MedComm - Future medicine最新文献

A recent study published in Nature by Lin et al. [1, 2], conducted at Xiamen University identified that lithocholic acid (LCA), a bile acid metabolite, mimics the anti-aging effects of caloric restriction (CR) by activating the TULP3-sirtuin-v-ATPase-AMPK axis. LCA binds to the receptor TUB-like protein 3 (TULP3), triggering allosteric activation of sirtuins (SIRT1-7), which deacetylate lysine residues (K52, K99, K191) on the V1E1 subunit of lysosomal v-ATPase. This deacetylation inhibits v-ATPase activity, activating AMPK through the lysosomal glucose-sensing pathway, fostering muscle rejuvenation in aged mice.

CR has long been associated with enhanced health and longevity in various species including yeasts, worms, flies, and mammals [3]. Although the precise underlying mechanisms of these benefits remain unclear, they potentially involve alterations in multiple metabolic, hormonal, and cellular signaling pathways. AMPK is at the core of this process as a crucial regulator that senses energy levels within cells. Despite the well-documented advantages of CR, long-term adherence to such a dietary regimens is often impractical for individuals [4]. Therefore, identifying pharmacological agents that could effectively mimic CR effects has emerged as a significant research area within the field of aging science. The presented study positions LCA as an effective analog for CR, offering a promising opportunity for therapeutic intervention.

Based on conventional wisdom, AMPK is primarily activated when energy stores are depleted and glucose levels are decreased [5]. However, the authors discovered that in CR mice, blood glucose did not fall to the levels that would reportedly trigger AMPK activation. This observation indicated that AMPK activation during CR was not directly driven by reduced glucose levels. To further explore this phenomenon, the authors added serum from CR mice to cell cultures and observed sustained AMPK activation even under high glucose concentrations (Figure 1A). This result suggests that a factor in the serum of CR mice can activate AMPK glucose level-independently. The authors conducted a comprehensive metabolomic analysis of the serum from CR mice using various mass spectrometric techniques, and registered significant changes in the abundance of 695 metabolites during CR. Notably, only LCA could recapitulate AMPK activation at physiological concentrations (compared to the control serum) (Figure 1B,C). Furthermore, AMPK activation has been observed in mice as well as in other model organisms, such as nematodes and Drosophila, upon LCA supplementation.

The authors further investigated the signaling pathway by which LCA activates AMPK. They observed that AMPK activation via either LCA or CR did not lead to an increase in AMP or cytosolic calcium levels. This finding ruled out traditional AMP- or calcium-dependent activation mechanisms. The authors explored the

Inflammation, as a complex biological response, can lead to tissue damage and pathological physiological changes, forming the basis for many chronic diseases. Stem cell-derived exosomes (SC-Exos), a type of nanoscale extracellular vesicle, possess advantages such as small volume, low immunogenicity, and drug-carrying capacity, demonstrating immense potential in the field of disease diagnostics and therapeutics. Current studies indicate that SC-Exos can not only alleviate inflammatory diseases by suppressing inflammatory cytokines and modulating the activation of macrophages through their immunomodulatory and regenerative properties but also show significant potential as carriers for anti-inflammatory drugs, presenting a promising therapeutic approach for inflammatory conditions. However, the current lack of systematic summaries of SC-Exos in the treatment of inflammatory diseases has impeded the development of standardized therapies and clinical applications. This review elucidates the methods of SC-Exo sourcing, isolation, characterization, and engineering, as well as their application, mechanisms of action, and efficacy in the treatment of inflammatory diseases such as periodontitis, osteoarthritis (OA), and inflammatory bowel disease. Integrating these findings, this review highlights that SC-Exos can attenuate a variety of inflammatory diseases by transporting a diverse range of molecules to modulate immune responses, thereby providing foundations for subsequent standardization of production and clinical trials.

Glioma, characterized by significant heterogeneity and aggressiveness, poses a formidable therapeutic challenge. Cuproptosis, a newly identified form of regulated cell death driven by copper imbalance, has recently emerged as a pivotal factor in tumor biology. However, its role in IDH1-mutant gliomas remains poorly understood. Through comprehensive bioinformatics analysis of publicly available datasets, we identified two distinct subtypes of IDH1-mutant gliomas based on cuproptosis regulator expression profiles. Subtype G1 exhibited elevated PD-L1 expression, increased pro-tumor immune infiltration, and worse clinical outcomes, whereas subtype G2 was enriched in antitumor immune cells and associated with improved prognosis. We identified FDX1 and SLC31A1 as critical prognostic markers, with their upregulation linked to PD-L1 expression. Mechanistically, we delineated a ceRNA regulatory axis involving COX10-AS1/miR-1-3p/FDX1 and SLC31A1 that drives glioma progression. Building on these insights, we developed a prognostic risk model integrating FDX1 and SLC31A1 expression, demonstrating robust predictive accuracy for patient outcomes and potential utility in guiding individualized treatment strategies. These findings advance our understanding of the molecular landscape in IDH1-mutant gliomas and underscore the potential of cuproptosis regulators as novel therapeutic targets and biomarkers for precision oncology.

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer, characterized by poor prognosis and limited therapeutic options. Although neoadjuvant chemotherapy (NACT) remains the established treatment approach, its suboptimal efficacy associated with TNBC highlight the urgent need for optimized treatment strategies to improve pathological complete response (pCR) rates. This review provides a comprehensive overview of recent advancements in neoadjuvant treatment for TNBC, emphasizing pivotal breakthroughs in therapeutic strategies and the ongoing pursuit of innovative approaches to enhance precision medicine. It emphasizes the clinical value of platinum-based agents, such as carboplatin and cisplatin, which have shown significant improvements in pCR rates, particularly in TNBC patients with BRCA mutations. Additionally, the review explores progress in targeted therapies, including PARP inhibitors, AKT inhibitors, and Antiangiogenic agents, showcasing their potential for personalized treatment approaches. The integration of immunotherapy, particularly immune checkpoint inhibitor like pembrolizumab and atezolizumab, with chemotherapy has demonstrated substantial efficacy in high-risk TNBC cases. Future research priorities include refining biomarker-driven strategies, optimizing therapeutic combinations, developing antibody-drug conjugates (ADCs) targeting TROP2 and other biomarkers, and reducing treatment-related toxicity to develop safer and highly personalized neoadjuvant therapies. Furthermore, artificial intelligence has also emerged as a transformative tool in predicting treatment response and optimizing therapeutic decision-making in TNBC. These advancements aim to improve long-term outcomes and quality of life for patients with TNBC.

In a recent study published in Nature Nanotechnology, You et al. describe how coating tumor autophagosomes with nanodots in situ offers a promising strategy for personalizing cancer vaccines in the treatment of tumors [1]. Here, we explore how titanium nitride-based MXene (Ti₂NX) nanodots help tumor autophagosomes escape fusion with lysosomes, allowing drainage to lymph nodes (LNs), and priming of T cells. This Research Highlight also summarizes the therapeutic effects of Ti₂NX nanodot-coated autophagosomes in different murine tumor models.

Autophagy is an essential intracellular process involving the formation of autophagosomes that degrade and recycle cellular components to maintain cellular homeostasis. Autophagosomes, double-membrane vesicles that engulf and transport intracellular material to lysosomes for degradation [2], are being exploited as vaccines in cancer immunotherapy based on their capacity to carry tumor antigens that can be taken up and cross-presented by antigen-presenting cells (APCs), such as dendritic cells (DCs). Autophagosomes are conventionally prepared intracellularly by increasing lysosomal pH, with compounds like Bafilomycin A1, chloroquine, hydroxychloroquine, or ammonium chloride [2], to prevent fusion with lysosomes and allow autophagosome isolation through cell disruption and gradient centrifugation. However, this conventional approach may reduce autophagosome immunogenicity as increasing lysosomal pH can promote the formation of multivesicular bodies (MVBs) that fuse with autophagosomes. You et al. developed 3 nm Ti₂NX nanodots that coat tumor-derived autophagosomes and inhibit autophagy by preventing autophagosome fusion with lysosomes or MVBs [1]. Unlike conventional autophagy inhibitors that affect autophagy in cancer and immune cells, Ti₂NX nanodots selectively target cancer cells and preserve immune cell function.

The fate of Ti₂NX nanodot-coated autophagosomes (NCAPs) follows a sophisticated and well-coordinated process (Figure 1) that begins with nanodots shielding phosphatidylinositol-4-phosphate (PI4P), expressed on the autophagosome surface, through molecular interactions (e.g., hydrogen bonding) with the phosphate groups of PI4P. This shielding prevents the recruitment of functional proteins, such as SNARE syntaxin 17, that mediate fusion of autophagosomes with lysosomes or MVBs. Subsequent accumulation of NCAPs within tumor cells induces intracellular stress, leading to inflammasome-associated pyroptosis and release of NCAPs from tumor cells for recognition and transport by migratory DCs to the LNs. The size range of NCAPs (200–700 nm) and presence of C-type lectin domains containing 9 A (CLEC9A) ligands on the surface of NCAPs enhance recognition by DCs.

Once in the LNs, NCAPs are processed by LN-resident and migratory DCs for cross-presentation. Tumor antigens carried

Coronary artery disease (CAD), the most common panvascular disease, can progress to chronic total occlusion (CTO). Drug-eluting stent (DES) is one of standard CAD treatments, but in-stent restenosis leading to CTO is challenging, with unclear optimal management. The efficacy of drug-coated balloons (DCB) for treating DES-related in-stent chronic total occlusion (IS-CTO) is undetermined. In this single-center retrospective cohort study of 198 patients with IS-CTO post-DES, 3-year outcomes of DCB, DES, and plain old balloon angioplasty (POBA) were compared, focusing on target vessel failure (TVF). DES showed the lowest TVF rate (DCB vs. DES vs. POBA: 31.8% vs. 17.1% vs. 51.6%, p < 0.01), mainly due to fewer revascularizations. Notably, the difference in TVF between DCB and DES became more apparent after the first year. DCB was an independent risk factor for late TVF (HR_adj = 6.51, 95% confidence interval [CI] = 2.45–18.84, p < 0.01), whereas POBA for early TVF compared to DCB (HR_adj = 5.01, 95% CI = 1.36–18.42, p = 0.02). While POBA-treated patients exhibited a higher target vessel myocardial infarction rate, the death rates were comparable across all cohorts. In conclusion, DES showed the lowest 3-year TVF rate, making it the most effective treatment for IS-CTO compared to DCB and POBA.

Immunotherapy has revolutionized cancer treatment in recent years, yet non-responsiveness of immunotherapy remains a challenge for cancer treatment. Therefore, the prediction method for potential clinical benefits of patients from immunotherapy is urgently needed. This study aims to develop an effective clinical practice assistance tool to evaluate the potential clinical benefits and therapy responsiveness of patients undergoing immunotherapy. We developed an immunotherapy resistance score (IRS), which performed well compared with conventional immunotherapy response indicators across different immunotherapy cohorts. Tumor microenvironment (TME) analysis showed that both immune and nonimmune features collectively impact immunotherapy responsiveness. Thus, IRS was constructed based on the TME features using machine learning approaches. The clinical application potential of IRS has been demonstrated in our in-house Harbin Medical University (HMU) cohort and an external validation cohort. Furthermore, we analyzed the correlation between IRS and pathways related to cancer therapy targets to explore the application potential of IRS in comprehensive cancer therapy. In conclusion, IRS is a robust tool for predicting patient immunotherapy prognosis, which has great potential to promote precise clinical therapy.

Most individuals with COVID-19, caused by SARS-CoV-2 infection, experience asymptomatic or mild-to-moderate symptoms, while a minority of patients may deteriorate to severe illness or fatal outcomes [1]. Severe COVID-19 can lead to critical complications, including respiratory distress and increased mortality rates [2]. One such complication is the development of “white lung” on chest radiographs (e.g., X-ray), characterized by extensive inflammation and fluid accumulation affecting 70%–80% of the lung area [3]. The appearance of white lung signals a critical stage in COVID-19 patients, profoundly impairing lung function, often requiring mechanical ventilation and ICU admission, and substantially increasing mortality risk [1, 2]. Despite extensive research into the pathophysiology of COVID-19, the mechanisms underlying “white lung” remain poorly understood.

Here, we performed single-cell RNA sequencing analysis of bronchoalveolar lavage fluid (BALF) to characterize the pathophysiology of “white lung” in COVID-19 (Figure 1A). BALF samples were collected from 16 patients with moderate (MO, n = 3), severe (SE, n = 6), and “white lung” (WL, n = 7) syndrome, as well as from 3 healthy controls (HC) (Figure 1A). After quality control filtering (Supporting Information S1: Figure S1A–C), we obtained transcriptome data sets from 136,015 cells (mean = 7159 cells/sample). Using uniform manifold approximation and projection (UMAP), we identified 7 major cell types (Supporting Information S1: Figure S1D) and, through sub-clustering, 44 distinct cell states representing diverse respiratory cell types (Supporting Information S1: Figure S1E). UMAP visualization (Supporting Information S1: Figure S1F) revealed substantial inter-group heterogeneity. The distribution of seven major clusters was portrayed through R_O/E (Supporting Information S1: Figure S1G) [1]. We observed an obvious expansion of NK and neutrophils in COVID-19 patients with “white lung” (Supporting Information S1: Figure S1G–J, Figure 1B). However, NK cells comprised < 0.5% of the total cell population in these patients (Supporting Information S1: Figure S1I), implying that their expansion is unlikely to be the primary driver of this complication. In contrast, neutrophils constituted up to 85% of BALF cells in COVID-19 patients with “white lung,” whereas this proportion did not exceed 25% in any other group (Figure 1B, Supporting Information S1: Figure S1H). PCA analysis clearly distinguished neutrophils from “white lung” patients from those in controls and patients with moderate and severe COVID-19 (Supporting Information S1: Figure S2A,B). Among BALF immune cells, neutrophils exhibited a significant association with “white lung” patients (Supporting Information S1: Figure S2C). These results suggested that neutrophil infiltration may be a key driver of “white lung” development in COVID-19.<

Muscle atrophy, characterized by the loss of muscle mass and function, is a hallmark of sarcopenia and cachexia, frequently associated with aging, malignant tumors, chronic heart failure, and malnutrition. Moreover, it poses significant challenges to human health, leading to increased frailty, reduced quality of life, and heightened mortality risks. Despite extensive research on sarcopenia and cachexia, consensus in their assessment remains elusive, with inconsistent conclusions regarding their molecular mechanisms. Muscle atrophy models are crucial tools for advancing research in this field. Currently, animal models of muscle atrophy used for clinical and basic scientific studies are induced through various methods, including aging, genetic editing, nutritional modification, exercise, chronic wasting diseases, and drug administration. Muscle atrophy models also include in vitro and small organism models. Despite their value, each of these models has certain limitations. This review focuses on the limitations and diverse applications of muscle atrophy models to understand sarcopenia and cachexia, and encourage their rational use in future research, therefore deepening the understanding of underlying pathophysiological mechanisms, and ultimately advancing the exploration of therapeutic strategies for sarcopenia and cachexia.