tbuckley/cabot-search huggingface dataset:
B cells mediate lung ischemia/reperfusion injury by recruiting classical monocytes via synergistic B cell receptor/TLR4 signaling
Authors: Khashayar Farahnak, Yun Zhu Bai, Yuhei Yokoyama, Deniz B. Morkan, Zhiyi Liu, Junedh M. Amrute, Alejandro De Filippis Falcon, Yuriko Terada, Fuyi Liao, Wenjun Li, Hailey M. Shepherd, Ramsey R. Hachem, Varun Puri, Kory J. Lavine, Andrew E. Gelman, Ankit Bharat, Daniel Kreisel, Ruben G. Nava
Journal: Journal of Clinical Investigation (2024)

Ischemia/reperfusion injury–mediated (IRI-mediated) primary graft dysfunction (PGD) adversely affects both short- and long-term outcomes after lung transplantation, a procedure that remains the only treatment option for patients suffering from end-stage respiratory failure. While B cells are known to regulate adaptive immune responses, their role in lung IRI is not well understood. Here, we demonstrated by intravital imaging that B cells are rapidly recruited to injured lungs, where they extravasate into the parenchyma. Using hilar clamping and transplant models, we observed that lung-infiltrating B cells produce the monocyte chemokine CCL7 in a TLR4-TRIF–dependent fashion, a critical step contributing to classical monocyte (CM) recruitment and subsequent neutrophil extravasation, resulting in worse lung function. We found that synergistic BCR-TLR4 activation on B cells is required for the recruitment of CMs to the injured lung. Finally, we corroborated our findings in reperfused human lungs, in which we observed a correlation between B cell infiltration and CM recruitment after transplantation. This study describes a role for B cells as critical orchestrators of lung IRI. As B cells can be depleted with currently available agents, our study provides a rationale for clinical trials investigating B cell–targeting therapies.
Dual elemental doping activated signaling pathway of angiogenesis and defective heterojunction engineering for effective therapy of MRSA-infected wounds
Authors: Jin Huang, Shuilin Wu, Yi Wang, Jie Shen, Chaofeng Wang, Yufeng Zheng, Paul K. Chu, Xiangmei Liu
Journal: Bioactive Materials (2024)

Multi-drug resistant bacterial infections pose a significant threat to human health. Thus, the development of effective bactericidal strategies is a pressing concern. In this study, a ternary heterostructure (Zn–CN/P-GO/BiS) comprised of Zn-doped graphite phase carbon nitride (g-C3N4), phosphorous-doped graphene oxide (GO) and bismuth sulphide (Bi2S3) is constructed for efficiently treating methicillin-resistant Staphylococcus aureus (MRSA)-infected wound. Zn doping-induced defect sites in g-C3N4 results in a reduced band gap (ΔE) and a smaller energy gap (ΔEST) between the singlet state S1 and triplet state T1, which favours two-photon excitation and accelerates electron transfer. Furthermore, the formation of an internal electric field at the ternary heterogeneous interface optimizes the charge transfer pathway, inhibits the recombination of electron-hole pairs, improves the photodynamic effect of g-C3N4, and enhances its catalytic performance. Therefore, the Zn–CN/P-GO/BiS significantly augments the production of reactive oxygen species and heat under 808 nm NIR (0.67 W cm−2) irradiation, leading to the elimination of 99.60% ± 0.07% MRSA within 20 min. Additionally, the release of essential trace elements (Zn and P) promotes wound healing by activating hypoxia-inducible factor-1 (HIF-1) and peroxisome proliferator-activated receptors (PPAR) signaling pathways. This work provides unique insight into the rapid antibacterial applications of trace element doping and two-photon excitation.
Site-specific albumin tagging with NIR-II fluorogenic dye for high-performance and super-stable bioimaging
Authors: Ningning Zhu, Jiajun Xu, Qi Su, Tianyang Han, Ding Zhou, Yuewei Zhang, Shoujun Zhu
Journal: Theranostics (2024)

Synthetic near-infrared-II (NIR-II) dyes are promising for deep tissue imaging, yet they are generally difficult to target a given biomolecule with high specificity. Furthermore, the interaction mechanism between albumin and cyanine molecules, which is usually regarded as uncertain "complexes" such as crosslinked nanoparticles, remains poorly understood.
Precision peptide theranostics: developing <i>N</i>- to <i>C</i>-terminus optimized theranostics targeting cholecystokinin-2 receptor
Authors: Marwa N. Rahimi, Alicia Corlett, Jessica Van Zuylekom, Marc Antoine Sani, Benjamin Blyth, Philip Thompson, Peter D. Roselt, Mohammad B. Haskali
Journal: Theranostics (2024)

Peptides are ideal for theranostic development as they afford rapid target accumulation, fast clearance from background tissue, and exhibit good tissue penetration.Previously, we developed a novel series of peptides that presented discreet folding propensity leading to an optimal candidate [ 68 Ga]Ga-DOTA-GA1 ([D-Glu]6-Ala-Tyr-NMeGly-Trp-NMeNle-Asp-Nal-NH2) with 50 pM binding affinity against cholecystokinin-2 receptors (CCK2R).However, we were confronted with challenges of unfavorably high renal uptake.Methods: A structure activity relationship study was undertaken of the lead theranostic candidate.Prudent structural modifications were made to the peptide scaffold to evaluate the contributions of specific N-terminal residues to the overall biological activity.Optimal candidates were then evaluated in nude mice bearing transfected A431-CCK2 tumors, and their biodistribution was quantitated ex vivo.Results: We identified and confirmed that D-Glu 3 to D-Ala 3 substitution produced 2 optimal candidates, [ 68 Ga]Ga-DOTA-GA12 and [ 68 Ga]Ga-DOTA-GA13.These radiopeptides presented with high target/background ratios, enhanced tumor retention, excellent metabolic stability in plasma and mice organ homogenates, and a 4-fold reduction in renal uptake, significantly outperforming their non-alanine counterparts.Conclusions: Our study identified novel radiopharmaceutical candidates that target the CCK2R.Their high tumor uptake and reduced renal accumulation warrant clinical translation.
Highly oriented hydrogels for tissue regeneration: design strategies, cellular mechanisms, and biomedical applications
Authors: Jiuping Wu, Zhihe Yun, Wenlong Song, Tao Yu, Wu Xue, Qinyi Liu, Xinzhi Sun
Journal: Theranostics (2024)

Many human tissues exhibit a highly oriented architecture that confers them with distinct mechanical properties, enabling adaptation to diverse and challenging environments. Hydrogels, with their water-rich "soft and wet" structure, have emerged as promising biomimetic materials in tissue engineering for repairing and replacing damaged tissues and organs. Highly oriented hydrogels can especially emulate the structural orientation found in human tissue, exhibiting unique physiological functions and properties absent in traditional homogeneous isotropic hydrogels. The design and preparation of highly oriented hydrogels involve strategies like including hydrogels with highly oriented nanofillers, polymer-chain networks, void channels, and microfabricated structures. Understanding the specific mechanism of action of how these highly oriented hydrogels affect cell behavior and their biological applications for repairing highly oriented tissues such as the cornea, skin, skeletal muscle, tendon, ligament, cartilage, bone, blood vessels, heart, etc., requires further exploration and generalization. Therefore, this review aims to fill that gap by focusing on the design strategy of highly oriented hydrogels and their application in the field of tissue engineering. Furthermore, we provide a detailed discussion on the application of highly oriented hydrogels in various tissues and organs and the mechanisms through which highly oriented structures influence cell behavior.
Cancer-associated fibroblast spatial heterogeneity and <i>EMILIN1</i> expression in the tumor microenvironment modulate TGF-β activity and CD8<sup>+</sup> T-cell infiltration in breast cancer
Authors: Chikako Kanno Honda, Sasagu Kurozumi, Takaaki Fujii, Didier Pourquier, Lakhdar Khellaf, Florence Boissiere, Jun Horiguchi, Tetsunari Oyama, Ken Shirabe, Jacques Colinge, Takehiko Yokobori, Andrei Turtoi
Journal: Theranostics (2024)

Rationale:The tumor microenvironment (TME) and its multifaceted interactions with cancer cells are major targets for cancer treatment.Single-cell technologies have brought major insights into the TME, but the resulting complexity often precludes conclusions on function.Methods: We combined single-cell RNA sequencing and spatial transcriptomic data to explore the relationship between different cancer-associated fibroblast (CAF) populations and immune cell exclusion in breast tumors.The significance of the findings was then evaluated in a cohort of tumors (N=75) from breast cancer patients using immunohistochemistry analysis.Results: Our data show for the first time the degree of spatial organization of different CAF populations in breast cancer.We found that IL-iCAFs, Detox-iCAFs, and IFNγ-iCAFs tended to cluster together, while Wound-myCAFs, TGFβ-myCAFs, and ECM-myCAFs formed another group that overlapped with elevated TGF-β signaling.Differential gene expression analysis of areas with CD8 + T-cell infiltration/exclusion within the TGF-β signaling-rich zones identified elastin microfibrillar interface protein 1 (EMILIN1) as a top modulated gene.EMILIN1, a TGF-β inhibitor, was upregulated in IFNγ-iCAFs directly modulating TGFβ immunosuppressive function.Histological analysis of 75 breast cancer samples confirmed that high EMILIN1 expression in the tumor margins was related to high CD8 + T-cell infiltration, consistent with our spatial gene expression analysis.High EMILIN1 expression was also associated with better prognosis of patients with breast cancer, underscoring its functional significance for the recruitment of cytotoxic T cells into the tumor area. Conclusion:Our data show that correlating TGF-β signaling to a CAF subpopulation is not enough because proteins with TGF-β-modulating activity originating from other CAF subpopulations can alter its activity.Therefore, therapeutic targeting should remain focused on biological processes rather than on specific CAF subtypes.
H-ferritin-nanocaged gadolinium nanoparticles for ultra-sensitive MR molecular imaging
Authors: Jianlin Zhang, Chang Yuan, Lingfei Kong, Feiyan Zhu, Wanzhong Yuan, Junying Zhang, Juanji Hong, Fang Deng, Qi Chen, Chen Chen, Tao Wang, Zhentao Zuo, Minmin Liang
Journal: Theranostics (2024)

Rationale: Magnetic resonance imaging (MRI) is a powerful diagnostic technology by providing high-resolution imaging.Although MRI is sufficiently valued in its resolving morphology, it has poor sensitivity for tracking biomarkers.Therefore, contrast agents are often used to improve MRI diagnostic sensitivity.However, the clinically used Gd chelates are limited in improving MRI sensitivity owing to their low relaxivity.The objective of this study is to develop a novel contrast agent to achieve a highly sensitive tracking of biomarkers in vivo.Methods: A Gd-based nanoprobe composed of a gadolinium nanoparticle encapsulated within a human H-ferritin nanocage (Gd-HFn) has been developed.The specificity and sensitivity of Gd-HFn were evaluated in vivo in tumor-bearing mice and apolipoprotein E-deficient mice (Apoe -/ -) by MRI.Results: The Gd-HFn probe shows extremely high relaxivity values (r1 = 549 s -1 mM -1 , r2 = 1555 s -1 mM -1 under a 1.5-T magnetic field; and r1 = 428 s -1 mM -1 and r2 = 1286 s -1 mM -1 under a 3.0-T magnetic field), which is 175-fold higher than that of the clinically standard Dotarem (Gd-DOTA, r1 =3.13 s -1 mM -1 ) under a 1.5-T magnetic field, and 150-fold higher under a 3.0-T magnetic field.Owing to the substantially enhanced relaxivity values, Gd-HFn achieved a highly sensitive tracking for the tumor targeting receptor of TfR1 and enabled the in vivo MRI visualization of tumors approaching the angiogenic switch.Conclusions: The developed Gd-HFn contrast agent makes MRI a more powerful tool by simultaneously providing functional and morphological imaging information, which paves the way for a new perspective in molecular imaging.
[<sup>161</sup>Tb]Tb-PSMA-617 radioligand therapy in patients with mCRPC: preliminary dosimetry results and intra-individual head-to-head comparison to [<sup>177</sup>Lu]Lu-PSMA-617
Authors: Andrea Schaefer-Schuler, Caroline Burgard, Arne Blickle, Stephan Maus, Christine Petrescu, Sven Petto, Mark Bartholomä, Tobias Stemler, Samer Ezziddin, Florian Rosar
Journal: Theranostics (2024)

Rationale: Evaluation of alternative radionuclides for use in prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) is currently focusing on 161 Tb, which may provide advantages by emitting additional Auger and conversion electrons.In this pilot study, we present preliminary dosimetry data for [ 161 Tb]Tb-PSMA-617 RLT in a direct comparison with [ 177 Lu]Lu-PSMA-617.Method: Six patients with metastatic castration-resistant prostate cancer (mCRPC) underwent treatment with [ 177 Lu]Lu-PSMA-617 and subsequently -after inadequate response -with [ 161 Tb]Tb-PSMA-617.Whole-body planar and SPECT imaging-based dosimetry of organs at risk (kidneys and salivary glands) and tumor lesions were calculated using IDAC for 177 Lu and OLINDA/EXM for 161 Tb.The therapeutic index (TI) of mean tumor-absorbed doses over relevant organs at risk was calculated.Results: Mean absorbed doses to organs at risk of PSMA-RLT were slightly higher for [ 161 Tb]Tb-PSMA-617 compared to [ 177 Lu]Lu-PSMA-617 (kidneys: 0.643 ± 0.247 vs. 0.545 ± 0.231 Gy/GBq, factor 1.18; parotid gland: 0.367 ± 0.198 vs. 0.329 ± 0.180 Gy/GBq, factor 1.10), but markedly higher regarding tumor lesions (6.10 ± 6.59 vs 2.59 ± 3.30 Gy/GBq, factor 2.40, p < 0.001).Consequently, the mean TI was higher for [ 161 Tb]Tb-PSMA-617 compared to [ 177 Lu]Lu-PSMA-617 for both, the kidneys (11.54 ± 9.74 vs. 5.28 ± 5.13, p = 0.002) and the parotid gland (16.77 ± 13.10 vs. 12.51 ± 18.09, p = 0.008). Conclusion:In this intra-individual head-to-head pilot study, [ 161 Tb]Tb-PSMA-617 delivered higher tumor-absorbed doses and resulted in superior TI compared to [ 177 Lu]Lu-PSMA-617.This preliminary data support 161 Tb as a promising radionuclide for PSMA-RLT in mCRPC.
Dual regulation of NEMO by Nrf2 and miR-125a inhibits ferroptosis and protects liver from endoplasmic reticulum stress-induced injury
Authors: Jihoon Tak, Min Sung Joo, Yun Seok Kim, Hyun Woo Park, Chang Hoon Lee, Gil-Chun Park, Shin Hwang, Sang Geon Kim
Journal: Theranostics (2024)

Rationale:The surge of severe liver damage underscores the necessity for identifying new targets and therapeutic agents.Endoplasmic reticulum (ER) stress induces ferroptosis with Gα12 overexpression.NF-κB essential modulator (NEMO) is a regulator of inflammation and necroptosis.Nonetheless, the regulatory basis of NEMO de novo synthesis and its impact on hepatocyte ferroptosis need to be established.This study investigated whether Nrf2 transcriptionally induces IKBKG (the NEMO gene) for ferroptosis inhibition and, if so, how NEMO induction protects hepatocytes against ER stress-induced ferroptosis.Methods: Experiments were conducted using human liver tissues, hepatocytes, and injury models, incorporating NEMO overexpression and Gα12 gene modulations.RNA sequencing, immunoblotting, immunohistochemistry, reporter assays, and mutation analyses were done.Results: NEMO downregulation connects closely to ER and oxidative stress, worsening liver damage via hepatocyte ferroptosis.NEMO overexpression protects hepatocytes from ferroptosis by promoting glutathione peroxidase 4 (GPX4) expression.This protective role extends to oxidative and ER stress.Similar shifts occur in nuclear factor erythroid-2-related factor-2 (Nrf2) expression alongside NEMO changes.Nrf2 is newly identified as an IKBKG (NEMO gene) transactivator.Gα12 changes, apart from Nrf2, impact NEMO expression, pointing to post-transcriptional control.Gα12 reduction lowers miR-125a, an inhibitor of NEMO, while overexpression has the opposite effect.NEMO also counters ER stress, which triggers Gα12 overexpression.Gα12's significance in NEMO-dependent hepatocyte survival is confirmed via ROCK1 inhibition, a Gα12 downstream kinase, and miR-125a.The verified alterations or associations within the targeted entities are validated in human liver specimens and datasets originating from livers subjected to exposure to other injurious agents.Conclusions: Hepatic injury prompted by ER stress leads to the suppression of NEMO, thereby facilitating ferroptosis through the inhibition of GPX4.IKBKG is transactivated by Nrf2 against Gα12 overexpression responsible for the increase of miR-125a, an unprecedented NEMO inhibitor, resulting in GPX4 induction.Accordingly, the induction of NEMO mitigates ferroptotic liver injury.
Fibroblasts facilitate lymphatic vessel formation in transplanted heart
Authors: Hui Gong, Ting Wang, Xiaotong Sun, Yuesheng Zhang, Yichao Qiu, Wenlong Sun, Yue Zhang, Peng Teng, Yanhua Hu, Xiaosheng Hu, Liang Ma, Qingbo Xu, Haige Zhao
Journal: Theranostics (2024)

Rationale: Lymphangiogenesis plays a critical role in the transplanted heart.The remodeling of lymphatics in the transplanted heart and the source of newly formed lymphatic vessels are still controversial, especially the mechanism of lymphangiogenesis remains limited. Methods:Heart transplantation was performed among BALB/c, C57BL/6J, Cag-Cre, Lyve1-CreER T2 ;Rosa26-tdTomato and Postn(2A-CreER T2 -wpre-pA)1;Rosa26-DTA mice.scRNA-seq, Elisa assay, Western blotting, Q-PCR and immunohistochemical staining were used to identify the cells and cell-cell communications of allograft heart.Cell depletion was applied to in vivo and in vitro experiments.Whole-mount staining and three-dimensional reconstruction depicted the cell distribution within transparent transplanted heart.Results: Genetic lineage tracing mice and scRNA-seq analysis have revealed that these newly formed lymphatic vessels mainly originate from recipient LYVE1 + cells.It was found that LECs primarily interact with activated fibroblasts.Inhibition of lymphatic vessel formation using a VEGFR3 inhibitor resulted in a decreased survival time of transplanted hearts.Furthermore, when activated fibroblasts were ablated in transplanted hearts, there was a significant suppression of lymphatic vessel generation, leading to earlier graft failure.Additional investigations have shown that activated fibroblasts promote tube formation of LECs primarily through the activation of various signaling pathways, including VEGFD/VEGFR3, MDK/NCL, and SEMA3C/NRP2.Interestingly, knockdown of VEGFD and MDK in activated fibroblasts impaired cardiac lymphangiogenesis after heart transplantation.Conclusions: Our study indicates that cardiac lymphangiogenesis primarily originates from recipient cells, and activated fibroblasts play a crucial role in facilitating the generation of lymphatic vessels after heart transplantation.These findings provide valuable insights into potential therapeutic targets for enhancing graft survival.
Depletion of ApoA5 aggravates spontaneous and diet-induced nonalcoholic fatty liver disease by reducing hepatic NR1D1 in hamsters
Authors: Jiabao Guo, Guolin Miao, Wenxi Zhang, Haozhe Shi, Pingping Lai, Yitong Xu, Lianxin Zhang, Gonglie Chen, Yufei Han, Ying Zhao, Geroge Liu, Ling Zhang, Yuhui Wang, Wei Huang, Xunde Xian
Journal: Theranostics (2024)

Background: ApoA5 mainly synthesized and secreted by liver is a key modulator of lipoprotein lipase (LPL) activity and triglyceride-rich lipoproteins (TRLs).Although the role of ApoA5 in extrahepatic triglyceride (TG) metabolism in circulation has been well documented, the relationship between ApoA5 and nonalcoholic fatty liver disease (NAFLD) remains incompletely understood and the underlying molecular mechanism still needs to be elucidated.Methods: We used CRISPR/Cas9 gene editing to delete Apoa5 gene from Syrian golden hamster, a small rodent model replicating human metabolic features.Then, the ApoA5-deficient (ApoA5 -/-) hamsters were used to investigate NAFLD with or without challenging a high fat diet (HFD).Results: ApoA5 -/-hamsters exhibited hypertriglyceridemia (HTG) with markedly elevated TG levels at 2300 mg/dL and hepatic steatosis on a regular chow diet, accompanied with an increase in the expression levels of genes regulating lipolysis and small adipocytes in the adipose tissue.An HFD challenge predisposed ApoA5 -/- hamsters to severe HTG (sHTG) and nonalcoholic steatohepatitis (NASH).Mechanistic studies in vitro and in vivo revealed that targeting ApoA5 disrupted NR1D1 mRNA stability in the HepG2 cells and the liver to reduce both mRNA and protein levels of NR1D1, respectively.Overexpression of human NR1D1 by adeno-associated virus 8 (AAV8) in the livers of ApoA5 -/-hamsters significantly ameliorated fatty liver without affecting plasma lipid levels.Moreover, restoration of hepatic ApoA5 or activation of UCP1 in brown adipose tissue (BAT) by cold exposure or CL316243 administration could significantly correct sHTG and hepatic steatosis in ApoA5 -/- hamsters.Conclusions: Our data demonstrate that HTG caused by ApoA5 deficiency in hamsters is sufficient to elicit hepatic steatosis and HFD aggravates NAFLD by reducing hepatic NR1D1 mRNA and protein levels, which provides a mechanistic link between ApoA5 and NAFLD and suggests the new insights into the potential therapeutic approaches for the treatment of HTG and the related disorders due to ApoA5 deficiency in the clinical trials in future.
Cancer diagnosis using label-free SERS-based exosome analysis
Authors: Yajuan Liu, Mei Li, Haisha Liu, Chao Kang, Cheng Wang
Journal: Theranostics (2024)

Exosomes, carrying distinctive biomolecules reflective of their parent cell's status and origin, show promise as liquid biopsy biomarkers for cancer diagnosis. However, their clinical translation remains challenging due to their relatively low concentration in body fluids. Surface-Enhanced Raman spectroscopy (SERS) has recently gained significant attention as a label-free and sensitive technique for exosome analysis. This review explores label-free SERS for exosome detection, covering exosome isolation and characterization methods, advancements in SERS substrates, and fingerprint analysis techniques using machine learning. Furthermore, we emphasize the challenges and offer insights into the future prospects of SERS-based exosome analysis to enhance cancer diagnosis.