Theranostics最新文献

Rationale: Fecal microbiota transplantation (FMT) is advantageous for treating intractable diseases via the microbiota-gut-organ axis. However, invasive administration of gut microbiota via nasal feeding tubes limits the widespread application of FMT. Here, we attempted to develop a novel strategy to deliver gut microbiota using nanocapsules. Methods: Single-cell nanocapsules were fabricated within 1 h by layer-by-layer assembly of silk fibroin and phosphatidylcholine to generate a protective nanoshell on the cell surface of complicated microbiota. The physical properties of the microbiota nanocapsules were analyzed. The protective effects of nanocapsules on the gastrointestinal tract were analyzed both in vitro and in vivo. The efficacy of FMT assisted by single-cell nanocapsules (NanoFMT) was evaluated using the inflammatory response, gut microbiota balance, and histopathological analysis in animal model. Results: The nanocapsules achieved a good coating ratio for a single type of microbe and complex microbiota, resulting in a remarkable increase in the survival rate of microbes in the gastrointestinal tract. NanoFMT improved the diversity and abundance of the gut microbiota better than common FMT in germ-free mice. Moreover, NanoFMT alleviated intestinal inflammation and positively reversed the microbiota balance in a mouse model of colitis compared with common FMT, assisted by the inherent anti-inflammatory effects of silk fibroin and phosphatidylcholine. Conclusions: Considering its rapid preparation, convenient delivery, and perfect therapeutic effect, we anticipate that NanoFMT may be a promising clinical candidate for next-generation FMT treatment.

Solid tissue biopsy is fundamental in guiding surgeons during intraoperative and peri-operative management of cancer patients. However, conventional histopathologic methods depend heavily on the expertise of trained pathologists, facing challenges in accuracy and efficiency. Methods: Here, we show that unbiased labeling of proteins within tissue sections using tumor-selective dyes enhances tumor-specific signals, enabling robust and accurate differentiation of tumors from normal tissues in less than 45 min. This diagnostic approach combines a tumor-selective dye labeling strategy and a three-dimensional (3D) histological electrophoresis separation strategy to visualize protein differences between tissues and exclude off-target interference. Results: We successfully diagnose and delineate malignant tissue from frozen and fresh surgical specimens from 34 patients across six types of cancer (mean AUC = 0.93). Furthermore, we apply this method to distinguish different histological characteristics in liver cancer surgical specimens, as well as identify and quantify the degree of inflammation in tumor-surrounding tissues. Conclusion: This rapid, accurate, unbiased, and marker-free approach may enhance intraoperative detection of multiple types of tumor specimens.

Rationale: Silybum marianum is used to protect against degenerative liver damage. The molecular mechanisms of its bioactive component, silybin, remained enigmatic, although membrane-stabilizing properties, modulation of membrane protein function, and metabolic regulation have been discussed for decades. Methods: Experiments were performed with hepatocyte cell lines and primary monocytes in vitro under both basal and stressed conditions, and in mice in vivo. Quantitative lipidomics was used to detect changes in phospholipids and triglycerides. Key findings were confirmed by Western blotting, quantitative PCR, microscopy, enzyme activity assays, metabolic flux studies, and functional relationships were investigated using selective inhibitors. Results: We show that specifically the stereoisomer silybin A decreases triglyceride levels and lipid droplet content, while enriching major phospholipid classes and maintaining a homeostatic phospholipid composition in human hepatocytes in vitro and in mouse liver in vivo under normal and pre-disease conditions. Conversely, in cell-based disease models of lipid overload and lipotoxic stress, silybin treatment primarily depletes triglycerides. Mechanistically, silymarin/silybin suppresses phospholipid-degrading enzymes, induces phospholipid biosynthesis to varying degrees depending on the conditions, and down-regulates triglyceride remodeling/biosynthesis, while inducing complex changes in sterol and fatty acid metabolism. Structure-activity relationship studies highlight the importance of the 1,4-benzodioxane ring configuration of silybin A in triglyceride reduction and the saturated 2,3-bond of the flavanonol moiety in phospholipid accumulation. Enrichment of hepatic phospholipids and intracellular membrane expansion are associated with a heightened biotransformation capacity. Conclusion: Our study deciphers the structural features of silybin contributing to hepatic lipid remodeling and suggests that silymarin/silybin protects the liver in individuals with mild metabolic dysregulation, involving a lipid class switch from triglycerides to phospholipids, whereas it may be less effective in disease states associated with severe metabolic dysregulation.

Rationale: Chronic kidney disease (CKD) is a progressively debilitating condition leading to kidney dysfunction and severe complications. While dysbiosis of the gut bacteriome has been linked to CKD, the alteration in the gut viral community and its role in CKD remain poorly understood. Methods: Here, we characterize the gut virome in CKD using metagenome-wide analyses of faecal samples from 425 patients and 290 healthy individuals. Results: CKD is associated with a remarkable shift in the gut viral profile that occurs regardless of host properties, disease stage, and underlying diseases. We identify 4,649 differentially abundant viral operational taxonomic units (vOTUs) and reveal that some CKD-enriched viruses are closely related to gut bacterial taxa such as Bacteroides, [Ruminococcus], Erysipelatoclostridium, and Enterocloster spp. In contrast, CKD-depleted viruses include more crAss-like viruses and often target Faecalibacterium, Ruminococcus, and Prevotella species. Functional annotation of the vOTUs reveals numerous viral functional signatures associated with CKD, notably a marked reduction in nicotinamide adenine dinucleotide (NAD⁺) synthesis capacity within the CKD-associated virome. Furthermore, most CKD viral signatures are reproducible in the gut viromes of diabetic kidney disease and several other common diseases, highlighting the considerable universality of disease-associated viromes. Conclusions: This research provides comprehensive resources and novel insights into the CKD-associated gut virome, offering valuable guidance for future mechanistic and therapeutic investigations.

The neuroprotection of acute ischemic stroke (AIS) patients to alleviate the reperfusion injury is a long-standing problem. Although the intra-arterial selective cooling saline infusion (IA-SCSI) is a promising technique to improve the outcome of AIS, the clinical results are not sufficiently satisfactory. Magnesium-containing solutions such as magnesium sulfate (MgSO₄) can protect cells by modulating the intracellular Ca²⁺ content in damaged cells, suggesting that they could be hypothermia infusion solution. In this study, we hypothesized that MgSO₄, as a novel hypothermia infusion solution (IA-SCMI), can promote AIS recovery. Methods: First, IA-SCMI was performed in rats subjected to the middle cerebral artery occlusion. The effect of combined hypothermia and MgSO₄ treatment on different neurovascular (NVU) cells after oxygen-glucose deprivation/reoxygenation (OGD/R) injury was examined. Results: Compared with the IA-SCSI or IA-MgSO₄ infusion alone, IA-SCMI offered the best protective effect by improving neurological defects, and alleviating brain integrity damage and CBF reduction. Meanwhile, in vitro results revealed that the combination of hypothermia and MgSO₄ provided maximum protection to the NVU cells, and this protective effect was mainly achieved through the regulation of Ca²⁺ homeostasis in different cells. Conclusion: MgSO₄ may be a promising hypothermia infusion solution to facilitate the recovery of neurological function in AIS patients.

Rationale: Circular RNA (circRNA) has gained attention as a promising platform for mRNA vaccines due to its stability, sustained protein expression, and intrinsic immunostimulatory properties. This study aimed to design and optimize a circRNA cancer vaccine platform by screening for efficient internal ribosome entry sites (IRES) and enhancing circRNA translation efficiency for improved cancer immunotherapy. Methods: We screened 29 IRES elements to identify the most efficient one for immune cell translation, ultimately discovering the Enterovirus A (EV-A) IRES. Using SHAPE-MaP technology, we analyzed the secondary structure of circRNA and introduced targeted mutations and deletions to optimize translation efficiency. Additionally, we investigated the regulatory roles of spacer sequences and microRNA recognition sites in circRNA design and examined the mechanisms behind IRES-mediated translation initiation. Results: The EV-A IRES was identified as the most efficient for immune cell translation. Structural modifications and optimization of spacer sequences enhanced the translation efficiency of circRNA. Comparative studies demonstrated that circRNA vaccines induced stronger T cell immune responses and exhibited superior tumor prevention and therapeutic efficacy compared to traditional linear mRNA vaccines. Conclusion: The optimized tumor antigen circRNA vaccine platform offers a stable, efficient alternative to conventional mRNA vaccines for cancer immunotherapy, with enhanced immune responses and improved therapeutic outcomes. This work lays the foundation for developing circRNA-based vaccines as a novel strategy for cancer treatment.

Rationale: Brown and beige adipocytes are specialized fat cells that dissipate energy in the form of heat, and hold therapeutic potential for obesity and metabolic diseases. Although in the classical viewpoint brown and beige adipocytes dissipate energy solely via uncoupling protein 1 (UCP1), emerging evidence suggests the importance of non-canonical UCP1-independent energy expenditure in regulating energy expenditure, especially in human beige adipocytes. Leucine zipper-, EF-hand-containing transmembrane protein 1 domain containing 1 (LETMD1) was recently identified as a key protein in maintaining UCP1 expression and the thermogenic activity of brown adipocytes in animal models. But the exact function of LETMD1 and its mechanism of action in human beige adipocytes are unclear. Methods: We tested the function of LETMD1 in human induced pluripotent stem cell (hiPSC)-derived beige adipocytes in vitro in both wildtype (WT) and UCP1 knockout (KO) background. Furthermore, human beige adipocytes harboring a doxycycline-inducible LETMD1 expression cassette were transplanted to NOD/SCID mice and the function of LETMD1 in human beige adipocytes was evaluated in the in vivo setting. RNA-Seq was conducted in normal and LETMD1-overexpressing human beige adipocytes to examine the genes and pathways regulated by LETMD1. Using a knock-in human iPSC line, a preclinical small molecule compound library was screened for compounds increasing LETMD1 expression in human beige adipocytes. The effects of the compound in inducing LETMD1 and UCP1-independent energy expenditure in beige adipocytes were examined in vitro and in animal models. Results: LETMD1 plays an essential role in engaging energy dissipation, in a manner independent of UCP1, in human beige adipocytes. Transplantation of LETMD1-overexpressing human beige adipocytes improved whole-body metabolism of the recipient mice independent of UCP1. Mechanistically LETMD1 enhances the transcription of PPARGC1A, a key regulator of mitochondrial biogenesis. The expression of genes related to UCP1-independent energy expenditure, including creatine futile cycle, was also stimulated upon LETMD1 overexpression. Using LETMD1 reporter human beige adipocytes, SP-8356 was identified as a compound significantly increasing LETMD1 expression. Oral administration of SP-8356 induced genes related to UCP1-independent energy expenditure in beige adipocytes, and counteracted body weight gain and metabolic disorders in mice. Conclusion: Increased LETMD1 action, either genetically or pharmacologically, enhances the non-canonical UCP1-independent energy expenditure in beige adipocytes.

Smart biomaterials with active environmental responsiveness have attracted widespread attention in recent years. Previous studies on bioactive glass (BG) have mainly focused on the property of bioactivity, while little attention has been paid to the property of smart response of BG. Herein, we propose the concept of Smart Bioactive Glass Composites (SBGC) which are capable of actively responding to the endogenous disease microenvironment or exogenous physical stimuli, thereby enabling active treatment of tissue defect sites and ultimately promoting tissue regeneration. In this review, the response characteristics of SBGC to different internal and external environments are described. Subsequently, the applications of SBGC in complex tissue defect repair of tumors, infections, and diabetes are reviewed. By deeply analyzing the recent progress of SBGC in different fields, this review will point out the direction for the research of next-generation BG.

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.

Skin injuries caused by physical, pathological, and chemical factors not only compromise appearance and barrier function but can also lead to life-threatening microbial infections, posing significant challenges for patients and healthcare systems. Artificial intelligence (AI) technology has demonstrated substantial advantages in processing and analyzing image information. Recently, AI-based methods and algorithms, including machine learning, deep learning, and neural networks, have been extensively explored in wound care and research, providing effective clinical decision support for wound diagnosis, treatment, prognosis, and rehabilitation. However, challenges remain in achieving a closed-loop care system for the comprehensive application of AI in wound management, encompassing wound diagnosis, monitoring, and treatment. This review comprehensively summarizes recent advancements in AI applications in wound repair. Specifically, it discusses AI's role in injury type classification, wound measurement (including area and depth), wound tissue type classification, wound monitoring and prediction, and personalized treatment. Additionally, the review addresses the challenges and limitations AI faces in wound management. Finally, recommendations for the application of AI in wound repair are proposed, along with an outlook on future research directions, aiming to provide scientific evidence and technological support for further advancements in AI-driven wound repair theranostics.