Translational research : the journal of laboratory and clinical medicine最新文献

Acute necrotizing encephalopathy (ANE) in children is a critical condition characterized by rapid progression, high mortality rates and potentially cytokine storm imvolvement. Early-stage ANE lacks distinctive clinical features, and its initial symptoms resemble those of febrile seizures (FS) despite differing outcomes. In this study, we utilized FS as a control to identify plasma biomarkers associated with the cytokine storm in ANE through plasma proteomic analysis. We identified 398 differentially expressed proteins in ANE patients, including 345 upregulated and 53 downregulated proteins, which were enriched in biological pathways such as antigen processing and presentation, cell chemotaxis, immune responses, metabolism, and cell matrix adhesion. Using weighted gene co-expression network analysis (WGCNA), we further identified protein modules and hub proteins related to the cytokine storm and ultimately selected eight key proteins (APOE, GAPDH, TPI1, SPP1, ENO1, COL1A1, LUM, and A2M) as immunopathogenic biomarkers. These findings were validated in an independent cohort using targeted quantitative proteomics, with ROC analysis demonstrating their diagnostic potential. This study provides a foundation for early ANE diagnosis and highlights promising targets for therapeutic intervention.

Post-traumatic rhabdomyolysis poses a significant threat to human life and health, primarily due to crush syndrome-associated acute kidney injury (CS-AKI). A critical factor contributing to this condition is the destruction of the tubular epithelial barrier, which results from the death of tubular epithelial cells (TECs) caused by myoglobin (Mb) accumulation. In this study, we identified a novel programmed cell death (PCD), termed PANoptosis, occurring in TECs in both in vivo and in vitro CS-AKI models. This process is induced by Mb, with RIG-I serving as the apical sensor molecule for damage-associated molecular patterns (DAMPs). RIG-I transfers Mb insult signals into the cell, where it aggregates with ASC, caspase-1, caspase-8, FADD, RIPK1, and RIPK3 forming the RIG-I PANoptosome. Attenuating RIG-I expression not only disrupts PANoptosome assembly and inhibits PANoptosis but also mitigates TECs damage. Consequently, targeting RIG-I activity may offer a promising avenue for developing novel therapies for post-traumatic rhabdomyolysis and other Mb-associated diseases that trigger cell death and pathology.

Cancer-associated fibroblasts (CAFs), representing the predominant stromal cell population within the solid tumor microenvironment (TME), are thought to play a significant role in facilitating tumorigenesis and progression. Nonetheless, recent experimental efforts to eradicate CAFs in solid tumors have inadvertently resulted in tumor progression, potentially due to the tumor-suppressive effects exhibited by specific CAF subtypes. Therefore, strategies that selectively target pro-tumorigenic CAFs may yield more favorable outcomes. Emerging evidence indicates that CAFs are instrumental in reprogramming lipid metabolism within TME, fostering a high-fat, immunosuppressive environment. To adapt to the hypoxic and nutrient-limited conditions of TME, cancer cells alter their metabolic processes, which subsequently influences the behavior of CAFs. The variability among CAF populations affects the metabolic pathways of cancer cells and neighboring immune cells. Despite the importance of these interactions, the discussion regarding lipid metabolism crosstalk between CAFs and the TME remains insufficiently explored in the literature. As a result, this study systematically reviews the various origins and heterogeneity of CAFs and closely investigates their roles in lipid metabolism reprogramming within the TME. Additionally, we analyze the metabolic interactions between CAFs and different components of the TME in solid tumors. Ultimately, we discuss potential therapeutic strategies and the challenges of targeting CAF lipid metabolism.

The development of colorectal cancer, which is a malignant tumor demonstrating high morbidity and mortality worldwide, involves complex molecular mechanisms and biological processes. Early-stage colorectal cancer patients do not exhibit obvious clinical symptoms; thus, they are often diagnosed with middle-stage to late-stage disease. The overall survival of advanced colorectal cancer patients with metastasis and treatment resistance is poor. Notably, tumor cell plasticity promotes tumorigenesis, metastasis, and therapeutic resistance, thus leading to the high incidence and mortality of colorectal cancer. In-depth studies of cellular plasticity are expected to lead to the identification of new therapeutic targets. In this review, we systematically summarize the role of cellular plasticity in colorectal cancer development and explore the regulatory mechanisms associated with cellular plasticity in colorectal cancer, with the aim of providing a theoretical basis for the development of innovative therapeutic strategies for this type of cancer.

Background: Calorie restriction holds the potential in alleviating metabolic disorders and inflammation. However, the effects of intermittent caloric restriction (ICR) on cardiometabolic diseases remain poorly understood. In this study, we aimed to assess the protective role of ICR in both prediabetic and diabetic heart injury.

Methods: Prediabetic and diabetic models were established using a high-fat diet and high-fat diet/streptozotocin in mice, respectively. Following the induction of prediabetes mellitus and diabetes mellitus, ICR was implemented to evaluate its therapeutic effect. As alterations of gasdermin D (GSDMD) expression were monitored, we investigated the relationship between the cardioprotective effect of ICR and GSDMD using human heart samples, GSDMD knockout mice and adeno-associated virus 9(AAV9). Through RNA-sequencing, the underlying mechanism of GSDMD-mediated diabetes-associated cardiac inflammation was further elucidated.

Results: Our study indicated that ICR prevented cardiac dysfunction by alleviating cardiac lipid overaccumulation in prediabetic mice. Conversely, the effect of ICR on lipid overaccumulation were limited in diabetic mice. Instead, the cardioprotective effect of ICR was mediated through the inhibition of GSDMD-mediated cardiomyocyte pyroptosis and inflammation response in diabetic mice. In human hearts, the expression level of GSDMD were positively correlated with diabetes-induced heart injuries. Furthermore, GSDMD deficiency mimicked the cardioprotective effects of ICR, while GSDMD overexpression in cardiomyocytes offset the cardioprotective effect of ICR in diabetic mice. Mechanistically, the upregulation of GSDMD activated secreted Frizzled-related protein 2 (sFRP2)/ATF6/NF-κB pathway, exacerbating cardiac inflammation in diabetic hearts. Moreover, the replenishment of recombinant sFRP2 offset the cardiac benefits of GSDMD deficiency in diabetic mice.

Conclusions: Our study demonstrated the prevention of prediabetic and diabetic heart injury by ICR were mediated by alleviating cardiac lipid overaccumulation and inflammation, respectively. Moreover, targeting GSDMD-dependent sFRP2/ATF6/ NF-κB pathway conferred the cardioprotective effects of ICR and could serve as a potential therapeutic strategy for diabetic heart failure.

Objective: Diabetic neuropathy and Charcot neuroarthropathy (CN) may compromise lower limb skeletal integrity. We performed a comprehensive comparative assessment of foot bone across multiple hierarchical parameters at nano, meso and micro scale orders.

Research design and methods: Calcaneal bone specimens obtained from individuals with CN (Group A; n = 12), diabetic neuropathy (Group B; n = 21), and healthy controls (Group C; n = 18). Trabecular microarchitecture was assessed using micro-computed tomography (micro-CT), mechanical strength through uniaxial compression, biochemical composition by infrared spectroscopy (FTIR), crystal dimensions with X-ray diffraction (XRD), tissue-level mechanical behaviour by nanoindentation and quantiative organic and mineral content of bone matrix by thermogravimetric analysis (TGA).

Results: Micro-CT revealed 35.9 % reduced trabecular thickness (0.25 ± 0.11 mm vs 0.39 ± 0.14 mm, p = 0.016), 57 % lower maximum load tolerance (218.85 ± 18.84 N vs 508.15 ± 100.98 N, p < 0.001) and 55 % reduced stiffness (51.62 ± 4.89 N/mm vs. 114.63 ± 13.74 N/mm, p < 0.001) in Group A compared to Group C, respectively. Mineral-to-matrix ratio (3.17 ± 0.68 vs. 4.75 ± 1.47, p < 0.001), collagen maturity index (1.25± 0.29 vs. 1.74 ± 0.50, p < 0.001) and organic fraction (44.95 ± 5.15 % vs 50.91 ± 4.85 %;p = 0.005) were lower in Group A compared to group C, respectively. The elastic modulus (8.13 ± 1.57 GPa vs. 18. 12± 1.96 GPa) and hardness (0.34 ± 0.07 GPa vs. 0.71 ± 0.13 GPa) were significantly reduced in group A compared to Group C (p < 0.001 for both), confirming compromised tissue-level mechanics of foot bones in CN. Bone samples from Group B showed intermediate values compared to either group A and C, respectively.

Conclusion: Charcot neuroarthropathy of foot is characterised by severe, multiscale impairments in bone architecture, composition, and mechanical function that contribute to heightened skeletal fragility and underscore the need for targeted interventions addressing bone quality.

Background: Atherosclerosis, a chronic inflammatory disease, presents significant "residual risk" even with effective lipid-lowering therapies, primarily due to persistent vascular inflammation. Apolipoprotein B100 (ApoB100) acquires pro-inflammatory properties upon modification and binds to cell-surface enolase 1 (ENO1), an immune modulator upregulated in inflammatory conditions. This interaction induces inflammatory responses via NF-κB activation. Targeting the ApoB100-ENO1 interaction may offer a novel strategy to reduce vascular inflammation and atherosclerosis progression.

Methods: We developed PP3m, a stabilized ApoB100-derived peptide, to selectively inhibit the ApoB100-ENO1 interaction. Single-cell RNA sequencing (scRNA-seq) data from human atherosclerotic plaques were reanalyzed to characterize ENO1 expression in myeloid cells. In vitro, PP3m's anti-inflammatory effects were evaluated across various macrophage models stimulated by diverse inflammatory stimuli. Outcomes included cytokine secretion, inflammatory gene expression, foam cell formation, oxidized low-density lipoprotein (oxLDL) uptake, and signaling pathways activation. In vivo, Ldlr^-/- mice fed an atherogenic diet were treated with PP3m to evaluate its effects on atherosclerosis progression, macrophage accumulation, and systemic inflammation.

Results: scRNA-seq analysis revealed that human atherosclerotic plaques harbor significantly more ENO1 macrophages, with ENO1 expression enriched in CD68⁺ M1 macrophages. Atherogenic stimuli induced ENO1 translocation to the plasma membrane in macrophages. In vitro, PP3m significantly attenuated inflammatory responses by suppressing IL-6 and CXCL8 secretion, reducing M1 polarization, and dose-dependently inhibiting oxLDL-induced foam cell formation and uptake. In vivo, PP3m reduced aortic lesion area, lipid content, and collagen deposition, accompanied by decreased macrophage accumulation in plaques and lower circulating pro-inflammatory cytokines. Importantly, these effects were independent of changes in plasma lipid profiles.

Conclusions: The ApoB100-ENO1 axis is a critical driver of macrophage-mediated inflammation in atherosclerosis. The novel peptide PP3m effectively inhibits this interaction, reducing vascular inflammation and plaque progression without altering lipid levels. PP3m represents a promising therapeutic candidate for cardiovascular disease by targeting residual inflammatory risk through a lipid-independent mechanism.

Background: Chronic obstructive pulmonary disease (COPD) is a chronic respiratory condition primarily caused by inhalation of harmful particles such as tobacco smoke. Cellular senescence serves as a key driver in its pathogenesis. Although endothelial progenitor cells (EPCs) have been shown to alleviate COPD by reducing inflammatory cell infiltration, the role and mechanisms underlying EPC senescence in this disease remain unclear.

Methods: A cigarette smoke (CS)-exposed COPD mouse model was established. Lung injury was assessed histologically, with concurrent quantification of neutrophil infiltration and cellular senescence levels in lung tissues. Pearson analysis evaluated the correlation between senescence severity and neutrophil numbers. In vivo neutrophil depletion was achieved using anti-Ly6G antibody, while GW4869 was used to inhibit exosome secretion from COPD-derived neutrophils. Neutrophils were then co-cultured with EPCs to assess their impact on EPC senescence and DNA damage. Proteomic analyses were employed to identify mechanisms of neutrophil-derived exosomes in COPD.

Results: COPD mice exhibited significant lung tissue damage, accelerated cellular senescence, and increased neutrophil infiltration. Senescence severity positively correlated with neutrophil proportion. Mechanistically, thrombospondin-1 (TSP-1) was highly expressed in COPD-derived neutrophils. Knockdown of neutrophil-derived exosomal TSP-1 alleviated EPC senescence. Furthermore, TSP-1 expression was regulated by transcription factor FOS, whereas TGF-β inhibition attenuated the promoting effects of TSP-1 overexpression on cellular senescence and lung injury in COPD mice.

Conclusion: This study demonstrates that neutrophil-derived exosomal TSP-1 aggravates EPC senescence and lung injury in COPD, revealing the pathogenic role of TSP-1 in disease progression and highlighting its potential as a therapeutic target.

Tubular dilation and cyst formation at the corticomedullary junction are distinct pathological features of nephronophthisis (NPH) and may be associated with disease progression. However, the mechanism of renal cyst formation in NPH is unclear. Increased cell proliferation is necessary for cyst formation. ZONAB, a tight junction-associated transcriptional regulatory factor, targets proliferative factors, such as CCND1 and PCNA. In this study, we explored the role of ZONAB in renal cyst formation and its possible mechanism in nphp1 knockout (nphp1^KO) mice. We found that the expression of ZONAB, CCND1, and PCNA was increased in the kidney tissue of the nphp1^KO mice but was mainly confined to renal cyst cells. ZONAB knockdown inhibited renal cyst formation and tubular dilatation and decreased the expression of CCND1 and PCNA in the nphp1^KO mice. We concluded that ZONAB plays an important role in renal cyst formation in the NPH, possibly through the regulation of CCND1 and PCNA.