Biomolecules & biomedicine最新文献

Histone methylation dysregulation is a crucial epigenetic driver of lung carcinogenesis; however, the role of lysine-specific demethylase 3A (KDM3A) in non-small cell lung cancer (NSCLC) remains inadequately understood. In this study, we established NSCLC cell models with both KDM3A overexpression and knockdown to investigate its functional impact. In vitro assays demonstrated that KDM3A depletion increased histone H3 lysine 9 dimethylation (H3K9me2), suppressed cell proliferation, and impaired migration and invasion by attenuating epithelial-mesenchymal transition (EMT) and the expression of matrix metalloproteinase-9 (MMP-9). Conversely, KDM3A overexpression led to reduced H3K9me2 levels, activated EMT, and enhanced metastatic potential. Mechanistically, KDM3A decreased H3K9me2 occupancy at the promoters of VIM and MMP-9, thus upregulating their expression. Additionally, KDM3A downregulated E-cadherin by activating the p-STAT3 pathway. In vivo, KDM3A knockdown significantly inhibited tumor growth in xenograft models. Clinical analyses revealed elevated KDM3A expression in metastatic NSCLC tissues, with a negative correlation between KDM3A and H3K9me2, and a positive association between KDM3A and FOXP3. These findings establish KDM3A as an epigenetic modulator of NSCLC progression through H3K9me2-dependent regulation of EMT and metastatic pathways, highlighting its therapeutic potential for NSCLC treatment.

Bowel perforation represents a prevalent and life-threatening emergency within general surgical pathology. This study aims to evaluate clinical and biochemical parameters that predict mortality in cases of bowel perforation. A retrospective analysis was performed on 144 patients who underwent surgical intervention for bowel perforation between 2019 and 2024. Key variables assessed included the albumin/creatinine ratio, age, serum albumin levels, CRP, and history of COVID-19. Mortality-associated variables were analyzed using univariate and multivariate logistic regression, as well as receiver operating characteristic (ROC) analysis. The mean age of the patients was 60 years, with 84 patients (58.3%) being male. The overall mortality rate was 25%. Independent predictors of mortality identified in the study included an albumin/creatinine ratio <3.38 (odds ratio [OR]: 12.666, p<0.001), age >66 years (OR: 3.273, p=0.036), and serum albumin levels <3 g/dL (OR: 5.653, p=0.002). ROC analysis indicated that the area under the curve (AUC) for the albumin/creatinine ratio was 0.879, establishing it as the parameter with the highest predictive accuracy for mortality. Among patients with a history of COVID-19, ischemia was the predominant cause of perforation (87.5%), while malignancy was the leading cause (41.4%) in those without a COVID-19 history. This difference in etiology was statistically significant (p<0.001). In conclusion, the albumin/creatinine ratio, age, and serum albumin levels are robust parameters for predicting mortality in bowel perforation cases. Furthermore, a history of COVID-19 significantly increases the risk of bowel perforation due to ischemia.

Acute lung injury (ALI) is driven by dysregulated inflammation, but how mitochondrial damage engages necroptosis in alveolar macrophages remains unclear. We aimed to define the mechanistic link between mitochondrial impairment and Zinc finger protein 1 (Zbp1)-mediated necroptosis in the murine alveolar macrophage-like cell line (MH-S). MH-S cells were stimulated with lipopolysaccharide (LPS) and profiled by RNA sequencing; necroptotic death was quantified by Calcein-AM/propidium iodide (PI) staining and lactate dehydrogenase (LDH) release, Zbp1 localization was examined by immunofluorescence microscopy, and Zbp1, receptor-interacting protein kinase 3 (RIPK3)/phospho-RIPK3 (p-RIPK3) and mixed lineage kinase domain-like protein (MLKL)/phospho-MLKL (p-MLKL) were measured by Western blotting. Mitochondrial status was assessed by mitochondrial reactive oxygen species (mtROS), mitochondrial membrane potential (ΔΨm; JC-1), mitochondrial permeability transition pore (MPTP) opening, adenosine triphosphate (ATP) content, and the markers ATP synthase F1 subunit alpha (ATP5a1), mitochondrial transcription factor A (TFAM), and translocase of outer mitochondrial membrane 20 (TOMM20); inflammatory responses were quantified by flow cytometry and qPCR. The mitochondria-targeted antioxidant Mito-TEMPO was used to interrogate the role of oxidative stress. LPS markedly increased Zbp1 transcription, coincident with upregulation of pro-inflammatory genes and activation of necroptosis; mitochondrial damage and elevated mtROS were critical upstream events for Zbp1 induction, driving RIPK3 and MLKL phosphorylation, necroptosis, and cytokine release. Mito-TEMPO restored mitochondrial function, lowered mtROS, downregulated Zbp1 and its necroptotic effectors (p-RIPK3, p-MLKL), and significantly reduced both necroptotic injury and inflammatory output. Collectively, mitochondrial dysfunction-driven mtROS initiates the Zbp1/RIPK3/MLKL necroptotic axis in alveolar macrophages, thereby amplifying pulmonary inflammation in ALI; targeting mtROS may mitigate necroptosis and protect against lung injury.

Sepsis is a common and life-threatening condition encountered in intensive care units (ICUs). Mesenchymal stromal cells (MSCs) and their small extracellular vesicles (EVs) have emerged as promising nanotherapeutics, particularly in the context of COVID-19. This study evaluates the efficacy and mechanisms of adipose-derived MSC EVs (ADMSC-EVs) in a lipopolysaccharide (LPS)-induced sepsis model. We quantified M2 macrophages and IL-10 in peripheral blood mononuclear cells (PBMCs) from both septic patients and healthy donors. ADMSCs and their EVs were isolated, and EVs were administered to LPS-challenged mice. Macrophage phenotypes in lung tissue were analyzed using flow cytometry and immunofluorescence. The biodistribution of EVs was traced with PKH67 green fluorescent cell linker dye (PKH-67), and the signaling pathways involved in macrophage reprogramming were examined. ADMSC-EVs efficiently entered macrophages, promoted M2 polarization, suppressed inflammation, and improved survival rates in septic mice. Biodistribution studies demonstrated widespread organ accumulation, with notable localization in the lungs, liver, and kidneys. Mechanistically, the EV cargo miR-21-5p targeted Pellino E3 ubiquitin protein ligase 1 (PELI1), driving M2 polarization in vivo, which was accompanied by increased IL-10 levels. These findings position ADMSC-EVs as a viable cell-free therapeutic approach for mitigating LPS-induced sepsis through the delivery of miR-21-5p to PELI1, thereby supporting further development of EV-based immunomodulatory strategies for sepsis management.

Diabetes mellitus (DM) disrupts cellular homeostasis and is characterized by mitochondrial structural and functional impairments similar to those found in other metabolic disorders. Mitochondrial dysfunction (MD) leads to the excessive production of reactive oxygen species (ROS), which are central to the progression of cardiovascular (CV) disease-the leading cause of mortality associated with DM. ROS-driven oxidative stress (OS) is implicated in cardiac injury in both clinical and experimental contexts. This review synthesizes recent literature on the role of MD in the development and progression of DM and its associated CV complications, highlighting disrupted pathways that regulate the balance between ROS production and antioxidant defenses. We summarize alterations in mitochondrial dynamics-including fusion, fission, and mitophagy-mtDNA damage, and impaired oxidative phosphorylation characterized by dysregulated mitochondrial membrane potential (ΔΨm), electron transport chain (ETC) defects, uncoupling, and substrate overload. Additionally, we discuss hyperglycemia-activated pathways such as polyol flux, AGE-RAGE interactions, protein kinase C/nicotinamide adenine dinucleotide phosphate (PKC/NADPH) oxidase activation, and poly(ADP-ribose) polymerase 1 (PARP-1)-mediated glyceraldehyde-3-phosphate dehydrogenase (GAPDH) inhibition, which contribute to inflammation, endothelial dysfunction, β-cell failure, insulin resistance, and micro/macrovascular injury. Diagnostic and biomarker strategies encompass mtDNA analysis, bioenergetic assays, metabolomics, proteomics, and imaging techniques including PET, MRI, and NIRS. Therapeutic approaches aimed at restoring mitochondrial function and mitigating OS include mitochondria-targeted antioxidants (such as MitoQ, CoQ10, SkQ1, SS-31, and Mito-TEMPO), metabolic drugs (including metformin and SGLT2 inhibitors), lifestyle modifications, and emerging gene-editing technologies. The interplay between mitochondria, ROS, and DM reflects a tightly regulated aspect of cellular physiology; while targeted and personalized strategies hold promise, they necessitate rigorous evaluation.

Pandoraea species are emerging multidrug-resistant pathogens increasingly associated with respiratory tract infections, particularly in cystic fibrosis patients. Despite their growing clinical relevance, these bacteria are underrepresented in the scientific literature. This review aims to consolidate existing evidence regarding Pandoraea species as emerging multidrug-resistant pathogens, with a focus on their taxonomy, diagnostic methodologies, antimicrobial resistance mechanisms, and treatment challenges. By identifying gaps in current therapeutic strategies and the limited clinical outcome data, this review underscores the necessity of advancing research into innovative interventions, such as bacteriophages, antimicrobial peptides, and combination therapies, to enhance patient management and infection control. A comprehensive literature search was conducted using PubMed and Google Scholar, employing relevant keywords to identify case reports, clinical studies, and in vitro research related to Pandoraea infections, resistance mechanisms, and therapeutic strategies. Our findings reveal a significant lack of comprehensive data on therapeutic approaches, particularly concerning bacteriophages, antimicrobial peptides, and combination antibiotic therapies. Furthermore, clinical data on treatment efficacy remain sparse, with the majority of evidence stemming from in vitro-studies rather than real-world clinical settings. This review emphasizes the urgent need for further research to address these knowledge deficits and to develop effective therapeutic interventions against Pandoraea infections.

Sclerostin is a key inhibitor of the Wnt signaling pathway, functioning by binding to the LRP5/6 receptor. This interaction inhibits beta-catenin expression, resulting in the downregulation of osteogenic markers, which contributes to the promotion of osteoporosis and an increase in osteoclast numbers. The primary objective of this research was to investigate the effects of sclerostin antibody (Scl-ab) on bone formation utilizing graft materials in tooth sockets, and to analyze the regulatory interaction between sclerostin and bone tissue through targeted sclerostin inhibition and stimulation of bone formation in tooth extraction sockets following local, single-dose administration. In this study, New Zealand male rabbits (3 months old, weighing 2.5-3 kg) were fully randomized to minimize bias. The experiments were conducted across five groups: a control group, a graft group, and three experimental groups receiving 100%, 75%, and 50% doses of Scl-ab. Calculated doses of Scl-ab were administered alongside the graft material in the extraction sockets, with results assessed at 2 and 4-week intervals. Cone-beam computed tomography indicated that the tooth extraction sockets treated with varying ratios of Scl-ab with graft material exhibited a statistically significant increase in the mean mandibular BV/TV ratio compared to the control and graft groups, with variations based on time and dosage. While bone volume improved over time, the most significant enhancement was observed in the 100% Scl-ab group. Additionally, the administration of different doses of Scl-ab significantly increased trabecular thickness of the alveolar bone compared to both the control (p < 0.001) and graft (p < 0.001) groups, with histological analysis corroborating these findings. The therapeutic application of Scl-ab facilitates early bone formation, and the localized inhibition of sclerostin secreted within the bone microenvironment targets potential bone regeneration.

Assessment of insulin resistance is increasingly emphasized in patients with systemic lupus erythematosus (SLE) due to its significant role in predicting kidney injury and cardiovascular risk. Given that sustained inflammation is a hallmark of SLE, the novel C-reactive protein (CRP)-triglyceride-glucose (TyG) index (CTI), which comprehensively reflects insulin resistance and inflammation, has emerged as a valuable biomarker. This study aimed to investigate the association between the CTI and the risk of lupus nephritis (LN) risk and further explore its predictive potential in SLE patients. A cohort of 195 SLE patients stratified by renal involvement or CTI tertiles were included. Spearman's correlation analysis was performed to assess the relationship between the CTI and clinical parameters of lupus activity. Logistic regression analysis was utilized to identify the association between the CTI and risk of LN. The receiver operating characteristic (ROC) curve was employed to evaluate the CTI and the TyG index in predicting LN. The results demonstrated significantly elevated CTI levels in the LN group compared to the non-LN group. Multivariate-adjusted regression analysis indicated that a unit increase in CTI corresponded to enhanced risk of LN (adjusted OR =2.062; 95% CI: 1.208 - 3.522), particularly among patients in the third tertile compared to those in the first tertile (adjusted OR = 4.368; 95% CI: 1.411 - 13.520).  Subgroup analysis revealed that SLE patients with a SLEDAI-2K score greater than 6 exhibited an increased LN risk associated with higher CTI levels. ROC analysis illustrated the higher sensitivity of CTI (AUC = 0.6592; 95%CI, 0.576 - 0.742) compared to the TyG index (AUC = 0.6327; 95%CI, 0.546 - 0.719) in predicting LN risk. These findings indicate that elevated CTI is strongly associated with an increased risk of LN, suggesting its potential as a valuable predictor of LN risk in SLE patients.

The Braden score, a bedside assessment tool for evaluating the risk of pressure ulcers and frailty, may identify vulnerabilities pertinent to outcomes in acute pancreatitis (AP). However, its prognostic significance in this context remains uncertain. This study aimed to determine whether the Braden score at admission predicts all-cause mortality in intensive care unit (ICU) patients with AP and whether it provides additional value to existing clinical models. In a retrospective single-center cohort study utilizing data from MIMIC-IV v3.1 (2008-2022), we included 1,985 adults diagnosed with AP. We analyzed the Braden score as both a continuous variable and a dichotomous variable (high-risk: ≤15 vs. low-risk: >15), with 30-day mortality as the primary endpoint (with secondary endpoints at 90, 180, and 360 days). Our methodology encompassed Kaplan-Meier analysis, multivariable Cox regression, restricted cubic splines, receiver operating characteristic curves, and calibration assessments. By the 30-day mark, a total of 230 deaths were recorded (11.6%). Each 1-point increase in the Braden score correlated with a 7.7% reduction in mortality risk (HR 0.923, 95% CI 0.873-0.976; p=0.005). Furthermore, patients categorized as low-risk experienced lower mortality rates compared to high-risk patients (HR 0.688, 95% CI 0.501-0.945; p=0.021). The discrimination capability at 30 days was moderate (AUC 0.67, 95% CI 0.63-0.71), with an optimal cutoff score of 15 (sensitivity 61%, specificity 65%) and good calibration; however, performance diminished over longer durations. Incorporating the Braden score into a baseline clinical model enhanced predictive accuracy (AUC 0.712 vs. 0.647; NRI 0.235; IDI 0.040; all p<0.001). The Braden score at ICU admission is independently associated with 30-day mortality in patients with AP, providing moderate, well-calibrated predictions and significant incremental value. This supports its application as an early and straightforward tool for risk stratification, pending prospective validation.

Iliac vein stenting (IVS) is an endovascular revascularization procedure for iliac venous outflow obstruction. We aimed to synthesize the efficacy and safety of IVS across iliac vein disease phenotypes and follow-up horizons. Following a pre-registered protocol (PROSPERO CRD42024606701), we systematically searched Embase, Scopus, PubMed, Web of Science, and Cochrane Library on October 5, 2024. Without restricting study design, we included English-language reports with at least 10 patients that reported at least one prespecified outcome (or convertible data) and excluded studies with additional core therapies or duplicated cohorts. Diseases were classified as non-thrombotic iliac vein compression syndrome (NIVCS), post iliac vein thrombotic syndrome (PIVTS), chronic iliac vein obstruction (CIVO, that is, NIVCS or PIVTS), and acute thrombotic iliac vein obstruction (ATIVO, that is, a CIVO patient with acute ipsilateral thrombosis). The primary outcome was cumulative primary patency (CPP); secondary outcomes comprised ulcer healing, edema and pain relief, quality-of-life improvement, revised Venous Clinical Severity Score change, and adverse events. CPPs at prespecified intervals were extracted for each disease category and pooled in separate meta-analyses. Twenty-seven studies (4,782 patients) were included; demographic, intraoperative, and outcome data were systematically abstracted. Pooled CPPs were consistently high, particularly for NIVCS, and were lower when thrombotic components were present (PIVTS and ATIVO), while other efficacy outcomes generally improved and serious complications were uncommon. In conclusion, across diverse iliac vein diseases and follow-up periods, IVS demonstrates good efficacy and safety; this unfunded study supports IVS as a prominent treatment option.