The genetic variants of LMNA cause an array of diseases that often affect the heart. LMNA-related cardiomyopathy exhibits high-penetrance and early-onset phenotypes that lead to late-stage heart failure or lethal arrhythmia. As a subtype of dilated cardiomyopathy and arrhythmogenic cardiomyopathy, LMNA-related cardiac dysfunction is resistant to existing cardiac therapeutic strategies, leaving a major unmet clinical need in cardiomyopathy management.
Aim of Review
Here we comprehensively summarize current knowledge about the genetic basis, disease models and pathological mechanisms of LMNA-related cardiomyopathy. Recent translational studies were highlighted to indicate new therapeutic modalities such as gene supplementation, gene silencing and genome editing therapy, which offer potential opportunities to overcome the difficulties in the development of specific drugs for this disease.
Key Scientific Concepts of Review
LMNA-related cardiomyopathy involves many diverse disease mechanisms that preclude small-molecule drugs that target only a small fraction of the mechanisms. Agreeing to this notion, the first-in-human clinical trial for this disease recently reported futility. By contrast, gene therapy offers the new hope to directly intervene LMNA variants and demonstrates a tremendous potential for breakthrough therapy for this disease. Concepts in this review are also applicable to studies of other genetic diseases that lack effective therapeutics.
{"title":"LMNA-related cardiomyopathy: From molecular pathology to cardiac gene therapy","authors":"Ze Wang, Jiahao Wu, Zhengyuan Lv, Ping Liang, Qirui Li, Yifei Li, Yuxuan Guo","doi":"10.1016/j.jare.2025.01.001","DOIUrl":"https://doi.org/10.1016/j.jare.2025.01.001","url":null,"abstract":"<h3>Background</h3>The genetic variants of <em>LMNA</em> cause an array of diseases that often affect the heart. <em>LMNA</em>-related cardiomyopathy exhibits high-penetrance and early-onset phenotypes that lead to late-stage heart failure or lethal arrhythmia. As a subtype of dilated cardiomyopathy and arrhythmogenic cardiomyopathy, <em>LMNA</em>-related cardiac dysfunction is resistant to existing cardiac therapeutic strategies, leaving a major unmet clinical need in cardiomyopathy management.<h3>Aim of Review</h3>Here we comprehensively summarize current knowledge about the genetic basis, disease models and pathological mechanisms of <em>LMNA</em>-related cardiomyopathy. Recent translational studies were highlighted to indicate new therapeutic modalities such as gene supplementation, gene silencing and genome editing therapy, which offer potential opportunities to overcome the difficulties in the development of specific drugs for this disease.<h3>Key Scientific Concepts of Review</h3><em>LMNA</em>-related cardiomyopathy involves many diverse disease mechanisms that preclude small-molecule drugs that target only a small fraction of the mechanisms. Agreeing to this notion, the first-in-human clinical trial for this disease recently reported futility. By contrast, gene therapy offers the new hope to directly intervene <em>LMNA</em> variants and demonstrates a tremendous potential for breakthrough therapy for this disease. Concepts in this review are also applicable to studies of other genetic diseases that lack effective therapeutics.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"30 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142988154","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 : 2025-01-16DOI: 10.1016/j.jare.2025.01.027
Xiankun Cao, Kexin Liu, Jinbo Yuan, Qi Hua, Kewei Rong, Tangjun Zhou, Wenxin He, Yichuan Pang, Xiao Yang, Yating Yu, Pu Zhang, Peixiang Ma, Yu Cao, Jie Zhao, Grant Morahan, Jiake Xu, An Qin
Introduction
Bone homeostasis between osteoclast bone resorption and osteoblastic bone formation is tightly regulated by a series of factors such as the receptor activator of nuclear factor-κB ligand (RANKL). Denosumab that neutralizes RANKL is effective and widely applied in the treatment of postmenopausal osteoporosis. However, factors that participated in the RANKL-related bone remodeling process in primary and secondary osteoporosis are less known.
Objectives
Revealing the novel transcriptional regulatory mechanism of RANKL is of great significance for the treatment of osteoporosis.
Methods
After differential expression genes (DEGs) intersection and screening, we generated Thioredoxin-interacting protein (Txnip) bone marrow-derived mesenchymal stromal cells (BMSCs) genetic knockout mice and performed bone histomorphometry and histological analysis. RNA-Sequencing, Western blotting and immunofluorescence staining verified Rankl downregulation. Co-immunoprecipitation and immunofluorescence staining were used for Rankl regulation mechanism exploration. A specific inhibitor was selected for treatment effect verification.
Results
Txnip knockout in BMSCs impaired its osteogenic differentiation, suppressed Rankl expression and subsequent osteoclast formation and thus led to increased bone mass. The regulatory function of Txnip on Rankl expression was revealed for the first time through the novel transcription-related Ecdysoneless (Ecd)-P300 axis. Pharmacological inhibition of Txnip can effectively prevent bilateral ovariectomy (OVX)-induced osteoporosis.
Conclusions
Inhibition of Txnip is an alternative way to suppress Rankl-mediated osteoblast and osteoclast crosstalk. This interesting finding rendered Txnip an ideal therapeutic target for the treatment of both ovariectomy-induced and diabetes-induced osteoporosis.
{"title":"Transcriptional regulation of Rankl by Txnip-Ecd in aging and diabetic related osteoporosis","authors":"Xiankun Cao, Kexin Liu, Jinbo Yuan, Qi Hua, Kewei Rong, Tangjun Zhou, Wenxin He, Yichuan Pang, Xiao Yang, Yating Yu, Pu Zhang, Peixiang Ma, Yu Cao, Jie Zhao, Grant Morahan, Jiake Xu, An Qin","doi":"10.1016/j.jare.2025.01.027","DOIUrl":"https://doi.org/10.1016/j.jare.2025.01.027","url":null,"abstract":"<h3>Introduction</h3>Bone homeostasis between osteoclast bone resorption and osteoblastic bone formation is tightly regulated by a series of factors such as the receptor activator of nuclear factor-κB ligand (RANKL). Denosumab that neutralizes RANKL is effective and widely applied in the treatment of postmenopausal osteoporosis. However, factors that participated in the RANKL-related bone remodeling process in primary and secondary osteoporosis are less known.<h3>Objectives</h3>Revealing the novel transcriptional regulatory mechanism of RANKL is of great significance for the treatment of osteoporosis.<h3>Methods</h3>After differential expression genes (DEGs) intersection and screening, we generated Thioredoxin-interacting protein (<em>Txnip</em>) bone marrow-derived mesenchymal stromal cells (BMSCs) genetic knockout mice and performed bone histomorphometry and histological analysis. RNA-Sequencing, Western blotting and immunofluorescence staining verified Rankl downregulation. Co-immunoprecipitation and immunofluorescence staining were used for Rankl regulation mechanism exploration. A specific inhibitor was selected for treatment effect verification.<h3>Results</h3><em>Txnip</em> knockout in BMSCs impaired its osteogenic differentiation, suppressed Rankl expression and subsequent osteoclast formation and thus led to increased bone mass. The regulatory function of Txnip on Rankl expression was revealed for the first time through the novel transcription-related Ecdysoneless (Ecd)-P300 axis. Pharmacological inhibition of Txnip can effectively prevent bilateral ovariectomy (OVX)-induced osteoporosis.<h3>Conclusions</h3>Inhibition of <em>Txnip</em> is an alternative way to suppress Rankl-mediated osteoblast and osteoclast crosstalk. This interesting finding rendered <em>Txnip</em> an ideal therapeutic target for the treatment of both ovariectomy-induced and diabetes-induced osteoporosis.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"9 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142988155","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}
Sweetpotato (Ipomoea batatas (L.) Lam.) is a genetically intricate hexaploid crop. The purple-fleshed variety, enriched with anthocyanin pigments, is an outstanding source for creating high-value functional products. Previous research on anthocyanin biosynthesis has primarily focused on the above-ground plant parts at the transcriptional level. However, the regulatory mechanisms underlying anthocyanin accumulation in underground tuberous roots of sweetpotato remain largely unexplored.
Objectives
This study aimed to elucidate the post-transcriptional and post-translational mechanisms of Ib-miR2111 and its target gene IbKFB in anthocyanin synthesis in sweetpotato.
Methods
Genetic manipulation techniques were used to validate the function of Ib-miR2111 and IbKFB in anthocyanin biosynthesis in sweetpotato. To investigate how IbKFB works, a series of protein interaction assays, including yeast two-hybrid (Y2H), bimolecular fluorescence complementation (BiFC), GST pull-down, co-immunoprecipitation (Co-IP), and ubiquitination, were conducted. Additionally, the impact of anthocyanin extracts from the genetically modified sweetpotato lines on inflammatory cells morphology, cytokine expression, and cell proliferation were evaluated using in vitro assays.
Results
Purple-fleshed sweetpotato (PFSP) lines exhibited elevated Ib-miR2111 expression compared to white-fleshed sweetpotato (WFSP), with an inverse expression pattern in IbKFB. Genetic manipulations, including overexpression, CRISPR/Cas9 knockouts, and targeted mutations, confirmed their critical roles in anthocyanin modulation. Furthermore, IbKFB’s interactions and ubiquitination with phenylalanine ammonia-lyase 1 (IbPAL1) and glyceraldehyde-3-phosphate dehydrogenase 1 (IbGAPCp1) were elucidated, revealing intricate regulatory mechanisms. Enhanced anthocyanin content showed significant effects on inflammatory cell morphology, cytokine expression, and cell proliferation.
Conclusion
This study provides new insights into the regulatory mechanisms of Ib-miR2111 and IbKFB in anthocyanin biosynthesis and suggests potential health benefits of anthocyanin-rich sweetpotatoes.
{"title":"Post-transcriptional and post-translational regulation of anthocyanin biosynthesis in sweetpotato by Ib-miR2111 and IbKFB: Implications for health promotion","authors":"Ruimin Tang, Cailiang Zhao, Jingjian Dong, Xiayu Liu, Lu Chang, Jianghui Li, Haitao Dong, Yuntao Lv, Zhuang Luo, Meiling Wu, Shan Shen, Qianwen Shan, Yuan Li, Qijun Chen, Runzhi Li, Liheng He, Qinghe Cao, Guiliang Tang, Xiaoyun Jia","doi":"10.1016/j.jare.2025.01.023","DOIUrl":"https://doi.org/10.1016/j.jare.2025.01.023","url":null,"abstract":"<h3>Introduction</h3>Sweetpotato (<em>Ipomoea batatas</em> (L.) Lam.) is a genetically intricate hexaploid crop. The purple-fleshed variety, enriched with anthocyanin pigments, is an outstanding source for creating high-value functional products. Previous research on anthocyanin biosynthesis has primarily focused on the above-ground plant parts at the transcriptional level. However, the regulatory mechanisms underlying anthocyanin accumulation in underground tuberous roots of sweetpotato remain largely unexplored.<h3>Objectives</h3>This study aimed to elucidate the post-transcriptional and post-translational mechanisms of Ib-miR2111 and its target gene <em>IbKFB</em> in anthocyanin synthesis in sweetpotato.<h3>Methods</h3>Genetic manipulation techniques were used to validate the function of Ib-miR2111 and IbKFB in anthocyanin biosynthesis in sweetpotato. To investigate how IbKFB works, a series of protein interaction assays, including yeast two-hybrid (Y2H), bimolecular fluorescence complementation (BiFC), GST pull-down, co-immunoprecipitation (Co-IP), and ubiquitination, were conducted. Additionally, the impact of anthocyanin extracts from the genetically modified sweetpotato lines on inflammatory cells morphology, cytokine expression, and cell proliferation were evaluated using <em>in vitro</em> assays.<h3>Results</h3>Purple-fleshed sweetpotato (PFSP) lines exhibited elevated Ib-miR2111 expression compared to white-fleshed sweetpotato (WFSP), with an inverse expression pattern in <em>IbKFB</em>. Genetic manipulations, including overexpression, CRISPR/Cas9 knockouts, and targeted mutations, confirmed their critical roles in anthocyanin modulation. Furthermore, IbKFB’s interactions and ubiquitination with phenylalanine ammonia-lyase 1 (IbPAL1) and glyceraldehyde-3-phosphate dehydrogenase 1 (IbGAPCp1) were elucidated, revealing intricate regulatory mechanisms. Enhanced anthocyanin content showed significant effects on inflammatory cell morphology, cytokine expression, and cell proliferation.<h3>Conclusion</h3>This study provides new insights into the regulatory mechanisms of Ib-miR2111 and <em>IbKFB</em> in anthocyanin biosynthesis and suggests potential health benefits of anthocyanin-rich sweetpotatoes.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"41 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986891","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}
Biomaterial scaffolds are critical for cell cultured meat production. polysaccharide scaffolds lack essential animal cell adhesion receptors, leading to significant challenges in cell proliferation and myogenic differentiation. Thus, enhancing cell adhesion and growth on polysaccharide scaffolds is strongly required to supply the gaps in cell-cultured meat production.
Objectives
This study aims to develop a multifunctional cell-responsive hydrogel scaffold for the in vitro production of myofibers and structured cell cultured meat through a “cell adhesion-proliferation-differentiation” strategy.
Methods
A polydopamine coating was applied to agarose hydrogel scaffolds using a dipping technique. The capability of scaffolds for myofiber preparation was assessed by evaluating cell adhesion, proliferation, and myogenic differentiation. Utilizing isolated porcine skeletal muscle satellite cells (PSMSCs), the feasibility of structured cell cultured pork tissue supported by agarose hydrogel film scaffolds was further investigated through three-dimensional imaging and scanning electron microscopy analysis. The physicochemical properties of the structured cell cultured pork tissue were evaluated through staining and texture analysis.
Results
The incorporation of a polydopamine coating facilitated a remarkable 100 % cell adhesion rate on agarose hydrogel scaffolds, which also demonstrated reusability. The agarose hydrogel scaffolds retained adequate mechanical properties, enabling the adhered cells to proliferate effectively and differentiate into myofiber. Moreover, isolated PSMSCs maintained growth potential on the agarose hydrogel scaffolds, thereby imparting the scaffolds with the ability to generate substantial quantities of multinucleated myofibers. Furthermore, we established a structured cell culture pork meat model, characterized by high-density myofibers and agarose hydrogel film scaffolds, which exhibited the texture and color typical of real pork.
Conclusion
The innovative agarose/polydopamine scaffold functions as a multifunctional platform for cell culture, offering novel avenues for the diversification and scalable production of cultured meat, and promising significant reductions in production costs for cell cultured meat.
{"title":"Versatile platforms of mussel-inspired agarose scaffold for cell cultured meat","authors":"Kaihao You, Lianghua Xie, Jiaxin Li, Qingying Liu, Lenan Zhuang, Wei Chen","doi":"10.1016/j.jare.2025.01.024","DOIUrl":"https://doi.org/10.1016/j.jare.2025.01.024","url":null,"abstract":"<h3>Introduction</h3>Biomaterial scaffolds are critical for cell cultured meat production. polysaccharide scaffolds lack essential animal cell adhesion receptors, leading to significant challenges in cell proliferation and myogenic differentiation. Thus, enhancing cell adhesion and growth on polysaccharide scaffolds is strongly required to supply the gaps in cell-cultured meat production.<h3>Objectives</h3>This study aims to develop a multifunctional cell-responsive hydrogel scaffold for the <em>in vitro</em> production of myofibers and structured cell cultured meat through a “cell adhesion-proliferation-differentiation” strategy.<h3>Methods</h3>A polydopamine coating was applied to agarose hydrogel scaffolds using a dipping technique. The capability of scaffolds for myofiber preparation was assessed by evaluating cell adhesion, proliferation, and myogenic differentiation. Utilizing isolated porcine skeletal muscle satellite cells (PSMSCs), the feasibility of structured cell cultured pork tissue supported by agarose hydrogel film scaffolds was further investigated through three-dimensional imaging and scanning electron microscopy analysis. The physicochemical properties of the structured cell cultured pork tissue were evaluated through staining and texture analysis.<h3>Results</h3>The incorporation of a polydopamine coating facilitated a remarkable 100 % cell adhesion rate on agarose hydrogel scaffolds, which also demonstrated reusability. The agarose hydrogel scaffolds retained adequate mechanical properties, enabling the adhered cells to proliferate effectively and differentiate into myofiber. Moreover, isolated PSMSCs maintained growth potential on the agarose hydrogel scaffolds, thereby imparting the scaffolds with the ability to generate substantial quantities of multinucleated myofibers. Furthermore, we established a structured cell culture pork meat model, characterized by high-density myofibers and agarose hydrogel film scaffolds, which exhibited the texture and color typical of real pork.<h3>Conclusion</h3>The innovative agarose/polydopamine scaffold functions as a multifunctional platform for cell culture, offering novel avenues for the diversification and scalable production of cultured meat, and promising significant reductions in production costs for cell cultured meat.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"4 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986894","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 : 2025-01-13DOI: 10.1016/j.jare.2025.01.002
Lili Qiu, David M. Frazer, Mengxiao Hu, Rui Song, Xiaoxue Liu, Xiyu Qin, Jie Ma, Jun Zhou, Zidi Tan, Fazheng Ren, Xiaoyu Wang, James F. Collins
Background
Iron plays a crucial role through various life stages of human. Iron homeostasis is primarily regulated by iron absorption which is mediated via divalent metal-ion transporter 1 (DMT1), and iron export protein ferroportin (FPN), as there is no active pathway for iron excretion from the body. Recent studies have shown that the magnitude of iron absorption changes through various life stages to meet changing iron requirements.
Aim of review
This review aims to provide an overview of recent researches on the regulation of iron absorption throughout mammalian life cycle, with the potential to reveal novel molecules and pathways at special stage of life. Such insights may pave the way for new treatments for disorders associated with aberrant iron homeostasis in the future.
Key scientific concepts of review
This review first summarize the mechanism and regulation of iron absorption throughout various life stages, highlighting that regulatory mechanisms have developed to precisely align iron absorption to iron requirements. In adults, iron absorption is enhanced when body is deficient of iron, conversely, iron absorption is reduced when iron demand decreases via systemic regulator Hepcidin and cellular regulation. In the elderly, age-related inflammation, hormonal changes, and chronic diseases may affect the production of Hepcidin, affecting iron absorption. In infants, intestinal iron absorption and its regulatory mechanism are different from that in adults and there might be an alternative pathway independent of DMT1 and FPN due to high iron absorption. Unique to the fetus, iron is absorbed from maternal stores for its own use through the placenta and is regulated by maternal iron status. This review also proposes directions for further studies, offering promising avenues for developing new treatments for disorders associated with aberrant iron homeostasis.
{"title":"Mechanism and regulation of iron absorption throughout the life cycle","authors":"Lili Qiu, David M. Frazer, Mengxiao Hu, Rui Song, Xiaoxue Liu, Xiyu Qin, Jie Ma, Jun Zhou, Zidi Tan, Fazheng Ren, Xiaoyu Wang, James F. Collins","doi":"10.1016/j.jare.2025.01.002","DOIUrl":"https://doi.org/10.1016/j.jare.2025.01.002","url":null,"abstract":"<h3>Background</h3>Iron plays a crucial role through various life stages of human. Iron homeostasis is primarily regulated by iron absorption which is mediated via divalent metal-ion transporter 1 (DMT1), and iron export protein ferroportin (FPN), as there is no active pathway for iron excretion from the body. Recent studies have shown that the magnitude of iron absorption changes through various life stages to meet changing iron requirements.<h3>Aim of review</h3>This review aims to provide an overview of recent researches on the regulation of iron absorption throughout mammalian life cycle, with the potential to reveal novel molecules and pathways at special stage of life. Such insights may pave the way for new treatments for disorders associated with aberrant iron homeostasis in the future.<h3>Key scientific concepts of review</h3>This review first summarize the mechanism and regulation of iron absorption throughout various life stages, highlighting that regulatory mechanisms have developed to precisely align iron absorption to iron requirements. In adults, iron absorption is enhanced when body is deficient of iron, conversely, iron absorption is reduced when iron demand decreases via systemic regulator Hepcidin and cellular regulation. In the elderly, age-related inflammation, hormonal changes, and chronic diseases may affect the production of Hepcidin, affecting iron absorption. In infants, intestinal iron absorption and its regulatory mechanism are different from that in adults and there might be an alternative pathway independent of DMT1 and FPN due to high iron absorption. Unique to the fetus, iron is absorbed from maternal stores for its own use through the placenta and is regulated by maternal iron status. This review also proposes directions for further studies, offering promising avenues for developing new treatments for disorders associated with aberrant iron homeostasis.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"28 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142974850","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}
In the environment, mycotoxins and fungicides frequently coexist, potentially causing synergistic risks to organisms. Epoxiconazole (EPO) and aflatoxin B1 (AFB1) are a common fungicide and mycotoxins, respectively, which are widely present in the environment and have toxic effects on multiple organs once entering the organism, but it is still unclear whether the co-exposure has a synergistic toxic effect.
Objectives
This study delves into the molecular mechanisms underlying the co-exposure to EPO and AFB1, emphasizing multi-organ toxicity in female zebrafish (F0 generation) and potential transgenerational impacts on the offspring embryos (F1 generation) through multi-omics approaches.
Results
Findings indicate that exposure to either EPO or AFB1, individually or combined, intensified intestinal pathological damage, decreased the expression of tight junction proteins, altered gut microbiota composition, and induced intestinal inflammation, with co-exposure causing more severe effects. RNA-seq analysis revealed an enrichment of ferroptosis and apoptosis pathways in the liver and ovaries of F0 zebrafish. Co-exposure markedly altered the expression of associated molecules, exacerbating pathological damage in these organs. Molecular docking studies revealed that AFB1 exhibited lower binding energies to Caspase3, GPX4 and IL-1β compared to EPO, suggesting that it may have a higher binding capacity. Furthermore, both single and combined exposures modified the expression of molecules related to apoptosis, inflammatory response, and ferroptosis in unexposed F1 embryos, with co-exposure demonstrating more significant biological effects, thereby confirming transgenerational toxicity.
Conclusion
The present study provides preliminary evidence on the potential mechanisms of combined exposure-induced multi-organ toxicity, highlighting ferroptosis of the liver and apoptosis of the ovary as key pathways. These findings provide new perspectives and methods for risk assessment of multiple environmental pollutants.
{"title":"Mechanistic insights into ferroptosis and apoptosis pathways: Synergistic effects of multi-organ toxicity and transgenerational effects induced by co-exposure of epoxiconazole and aflatoxin B1 in zebrafish","authors":"Ruike Wang, Qi Zhang, Gang Chen, Ruirui Kou, Cuiqin Zhang, Yanhua Wang, Jing Wang, Yueqing Huang, Chen Chen","doi":"10.1016/j.jare.2025.01.020","DOIUrl":"https://doi.org/10.1016/j.jare.2025.01.020","url":null,"abstract":"<h3>Introduction</h3>In the environment, mycotoxins and fungicides frequently coexist, potentially causing synergistic risks to organisms. Epoxiconazole (EPO) and aflatoxin B1 (AFB1) are a common fungicide and mycotoxins, respectively, which are widely present in the environment and have toxic effects on multiple organs once entering the organism, but it is still unclear whether the co-exposure has a synergistic toxic effect.<h3>Objectives</h3>This study delves into the molecular mechanisms underlying the co-exposure to EPO and AFB1, emphasizing multi-organ toxicity in female zebrafish (F0 generation) and potential transgenerational impacts on the offspring embryos (F1 generation) through multi-omics approaches.<h3>Results</h3>Findings indicate that exposure to either EPO or AFB1, individually or combined, intensified intestinal pathological damage, decreased the expression of tight junction proteins, altered gut microbiota composition, and induced intestinal inflammation, with co-exposure causing more severe effects. RNA-seq analysis revealed an enrichment of ferroptosis and apoptosis pathways in the liver and ovaries of F0 zebrafish. Co-exposure markedly altered the expression of associated molecules, exacerbating pathological damage in these organs. Molecular docking studies revealed that AFB1 exhibited lower binding energies to Caspase3, GPX4 and IL-1β compared to EPO, suggesting that it may have a higher binding capacity. Furthermore, both single and combined exposures modified the expression of molecules related to apoptosis, inflammatory response, and ferroptosis in unexposed F1 embryos, with co-exposure demonstrating more significant biological effects, thereby confirming transgenerational toxicity.<h3>Conclusion</h3>The present study provides preliminary evidence on the potential mechanisms of combined exposure-induced multi-organ toxicity, highlighting ferroptosis of the liver and apoptosis of the ovary as key pathways. These findings provide new perspectives and methods for risk assessment of multiple environmental pollutants.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"89 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142974868","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 : 2025-01-13DOI: 10.1016/j.jare.2025.01.022
Ping-Shuang Lu, Shao-Chen Sun
Background
Mycotoxin, a secondary metabolite of fungus, found worldwide and concerning in crops and food, causing multiple acute and chronic toxicities. Its toxic profile includes hepatotoxicity, carcinogenicity, teratogenicity, estrogenicity, immunotoxicity, and neurotoxicity, leading to deleterious impact on human and animal health. Emerging evidence suggests that it adversely affects perinatal health, progeny by its ability to cross placental barriers.
Aim of Review
Due to its wide occurrence and potential toxicity on reproductive health, it is essential to understand the mechanisms of mycotoxin-related reproductive toxicity. This review summarizes the toxicities and mechanisms of mycotoxin on maternal and offspring reproduction among mammalian species. Approaches for effective mycotoxin alleviation are also discussed, providing strategies against mycotoxin contamination.
Key Scientific Concepts of Review
The profound mycotoxin toxicities in female mammalian reproduction affect follicle assembly, embryo development, and fetus growth, thereby decreasing offspring fertility. Factors from endocrine system such as hypothalamic-pituitary–gonadal axis and gut-ovarian axis, placenta ABC transporters, organelle and cytoskeleton dynamics, cell cycle control, genomic stability, and redox homeostasis are found to be closely related to mycotoxin toxicities. Approaches from physical, chemical, biological, and supplementation of natural antioxidants are discussed for the mycotoxin elimination, while their applications are not widespread. Available ways for mycotoxin and its toxicities alleviation need further study. Since a species-, time-, and dose-specific response might exist in mycotoxin toxicities, more consideration should be given to the protocols for mycotoxin toxicity studies, such as experimental animal models, exposure duration, and dosage. Specific mechanism for mycotoxin, especially form a molecular biology perspective, could be investigated with multi-omics technologies and advanced imaging techniques. Mass spectrometry with algorithms may provide more accurate exposure assessments, and be further helpful to identify the high-risk individuals in the future.
{"title":"Mycotoxin toxicity and its alleviation strategy on female mammalian reproduction and fertility","authors":"Ping-Shuang Lu, Shao-Chen Sun","doi":"10.1016/j.jare.2025.01.022","DOIUrl":"https://doi.org/10.1016/j.jare.2025.01.022","url":null,"abstract":"<h3>Background</h3>Mycotoxin, a secondary metabolite of fungus, found worldwide and concerning in crops and food, causing multiple acute and chronic toxicities. Its toxic profile includes hepatotoxicity, carcinogenicity, teratogenicity, estrogenicity, immunotoxicity, and neurotoxicity, leading to deleterious impact on human and animal health. Emerging evidence suggests that it adversely affects perinatal health, progeny by its ability to cross placental barriers.<h3>Aim of Review</h3>Due to its wide occurrence and potential toxicity on reproductive health, it is essential to understand the mechanisms of mycotoxin-related reproductive toxicity. This review summarizes the toxicities and mechanisms of mycotoxin on maternal and offspring reproduction among mammalian species. Approaches for effective mycotoxin alleviation are also discussed, providing strategies against mycotoxin contamination.<h3>Key Scientific Concepts of Review</h3>The profound mycotoxin toxicities in female mammalian reproduction affect follicle assembly, embryo development, and fetus growth, thereby decreasing offspring fertility. Factors from endocrine system such as hypothalamic-pituitary–gonadal axis and gut-ovarian axis, placenta ABC transporters, organelle and cytoskeleton dynamics, cell cycle control, genomic stability, and redox homeostasis are found to be closely related to mycotoxin toxicities. Approaches from physical, chemical, biological, and supplementation of natural antioxidants are discussed for the mycotoxin elimination, while their applications are not widespread. Available ways for mycotoxin and its toxicities alleviation need further study. Since a species-, time-, and dose-specific response might exist in mycotoxin toxicities, more consideration should be given to the protocols for mycotoxin toxicity studies, such as experimental animal models, exposure duration, and dosage. Specific mechanism for mycotoxin, especially form a molecular biology perspective, could be investigated with multi-omics technologies and advanced imaging techniques. Mass spectrometry with algorithms may provide more accurate exposure assessments, and be further helpful to identify the high-risk individuals in the future.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"49 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142974849","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}
The acidic microenvironment caused by excessive lactate accumulation could inhibit immune lymphocytes antitumor activity and promote the immune escape of tumor cells. Baicalin is an active flavonoid isolated from Scutellaria baicalensis Georgi, a traditional Chinese medicinal herb with antioxidant and anti-inflammatory properties.
Objectives
The present study aims to investigate whether and how baicalin inhibits oral squamous cell carcinoma (OSCC) acidic microenvironment and attenuates immune escape.
Methods
Baicalin was dose-dependently administrated to OSCC cells (0–50 μmol/L). Co-culture system was constructed by OSCC cells and activated PBMCs. The proliferation and migration of OSCC cells were tested by CCK-8, colony formation, EdU, transwell assays. The cytokines were tested by ELISA kits. Mechanistical exploration was verified by RNA immunoprecipitation (RIP), fluorescence in situ hybridization (FISH) and RNA stability assays.
Results
Results indicated that baicalin dose-dependently repressed the proliferation and migration of OSCC cells, and strengthened the antitumor immune activity of activated PBMCs to OSCC cells. Moreover, baicalin repressed the lactate accumulation, acidification and m6A modification level of OSCC cells. Molecular docking and MeRIP-Seq revealed that baicalin targeted LDHA via m6A-IGF2BP3-dependent manner to reduce lactate accumulation and PD-L1 expression in co-culture microenvironment.
Conclusion
This study revealed the anti-tumor activity of baicalin for OSCC by reducing lactate accumulation and attenuating the immune escape in tumor microenvironment, which provided a novel insight to improve our understanding in the treatment of traditional Chinese medicine on human cancer.
{"title":"Baicalin attenuates the immune escape of oral squamous cell carcinoma by reducing lactate accumulation in tumor microenvironment","authors":"Yameng Cui, Jingwen Liu, Xi Wang, Yulin Wu, Yunhan Chang, Xin Hu, Wei Zhao","doi":"10.1016/j.jare.2025.01.021","DOIUrl":"https://doi.org/10.1016/j.jare.2025.01.021","url":null,"abstract":"<h3>Introduction</h3>The acidic microenvironment caused by excessive lactate accumulation could inhibit immune lymphocytes antitumor activity and promote the immune escape of tumor cells. Baicalin is an active flavonoid isolated from Scutellaria baicalensis Georgi, a traditional Chinese medicinal herb with antioxidant and anti-inflammatory properties.<h3>Objectives</h3>The present study aims to investigate whether and how baicalin inhibits oral squamous cell carcinoma (OSCC) acidic microenvironment and attenuates immune escape.<h3>Methods</h3>Baicalin was dose-dependently administrated to OSCC cells (0–50 μmol/L). Co-culture system was constructed by OSCC cells and activated PBMCs. The proliferation and migration of OSCC cells were tested by CCK-8, colony formation, EdU, transwell assays. The cytokines were tested by ELISA kits. Mechanistical exploration was verified by RNA immunoprecipitation (RIP), fluorescence in situ hybridization (FISH) and RNA stability assays.<h3>Results</h3>Results indicated that baicalin dose-dependently repressed the proliferation and migration of OSCC cells, and strengthened the antitumor immune activity of activated PBMCs to OSCC cells. Moreover, baicalin repressed the lactate accumulation, acidification and m<sup>6</sup>A modification level of OSCC cells. Molecular docking and MeRIP-Seq revealed that baicalin targeted LDHA via m<sup>6</sup>A-IGF2BP3-dependent manner to reduce lactate accumulation and PD-L1 expression in co-culture microenvironment.<h3>Conclusion</h3>This study revealed the anti-tumor activity of baicalin for OSCC by reducing lactate accumulation and attenuating the immune escape in tumor microenvironment, which provided a novel insight to improve our understanding in the treatment of traditional Chinese medicine on human cancer.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"29 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142975194","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}
Dihydropyrimidine dehydrogenase (DPD) is a major determinant of cancer 5-fluorouracyl (5-FU) resistance via its direct degradation. However, the mechanisms of tumoral DPD upregulation have not been fully understood.
Objectives
This study aimed to explore the role of S1PR2 in the regulation of tumoral DPD expression, identifying S1PR2 as the potential target for reversing 5-FU resistance.
Methods
Western blot was used to analyze S1PR2 expression in cultured cancer cells and human colorectal cancer (CRC) tissues. 5-FU resistance was estimated in mouse xenografts of HT-29sh-S1PR2 and SW480S1PR2 cells. HPLC-UV was used to measure 5-FU levels in the xenografts. Chromatin immunoprecipitation (ChIP) was used to analyze the binding of YAP1/TEAD1 to the TWIST1 promoter. A luciferase reporter was used to analyze the binding of TWIST1 to the DPYD promoter.
Results
S1PR2 was highly expressed in cancer cell lines and human CRC tissues. Activation of S1PR2 upregulated DPD expression, leading to 5-FU resistance. Mechanistically, activated S1PR2 upregulated nuclear TWIST1 by activating the Hippo/TEAD1-TWIST1 pathway. Nuclear TWIST1 interacted with the JMJD3-RNA Pol II complex, resulting in the interaction of TWIST1 with the DPYD promoter, thus increasing H3K27me3-enriched DPYD transcription. These findings were confirmed in xenografted human colon cancer cells in nude mice. Transfection with an S1PR2 expression vector led to the upregulation of DPD, blunting the sensitivity of SW480S1PR2 cells to 5-FU by 45.14 %. Conversely, knockdown of S1PR2 resulted in a decrease of DPD, thus increasing the sensitivity of HT-29sh-S1PR2 cells to 5-FU by 62.12 %. Molecular analysis of these xenografts confirmed the role of S1PR2 in upregulating DPD expression by activating the Hippo/TEAD1-JMJD3 pathway.
Conclusions
Activation of S1PR2 upregulated DPD expression by activating the Hippo/TWIST1-JMJD3 pathway. S1PR2 is therefore a potential target for novel inhibitors that may reverse 5-FU resistance in cancer therapy.
{"title":"Activation of sphingosine-1-phosphate receptor 2 (S1PR2) upregulates dihydropyrimidine dehydrogenase (DPD) expression in colon cancer cells","authors":"Zhi-Kun Guo, Xin-Feng Wu, Ming-Yong Tan, Wei-Shi Liang, Yu-Meng Yang, Zhen-Zhen Chu, Rui Xu, Ke-Qin Li, Yu-Yao Cheng, Ying-Zhi Zhang, Yu-Hang Zhang, Yong Hai, Shu-Xiang Cui, Xian-Jun Qu","doi":"10.1016/j.jare.2025.01.006","DOIUrl":"https://doi.org/10.1016/j.jare.2025.01.006","url":null,"abstract":"<h3>Introduction</h3>Dihydropyrimidine dehydrogenase (DPD) is a major determinant of cancer 5-fluorouracyl (5-FU) resistance via its direct degradation. However, the mechanisms of tumoral DPD upregulation have not been fully understood.<h3>Objectives</h3>This study aimed to explore the role of S1PR2 in the regulation of tumoral DPD expression, identifying S1PR2 as the potential target for reversing 5-FU resistance.<h3>Methods</h3>Western blot was used to analyze S1PR2 expression in cultured cancer cells and human colorectal cancer (CRC) tissues. 5-FU resistance was estimated in mouse xenografts of HT-29<sup>sh-S1PR2</sup> and SW480<sup>S1PR2</sup> cells. HPLC-UV was used to measure 5-FU levels in the xenografts. Chromatin immunoprecipitation (ChIP) was used to analyze the binding of YAP1/TEAD1 to the <em>TWIST1</em> promoter. A luciferase reporter was used to analyze the binding of TWIST1 to the <em>DPYD</em> promoter.<h3>Results</h3>S1PR2 was highly expressed in cancer cell lines and human CRC tissues. Activation of S1PR2 upregulated DPD expression, leading to 5-FU resistance. Mechanistically, activated S1PR2 upregulated nuclear TWIST1 by activating the Hippo/TEAD1-TWIST1 pathway. Nuclear TWIST1 interacted with the JMJD3-RNA Pol II complex, resulting in the interaction of TWIST1 with the <em>DPYD</em> promoter, thus increasing H3K27me3-enriched <em>DPYD</em> transcription. These findings were confirmed in xenografted human colon cancer cells in nude mice. Transfection with an S1PR2 expression vector led to the upregulation of DPD, blunting the sensitivity of SW480<sup>S1PR2</sup> cells to 5-FU by 45.14 %. Conversely, knockdown of S1PR2 resulted in a decrease of DPD, thus increasing the sensitivity of HT-29<sup>sh-S1PR2</sup> cells to 5-FU by 62.12 %. Molecular analysis of these xenografts confirmed the role of S1PR2 in upregulating DPD expression by activating the Hippo/TEAD1-JMJD3 pathway.<h3>Conclusions</h3>Activation of S1PR2 upregulated DPD expression by activating the Hippo/TWIST1-JMJD3 pathway. S1PR2 is therefore a potential target for novel inhibitors that may reverse 5-FU resistance in cancer therapy.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"4 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142974863","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 : 2025-01-12DOI: 10.1016/j.jare.2025.01.017
Zhongnan Lin, Yining Xu, Hongyi Jiang, Wen Zeng, Yuhan Wang, Liang Zhu, Chihao Lin, Chao Lou, Hanting Shen, Han Ye, Yean Gu, Huachen Yu, Xiaoyun Pan, Lin Zheng
Introduction
Cyclin-Dependent Kinase 8 (CDK8), a CDK family member, regulates the development of inflammatory processes through transcriptional activation. The involvement of CDK8 in osteoarthritis (OA) progression is not yet understood.
Objectives
This study aims to investigate whether CDK8, through its transcriptional regulatory functions, collaborates with NF-κB in chondrocytes to regulate the transcription of senescence-associated secretory phenotype (SASP) genes, thereby exacerbating the inflammatory microenvironment in the progression of osteoarthritis (OA), and to explore the specific mechanisms involved.
Methods
The effects of CDK8 silencing or overexpression will be assessed by measuring OA pathological markers through H&E staining, immunoblotting, Western blot, qRT-PCR, immunofluorescence and ELISA. The DMM surgery mouse model will be used as the OA model, and the PAM and Von Frey tests will be employed to measure the pain threshold in mice. Luciferase and ChIP assays will be conducted to explore the transcriptional regulation and elongation mechanisms of CDK8.
Result
CDK8 influences OA advancement by being recruited to the SASP promoter region in cooperation with NF-κB, leading to the elongation phosphorylation of Rpb1 CTD within the context of NF-κB-induced gene specificity, thereby regulating SASP transcription. The SASP secreted by chondrocytes during this process promotes the inflammatory microenvironment in the joint and drives macrophage differentiation into osteoclasts, further worsening the severity of osteoarthritis.
Conclusion
The SASP secreted by chondrocytes during the OA process plays a crucial role in worsening the severity of the disease. Inhibiting CDK8 expression can decrease its secretion by downregulating the transcription levels of SASP, which are co-regulated by CDK8 and NF-κB. This could offer a new target for osteoarthritis treatment.
{"title":"CDK8 mediated inflammatory microenvironment aggravates osteoarthritis progression","authors":"Zhongnan Lin, Yining Xu, Hongyi Jiang, Wen Zeng, Yuhan Wang, Liang Zhu, Chihao Lin, Chao Lou, Hanting Shen, Han Ye, Yean Gu, Huachen Yu, Xiaoyun Pan, Lin Zheng","doi":"10.1016/j.jare.2025.01.017","DOIUrl":"https://doi.org/10.1016/j.jare.2025.01.017","url":null,"abstract":"<h3>Introduction</h3>Cyclin-Dependent Kinase 8 (CDK8), a CDK family member, regulates the development of inflammatory processes through transcriptional activation. The involvement of CDK8 in osteoarthritis (OA) progression is not yet understood.<h3>Objectives</h3>This study aims to investigate whether CDK8, through its transcriptional regulatory functions, collaborates with NF-κB in chondrocytes to regulate the transcription of senescence-associated secretory phenotype (SASP) genes, thereby exacerbating the inflammatory microenvironment in the progression of osteoarthritis (OA), and to explore the specific mechanisms involved.<h3>Methods</h3>The effects of CDK8 silencing or overexpression will be assessed by measuring OA pathological markers through H&E staining, immunoblotting, Western blot, qRT-PCR, immunofluorescence and ELISA. The DMM surgery mouse model will be used as the OA model, and the PAM and Von Frey tests will be employed to measure the pain threshold in mice. Luciferase and ChIP assays will be conducted to explore the transcriptional regulation and elongation mechanisms of CDK8.<h3>Result</h3>CDK8 influences OA advancement by being recruited to the SASP promoter region in cooperation with NF-κB, leading to the elongation phosphorylation of Rpb1 CTD within the context of NF-κB-induced gene specificity, thereby regulating SASP transcription. The SASP secreted by chondrocytes during this process promotes the inflammatory microenvironment in the joint and drives macrophage differentiation into osteoclasts, further worsening the severity of osteoarthritis.<h3>Conclusion</h3>The SASP secreted by chondrocytes during the OA process plays a crucial role in worsening the severity of the disease. Inhibiting CDK8 expression can decrease its secretion by downregulating the transcription levels of SASP, which are co-regulated by CDK8 and NF-κB. This could offer a new target for osteoarthritis treatment.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"13 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968314","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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