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.
{"title":"Revolutionizing drug delivery: low-intensity pulsed ultrasound (LIPUS)-driven deep penetration into hypoxic tumor microenvironments of cholangiocarcinoma.","authors":"Sera Hong, Jaihwan Kim, Gujin Chung, Donghyuk Lee, Joon Myong Song","doi":"10.7150/thno.99981","DOIUrl":"10.7150/thno.99981","url":null,"abstract":"<p><p><b>Background:</b> 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. <b>Methods:</b> 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. <b>Results:</b> 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. <b>Conclusion:</b> LIPUS adjuvant therapy promises improved cancer treatment outcomes and offers a safe and innovative therapeutic strategy for CCA and other hypoxic tumors.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 1","pages":"30-51"},"PeriodicalIF":12.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667228/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"A molecularly distinct cell type in the midbrain regulates intermale aggression behaviors in mice.","authors":"Chunyang Li, Cheng Miao, Yao Ge, Jiaxing Wu, Panpan Gao, Songlin Yin, Pei Zhang, Hongbin Yang, Bo Tian, Wenqiang Chen, Xiao Qian Chen","doi":"10.7150/thno.101658","DOIUrl":"10.7150/thno.101658","url":null,"abstract":"<p><p><b>Rationale</b>: 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, <i>Tachykinin 2</i>-expressing (Tac2<sup>+</sup>) neurons, located in the dorsomedial PAG (dmPAG) and their modulation of aggressive behavior in mice. <b>Methods</b>: We combined activity mapping, <i>in vivo</i> Ca<sup>2+</sup> recording, chemogenetic and pharmacological manipulation, and a viral-based translating ribosome affinity purification (TRAP) profiling using a mouse resident-intruder model. <b>Results</b>: We revealed that dmPAG<sup>Tac2</sup> neurons are selectively activated by fighting behaviors. Chemogenetic activation of these neurons evoked fighting behaviors, while inhibition or genetic ablation of dmPAG<sup>Tac2</sup> neurons attenuated fighting behaviors. TRAP profiling of dmPAG<sup>Tac2</sup> 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. <b>Conclusions</b>: We identify dmPAG<sup>Tac2</sup> 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.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 2","pages":"707-725"},"PeriodicalIF":12.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671387/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"Orchestrating the frontline: HDAC3-miKO recruits macrophage reinforcements for accelerated myelin debris clearance after stroke.","authors":"Jiaying Li, Chenran Wang, Yue Zhang, Yichen Huang, Ziyu Shi, Yuwen Zhang, Yana Wang, Shuning Chen, Yiwen Yuan, He Wang, Leilei Mao, Yanqin Gao","doi":"10.7150/thno.103449","DOIUrl":"10.7150/thno.103449","url":null,"abstract":"<p><p><b><i>Rational:</i></b> 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. <b><i>Methods</i></b> <i>:</i> 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 <i>ex vivo</i> 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. <b><i>Results</i></b> <i>:</i> 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. <b><i>Conclusions</i></b> <i>:</i> 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.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 2","pages":"632-655"},"PeriodicalIF":12.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671378/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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。
{"title":"Big data analytics and scRNA-seq in human aortic aneurysms and dissections: role of endothelial MerTK.","authors":"Shijie Liu, Jinzi Wu, Oishani Banerjee, Bingzhong Xue, Hang Shi, Zufeng Ding","doi":"10.7150/thno.103851","DOIUrl":"10.7150/thno.103851","url":null,"abstract":"<p><p><b>Rationale:</b> 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. <b>Methods:</b> Single-cell RNA sequencing (scRNA-seq) analysis in human AAAD samples and RNA-seq big data analytics, combined with our unique <i>MerTK<sup>flox/flox</sup>/Tie2<sup>Cre</sup></i> mouse model with MerTK deficiency in endothelial cells (ECs), were applied to define the role of endothelial MerTK in AAAD. <b>Results:</b> 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 <i>in vivo</i> data showed a significantly higher incidence of AAAD in MerTK <i><sup>flox/flox</sup>/Tie2<sup>Cre</sup></i> mice compared to that of their littermate controls of MerTK <i><sup>flox/flox</sup></i> mice (100% vs. 11.1%). MerTK deficiency in ECs induces both endothelial dysfunction and SMC phenotypic alterations, subsequently promoting AAAD development. <b>Conclusions:</b> Our findings indicate that endothelial MerTK impairment and subsequent endothelial dysfunction and SMC phenotypic alterations represent novel mechanisms promoting AAAD.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 1","pages":"202-215"},"PeriodicalIF":12.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667232/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"Vascularized tumor on a microfluidic chip to study mechanisms promoting tumor neovascularization and vascular targeted therapies.","authors":"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","doi":"10.7150/thno.95334","DOIUrl":"10.7150/thno.95334","url":null,"abstract":"<p><p>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 <i>in vivo</i> but can be captured using microfluidic chip technology and patient derived cells. Herein, we established an <i>on chip</i> 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. <b>Methods:</b> 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 <i>on chip</i>, we compared therapy with bevacizumab <i>on chip</i> with an <i>in vivo</i> model of the same tumor. <b>Results:</b> 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 <i>on chip</i> approach enabled assessment of endothelial cell biology, vessel's functionality, drug delivery, and molecular expression of PSMA. <b>Conclusion:</b> Observations in the vascularized tumor <i>on chip</i> 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 <i>in vitro</i> and <i>in vivo</i> models.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 3","pages":"766-783"},"PeriodicalIF":12.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11700857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142955419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"Silk fibroin-based hydrogels for cartilage organoids in osteoarthritis treatment.","authors":"Congyi Shen, Ziyang Zhou, Ruiyang Li, Shike Yang, Dongyang Zhou, Fengjin Zhou, Zhen Geng, Jiacan Su","doi":"10.7150/thno.103491","DOIUrl":"10.7150/thno.103491","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 2","pages":"560-584"},"PeriodicalIF":12.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671376/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142914824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"Targeted demethylation of cathepsin D via epigenome editing rescues pathology in Alzheimer's disease mouse model.","authors":"Moonsu Park, Hongji Ryu, Suyeon Heo, Boyoung Kim, Junhang Park, Key-Hwan Lim, Sang-Bae Han, Hanseul Park","doi":"10.7150/thno.103455","DOIUrl":"10.7150/thno.103455","url":null,"abstract":"<p><p><b>Background:</b> 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. <b>Methods:</b> 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 <i>in vivo</i> brains. <b>Results:</b> Treatment with Ctsd-targeted dCas9-Tet1 in primary neurons overexpressing mutant APP (mutAPP) reduced Aβ peptide levels and the Aβ42/40 ratio. Additionally, <i>in vivo</i> demethylation of Ctsd via dCas9-Tet1 in 5xFAD mice significantly altered Aβ levels and alleviated cognitive and behavioral deficits. <b>Conclusion:</b> These findings offer valuable insights into developing epigenome editing-based gene therapy strategies for AD.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 2","pages":"428-438"},"PeriodicalIF":12.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671390/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"Photobiomodulation: shining a light on depression.","authors":"Lian Wang, Liwei Mao, Zhihai Huang, Jeffrey A Switzer, David C Hess, Quanguang Zhang","doi":"10.7150/thno.104502","DOIUrl":"10.7150/thno.104502","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 2","pages":"362-383"},"PeriodicalIF":12.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671386/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"Inhibition of Bruton's tyrosine kinase restricts neuroinflammation following intracerebral hemorrhage.","authors":"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","doi":"10.7150/thno.101024","DOIUrl":"10.7150/thno.101024","url":null,"abstract":"<p><p><b>Background:</b> 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. <b>Methods:</b> 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<sup>+</sup> 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. <b>Results:</b> 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<sup>+</sup> 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<sup>+</sup> myeloid cells. <b>Conclusion:</b> Our findings demonstrate that BTK inhibition attenuates neuroinflammation and ICH injury, which warrants further investigation as a potential therapy for ICH.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 2","pages":"494-508"},"PeriodicalIF":12.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671375/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}