 FAP 介导的纤维化在 PIOOA 的病理生理学中起着关键作用。因此，以这些通路为靶点可通过缓解肌肉纤维化为控制 PIOOA 提供一种潜在的治疗策略。

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引用次数: 0

Unravelling the impact of QRICH1 modulation on endoplasmic reticulum stress and neuronal apoptosis in traumatic brain injury 揭示QRICH1调节对外源性脑损伤内质网应激和神经元凋亡的影响。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-12-09 DOI: 10.1016/j.bbadis.2024.167621

Shixin Wang , Yubo Ren , Aojie Duan , Dengfeng Lu , Guangjie Liu , Lei Meng , Yu Zhang , Renjie Shou , Haiying Li , Zhong Wang , Zongqi Wang , Xiaoou Sun

Background

Traumatic brain injury (TBI) is a major public health concern with high morbidity and mortality rates. Secondary brain injury, marked by inflammatory responses and apoptosis, worsens TBI outcomes. The endoplasmic reticulum stress (ERS) response has been implicated in secondary brain injury, with Glutamine Rich 1 Gene (QRICH1) emerging as a potential mediator. However, the precise role of QRICH1 in TBI pathogenesis and its therapeutic implications remain unclear.

Methods

Controlled cortical impact mouse and Lipopolysaccharide-stimulated primary neuron models were used. Behavioral assessments, including the modified Garcia score, Y-maze test, and open-field test, were used to evaluate postoperative recovery in mice. QRICH1 neuron conditional knockout (cKO) mice were used to assess QRICH1 function, whereas adeno-associated virus (AAV)-mediated gene manipulation was used to modulate QRICH1 expression in cortical neurons.

Results

QRICH1 expression was upregulated in the brain tissue of TBI mice, particularly 24 h post-injury, as shown by western blot analysis and immunofluorescence staining. QRICH1 is localized within neuronal nuclei, suggesting a role in cellular stress responses. QRICH1 cKO improved behavioral outcomes post-TBI, whereas AAV-mediated QRICH1 overexpression exacerbated secondary brain injury, characterized by increased ERS-related protein expression and neuronal death. Conversely, AAV-mediated QRICH1 knockdown reduced secondary brain injury as evidenced by decreased ERS-related protein expression and neuronal death.

Conclusion

QRICH1 plays a critical role in exacerbating ERS and apoptosis, and influences neuronal fate in secondary brain injury. Its involvement in the ERS pathway and in the induction of neuronal apoptosis post-TBI highlights QRICH1 as a potential therapeutic target for TBI treatment.

背景：外伤性脑损伤（TBI）是一个发病率和死亡率高的主要公共卫生问题。继发性脑损伤以炎症反应和细胞凋亡为特征，使TBI预后恶化。内质网应激（ERS）反应与继发性脑损伤有关，谷氨酰胺富1基因（QRICH1）成为潜在的中介。然而，QRICH1在TBI发病机制中的确切作用及其治疗意义尚不清楚。方法：采用控制性皮质冲击小鼠模型和脂多糖刺激原代神经元模型。行为评估，包括改良加西亚评分、y迷宫测试和开放场测试，用于评估小鼠术后恢复情况。QRICH1神经元条件敲除（cKO）小鼠用于评估QRICH1功能，而腺相关病毒（AAV）介导的基因操作用于调节皮质神经元中QRICH1的表达。结果：western blot和免疫荧光染色结果显示，TBI小鼠脑组织中QRICH1表达上调，尤其是损伤后24 h。QRICH1定位于神经元核内，提示其在细胞应激反应中起作用。QRICH1 cKO改善了tbi后的行为结果，而aav介导的QRICH1过表达加重了继发性脑损伤，其特征是ers相关蛋白表达增加和神经元死亡。相反，aav介导的QRICH1敲低可以减少继发性脑损伤，这可以通过降低ers相关蛋白表达和神经元死亡来证明。结论：QRICH1在继发性脑损伤中加重ERS和细胞凋亡，影响神经元命运中起关键作用。QRICH1参与脑外伤后ERS通路和神经元凋亡的诱导，使其成为脑外伤治疗的潜在治疗靶点。

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引用次数: 0

Unravelling metabolite-microbiome interactions in inflammatory bowel disease through AI and interaction-based modelling 通过人工智能和基于相互作用的建模揭示炎症性肠病中代谢物-微生物组的相互作用。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-12-09 DOI: 10.1016/j.bbadis.2024.167618

Rebecca Hodgkiss , Animesh Acharjee

Inflammatory Bowel Diseases (IBDs) are chronic inflammatory disorders of the gastrointestinal tract and colon affecting approximately 7 million individuals worldwide. The knowledge of specific pathology and aetiological mechanisms leading to IBD is limited, however a reduced immune system, antibiotic use and reserved diet may initiate symptoms. Dysbiosis of the gut microbiome, and consequently a varied composition of the metabolome, has been extensively linked to these risk factors and IBD. Metagenomic sequencing and liquid-chromatography mass spectrometry (LC-MS) of N = 220 fecal samples by Fransoza et al., provided abundance data on microbial genera and metabolites for use in this study. Identification of differentially abundant microbes and metabolites was performed using a Wilcoxon test, followed by feature selection of random forest (RF), gradient-boosting (XGBoost) and least absolute shrinkage operator (LASSO) models. The performance of these features was then validated using RF models on the Human Microbiome Project 2 (HMP2) dataset and a microbial community (MICOM) model was utilised to predict and interpret the interactions between key microbes and metabolites. The Flavronifractor genus and microbes of the families Lachnospiraceae and Oscillospiraceae were found differential by all models. Metabolic pathways commonly influenced by such microbes in IBD were CoA biosynthesis, bile acid metabolism and amino acid production and degradation.

This study highlights distinct interactive microbiome and metabolome profiles within IBD and the highly potential pathways causing disease pathology. It therefore paves way for future investigation into new therapeutic targets and non-invasive diagnostic tools for IBD.

炎症性肠病（IBDs）是胃肠道和结肠的慢性炎症性疾病，影响全球约700万人。导致IBD的具体病理和病因机制的知识是有限的，然而免疫系统降低，抗生素的使用和保留饮食可能会引发症状。肠道微生物群的生态失调，以及由此导致的代谢组的不同组成，已被广泛地与这些危险因素和IBD联系起来。Fransoza等人对N = 220份粪便样本进行宏基因组测序和液相色谱质谱分析（LC-MS），为本研究提供了丰富的微生物属和代谢物数据。使用Wilcoxon检验鉴定差异丰度的微生物和代谢物，然后使用随机森林（RF）、梯度增强（XGBoost）和最小绝对收缩算子（LASSO）模型进行特征选择。然后使用人类微生物组计划2 （HMP2）数据集上的RF模型验证这些特征的性能，并使用微生物群落（MICOM）模型来预测和解释关键微生物与代谢物之间的相互作用。所有模型均发现黄酮类植物属和微生物在毛螺科和示波螺科中存在差异。这些微生物在IBD中通常影响的代谢途径是辅酶a生物合成、胆汁酸代谢和氨基酸的产生和降解。这项研究强调了IBD中独特的相互作用微生物组和代谢组谱，以及引起疾病病理的高度潜在途径。因此，它为未来研究IBD的新治疗靶点和非侵入性诊断工具铺平了道路。

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