Journal of Translational Medicine最新文献

Background: Periodontitis (PD) is a chronic infectious and inflammatory disease characterized by alveolar bone loss. The distinctive activity of immune cells critically exacerbates bone resorption in PD. Myeloid-derived suppressor cells (MDSCs) are known to contribute to various chronic inflammatory conditions, but their role in the pathogenesis and progression of PD remains poorly understood.

Methods: We used single-cell transcriptomic analysis with human gingival samples and animal models of experimental periodontitis to examine the role of M-MDSCs in PD. We also explored the therapeutic effect of depleting MDSCs on PD in vivo. Additionally, the mechanisms of long non-coding RNA Neat1 and the pathway of NF-κB-dependent "canonical NLRP3 inflammasome activation" in MDSCs were investigated in PD.

Results: In this study, we revealed that monocytic (M)-MDSCs were significantly increased in inflamed gingiva of PD patients compared to healthy individuals. Expansion of M-MDSCs was also observed in the mouse model of ligature-induced periodontitis, and depletion of MDSCs in PD mice could ameliorate alveolar bone loss and reduce periodontal inflammation. Mechanistically, we found that long non-coding RNA Neat1 was significantly upregulated in M-MDSCs, which achieved this proinflammatory effect by activating NF-κB signaling in PD. Furthermore, the pathway of NF-κB-dependent "canonical NLRP3 inflammasome activation" was confirmed in the PD mouse model, accompanied by increased secretion of proinflammatory cytokines that drive alveolar bone loss, including IL-1β, IL-6 and TNF-α.

Conclusions: In conclusion, this study highlights the pivotal proinflammatory role of M-MDSCs in PD and suggests that targeting these cells may represent a novel immunotherapeutic approach. Future research could focus on strategies to specifically target MDSCs for the treatment of periodontitis.

Background: Gastrointestinal (GI) cancers account for more than one-third of cancer-related mortality, and the prognosis for late-stage patients remains poor. Immunotherapy has been proven to extend the survival of patients at advanced stages; however, challenges persist in patient selection and overcoming drug resistance. Tumor-infiltrating lymphocytes (TILs) and tertiary lymphoid structures (TLS) in the tumor microenvironment (TME) have been found to be associated with anti-tumor immune responses. 'Hot tumors' with high levels of infiltration tend to respond better to immune checkpoint inhibitor (ICI) therapy, making them potential biomarkers for ICI treatment.

Methods: To explore potential biomarkers for predicting immunotherapy response and prognosis in GI cancers, we downloaded the gene expression profiles of seven GI cancers from The Cancer Genome Atlas (TCGA) database and characterized their TME, classifying the samples into hot/cold tumor subgroups. Furthermore, we developed a computational framework to construct cancer-specific hot tumor classification models with only a few genes. External independent datasets and qPCR experiments were used to verify the performance of our few-gene models.

Results: We constructed cancer-specific few-gene models to identify hot tumors for GI cancers with only two to nine genes. The results showed that B cells are important for hot tumor determination, and the identified hot tumors are significantly associated with TLS. They not only overexpress TLS marker genes but are also associated with the presence of TLS in whole-slide images. Further, a two-gene qPCR model was developed to effectively distinguish between hot and cold tumor subgroups in cholangiocarcinoma, providing an opportunity for stratifying patients with hot tumors in clinical settings.

Conclusions: In conclusion, our established few-gene models, which can be easily integrated into clinical practice, can distinguish hot and cold tumor subgroups, and may serve as potential biomarkers for predicting ICI response.

Background: This study analyzes the long-term outcomes of metabolic bariatric surgery (MBS), focusing on weight loss, nutritional deficiencies, and patient satisfaction. We evaluate different surgical techniques to identify their impact on these outcomes.

Methods: A five-year retrospective analysis was conducted on 249 patients who underwent MBS at a specialized center. Baseline characteristics included an average age of 38.5 years, weight of 118.5 kg, and BMI of 43.2 kg/m². Weight loss outcomes were assessed using mean excess weight loss (%EWL) at 60 months. Surgical techniques included laparoscopic sleeve gastrectomy (LSG), one anastomosis gastric bypass (OAGB), and Roux-en-Y gastric bypass (RYGB). Nutritional deficiencies and patient-reported quality of life were also evaluated.

Results: The mean %EWL at 60 months was 92.1% ± 25.8% (p = 0.013). While LSG and OAGB showed similar weight loss patterns, RYGB resulted in further weight reduction from the third year onwards. Patients revised from LSG to RYGB had significantly greater weight loss (102.1%) compared to those revised to mini-gastric bypass (MGB) (84.6%, p < 0.05). Nutritional deficiencies were prevalent, with 41.2% of revised LSG patients experiencing iron deficiency and 14.3% developing new vitamin D deficiencies (p < 0.05). Most patients (85%) reported improvements in quality of life, and 85% expressed a willingness to undergo surgery again (p = 0.0028).

Conclusions: MBS resulted in substantial and sustained weight loss, particularly in RYGB patients. Surgical revisions, especially from LSG to RYGB, were associated with greater weight loss but also increased nutritional risks. Persistent iron and vitamin D deficiencies highlight the necessity of individualized supplementation and long-term monitoring. Type-targeted supplementation represents an innovative approach to optimizing long-term nutritional support in bariatric patients. Future studies with larger cohorts and validated tools are needed to confirm these findings and strengthen clinical guidelines.

Trial registration: This study is registered at ClinicalTrials.gov (NCT06664580).

Background: Fatigue has a significant impact on physical performance and quality of life in older adults, but is subjectively assessed in the Fried phenotype, so early deterioration may be overlooked. This study explores whether repetitive handgrip strength (HGS) provides an objective method of differentiating levels of frailty by comparing fatigue and recovery ratios with subjective measures and their correlations with frailty indicators.

Methods: Participants (n = 217) were included based on mobility and cognitive function (MMSE > 17), with exclusions for neuromuscular disease or hand injury. The protocol consisted of two 10-maximal grip assessments one hour apart, calculating fatigue ratios 1 and 2 (maximum/mean force) at each session and recovery ratios between sessions. Logistic regression analysed associations between Fried's criteria components (Unintentional Weight Loss, Exhaustion Single Question, Multidimensional Fatigue Inventory (MFI), Short Physical Performance Battery (SPPB), Physical Activity Scale for the Elderly (PASE), standard Maximum HGS, Fatigue Ratio, and Recovery Ratio).

Results: Among the participants (58 non-frail, 68 pre-frail, 91 frail; ages 74.7, 79.4, 83.8 years), significant differences were found for Fatigue Ratio 1 of 1.12 (non-frail), 1.23 (pre-frail), 1.40 (frail), Fatigue Ratio 2 of 1.12, 1.21, 1.45, and Recovery Ratio of 1.03, 1.01, 0.90, respectively. Fatigue Ratios 1, 2 and Recovery correlated more strongly with frailty status (r = 0.67, 0.69, -0.68) than MFI (r = 0.50), standard maximum HGS (r = -0.51) or a single fatigue question (r = 0.21). In logistic regression for predicting fatigue (MFI), Fatigue Ratio (OR = 1.51, p < 0.001) and Recovery Ratio (OR = 0.83, p = 0.022) were stronger predictors than single-question fatigue (OR = 1.15, p = 0.047) and maximum HGS. For predicting frailty, physical performance (SPPB) was the strongest predictor (OR = 0.72, p < 0.001), followed by Fatigue Ratio 1 (OR = 1.28, p < 0.001), with a higher Recovery Ratio reducing frailty risk (OR = 0.86, p = 0.050).

Conclusion: The repetitive HGS protocol is equivalent to the SPPB in assessing frailty and outperforms standard HGS and subjective fatigue measures. This objective method supports the identification of frailty by measuring strength, fatigue resistance and recovery capacity.

Background: 3-hydroxy-3-methylglutaryl-coenzymOHBe A(HMG-CoA) lyase (HMGCL) catalyzes the cleavage of HMG-CoA into acetyl-CoA and acetoacetic acid and serves as a rate-limiting enzyme in the metabolism of ketone bodies. While HMGCL is involved in various biological processes, its specific role in osteosarcoma remains unclear.

Methods: Using data from a public database of osteosarcoma patients, we investigated the expression and prognostic value of HMGCL. The effects of HMGCL on the proliferation, migration, and invasion of osteosarcoma cells were assessed using CCK-8 assays, wound healing tests, and transwell invasion assays. We explored and validated the specific molecular mechanisms by which HMGCL influences osteosarcoma through transcriptome sequencing. Finally, we established a subcutaneous tumor formation model in nude mice to investigate the function of HMGCL in vivo.

Results: The expression of HMGCL is downregulated in osteosarcoma and correlates with the prognosis of osteosarcoma patients. Overexpression of HMGCL can inhibit the proliferation, migration, and invasion of osteosarcoma cells, as well as tumor growth in vivo. Through our investigation of the underlying mechanism, we found that HMGCL may inhibit the activation of the PI3K/AKT/mTOR signaling pathway via its product, β-HB. This inhibition promotes the phosphorylation of ULK1, thereby facilitating autophagy in osteosarcoma cells and enhancing the malignancy of the disease.

Conclusion: HMGCL inhibits the activation of the PI3K/AKT/mTOR signaling pathway mediated by β-HB, thereby reducing the proliferation, migration, and invasion of osteosarcoma cells while promoting autophagy. HMGCL may represent a new target for the treatment of osteosarcoma, offering new hope for patients with this disease.

Background: Osteosarcoma (OS) is recognized as a prevalent primary bone malignancy, particularly affecting adolescents during their growth spurts. Despite its clinical significance, the underlying biological characteristics and associated prognostic factors remain incompletely understood. The identification of novel molecular players involved in osteosarcoma progression could enhance our understanding of its pathogenesis and potentially inform patient management strategies.

Methods: In this study, we investigated the expression levels of Spindle and Centriole-Associated Protein 1 (SPICE1) in OS cells and tissues through quantitative analyses. We performed in vitro and in vivo experiments to evaluate the proliferation effects of SPICE1 on OS cells. Additionally, we explored the mechanistic interactions between SPICE1, Fatty Acid Synthase (FASN), and ubiquitin-specific peptidase 10 (USP10) through co-immunoprecipitation and mutation analyses, including the design of a peptide to inhibit the SPICE1-FASN interaction.

Results: Our findings revealed that SPICE1 is significantly overexpressed in OS samples. Furthermore, this high expression correlates with poor patient prognosis. The elevated levels of SPICE1 were found to promote OS cell proliferation by inhibiting the ubiquitination of FASN, consequently enhancing FASN protein stability. Additionally, SPICE1 was shown to facilitate the interaction between USP10 and FASN, promoting FASN deubiquitination, with specific amino acid interactions identified between USP10 and FASN that are necessary for this process.

Conclusion: This study elucidates the role of SPICE1 as a potential oncogene in OS, highlighting its contribution to tumor growth through the modulation of FASN stability. Importantly, our results suggest that targeting the SPICE1/USP10/FASN signaling axis could offer a novel therapeutic approach for treating OS. Future investigations should focus on the development of specific inhibitors that disrupt this pathway, ultimately leading to improved clinical outcomes for patients with OS.

Background: Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy with limited therapeutic options. To improve patients management and treatment, more precise stratification strategies are needed. This study aimed to characterize the phenogenomic landscapes of MPM and to understand their influence on patients clinical outcomes.

Methods: We conducted a phenogenomic analysis on 22 MPM patients using two high throughput approaches: imaging mass cytometry (IMC) with whole exome sequencing (WES). Resulting profiles were addressed for their clinical relevance to predict patients prognosis.

Results: IMC revealed a highly heterogeneous tumor microenvironment (TME) with distinct tumor cell subpopulations. Notably, we identified a novel sarcomatoid-like cellular cluster associated with poor prognosis. The TME was also infiltrated with immune cells including macrophages and CD4⁺ T lymphocytes, that were more abundant in patients with favorable clinical outcomes. WES identified a complex genomic landscape with limited prognostic value for individual genetic alterations. However, tumor mutational burden (TMB) emerged as a potential predictive biomarker, inversely correlating with immune cell infiltration, particularly macrophages and CD4⁺ T lymphocytes.

Conclusions: Our findings underscore the intricate interplay between the tumor genome, TME composition, and clinical outcomes in MPM. These data support the potential of integrating genomic and TME profiling to develop more precise patient stratification strategies and potentially optimize therapeutic approaches, including immunotherapy.

Background: In the last two decades, many studies based on omics technologies have contributed to defining the clinical, immunological, and histological fingerprints of chronic antibody-mediated rejection (CAMR), the leading cause of long-term kidney allograft failure. However, the full biological machinery underlying CAMR has only been partially defined, likely due to the fact thatsingle-omics technologies capture only specific aspects of the biological system and fail to provide a comprehensive understanding of this clinical complication.

Methods: This study integrated mass spectrometry-based proteomic profiling of serum samples from 19 patients with clinical and histological evidence of CAMR and 26 kidney transplant recipients with normal graft function and histology (CTR) with transcriptomic analysis of peripheral blood mononuclear cells (PBMCs) from an independent cohort of 10 CAMR and 8 CTR patients. Data analysis was conducted using unsupervised hierarchical clustering (multidimensional scaling with k-means) and Spearman's correlation test. Partial least squares discriminant analysis (PLS-DA) with the importance in projection (VIP) score identified key proteins differentiating CAMR from CTR. ELISA was used to validate the omics results.

Results: Proteomic analysis identified 18 proteins that significantly differentiated CAMR from CTR (p < 0.01): five were more abundant (CHI3L1, LYZ, PRSS2, CPQ, IGLV3-32), while 13 were less abundant (SERPINA5, SERPING1, KNG1, CAMP, VNN1, BTD, WDR1, PON3, AHNAK2, MELTF, CA1, CD44, CUL1). Transcriptomic profiling revealed 6 downregulated and 33 upregulated genes in CAMR versus CTR (p < 0.01). Notably, only 2 biological elements were significantly deregulated in both omics analyses: chitinase-3-like protein 1 (CHI3L1) and plasma protease inhibitor C1 (SERPING1). CHI3L1, previously associated with the severity of tissue damage in kidney diseases, was up-regulated in CAMR in both transcriptomics and proteomics, while SERPING1, a serine esterase inhibitor that blocks the classical and lectin pathway of complement, was up-regulated in CAMR in transcriptomics but down-regulated in proteomics. ELISA validated the omics results, and the ROC curve showed that CHI3L1 has good discrimination power between CAMR and CTR (AUC of ROC curve of 0.81).

Conclusions: Our multi-omics data, although performed in a relatively small cohort of patients, revealed new systemic biological elements involved in the pathogenesis of CAMR and identified CHI3L1 as a new potential biomarker and/or therapeutic target for this important clinical complication. Future validation of these findings in larger patient cohorts should be conducted to better evaluate their clinical utility.

Importance: Ovarian aging has become a focal point in current research on female aging and refers to the gradual decline in ovarian function as women age. Numerous factors influence ovarian aging, among which mitochondrial function is one because it plays a crucial role by affecting oocytes and granulosa cells. Mitochondrial deterioration not only leads to a decrease in oocyte quality but also hinders follicle development, further impacting women's reproductive health and fertility.

Objective: This review summarizes and integrates research on the impact of mitochondrial function on ovarian aging, outlining the mechanisms by which mitochondria regulate the functions of oocytes and granulosa cells. This study aims to provide potential therapeutic directions to mitigate mitochondrial decline and support female reproductive health.

Evidence review: According to a 2023 study published in Cell, factors such as oxidative stress, mitochondrial dysfunction, chronic inflammation, and telomere shortening collectively drive ovarian aging, directly affecting female fertility. Among these factors, mitochondrial dysfunction plays a key role. This study reviewed literature from databases such as PubMed, Google Scholar, and CNKI, using keywords such as "mitochondrial dysfunction", "decline in oocyte quality and quantity", and "ovarian aging", aiming to summarize current research on the mechanisms of the impact of mitochondrial dysfunction on ovarian aging and provide theoretical support for future exploration of related therapeutic strategies.

Findings: The main characteristics of ovarian aging include a decline in oocyte quantity and quality, fluctuations in hormone levels, and a reduction in granulosa cell function. Studies have shown that mitochondria affect fertility by regulating cellular energy metabolism, exacerbating oxidative stress, causing mitochondrial DNA (mtDNA) damage, and impacting the physiological function of granulosa cells within the ovary, gradually diminishing the ovarian reserve.

Conclusion: This review focuses on analyzing the effects of mitochondrial decline on energy production in oocytes and granulosa cells, the accumulation of reactive oxygen species (ROS), and the calcium ion (Ca²⁺) concentration, which all contribute to the ovarian aging process, and understanding them will provide new insights into the mechanisms of ovarian aging.

Relevance: Therapeutic interventions targeting mitochondrial dysfunction may help delay ovarian aging and improve female reproductive health.

Background: spinal cord injury (SCI) disrupts the gut microbiota, worsening the injury's impact. Fecal microbiota transplantation (FMT) is increasingly recognized as a promising strategy to improve neural function post-SCI, yet its precise mechanisms are still far from clear. The present study aims to elucidate how FMT influences motor function recovery and its underlying mechanisms utilizing a SCI mouse model.

Methods: Mice with SCI received FMT from healthy donors. We used 16 S rRNA amplicon sequencing to analyze the alterations of gut microbes. Pathological alterations in the spinal cord tissue, including neuronal survival, axonal regeneration, cell proliferation, and neuroinflammation, were assessed among experimental groups. Additionally, RNA sequencing (RNA-seq) was used to explore alterations in relevant signaling pathways.

Results: Significant shifts in gut microbiota composition following SCI were observed through 16 S rRNA analysis. On day 7 post-SCI, the FMT group exhibited a significantly higher diversity of gut microbiota compared to the ABX group, with the composition in the FMT group more closely resembling that of healthy mice. FMT promoted neuronal survival and axonal regeneration, leading to notable improvements in motor function compared to control mice. Immunofluorescence staining showed increased neuronal survival, alleviated extracellular matrix (ECM) deposition, diminished glial scar formation, and reduced inflammation in FMT-treated mice. RNA-seq analysis indicated that FMT induced transcriptomic changes associated with material metabolism, ECM remodeling, and anti-inflammatory responses.

Conclusions: FMT restored gut microbiota balance in SCI mice, mitigated inflammation, and promoted ECM remodeling, establishing an optimal environment for neural recovery. These findings demonstrated that FMT may represent a valuable approach to enhance functional recovery following SCI.