Pub Date : 2025-02-18eCollection Date: 2025-01-01DOI: 10.7150/thno.103983
Guangze Sang, Bingkai Wang, Yujie Xie, Yu Chen, Feng Yang
Inflammatory bowel disease (IBD) is a chronic condition affecting the intestines, marked by immune-mediated inflammation. This disease is known for its recurrent nature and the challenges it presents in treatment. Recently, probiotic have gained attention as a promising alternative to traditional small molecular drugs and monoclonal antibody chemotherapies for IBD. Probiotic, recognized as a "living" therapeutic agent, offers targeted treatment with minimal side effects and the flexibility for biological modifications, making them highly effective for IBD management. This comprehensive review presents the latest advancements in engineering probiotic-based materials, ranging from basic treatment mechanisms to the modification techniques used in IBD management. It delves deep into how probiotic produces therapeutic effects in the intestinal environment and discusses various strategies to enhance probiotic's efficacy, including genetic modifications and formulation improvements. Additionally, the review addresses the challenges, practical application conditions, and future research directions of probiotic-based therapies in IBD treatment, providing insights into their feasibility and potential clinical implications.
{"title":"Engineered Probiotic-Based Biomaterials for Inflammatory Bowel Disease Treatment.","authors":"Guangze Sang, Bingkai Wang, Yujie Xie, Yu Chen, Feng Yang","doi":"10.7150/thno.103983","DOIUrl":"https://doi.org/10.7150/thno.103983","url":null,"abstract":"<p><p>Inflammatory bowel disease (IBD) is a chronic condition affecting the intestines, marked by immune-mediated inflammation. This disease is known for its recurrent nature and the challenges it presents in treatment. Recently, probiotic have gained attention as a promising alternative to traditional small molecular drugs and monoclonal antibody chemotherapies for IBD. Probiotic, recognized as a \"living\" therapeutic agent, offers targeted treatment with minimal side effects and the flexibility for biological modifications, making them highly effective for IBD management. This comprehensive review presents the latest advancements in engineering probiotic-based materials, ranging from basic treatment mechanisms to the modification techniques used in IBD management. It delves deep into how probiotic produces therapeutic effects in the intestinal environment and discusses various strategies to enhance probiotic's efficacy, including genetic modifications and formulation improvements. Additionally, the review addresses the challenges, practical application conditions, and future research directions of probiotic-based therapies in IBD treatment, providing insights into their feasibility and potential clinical implications.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 8","pages":"3289-3315"},"PeriodicalIF":12.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905135/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143650612","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}
Pub Date : 2025-02-18eCollection Date: 2025-01-01DOI: 10.7150/thno.109104
Yan-Chao Liu, Yu-Chen Deng, Zi-Tao Zhu, Bo Rao, Hong-Lei Shang, Li-Ke Wang, Tao Li, Ya-Rong Wang, Jian-Zhi Wang, Qing-Ping Zhang, Yang Gao, Hai-Bo Xu
Rationale: The prelimbic cortex (PrL), enriched with oxytocin (OXT) receptors, plays a critical role in memory consolidation. However, the role of OXT in social memory consolidation within the PrL microcircuit remains poorly understood. Methods: To examine the role of OXT signaling in social memory consolidation, we used OXT biosensors and loss-of-function approaches, including tetanus toxin-mediated silencing of OXT neurons in the paraventricular nucleus (PVNOXT), optogenetic inhibition of the PVNOXT-PrL pathway during rapid-eye-movement (REM) sleep, and local administration of an OXT receptor antagonist in the PrL. In vivo molecular biosensors for vasoactive intestinal peptide (VIP), somatostatin, and presynaptic calcium imaging were employed to assess inhibitory signaling in the PrL microcircuit. Optogenetic activation of the PVNOXT-PrL pathway and intranasal OXT were used to evaluate resilience to chronic sleep deprivation-induced social memory deficits. Results: We identified that REM-sleep OXT release via the PVN to PrL pathway supports social memory consolidation. OXT signaling deficiency reduces the activity of VIP and parvalbumin (PV) neurons, thereby disrupting the inhibitory balance between somatic inhibition mediated by PV neurons and dendritic disinhibition mediated by VIP neurons in PrL microcircuits during REM sleep. Chronic sleep deprivation (SD) disrupts OXT release and inhibitory balance, leading to pyramidal neuron hyperactivity and social memory impairments. Notably, REM-sleep-specific activation of the PVNOXT-PrL pathway or intranasal OXT restores inhibitory balance and rescues social memory deficits in SD mice. Conclusion: Our results reveal how OXT modulates inhibitory balance in the PrL microcircuit to support social memory consolidation during REM sleep, suggesting potential therapeutic strategies for treating sleep-related memory disorders.
{"title":"Oxytocin modulates inhibitory balance in the prelimbic cortex to support social memory consolidation during REM sleep.","authors":"Yan-Chao Liu, Yu-Chen Deng, Zi-Tao Zhu, Bo Rao, Hong-Lei Shang, Li-Ke Wang, Tao Li, Ya-Rong Wang, Jian-Zhi Wang, Qing-Ping Zhang, Yang Gao, Hai-Bo Xu","doi":"10.7150/thno.109104","DOIUrl":"https://doi.org/10.7150/thno.109104","url":null,"abstract":"<p><p><b>Rationale:</b> The prelimbic cortex (PrL), enriched with oxytocin (OXT) receptors, plays a critical role in memory consolidation. However, the role of OXT in social memory consolidation within the PrL microcircuit remains poorly understood. <b>Methods:</b> To examine the role of OXT signaling in social memory consolidation, we used OXT biosensors and loss-of-function approaches, including tetanus toxin-mediated silencing of OXT neurons in the paraventricular nucleus (PVN<sup>OXT</sup>), optogenetic inhibition of the PVN<sup>OXT</sup>-PrL pathway during rapid-eye-movement (REM) sleep, and local administration of an OXT receptor antagonist in the PrL. <i>In vivo</i> molecular biosensors for vasoactive intestinal peptide (VIP), somatostatin, and presynaptic calcium imaging were employed to assess inhibitory signaling in the PrL microcircuit. Optogenetic activation of the PVN<sup>OXT</sup>-PrL pathway and intranasal OXT were used to evaluate resilience to chronic sleep deprivation-induced social memory deficits. <b>Results:</b> We identified that REM-sleep OXT release via the PVN to PrL pathway supports social memory consolidation. OXT signaling deficiency reduces the activity of VIP and parvalbumin (PV) neurons, thereby disrupting the inhibitory balance between somatic inhibition mediated by PV neurons and dendritic disinhibition mediated by VIP neurons in PrL microcircuits during REM sleep. Chronic sleep deprivation (SD) disrupts OXT release and inhibitory balance, leading to pyramidal neuron hyperactivity and social memory impairments. Notably, REM-sleep-specific activation of the PVN<sup>OXT</sup>-PrL pathway or intranasal OXT restores inhibitory balance and rescues social memory deficits in SD mice. <b>Conclusion:</b> Our results reveal how OXT modulates inhibitory balance in the PrL microcircuit to support social memory consolidation during REM sleep, suggesting potential therapeutic strategies for treating sleep-related memory disorders.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 8","pages":"3257-3274"},"PeriodicalIF":12.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143650829","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}
Pub Date : 2025-02-18eCollection Date: 2025-01-01DOI: 10.7150/thno.107488
Linlin Bai, Yanan Pang, Ting Wang, Shengzhou Wang, Kaiming Guo, Tian Xuan, Ziqin Zhang, Dianwei Liu, Feng Qian, Yan Zheng, Gang Jin, Rui Wang
Rationale: The ultrasensitive and accurate detection of driver mutations is critical for early cancer screening and precision medicine. Current methods face challenges in balancing sensitivity, specificity, and speed, which limits their clinical utility. Therefore, a rapid, sensitive, and specific method is essential for detecting cancer-related SNPs. Methods: This study introduces SPEAR (Specific Point mutation Evaluation via CRISPR-Cas Assisted Recognition), a novel methodology combining NEAR (Nicking Enzyme Amplification Reaction) isothermal amplification with SNP-specific recognition by Cas12b RNP in a one-pot configuration to detect cancer-related single nucleotide polymorphisms (SNPs). SPEAR leverages the power of NEAR isothermal amplification to efficiently amplify target DNA, followed by Cas12b RNP for SNP-specific recognition. This integrated approach ensures a rapid and precise mutation detection system in a single reaction. Results: The method was applied to blood samples for the detection of cancer-related mutations, with results obtained in approximately 30 min. The SPEAR enables detection of gene mutations at the single-molecule level and it can detect targets at a 0.1% ratio despite strong background interference. The method exhibits single-base resolution specificity, allowing for the detection of multiple SNPs in a single reaction. It outperforms first-generation sequencing (FGS) in both convenience and sensitivity, while remaining compatible with next-generation sequencing (NGS). Conclusion: SPEAR offers a rapid, sensitive, and convenient approach to detect cancer-related SNPs, with significant potential for clinical applications, including real-time detection and molecular diagnostics in precision medicine.
{"title":"SPEAR: CRISPR-mediated ultrasensitive, specific and rapid one-pot detection strategy for cancer-related SNPs.","authors":"Linlin Bai, Yanan Pang, Ting Wang, Shengzhou Wang, Kaiming Guo, Tian Xuan, Ziqin Zhang, Dianwei Liu, Feng Qian, Yan Zheng, Gang Jin, Rui Wang","doi":"10.7150/thno.107488","DOIUrl":"https://doi.org/10.7150/thno.107488","url":null,"abstract":"<p><p><b>Rationale:</b> The ultrasensitive and accurate detection of driver mutations is critical for early cancer screening and precision medicine. Current methods face challenges in balancing sensitivity, specificity, and speed, which limits their clinical utility. Therefore, a rapid, sensitive, and specific method is essential for detecting cancer-related SNPs. <b>Methods:</b> This study introduces SPEAR (Specific Point mutation Evaluation via CRISPR-Cas Assisted Recognition), a novel methodology combining NEAR (Nicking Enzyme Amplification Reaction) isothermal amplification with SNP-specific recognition by Cas12b RNP in a one-pot configuration to detect cancer-related single nucleotide polymorphisms (SNPs). SPEAR leverages the power of NEAR isothermal amplification to efficiently amplify target DNA, followed by Cas12b RNP for SNP-specific recognition. This integrated approach ensures a rapid and precise mutation detection system in a single reaction. <b>Results:</b> The method was applied to blood samples for the detection of cancer-related mutations, with results obtained in approximately 30 min. The SPEAR enables detection of gene mutations at the single-molecule level and it can detect targets at a 0.1% ratio despite strong background interference. The method exhibits single-base resolution specificity, allowing for the detection of multiple SNPs in a single reaction. It outperforms first-generation sequencing (FGS) in both convenience and sensitivity, while remaining compatible with next-generation sequencing (NGS). <b>Conclusion:</b> SPEAR offers a rapid, sensitive, and convenient approach to detect cancer-related SNPs, with significant potential for clinical applications, including real-time detection and molecular diagnostics in precision medicine.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 8","pages":"3275-3288"},"PeriodicalIF":12.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905141/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143650925","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}
Inspired by the remarkable success of CAR-T therapy in hematologic malignancies, research is increasingly focused on adapting this treatment for solid tumors. However, CAR-T efficacy remains limited due to its exhaustion and shortened persistence. Transcription factors and epigenetic modifications play pivotal roles in modulating T cell differentiation and functionality, which have been leveraged in numerous strategies to promote the formation of long-lasting memory cells with stem-like properties and supercharging CAR-T performance. This review highlights pivotal transcriptional factors, such as c-Jun and FOXO1, which enhance and sustain T cell effector function, diminishes exhaustion, and epigenetic regulators like TET2 and DNMT3A, whose knockout promotes memory T subsets formation. We explore their interconnections, downstream targets, biological impacts, and the potential application risks of certain candidates, providing a comprehensive theoretical framework for supercharging CAR-T therapies through transcriptional and epigenetic interventions.
{"title":"Supercharging CAR-T cells through transcriptional and epigenetic armoring.","authors":"Diyuan Qin, Yanna Lei, Pei Shu, Yugu Zhang, Yuin-Han Loh, Yongsheng Wang, Qijing Li","doi":"10.7150/thno.107908","DOIUrl":"https://doi.org/10.7150/thno.107908","url":null,"abstract":"<p><p>Inspired by the remarkable success of CAR-T therapy in hematologic malignancies, research is increasingly focused on adapting this treatment for solid tumors. However, CAR-T efficacy remains limited due to its exhaustion and shortened persistence. Transcription factors and epigenetic modifications play pivotal roles in modulating T cell differentiation and functionality, which have been leveraged in numerous strategies to promote the formation of long-lasting memory cells with stem-like properties and supercharging CAR-T performance. This review highlights pivotal transcriptional factors, such as c-Jun and FOXO1, which enhance and sustain T cell effector function, diminishes exhaustion, and epigenetic regulators like TET2 and DNMT3A, whose knockout promotes memory T subsets formation. We explore their interconnections, downstream targets, biological impacts, and the potential application risks of certain candidates, providing a comprehensive theoretical framework for supercharging CAR-T therapies through transcriptional and epigenetic interventions.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 8","pages":"3345-3367"},"PeriodicalIF":12.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143650929","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}
Pub Date : 2025-02-18eCollection Date: 2025-01-01DOI: 10.7150/thno.100793
Rui Li, Jie He, Chaoqun Liu, Zesheng Jiang, Jiasheng Qin, Kun Liang, Zhuocheng Ji, Liang Zhao
Rationale: Tumor cell epigenetics, especially chromosome accessibility, has been reported to be closely related to the tumor immune landscape and immunotherapy. However, the exact mechanism remains unknown. Methods: Whole-exome sequencing was used to analyze 13 colorectal tumor samples treated with PD1 immunotherapy. The assays for transposase-accessible chromatin using sequencing (ATAC-seq) and RNA sequencing were used to detect tumor cells' chromosome accessibility status and screen regulatory pathways. Results: Polybromo-1 (PBRM1) was one of the 12 genes with the highest frequency of somatic mutations associated with immunotherapy sensitivity. PBRM1/Pbrm1 deficiency in colorectal cancer promoted PD-1 immunotherapy sensitivity and chemotaxis of CD8+ T and NK cells in the microenvironment in vivo and in vitro. ATAC sequencing revealed that deletion of Pbrm1, a critical component of the SWI/SNF complex, increased chromosomal accessibility in tumor cells and triggered the release of cytokines, such as CCL5 and CXCL10, by activating the NF-κB signaling pathway. Application of ACBL1, a PROC inhibitor of PBRM1, in BALB/C mice or colorectal patient-derived tumor organoids (PDTOs) significantly promoted the sensitivity to PD1 antibody immunotherapy. Conclusions: Our study established that PBRM1/Pbrm1 deficiency was positively correlated with PD1 immunotherapeutic sensitivity in colorectal cancer. The underlying molecular mechanisms involved regulation of chromosome accessibility, activation of the NF-κB signaling pathway, and immune cell infiltration in the microenvironment. These findings identify potential molecular targets for enhancing immunotherapy for colorectal cancer.
{"title":"PBRM1 deficiency enhances PD1 immunotherapeutic sensitivity via chromosomal accessibility in colorectal cancer.","authors":"Rui Li, Jie He, Chaoqun Liu, Zesheng Jiang, Jiasheng Qin, Kun Liang, Zhuocheng Ji, Liang Zhao","doi":"10.7150/thno.100793","DOIUrl":"10.7150/thno.100793","url":null,"abstract":"<p><p><b>Rationale:</b> Tumor cell epigenetics, especially chromosome accessibility, has been reported to be closely related to the tumor immune landscape and immunotherapy. However, the exact mechanism remains unknown. <b>Methods:</b> Whole-exome sequencing was used to analyze 13 colorectal tumor samples treated with PD1 immunotherapy. The assays for transposase-accessible chromatin using sequencing (ATAC-seq) and RNA sequencing were used to detect tumor cells' chromosome accessibility status and screen regulatory pathways. <b>Results:</b> Polybromo-1 (PBRM1) was one of the 12 genes with the highest frequency of somatic mutations associated with immunotherapy sensitivity. PBRM1/Pbrm1 deficiency in colorectal cancer promoted PD-1 immunotherapy sensitivity and chemotaxis of CD8<sup>+</sup> T and NK cells in the microenvironment <i>in vivo</i> and <i>in vitro.</i> ATAC sequencing revealed that deletion of Pbrm1, a critical component of the SWI/SNF complex, increased chromosomal accessibility in tumor cells and triggered the release of cytokines, such as CCL5 and CXCL10, by activating the NF-κB signaling pathway. Application of ACBL1, a PROC inhibitor of PBRM1, in BALB/C mice or colorectal patient-derived tumor organoids (PDTOs) significantly promoted the sensitivity to PD1 antibody immunotherapy. <b>Conclusions:</b> Our study established that PBRM1/Pbrm1 deficiency was positively correlated with PD1 immunotherapeutic sensitivity in colorectal cancer. The underlying molecular mechanisms involved regulation of chromosome accessibility, activation of the NF-κB signaling pathway, and immune cell infiltration in the microenvironment. These findings identify potential molecular targets for enhancing immunotherapy for colorectal cancer.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 8","pages":"3316-3331"},"PeriodicalIF":12.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143650911","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}
Pub Date : 2025-02-18eCollection Date: 2025-01-01DOI: 10.7150/thno.106592
Anna Pees, Christopher Daniel Morrone, Junchao Tong, Jian Rong, Tuo Shao, Darcy Wear, Steven H Liang, Wai Haung Yu, Neil Vasdev
The endocannabinoid system is a critical brain signaling pathway that is dysregulated in various brain disorders, including Alzheimer's disease (AD). Cannabinoid-targeted therapies and imaging approaches have gained increasing interest; however, the biological impact of the endocannabinoid system in disease needs further validation. We aimed to study changes in cannabinoid receptor 1 (CB1) and monoacylglycerol lipase (MAGL), components of endocannabinoid signaling and degradation, in a mouse model of AD by PET imaging. Methods: [18F]FMPEP-d2 and [18F]MAGL-2102 were produced on a commercial radiosynthesis module. PET-CT images with both tracers were acquired in a knock-in mouse model of AD bearing mutated human amyloid precursor protein (AppNL-G-F ) at 3 ages, and compared to wild-type mice. Excised brains were used for in vitro autoradiography with [18F]FMPEP-d2 and [18F]MAGL-2102, immunofluorescence, and western blotting. Male wild-type and 5xFAD mice were chronically treated with MAGL inhibitor JZL184 and imaged with [18F]MAGL-2102 two days after ending treatment. Results: PET imaging showed sex-, age- and genotype-dependent changes in CB1 and MAGL availability. At 4-months (early-stage β-amyloid pathology), female AppNL-G-F mice had lower CB1 availability, and MAGL availability was increased in male AppNL-G-F, compared to wild-types. At 8-months, no genotype differences in CB1 were observed, yet MAGL availability was reduced in AppNL-G-F frontal cortex, and male AppNL-G-F mice exhibited higher MAGL than transgenic females brain-wide. At 12-months (late-stage β-amyloid pathology), significantly lower uptake of [18F]FMPEP-d2 was observed in AppNL-G-F compared to wild-type, with no changes in [18F]MAGL-2102 binding. AppNL-G-F plaque staging was confirmed by Thioflavin-S staining. Imaging findings were supplemented by autoradiography, immunofluorescence, and western blots. [18F]MAGL-2102 availability was responsive to target engagement of the MAGL inhibitor JZL184 in wild-type and 5xFAD mice. Conclusions: The present study showed dynamic age-, sex- and pathology-related changes in CB1 and MAGL availability from early-stage β-amyloid pathology, suggesting that the endocannabinoid system is a useful target for diagnostics and treatment of AD. Finally, these results highlight that endocannabinoid sex differences should be considered in diagnostics and drug development.
{"title":"Sex- and age-specific sensitivities of the endocannabinoid system in Alzheimer's disease revealed by PET imaging with [<sup>18</sup>F]FMPEP-<i>d</i> <sub>2</sub> and [<sup>18</sup>F]MAGL-2102.","authors":"Anna Pees, Christopher Daniel Morrone, Junchao Tong, Jian Rong, Tuo Shao, Darcy Wear, Steven H Liang, Wai Haung Yu, Neil Vasdev","doi":"10.7150/thno.106592","DOIUrl":"https://doi.org/10.7150/thno.106592","url":null,"abstract":"<p><p>The endocannabinoid system is a critical brain signaling pathway that is dysregulated in various brain disorders, including Alzheimer's disease (AD). Cannabinoid-targeted therapies and imaging approaches have gained increasing interest; however, the biological impact of the endocannabinoid system in disease needs further validation. We aimed to study changes in cannabinoid receptor 1 (CB1) and monoacylglycerol lipase (MAGL), components of endocannabinoid signaling and degradation, in a mouse model of AD by PET imaging. <b>Methods:</b> [<sup>18</sup>F]FMPEP-<i>d</i> <sub>2</sub> and [<sup>18</sup>F]MAGL-2102 were produced on a commercial radiosynthesis module. PET-CT images with both tracers were acquired in a knock-in mouse model of AD bearing mutated human amyloid precursor protein (<i>App<sup>NL-G-F</sup></i> ) at 3 ages, and compared to wild-type mice. Excised brains were used for <i>in vitro</i> autoradiography with [<sup>18</sup>F]FMPEP-<i>d</i> <sub>2</sub> and [<sup>18</sup>F]MAGL-2102, immunofluorescence, and western blotting. Male wild-type and 5xFAD mice were chronically treated with MAGL inhibitor JZL184 and imaged with [<sup>18</sup>F]MAGL-2102 two days after ending treatment. <b>Results:</b> PET imaging showed sex-, age- and genotype-dependent changes in CB1 and MAGL availability. At 4-months (early-stage β-amyloid pathology), female <i>App<sup>NL-G-F</sup></i> mice had lower CB1 availability, and MAGL availability was increased in male <i>App<sup>NL-G-F</sup></i> <sub>,</sub> compared to wild-types<sub>.</sub> At 8-months, no genotype differences in CB1 were observed, yet MAGL availability was reduced in <i>App<sup>NL-G-F</sup></i> frontal cortex, and male <i>App<sup>NL-G-F</sup></i> mice exhibited higher MAGL than transgenic females brain-wide. At 12-months (late-stage β-amyloid pathology), significantly lower uptake of [<sup>18</sup>F]FMPEP-<i>d</i> <sub>2</sub> was observed in <i>App<sup>NL-G-F</sup></i> compared to wild-type, with no changes in [<sup>18</sup>F]MAGL-2102 binding. <i>App<sup>NL-G-F</sup></i> plaque staging was confirmed by Thioflavin-S staining. Imaging findings were supplemented by autoradiography, immunofluorescence, and western blots. [<sup>18</sup>F]MAGL-2102 availability was responsive to target engagement of the MAGL inhibitor JZL184 in wild-type and 5xFAD mice. <b>Conclusions:</b> The present study showed dynamic age-, sex- and pathology-related changes in CB1 and MAGL availability from early-stage β-amyloid pathology, suggesting that the endocannabinoid system is a useful target for diagnostics and treatment of AD. Finally, these results highlight that endocannabinoid sex differences should be considered in diagnostics and drug development.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 8","pages":"3368-3385"},"PeriodicalIF":12.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905134/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143650841","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}
Pub Date : 2025-02-18eCollection Date: 2025-01-01DOI: 10.7150/thno.100295
Xi Qin, Keren Zhou, Lei Dong, Lu Yang, Wei Li, Zhenhua Chen, Chao Shen, Li Han, Yangchan Li, Anthony K N Chan, Sheela Pangeni Pokharel, Ying Qing, Meiling Chen, Kitty Wang, Keith Leung, Lillian Sau, Chun-Wei Chen, Xiaolan Deng, Rui Su, Jianjun Chen
Rationale: Despite substantial advancement in the treatment of B-cell acute lymphoblastic leukemia (B-ALL), it remains a leading cause of cancer mortality in children due to the high relapse rate. Moreover, the long-term survival rates for adult B-ALL patients are still less than 40%. The B-ALL patients carrying MLL rearrangements or BCR-ABL fusion represent high-risk B-ALL subtypes that face particularly dismal prognoses. This study aims to identify innovative therapeutic vulnerability for high-risk B-ALL. Methods: The CRISPR-Cas9 screen was conducted to pinpoint genes essential for high-risk B-ALL cell survival/growth. Both in vitro and in vivo models were then employed to investigate the pathological role of ZNF217 in high-risk B-ALL. To characterize the downstream functionally essential targets of ZNF217, we performed RNA-seq and CUT&RUN-seq, followed by integrative bioinformatics analysis and experimental validation. Results: Through the focused CRISPR-Cas9 screening, ZNF217 emerged as the most essential gene for the cell survival/growth of B-ALL driven by MLL rearrangement or BCR-ABL. Through in vitro gain- and loss-of-function assays, we demonstrated that ZNF217 is indeed required for B-ALL cell survival/growth. Moreover, we established the B-ALL xenograft model and patient-derived xenograft (PDX) model and demonstrated that ZNF217 depletion significantly suppressed B-ALL progression and substantially extended the survival of recipient mice. Through integrative multiple-omics analysis, we elucidated that ZNF217 exerts its oncogenic role in B-ALL through both CoREST-dependent and CoREST-independent mechanisms. Furthermore, we characterized FOS as a functionally essential downstream target of ZNF217, and ZNF217 inhibited FOS expression in a CoREST-independent manner. Conclusions: Our findings highlight ZNF217 as a promising therapeutic target for the treatment of high-risk B-ALL, such as those carrying MLL-rearrangements or BCR-ABL fusion.
{"title":"CRISPR screening reveals ZNF217 as a vulnerability in high-risk B-cell acute lymphoblastic leukemia.","authors":"Xi Qin, Keren Zhou, Lei Dong, Lu Yang, Wei Li, Zhenhua Chen, Chao Shen, Li Han, Yangchan Li, Anthony K N Chan, Sheela Pangeni Pokharel, Ying Qing, Meiling Chen, Kitty Wang, Keith Leung, Lillian Sau, Chun-Wei Chen, Xiaolan Deng, Rui Su, Jianjun Chen","doi":"10.7150/thno.100295","DOIUrl":"https://doi.org/10.7150/thno.100295","url":null,"abstract":"<p><p><b>Rationale:</b> Despite substantial advancement in the treatment of B-cell acute lymphoblastic leukemia (B-ALL), it remains a leading cause of cancer mortality in children due to the high relapse rate. Moreover, the long-term survival rates for adult B-ALL patients are still less than 40%. The B-ALL patients carrying MLL rearrangements or BCR-ABL fusion represent high-risk B-ALL subtypes that face particularly dismal prognoses. This study aims to identify innovative therapeutic vulnerability for high-risk B-ALL. <b>Methods:</b> The CRISPR-Cas9 screen was conducted to pinpoint genes essential for high-risk B-ALL cell survival/growth. Both <i>in vitro</i> and <i>in vivo</i> models were then employed to investigate the pathological role of ZNF217 in high-risk B-ALL. To characterize the downstream functionally essential targets of ZNF217, we performed RNA-seq and CUT&RUN-seq, followed by integrative bioinformatics analysis and experimental validation. <b>Results:</b> Through the focused CRISPR-Cas9 screening, <i>ZNF217</i> emerged as the most essential gene for the cell survival/growth of B-ALL driven by MLL rearrangement or BCR-ABL. Through <i>in vitro</i> gain- and loss-of-function assays, we demonstrated that ZNF217 is indeed required for B-ALL cell survival/growth. Moreover, we established the B-ALL xenograft model and patient-derived xenograft (PDX) model and demonstrated that <i>ZNF217</i> depletion significantly suppressed B-ALL progression and substantially extended the survival of recipient mice. Through integrative multiple-omics analysis, we elucidated that ZNF217 exerts its oncogenic role in B-ALL through both CoREST-dependent and CoREST-independent mechanisms. Furthermore, we characterized FOS as a functionally essential downstream target of ZNF217, and ZNF217 inhibited FOS expression in a CoREST-independent manner. <b>Conclusions:</b> Our findings highlight ZNF217 as a promising therapeutic target for the treatment of high-risk B-ALL, such as those carrying MLL-rearrangements or BCR-ABL fusion.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 8","pages":"3234-3256"},"PeriodicalIF":12.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143650607","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}
Pub Date : 2025-02-18eCollection Date: 2025-01-01DOI: 10.7150/thno.104900
Xiaoyun Chen, Fangqi Chen, Sujie Jia, Qianjin Lu, Ming Zhao
Antigen-presenting fibroblasts are a newly recognized subset that challenges the traditional view of these cells as mere structural components. Under pathological or environmental stimuli, fibroblasts acquire antigen-presenting capabilities through the expression of MHC-II molecules and co-stimulatory factors, enabling them to interact with T cells and modulate immune responses. These specialized fibroblasts have been identified across various tissues and diseases, where they play context-dependent roles, either amplifying immune dysregulation or contributing to immune homeostasis. This review synthesizes recent advances in understanding the origins, activation, and functions of antigen-presenting fibroblasts. It highlights their role in promoting pathogenic immune responses and offering therapeutic opportunities through targeted modulation. Advancing our understanding of antigen-presenting fibroblasts holds great promise for developing innovative approaches to immune modulation and therapy across a range of diseases.
{"title":"Antigen-presenting fibroblasts: emerging players in immune modulation and therapeutic targets.","authors":"Xiaoyun Chen, Fangqi Chen, Sujie Jia, Qianjin Lu, Ming Zhao","doi":"10.7150/thno.104900","DOIUrl":"https://doi.org/10.7150/thno.104900","url":null,"abstract":"<p><p>Antigen-presenting fibroblasts are a newly recognized subset that challenges the traditional view of these cells as mere structural components. Under pathological or environmental stimuli, fibroblasts acquire antigen-presenting capabilities through the expression of MHC-II molecules and co-stimulatory factors, enabling them to interact with T cells and modulate immune responses. These specialized fibroblasts have been identified across various tissues and diseases, where they play context-dependent roles, either amplifying immune dysregulation or contributing to immune homeostasis. This review synthesizes recent advances in understanding the origins, activation, and functions of antigen-presenting fibroblasts. It highlights their role in promoting pathogenic immune responses and offering therapeutic opportunities through targeted modulation. Advancing our understanding of antigen-presenting fibroblasts holds great promise for developing innovative approaches to immune modulation and therapy across a range of diseases.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 8","pages":"3332-3344"},"PeriodicalIF":12.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905139/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143650879","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}