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Revolutionizing drug delivery: low-intensity pulsed ultrasound (LIPUS)-driven deep penetration into hypoxic tumor microenvironments of cholangiocarcinoma. 革命性的药物输送:低强度脉冲超声(LIPUS)驱动的对胆管癌缺氧肿瘤微环境的深度渗透。
IF 12.4 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-01 DOI: 10.7150/thno.99981
Sera Hong, Jaihwan Kim, Gujin Chung, Donghyuk Lee, Joon Myong Song

Background: Hypoxia is a major obstacle in the treatment of solid tumors because it causes immune escape and therapeutic resistance. Drug penetration into the hypoxic regions of tumor microenvironment (TME) is extremely limited. This study proposes using the unidirectional fluid flow property of low-intensity pulsed ultrasound (LIPUS) to overcome drug penetration limitations in the TME. LIPUS is gaining attention as a therapeutic modality for cancer owing to its safety and efficacy. Methods: LIPUS parameters, such as the intensity, duty cycle (DC), and duration, were optimized to enhance drug delivery into the hypoxic regions of the TME in cholangiocarcinoma (CCA). Transparent tumor imaging using the tissue optical clearing method (CLARITY) enabled 3D visualization and quantitative assessment of drug delivery and therapeutic efficacy in relation to blood vessels in an intact tumor at the micrometer level. The antitumor efficacy of LIPUS-assisted chemotherapy was evaluated in a CCA xenograft mouse model. Results: LIPUS significantly enhanced drug delivery efficacy into the hypoxic region of the TME in CCA. Under optimal conditions, i.e., a DC of 45% and a spatial-peak temporal-average intensity (Ispta) of 0.5 W/cm², drug penetration, including liposomal nanoparticles and chemotherapeutic agents gemcitabine and cisplatin, was improved by approximately 1.8-fold, resulting in a fivefold increase in apoptotic cancer cell death and a significant reduction in CCA growth. Notably, drug penetration and efficacy were more significantly affected by DC compared to the spatial-peak pulse-average intensity (Isppa). The efficacy saturated at Ispta values above 0.5 W/cm² under a 45% DC. Furthermore, we confirm that LIPUS induces non-thermal effects without causing cell damage, ensuring biosafety. These findings highlight the potential of LIPUS as a non-invasive strategy for treating hypoxic tumors. Conclusion: LIPUS adjuvant therapy promises improved cancer treatment outcomes and offers a safe and innovative therapeutic strategy for CCA and other hypoxic tumors.

背景:缺氧是实体瘤治疗的主要障碍,因为它会引起免疫逃逸和治疗抵抗。药物渗透到肿瘤微环境(TME)的缺氧区是非常有限的。本研究提出利用低强度脉冲超声(LIPUS)的单向流体流动特性来克服药物在TME中的渗透限制。LIPUS由于其安全性和有效性,作为一种治疗癌症的方式越来越受到关注。方法:优化LIPUS参数,如强度、占空比(DC)和持续时间,以促进药物进入胆管癌(CCA) TME缺氧区。使用组织光学清除方法(CLARITY)的透明肿瘤成像能够在微米水平上对完整肿瘤中与血管相关的药物输送和治疗效果进行3D可视化和定量评估。在CCA异种移植小鼠模型中评价lipus辅助化疗的抗肿瘤效果。结果:LIPUS可显著提高CCA TME缺氧区给药效果。在最佳条件下,即DC为45%,空间-峰值-时间-平均强度(Ispta)为0.5 W/cm²,药物穿透性(包括脂质体纳米颗粒和化疗药物吉西他滨和顺铂)提高了约1.8倍,导致凋亡癌细胞死亡增加了5倍,CCA生长显著减少。与空间峰脉冲平均强度(Isppa)相比,DC对药物穿透性和药效的影响更为显著。在45%的直流条件下,当Ispta值大于0.5 W/cm²时,效果达到饱和。此外,我们证实LIPUS诱导非热效应而不引起细胞损伤,确保生物安全性。这些发现突出了LIPUS作为治疗缺氧肿瘤的非侵入性策略的潜力。结论:LIPUS辅助治疗有望改善癌症治疗效果,为CCA和其他缺氧肿瘤提供了一种安全、创新的治疗策略。
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引用次数: 0
A molecularly distinct cell type in the midbrain regulates intermale aggression behaviors in mice. 中脑中一种分子上截然不同的细胞类型调控着小鼠的攻击行为。
IF 12.4 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-01 DOI: 10.7150/thno.101658
Chunyang Li, Cheng Miao, Yao Ge, Jiaxing Wu, Panpan Gao, Songlin Yin, Pei Zhang, Hongbin Yang, Bo Tian, Wenqiang Chen, Xiao Qian Chen

Rationale: The periaqueductal gray (PAG) is a central hub for the regulation of aggression, whereas the circuitry and molecular mechanisms underlying this regulation remain uncharacterized. In this study, we investigate the role of a distinct cell type, Tachykinin 2-expressing (Tac2+) neurons, located in the dorsomedial PAG (dmPAG) and their modulation of aggressive behavior in mice. Methods: We combined activity mapping, in vivo Ca2+ recording, chemogenetic and pharmacological manipulation, and a viral-based translating ribosome affinity purification (TRAP) profiling using a mouse resident-intruder model. Results: We revealed that dmPAGTac2 neurons are selectively activated by fighting behaviors. Chemogenetic activation of these neurons evoked fighting behaviors, while inhibition or genetic ablation of dmPAGTac2 neurons attenuated fighting behaviors. TRAP profiling of dmPAGTac2 neurons revealed an enrichment of serotonin-associated transcripts in response to fighting behaviors. Finally, we validated these effects by selectively administering pharmacological agents to the dmPAG, reversing the behavioral outcomes induced by chemogenetic manipulation. Conclusions: We identify dmPAGTac2 neurons as critical modulators of aggressive behavior in mouse and thus suggest a distinct molecular target for the treatment of exacerbated aggressive behaviors in populations that exhibit high-level of violence.

理论基础:导水管周围灰质(PAG)是攻击行为调控的中枢,而这种调控背后的电路和分子机制尚未被明确。在这项研究中,我们研究了一种独特的细胞类型,Tachykinin 2表达(Tac2+)神经元,位于背内侧PAG (dmPAG)及其在小鼠攻击行为中的调节作用。方法:我们结合了活性定位,体内Ca2+记录,化学发生和药理学操作,以及基于病毒的翻译核糖体亲和纯化(TRAP)分析,使用小鼠常驻入侵者模型。结果:dmPAGTac2神经元被战斗行为选择性激活。这些神经元的化学发生激活引起了战斗行为,而抑制或基因消融dmPAGTac2神经元则减弱了战斗行为。dmPAGTac2神经元的TRAP分析显示,在对抗行为的反应中,血清素相关转录物的富集。最后,我们通过选择性地给dmPAG药理学药物来验证这些效应,逆转了化学遗传学操作引起的行为结果。结论:我们确定dmPAGTac2神经元是小鼠攻击行为的关键调节因子,从而为治疗表现出高度暴力的人群中加剧的攻击行为提供了一个独特的分子靶点。
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引用次数: 0
Orchestrating the frontline: HDAC3-miKO recruits macrophage reinforcements for accelerated myelin debris clearance after stroke. 协调前线:HDAC3-miKO 招募巨噬细胞增援,加速中风后髓鞘碎片的清除。
IF 12.4 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-01 DOI: 10.7150/thno.103449
Jiaying Li, Chenran Wang, Yue Zhang, Yichen Huang, Ziyu Shi, Yuwen Zhang, Yana Wang, Shuning Chen, Yiwen Yuan, He Wang, Leilei Mao, Yanqin Gao

Rational: White matter has emerged as a key therapeutic target in ischemic stroke due to its role in sensorimotor and cognitive outcomes. Our recent findings have preliminarily revealed a potential link between microglial HDAC3 and white matter injury following stroke. However, the mechanisms by which microglial HDAC3 mediates these effects remain unclear. Methods : We generated microglia-specific HDAC3 knockout mice (HDAC3-miKO). DTI, electrophysiological technique and transmission electron microscopy were used to assess HDAC3-miKO's effects on white matter. RNA sequencing, flow cytometry, immunofluorescence staining and ex vivo phagocytosis assay were conducted to investigate the mechanism by which HDAC3-miKO ameliorated white matter injury. Macrophage depletion and reconstitution experiments further confirmed the involvement of macrophage CCR2 in the enhanced white matter repair and sensorimotor function in HDAC3-miKO mice. Results : HDAC3-miKO promoted post-stroke oligodendrogenesis and long-term histological and functional integrity of white matter without affecting early-stage white matter integrity. In the acute phase, HDAC3-deficient microglia showed enhanced chemotaxis, recruiting macrophages to the infarct core probably by CCL2/CCL7, where dMBP-labelled myelin debris surged and coincided with their infiltration. Infiltrated macrophages outperformed resident microglia in myelin phagocytosis, potentially serving as true pioneers in myelin debris clearance. Although macrophage phagocytosis potential was similar between HDAC3-miKO and WT mice, increased macrophage numbers in HDAC3-miKO accelerated myelin debris clearance. Reconstitution with CCR2-KO macrophages in HDAC3-miKO mice slowed this clearance, reversing HDAC3-miKO's beneficial effects. Conclusions : Our study demonstrates that HDAC3-deficient microglia promote post-stroke remyelination by recruiting macrophages to accelerate myelin debris clearance, underscoring the essential role of infiltrated macrophages in HDAC3-miKO-induced beneficial outcomes. These findings advance our understanding of microglial HDAC3's role and suggest therapeutic potential for targeting microglial HDAC3 in ischemic stroke.

理性:由于白质在感觉运动和认知结果中的作用,它已成为缺血性中风的关键治疗靶点。我们最近的研究结果初步揭示了脑卒中后小胶质细胞HDAC3与白质损伤之间的潜在联系。然而,小胶质细胞HDAC3介导这些作用的机制尚不清楚。方法:制备小胶质细胞特异性HDAC3敲除小鼠(HDAC3- miko)。采用DTI、电生理技术和透射电镜观察HDAC3-miKO对脑白质的影响。通过RNA测序、流式细胞术、免疫荧光染色和体外吞噬实验,探讨HDAC3-miKO改善脑白质损伤的机制。巨噬细胞耗损和重构实验进一步证实了巨噬细胞CCR2参与HDAC3-miKO小鼠白质修复和感觉运动功能的增强。结果:HDAC3-miKO在不影响早期白质完整性的情况下促进脑卒中后少突胶质细胞形成和长期白质组织学和功能完整性。在急性期,hdac3缺失的小胶质细胞表现出增强的趋化性,可能通过CCL2/CCL7将巨噬细胞招募到梗死核心,dmbp标记的髓磷脂碎片激增,并与它们的浸润相一致。浸润的巨噬细胞在髓磷脂吞噬方面优于驻留的小胶质细胞,可能成为髓磷脂碎片清除的真正先驱。尽管HDAC3-miKO和WT小鼠的巨噬细胞吞噬电位相似,但HDAC3-miKO中巨噬细胞数量的增加加速了髓磷脂碎片的清除。在HDAC3-miKO小鼠中重建CCR2-KO巨噬细胞减缓了这种清除,逆转了HDAC3-miKO的有益作用。结论:我们的研究表明,hdac3缺失的小胶质细胞通过招募巨噬细胞加速髓磷脂碎片的清除来促进脑卒中后的再髓鞘形成,强调了浸润的巨噬细胞在hdac3 - miko诱导的有益结果中的重要作用。这些发现促进了我们对小胶质细胞HDAC3的作用的理解,并提示靶向小胶质细胞HDAC3在缺血性卒中中的治疗潜力。
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引用次数: 0
Big data analytics and scRNA-seq in human aortic aneurysms and dissections: role of endothelial MerTK. 大数据分析和scRNA-seq在人主动脉瘤和夹层中的作用:内皮MerTK的作用。
IF 12.4 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-01 DOI: 10.7150/thno.103851
Shijie Liu, Jinzi Wu, Oishani Banerjee, Bingzhong Xue, Hang Shi, Zufeng Ding

Rationale: Aortic aneurysms and dissections (AAD) cause more than 10,000 deaths in the United States each year. However, there are no medications that can effectively prevent the pathogenesis of AAD. MER proto-oncogene tyrosine kinase (MerTK) is a key receptor for efferocytosis, a process for the clearance of apoptotic cells. Here, we mainly focused on ascending aortic aneurysms and dissections (AAAD) and investigated the role of endothelial MerTK in AAAD progression. Methods: Single-cell RNA sequencing (scRNA-seq) analysis in human AAAD samples and RNA-seq big data analytics, combined with our unique MerTKflox/flox/Tie2Cre mouse model with MerTK deficiency in endothelial cells (ECs), were applied to define the role of endothelial MerTK in AAAD. Results: Through comparative analyses of scRNA-seq in human AAAD (communications of ECs with other cells) and comprehensive big data analytics including about 600,000 cross analyses, we found that the expression of endothelial MerTK is significantly inhibited in human AAAD, resulting in decreased ability of ECs to engulf antigen presenting cells, phagocytes, leukocytes, blood cells and myeloid cells. Our in vivo data showed a significantly higher incidence of AAAD in MerTK flox/flox/Tie2Cre mice compared to that of their littermate controls of MerTK flox/flox mice (100% vs. 11.1%). MerTK deficiency in ECs induces both endothelial dysfunction and SMC phenotypic alterations, subsequently promoting AAAD development. Conclusions: Our findings indicate that endothelial MerTK impairment and subsequent endothelial dysfunction and SMC phenotypic alterations represent novel mechanisms promoting AAAD.

理由:在美国,每年有超过1万人死于主动脉瘤和夹层(AAD)。然而,目前还没有药物可以有效预防AAD的发病机制。MER原癌基因酪氨酸激酶(MerTK)是efferocytosis的关键受体,efferocytosis是清除凋亡细胞的一个过程。在这里,我们主要关注升主动脉瘤和夹层(AAAD),并研究内皮MerTK在AAAD进展中的作用。方法:对人AAAD样本进行单细胞RNA测序(scRNA-seq)分析和RNA-seq大数据分析,结合我们独特的内皮细胞MerTKflox/flox/Tie2Cre MerTKflox/ Tie2Cre MerTK缺失小鼠模型,明确内皮细胞MerTK在AAAD中的作用。结果:通过对人AAAD(内皮细胞与其他细胞的通讯)中scRNA-seq的比较分析和包括约60万次交叉分析的综合大数据分析,我们发现内皮细胞MerTK的表达在人AAAD中被显著抑制,导致内皮细胞吞噬抗原提呈细胞、吞噬细胞、白细胞、血细胞和髓细胞的能力下降。我们的体内数据显示,与同窝MerTK flox/flox小鼠相比,MerTK flox/flox/Tie2Cre小鼠的AAAD发病率明显更高(100% vs 11.1%)。内皮细胞中MerTK缺乏可诱导内皮功能障碍和SMC表型改变,从而促进AAAD的发展。结论:我们的研究结果表明,内皮MerTK损伤和随后的内皮功能障碍和SMC表型改变是促进AAAD的新机制。
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引用次数: 0
Vascularized tumor on a microfluidic chip to study mechanisms promoting tumor neovascularization and vascular targeted therapies. 微流控芯片上的血管化肿瘤,研究促进肿瘤新生血管和血管靶向治疗的机制。
IF 12.4 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-01 DOI: 10.7150/thno.95334
Magdalena Skubal, Benedict Mc Larney, Ngan Bao Phung, Juan Carlos Desmaras, Abdul Vehab Dozic, Alessia Volpe, Anuja Ogirala, Camila Longo Machado, Jakob Djibankov, Vladimir Ponomarev, Jan Grimm

The cascade of events leading to tumor formation includes induction of a tumor supporting neovasculature, as a primary hallmark of cancer. Developing vasculature is difficult to evaluate in vivo but can be captured using microfluidic chip technology and patient derived cells. Herein, we established an on chip approach to investigate the mechanisms promoting tumor vascularization and vascular targeted therapies via co-culture of cancer spheroids and endothelial cells in a three dimensional environment. Methods: We investigated both, tumor neovascularization and therapy, via co-culture of human derived endothelial cells and adjacently localized metastatic renal cell carcinoma spheroids on a commercially available microfluidic chip system. Metastatic renal cell carcinoma spheroids adjacent to primary vessels model tumor, and induce vessels to sprout neovasculature towards the tumor. We monitored real time changes in vessel formation, probed the interactions of tumor and endothelial cells, and evaluated the role of important effectors in tumor vasculature. In addition to wild type endothelial cells, we evaluated endothelial cells that overexpress Prostate Specific Membrane Antigen (PSMA), that has emerged as a marker of tumor associated neovasculature. We characterized the process of neovascularization on the microfluidic chip stimulated by enhanced culture medium and the investigated metastatic renal cell carcinomas, and assessed endothelial cells responses to vascular targeted therapy with bevacizumab via confocal microscopy imaging. To emphasize the potential clinical relevance of metastatic renal cell carcinomas on chip, we compared therapy with bevacizumab on chip with an in vivo model of the same tumor. Results: Our model permitted real-time, high-resolution observation and assessment of tumor-induced angiogenesis, where endothelial cells sprouted towards the tumor and mimicked a vascular network. Bevacizumab, an antiangiogenic agent, disrupted interactions between vessels and tumors, destroying the vascular network. The on chip approach enabled assessment of endothelial cell biology, vessel's functionality, drug delivery, and molecular expression of PSMA. Conclusion: Observations in the vascularized tumor on chip permitted direct and conclusive quantification of vascular targeted therapies in weeks as opposed to months in a comparable animal model, and bridged the gap between in vitro and in vivo models.

导致肿瘤形成的一系列事件包括肿瘤支持新血管系统的诱导,这是癌症的主要标志。血管的发育很难在体内评估,但可以通过微流控芯片技术和患者来源的细胞来捕获。在此,我们建立了一种芯片方法,通过在三维环境中共同培养肿瘤球体和内皮细胞来研究促进肿瘤血管化和血管靶向治疗的机制。方法:我们通过在市卖的微流控芯片系统上共同培养人源性内皮细胞和邻近的转移性肾细胞癌球体来研究肿瘤的新生血管和治疗。转移性肾细胞癌球体邻近原发血管形成肿瘤模型,并诱导血管向肿瘤方向新生血管。我们监测血管形成的实时变化,探索肿瘤和内皮细胞的相互作用,并评估重要效应器在肿瘤血管系统中的作用。除了野生型内皮细胞外,我们还评估了过度表达前列腺特异性膜抗原(PSMA)的内皮细胞,PSMA已成为肿瘤相关血管的标志物。我们在微流控芯片上通过强化培养基刺激和研究转移性肾细胞癌来表征新生血管的过程,并通过共聚焦显微镜成像评估内皮细胞对贝伐单抗血管靶向治疗的反应。为了强调芯片转移性肾细胞癌的潜在临床相关性,我们将贝伐单抗芯片治疗与同一肿瘤的体内模型进行了比较。结果:我们的模型允许实时、高分辨率地观察和评估肿瘤诱导的血管生成,其中内皮细胞向肿瘤生长并模拟血管网络。贝伐单抗是一种抗血管生成药物,破坏血管和肿瘤之间的相互作用,破坏血管网络。芯片方法可以评估内皮细胞生物学、血管功能、药物传递和PSMA的分子表达。结论:芯片上血管化肿瘤的观察可以在几周内直接和结论性地量化血管靶向治疗,而不是在可比的动物模型中数月,并且弥合了体外和体内模型之间的差距。
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引用次数: 0
Erratum: Octopod PtCu Nanoframe for Dual-Modal Imaging-Guided Synergistic Photothermal Radiotherapy: Erratum. 用于双模成像引导的协同光热放疗的章鱼PtCu纳米框架:勘误。
IF 12.4 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-01 DOI: 10.7150/thno.107893
Jinghua Li, Xiangyang Zu, Gaofeng Liang, KeKe Zhang, Yuliang Liu, Ke Li, Zhong Luo, Kaiyong Cai

[This corrects the article DOI: 10.7150/thno.22557.].

[此更正文章DOI: 10.7150/thno.22557.]。
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引用次数: 0
Silk fibroin-based hydrogels for cartilage organoids in osteoarthritis treatment. 基于丝素蛋白的软骨类器官水凝胶治疗骨关节炎。
IF 12.4 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-01 DOI: 10.7150/thno.103491
Congyi Shen, Ziyang Zhou, Ruiyang Li, Shike Yang, Dongyang Zhou, Fengjin Zhou, Zhen Geng, Jiacan Su

Osteoarthritis (OA) is a common joint disease characterized by cartilage degeneration. It can cause severe pain, deformity and even amputation risk. However, existing clinical treatment methods for cartilage repair present certain deficiencies. Meanwhile, the repair effect of cartilage tissue engineering is also unsatisfactory. Cartilage organoids are multicellular aggregates with cartilage-like three-dimensional structure and function. On the one hand, cartilage organoids can be used to explore the pathogenesis of OA by constructing disease models. On the other hand, it can be used as filler for rapid cartilage repair. Extracellular matrix (ECM)-like three-dimensional environment is the key to construct cartilage organoids. Silk fibroin (SF)-based hydrogels not only have ECM-like structure, but also have unique mechanical properties and remarkable biocompatibility. Therefore, SF-based hydrogels are considered as ideal biomaterials for constructing cartilage organoids. In this review, we reviewed the studies of cartilage organoids and SF-based hydrogels. The advantages of SF-based hydrogels in constructing cartilage organoids and the iterative optimization of cartilage organoids through designing hydrogels by using artificial intelligence (AI) calculation are also discussed. This review aims to provide a theoretical basis for the treatment of OA using SF-based biomaterials and cartilage organoids.

骨关节炎(OA)是一种常见的关节疾病,其特征是软骨变性。它会导致严重的疼痛、畸形甚至截肢的风险。然而,临床现有的软骨修复治疗方法存在一定的不足。同时,软骨组织工程的修复效果也不尽人意。软骨类器官是具有软骨样三维结构和功能的多细胞聚集体。一方面,软骨类器官可以通过构建疾病模型来探索OA的发病机制。另一方面,它可以作为快速修复软骨的填充物。细胞外基质(Extracellular matrix, ECM)样三维环境是构建软骨类器官的关键。丝素(SF)基水凝胶不仅具有类似ecm的结构,而且具有独特的力学性能和显著的生物相容性。因此,sf基水凝胶被认为是构建软骨类器官的理想生物材料。本文综述了软骨类器官和sf基水凝胶的研究进展。讨论了基于sf的水凝胶在构建软骨类器官方面的优势,以及利用人工智能(AI)计算设计水凝胶对软骨类器官进行迭代优化。本文综述旨在为利用sf基生物材料和软骨类器官治疗骨性关节炎提供理论依据。
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引用次数: 0
Targeted demethylation of cathepsin D via epigenome editing rescues pathology in Alzheimer's disease mouse model. 通过表观基因组编辑靶向组织蛋白酶D去甲基化可挽救阿尔茨海默病小鼠模型的病理。
IF 12.4 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-01 DOI: 10.7150/thno.103455
Moonsu Park, Hongji Ryu, Suyeon Heo, Boyoung Kim, Junhang Park, Key-Hwan Lim, Sang-Bae Han, Hanseul Park

Background: Cathepsin D (Ctsd) has emerged as a promising therapeutic target for Alzheimer's disease (AD) due to its role in degrading intracellular amyloid beta (Aβ). Enhancing Ctsd activity could reduce Aβ42 accumulation and restore the Aβ42/40 ratio, offering a potential AD treatment strategy. Methods: This study explored Ctsd demethylation in AD mouse models using dCas9-Tet1-mediated epigenome editing. We identified dCas9-Tet1 as an effective tool for demethylating the endogenous Ctsd gene in primary neurons and in vivo brains. Results: Treatment with Ctsd-targeted dCas9-Tet1 in primary neurons overexpressing mutant APP (mutAPP) reduced Aβ peptide levels and the Aβ42/40 ratio. Additionally, in vivo demethylation of Ctsd via dCas9-Tet1 in 5xFAD mice significantly altered Aβ levels and alleviated cognitive and behavioral deficits. Conclusion: These findings offer valuable insights into developing epigenome editing-based gene therapy strategies for AD.

背景:组织蛋白酶D (Ctsd)由于其降解细胞内β淀粉样蛋白(a β)的作用而成为阿尔茨海默病(AD)的一个有希望的治疗靶点。增强Ctsd活性可减少a β42积累,恢复a β42/40比值,为AD的治疗提供了潜在的策略。方法:利用dcas9 - tet1介导的表观基因组编辑技术,研究AD小鼠模型中Ctsd的去甲基化。我们发现dCas9-Tet1是一个有效的工具去甲基化内源性Ctsd基因在初级神经元和活体大脑。结果:ctsd靶向dCas9-Tet1处理过表达突变体APP (mutAPP)的原代神经元,可降低Aβ肽水平和Aβ42/40比值。此外,5xFAD小鼠体内通过dCas9-Tet1对Ctsd进行去甲基化,显著改变了Aβ水平,减轻了认知和行为缺陷。结论:这些发现为开发基于表观基因组编辑的AD基因治疗策略提供了有价值的见解。
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引用次数: 0
Photobiomodulation: shining a light on depression. 光生物调节:照亮抑郁。
IF 12.4 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-01 DOI: 10.7150/thno.104502
Lian Wang, Liwei Mao, Zhihai Huang, Jeffrey A Switzer, David C Hess, Quanguang Zhang

Depression is a prevalent public health issue, characterized by persistent low mood, impaired concentration, and diminished motivation. Photobiomodulation (PBM), which involves the application of red or near-infrared light, modulates physiological processes by enhancing cerebral blood flow, reducing inflammation, inhibiting apoptosis, and promoting neurogenesis. PBM can be administered transcranially or through systemic approaches, offering a potentially effective intervention for depression. This review discusses the characteristics of PBM, its underlying neurobiological mechanisms, and relevant physical parameters. Recent progress in both animal and clinical research underscores PBM's therapeutic potential for depression and emphasizes the need for further studies to establish a robust theoretical basis for standardized treatment protocols.

抑郁症是一种普遍存在的公共健康问题,其特征是持续情绪低落、注意力不集中和动力减退。光生物调节(PBM)涉及到红光或近红外光的应用,通过增强脑血流量、减少炎症、抑制细胞凋亡和促进神经发生来调节生理过程。PBM可以经颅或通过系统的方法进行管理,为抑郁症提供了潜在的有效干预。本文综述了PBM的特点,其潜在的神经生物学机制和相关的物理参数。动物和临床研究的最新进展强调了PBM治疗抑郁症的潜力,并强调需要进一步研究以建立标准化治疗方案的坚实理论基础。
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引用次数: 0
Inhibition of Bruton's tyrosine kinase restricts neuroinflammation following intracerebral hemorrhage. 抑制布鲁顿酪氨酸激酶限制脑出血后的神经炎症。
IF 12.4 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-01 DOI: 10.7150/thno.101024
Hongying Hao, Tingyu Yin, Tuo Li, Xu Zhou, Honglei Ren, Mingming Liu, Huachen Huang, Caiyun Qi, Yuwen Xiu, Wenjin Qiu, Danni Wang, Mengxuan Shi, Xiaoying Wang, Aaron S Dumont, Qiang Liu

Background: Intracerebral hemorrhage (ICH) is a devastating form of stroke with a lack of effective treatments. Following disease onset, ICH activates microglia and recruits peripheral leukocytes into the perihematomal region to amplify neural injury. Bruton's tyrosine kinase (BTK) controls the proliferation and survival of various myeloid cells and lymphocytes. However, the role of BTK in neuroinflammation and ICH injury remains poorly understood. Methods: Peripheral blood samples were collected from ICH patients and healthy controls to measure BTK expression profile in immune cell subsets. C57BL/6 mice were used to measure BTK expression and the activity of immune cell subsets following ICH induction. Neurological tests, brain water content, Evans blue leakage, MRI were used to assess the therapeutic effects of ibrutinib on ICH injury. Flow cytometry was used to investigate immune cell infiltration and microglial activity. Microglia were depleted using a CSF1R inhibitor PLX5622. Gr-1+ myeloid cells and B cells were depleted using monoclonal antibodies. Microglia-like BV2 cells were cultured to test the effects of BTK inhibition on these cells. Results: In humans and mice, we found that BTK was remarkably upregulated in myeloid cells after ICH. Inhibition of BTK using ibrutinib led to reduced neurological deficits, perihematomal edema, brain water content and blood-brain barrier disruption. BTK inhibition suppressed the inflammatory activity of microglia and brain infiltration of leukocytes. In contrast, BTK inhibition did not alter the counts of peripheral immune cells other than B cells. Further, the depletion of microglia or Gr-1+ myeloid cells ablated the protective effects of BTK inhibition against ICH injury. Notably, the depletion of B cells did not alter the protective effects of BTK inhibition against ICH injury. This suggests that the benefit of BTK inhibition in ICH mainly involves its impact on microglia and Gr-1+ myeloid cells. Conclusion: Our findings demonstrate that BTK inhibition attenuates neuroinflammation and ICH injury, which warrants further investigation as a potential therapy for ICH.

背景:脑出血(ICH)是一种破坏性的中风形式,缺乏有效的治疗。在疾病发作后,脑出血激活小胶质细胞并将外周白细胞招募到血肿周围区域以扩大神经损伤。布鲁顿酪氨酸激酶(BTK)控制着各种髓细胞和淋巴细胞的增殖和存活。然而,BTK在神经炎症和脑出血损伤中的作用仍然知之甚少。方法:采集脑出血患者和健康对照者外周血,检测免疫细胞亚群中BTK的表达谱。采用C57BL/6小鼠检测ICH诱导后免疫细胞亚群的BTK表达和活性。采用神经学检查、脑含水量、Evans蓝漏、MRI评价伊鲁替尼对脑出血损伤的治疗效果。流式细胞术检测免疫细胞浸润及小胶质细胞活性。使用CSF1R抑制剂PLX5622去除小胶质细胞。用单克隆抗体去除Gr-1+骨髓细胞和B细胞。培养小胶质样BV2细胞,检测BTK抑制对这些细胞的影响。结果:在人类和小鼠中,我们发现脑出血后髓细胞中BTK显著上调。使用依鲁替尼抑制BTK可减少神经功能缺损、血肿周围水肿、脑含水量和血脑屏障破坏。BTK抑制抑制了小胶质细胞的炎症活性和脑内白细胞的浸润。相比之下,BTK抑制不改变除B细胞外的外周免疫细胞计数。此外,小胶质细胞或Gr-1+髓系细胞的缺失削弱了BTK抑制对脑出血损伤的保护作用。值得注意的是,B细胞的消耗并没有改变BTK抑制对脑出血损伤的保护作用。这表明抑制BTK在脑出血中的益处主要涉及其对小胶质细胞和Gr-1+髓细胞的影响。结论:我们的研究结果表明BTK抑制可减轻神经炎症和脑出血损伤,值得进一步研究作为脑出血的潜在治疗方法。
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Theranostics
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