Accurately recognizing and regulating the transition time of macrophages to a pro- (M1-like) or anti-inflammatory (M2-like) state is essential for improving chronic inflammation in pressure injuries (PIs).
Objective
This study aimed to evaluate the effectiveness of infrared thermography (IRT) in measuring wound temperature of PIs for the purpose of guiding treatment in regulating chronic inflammation.
Methods
The healing process of 21 patients with PIs was monitored using IRT prospectively followed for 30 days. The wound temperature changing pattern of different healing outcomes were analyzed and calculated the optimal wound temperature range to guide the treatment time of anti-inflammation for 100 patients with PIs accurately. Additionally, the molecular mechanisms underlying the observed temperature changes in a mouse model of PI were investigated, and the effect of IRT-guided chronic inflammation targeting ferroptosis modulation on PIs was validated.
Results
The application of IRT to monitor PIs temperatures outside the 36.23 °C to 37.37 °C range is indicative of a potential risk indicator, which allows for the timely guidance of treatment to markedly enhance the efficacy of PIs healing outcomes. This wound temperature change was also observed during the process of PIs healing in mice, as a result of the imbalance of M1-like/M2-like macrophages and the subsequent chronic inflammation. Mechanically, evidence indicates that ferroptosis is hyperactivated in PIs, and the enrichment of M1-like macrophages with iNOS/NO• can enhance their resistance to ferroptosis compared with M2-like macrophages, resulting in the imbalance of M1-like/M2-like macrophages and subsequent alteration of wound temperature.
Conclusions
The modulation of M2-like macrophage resistance to ferroptosis in PIs by NO• donors, suggesting by IRT-monitored temperature changes, has been demonstrated to significantly improve chronic inflammation. This establishes a foundation for the application of IRT to direct a therapeutic strategy for the precise promotion of PIs healing.
{"title":"Modulation of Macrophage ferroptosis under the guide of infrared thermography promotes the healing of pressure injuries","authors":"Xiaoqiong Jiang, Xuanlong Zhang, Huiming Deng, Lulu Lin, Yu Wang, Yuqi Wang, Jiayi Huang, Ningning Yang, Shi Xu, Jian Wang, Keqing Shi, Ke Tao, Zimiao Chen, Fuman Cai, Kailiang Zhou, Jian Xiao","doi":"10.1016/j.jare.2025.04.039","DOIUrl":"https://doi.org/10.1016/j.jare.2025.04.039","url":null,"abstract":"<h3>Background</h3>Accurately recognizing and regulating the transition time of macrophages to a pro- (M1-like) or anti-inflammatory (M2-like) state is essential for improving chronic inflammation in pressure injuries (PIs).<h3>Objective</h3>This study aimed to evaluate the effectiveness of infrared thermography (IRT) in measuring wound temperature of PIs for the purpose of guiding treatment in regulating chronic inflammation.<h3>Methods</h3>The healing process of 21 patients with PIs was monitored using IRT prospectively followed for 30 days. The wound temperature changing pattern of different healing outcomes were analyzed and calculated the optimal wound temperature range to guide the treatment time of anti-inflammation for 100 patients with PIs accurately. Additionally, the molecular mechanisms underlying the observed temperature changes in a mouse model of PI were investigated, and the effect of IRT-guided chronic inflammation targeting ferroptosis modulation on PIs was validated.<h3>Results</h3>The application of IRT to monitor PIs temperatures outside the 36.23 °C to 37.37 °C range is indicative of a potential risk indicator, which allows for the timely guidance of treatment to markedly enhance the efficacy of PIs healing outcomes. This wound temperature change was also observed during the process of PIs healing in mice, as a result of the imbalance of M1-like/M2-like macrophages and the subsequent chronic inflammation. Mechanically, evidence indicates that ferroptosis is hyperactivated in PIs, and the enrichment of M1-like macrophages with iNOS/NO• can enhance their resistance to ferroptosis compared with M2-like macrophages, resulting in the imbalance of M1-like/M2-like macrophages and subsequent alteration of wound temperature.<h3>Conclusions</h3>The modulation of M2-like macrophage resistance to ferroptosis in PIs by NO• donors, suggesting by IRT-monitored temperature changes, has been demonstrated to significantly improve chronic inflammation. This establishes a foundation for the application of IRT to direct a therapeutic strategy for the precise promotion of PIs healing.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"6 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-25DOI: 10.1016/j.jare.2025.04.030
Meihui Tao, Li Wang, Chaoyue Chen, Mengfan Tang, Yanping Wang, Jingyue Zhang, Xi Zhao, Qinyu Feng, Junfa Chen, Wei Yan, Rong Lin, Yu Fu
Introduction
Abnormalities in inflammation resolution function are intimately linked to chronic inflammation, and proresolution therapies may offer novel opportunities for IBD treatment. Developmental endothelial locus 1 (DEL-1), a natural modulator of tissue immunity and inflammation resolution, has not been studied in IBD.
Objectives
We aimed to investigate the expression and functions of DEL-1 in IBD.
Methods
Assessment of DEL-1 expression in patients, murine models, and cellular levels. To explore the effects of DEL-1 in the acute and recovery phases of inflammation, overexpression plasmids, adeno-associated viruses for DEL-1 knockdown, and DEL-1-Fc fusion proteins were administered to cells and mice. Additionally, the potential mechanism of DEL-1 in IBD was demonstrated using flow cytometry, RNA-Seq, ChIP, dual-luciferase reporter assays and 16S rRNA.
Results
DEL-1 levels were significantly reduced in IBD patients, colitis mice and macrophages, while the levels increased with inflammation to resolve. Transfection with DEL-1 overexpression plasmid or DEL-1-Fc intervention reduces levels of inflammatory cytokines in both phases and upregulates reparative gene levels in the recovery phase. DEL-1 knockdown inhibits inflammation resolution of colitis. Mechanistically, we demonstrated that DEL-1 inhibits Cmpk2-dependent mtDNA synthesis, thereby inhibiting the cGAS-STING pathway to ameliorate intestinal inflammation. Moreover, DEL-1 promotes reparative macrophage transition in the repair model of colitis. Spi1 was identified as a transcription factor that regulates Cmpk2 and the reparative gene Il10. Intervention with overexpression plasmid of Spi1 or Cmpk2 or the STING agonist DMXAA reverses the effects of DEL-1. In parallel, DEL-1 also inhibits neutrophil recruitment, repairs the intestinal barrier, and improves intestinal microbiota dysbiosis.
Conclusion
We report the first demonstration that DEL-1 significantly ameliorates colonic inflammation in colitis mice. Our findings elucidate a novel mechanism wherein DEL-1 exerts its protective effects by suppressing the Cmpk2-cGAS-STING pathway and promoting reparative macrophage transition. These results collectively position DEL-1 as a promising therapeutic avenue for IBD.
{"title":"Developmentally endothelial locus-1 facilitates intestinal inflammation resolution by suppressing the Cmpk2-cGAS-STING pathway and promoting reparatory macrophage transition","authors":"Meihui Tao, Li Wang, Chaoyue Chen, Mengfan Tang, Yanping Wang, Jingyue Zhang, Xi Zhao, Qinyu Feng, Junfa Chen, Wei Yan, Rong Lin, Yu Fu","doi":"10.1016/j.jare.2025.04.030","DOIUrl":"https://doi.org/10.1016/j.jare.2025.04.030","url":null,"abstract":"<h3>Introduction</h3>Abnormalities in inflammation resolution function are intimately linked to chronic inflammation, and proresolution therapies may offer novel opportunities for IBD treatment. Developmental endothelial locus 1 (DEL-1), a natural modulator of tissue immunity and inflammation resolution, has not been studied in IBD.<h3>Objectives</h3>We aimed to investigate the expression and functions of DEL-1 in IBD.<h3>Methods</h3>Assessment of DEL-1 expression in patients, murine models, and cellular levels. To explore the effects of DEL-1 in the acute and recovery phases of inflammation, overexpression plasmids, adeno-associated viruses for DEL-1 knockdown, and DEL-1-Fc fusion proteins were administered to cells and mice. Additionally, the potential mechanism of DEL-1 in IBD was demonstrated using flow cytometry, RNA-Seq, ChIP, dual-luciferase reporter assays and 16S rRNA.<h3>Results</h3>DEL-1 levels were significantly reduced in IBD patients, colitis mice and macrophages, while the levels increased with inflammation to resolve. Transfection with DEL-1 overexpression plasmid or DEL-1-Fc intervention reduces levels of inflammatory cytokines in both phases and upregulates reparative gene levels in the recovery phase. DEL-1 knockdown inhibits inflammation resolution of colitis. Mechanistically, we demonstrated that DEL-1 inhibits Cmpk2-dependent mtDNA synthesis, thereby inhibiting the cGAS-STING pathway to ameliorate intestinal inflammation. Moreover, DEL-1 promotes reparative macrophage transition in the repair model of colitis. Spi1 was identified as a transcription factor that regulates Cmpk2 and the reparative gene Il10. Intervention with overexpression plasmid of Spi1 or Cmpk2 or the STING agonist DMXAA reverses the effects of DEL-1. In parallel, DEL-1 also inhibits neutrophil recruitment, repairs the intestinal barrier, and improves intestinal microbiota dysbiosis.<h3>Conclusion</h3>We report the first demonstration that DEL-1 significantly ameliorates colonic inflammation in colitis mice. Our findings elucidate a novel mechanism wherein DEL-1 exerts its protective effects by suppressing the Cmpk2-cGAS-STING pathway and promoting reparative macrophage transition. These results collectively position DEL-1 as a promising therapeutic avenue for IBD.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"25 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gastric cancer (GC) is a common malignancy, which is associated with high rates of morbidity and mortality. Despite therapeutic advancements, there is an overall lack of effective treatment options for patients with GC, particularly those with advanced and metastatic disease. The roles of circular (circ)RNAs in tumorigenesis are being increasingly recognized, among which circRNAs are defined as miRNA/protein sponges, scaffolds, or protein coding templates.
Objectives
The aim of the present study is to investigate the functions of circATM in GC and elucidate the underlying molecular mechanism.
Methods
By circRNA sequencing in GC tissues, we identified a novel 526 nt circRNA, circATM, generating from exons 3–6 of the ATM gene. Through circRNA pull-down and RNA immunoprecipitation assays, we identified PARP1 as one of circATM binding proteins. The EdU, colony formation, wound healing, dual-luciferase reporter, cell cycle assays were employed to evaluated circATM functions in vitro. The GC xenograft model was used to determine the role of circATM in vivo.
Results
Knocking down circATM promoted GC cells growth in vivo and in vitro. Meanwhile, the overexpression of circATM increased the levels of p16, p21, and p27, and decreased those of β-catenin and c-Myc. Furthermore, we identified PARP1 as a circATM-interacting partner. Mechanistically, circATM bound to the zinc finger motif of Ⅱ–Ⅲ domains of PARP1 to block its recruitment to sites of DNA damage, triggering cell cycle arrest and sequestering β-catenin from the PARP1/β-catenin/TCF4 complex, leading to the suppression of Wnt/β-catenin signaling. Additionally, circATM facilitated the ubiquitin–proteasome degradation of PARP1, further jeopardizing its ability to mediate DNA damage repair.
Conclusion
Taken together, we defined circATM as a novel gastric tumor suppressor via interacting with PARP1, which indicate that circATM may be a promising biomarker for the diagnosis and therapy of GC.
{"title":"Circular RNA circATM binds PARP1 to suppress Wnt/β-catenin signaling and induce cell cycle arrest in gastric cancer cells","authors":"Xiaohui Zhu, Xiaojing Zhang, Ying Qin, Yang Chen, Xianling Feng, Shiqi Deng, Fan Hu, Yuan Yuan, Xiaonuan Luo, Kaining Du, Shanshan Chang, Xinmin Fan, Hassan Ashktorab, Duane Smoot, Zhe Jin, Yin Peng","doi":"10.1016/j.jare.2025.04.033","DOIUrl":"https://doi.org/10.1016/j.jare.2025.04.033","url":null,"abstract":"<h3>Introduction</h3>Gastric cancer (GC) is a common malignancy, which is associated with high rates of morbidity and mortality. Despite therapeutic advancements, there is an overall lack of effective treatment options for patients with GC, particularly those with advanced and metastatic disease. The roles of circular (circ)RNAs in tumorigenesis are being increasingly recognized, among which circRNAs are defined as miRNA/protein sponges, scaffolds, or protein coding templates.<h3>Objectives</h3>The aim of the present study is to investigate the functions of circATM in GC and elucidate the underlying molecular mechanism.<h3>Methods</h3>By circRNA sequencing in GC tissues, we identified a novel 526 nt circRNA, circATM, generating from exons 3–6 of the <em>ATM</em> gene. Through circRNA pull-down and RNA immunoprecipitation assays, we identified PARP1 as one of circATM binding proteins. The EdU, colony formation, wound healing, dual-luciferase reporter, cell cycle assays were employed to evaluated circATM functions <em>in vitro</em>. The GC xenograft model was used to determine the role of circATM <em>in vivo</em>.<h3>Results</h3>Knocking down circATM promoted GC cells growth <em>in vivo</em> and <em>in vitro</em>. Meanwhile, the overexpression of circATM increased the levels of p16, p21, and p27, and decreased those of β-catenin and c-Myc. Furthermore, we identified PARP1 as a circATM-interacting partner. Mechanistically, circATM bound to the zinc finger motif of Ⅱ–Ⅲ domains of PARP1 to block its recruitment to sites of DNA damage, triggering cell cycle arrest and sequestering β-catenin from the PARP1/β-catenin/TCF4 complex, leading to the suppression of Wnt/β-catenin signaling. Additionally, circATM facilitated the ubiquitin–proteasome degradation of PARP1, further jeopardizing its ability to mediate DNA damage repair.<h3>Conclusion</h3>Taken together, we defined circATM as a novel gastric tumor suppressor via interacting with PARP1, which indicate that circATM may be a promising biomarker for the diagnosis and therapy of GC.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"72 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-24DOI: 10.1016/j.jare.2025.04.015
Maria Dolores Salinas, Carlos M. Martínez, Francisco J. Roca, David García-Bernal, Marta Martínez-Morga, Juan R. Rodríguez-Madoz, Felipe Prósper, Agustín G. Zapata, Jose María Moraleda, Salvador Martínez, Rut Valdor
Introduction
Pericytes (PCs) are mural cells exhibiting some mesenchymal stem cell (MSC) properties and contribute to tissue regeneration after injury. We have previously shown that glioblastoma cancer cells induce in PCs, a pathogenic upregulation of chaperone-mediated autophagy (CMA) which modulates immune functions and MSC-like properties to support tumor growth.
Objectives
The aim of the study was to interrogate the role of CMA-regulated MSC properties in PCs in the context of tissue repair during inflammation triggered by a demyelinating injury.
Methods
Studies of RNA-seq were done PCs with (WT) and without (LAMP-2A KO) CMA. Cell characterization related to stemness, lineage and morphology was done in WT and KO PCs. Secretome analysis and cell differentiation assay using the supernatants from CMA-efficient and deficient PCs cultures was done in mesenchymal cells. Inflammatory response of brain cells was assessed with WT and KO PCs secretome. To corroborate in vitro results, CMA modulation in response to inflammation in PCs and tissue repair markers were measured in the lesion areas of a demyelination mouse model and correlated with the tissue reparation after intravenous PC administration. An inflammatory mediator was used to study effects on PC-CMA activity.
Results
We found that inflammatory mediators such as IFNγ downregulate CMA in PCs, suppressing PC stemness and promoting a pro-inflammatory secretome. Restoration of PC CMA activity during inflammation maintains PC MSC properties and induces an MSC-like proteome which decreases inflammation and promotes tissue repair. We identified secreted proteins involved in regenerative and protective processes, and therefore, necessary to restore brain tissue homeostasis after inflammation induced by a demyelinating injury.
Conclusion
we show that manipulation of CMA activity in host PCs could be a useful therapeutical approach in the context of brain inflammation, which might be extended to other diseases where the pericyte has a key role in response to inflammation.
{"title":"Chaperone-mediated autophagy sustains pericyte stemness necessary for brain tissue homeostasis","authors":"Maria Dolores Salinas, Carlos M. Martínez, Francisco J. Roca, David García-Bernal, Marta Martínez-Morga, Juan R. Rodríguez-Madoz, Felipe Prósper, Agustín G. Zapata, Jose María Moraleda, Salvador Martínez, Rut Valdor","doi":"10.1016/j.jare.2025.04.015","DOIUrl":"https://doi.org/10.1016/j.jare.2025.04.015","url":null,"abstract":"<h3>Introduction</h3>Pericytes (PCs) are mural cells exhibiting some mesenchymal stem cell (MSC) properties and contribute to tissue regeneration after injury. We have previously shown that glioblastoma cancer cells induce in PCs, a pathogenic upregulation of chaperone-mediated autophagy (CMA) which modulates immune functions and MSC-like properties to support tumor growth.<h3>Objectives</h3>The aim of the study was to interrogate the role of CMA-regulated MSC properties in PCs in the context of tissue repair during inflammation triggered by a demyelinating injury.<h3>Methods</h3>Studies of RNA-seq were done PCs with (WT) and without (LAMP-2A KO) CMA. Cell characterization related to stemness, lineage and morphology was done in WT and KO PCs. Secretome analysis and cell differentiation assay using the supernatants from CMA-efficient and deficient PCs cultures was done in mesenchymal cells. Inflammatory response of brain cells was assessed with WT and KO PCs secretome. To corroborate <em>in vitro</em> results, CMA modulation in response to inflammation in PCs and tissue repair markers were measured in the lesion areas of a demyelination mouse model and correlated with the tissue reparation after intravenous PC administration. An inflammatory mediator was used to study effects on PC-CMA activity.<h3>Results</h3>We found that inflammatory mediators such as IFNγ downregulate CMA in PCs, suppressing PC stemness and promoting a pro-inflammatory secretome. Restoration of PC CMA activity during inflammation maintains PC MSC properties and induces an MSC-like proteome which decreases inflammation and promotes tissue repair. We identified secreted proteins involved in regenerative and protective processes, and therefore, necessary to restore brain tissue homeostasis after inflammation induced by a demyelinating injury.<h3>Conclusion</h3>we show that manipulation of CMA activity in host PCs could be a useful therapeutical approach in the context of brain inflammation, which might be extended to other diseases where the pericyte has a key role in response to inflammation.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"14 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-24DOI: 10.1016/j.jare.2025.04.024
YuFan Bu, Chang Zhao, Yewen Qian, Lingxiang Chen, Kaiyuan Zhu, Han Wu, Guoqing Liao, Haosheng Li, Lishuai Mu, Yonghua Que, Deyang Wang, Yuhong Wei, Guangyao Li, Tingli Zhang, Jiangdong Ren, Guangxin Huang, Shu Hu
Introduction
This study explores the role of circPAFAH1B2 in osteoarthritis (OA) by investigating its influence on nuclear-mitochondrial communication, a largely unexplored area in OA progression. By uncovering how circPAFAH1B2 regulates mitochondrial function, the study aims to identify novel therapeutic targets for OA prevention and treatment.
Objectives
This study aimed to identify the regulatory role of circPAFAH1B2 in nuclear-mitochondrial communication within chondrocytes and cartilage homeostasis.
Methods
circPAFAH1B2 expression was determined via quantitative real-time polymerase chain reaction (qRT-PCR) and in situ hybridization. RNA pulldown experiments, proteomic analyses, and RNA immunoprecipitation were conducted to identify the downstream targets of circPAFAH1B2. Gain- and loss-of-function assays were performed to evaluate the regulatory roles of circPAFAH1B2 and the molecular chaperone caseinolytic peptidase B protein homolog (ClpB) in mitochondrial function and chondrocyte homeostasis in cartilage. Cross-linking immunoprecipitation and sequencing were performed to identify binding sites between circPAFAH1B2 and ClpB.
Results
circPAFAH1B2 was upregulated in OA and localized to the cytoplasm of chondrocytes. In vivo and in vitro experiments demonstrated that increased levels of circPAFAH1B2 induced mitochondrial dysfunction and promoted cartilage degeneration. Mechanistic investigations revealed that circPAFAH1B2 bound to and restricted the mitochondrial import of the molecular chaperone ClpB, which disaggregates misfolded mitochondrial proteins, stabilizes mitochondrial homeostasis, and maintains chondrocyte homeostasis. We characterized the binding sites of circPAFAH1B2 and ClpB, and demonstrated that mutation of these sites effectively suppressed circPAFAH1B2-mediated OA phenotypes.
Conclusions
Our findings indicate that circPAFAH1B2 acts as a molecular decoy blocking ClpB mitochondrial translocation, driving mitochondria-dependent cartilage degradation, which may provide novel therapeutic targets for OA.
{"title":"CircPAFAH1B2 induces chondrocytes mitochondrial dysfunction and promotes cartilage degeneration through binding molecular chaperone ClpB","authors":"YuFan Bu, Chang Zhao, Yewen Qian, Lingxiang Chen, Kaiyuan Zhu, Han Wu, Guoqing Liao, Haosheng Li, Lishuai Mu, Yonghua Que, Deyang Wang, Yuhong Wei, Guangyao Li, Tingli Zhang, Jiangdong Ren, Guangxin Huang, Shu Hu","doi":"10.1016/j.jare.2025.04.024","DOIUrl":"https://doi.org/10.1016/j.jare.2025.04.024","url":null,"abstract":"<h3>Introduction</h3>This study explores the role of circPAFAH1B2 in osteoarthritis (OA) by investigating its influence on nuclear-mitochondrial communication, a largely unexplored area in OA progression. By uncovering how circPAFAH1B2 regulates mitochondrial function, the study aims to identify novel therapeutic targets for OA prevention and treatment.<h3>Objectives</h3>This study aimed to identify the regulatory role of circPAFAH1B2 in nuclear-mitochondrial communication within chondrocytes and cartilage homeostasis.<h3>Methods</h3>circPAFAH1B2 expression was determined via quantitative real-time polymerase chain reaction (qRT-PCR) and <em>in situ</em> hybridization. RNA pulldown experiments, proteomic analyses, and RNA immunoprecipitation were conducted to identify the downstream targets of circPAFAH1B2. Gain- and loss-of-function assays were performed to evaluate the regulatory roles of circPAFAH1B2 and the molecular chaperone caseinolytic peptidase B protein homolog (ClpB) in mitochondrial function and chondrocyte homeostasis in cartilage. Cross-linking immunoprecipitation and sequencing were performed to identify binding sites between circPAFAH1B2 and ClpB.<h3>Results</h3>circPAFAH1B2 was upregulated in OA and localized to the cytoplasm of chondrocytes. In vivo and in vitro experiments demonstrated that increased levels of circPAFAH1B2 induced mitochondrial dysfunction and promoted cartilage degeneration. Mechanistic investigations revealed that circPAFAH1B2 bound to and restricted the mitochondrial import of the molecular chaperone ClpB, which disaggregates misfolded mitochondrial proteins, stabilizes mitochondrial homeostasis, and maintains chondrocyte homeostasis. We characterized the binding sites of circPAFAH1B2 and ClpB, and demonstrated that mutation of these sites effectively suppressed circPAFAH1B2-mediated OA phenotypes.<h3>Conclusions</h3>Our findings indicate that circPAFAH1B2 acts as a molecular decoy blocking ClpB mitochondrial translocation, driving mitochondria-dependent cartilage degradation, which may provide novel therapeutic targets for OA.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"37 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Severe combined immunodeficiency (SCID) mini-pigs are a highly versatile model for human disease research and regenerative medicine.
Objectives
This study aims to generate a novel JAK3-deficient mini-pig model with a human-like immune system and to elucidate how JAK3 plays an important role in immune system.
Methods
JAK3 and RAG2 knockout (KO) mini-pigs were generated using CRISPR/Cas9 and somatic cell nuclear transfer. These mini-pigs were transferred to a sterilized isolator within a specific pathogen-free facility. Phenotypic characteristics and clinical manifestations were analyzed through histological and hematological analysis of SCID mini-pigs to explore the unique role of JAK3 in immune functions.
Results
JAK3 KO was characterized by defects in T and NK cells, very low levels of B cells, and a complete absence of thymus and lymph nodes. Notably, JAK3 KO mini-pigs had significantly reduced numbers of monocytes in peripheral blood, macrophages in tissue, and inflammatory cytokines, suggesting that JAK3 KO can induce a broad immunodeficiency that extends to the myeloid system as well as the lymphoid. Moreover, JAK3 KO mini-pigs had intestinal abnormalities similar to those of patients.
Conclusion
These results suggest that JAK3 KO mini-pigs can be used as an effective model for the development of therapies for SCID patients, as well as for regenerative medicine applications such as the development of patient-specific artificial organs.
引言严重联合免疫缺陷（SCID）迷你猪是一种用途广泛的人类疾病研究和再生医学模型。研究目的本研究旨在产生一种具有类人免疫系统的新型 JAK3 缺陷迷你猪模型，并阐明 JAK3 如何在免疫系统中发挥重要作用。这些迷你猪被转移到特定无病原体设施内的消毒隔离器中。结果JAK3 KO的特征是T细胞和NK细胞缺陷、B细胞水平极低以及胸腺和淋巴结完全缺失。值得注意的是，JAK3 KO 小猪外周血中的单核细胞、组织中的巨噬细胞和炎症细胞因子的数量显著减少，这表明 JAK3 KO 可诱导广泛的免疫缺陷，并延伸到骨髓系统和淋巴系统。这些结果表明，JAK3 KO 小猪可作为一种有效的模型，用于开发 SCID 患者的疗法，以及再生医学应用，如开发患者特异性人工器官。
{"title":"JAK3-deficient mimi-pigs exhibit impaired lymphoid organogenesis, intestinal structure, and leukocyte/cytokine production","authors":"Pil-Soo Jeong, Hae-Jun Yang, Young-Ho Park, Yeung Bae Jin, Bong-Seok Song, Jung Joo Hong, Seung Hwan Lee, Jong-Hee Lee, Kyung Seob Lim, Kang-Jin Jeong, Philyong Kang, Hwal-Yong Lee, Hee-Chang Son, Han-Na Kim, Seung-Min Ha, Eun-Ha Hwang, Jae-Jin Cha, Yena Jung, Seon-A Choi, Sanghoon Lee, Sun-Uk Kim","doi":"10.1016/j.jare.2025.04.036","DOIUrl":"https://doi.org/10.1016/j.jare.2025.04.036","url":null,"abstract":"<h3>Introduction</h3>Severe combined immunodeficiency (SCID) mini-pigs are a highly versatile model for human disease research and regenerative medicine.<h3>Objectives</h3>This study aims to generate a novel <em>JAK3</em>-deficient mini-pig model with a human-like immune system and to elucidate how JAK3 plays an important role in immune system.<h3>Methods</h3><em>JAK3</em> and <em>RAG2</em> knockout (KO) mini-pigs were generated using CRISPR/Cas9 and somatic cell nuclear transfer. These mini-pigs were transferred to a sterilized isolator within a specific pathogen-free facility. Phenotypic characteristics and clinical manifestations were analyzed through histological and hematological analysis of SCID mini-pigs to explore the unique role of JAK3 in immune functions.<h3>Results</h3><em>JAK3</em> KO was characterized by defects in T and NK cells, very low levels of B cells, and a complete absence of thymus and lymph nodes. Notably, <em>JAK3</em> KO mini-pigs had significantly reduced numbers of monocytes in peripheral blood, macrophages in tissue, and inflammatory cytokines, suggesting that <em>JAK3</em> KO can induce a broad immunodeficiency that extends to the myeloid system as well as the lymphoid. Moreover, <em>JAK3</em> KO mini-pigs had intestinal abnormalities similar to those of patients.<h3>Conclusion</h3>These results suggest that <em>JAK3</em> KO mini-pigs can be used as an effective model for the development of therapies for SCID patients, as well as for regenerative medicine applications such as the development of patient-specific artificial organs.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"3 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-22DOI: 10.1016/j.jare.2025.04.027
Pyeong Geun Choi, Hee Soo Kim, So-Hyun Park, Hyo-Deok Seo, Jeong-Hoon Hahm, Yang Hoon Huh, Tail-Il Jeon, Jiyun Ahn, Chang Hwa Jung
Introduction
Frailty is characterized by an increased vulnerability to disease and physical debilitation due to a decline in the body’s capacity to maintain homeostasis during aging. Therefore, effective management of frailty is crucial for promoting health. Although the role of niclosamide (NIC), an autophagy promoter, has been studied for the treatment of cancer, infectious diseases, and metabolic disorders, no research has focused on its effects on aging.
Objectives
In this study, we aimed to evaluate the effects of NIC on the aging process and assess its potential as a novel anti-aging therapeutic agent.
Methods
We evaluated the effects of NIC on frailty, physical function, and metabolic function using Caenorhabditis elegans (C. elegans) and aging mouse models. NIC effectiveness was assessed using behavioral experiments, histological analysis, and molecular biological analysis.
Results
We identified NIC as a compound that enhanced exercise capacity and metabolism, thereby alleviating frailty. Briefly, NIC extended the lifespan and improved frailty-related phenotypes in C. elegans, and effectively ameliorated frailty in aging mice, particularly in muscle aging. Additionally, NIC treatment suppressed the muscle atrophy-related ubiquitin–proteasome system induced by mammalian target of rapamycin complex 1 (mTORC1) hyperactivation, while enhancing autophagic flux, another aspect of proteostasis. Furthermore, mRNA-seq analysis revealed that NIC improved metabolism-related functions.
Conclusion
Collectively, these findings suggest that NIC is a promising novel candidate for the prevention of frailty.
{"title":"Niclosamide extends health span and reduces frailty by ameliorating mTORC1 hyperactivation in aging models","authors":"Pyeong Geun Choi, Hee Soo Kim, So-Hyun Park, Hyo-Deok Seo, Jeong-Hoon Hahm, Yang Hoon Huh, Tail-Il Jeon, Jiyun Ahn, Chang Hwa Jung","doi":"10.1016/j.jare.2025.04.027","DOIUrl":"https://doi.org/10.1016/j.jare.2025.04.027","url":null,"abstract":"<h3>Introduction</h3>Frailty is characterized by an increased vulnerability to disease and physical debilitation due to a decline in the body’s capacity to maintain homeostasis during aging. Therefore, effective management of frailty is crucial for promoting health. Although the role of niclosamide (NIC), an autophagy promoter, has been studied for the treatment of cancer, infectious diseases, and metabolic disorders, no research has focused on its effects on aging.<h3>Objectives</h3>In this study, we aimed to evaluate the effects of NIC on the aging process and assess its potential as a novel anti-aging therapeutic agent.<h3>Methods</h3>We evaluated the effects of NIC on frailty, physical function, and metabolic function using <em>Caenorhabditis elegans</em> (<em>C. elegans</em>) and aging mouse models. NIC effectiveness was assessed using behavioral experiments, histological analysis, and molecular biological analysis.<h3>Results</h3>We identified NIC as a compound that enhanced exercise capacity and metabolism, thereby alleviating frailty. Briefly, NIC extended the lifespan and improved frailty-related phenotypes in <em>C. elegans</em>, and effectively ameliorated frailty in aging mice, particularly in muscle aging. Additionally, NIC treatment suppressed the muscle atrophy-related ubiquitin–proteasome system induced by mammalian target of rapamycin complex 1 (mTORC1) hyperactivation, while enhancing autophagic flux, another aspect of proteostasis. Furthermore, mRNA-seq analysis revealed that NIC improved metabolism-related functions.<h3>Conclusion</h3>Collectively, these findings suggest that NIC is a promising novel candidate for the prevention of frailty.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"13 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
G-protein-coupled bile acid receptor (TGR5) is a member of G-protein-coupled receptor (GPCR) superfamily that participates in regulating macrophage polarization and resolving inflammatory diseases. Sauchinone is Saururus chinensis derived natural product with anti-inflammatory activity. Still, whether Sauchinone could regulate macrophage polarization and its direct target remain to explore.
Objectives
This study aims to demonstrate the direct target of Sauchinone, its influences on macrophage polarization and its pharmacological actions on imiquimod (IMQ) induced mouse psoriasis model.
Methods
We detected the TGR5 agonistic activity of Sauchinone in mouse/human TGR5/ cAMP response elements (CRE)/HEK293 stable cell lines and verified its direct effect on mouse/human macrophages by Cellular thermal shift assay (CETSA) and by examining downstream CREB phosphorylation. Afterwards, we discovered the activity of Sauchinone on regulating macrophage M1/M2 polarization in Bone marrow-derived macrophages (BMDM) by detecting M1/M2 markers through Enzyme-linked immunosorbent assay (ELISA), Real-time polymerase chain reaction (RT-qPCR), Western blot and Fluorescence-activated cell sorting (FACS). We further utilized macrophages derived from Tgr5-/- mice or introduce TGR5 specific inhibitor, TGR5 si-RNA and PKA inhibitor to determine whether Sauchinone regulate macrophage polarization through TGR5. We then prepared Sauchinone cream formulation to disclose its pharmacological action in IMQ induced mouse psoriasis model and use FACS and immunofluorescence to verified its action on macrophage polarization in psoriatic skin. Moreover, we tested the protective actions of Sauchinone cream in IMQ treated Tgr5-/- mice to verify that Sauchinone alleviated psoriasis in TGR5 dependent manner.
Results
Sauchinone is a novel TGR5 agonist without human/mouse species selectivity. Sauchinone rectified macrophage M1 polarization through activating TGR5. Topical use of Sauchinone cream ameliorates IMQ induced psoriasis and regulates macrophage polarization in psoriatic skins. Sauchinone cream alleviated psoriasis in TGR5 dependent manner.
Conclusion
Our work identified Sauchinone as a novel TGR5 agonist that could ameliorate IMQ induced murine psoriasis by regulating macrophage polarization.
{"title":"A novel TGR5 agonist Sauchinone ameliorates IMQ induced murine psoriasis by regulating macrophage polarization","authors":"Hao-yu Wang, Su-ling Huang, Jing Ren, Li-yan Peng, Lin-rui Chen, Lu-yao Qi, Ke-han Zhu, Chun-lan Feng, Rong Zhou, Yi-pei Gu, Lu Cao, Ying Leng, Qin-shi Zhao, Wei Tang","doi":"10.1016/j.jare.2025.04.034","DOIUrl":"https://doi.org/10.1016/j.jare.2025.04.034","url":null,"abstract":"<h3>Introduction</h3>G-protein-coupled bile acid receptor (TGR5) is a member of G-protein-coupled receptor (GPCR) superfamily that participates in regulating macrophage polarization and resolving inflammatory diseases. Sauchinone is Saururus chinensis derived natural product with anti-inflammatory activity. Still, whether Sauchinone could regulate macrophage polarization and its direct target remain to explore.<h3>Objectives</h3>This study aims to demonstrate the direct target of Sauchinone, its influences on macrophage polarization and its pharmacological actions on imiquimod (IMQ) induced mouse psoriasis model.<h3>Methods</h3>We detected the TGR5 agonistic activity of Sauchinone in mouse/human TGR5/ cAMP response elements (CRE)/HEK293 stable cell lines and verified its direct effect on mouse/human macrophages by Cellular thermal shift assay (CETSA) and by examining downstream CREB phosphorylation. Afterwards, we discovered the activity of Sauchinone on regulating macrophage M1/M2 polarization in Bone marrow-derived macrophages (BMDM) by detecting M1/M2 markers through Enzyme-linked immunosorbent assay (ELISA), Real-time polymerase chain reaction (RT-qPCR), Western blot and Fluorescence-activated cell sorting (FACS). We further utilized macrophages derived from <em>Tgr5</em><sup>-/-</sup> mice or introduce TGR5 specific inhibitor, TGR5 si-RNA and PKA inhibitor to determine whether Sauchinone regulate macrophage polarization through TGR5. We then prepared Sauchinone cream formulation to disclose its pharmacological action in IMQ induced mouse psoriasis model and use FACS and immunofluorescence to verified its action on macrophage polarization in psoriatic skin. Moreover, we tested the protective actions of Sauchinone cream in IMQ treated <em>Tgr5</em><sup>-/-</sup> mice to verify that Sauchinone alleviated psoriasis in TGR5 dependent manner.<h3>Results</h3>Sauchinone is a novel TGR5 agonist without human/mouse species selectivity. Sauchinone rectified macrophage M1 polarization through activating TGR5. Topical use of Sauchinone cream ameliorates IMQ induced psoriasis and regulates macrophage polarization in psoriatic skins. Sauchinone cream alleviated psoriasis in TGR5 dependent manner.<h3>Conclusion</h3>Our work identified Sauchinone as a novel TGR5 agonist that could ameliorate IMQ induced murine psoriasis by regulating macrophage polarization.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"3 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-22DOI: 10.1016/j.jare.2025.04.031
Extrachromosomal DNA (ecDNA) plays an important role in the initiation and progression of cancerous tumors. Although Circle-seq and other genetic tech…
{"title":"A novel CRISPR-Cas9 nickase-mediated rolling circle amplification (CRIRCA) technique for gene identification and quantitative analysis of extrachromosomal DNA","authors":"","doi":"10.1016/j.jare.2025.04.031","DOIUrl":"https://doi.org/10.1016/j.jare.2025.04.031","url":null,"abstract":"Extrachromosomal DNA (ecDNA) plays an important role in the initiation and progression of cancerous tumors. Although Circle-seq and other genetic tech…","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"17 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-22DOI: 10.1016/j.jare.2025.04.035
Xiujuan Wang, Xinshan Zhang, Yuanyuan Liu, Lei Ru, Guochao Yan, Yunmin Xu, Youjian Yu, Zhujun Zhu, Yong He
Introduction
Salicylic acid (SA) is essential for immune response signal transduction in higher plants, with its signaling thought to be enhanced through interactions with reactive oxygen species (ROS). However, the exact mechanisms behind this SA self-amplifying signaling are still not well understood.
Objectives
In this study, we report the involvement of the miR398b-SlCSD1 module in the SA-H2O2 amplifying feedback loop in tomato (Solanum lycopersicum).
Methods
Experiments were conducted using various concentrations of SA to assess its impact on ROS metabolism and the expression of SlCSD1 and sly-miR398. CRISPR/Cas9 was employed to knock out sly-miR398 and SlCSD1. Bioinformatics analyses, dual-luciferase reporter assays (Dual-Luc), and electrophoretic mobility shift assays (EMSA) were used to identify SA-responsive transcription factors and validate their regulation of sly-miR398b. The role of miR398 in endogenous SA synthesis was examined using overexpression and knockout tomato lines.
Results
Low SA concentrations stimulated H2O2 accumulation, increased superoxide dismutase (SOD) activity, and suppressed sly-miR398 expression, effects absent in NahG plants with reduced SA levels. Knockout of SlCSD1 via CRISPR/Cas9 partially inhibited SA-induced H2O2 accumulation, confirming SlCSD1′s role in SA-dependent H2O2 signaling. Furthermore, Dual-Luc and EMSA results revealed that TGACG-sequence-specific binding protein 2 (TGA2) mediated the regulation of miR398-SlCSD1 module by SA in tomato. Additionally, overexpression and mutation of sly-miR398b promoted SA synthesis via the phenylalanine ammonia-lyase (PAL) and isochorismate synthase (ICS) pathways, highlighting its regulatory role in SA biosynthesis.
Conclusion
Taken together, our results shed light on the involvement of the miR398-SlCSD1 module in the SA-H2O2 amplifying feedback loop, providing new insights into SA signaling in tomato. These findings contribute to understanding SA-ROS interactions and offer a potential strategy for enhancing stress tolerance in crops by targeting microRNA-regulated pathways.
引言水杨酸（SA）是高等植物免疫应答信号转导的必需物质，其信号转导被认为是通过与活性氧（ROS）的相互作用而增强的。本研究报告了miR398b-SlCSD1模块参与番茄（Solanum lycopersicum）SA-H2O2放大反馈环路的情况。采用 CRISPR/Cas9 基因敲除 sly-miR398 和 SlCSD1。生物信息学分析、双荧光素酶报告分析（Dual-Luc）和电泳迁移分析（EMSA）被用来鉴定SA反应性转录因子并验证它们对sly-miR398b的调控作用。结果低浓度的SA刺激了H2O2的积累，增加了超氧化物歧化酶（SOD）的活性，抑制了sly-miR398的表达，而在SA水平降低的NahG植株中却没有这些效应。通过 CRISPR/Cas9 敲除 SlCSD1 部分抑制了 SA 诱导的 H2O2 积累，证实了 SlCSD1 在 SA 依赖性 H2O2 信号转导中的作用。此外，Dual-Luc和EMSA结果显示，TGACG序列特异性结合蛋白2（TGA2）介导了SA对miR398-SlCSD1模块的调控。此外，sly-miR398b 的过表达和突变促进了 SA 通过苯丙氨酸氨解酶（PAL）和异樱桃酸合成酶（ICS）途径的合成，突出了其在 SA 生物合成中的调控作用。这些发现有助于理解 SA-ROS 相互作用，并为通过靶向 microRNA 调控途径增强作物抗逆性提供了一种潜在策略。
{"title":"miR398-SlCSD1 module participates in the SA-H2O2 amplifying feedback loop in Solanum lycopersicum","authors":"Xiujuan Wang, Xinshan Zhang, Yuanyuan Liu, Lei Ru, Guochao Yan, Yunmin Xu, Youjian Yu, Zhujun Zhu, Yong He","doi":"10.1016/j.jare.2025.04.035","DOIUrl":"https://doi.org/10.1016/j.jare.2025.04.035","url":null,"abstract":"<h3>Introduction</h3>Salicylic acid (SA) is essential for immune response signal transduction in higher plants, with its signaling thought to be enhanced through interactions with reactive oxygen species (ROS). However, the exact mechanisms behind this SA self-amplifying signaling are still not well understood.<h3>Objectives</h3>In this study, we report the involvement of the miR398b-SlCSD1 module in the SA-H<sub>2</sub>O<sub>2</sub> amplifying feedback loop in tomato (<em>Solanum lycopersicum</em>).<h3>Methods</h3>Experiments were conducted using various concentrations of SA to assess its impact on ROS metabolism and the expression of SlCSD1 and sly-miR398. CRISPR/Cas9 was employed to knock out sly-miR398 and SlCSD1. Bioinformatics analyses, dual-luciferase reporter assays (Dual-Luc), and electrophoretic mobility shift assays (EMSA) were used to identify SA-responsive transcription factors and validate their regulation of sly-miR398b. The role of miR398 in endogenous SA synthesis was examined using overexpression and knockout tomato lines.<h3>Results</h3>Low SA concentrations stimulated H<sub>2</sub>O<sub>2</sub> accumulation, increased superoxide dismutase (SOD) activity, and suppressed sly-miR398 expression, effects absent in NahG plants with reduced SA levels. Knockout of SlCSD1 via CRISPR/Cas9 partially inhibited SA-induced H<sub>2</sub>O<sub>2</sub> accumulation, confirming SlCSD1′s role in SA-dependent H<sub>2</sub>O<sub>2</sub> signaling. Furthermore, Dual-Luc and EMSA results revealed that TGACG-sequence-specific binding protein 2 (TGA2) mediated the regulation of miR398-SlCSD1 module by SA in tomato. Additionally, overexpression and mutation of sly-miR398b promoted SA synthesis via the phenylalanine ammonia-lyase (PAL) and isochorismate synthase (ICS) pathways, highlighting its regulatory role in SA biosynthesis.<h3>Conclusion</h3>Taken together, our results shed light on the involvement of the miR398-SlCSD1 module in the SA-H<sub>2</sub>O<sub>2</sub> amplifying feedback loop, providing new insights into SA signaling in tomato. These findings contribute to understanding SA-ROS interactions and offer a potential strategy for enhancing stress tolerance in crops by targeting microRNA-regulated pathways.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"6 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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