Military Medical Research最新文献

Background: Radiofrequency ablation (RFA) is an efficient treatment with unlimited potential for liver cancer that can effectively reduce patient mortality. Understanding the biological process related with RFA treatment is important for improving treatment strategy. This study aimed to identify the critical targets for regulating the efficacy of RFA.

Methods: The RFA treatment in hepatocellular carcinoma (HCC) tumor models in vivo, was analyzed by RNA sequencing technology. The heat treatment in vitro for HCC tumor cells was also constructed to explore the mechanism after RFA treatment in tumor cells. Nanoparticles with high affinity to tumor cells were applied as a new therapy to interfere with the expression of maternal embryonic leucine zipper kinase (MELK).

Results: It was found that RFA treatment upregulated MELK expression, and MELK inhibition promoted RFA efficacy by immunogenic cell death and the antitumor response, including anti-tumoral macrophage polarization and increased CD8⁺ T cell cytotoxicity in HCC. Mechanically, MELK binds to fatty acid-binding protein 5 (FABP5), and affects its ubiquitination through the K48R pathway to increase its stability, thereby activating protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling axis to weaken the RFA-mediated antitumor effect. In addition, the synthesis of arginylglycylaspartic acid (RGD)-lipid nanoparticles (LNPs) targeting tumor cell-intrinsic MELK enhanced RFA efficacy in HCC.

Conclusion: MELK is a therapeutic target by regulating RFA efficacy in HCC, and targeting MELK via RGD-LNPs provides new insight into improving RFA efficacy in HCC clinical treatment and combating the malignant progression of liver cancer.

Background: With the increasing risk of nuclear exposure, more attention has been paid to the prevention and treatment of acute radiation syndrome (ARS). Although amino acids are key nutrients involved in hematopoietic regulation, the impacts of amino acids on bone marrow hematopoiesis following irradiation and the associated mechanisms have not been fully elucidated. Hence, it is of paramount importance to study the changes in amino acid metabolism after irradiation and their effects on hematopoiesis as well as the related mechanisms.

Methods: The content of serum amino acids was analyzed using metabolomic sequencing. The survival rate and body weight of the irradiated mice were detected after altering the methionine content in the diet. Extracellular matrix (ECM) protein analysis was performed via proteomics analysis. Inflammatory factors were examined by enzyme-linked immunosorbent assay (ELISA). Flow cytometry, Western blotting, and immunofluorescence were employed to determine the mechanism by which S100 calcium-binding protein A4 (S100A4) regulates macrophage polarization.

Results: The survival time of irradiated mice was significantly associated with alterations in multiple amino acids, particularly methionine. A high methionine diet promoted irradiation tolerance, especially in the recovery of bone marrow hematopoiesis, yet with dose limitations. Folate metabolism could partially alleviate the dose bottleneck by reducing the accumulation of homocysteine. Mechanistically, high methionine levels maintained the abundance of ECM components, including collagens and glycoproteins, in the bone marrow post-irradiation, among which the level of S100A4 was significantly changed. S100A4 regulated macrophage polarization via the STAT3 pathway, inhibited bone marrow inflammation and facilitated the proliferation and differentiation of hematopoietic stem/progenitor cells.

Conclusions: We have demonstrated that an appropriate elevation in dietary methionine enhances irradiation tolerance in mice and explains the mechanism by which methionine regulates bone marrow hematopoiesis after irradiation.

Cancer is a global health problem and one of the leading causes of mortality. Immune checkpoint inhibitors have revolutionized the field of oncology, emerging as a powerful treatment strategy. A key pathway that has garnered considerable attention is programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1). The interaction between PD-L1 expressed on tumor cells and PD-1 reduces the innate immune response and thus compromises the capability of the body's immune system. Furthermore, it controls the phenotype and functionality of innate and adaptive immune components. A range of monoclonal antibodies, including avelumab, atezolizumab, camrelizumab, dostarlimab, durvalumab, sinitilimab, toripalimab, and zimberelimab, have been developed for targeting the interaction between PD-1 and PD-L1. These agents can induce a broad spectrum of autoimmune-like complications that may affect any organ system. Recent studies have focused on the effect of various natural compounds that inhibit immune checkpoints. This could contribute to the existing arsenal of anticancer drugs. Several bioactive natural agents have been shown to affect the PD-1/PD-L1 signaling axis, promoting tumor cell apoptosis, influencing cell proliferation, and eventually leading to tumor cell death and inhibiting cancer progression. However, there is a substantial knowledge gap regarding the role of different natural compounds targeting PD-1 in the context of cancer. Hence, this review aims to provide a common connection between PD-1/PD-L1 blockade and the anticancer effects of distinct natural molecules. Moreover, the primary focus will be on the underlying mechanism of action as well as the clinical efficacy of bioactive molecules. Current challenges along with the scope of future research directions targeting PD-1/PD-L1 interactions through natural substances are also discussed.

Among the existing research on the treatment of disorders of consciousness (DOC), deep brain stimulation (DBS) offers a highly promising therapeutic approach. This comprehensive review documents the historical development of DBS and its role in the treatment of DOC, tracing its progression from an experimental therapy to a detailed modulation approach based on the mesocircuit model hypothesis. The mesocircuit model hypothesis suggests that DOC arises from disruptions in a critical network of brain regions, providing a framework for refining DBS targets. We also discuss the multimodal approaches for assessing patients with DOC, encompassing clinical behavioral scales, electrophysiological assessment, and neuroimaging techniques methods. During the evolution of DOC therapy, the segmentation of central nuclei, the recording of single-neurons, and the analysis of local field potentials have emerged as favorable technical factors that enhance the efficacy of DBS treatment. Advances in computational models have also facilitated a deeper exploration of the neural dynamics associated with DOC, linking neuron-level dynamics with macroscopic behavioral changes. Despite showing promising outcomes, challenges remain in patient selection, precise target localization, and the determination of optimal stimulation parameters. Future research should focus on conducting large-scale controlled studies to delve into the pathophysiological mechanisms of DOC. It is imperative to further elucidate the precise modulatory effects of DBS on thalamo-cortical and cortico-cortical functional connectivity networks. Ultimately, by optimizing neuromodulation strategies, we aim to substantially enhance therapeutic outcomes and greatly expedite the process of consciousness recovery in patients.

Mood disorders include a set of psychiatric manifestations of increasing prevalence in our society, being mainly represented by major depressive disorder (MDD) and bipolar disorder (BD). The etiopathogenesis of mood disorders is extremely complex, with a wide spectrum of biological, psychological, and sociocultural factors being responsible for their appearance and development. In this sense, immune system dysfunction represents a key mechanism in the onset and pathophysiology of mood disorders, worsening mainly the central nervous system (neuroinflammation) and the periphery of the body (systemic inflammation). However, these alterations cannot be understood separately, but as part of a complex picture in which different factors and systems interact with each other. Psychoneuroimmunoendocrinology (PNIE) is the area responsible for studying the relationship between these elements and the impact of mind-body integration, placing the immune system as part of a whole. Thus, the dysfunction of the immune system is capable of influencing and activating different mechanisms that promote disruption of the psyche, damage to the nervous system, alterations to the endocrine and metabolic systems, and disruption of the microbiota and intestinal ecosystem, as well as of other organs and, in turn, all these mechanisms are responsible for inducing and enhancing the immune dysfunction. Similarly, the clinical approach to these patients is usually multidisciplinary, and the therapeutic arsenal includes different pharmacological (for example, antidepressants, antipsychotics, and lithium) and non-pharmacological (i.e., psychotherapy, lifestyle, and electroconvulsive therapy) treatments. These interventions also modulate the immune system and other elements of the PNIE in these patients, which may be interesting to understand the therapeutic success or failure of these approaches. In this sense, this review aims to delve into the relationship between immune dysfunction and mood disorders and their integration in the complex context of PNIE. Likewise, an attempt will be made to explore the effects on the immune system of different strategies available in the clinical approach to these patients, in order to identify the mechanisms described and their possible uses as biomarkers.