Theranostics最新文献

Rationale: The level of miR-206-3p in the plasma and temporal cortex is increased in Alzheimer's disease (AD) patients. miR-206-3p antagomir injected into hippocampus ameliorates cognitive deficits by enhancing the level of BDNF. However, the trauma caused by brain injection and susceptibility to degradation limit its application. Methods: To overcome these challenges, we constructed engineered extracellular vesicles derived from mesenchymal stem cell (MSC-EVs) loaded with miR-206-3p antagomir (MSC-EVs-anta) by electroporation technology, and explored the therapeutic effects of MSC-EVs-anta delivered by intranasal administration on AD mice. Transcriptome sequencing and LC-MS/MS proteomic analysis were employed to disclose the mechanism underlying the attenuation of AD phenotypes by MSC-EVs-anta. Results: MSC-EVs-anta had favorable neuroprotection by promoting neurite outgrowth in vitro. Following intranasal administration, MSC-EVs-anta improved learning and memory deficits, promoted hippocampal neurogenesis and synaptic plasticity, and alleviated Aβ deposition. Compared with MSC-EVs or miR-206-3p antagomir alone, MSC-EVs-anta showed superior therapeutic effects. Mechanistically, MSC-EVs-anta significantly upregulated brain-derived neurotrophic factor (BDNF) in AD mice, and activated the BDNF/TrkB signaling pathway. The data from two-omics analyses demonstrated that the differentially expressed proteins and genes significantly regulated by MSC-EVs-anta were primarily enriched in the pathways involved in neurogenesis and synapse. Conclusions: Our findings highlight the intranasal administration of MSC-EVs-anta as a promising strategy for the treatment of AD.

Rationale: Osteoclasts are giant bone-resorbing cells that need vigorous mitochondrial respiration to support their activation. Rc3h1, an RNA-binding protein, precisely governs the homeostasis of mRNA. However, the precise role of Rc3h1 in regulating iron metabolism and mitochondrial respiration in osteoclasts is not yet understood. Methods: We generated Rc3h1-deficient mice in osteoclast precursors and mature osteoclasts. The bone mass and osteoclast activity in bone tissues were evaluated. Moreover, we assessed the differentiation, bone resorption, iron content, and mitochondrial function of osteoclasts in vitro. In the end, the target gene of Rc3h1 and its role in mediating the effect of Rc3h1 on mitochondrial respiration in osteoclasts were further investigated. Results: Mice lacking Rc3h1 exhibit low bone mass. In addition, Rc3h1 deletion in osteoclasts significantly promotes osteoclast activation. Mechanistically, Rc3h1 post-transcriptionally represses the expression of transferrin receptor 1 (Tfr1), restricting iron absorption and mitochondrial respiration in osteoclasts. Inhibition of Tfr1 in Rc3h1-deficient osteoclasts diminishes excessive osteoclast formation and mitochondrial respiration. Conclusion: These findings suggest that Rc3h1 has a negative effect on osteoclast activation via limiting iron resorption and mitochondrial respiration. Finally, targeting the Rc3h1/Tfr1 axis might represent a potential therapeutic approach for bone-loss diseases.

Rationale: Endotoxemia, caused by lipopolysaccharides, triggers systemic inflammation and myocardial injury by disrupting mitochondrial homeostasis. This study examines the roles of dual specificity phosphatase 1 (Dusp1) and phosphoglycerate mutase family member 1 (Pgam1) in this process. Methods: This study utilized cardiomyocyte-specific Dusp1 knockout (Dusp1^Cko ) and transgenic (Dusp1^Tg ) mice, alongside Pgam1 knockout (Pgam1^Cko ) mice, subjected to LPS-induced endotoxemia. Echocardiography was performed to assess cardiac function. Mitochondrial integrity was evaluated using molecular techniques, including qPCR and Seahorse assays. Additionally, molecular docking studies and Western blot analyses were conducted to explore the interaction between Pgam1 and Dusp1. Results: Using single-cell sequencing and human sample databases, Dusp1 emerged as a novel biomarker for endotoxemia-induced myocardial dysfunction. Experiments with cardiomyocyte-specific Dusp1 knockout (Dusp1^Cko ) and Dusp1 transgenic (Dusp1^Tg ) mice showed that Dusp1 deficiency worsens, while overexpression improves, heart function during LPS-induced myocardial injury. This effect is mediated by regulating inflammation and cardiomyocyte viability. Molecular analyses revealed that LPS exposure leads to Dusp1 dephosphorylation at Ser364, increasing its degradation. Stabilizing Dusp1 phosphorylation enhances mitochondrial function through mitochondrial quality control (MQC), including dynamics, mitophagy, and biogenesis. Functional studies identified Pgam1 as an upstream phosphatase interacting with Dusp1. Pgam1 ablation reduced LPS-induced cardiomyocyte dysfunction and mitochondrial disorder. Conclusions: Pgam1-mediated dephosphorylation of Dusp1 disrupts mitochondrial quality control, leading to myocardial dysfunction in endotoxemia. Targeting the Pgam1-Dusp1 axis represents a promising therapeutic strategy for improving cardiac outcomes in patients with endotoxemia.

Proteins face several challenges in biomedicine, including issues with antibody production, degradation by proteases, rapid clearance by the kidneys, and short half-lives. To address these problems, various nano delivery systems have been developed, with virus-like particles (VLPs) emerging as a leading solution. VLPs, which are self-assembled protein complexes, offer effective encapsulation and transport of proteins. They provide enhanced stability, extended circulation time, preserved biological activity, improved targeting for therapies or imaging, and reduced side effects due to minimized systemic exposure. This review explores various methods for encapsulating proteins within VLPs. It assesses the benefits and limitations of each method and their applications in imaging, therapeutic enzyme delivery, vaccines, immunotherapy, nanoreactors, and biosensors. Future advancements in VLPs will depend on improving packaging methods, controlling protein loading, optimizing assembly techniques, and enhancing capsid design. The review also discusses current challenges and proposes solutions to advance the use of VLPs in various applications.

[This corrects the article DOI: 10.7150/thno.61178.].

Rationale: More than half of the patients with type II diabetes mellitus (T2D) develop diabetic cardiomyopathy (DCM). Glycemic control alone cannot effectively prevent or alleviate DCM. Methods: Herein, we concentrated on the variations in levels of metabolites between DCM and T2D patients without cardiomyopathy phenotype. In high-fat diet/low-dose streptozotocin-induced T2D and leptin receptor-deficient diabetic mouse models, we investigated the effect of altering branched-chain amino acids (BCAAs) levels on DCM. Results: We discovered that the levels of plasma BCAAs are notably lower in 15 DCM patients compared to 19 T2D patients who do not exhibit cardiomyopathy phenotype, using nuclear magnetic resonance analysis. This finding was further validated in two additional batches of samples, 123 DCM patients and 129 T2D patients based on the BCAA assay kit, and 30 DCM patients and 30 T2D patients based on the LC-MS/MS method, respectively. Moreover, it is verified that BCAA deficiency aggravated, whereas BCAA supplementation alleviated cardiomyopathy phenotypes in diabetic mice. Furthermore, BCAA deficiency promoted cardiac fibroblast activation by stimulating autophagy in DCM mice. Mechanistically, BCAA deficiency activated autophagy via the AMPK-ULK1 signaling pathway in cardiac fibroblasts. Using pharmacological approaches, we validated our findings that autophagy inhibition relieved, whereas autophagy activation aggravated, DCM phenotypes. Conclusions: Taken together, we describe a novel perspective wherein BCAA supplementation may serve as a potential therapeutic agent to mitigate DCM and fibrosis. Our findings provide insights for the development of preventive measures for DCM.

Background: Distinguishing unilateral aldosterone-producing adenomas (APA) from idiopathic hyperaldosteronism (IHA), nonfunctional adrenal adenoma (NFA), and pheochromocytoma (PHEO) within primary aldosteronism (PA) presents a significant challenge. Studies have demonstrated high levels of chemokine receptor (CXCR) 4 expression in APA, thereby validating the use of ⁶⁸Ga-labeled CXCR4 PET/CT for detecting APA. This study evaluates the efficacy of [¹⁸F]AlF-NOTA-pentixather PET/CT in distinguishing APA from other PA types. Methods: In the initial experiment, a comparative analysis was conducted to evaluate the diagnostic efficacy of [¹⁸F]AlF-NOTA-T140 PET/CT and [¹⁸F]AlF-NOTA-pentixather PET/CT for APA in 3 patients with PA. Based on the preliminary findings, [¹⁸F]AlF-NOTA-pentixather PET/CT was subsequently performed on 45 patients with suspected PA and 5 controls. Lesions exhibiting higher tracer uptake than normal adrenal glands were considered positive and referred for adrenalectomy. Prior to surgery, adrenal venous sampling (AVS) was performed in 71.1% of patients to assess laterality. Postoperative follow-up was conducted in 91.1% of patients. The semi-quantitative analysis involved assessing maximum standardized uptake value (SUVmax), LLR (lesion-to-liver ratio), and lesion-to-contralateral ratio (LCR). Correlations were made between PET/CT findings, histopathology results, outcomes, and AVS. Results: In terms of diagnosing APA, [¹⁸F]AlF-NOTA-pentixather PET/CT demonstrated a sensitivity of 100%, specificity of 91.7%, and accuracy of 95.8%. The mean SUVmax for APAs (25.62 ± 12.71, n = 24) was significantly higher compared to non-APA cases (7.24 ± 3.27, n = 24, P < 0.0001). An optimal SUVmax threshold of 11.60 accurately predicted the presence of APA with a sensitivity of 95.8%, specificity of 96.0%, and accuracy of 93.9%. A cutoff value for LCR at 1.38 provided 95.8% sensitivity and 92.0% specificity, while an LLR cutoff at 5.28 yielded a sensitivity rate of 91.7% and a specificity rate of 92.0%. Positive findings on PET/CT scans were completely consistent with AVS results. All patients with positive lesions derived significant benefits from surgical intervention. Conclusion: [¹⁸F]AlF-NOTA-pentixather PET/CT seems to be highly related to AVS and could be a noninvasive method for diagnosing APA in patients with PA.

Rationale: Metabolic dysfunction is one of the key pathological events after ischemic stroke. Disruption of cerebral blood flow impairs oxygen and energy substrate delivery, leading to mitochondrial oxidative phosphorylation dysfunction and cellular bioenergetic stress. Investigating the effects of circSCMH1, a brain repair-related circular RNA, on metabolism may identify novel therapeutic targets for stroke treatment. Methods: CircSCMH1 was encapsulated into brain-targeting extracellular vesicles (EVs) mediated by rabies virus glycoprotein (RVG). Using a mouse model of photothrombotic (PT) stroke, we employed metabolomics and transcriptomics, combined with western blotting and behavioral experiments, to identify the metabolic targets regulated in RVG-circSCMH1-EV-treated mice. Additionally, immunofluorescence staining, chromatin immunoprecipitation (ChIP), pull-down, and western blotting were utilized to elucidate the underlying mechanisms. Results: The targeted delivery of circSCMH1 via RVG-EVs was found to promote post-stroke brain repair by enhancing mitochondrial fusion and inhibiting mitophagy through suppression of kynurenine 3-monooxygenase (KMO) expression. Mechanistically, circSCMH1 exerted its inhibitory effect on KMO expression by binding to the transcription activator STAT5B, thereby impeding its nuclear translocation. Conclusions: Our study reveals a novel mechanism by which circSCMH1 downregulates KMO expression, thereby enhancing mitochondrial fusion and inhibiting mitophagy, ultimately facilitating post-stroke brain repair. These findings shed new light on the role of circSCMH1 in promoting stroke recovery and underscore its potential as a therapeutic target for the treatment of ischemic stroke.

Background: Diagnosis and treatment efficacy of major depressive disorder (MDD) currently lack stable and reliable biomarkers. Previous research has suggested a potential association between immune cells, cytokines, and the pathophysiology and treatment of MDD. Objective: This study aims to investigate the relationship between immune cells, cytokines, and the diagnosis of MDD and treatment response, further utilizing machine learning algorithms to develop robust diagnostic and treatment response prediction models. Methods: Using mass cytometry by time-of-flight (CyTOF) technology and high-throughput cytokine detection, we analyzed 63 types of immune cells from 134 pre-treatment MDD patients. Among these patients, plasma data for 440 cytokines were obtained from 84 individuals. Additionally, we conducted the same set of immune cell and cytokine analyses on 50 healthy controls (HC). An 8-week follow-up was conducted to observe post-treatment changes in immune cells and cytokines. Results: By combing eight machine-learning algorithms with CyTOF and cytokine data, we constructed a diagnostic model for MDD patient with 16 indicators, achieving an AUC of 0.973 in the internal validation set. Additionally, a treatment response prediction model based 7 cytokines was developed, resulting in an AUC of 0.944 in the internal validation set. Furthermore, Mfuzz time-series analysis revealed that cytokines such as Basic fibroblast growth factor (bFGF), Interleukin 13 (IL-13), and Interleukin 1 receptor, type I (IL1R1) that revert towards normal levels after 8 weeks of treatment, suggesting their potential as therapeutic targets for MDD. Conclusions: Our diagnostic model derived from CyTOF and cytokines demonstrates high diagnostic value. However, relying solely on immune cells may not provide optimal predictions for antidepressant treatment response. In contrast, leveraging cytokines has proven valuable, leading to the construction of a seven-factor treatment response prediction model. Importantly, we observed that several significantly altered cytokines in MDD can normalize following antidepressant treatment, indicating their potential as therapeutic targets.