tbuckley/cabot-search huggingface dataset:
ROS-responsive MnO2 mesoporous hydrogel to modulate liver-muscle crosstalk and mitigate NAFLD-associated sarcopenia via exosomal miR-582-5p delivery
Authors: Songling Jiang, Tae Min Kim, Sung Young Park, Eun-Jung Jin
Journal: Theranostics (2025)

Background: The interrelation between non-alcoholic fatty liver disease (NAFLD) and sarcopenia has emerged as a significant concern due to its systemic impact on metabolic health. However, therapeutic approaches targeting the liver-muscle axis remain underdeveloped. Oxidative stress and inflammatory pathways are key mediators of this crosstalk, exacerbating disease progression. This study aims to develop a reactive oxygen species (ROS)-responsive MnO2 mesoporous PD (HA) hydrogel to modulate this axis and investigate its therapeutic efficacy in NAFLD-associated sarcopenia. Methods: MnO2 mesoporous PD (HA) hydrogels were synthesized with ROS-sensitive properties and characterized for rheological, fluorescence, and conductivity responses. A HepG2-C2C12 co-culture model mimicked the NAFLD-muscle wasting interplay, while high-fat diet (HFD)-induced NAFLD mouse models were used for in vivo evaluations. Cellular stress markers, exosomal miR-582-5p signaling, and atrogenic pathways were assessed using immunofluorescence, qRT-PCR, and histological analyses. Results: Pathway analysis of HFD-induced NAFLD showed upregulation of lipid metabolism and inflammatory signaling, promoting muscle atrophy via exosomal miR-582-5p. The MnO2 mesoporous hydrogel significantly reduced oxidative stress and inflammation in the HepG2-C2C12 co-culture. In vivo, hydrogel implantation in HFD mice mitigated hepatic fibrosis, reduced ROS accumulation, preserved muscle fiber integrity, and downregulated atrogenic markers. Conclusions: The MnO2 mesoporous PD (HA) hydrogel presents a dual-targeting therapeutic strategy for NAFLD and sarcopenia by attenuating oxidative stress and modulating liver-muscle axis signaling. These findings provide a foundation for innovative interventions targeting metabolic comorbidities.
Nanoparticle-assisted targeting of heart lesions with cardiac myofibroblasts: Combined gene and cell therapy
Authors: Miriam Schiffer, Kevin Wagner, Esther Carls, Julia Nicke, Michael Hesse, Raluca M Fratila, Staffan Hildebrand, Dietmar Eberbeck, Timo Mohr, Mona Malek Mohammadi, Jesus Martinez de la Fuente, Bernd K Fleischmann, Wilhelm Roell
Journal: Theranostics (2025)

Rationale: The cardiac scar is an area rich in collagen. It is populated by myofibroblasts and lacks Connexin 43 expressing cardiomyocytes. Myocardial infarctions have so far proven little amenable to gene- and cell-based therapeutic interventions. Our aim was to establish an experimental approach with translational potential for effective cell-based gene therapy of the cardiac scar. Methods: We have developed a targeting strategy for myocardial infarctions by grafting ex vivo lentivirus-transduced and magnetic nanoparticle-loaded embryonic cardiac myofibroblasts into mouse hearts with magnetic steering. Results: Our approach yielded highly efficient targeting and cell grafting into the cardiac scar. Engraftment rates of myofibroblasts proved very high (30% of injected cells) due to cell proliferation and a low apoptosis rate. We also demonstrate that grafting lentivirus-transduced Connexin 43 overexpressing myofibroblasts into the lesion resulted in increased Connexin 43 protein content and strong protection against ventricular arrhythmias in vivo, as their incidence was reduced by ~ 50% at 2- and 8 weeks after myocardial infarction. Conclusion: The combination of ex vivo gene and in vivo cell therapy, along with magnetic steering of cardiac myofibroblasts, enables, efficient targeting of the cardiac scar and can even modulate its functional properties.
Biomimetic piezoelectric hydrogel system for energy metabolism reprogramming in spinal cord injury repair
Authors: Guoliang Shi, Tianqi Su, Junyang Li, Aoao Wang, Gan Gao, Benzhang Tao, Nantian Chen, Lu Tian, Jun Yan, Lingzhou Zhao, Jianning Zhang, Yantao Zhao
Journal: Theranostics (2025)

Rationale: Spinal cord injury (SCI) leads to limited regenerative capacity and severe energy deficiency in the injury microenvironment. This study aimed to develop a biomimetic piezoelectric hydrogel system that could recapitulate the native tissue microenvironment while enabling wireless physical regulation for SCI repair. Methods: A piezoelectric hydrogel was fabricated by integrating K0.5Na0.5NbO3 (KNN) nanoparticles with porous decellularized spinal cord matrix gel (pDG). The hydrogel's effects on vascular endothelial cell migration, neural stem cell differentiation, and ATP synthesis were evaluated in vitro. RNA sequencing was performed to identify key regulatory pathways. The therapeutic efficacy was assessed in a rat model of spinal cord hemisection, examining motor function and angiogenesis. Results: The piezoelectric hydrogel demonstrated excellent biocompatibility and significantly enhanced vascular endothelial cell and neural cell migration. Under ultrasonic stimulation, the hydrogel promoted neural stem cell differentiation into neurons more effectively than control hydrogels. The piezoelectric stimulation increased ATP synthesis and calcium ion flux, activating the Ca2+/Camk2b/PGC-1α signaling axis. In vivo studies showed that implantation of the piezoelectric hydrogel combined with ultrasound stimulation significantly improved motor function recovery and promoted angiogenesis. Conclusion: The piezoelectric hydrogel system presents an effective strategy for SCI repair through energy metabolism reprogramming and demonstrates promising potential in neural tissue engineering applications.
A natural small molecule isoginkgetin alleviates hypercholesterolemia and atherosclerosis by targeting ACLY
Authors: Zhidan Zhang, Meijie Chen, Yitong Xu, Zhihua Wang, Zhenghong Liu, Chenyang He, Fanshun Zhang, Xiaojun Feng, Xiayun Ni, Yuanli Chen, Jixia Wang, Xinmiao Liang, Zhifu Xie, Jingya Li, Maciej Banach, Jaroslav Pelisek, Yuqing Huo, Yunhui Hu, Paul C Evans, Li Wang, Xiao-Yu Tian, Jianbo Xiao, Yuhua Shang, Yijun Zheng, Xunde Xian, Jianping Weng, Suowen Xu
Journal: Theranostics (2025)

Rationale: Atherosclerotic cardiovascular disease (ASCVD) represents the predominant cause of mortality and morbidity globally. Given the established role of hypercholesterolemia as a significant risk factor for ASCVD, the discovery of new lipid-lowering medications is of paramount importance. ATP citrate lyase (ACLY) is a crucial enzyme in cellular metabolism, providing acetyl-CoA as the building block for the biosynthesis of fatty acids and cholesterol. Consequently, it has emerged as a promising drug target for innovative treatments of lipid metabolic disorders. Methods: Virtual screening of a natural product library was performed to identify small-molecule ACLY inhibitors, leading to the discovery of isoginkgetin (ISOGK). The lipid-lowering and anti-atherosclerotic effects of ISOGK were validated in hypercholesterolemic diet-induced animal models (mice and hamsters). The inhibitory effects of ISOGK on ACLY enzymatic activity were measured using commercial assay kits. The direct interaction between ISOGK and ACLY was confirmed by surface plasmon resonance (SPR) and cellular thermal shift assays (CETSA). Liver-specific ACLY knockdown mice were generated using GalNAc-conjugated siRNA (GalNAc-siAcly). Results: ISOGK directly bind to ACLY and inhibit its enzymatic activity in vitro and in vivo. By inhibiting ACLY, ISOGK treatment thus alleviates hypercholesterolemia and atherosclerosis in mice and hamsters. However, ISOGK fails to attenuate lipid accumulation and the expression of lipid-metabolism related genes in Acly knockout or depleted hepatocytes. In vivo, the lipid-lowering and anti-atherosclerotic effects of ISOGK were reversed by hepatic knockdown of Acly via treatment with GalNAc-siAcly in mice. Conclusions: Taken together, the present study identifies ISOGK as an effective and naturally-occurring small-molecule inhibitor of ACLY that limits hypercholesterolemia and atherosclerosis. ISOGK thus serves as a promising drug lead in cardiovascular therapeutics.
Nanomaterials-mediated adenosine pathway inhibition for strengthening cancer immunotherapy
Authors: Wenhu Zhu, Fei Wu, Zhanhong Qiao, Ming Zhao, Haiyang Hu
Journal: Theranostics (2025)

Immunotherapy has developed into an attractive tumor treatment strategy. However, the existence of an immunosuppressive tumor microenvironment (ITME) greatly reduces the efficacy of immunotherapy. Adenosine (ADO) is one of the vital negative feedbacks in ITME, which inhibits antigen presentation and immune cell activation by binding to adenosine receptors (ADORs), thus tremendously suppressing immune response. Currently, the treatment effect of numerous inhibitors targeting the ADO pathway has been demonstrated in early clinical trials of various tumors. Nevertheless, the clinical application of these inhibitors is still plagued by diverse issues, such as short half-life, a single administration route, low bioavailability, etc. With the progress of nanotechnology, the delivery system of ADO inhibitors based on nanomaterials can solve the above problems. This review discusses the utilization of nanomaterials as a prospective method to inhibit ADO pathway and enhance immunotherapy outcomes. Specifically, the immunosuppressive mechanisms of ADO are summarized, and the corresponding intervention strategies are proposed. Then plentiful nanomaterials targeting the ADO pathway are highlighted, including phospholipids and polymers-based nanomaterials, mesoporous nanomaterials, biomimetic nanomaterials and metal-based nanomaterials. Finally, the outlook and challenges about nanomaterials-mediated ADO pathway inhibition were outlined, expecting to promote the clinical application of ADO inhibitor nanomedicines.
Improved optogenetic modification of the spiral ganglion neurons for future optical cochlear implants
Authors: Anupriya Thirumalai, Jana Henseler, Marzieh Enayati, Kathrin Kusch, Roland Hessler, Tobias Moser, Antoine Tarquin Huet
Journal: Theranostics (2025)

Optogenetic stimulation has become a promising approach for restoring lost body function. For example, partial restoration of vision has been achieved in a blind patient and preclinical proof-of-concept has been demonstrated for optogenetic hearing restoration. In preparation for clinical translation of hearing restoration, efficient and safe optogenetic modification of spiral ganglion neurons (SGNs) in the mature cochlea remained to be developed. Methods: Here, we established microcatheter-based administration of adeno-associated virus (AAV) into scala tympani of the cochlea of Mongolian gerbils and compared it to the previously developed direct AAV-injection into the spiral ganglion. We probed the potential of AAV-PHP.S to express channelrhodopsins (ChRs) under the control of the human synapsin promotor in mature SGNs of hearing and deafened gerbils. Results: Using the microcatheter approach, but not with the AAV-modiolus injection, we achieved reliable ChR expression in SGN enabling optogenetic stimulation of the auditory pathway in 80% of the treated animals. Yet, the efficiency of SGN transduction was modest with only ~30% ChR-expressing SGNs. Moreover, we encountered off-target expression in hair cells in hearing gerbils in both approaches. We did not detect ChR expression in the central nervous system using microcatheter administration. Comparing optogenetic auditory brainstem responses of gerbils with and without hair cell transduction confirmed that SGNs were the primary site of optogenetic stimulation of the pathway. Conclusions: The AAV.PHP-S microcatheter administration via the round window with pressure relief at the round window is a reliable approach to optogenetically modify the SGNs in order to restore hearing with future optical cochlear implants.
Serine supplementation suppresses hypoxia-induced pathological retinal angiogenesis
Authors: Hitomi Yagi, Chenxi Qiu, Yan Zeng, Myriam Boeck, Shen Nian, Chuck T Chen, Jarrod C Harman, Taku Kasai, Jeff Lee, Victoria Hirst, Katherine Neilsen, Chaomei Wang, Kiran Bora, Meenakshi Maurya, Tori Rodrick, Matthew Grumbine, Yuelin Yang, Zhanqing Hua, Ian R Sweet, Sasha A Singh, Masanori Aikawa, Jing Chen, Zhongjie Fu
Journal: Theranostics (2025)

Rationale: Pathological retinal angiogenesis with irregular and fragile vessels (also termed neovascularization, a response to hypoxia and dysmetabolism) is a leading cause of vision loss in all age groups. This process is driven in part through the energy deficiency in retinal neurons. Sustaining neural retinal metabolism with adequate nutrient supply may help prevent vision-threatening neovascularization. Low circulating serine levels are associated with neovascularization in macular telangiectasia and altered serine/glycine metabolism has been suggested in retinopathy of prematurity. We here explored the role of serine metabolism in suppressing hypoxia-driven retinal neovascularization using oxygen-induced retinopathy (OIR) mouse model. Methods: We administered wild-type C57BL/6J OIR pups with systemic serine or provided the nursing dam with a serine/glycine-deficient diet during the relative hypoxic phase, followed by analysis of retinal vasculature at postnatal (P) 17, the time of peak neovascularization. Retinas from P17 OIR pups with either systemic serine supplementation or vehicle control were subjected to metabolomics, lipidomics, proteomics, and single-cell RNA sequencing. To validate the role of mitochondrial fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) in mediating serine protection against OIR, we treated OIR pups with inhibitors to block FAO or OXPHOS along with either serine or vehicle. The potential transcriptional mediator and pro-angiogenic signals were validated by western blotting. Results: Systemic serine supplementation reduced retinal neovascularization, while maternal dietary serine/glycine deficiency exacerbated it. FAO was essential in mediating serine protective effects, and serine supplementation increased levels of phosphatidylcholine, the most abundant phospholipids in the retina. Serine treatment a) increased the abundance of proteins involved in OXPHOS in retinas, b) increased the expression of mitochondrial respiration-related genes, and c) decreased the expression of pro-angiogenic genes in rod photoreceptor cluster. Serine suppression of retinal neovascularization was dependent on mitochondrial energy production. High mobility group box 1 protein (HMGB1) was identified as a potential key mediator of serine suppression of pro-angiogenic signals in hypoxic retinas. Conclusions: Our findings suggest that serine supplementation may serve as a potential therapeutic approach for neovascular eye diseases by enhancing retinal mitochondrial metabolism and lipid utilization, suppressing the key drivers of uncontrolled angiogenesis.
Targeted radioligand therapy: physics and biology, internal dosimetry and other practical aspects during <sup>177</sup>Lu/<sup>225</sup>Ac treatment in neuroendocrine tumors and metastatic prostate cancer
Authors: Habibollah Dadgar, Ali Pashazadeh, Nasim Norouzbeigi, Majid Assadi, Batool Al-Balooshi, Richard P Baum, Akram Al-Ibraheem, Mohamad Haidar, Mohsen Beheshti, Parham Geramifar, Reza Vali, Seyed Mohammadi, Swagat Dash, Vindhya Malasani, Andrea Cimini, Maria Ricci, Abdulredha A Esmail, Sarah Murad, Fahad Marafi, Giorgio Treglia, Aysar Najeh Khalaf, Farah M Anwar, Sharjeel Usmani, Yehia Omar, Haider Muhsin, Igore E Tyurin, Andrew Zakhary, Sahar Al-Sebaie, Danny Mena Cortes, Maryam AlHashim, Hossein Arabi, Habib Zaidi
Journal: Theranostics (2025)

Radioligand therapy (RLT) has garnered significant attention due to the recent emergence of innovative and effective theranostic agents, which showed promising therapeutic and prognostic results in various cancers. Moreover, understanding the interaction between different types of radiation and biological tissues is essential for optimizing therapeutic interventions These concepts directly apply to clinical RLTs and play a crucial role in determining the efficacy and toxicity profile of different radiopharmaceutical agents. Personalized dosimetry is a powerful tool that aids in estimating patient-specific absorbed doses in both tumors and normal organs. Dosimetry in RLT is an area of active investigation, as our current understanding of the relationship between absorbed dose and tissue damage is primarily derived from external-beam radiation therapy. Further research is necessary to comprehensively comprehend this relationship in the context of RLTs. In the present review, we present a thorough examination of the involvement of 177Lu/225Ac radioisotopes in the induction of direct and indirect DNA damage, as well as their influence on the initiation of DNA repair mechanisms in cancer cells of neuroendocrine tumors and metastatic prostate cancer. Current data indicate that high-energy α-emitter radioisotopes can directly impact DNA structure by causing ionization, leading to the formation of ionized atoms or molecules. This ionization process predominantly leads to the formation of irreparable and intricate double-strand breaks (DSBs). On the other hand, the majority of DNA damage caused by β-emitter radioisotopes is indirect, as it involves the production of free radicals and subsequent chemical reactions. Beta particles themselves can also physically interact with the DNA molecule, resulting in single-strand breaks (SSBs) and potentially reversible DSBs.
Extracellular vesicles play a central role in linking podocyte injury to mesangial activation in glomerular disease
Authors: Zhao Liu, Xi Liu, Yi Zhou, Xin Wen, Jie Xu, Meizhi He, Jiongcheng Chen, Nan Jia, Youhua Liu
Journal: Theranostics (2025)

Background: Podocyte injury leading to proteinuria is the primary feature of a vast majority of glomerular diseases, while mesangial cell activation is the hallmark of glomerulosclerosis. Whether and how these two events are connected remains elusive. In this study, we investigated the role of extracellular vesicles (EVs) in linking podocyte injury to mesangial activation in glomerular disease. Methods: EVs were characterized by nanoparticle tracking analysis and electron microscopy. Differentially expressed proteins from podocyte-derived EVs were analyzed by protein microarray. The role and mechanism by which EVs-packaged sonic hedgehog (Shh) mediates mesangial cell activation were investigated in vitro and in vivo. Results: An increased production of EVs in mouse podocytes (MPC5) was observed after injury induced by angiotensin II (Ang II). Shh and N-Shh were identified as major constituents of the proteins encapsulated in EVs isolated from Ang II-treated MPC5 cells (Ang II-EVs). In vitro, Ang II-EVs induced the activation and proliferation of rat mesangial cells (HBZY-1), whereas inhibition of EV secretion with dimethyl amiloride, depletion of EVs from conditioned media or knockdown of Shh expression abolished the ability of Ang II-EVs to induce HBZY-1 activation. In vivo, intravenous injection of Ang II-EVs exacerbated glomerulosclerosis, which was negated by hedgehog inhibitor. Furthermore, blocking EV secretion also ameliorated glomerulosclerosis in mouse model of glomerular disease. Conclusions: These findings suggest that podocyte injury can cause mesangial cell activation and glomerulosclerosis by releasing Shh-enriched EVs. Therefore, strategies targeting EVs may be a novel way to ameliorate proteinuric kidney disease.
Oncogenic β-catenin stimulation of cofilin 1-mediated macropinocytosis is druggable for cancer
Authors: Baohui Zhang, Xiaochen Gai, Bufu Tang, Linlin Chen, Yuting Wu, Weiwei Deng, Jiate Liu, Lanting Hao, Fangming Liu, Hongbing Zhang
Journal: Theranostics (2025)

Rationale: Although β-catenin is frequently activated in various cancers, no targeted therapies have been approved for clinical use. Methods: High-throughput drug screening was performed to identify potential compounds against β-catenin-activated tumors. The efficacy of identified compounds was assessed in orthotopic β-catenin-driven hepatocellular carcinoma model mice. Results: OSI-027 emerged as the most potent agent that selectively inhibited β-catenin-mutant cells. Mechanistically, β-catenin enhanced the transcription of Cofilin 1 (CFL1), a key stimulator of macropinocytosis, and directly interacted with CFL1 to prevent its inactivation. OSI-027 induced macropinocytosis and subsequently led to methuosis-like cell death of β-catenin-mutant cells. Moreover, both excessive macropinocytosis induced by OSI-027 and macropinocytosis inhibition via CFL1 depletion suppressed β-catenin-driven tumor growth in orthotopic hepatocellular carcinoma model mice. Conclusion: Targeting macropinocytosis represents a promising therapeutic strategy for β-catenin mutant cancers.
KMV-mediated cardiomyocyte-to-endothelial cell signaling drives capillary rarefaction to promote heart failure following pressure overload
Authors: Chenxi Gao, Yudong Xia, Chaofang Li, Tao Zhou, Wenyu Zhang, Hao Cheng, Xiaojin Zhang, Yunhao Yu, Chuanfu Li, Zhengnian Ding, Jun Wu, Li Liu
Journal: Theranostics (2025)

Rationale: Pressure overload (PO)-induced heart failure (HF) is a global health burden with poor outcomes. Cardiomyocyte hypertrophy and capillary rarefaction are two features and drivers of PO-induced HF. Metabolism is altered in hypertrophic cardiomyocytes; however, the metabolites secreted by hypertrophic cardiomyocytes to paracrinally regulate capillary density remain to be identified. Methods: PO-induced HF was established by transverse aortic constriction in mice. Metabolite secretion was examined by nontargeted metabolomics and enzyme-linked immunosorbent assays. Gene expression was examined by RNA-sequencing and immunoblotting. Protein-promoter binding was examined by chromatin immunoprecipitation-PCR. Cardiomyocyte hypertrophy and cardiac capillary density were examined by immunostaining for -actinin and CD31, respectively. In vitro angiogenesis was indicated by proliferation, migration, tube formation, and angiogenic factor expression of endothelial cells (ECs). EC senescence was determined by SA--gal staining and p16 and p21 expression. Results: There was a negative correlation between cardiomyocyte size and capillary density in PO-induced failing hearts, and hypertrophic cardiomyocytes paracrinally inhibited angiogenesis of ECs. 3-Methyl-2-oxovaleric acid (KMV) was the most upregulated metabolite secreted by hypertrophic cardiomyocytes. Notably, KMV treatment resulted in EC senescence and angiogenesis inhibition in vitro and exaggerated PO-induced EC senescence, capillary rarefaction, and cardiac dysfunction of mice in vivo. Additionally, KMV increased expression and nuclear accumulation of mesenchyme homeobox 2 (Meox2) in ECs, whereas Meox2 knockdown diminished KMV-induced EC senescence and angiogenesis inhibition. Furthermore, Meox2 directly bound to the promoter of the senescence-related gene p21 in ECs, and this binding was enhanced by KMV. Conclusions: The data suggest that hypertrophic cardiomyocytes secrete elevated levels of KMV, which paracrinally increases nuclear accumulation of Meox2 in ECs, where Meox2 binds to the promoter of p21 and thereby triggers EC senescence and subsequent angiogenesis impairment, ultimately driving capillary rarefaction to promote PO-induced HF. The findings identified KMV as a novel metabolite secreted by hypertrophic cardiomyocytes that triggered EC senescence to drive PO-induced capillary rarefaction and subsequent HF development. Targeting this KMV-mediated cardiomyocyte-to-EC signaling has therapeutic potential in the management of PO-induced HF in patients.
Nrf2 and HIF1α converge to arsenic-induced metabolic reprogramming and the formation of the cancer stem-like cells: Erratum
Authors: Zhuoyue Bi, Qian Zhang, Yao Fu, Priya Wadgaonkar, Wenxuan Zhang, Bandar Almutairy, Liping Xu, M'Kya Rice, Yiran Qiu, Chitra Thakur, Fei Chen
Journal: Theranostics (2025)

[This corrects the article DOI: 10.7150/thno.42903.].