Theranostics最新文献

The human body is an intricate system, where diverse and complex signaling among different organs sustains physiological activities. The eye, as a primary organ for information acquisition, not only plays a crucial role in visual perception but also, as increasing evidence suggests, exerts a broad influence on the entire body through complex circuits upon receiving light signals which is called non-image-forming vision. However, the extent and mechanisms of light's impact on the body through the eyes remain insufficiently explored. There is also a dearth of comprehensive reviews elucidating the intricate interplay between light, the eye, and the systemic connections to the entire body. Herein, we propose the concept of the light-eye-body axis to systematically encapsulate the extensive non-image-forming effects of light signals received by the retina on the entire body. We reviewed the visual-neural structure basis of the light-eye-body axis, summarized the mechanism by which the eyes regulate the whole body and the current research status and challenges within the physiological and pathological processes involved in the light-eye-body axis. Future research should aim to expand the influence of the light-eye-body axis and explore its deeper mechanisms. Understanding and investigating the light-eye-body axis will contribute to improving lighting conditions to optimize health and guide the establishment of phototherapy standards in clinical practice.

Rationale: The hyperactivity of lateral habenula (LHb) has been implicated in the pathophysiology of depression, but the regulatory mechanisms of inhibitory synapses in this context remains unclear. MDGA1 and neuroligin2 (Nlgn2), both regulators of inhibitory synapses, selectively interact in the LHb. We aimed to investigate if their interaction contributes to chronic restrained stress (CRS)-induced depression by modulating inhibitory synapses. Methods: Transgenic mouse models were established to conditional knockout/recover of MDGA1 expression or knockin Nlgn2 variant incapable of binding MDGA1 in the LHb, using viral Cre-recombinase expression. Synaptic function and density were assessed through electrophysiology and immunostaining, respectively. An acute restrained stress (ARS) model and chemogenetic activation of the lateral hypothalamus (LH) were used to stimulate the LHb. Behavioral tests related to depression were conducted following CRS. Results: MDGA1 and Nlgn2 selectively interacted in the LHb, which was elevated following CRS. Germline knockout of MDGA1 increased inhibitory transmission and GABAergic synapse density in the LHb, effects that were reversed by adult re-expression of MDGA1. Introduction of the Nlgn2 variant incapable of binding MDGA1 similarly enhanced inhibitory transmission and increased GABAergic synapse density in the LHb. Both germline MDGA1 deficiency and introduction of the Nlgn2 variant mitigated ARS- and LH activation-induced LHb neuron hyperactivation. MDGA1 deficiency in the LHb during adulthood increased inhibitory synaptic strength and conferred significant resistance to CRS-induced depressive behaviors, similar to the effects of introducing the Nlgn2 variant in the LHb. Conclusions: Our findings suggests that MDGA1-mediated suppression of Nlgn2 facilitates depression onset through limiting GABAergic synapse formation within the LHb. Targeting MDGA1/Nlgn2 complexes residing at GABAergic synapses within the lateral habenula may be viable for alleviating core behavioral symptoms of major depression.

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.

The quest for a cancer-specific positron emission tomography (PET) tracer has been ongoing for decades. Current evidence shows that targeting amino acid metabolism dysregulation is a valid alternative cancer detection method and can complement the conventional approach, which relies on targeting increased glucose metabolism. The rate of amino acid metabolism in all major organs is mostly equally low and does not change in any physiological dynamics. The amino acid metabolism rate only spikes in malignant tissues. PET imaging targeting LAT1 (L-type amino acid transporter 1) demonstrated accurate cancer imaging of various cancer types with nearly negligible background uptake. LAT1 is a pan-cancer biomarker of amino acid metabolism dysregulation. The upregulated LAT1 expression in cancer cells depicts their dynamic behavior and aggressiveness. This review discussed PET radiotracers developed as a LAT1-specific agent and how this new class of cancer-specific radiopharmaceuticals could deliver PET images with clinical properties we yearn for, such as high specificity toward various malignancies, robust non-cancer exclusion (mainly inflammatory reactions), accurate malignant lesion delineation, representative therapeutic monitoring, and long-term prognostication.

Vulnerable plaques, which are high-risk features of atherosclerosis, constitute critical elements in the disease's progression due to their formation and rupture. Macrophages and macrophage-derived foam cells are pivotal in inducing vulnerability within atherosclerotic plaques. Thus, understanding macrophage contributions to vulnerable plaques is essential for advancing the comprehension of atherosclerosis and devising novel therapeutic and diagnostic strategies. This review provides an overview of the pathological characteristics of vulnerable plaques, emphasizes macrophages' critical role, and discusses advanced strategies for their diagnosis and treatment. It aims to present a comprehensive macrophage-centered perspective for addressing vulnerable plaques in atherosclerosis.

Rationale: Colorectal cancer (CRC) is a leading cause of cancer-related mortality. Epigenetic modifications play a significant role in the progression of CRC. KAT7, a histone acetyltransferase, has an unclear role in CRC. Methods: In this research, we analyzed the expression of KAT7 in CRC patients and its correlation with prognosis using the GEO database, western blot, and immunohistochemistry. We assessed the impact of KAT7 on CRC cell functions through cell viability, colony formation, flow cytometry, scratch, and transwell assays. Mechanistic insights were obtained via RNA sequencing and ChIP-qPCR. Additionally, we evaluated the effects of KAT7 on CRC growth and metastasis in vivo using mouse subcutaneous tumor and lung metastasis models. Results: In this study, we discovered an upregulated KAT7 signaling pathway in CRC and its association with poor patient survival. Knockdown of KAT7 promotes apoptosis and inhibits proliferation, migration, and invasion of CRC cells. Conversely, KAT7 overexpression enhanced these cellular processes. In vivo assays confirmed that knockdown of KAT7 can inhibit CRC proliferation and lung metastasis. Mechanistically, KAT7 acetylated histone H3 at lysine 14 (H3K14) to enhance MRAS transcription, which activated the MAPK/ERK pathway and promoted tumorigenesis. The enzymatic function of KAT7 as an acetyltransferase is crucial for the advancement of colorectal cancer. In KAT7 knockdown CRC cells, re-expression of KAT7, but not an acetyltransferase-deficient mutant, rescued MRAS expression, ERK phosphorylation, and CRC tumorigenesis. Conclusion: We found that KAT7 is highly expressed in CRC patients, and those with high KAT7 expression have a worse prognosis. KAT7 enhances MRAS gene transcription by promoting H3K14 acetylation, thereby activating the MAPK/ERK pathway and promoting malignant phenotypes of CRC. In summary, KAT7 represents a promising target for CRC therapy.

Rationale: Myocardial ischemia/reperfusion (I/R) injury leads to irreversible cardiomyocyte death and aggravates myocardial infarction. Deubiquitinating enzymes (DUBs) are essential for maintaining substrate protein stability and functionality, playing significant roles in cardiac pathophysiology. In this study, we aimed to clarify the regulatory role of a DUB, Myb-like, SWIRM, and MPN domains 1 protein (MYSM1), in myocardial I/R injury and explore the molecular mechanism behind. Methods and Results: Firstly, it was found that the expression of MYSM1 positively correlates with myocardial I/R injury. Genetic knockdown of MYSM1 significantly conferred protection against I/R injury in hearts. Correspondingly, AAV9-mediated cardiomyocyte-specific knockdown of MYSM1 had a therapeutic effect on myocardial I/R injury. Through a comprehensive proteome-wide quantitative analysis, we identified signal transducer and activator of transcription 1 (STAT1) as the direct substrate of MYSM1. Mechanistically, MYSM1 mediated the K63-linked deubiquitination and stabilization of STAT1 at position K379 via its MPN metalloprotease domain. Additionally, MYSM1 initiates the expression of necroptosis-related genes by promoting the transcription factor function of STAT1. Conclusion: This study illustrated a MYSM1-STAT1 axis in regulating myocardial I/R injury and identified MYSM1 as a pharmacological target for myocardial I/R injury.

Lactate is an indispensable substance in various cellular physiological functions and plays regulatory roles in different aspects of energy metabolism and signal transduction. Lactylation (Kla), a key pathway through which lactate exerts its functions, has been identified as a novel posttranslational modification (PTM). Research indicates that Kla is an essential balancing mechanism in a variety of organisms and is involved in many key cellular biological processes through different pathways. Kla is closely related to disease development and represents a potential and important new drug target. In line with existing reports, we searched for newly discovered Kla sites on histone and nonhistone proteins; reviewed the regulatory mechanisms of Kla (particularly focusing on the enzymes directly involved in the reversible regulation of Kla, including "writers" (modifying enzymes), "readers" (modification-binding enzymes), and "erasers" (demodifying enzymes); and summarized the crosstalk between different PTMs to help researchers better understand the widespread distribution of Kla and its diverse functions. Furthermore, considering the "double-edged sword" role of Kla in both physiological and pathological contexts, this review highlights the "beneficial" biological functions of Kla in physiological states (energy metabolism, inflammatory responses, cell fate determination, development, etc.) and its "detrimental" pathogenic or inducive effects on pathological processes, particularly malignant tumors and complex nontumor diseases. We also clarify the molecular mechanisms of Kla in health and disease, and discuss its feasibility as a therapeutic target. Finally, we describe the detection technologies for Kla and their potential applications in diagnosis and clinical settings, aiming to provide new insights for the treatment of various diseases and to accelerate translation from laboratory research to clinical practice.

Rationale: Physical exercise is essential for skeletal integrity and bone health. The gut microbiome, as a pivotal modulator of overall physiologic states, is closely associated with skeletal homeostasis and bone metabolism. However, the potential role of intestinal microbiota in the exercise-mediated bone gain remains unclear. Methods: We conducted microbiota depletion and fecal microbiota transplantation (FMT) in ovariectomy (OVX) mice and aged mice to investigate whether the transfer of gut ecological traits could confer the exercise-induced bone protective effects. The study analyzed the gut microbiota and metabolic profiles via 16S rRNA gene sequencing and LC-MS untargeted metabolomics to identify key microbial communities and metabolites responsible for bone protection. Transcriptome sequencing and RNA interference were employed to explore the molecular mechanisms. Results: We found that gut microbiota depletion hindered the osteogenic benefits of exercise, and FMT from exercised osteoporotic mice effectively mitigated osteopenia. Comprehensive profiling of the microbiome and metabolome revealed that the exercise-matched FMT reshaped intestinal microecology and metabolic landscape. Notably, alterations in bile acid metabolism, specifically the enrichment of taurine and ursodeoxycholic acid, mediated the protective effects on bone mass. Mechanistically, FMT from exercised mice activated the apelin signaling pathway and restored the bone-fat balance in recipient MSCs. Conclusion: Our study underscored the important role of the microbiota-metabolic axis in the exercise-mediated bone gain, heralding a potential breakthrough in the treatment of osteoporosis.

Rationale: Pulmonary arterial hypertension (PAH) is a life-threatening disorder characterized by increased pulmonary blood pressures and regional inhomogeneities in flows, with diagnostic and treatment challenges arising from diverse underlying pathogenic mechanisms. Conventional in vitro models often obscure the mechanistic nuances of PAH by failing to replicate the dynamic mechanical environment of the diseased lung, limiting the identification of specific molecular patterns. To address this, we employed an in vitro shear stress model simulating physiological or pathological conditions to explore the transcriptional heterogeneity of human pulmonary microvascular endothelial cells (hPMECs) from PAH patients and healthy controls within their respective biomechanical context. Methods & Results: hPMECs from PAH patients and controls were exposed to static, low shear stress (LSS), and high shear stress (HSS) conditions, followed by bulk RNA-sequencing. While increasing shear stress resulted in a greater number of differentially expressed genes, traditional grouped analysis showed minimal overall transcriptional differences. Further, pathway enrichment analysis indicated common shear-induced responses in both groups, suggesting that standard analysis methods may mask meaningful disease-specific changes. Crucially, detailed dimensionality reduction analyses revealed pronounced inter-patient variability among PAH donors in response to increasing shear stress, facilitating the identification of 398 genes driving this transcriptional heterogeneity. Unsupervised clustering of these high-variability genes enabled the sub-classification of patients based on their unique transcriptomic profiles, each linked to specific combinations of PAH associated pathogenic pathways such as mesenchymal transition, inflammation, metabolism, extracellular matrix remodeling, and cell cycle/DNA damage signaling. Importantly, re-analysis of published peripheral blood mononuclear cell (PBMC) omics data from PAH patients confirmed the clinical feasibility to utilize these high-variability genes as a non-invasive, accessible approach for molecular patient stratification. Conclusion: Our study uncovers patient-specific transcriptomic patterns in PAH, providing a novel molecular sub-classification strategy. These findings represent a significant step toward personalized molecular diagnostics in PAH and eventual therapeutic interventions for clinically well-defined PAH patients, with potential applications in clinically accessible cell populations such as PBMCs.