Zhen Qin, Jinhong Chen, Fang Liu, Bingbing Li, Chenchen Zhang, Xiuxiu Wang, Lin Liu, Mingke Wang, Tingfang Wang, Su Wang, Feifei Yu, Shifeng Wang, Jishun Yang
Jellyfish stings have become a common injury among fishermen and divers. Severe jellyfish stings could worsen cardiac function and even cause cardiac complications, ultimately leading to cardiac failure (CF). Currently, there are no effective drugs available. Single cell sequencing revealed alpha‐1 acid glycoprotein (AAG), an energy regulatory protein targeting to glycogen, was highly expressed in jellyfish stings‐induced CF patients. However, the mechanism remains elusive. It is postulated that AAG could increase glycogen metabolism, protecting against jellyfish stings‐induced CF. AAG deletion exacerbated CF, while exogenous and endogenous AAG ameliorated CF. AAG also rescued the decline triggered by the AAG knockout (KO). Intriguingly, AAG improved cardiac function and metabolic adaptation by glycogen‐driven ATP production, shifting mitochondrial/glycolytic ATP production towards glycolysis. Sorted by single‐cell RNA sequencing and spatial transcription technology, CC‐chemokine receptor 5 (CCR5) and Peroxisome proliferator‐activated receptor‐gamma coactivator‐1alpha (PGC‐1α) were differentially expressed. Mechanistically, CCR5 inhibitor MVC abolished AAG's protective effect and PGC‐1α overexpression. Collectively, jellyfish stings‐induced CF was ameliorated through AAG‐mediated glycogen‐driven ATP production, promoting glycolytic/mitochondrial metabolic switches to rely energetically primarily on glycolysis, which might serve as a therapeutic target of CF.
{"title":"Jellyfish stings‐induced cardiac failure was ameliorated through AAG‐mediated glycogen‐driven ATP production","authors":"Zhen Qin, Jinhong Chen, Fang Liu, Bingbing Li, Chenchen Zhang, Xiuxiu Wang, Lin Liu, Mingke Wang, Tingfang Wang, Su Wang, Feifei Yu, Shifeng Wang, Jishun Yang","doi":"10.1002/exp.20230089","DOIUrl":"https://doi.org/10.1002/exp.20230089","url":null,"abstract":"Jellyfish stings have become a common injury among fishermen and divers. Severe jellyfish stings could worsen cardiac function and even cause cardiac complications, ultimately leading to cardiac failure (CF). Currently, there are no effective drugs available. Single cell sequencing revealed alpha‐1 acid glycoprotein (AAG), an energy regulatory protein targeting to glycogen, was highly expressed in jellyfish stings‐induced CF patients. However, the mechanism remains elusive. It is postulated that AAG could increase glycogen metabolism, protecting against jellyfish stings‐induced CF. AAG deletion exacerbated CF, while exogenous and endogenous AAG ameliorated CF. AAG also rescued the decline triggered by the AAG knockout (KO). Intriguingly, AAG improved cardiac function and metabolic adaptation by glycogen‐driven ATP production, shifting mitochondrial/glycolytic ATP production towards glycolysis. Sorted by single‐cell RNA sequencing and spatial transcription technology, CC‐chemokine receptor 5 (CCR5) and Peroxisome proliferator‐activated receptor‐gamma coactivator‐1alpha (PGC‐1α) were differentially expressed. Mechanistically, CCR5 inhibitor MVC abolished AAG's protective effect and PGC‐1α overexpression. Collectively, jellyfish stings‐induced CF was ameliorated through AAG‐mediated glycogen‐driven ATP production, promoting glycolytic/mitochondrial metabolic switches to rely energetically primarily on glycolysis, which might serve as a therapeutic target of CF.","PeriodicalId":503118,"journal":{"name":"Exploration","volume":"1044 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140445949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Junjie Tang, Yadong Liu, Yifan Xue, Zhaozhong Jiang, Baizhu Chen, Jie Liu
Prodrug‐based self‐assembled nanoparticles (PSNs) with tailored responses to tumor microenvironments show a significant promise for chemodynamic therapy (CDT) by generating highly toxic reactive oxygen species (ROS). However, the insufficient level of intracellular ROS and the limited drug accumulation remain major challenges for further clinical transformation. In this study, the PSNs for the delivery of artesunate (ARS) are demonstrated by designing the pH‐responsive ARS‐4‐hydroxybenzoyl hydrazide (HBZ)‐5‐amino levulinic acid (ALA) nanoparticles (AHA NPs) with self‐supplied ROS for excellent chemotherapy and CDT. The PSNs greatly improved the loading capacity of artesunate and the ROS generation from endoperoxide bridge using the electron withdrawing group attached directly to C10 site of artesunate. The ALA and ARS‐HBZ could be released from AHA NPs under the cleavage of hydrazone bonds triggered by the acidic surroundings. Besides, the ALA increased the intracellular level of heme in mitochondria, further promoting the ROS generation and lipid peroxidation with ARS‐HBZ for excellent anti‐tumor effects. Our study improved the chemotherapy of ARS through the chemical modification, pointing out the potential applications in the clinical fields.
{"title":"Endoperoxide‐enhanced self‐assembled ROS producer as intracellular prodrugs for tumor chemotherapy and chemodynamic therapy","authors":"Junjie Tang, Yadong Liu, Yifan Xue, Zhaozhong Jiang, Baizhu Chen, Jie Liu","doi":"10.1002/exp.20230127","DOIUrl":"https://doi.org/10.1002/exp.20230127","url":null,"abstract":"Prodrug‐based self‐assembled nanoparticles (PSNs) with tailored responses to tumor microenvironments show a significant promise for chemodynamic therapy (CDT) by generating highly toxic reactive oxygen species (ROS). However, the insufficient level of intracellular ROS and the limited drug accumulation remain major challenges for further clinical transformation. In this study, the PSNs for the delivery of artesunate (ARS) are demonstrated by designing the pH‐responsive ARS‐4‐hydroxybenzoyl hydrazide (HBZ)‐5‐amino levulinic acid (ALA) nanoparticles (AHA NPs) with self‐supplied ROS for excellent chemotherapy and CDT. The PSNs greatly improved the loading capacity of artesunate and the ROS generation from endoperoxide bridge using the electron withdrawing group attached directly to C10 site of artesunate. The ALA and ARS‐HBZ could be released from AHA NPs under the cleavage of hydrazone bonds triggered by the acidic surroundings. Besides, the ALA increased the intracellular level of heme in mitochondria, further promoting the ROS generation and lipid peroxidation with ARS‐HBZ for excellent anti‐tumor effects. Our study improved the chemotherapy of ARS through the chemical modification, pointing out the potential applications in the clinical fields.","PeriodicalId":503118,"journal":{"name":"Exploration","volume":" 15","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139788632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cornea is the major barrier to drug delivery to the eye, which results in low bioavailability and poor efficacy of topical eye treatment. In this work, we first select cornea‐binding aptamers using tissue‐SELEX on pig cornea. The top two abundant aptamers, Cornea‐S1 and Cornea‐S2, could bind to pig cornea, and their Kd values to human corneal epithelial cells (HCECs) were 361 and 174 nм, respectively. Aptamer‐functionalized liposomes loaded with cyclosporine A (CsA) were developed as a treatment for dry eye diseases. The Kd of Cornea‐S1‐ or Cornea‐S2‐functionalized liposomes reduces to 1.2 and 15.1 nм, respectively, due to polyvalent binding. In HCECs, Cornea‐S1 or Cornea‐S2 enhanced liposome uptake within 15 min and extended retention to 24 h. Aptamer CsA liposomes achieved similar anti‐inflammatory and tight junction modulation effects with ten times less CsA than a free drug. In a rabbit dry eye disease model, Cornea‐S1 CsA liposomes demonstrated equivalence in sustaining corneal integrity and tear break‐up time when compared to commercial CsA eye drops while utilizing a lower dosage of CsA. The aptamers obtained from cornea‐SELEX can serve as a general ligand for ocular drug delivery, suggesting a promising avenue for the treatment of various eye diseases and even other diseases.
{"title":"Cornea‐SELEX for aptamers targeting the surface of eyes and liposomal drug delivery","authors":"Ka-Ying Wong, Yibo Liu, Man-Sau Wong, Juewen Liu","doi":"10.1002/exp.20230008","DOIUrl":"https://doi.org/10.1002/exp.20230008","url":null,"abstract":"Cornea is the major barrier to drug delivery to the eye, which results in low bioavailability and poor efficacy of topical eye treatment. In this work, we first select cornea‐binding aptamers using tissue‐SELEX on pig cornea. The top two abundant aptamers, Cornea‐S1 and Cornea‐S2, could bind to pig cornea, and their Kd values to human corneal epithelial cells (HCECs) were 361 and 174 nм, respectively. Aptamer‐functionalized liposomes loaded with cyclosporine A (CsA) were developed as a treatment for dry eye diseases. The Kd of Cornea‐S1‐ or Cornea‐S2‐functionalized liposomes reduces to 1.2 and 15.1 nм, respectively, due to polyvalent binding. In HCECs, Cornea‐S1 or Cornea‐S2 enhanced liposome uptake within 15 min and extended retention to 24 h. Aptamer CsA liposomes achieved similar anti‐inflammatory and tight junction modulation effects with ten times less CsA than a free drug. In a rabbit dry eye disease model, Cornea‐S1 CsA liposomes demonstrated equivalence in sustaining corneal integrity and tear break‐up time when compared to commercial CsA eye drops while utilizing a lower dosage of CsA. The aptamers obtained from cornea‐SELEX can serve as a general ligand for ocular drug delivery, suggesting a promising avenue for the treatment of various eye diseases and even other diseases.","PeriodicalId":503118,"journal":{"name":"Exploration","volume":" 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139789930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Designing a high‐performance cathode is essential for the development of proton‐conducting solid oxide fuel cells (H‐SOFCs), and nanocomposite cathodes have proven to be an effective means of achieving this. However, the mechanism behind the nanocomposite cathodes' remarkable performance remains unknown. Doping the Co element into BaZrO3 can result in the development of BaCoO3 and BaZr0.7Co0.3O3 nanocomposites when the doping concentration exceeds 30%, according to the present study. The construction of the BaCoO3/BaZr0.7Co0.3O3 interface is essential for the enhancement of the cathode catalytic activity, as demonstrated by thin‐film studies using pulsed laser deposition to simulate the interface of the BCO and BZCO individual particles and first‐principles calculations to predict the oxygen reduction reaction steps. Eventually, the H‐SOFC with a BaZr0.4Co0.6O3 cathode produces a record‐breaking power density of 2253 mW cm−2 at 700°C.
{"title":"Unveiling the importance of the interface in nanocomposite cathodes for proton‐conducting solid oxide fuel cells","authors":"Yanru Yin, Yifan Wang, Nan Yang, Lei Bi","doi":"10.1002/exp.20230082","DOIUrl":"https://doi.org/10.1002/exp.20230082","url":null,"abstract":"Designing a high‐performance cathode is essential for the development of proton‐conducting solid oxide fuel cells (H‐SOFCs), and nanocomposite cathodes have proven to be an effective means of achieving this. However, the mechanism behind the nanocomposite cathodes' remarkable performance remains unknown. Doping the Co element into BaZrO3 can result in the development of BaCoO3 and BaZr0.7Co0.3O3 nanocomposites when the doping concentration exceeds 30%, according to the present study. The construction of the BaCoO3/BaZr0.7Co0.3O3 interface is essential for the enhancement of the cathode catalytic activity, as demonstrated by thin‐film studies using pulsed laser deposition to simulate the interface of the BCO and BZCO individual particles and first‐principles calculations to predict the oxygen reduction reaction steps. Eventually, the H‐SOFC with a BaZr0.4Co0.6O3 cathode produces a record‐breaking power density of 2253 mW cm−2 at 700°C.","PeriodicalId":503118,"journal":{"name":"Exploration","volume":"7 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139886935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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