Journal of Advanced Research最新文献

{"title":"Advances in high-throughput drug screening based on pharmacotranscriptomics","authors":"Liansheng Qiao, Xiaoqian Huo, Wenting Huang, Zewen Wang, Yue Ren, Yanxia Liu, Qun Li, Yanling Zhang","doi":"10.1016/j.jare.2025.09.006","DOIUrl":"https://doi.org/10.1016/j.jare.2025.09.006","url":null,"abstract":"<h3>Background</h3>Drug screening constitutes the predominant paradigm for novel drug discovery. With the development of omics, drug screening has gradually developed into pharmacotranscriptomics-based drug screening (PTDS), which is different from target-based and phenotype-based drug screening. PTDS is a rapidly evolving interdisciplinary field that concurrently demands overcoming large-scale pharmacotranscriptomics profiling and computational challenges inherent to high-dimensional feature data.Aim of review: This review aims to summarize the developmental trajectory and research advancements in PTDS, with a focus on large-scale pharmacotranscriptomics profiling and artificial intelligence-driven data mining. It elucidates the appropriate application fields of PTDS in comparison to traditional drug screening paradigms, thereby providing novel perspectives for the technological evolution and implementation of PTDS.Key scientific concepts of review: PTDS can detect gene expression changes following drug perturbation in cells on a large scale and analyze the efficacy of drug-regulated gene sets, signaling pathways, and even complex diseases by combining artificial intelligence. The technical evolution of PTDS is systematically summarized, encompassing advancements in high-throughput PTDS detection technologies and data analysis methods. PTDS is categorized into microarray, targeted transcriptomics, and RNA-seq. Data analysis of PTDS involves ranking, unsupervised learning, and supervised learning algorithms. All these methods remain active in research and industry, coexisting to address evolving drug screening needs. On this basis, the roles of PTDS in promoting pathway-based drug screening strategies are deeply explored for drug discovery and drug combination design. Meanwhile, we also focus on the application of PTDS in screening and mechanism analysis of traditional Chinese medicine (TCM), which reflects that PTDS is suitable for detecting the complex efficacy of drugs, especially TCM. PTDS is an important development direction for high-throughput screening. By combining with artificial intelligence, PTDS will greatly revolutionize our understanding of drug screening and promote new drug research and development.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"43 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145043606","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}

{"title":"Tirzepatide retention in iWAT with mesoporous polydopamine encapsulation enhances weight loss through leptin receptor signaling","authors":"Lin Mi, Tan Li, Xiaoxin Xiang, Yimin Zhou, Na Xiong, Yanyu Chen, Jiaoting Chen, Sijia Shang, Shumeng Chen, Wai W. Cheung, Zecong Xiao, Yanming Chen, Jiahai Wang, Jun Peng, Xintao Shuai, Guojun Shi","doi":"10.1016/j.jare.2025.09.009","DOIUrl":"https://doi.org/10.1016/j.jare.2025.09.009","url":null,"abstract":"<h3>Introduction</h3>Tirzepatide (TZP), a dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor agonist, has been showing superior benefits in weight loss and glucose lowering in patients with obesity, while the tissue-specific mechanisms of TZP as well as its side effects remain to be investigated.<h3>Objectives</h3>We aimed to explore whether localized injection of TZP into inguinal white adipose tissue (iWAT) would be as effective as subcutaneous injection for weight loss, in order to understand the local effects and signaling pathways of TZP for precision medicine.<h3>Methods</h3>Mesoporous polydopamine was synthesized and mixed with TZP for encapsulation (MPDA@TZP), followed by characterization of its retention in iWAT after local injection. Both diet-induced obesity (DIO) mice and <em>db/db</em> mice received local injection of TZP, and transcriptomic analysis of iWATs was performed. iWATs were also dissected for <em>ex vivo</em> assays.<h3>Results</h3>MPDA@TZP successfully increased the retention time of TZP in the iWAT of mice and had a more dramatic effect on weight loss and improvement in plasma lipid profiles compared to TZP alone in DIO mice, while showing comparable glucose-lowering efficacy. Transcriptomic analysis indicated that iWAT injection of MPDA@TZP improved leptin resistance, beiging, lipid metabolism, mitochondrial activity and branched-chain amino acid (BCAA) catabolism in iWAT. Leptin receptor deficiency in <em>db/db</em> mice abolished the weight reduction effect of MPDA@TZP via iWAT local injection compared to that in DIO mice, while the glucose-lowering effects were comparable in both <em>db/db</em> and DIO mice.<h3>Conclusion</h3>These findings indicate that the retention of TZP in iWAT via MPDA encapsulation amplified its effect on weight loss in mice through leptin receptor signaling compared with TZP alone, which provides new insights into the tissue-specific mechanism and alternative delivery strategies of TZP for targeting specific WAT tissues.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"23 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145043607","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}

{"title":"Decoding the functional network of circular RNAs encoding proteins in hepatocellular carcinoma: from carcinogenesis to clinical transformation","authors":"Jundan Zheng, Tianle He, Jiaxin Chen, Jixin Zhao, Shuobo Zhang, Zhenguo Yang","doi":"10.1016/j.jare.2025.09.017","DOIUrl":"https://doi.org/10.1016/j.jare.2025.09.017","url":null,"abstract":"<h3>Background</h3>Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy with limited therapeutic options. Circular RNAs (circRNAs) have emerged as key regulators in HCC. They influence oncogenic pathways by acting as microRNA (miRNA) sponges, protein interaction mediators, and exosomal messengers, and their protein-coding potential further boosts their functional importance in cancer progression.<h3>Aim of review</h3>This review aims to evaluate the roles of circRNA-encoded proteins in HCC metastasis, apoptosis, therapy resistance, and metabolic reprogramming. It also discusses the latest detection methods and RNA-based therapeutic strategies.<h3>Key scientific concepts of review</h3>circRNAs-encoded proteins can modulate key cellular processes and serve as promising biomarkers and therapeutic targets. The review integrates findings across cancer types and emphasizes current challenges in delivery, detection sensitivity, and mechanistic elucidation Tackling these issues will be essential for translating circRNA-derived proteins into precision medicine for HCC.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"8 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145043605","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}

{"title":"Mechanism insights into the regulation of the LuxS/AI-2 quorum sensing system on the formation of viable but nonculturable state in biofilm cells of beer-spoilage Lactiplantibacillus plantarum","authors":"Xuchen Li, Guoqing Wei, Wenhui Wang, Hongliang Liu, Qianqian Xin, Zhijian Wang, Pengdong Sun, Ting Ding, Jingyuan Li, Yang Deng","doi":"10.1016/j.jare.2025.09.010","DOIUrl":"https://doi.org/10.1016/j.jare.2025.09.010","url":null,"abstract":"<h3>Introduction</h3>Beer spoilage <em>Lactiplantibacillus plantarum</em> poses a significant challenge in brewing due to biofilm formation and entry into the viable but nonculturable (VBNC) state, evading detection and resisting sterilization. The LuxS/AI-2 quorum sensing (QS) system is implicated in stress adaptation, yet its regulatory role in biofilm-associated VBNC transition remains poorly understood<h3>Objectives</h3>This study aims to elucidate how the <em>luxS</em> gene regulates VBNC-state formation in biofilm-embedded <em>L. plantarum</em> under hop-derived <em>iso</em>-α-acid stress and to identify molecular mechanisms underlying QS-mediated adaptation and resuscitation.<h3>Methods</h3>Wild-type and genetically engineered <em>L. plantarum</em> strains (Δ<em>luxS</em>, <em>luxS</em>-overexpressing) were exposed to <em>iso</em>-α-acids to induce VBNC states. Morphological changes were analyzed via scanning electron microscopy. Temporal <em>luxS</em> expression and AI-2 levels were quantified using qRT-PCR and bioluminescence assays. Multi-omics (transcriptomics, proteomics, ChIP-seq) and phenotypic analyses assessed metabolic reprogramming, gene regulation, and resuscitation dynamics.<h3>Results</h3>Iso-α-acids (27 mg/L) induced complete VBNC transition in biofilms within 12 h, with cells exhibiting reduced volume and surface polymer deposition. <em>luxS</em> expression and AI-2 levels synchronized during induction, peaking at 4 h. Overexpression of <em>luxS</em> accelerated VBNC entry and enhanced resuscitation (&gt;10³ CFU/mL recovery), while Δ<em>luxS</em> impaired both processes. Multi-omics revealed <em>luxS</em> activation of carbohydrate metabolism (e.g., <em>pgmB</em>, <em>rbsUDK</em> operon) and stress-response genes (<em>nrdD</em>, <em>pepc</em>). ChIP-seq confirmed direct LuxS binding to promoter regions of these genes, orchestrating energy homeostasis and oxidative defense via pentose phosphate and ABC transporter pathways.<h3>Conclusion</h3>The LuxS/AI-2 QS system governs biofilm-to-VBNC transition in <em>L. plantarum</em> by modulating metabolic resilience and stress adaptation. These findings provide a molecular framework for targeting QS pathways to mitigate biofilm persistence and spoilage risks in brewing industries.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"59 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145043604","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}

{"title":"Design of strictly orthogonal biosensors for maximizing renewable biofuel overproduction","authors":"Tong Wu, Dongli Yan, Sheng Lin, Ran Zhang, Yuhan Wang, Min Li, Shengzhu Yu, Xiaoyan Ma, Zhenya Chen, Yi-Xin Huo","doi":"10.1016/j.jare.2025.09.015","DOIUrl":"https://doi.org/10.1016/j.jare.2025.09.015","url":null,"abstract":"<h3>Introduction</h3>Transcription factors (TFs) activate transcriptional initiation by binding specific signal molecules (SMs), yet designing TFs to precisely target non-natural SMs remains challenging.<h3>Objectives</h3>Using transcriptional activator BmoR as an example, a machine-learning based model named BT to predict three crucial residue regions (CRRs) was generated. This study aimed to achieve BmoR with strict SM orthogonality (SSO).<h3>Methods</h3>Random forest algorithm was used to generate a model BT that pinpointed crucial residue regions (CRRs). The BmoR-SM complexes in the prediction dataset of Model BT were batch-simulated using a computational pipeline via Discovery Studio. Semi-rational engineering of the residues in the CRRs generated BmoR mutants with strict SM orthogonality (SSO), validated through MicroScale Thermophoresis (MST) affinity assays. The SSO-enabled BmoR-based biosensor was used to screen microbial overproducers for 3-L fed-batch fermentation.<h3>Results</h3>The transcription activation effects of 245 TF-SM complexes were experimentally verified<strong>,</strong> providing the training and test dataset to generate a machine-learning based model BT with 88.5 % accuracy. The binding between 5,700 BmoR mutants and four SMs was simulated by Discovery Studio, generating 22,800 complexes to output BmoR-SM hydrogen bond (BSH) counts. BSH counts combined with supplementary parameters to form a prediction dataset. The CRRs containing totally 36 residues were successfully predicted by Model BT. The CRRs were semi-rational modified to obtain BmoR mutants with SSO. The SSO-enabled BmoR-based biosensor effectively screened a strain yielding 12.6 g/L isopentanol.<h3>Conclusion</h3>By demonstrating the dominant role of the HB in TF-SM interactions and establishing a machine learning-guided framework for TF evolution, this work advances rational design principles for engineering TFs with precise molecular recognition, offering broad applications in synthetic biology and metabolic engineering.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"68 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145043609","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}

{"title":"Epigenetic orchestration of cancer-immune dynamics: mechanisms, technologies, and clinical advancements","authors":"Yuanjun Lu, Shuoshuo Ma, Yau-Tuen Chan, Ya Wu, Yibin Feng, Ning Wang","doi":"10.1016/j.jare.2025.08.057","DOIUrl":"https://doi.org/10.1016/j.jare.2025.08.057","url":null,"abstract":"<h3>Background</h3>Epigenetic dysregulation plays a pivotal role in cancer immune evasion by orchestrating tumour antigen silencing, immune cell dysfunction, and the formation of an immunosuppressive microenvironment. By disrupting successive phases of the cancer–immunity cycle—from antigen presentation to T cell exhaustion—these aberrations facilitate immune escape and tumour progression, highlighting the need for targeted epigenetic intervention.<h3>Aim of review</h3>This review systematically dissects how epigenetic alterations impair anti-tumour immunity at each stage of the CI cycle. It not only integrates fragmented mechanistic evidence but also emphasizes underexplored crosstalk between specific epigenetic regulators and immune cell types. It further highlights emerging technologies—such as single-cell epigenomics, spatial multi-omics, and CRISPR-based screens—that are driving discovery of novel therapeutic targets and refining patient stratification.Key scientific concepts of review.We discuss how epigenetic interventions, alone or in combination with immunotherapies, can reinvigorate immune responses and overcome resistance to current treatments. A particular focus is given to how integrative high-resolution platforms are mapping immunoepigenetic landscapes, enabling mechanism-informed, precision immunotherapy strategies. By bridging epigenetic regulation with translational immuno-oncology, this review outlines a future where epigenetic reprogramming becomes central to overcoming immune evasion in cancer.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"34 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145043608","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}

{"title":"SAMHD1 promotes cardiac repair post myocardial infarction by targeting NR4a1 to regulate macrophage metabolic reprogramming","authors":"Yu-Lan Ma, Hai-Yang Ni, Zhen Guo, Feng-Ming Guo, Ming-Yu Wang, Pan Wang, Yi-Peng Gao, Chun-Yan Kong, Qi-Zhu Tang","doi":"10.1016/j.jare.2025.09.018","DOIUrl":"https://doi.org/10.1016/j.jare.2025.09.018","url":null,"abstract":"<h3>Introduction</h3>Myocardial infarction (MI) is one of the leading causes of high mortality worldwide. Accumulating evidence suggests that macrophages emerge as the predominant immune population within the post-MI cardiac environment, serving as critical modulators that coordinate inflammatory cascades during myocardial repair.<h3>Objectives</h3>The main objective of this study was to explore the effects of sterile alpha motif and HD domain-containing protein 1 (SAMHD1) on myocardial remodeling post-MI and to elucidate its potential mechanism.We used MI mouse model ligation of the left anterior descending coronary artery (LAD) to investigate the role of SAMHD1 in MI. To assess the role of SAMHD1 in MI, we generated both macrophage-specific knockout and overexpression mice. To investigate the mechanisms by which SAMHD1 regulates MI progression, we employed transcriptomics sequencing and nontargeted metabolomics.<h3>Results</h3>SAMHD1 was significantly upregulated in mouse cardiac macrophages on day 3 post-MI and was closely associated with immune responses. We found that SAMHD1 deficiency facilitated myocardial repair. We found that SAMHD1 deficiency confers cardioprotection through metabolic reprogramming mechanisms: increased mitochondrial oxidative phosphorylation capacity coupled with increased production of the anti-inflammatory metabolite itaconic acid and suppression of the pentose phosphate pathway and lactate biosynthesis. We found that these metabolic shifts facilitated macrophage differentiation by promoting a transition toward reparative macrophage populations. Furthermore, SAMHD1 deficiency drives macrophage phenotypic switching through the transcriptional suppression of NR4a1. More importantly, we have shown that SAMHD1 deficiency promotes the interaction between NR4a1 and Pparγ, which facilitates NR4a1 ubiquitination-dependent degradation.<h3>Conclusion</h3>Our study revealed that macrophage-specific SAMHD1 deletion confers post-MI cardioprotection. More importantly, we demonstrated that NR4a1, a downstream target of SAMHD1, mediates the cardioprotective effects of SAMHD1 deficiency post-MI by regulating the remodeling of macrophage energy metabolism to promote the macrophage reparative phenotype.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"24 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145043610","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}

{"title":"Targeting CIRP and IL-6R-mediated microglial inflammation to improve outcomes in intracerebral hemorrhage","authors":"Lisha Ye, Xiaoyan Tang, Fangming Liu, Tianjiao Wei, Ting Xu, Zhenglin Jiang, Lihua Xu, Chao Xiang, Xiaoyu Yuan, Lihua Shen, Jianjun Gu, Qianqian Luo, Guohua Wang","doi":"10.1016/j.jare.2025.09.012","DOIUrl":"https://doi.org/10.1016/j.jare.2025.09.012","url":null,"abstract":"<h3>Introduction</h3>Cold-inducible RNA-binding protein (CIRP) is an emerging inflammatory mediator implicated in neuronal injury following intracerebral hemorrhage (ICH). However, the underlying mechanisms by which CIRP contributes to neuroinflammation remain unclear.<h3>Objectives</h3>To investigate the role of neuron-derived CIRP in activating microglial inflammation via IL-6 receptor (IL-6R) signaling after ICH and to evaluate the therapeutic potential of targeting CIRP and IL-6R using a designed peptide inhibitor.<h3>Methods</h3>Single-cell RNA sequencing was performed to identify key genes and pathways involved in microglial responses post-ICH. A peptide inhibitor, Tat-CIRP-CMA (TCC), was designed to target CIRP and IL-6R and tested in both <em>in vitro</em> (oxygen-glucose deprivation model) and <em>in vivo</em> (rat ICH model) systems. The effects of TCC on neuronal CIRP release, microglial activation, inflammation, and phagocytic function were assessed. A microglia-specific IL-6Rα knockout mouse model was used to further validate the functional relevance of the IL-6R/ signal transducer and activator of transcription 3 (STAT3) pathway. Clinical analysis of human ICH patients evaluated the correlation between peripheral CIRP expression and infarct volume.<h3>Results</h3>Neuron-derived CIRP activates microglia through IL-6R and downstream STAT3 signaling, driving pro-inflammatory responses in ICH. TCC treatment significantly reduced neuronal CIRP release, suppressed microglial activation, and decreased inflammatory cytokine levels. TCC inhibited the IL-6R /STAT3 pathway and enhanced microglial phagocytosis of red blood cells. Microglia-specific IL-6Rα deletion mirrored the anti-inflammatory and neuroprotective effects observed with TCC, reducing hematoma volume and improving sensory and behavioral outcomes. In human ICH patients, elevated peripheral CIRP expression positively correlated with infarct volume, supporting its value as a biomarker for ICH severity and prognosis.<h3>Conclusion</h3>CIRP plays a pivotal role in post-ICH neuroinflammation by acting on IL-6R in microglia. The TCC peptide inhibitor effectively reduces CIRP-IL-6R mediated inflammation and supports neuroprotection. CIRP represents a promising therapeutic target and biomarker for ICH.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"87 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025905","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}

{"title":"Glycoursodeoxycholic acid 3 sulfate sodium links hemodynamics and bile acid metabolism in aortic stenosis","authors":"Min Zhu, Kun Hua, Huiqing Wang, Zhiyuan Guan, Zexin Tong, Juan Gao, Quanyou Shi, Hu Wang, Shen Yan, Yuhua Liu, Qingqing Shi, Tan Xu, Jiaxing Wang, Tianqi Chang, Yuzhou Xue, Yaobo Zhao, Yiwen Fu, Huiping Zheng, Xinheng Feng, Shaomei Shang, Ming Xu","doi":"10.1016/j.jare.2025.09.011","DOIUrl":"https://doi.org/10.1016/j.jare.2025.09.011","url":null,"abstract":"<h3>Introduction</h3>Aortic stenosis (AS) involves aortic obstruction, pressure overload, reduced cardiac output, and impaired organ arterial hemodynamics. Many patients remain at risk of rehospitalization or death after transcatheter aortic valve replacement (TAVR) due to unclear mechanisms. Our previous studies linked bile acids (BAs) metabolism to heart-other organ crosstalk, but the BAs-hemodynamics interplay in AS remains unclear.<h3>Objectives</h3>To investigate metabolic abnormalities in AS, focusing on the role of BA metabolism in AS pathogenesis and the underlying mechanisms.<h3>Methods</h3>An acute canine model of AS was established via intra-aortic balloon catheter-induced transverse aortic obstruction (ITAO). Computational fluid dynamics (CFD) simulation was performed to assess the arterial hemodynamics of the aorta and other organs. Untargeted/targeted metabolomics and transcriptomics were performed in ITAO and deleting ITAO (deITAO) canines. The findings were validated in 33 controls and 30 AS patients. Metabolic predictive performance was assessed by the area under the receiver-operating characteristic (AUROC) curve. Transcriptomic and western blot analyses were used to assess the effects of glycoursodeoxycholic acid (GUDCA) and glycoursodeoxycholic acid 3 sulfate sodium (GUDCA-3S) on isoproterenol (ISO)-induced myocardial remodeling.<h3>Results</h3>ITAO replicated AS hemodynamics (reduced cardiac output, increased aortic velocity), reversed post-deITAO. CFD revealed that ITAO increased organ (e.g., liver) artery pressure, improved after deITAO. Untargeted metabolomics identified 1583 differentially abundant metabolites; transcriptomics revealed 291 DEGs enriched in BA biosynthesis. Targeted BA analysis revealed that GUDCA-3S was elevated in ITAO canines, correlated with aortic velocity (R = -0.4822, <em>P</em> = 0.0002) and BNP (R = 0.3836, <em>P</em> = 0.0019) in AS patients, and exhibited superior AS diagnostic performance (AUROC = 0.844, <em>P</em> &lt; 0.001). Reduced aortic flow upregulated hepatic SULT2A1, driving GUDCA sulfonation to GUDCA-3S and weakening GUDCA’s cardioprotection by impairing IL-17/NF-κB signaling inhibition in ISO-induced cardiomyocytes.<h3>Conclusions</h3>BA metabolism dysfunction responds to cardiac hemodynamic changes, with GUDCA-3S linking cardiac hemodynamics and BA metabolism in AS.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"16 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025906","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}

{"title":"Multifunctional antifreeze gelatin-based ionic conductive organohydrogel coupled with electrical stimulation for monitoring and accelerated wound healing","authors":"Lantao Wang, Zhengfeng Lu, Qingxin Wu, Shuting Peng, Zhengxiao Wang, Wenxiu Chen, Xiaofei Qin","doi":"10.1016/j.jare.2025.09.007","DOIUrl":"https://doi.org/10.1016/j.jare.2025.09.007","url":null,"abstract":"<h3>Introduction</h3>Traditional hydrogels with poor mechanical properties and lack of biological activities severely limit their application in wound therapy. Designing multifunctional hydrogels for monitoring and accelerating wound healing remains imperative.<h3>Objectives</h3>The aim of this study is to develop a multifunctional antifreeze ionic conductive Gel-TBA@organohydrogel with antibacterial, anti-inflammatory and antioxidant properties for monitoring and wound treatment.<h3>Methods</h3>The Gel-TBA@organohydrogel were developed through simply adding 2,3,4-trihydroxybenzaldehyde (TBA) into the gelatin (Gel) solution, and further immersed in water/glycerol binary solvent containing ZnSO₄ for solvent replacement and salting out. Meanwhile, the antifreeze, antibacterial, anti-inflammatory, antioxidant, conductive and biocompatible properties of the organohydrogels were systematically evaluated. Also, the sensing measurements of the Gel-TBA@organohydrogel were carried out to monitor human behaviors, wound exudates and humidity. Furthermore, the wound healing ability of the organohydrogels in combination with electrical stimulation (ES) was investigated by in vivo and ex vivo experiments.<h3>Results</h3>Assisted by TBA addition and binary solvent immersion, Gel-TBA@organohydrogel not only exhibits significant antibacterial and ROS scavenging capabilities, but also has commendable mechanical properties (tensile strain: 346 %, toughness: 1.54 MJ/m³) due to the Schiff base reaction, hydrogen bonding and coordination interaction. In addition, it shows significant conductive sensitivity in the strain range of 60 % to 150 % (GF = 1.54). Interestingly, the organohydrogels exhibit excellent anti-freezing capacity that maintains mechanical strength and electrical properties at −18 °C. Furthermore, Gel-TBA@organohydrogel has good sensing capabilities, responding to wound exudates, humidity and body movement. In vivo experiments showed that the wound healing rate of Gel-TBA@organohydrogel co-treated with ES reached 98.59 % on day 14, with high expression of collagen deposition (90.10 ± 2.35 %), which promoted wound healing and new tissue regeneration.<h3>Conclusion</h3>The Gel-TBA@organohydrogel holds promise for applications in sensing and wound healing, wherein it shows multifunctional abilities and can detect wound exudates and motion behavior, thereby enabling the effective wound care management.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"56 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025912","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}