tbuckley/cabot-search huggingface dataset:
Exosomes of human adipose stem cells mitigate irradiation injury to salivary glands by inhibiting epithelial-mesenchymal transition through miR-199a-3p targeting Twist1 and regulating TGFβ1/Smad3 pathway
Authors: Xiaotong Guo, Zhu Huang, Fan Wu, Wentao Jiang, Yiyang Li, Tao Wang, Simon D Tran, Zhengmei Lin, Xinyun Su
Journal: Theranostics (2024)

Rationale: Currently, irradiation-injured salivary glands (IR-SG) lack effective clinical treatment options. Emerging treatments using exosomes (Exo) have shown promising outcomes for various diseases. However, the efficacy of exosome in treating IR-SG remains unexplored. This study aimed to use exosomes to restore IR-SG function and to explore their underlying mechanisms. Methods: Exosomes isolated from human adipose-derived stem cell (ADSC-Exo) were injected into C57BL/6 mice that had their salivary glands injured with 14Gy. RNA sequencing profiled differentially expressed miRNAs and mRNAs of IR-SG. Epithelial-mesenchymal transition (EMT) mechanisms were further examined using SMG-C6 cells. Results: Exo-treated mice had a 96% increase in saliva secretion, higher cell proliferation, upregulated tissue repair/regeneration genes, and preserved functional cells with fewer collagen fibers compared to saline-treated mice. Exo treatment increased the expression of epithelial cell markers while decreasing mesenchymal cell markers. Notably, miR-199a-3p was significantly upregulated in Exo-treated mice, promoting cell growth and reducing EMT. Twist1, an EMT transcription factor, was identified as a direct target of miR-199a-3p and confirmed by luciferase assays. Twist1 overexpression promoted EMT, but Exo treatment or Twist1 knockdown reduced EMT marker expression and inactivated the TGFβ1/Smad3 pathway. Conclusions: ADSC-Exo is a promising therapy for IR-SG, primarily by mitigating EMT through miR-199a-3p targeting Twist1 and regulating the TGFβ1/Smad3 pathway.
Multiple crosslinked, self-healing, and shape-adaptable hydrogel laden with pain-relieving chitosan@borneol nanoparticles for infected burn wound healing
Authors: Zexing Deng, Yi Guo, Xuefeng Wang, Jiajie Song, Guan Yang, Litong Shen, Yuheng Wang, Xin Zhao, Baolin Guo, Wen Wang
Journal: Theranostics (2024)

Rationale: Next-generation wound dressings with multiple biological functions hold promise for addressing the complications and pain associated with burn wounds. Methods: A hydrogel wound dressing loaded with a pain-relieving drug was developed for treating infected burn wounds. Polyvinyl alcohol chemically grafted with gallic acid (PVA-GA), sodium alginate chemically grafted with 3-aminobenzeneboronic acid (SA-PBA), Zn2+, and chitosan-coated borneol nanoparticles with anti-inflammatory and pain-relieving activities were combined to afford a nanoparticle-loaded hydrogel with a PVA-GA/Zn2+/SA-PBA network crosslinked via multiple physicochemical interactions. Results: The developed hydrogel demonstrated adhesiveness, self-healing, shape adaptability, injectability, degradability, conformity to complicated wound surfaces, and other desirable biological functions, including a pH-responsive drug release behavior and antibacterial, antioxidant, anti-inflammatory, and proangiogenic activities. In a murine scald wound model, the hydrogel effectively prevented infection by Staphylococcus aureus and downregulated pain perception (measured using mouse grimace scale scores and hind paw lifting and licking times), thereby accelerating wound healing. Conclusion: This study provides broad prospects for the development of new hydrogel systems that can substantially improve the dynamic management of infected burn wounds.
Unveiling urinary extracellular vesicle mRNA signature for early diagnosis and prognosis of bladder cancer
Authors: Ning Sun, Zhaowei Zhang, Xiaoqing Yang, Jingqi Li, Qiang Li, Jingjing Kang, Yongchun Wei, Xiaoxuan Yu, Rui Du, Xiaoqin Hong, Guangming Liu, Hongmei Gao, Dingbin Liu
Journal: Theranostics (2024)

Background: Bladder cancer (BC) ranks as one of the most prevalent cancers.Its early diagnosis is clinically essential but remains challenging due to the lack of reliable biomarkers.Extracellular vesicles (EVs) carry abundant biological cargoes from parental cells, rendering them as promising cancer biomarkers.Herein, we revealed that urinary EVs (uEVs) mRNA signature could serve as non-invasive biomarker for the early diagnosis and prognostic assessment for BC.Methods: Transcriptomic sequencing was conducted to reveal the mRNA signature of EVs collected from normal cell line and different grades of BC cell lines.Candidate EV-mRNA biomarkers were further profiled using clinical urine samples (n = 97, including healthy controls, BC patients and post-surgery BC patients) by RT-qPCR.Results: Three mRNAs (SRGN, FLI1, and MACROH2A2) within uEV were identified as potential biomarkers for BC, providing an area under the receiver operating characteristic curve (AUC) of 0.973 for BC diagnosis.Moreover, the uEV-mRNA panel could discriminate early-stage BC patients from healthy controls with an AUC of 0.969.Finally, we found that the uEV-mRNAs were significantly down-regulated in the post-surgery urine samples of BC patients.Conclusions: Given the facile and non-intrusive nature of urine collection, the identified uEV-mRNAs could serve as potential liquid-biopsy biomarkers for the early diagnosis and prognosis of BC.
Revisiting the unobtrusive role of exogenous stem cells beyond neural circuits replacement in spinal cord injury repair
Authors: Runlin Wen, Ge Long, Xinghui He, Kai Zhang, Wanrong Ma, Yeyu Shen, Zhifeng Xiao, Yannan Zhao, Dingyang Liu, Jianwu Dai, Xing Li
Journal: Theranostics (2024)

Rationale: Stem cell transplantation is a promising strategy to establish neural relays in situ for spinal cord injury (SCI) repair. Recent research has reported short-term survival of exogenous cells, irrespective of immunosuppressive drugs (ISD), results in similar function recovery, though the mechanisms remain unclear. This study aims to validate this short-term repair effect and the potential mechanisms in large animals. Methods: In this study, human spinal cord neural progenitor cells (hscNPCs) and human umbilical cord mesenchymal stem cells (hUMSCs) were transplanted into two different SCI model without ISD, respectively; Immunofluorescence was utilized to visualize neuronal regeneration and angiogenesis in the lesion site. Motor evoked potentials (MEPs) were detected to assess the integrity of motor pathways. And RNA sequencing was used to observe transcriptomic changes at the edge of the lesion. Results: The findings revealed hscNPCs failed to survive long-term, but the dogs exhibited better motor function recovery. Moreover, hscNPCs remodeled the injury microenvironment shortly after transplantation by reducing inflammation and enhancing angiogenesis, leading to increased endogenous neuronal regeneration. Similarly, hUMSCs neither survive long-term nor directly reconstruct neural circuits. However, basal functional recovery and endogenous neuronal regeneration were also detected in monkeys with hUMSCs. Conclusions: Exogenous short-term transplantation of stem cells in large animal SCI models does not restore basal function by directly replacing neural circuits throughout the lesion site. Rather, it does so by remodeling the lesion microenvironment in the early stages of transplantation to promote endogenous neural regeneration.
Millisecond-level transient heating and temperature monitoring technique for ultrasound-induced thermal strain imaging
Authors: Mengyue Chen, Zhiyu Sheng, Ran Wei, Bohua Zhang, Howuk Kim, Huaiyu Wu, Yu Chu, Qiyang Chen, Andrew Breon, Sibo Li, Matthew B. Wielgat, Dhanansayan Shanmuganayagam, Edith Tzeng, Xuecang Geng, Kang Kim, Xiaoning Jiang
Journal: Theranostics (2024)

Background: Ultrasound-induced thermal strain imaging (US-TSI) is a promising ultrasound imaging modality that has been demonstrated in preclinical studies to identify a lipid-rich necrotic core of an atherosclerotic plaque.However, human physiological motion, e.g., cardiac pulsation, poses challenges in implementing US-TSI applications, where achieving a millisecond-level temperature rise by delivering acoustic energy from a compact US-TSI probe is a key requirement.This study aims to develop a transient ultrasound heating and thermocouple monitoring technique at the millisecond level for US-TSI applications.Methods: We designed, prototyped, and characterized a novel US-TSI probe that includes a high-power, 3.5 MHz heating transducer with symmetrical dual 1D concave array.Additionally, millisecond-level temperature monitoring was demonstrated with fast-response thermocouples in laser-and ultrasound-induced thermal tests.Subsequently, we demonstrated the prototyped US-TSI probe can produce a desired temperature rise in a millisecond-short time window in vitro phantom and in vivo animal tests.Results: The prototyped US-TSI probe delivered zero-to-peak acoustic pressure up to 6.2 MPa with a 90 VPP input voltage.Both laser-and ultrasound-induced thermal tests verified that the selected thermocouples can monitor temperature change within 50 ms.The fast-response thermocouple confirmed the transient heating ability of the US-TSI probe, achieving a 3.9 °C temperature rise after a 25 ms heating duration (50% duty cycle) in the gel phantom and a 2.0 °C temperature rise after a 50 ms heating duration (50% duty cycle) in a pig model. Conclusions:We successfully demonstrated a millisecond-level transient heating and temperature monitoring technique utilizing the novel US-TSI probe and fast-response thermocouples.The reported transient ultrasound heating and thermocouple monitoring technique is promising for future in vivo human subject studies in US-TSI or other ultrasound-related thermal investigations.
<i>Leuconostoc citreum</i> enhances the colonization ability of <i>Lactiplantibacillus plantarum</i> in the gut by synergistically modifying the intestinal niche
Authors: Shuaiming Jiang, Zeng Zhang, Siyuan Shen, Jiahe Li, Shunyong Su, Lingwei Du, Wenyao Ma, Jiachao Zhang
Journal: Gut Microbes (2024)

Lactiplantibacillus plantarum HNU082 (Lp082) exhibits a wide range of health-modulating effects. However, its limited ability to colonize the intestines has hindered long-term effects. To enhance the colonization capability of Lp082, we conducted an intermittent intervention trial in mice and humans. After two interventions, Lp082 strain rapidly mutated after the second intervention, with a greater number of mutations observed in the human gut. By analyzing the abundance of Lp082 and fluctuations of gut microbiota, the key microbial factors that promote Lp082 colonization were identified. Through examination of the abundance changes and correlation analysis, we identified Leuconostoc citreum as the most positively correlated species with Lp082, and its synergistic effect on Lp082 colonization was verified in vivo. Coadministration of L. citreum more than doubled Lp082 abundance through the regulation of other bacterial species in the gut, reducing the number of species competing with Lp082 and increasing the beneficial fecal metabolite levels in the host intestine. This study provides a viable strategy for enhancing the colonization capability of L. plantarum, ensuring the long-term effectiveness of probiotics in the gut.
OTUB2 contributes to vascular calcification in chronic kidney disease via the YAP-mediated transcription of PFKFB3
Authors: Yalan Li, Xiaoyue Chen, Xueqiang Xu, Cheng Chen, Min Min, Dongmei Liang, Jiafa Ren, Huijuan Mao
Journal: Theranostics (2024)

Rationale: Chronic kidney disease (CKD) is a global public health issue, with vascular calcification (VC) being a common and deadly complication.Despite its prevalence, the underlying mechanisms of VC remain unclear.In this study, we aimed to investigate whether and how Otubain-2 (OTUB2) contributes to VC. Methods: The relationship between OTUB2 and VC was examined via immunohistochemical and immunofluorescence staining of discarded calcified radial arteries from uremic patients who underwent arteriovenous fistula operations.Additionally, mice were fed a 0.2% adenine diet supplemented with 1.2% phosphorus to establish a model of CKD-related VC.Vascular smooth muscle cell (VSMC)-specific OTUB2 knockout and overexpression were performed in vivo via the delivery of adeno-associated virus 9 vectors to manipulate the expression of OTUB2.Additionally, a calcified VSMC model was established to explore the roles of OTUB2 in VC by evaluating changes in osteogenic marker expression and calcium deposition.Results: Our results revealed a significant upregulation of OTUB2 expression during VC progression.OTUB2 overexpression upregulated the expression of osteogenic markers and exacerbated VSMC calcification, as verified by Von Kossa and Alizarin red staining.Conversely, VSMC-specific OTUB2 deficiency significantly mitigated adenine diet-induced VC in CKD mice.OTUB2 knockdown or inhibition decreased Yes-associated protein (YAP) abundance.Mechanistically, OTUB2 bound to YAP, decreasing its K48-linked polyubiquitination and inhibiting its subsequent degradation.Knockdown or inhibition of YAP abolished the effect of OTUB2 overexpression on VSMC calcification, indicating a YAP-mediated mechanism.Furthermore, the YAP/TEAD1 complex bound to the promoter of PFKFB3, increasing its transcriptional activity, as determined by CUT&RUN-qPCR.The knockdown or inhibition of PFKFB3 alleviated the procalcific effects of OTUB2.Conclusions: Our findings indicate that OTUB2 promotes VC at least partially by activating the YAP-PFKFB3 signaling pathway.Targeting OTUB2 may be an appealing therapeutic strategy for VC.
Acylglycerol kinase inhibits macrophage anti-tumor activity via limiting mtDNA release and cGAS-STING-type I IFN response
Authors: Qiuyang Du, Na Ning, Xiujuan Zhao, Feifan Liu, Si Zhang, Yuting Xia, Fei Li, Shijie Yuan, Xiaorong Xie, Mengdi Zhu, Zehan Huang, Zhaohui Tang, Jing Wang, Ran He, Xiang-Ping Yang
Journal: Theranostics (2024)

Background: Tumor associated macrophages (TAMs) are critical components in regulating the immune statuses of the tumor microenvironments.Although TAM has been intensively studied, it is unclear how mitochondrial proteins such as AGK regulate the TAMs' function.Methods: We investigated the AGK function in TAMs using macrophage-specific Agk deficient mice with B16 and LLC syngeneic tumor models.Flow cytometry was used to evaluate the stemness and activation of CD8 + T cells.The enhanced release of mtDNA into the cytosol in the Agk-deficient BMDMs was measured by RT-PCR and immunofluorescence; the cGAS-STING-type I IFN pathway was evaluated by immunoblotting.Mitochondria functions were evaluated by electron microscope and seahorse equipment.Results: We have noted an increased expression of AGK in TAMs of multiple tumor types, which was negatively correlates with the tumor tissue immune scores.In the B16 and LLC tumor models, macrophage Agk-deficient mice have reduced tumor growth and enhanced populations of CD8 + Tpex.AGK-deficient macrophages have increased mitochondrial damage and mtDNA release into the cytosol, which leads to enhanced cGAS-STING-type I IFN activation.Blockade of the type I IFN signaling pathway with anti-IFNAR reversed the phenotype in Agk-deficient mice.Conclusions: Our findings define a critical role of AGK in maintaining the macrophage mitochondrial homeostasis that is associated with mtDNA release and following cGAS-STING activation and type I IFN pathway.Targeting AGK in TAMs may represent a novel strategy to enhance anti-tumoral activity.
JARID1D-dependent androgen receptor and JunD signaling activation of osteoclast differentiation inhibits prostate cancer bone metastasis through demethylating H3K4
Authors: Yaohua Hu, Zhite Zhao, Qinghua Xie, Hui Li, Chenyang Zhang, Xinglin He, Yifan Ma, Caiqin Zhang, Qinlong Li, Changhong Shi
Journal: Theranostics (2024)

Rationale: Bone metastasis and skeletal-related complications are primary causes of mortality in advanced-stage prostate cancer (PCa). Epigenetic regulation, particularly histone modification, plays a key role in this process; however, the underlying mechanisms remain elusive. Methods and Results: In mouse models, JARID1D was an important mediator of both visceral and bone metastases. Chromatin immunoprecipitation (ChIP) and immunofluorescence (IF) techniques showed that the H3K4me3 demethylation activity of JARID1D is a key factor in the dynamic regulation of androgen receptor (AR) expression. Further analysis using western blotting and bone culture systems indicated that knocking down JARID1D enhanced the expression of monoamine oxidase A (MAOA) through the AR signaling pathway, leading to increased secretion of the nuclear factor kappa B (NF-κB) ligand receptor activator (RANKL) by PCa cells. This in turn promotes osteoclast differentiation and facilitates bone metastasis. In addition, single-cell sequencing results indicated that a reduction in JARID1D levels directly affected osteoclasts, stimulated JunD transcription, and accelerated PCa bone metastasis progression. Finally, both in vivo and in vitro experiments confirmed that the JARID1D agonist JIB-04 effectively blocked these molecular pathways, thereby delaying the onset of bone metastasis in PCa. Conclusions: These insights provide a theoretical foundation for targeting JARID1D and related molecules in the treatment of PCa bone metastasis.
A novel ROR1-targeting antibody-PROTAC conjugate promotes BRD4 degradation for solid tumor treatment
Authors: Lei Wang, Yong Ke, Qunye He, Pameila Paerhati, Weiliang Zhuang, Yali Yue, Junjun Liu, Jiawei Zhang, Lulu Huang, Qiang Yin, Huifang Zong, Jianwei Zhu, Baohong Zhang
Journal: Theranostics (2024)

Rationale: Proteolysis Targeting Chimeras (PROTACs) are bifunctional compounds that have been extensively studied for their role in targeted protein degradation (TPD).The capacity to degrade validated or undruggable targets provides PROTACs with significant potency in cancer therapy.However, the clinical application of PROTACs is limited by their poor in vivo potency and unfavorable pharmacokinetic properties.Methods: In this study, a novel degrader-antibody conjugate (DAC) was developed by conjugating the BRD4-degrading PROTAC with the ROR1 (receptor tyrosine kinase-like orphan receptor 1) antibody.The in vitro affinity, internalization efficacy, degradation, and cytotoxic activity of the ROR1 DAC were assessed.The pharmacokinetics, antitumor activity, and acute toxicity of ROR1 DAC were evaluated in mouse models.RNA sequencing (RNA-seq) and immunohistochemistry were performed to analyze the therapeutic efficacy mediated by the combination of ROR1 DAC and anti-mouse programmed cell death protein 1 (αmPD1) mAb. Results:The ROR1 DAC exhibited strong degradation activity and cytotoxicity following antigen binding and internalization.Compared to unconjugated PROTAC, the ROR1 DAC demonstrated improved pharmacokinetics and potent antitumor efficacy in PC3 and MDA-MB-231 xenograft mouse models.Furthermore, enhanced antitumor activity and immune cell infiltration within solid tumors were observed when combined with αmPD-1 mAb in C57BL/6J mice.RNA sequencing revealed that the enhanced immune response associated with the combination treatment is related to tumor microenvironment modulation, including the upregulation of Th1-biased cytokines.Moreover, the ROR1 DAC exhibited a favorable safety profile in an acute toxicity study.Conclusions: These results indicate that the degrader-antibody conjugate is a promising candidate for tumor-specific degradation and effective cancer therapy.
PCBP2-dependent secretion of miRNAs via extracellular vesicles contributes to the EGFR-driven angiogenesis
Authors: Hou-Fu Xia, Xiao-Le Wang, He-Jing Zhang, Kui-Ming Wang, Lin-Zhou Zhang, Yang Yang, Xin Shi, Gang Chen
Journal: Theranostics (2024)

Rationale:The EGFR-driven angiogenesis is crucial in solid tumors, particularly through the delivery of biomolecules via extracellular vesicles (EVs), but the mechanism by which EGFR regulates EV cargo is still unclear.Methods: First, cell co-culture and murine tumor models were employed to examine the impact of EGFR overexpression on the pro-angiogenic properties of small EVs (sEVs) derived from oral squamous cell carcinoma (OSCC).Small RNA sequencing was then used to compare the miRNA profiles of OSCC-sEVs with and without EGFR overexpression, followed by functional enrichment and motif analyses of the differentially expressed miRNAs.Next, miRNA pull-down assays were conducted to identify potential molecules involved in sorting these miRNAs.Finally, the role of the candidate sorting protein was validated using existing public database, tissue samples, cell lines, and murine tumor models.Results: EGFR overexpression significantly enhances the pro-angiogenic effects of OSCC-sEVs, accompanied by a marked increase in the content of nucleic acid cargo carried in these sEVs.Small-RNA sequencing identified a group of miRNAs that were significantly enriched in OSCC-sEVs due to EGFR overexpression, which primarily functioned in angiogenesis and shared a characteristic "GGGU" motif.EGFR overexpression also strengthened the binding of PCBP2 with miRNAs containing this "GGGU" motif, thereby promoting their secretion through sEVs to support tumor angiogenesis.Mechanismly, EGFR overexpression upregulates PCBP2 protein content by activating its transcription rather than regulating the mRNA stability in OSCC cells.Additionally, depletion of PCBP2 impaired the EGFR-driven tumor angiogenesis by inhibiting the secretion of pro-angiogenic miRNAs through sEVs.Conclusions: EGFR boosts PCBP2 expression via transcriptional regulation, which then promotes the loading of specific miRNAs into sEVs by binding to the "GGGU" motif, thereby driving tumor angiogenesis.
Protein serine/threonine phosphatases in tumor microenvironment: a vital player and a promising therapeutic target
Authors: Yiyang Liu, Feng Xia, Chang Zhu, Jia Song, Bufu Tang, Bixiang Zhang, Zhao Huang
Journal: Theranostics (2024)

The tumor microenvironment (TME) is involved in cancer initiation and progression. With advances in the TME field, numerous therapeutic approaches, such as antiangiogenic treatment and immune checkpoint inhibitors, have been inspired and developed. Nevertheless, the sophisticated regulatory effects on the biological balance of the TME remain unclear. Decoding the pathological features of the TME is urgently needed to understand the tumor ecosystem and develop novel antitumor treatments. Protein serine/threonine phosphatases (PSPs) are responsible for inverse protein phosphorylation processes. Aberrant expression and dysfunction of PSPs disturb cellular homeostasis, reprogram metabolic processes and reshape the immune landscape, thereby contributing to cancer progression. Some therapeutic implications, such as the use of PSPs as targets, have drawn the attention of researchers and clinicians. To date, the effects of PSP inhibitors are less satisfactory in real-world practice. With breakthroughs in sequencing technologies, scientists can decipher TME investigations via multiomics and higher resolution. These benefits provide an opportunity to explore the TME in a more comprehensive manner and inspire more findings concerning PSPs in the TME. The current review starts by introducing the canonical knowledge of PSPs, including their members, structures and posttranslational modifications for activities. We then summarize the functions of PSPs in regulating cellular homeostasis. In particular, we specified the up-to-date roles of PSPs in modulating the immune microenvironment, adopting hypoxia, reprogramming metabolic processes, and responding to extracellular matrix remodeling. Finally, we introduce preclinical PSP inhibitors with translational value and conclude with clinical trials of PSP inhibitors for cancer treatment.