Military Medical Research最新文献

Background: Repetitive mild traumatic brain injury (rmTBI) is a significant risk factor for neurodegeneration, characterized by pathological protein deposition and persistent neuroinflammation. Research has observed increased interleukin-33 (IL-33) levels in the peripheral blood of patients with rmTBI, suggesting IL-33 may participate in regulating the pathological development of rmTBI. The study aims to elucidate the impact and mechanism of IL-33 in the progression of neuropathology following rmTBI, and to explore its potential as a therapeutic target to improve the neurological outcome.

Methods: The study employed an rmTBI mouse model using the wild-type (WT) and IL-33 knockout mice. Cognitive function was assessed via the Y-maze and Barnes tests. The main cell type expressing IL-33 and its receptor, suppression of tumorigenicity 2 (ST2), was then investigated in the mouse brain through immunofluorescence colocalization. As the primary neural cell responsible for ST2 expression, microglia were studied in vitro using the BV2 cell line. The effects of lipid droplets (LDs) accumulation and amyloid-beta (Aβ) phagocytosis were measured to elucidate the impact of IL-33 on BV2 cells' phagocytosis. Additionally, HT22 neuronal apoptosis was assessed by flow cytometry. Finally, the cognitive effects of intranasal administration of IL-33 were evaluated in mice.

Results: IL-33KO mice exhibited pronounced cognitive impairment after rmTBI. In the mouse brain, astrocytes were identified as the primary source of IL-33 secretion, while microglia predominantly expressed ST2. Transcriptome sequencing revealed that IL-33 significantly influenced phagocytosis function. IL-33 mitigated LDs accumulation in BV2 cells and enhanced Aβ phagocytosis in vitro. In addition, the culture medium of BV2 cells with activated IL-33/ST2 signaling reduced HT22 neuronal apoptosis and axonal damage. Furthermore, intranasal administration of IL-33 was observed to be effective in alleviating neurodegeneration and cognitive outcome of rmTBI mice.

Conclusions: Dysfunction of the IL-33/ST2 axis following rmTBI leads to cognitive dysfunction via impairing microglial phagocytosis capacity and promoting neuronal damage. IL-33 would be a promising therapeutic target for alleviating neurodegeneration following rmTBI.

Conventional diagnostic and therapeutic approaches in orthopedics are frequently time intensive and associated with elevated rates of diagnostic error, underscoring the urgent need for more efficient tools to improve the current situation. Recently, artificial intelligence (AI) has been increasingly integrated into orthopedic practice, providing data-driven approaches to support diagnostic and therapeutic processes. With the continuous advancement of AI technologies and their incorporation into routine orthopedic workflows, a comprehensive understanding of AI principles and their clinical applications has become increasingly essential. The review commences with a summary of the core concepts and historical evolution of AI, followed by an examination of machine learning and deep learning frameworks designed for orthopedic clinical and research applications. We then explore various AI-based applications in orthopedics, including image analysis, disease diagnosis, and treatment approaches such as surgical assistance, drug development, rehabilitation support, and personalized therapy. These applications are designed to help researchers and clinicians gain a deeper understanding of the current applications of AI in orthopedics. The review also highlights key challenges and limitations that affect the practical use of AI, such as data quality, model generalizability, and clinical validation. Finally, we discuss possible future directions for improving AI technologies and promoting their safe and effective integration into orthopedic care.

Tendon-related diseases (TRDs) are increasingly common in the current aging society and impose a significant burden on patients. Despite therapeutic advances, the pathophysiology of TRDs remains poorly understood, hindering effective clinical management. The macrophages are highly plastic immune cells involved in the maintenance of in vivo homeostasis and the injury-healing process. Their dual role in TRDs has been widely investigated, either promoting tenogenic and chondrogenic differentiation or amplifying inflammatory response, underscoring their therapeutic potential for TRDs treatment. Therefore, the review aims to summarize the roles of macrophages in the healing of TRDs, characterized by limited regenerative capacity, and examine strategies for the modulation of macrophage phenotypes to accelerate the regeneration process. Finally, we review applications involving macrophage modulation within the context of tissue engineering of TRDs, providing novel insights for the design of biomaterials-based targeted delivery systems.

Background: Organ transplantation recipients encounter significant risks from acute or chronic infections that threaten graft survival. BK virus (BKV) and JC virus (JCV) are two prominent opportunistic infection viruses, and they may cause polyomavirus-associated nephropathy and graft kidney loss in patients who are in an immunosuppressed state after kidney transplantation. Hence, timely detection and sustained monitoring of the viral load are indispensable. However, the current diagnostic methods remain limited, and the development of new molecular detection technology is extremely urgent.

Methods: The sequences and concentrations of clustered regularly interspaced short palindromic repeats (CRISPR) RNA (crRNA), the concentration of Cas13a, and the primers for recombinase polymerase amplification (RPA) were optimized for BKV and JCV detection. Next, a novel microfluidic dual-droplet chip was designed and fabricated, and it was integrated with CRISPR (ddCRISPR) to simultaneously qualitatively detect BKV and JCV. Subsequently, the ddCRISPR assay was verified using clinical samples. Then, a lateral flow strip combined with CRISPR (LFCRISPR) was developed for the detection of BKV and JCV in resource-limited settings.

Results: A one-pot RPA-CRISPR reaction system was established and optimized for BKV and JCV detection. ddCRISPR can simultaneously and rapidly detect BKV and JCV with high sensitivity (10 copies/ml for BKV and 1 copy/ml for JCV), and provide absolute quantification, which is suitable for viral load detection and conducive to personalized and precise treatment for organ transplant recipients. LFCRISPR simplified the operational process through a simple visual readout, facilitating virus screening after organ transplantation.

Conclusions: These platforms incorporate molecular testing into the transplantation treatment model, thereby reducing costs, prolonging the survival time of the graft, improving the clinical outcomes of postoperative management in kidney transplantation, and enhancing the patients' quality of life.

The heterogeneity and invasiveness of cancer cells pose serious challenges in cancer diagnosis and treatment. Advancements and innovations in metal-based nanomedicines provide novel avenues for addressing these challenges. Metal-based nanomedicines possess unique physicochemical properties that enable their interaction with living organisms, thereby inducing complex biological responses. These nanomaterials have been extensively used to enhance the contrast and sensitivity of cancer imaging and to amplify the distinction between cancerous and healthy tissues. Moreover, these nanomaterials can effectively combat a wide spectrum of cancers through various methods, including drug delivery, radiotherapy, photothermal therapy (PTT), photodynamic therapy (PDT), sonodynamic therapy (SDT), biocatalytic therapy, ion interference therapy (IIT), and immunotherapy. Currently, there is still a need for a comprehensive summary on the metal-based nanomaterials for cancer diagnosis and treatment. Herein, we present a systematic and complete overview of action mechanisms and the applications of metal-based nanomaterials in cancer theranostics. A summary of common strategies for synthesizing and modifying metal-based nanomedicines is presented, and their biosafety is analyzed. Then, the latest developments in their applications for cancer imaging and anticancer treatment are provided. Finally, the key technical challenges and reasonable perspectives of metal-based nanomedicines for cancer theranostics in clinical applications are discussed.

Background: PANoptosis has been identified as a robust inflammatory cell death pathway triggered upon host defense against invaded pathogens such as bacteria and viruses, however, pathogen-free tumor PANoptosis has not been achieved yet. Reactive oxygen and nitrogen species capable of inducing robust and diverse cell death pathways such as pyroptosis, apoptosis, and necroptosis are supposed to be the potential triggers for tumor PANoptosis by ultrasound (US)-controlled sono-piezodynamic therapy.

Methods: S-nitrosothiols (SNO)-zinc peroxide (ZnO₂)@cyclic dinucleotide (CDN)@mesoporous tetragonal barium titanate (mtBTO) nanoparticles (NZCB NPs) were synthesized by hydrothermal method with subsequent annealing, in situ growth, and finally surface functionalization. Scanning electron microscopy, transmission electron microscopy, X-ray diffraction, atomic force microscopy, Fourier transform infrared spectroscopy, and electron spin resonance were used for materials characterizations. Murine melanoma B16 cells are employed to investigate the in vitro US-initiated tumor PANoptosis by NZCB NPs. In vivo US-initiated tumor PANoptosis was investigated on B16 tumor-bearing C57BL/6J mice.

Results: A "boiling-bubbling" strategy is developed to endow the piezoelectric BTO nanocatalysts, with mesoporous architecture, which enables the encapsulation of the immune-agonist CDN (9.4 wt%) to initiate innate immunity of the host. Then, SNO-functionalized ZnO₂ was further employed to cap the mesoporous nanocatalysts, forming multifunctional piezocatalytic NZCB NPs. Under US irradiation, intracellular massive reactive oxygen and nitrogen species such as superoxide anion radicals, nitric oxide (NO), and peroxynitrite (ONOO^-) could be produced from the piezoelectric NZCB NPs, which, synergized with CDN-triggered antitumoral immunity, lead to highly immunogenic tumor PANoptosis by NZCB NPs through the tumor microenvironment remodeling. Intratumoral injection of NZCB NPs leads to substantial tumor PANoptosis with immune potentiation, ultimately destroying the tumor xenografts effectively.

Conclusion: The present work presents the mesostructure design of piezocatalytic nanomaterials and the crosstalk between oxidative stress and antitumor immunity within the tumor, facilitating promising tumor PANoptosis by nanocatalytic oxidation with high effectiveness and biocompatibility.

Background: Cartilage repair remains a considerable challenge in regenerative medicine. Despite extensive research on biomaterials for cartilage repair in recent years, issues such as prolonged repair cycles and suboptimal outcomes persist. Organoids, miniature three-dimensional (3D) tissue structures derived from the directed differentiation of stem or progenitor cells, mimic the structure and function of natural organs. Therefore, the construction of cartilage organoids (COs) holds great promise as a novel strategy for cartilage repair.

Methods: This study employed a digital light processing system to perform 3D bioprinting of a DNA-silk fibroin (DNA-SF) hydrogel sustained-release system (DSRGT) with bone-marrow mesenchymal stem cells (BMSCs) to construct millimeter-scale cerebral organoids. COs at different developmental stages were characterized, and the COs with the best cartilage phenotype were selected for in vivo cartilage repair in a rat articular cartilage defect model.

Results: This study developed a DSRGT by covalently grafting glucosamine (which promotes cartilage matrix synthesis) and TD-198946 (which promotes chondrogenic differentiation) onto a hydrogel using acrylic acid-polyethylene glycol-N-hydroxysuccinimide (AC-PEG-NHS). In vitro, 4-week COs exhibited higher SRY-box transcription factor 9 (SOX9), type II collagen (Col II), and aggrecan (ACAN) expression and lower type I collagen (Col I) and type X collagen (Col X) expression, indicating that 4 weeks is the optimal culture duration for hyaline cartilage development. In vivo, the mitogen-activated protein kinase (MAPK) signaling pathway was upregulated in 4-week COs, enabling cartilage repair within 8 weeks. Transcriptomic analysis revealed that cartilage regenerated with 4-week COs presented gene expression profiles resembling those of healthy cartilage.

Conclusions: This study employs DSRGT to construct COs, providing an innovative strategy for the regeneration of cartilage defects.

Recent advances in next-generation sequencing and bioinformatics have driven growing interest in the distinct roles of intratumoral microbiota, particularly intracellular bacteria, during tumor evolution. These bacteria increase the likelihood of metastasis, play important roles in cancer progression, and impact therapy efficiency. The present review explores the sources, mechanisms of invasion into cancer cells, and potential survival strategies of intracellular bacteria in neoplasms, highlighting their critical role in cancer development. We also examine the heterogeneity and intricate interplay of intratumoral microbial communities with immune and cancer cells, emphasizing their potential roles in modulating host genetics, epigenetics, and immunity. Finally, we discuss novel approaches to targeting intracellular bacteria, particularly engineered drug delivery systems, and synthetic biology, which aim to enhance bacterial clearance, reprogram the tumor immune microenvironment, and enhance the efficacy of chemotherapy and immunotherapy. As a result, this review provides new insights to guide future investigations and support the development of microbiota-based interventions in oncology.