Biomolecules & biomedicine最新文献

Sentinel lymph node biopsy (SLNB) is a pivotal technique employed to assess the necessity for axillary lymph node dissection (ALND), evaluated during the preoperative phase through clinical and radiological findings. The preoperative identification of sentinel lymph node metastasis has gained paramount importance in the surgical management of breast cancer. Tumor budding (TB) has emerged as a significant prognostic marker across various cancers, including breast cancer, where it is instrumental in detecting lymph node metastasis. This study aims to investigate the role of tumor budding in predicting sentinel lymph node metastasis in preoperative breast biopsies. We included patients diagnosed with breast cancer, specifically those with invasive ductal carcinoma (IDC), who underwent preoperative needle biopsy and subsequent evaluation of postoperative surgical specimens, as well as SLNB at our medical center. The histological slides of these cases were reevaluated, and tumor cell clusters comprising up to four cells were classified as TB. Lymph nodes exhibiting tumor cell involvement, limited to macrometastasis, were classified as positive. A total of 65 patients were enrolled in the study. Among these, 36 patients exhibited TB in their preoperative biopsies, while 29 did not. The median tumor sizes were 20 mm (range: 6-50 mm) in the TB-positive group and 19 mm (range: 2-50 mm) in the TB-negative group (p=0.3). Sentinel lymph node metastasis was detected in 18 patients with TB, compared to only five patients without TB, a difference that was statistically significant (p=0.006). We conclude that evaluating tumor budding in breast tru-cut specimens, in conjunction with clinical and radiological findings, may enhance the preoperative assessment of breast cancer cases requiring SLNB.

The transfer of molecular cargo in exosomes plays a crucial role in cancer progression, influencing metabolic processes, angiogenesis, immune interactions, and invasive capabilities. This review synthesizes current evidence on how exosomes modulate tumor metabolism and drive drug resistance, and outlines therapeutic opportunities. We searched PubMed, Scopus, Web of Science, and Google Scholar for English-language studies using terms related to exosomes/extracellular vesicles, glycolysis, oxidative phosphorylation (OXPHOS), lipid metabolism, and drug resistance/chemoresistance, and integrated the literature qualitatively. Evidence indicates that exosomes reprogram tumor and stromal metabolism by delivering enzymes and non-coding RNAs that boost glycolysis and dampen OXPHOS, activate cancer-associated fibroblasts and extracellular matrix (ECM) remodeling, and modulate ferroptosis. They stimulate angiogenesis (e.g., via vascular endothelial growth factor (VEGF)/Wnt pathways) and promote immune escape through programmed death-ligand 1 (PD-L1), transforming growth factor beta (TGF-β), and macrophage reprogramming. Exosomal integrins and proteases contribute to epithelial-mesenchymal transition (EMT), organotropism, and pre-metastatic niche formation. Critically, exosomes propagate chemoresistance by exporting drugs and spreading determinants-including P-gp/BCRP/MRP-1, anti-apoptotic proteins, and regulatory RNAs-to previously sensitive cells; adipose-derived vesicles and lipid cargos further reinforce metabolic plasticity and therapy resistance. Given their stability, nanoscale dimensions, and ability to cross the blood-brain barrier, exosomes are promising vectors for targeted delivery; engineered vesicles can enhance chemotherapy responsiveness and counteract resistance, particularly alongside immunotherapy. In summary, interventions that disrupt exosome biogenesis, cargo loading, or uptake-paired with engineered exosomes for precision delivery-could mitigate drug resistance, metastasis, and immune evasion and advance more effective cancer treatment.

Endometrial mesonephric-like adenocarcinoma (MLA) is a rare subtype of uterine corpus endometrial carcinoma (UCEC) first described in 2016. The clinicopathological features, treatment options, and prognosis of endometrial MLA remain poorly understood. In this study, we retrospectively analyzed the clinicopathological characteristics, molecular features, treatment regimens, and outcomes of 11 patients diagnosed with endometrial MLA. The most prevalent symptom observed was postmenopausal bleeding. Notably, 78% (7 out of 9) of patients were diagnosed at advanced FIGO stages (II-IV), with four cases presenting with distant metastasis upon initial examination. Multivisceral metastases were identified in three cases, with lung metastases being the most common, occurring in 45% of patients. The median progression-free survival (PFS) was 16 months (95% confidence intervals: 6-26). All tumors tested negative for progesterone receptors (PR), while 91% of patients (10 out of 11) were negative for estrogen receptors (ER). Most patients exhibited positive immunohistochemical staining for "mesonephric-like" markers, including GATA-binding protein 3 (GATA-3), thyroid transcription factor-1 (TTF-1), and CD10. Furthermore, 91% of patients showed a wild-type p53 immunostaining pattern. Among the 11 patients, five underwent KRAS mutation testing, revealing KRAS mutations in all tested individuals (p.G12D in 2/5, p.G12A in 1/5, p.G12V in 1/5, and p.G13D in 1/5). These findings indicate that 78% of endometrial MLA patients were diagnosed at an advanced stage and suggest that this subtype may exhibit more aggressive behavior compared to endometrial endometrioid carcinoma. The consistent presence of KRAS mutations in patients who underwent testing highlights the potential role of KRAS in the initiation and progression of endometrial MLA, positioning it as a promising therapeutic target.

Cardiovascular disorders are closely linked to metabolic syndrome and remain a leading cause of mortality worldwide, despite advances in early detection and treatment. Adipokines, cardiokines, and myokines play critical roles in maintaining systemic metabolic homeostasis. In this study, we measured serum levels of fatty acid binding protein 4 (FABP4), follistatin-like 1 (FSTL1), irisin, and adiponectin in 243 male patients undergoing elective coronary angiography. We investigated the associations of these biomarkers with coronary artery disease (CAD) and their correlation with metabolic syndrome status. FSTL1 levels were predicted using a Particle Swarm Optimization-enhanced Adaptive Neuro-Fuzzy Inference System (PSO-ANFIS) based on artificial intelligence. Patients with CAD exhibited significantly lower FABP4 levels (p<0.0001), and low FABP4 levels emerged as an independent predictor of CAD in logistic regression analysis (odds ratio 0.903, 95% CI 0.825-0.987, p=0.025). The combination of adiponectin, FSTL1, and irisin as a biomarker strategy demonstrated high sensitivity and specificity for diagnosing metabolic syndrome (AUC = 0.92, 95% CI 0.88-0.96). Both FSTL1 and adiponectin independently correlated with metabolic syndrome (p<0.001, odds ratio 1.039, 95% CI 1.025-1.054; p<0.001, odds ratio 0.979, 95% CI 0.971-0.988, respectively). The prediction of FSTL1 levels using PSO-ANFIS supports the concept of harmonization among metabolic messengers. These findings underscore the potential of FABP4 and FSTL1 as valuable biomarkers for diagnosing metabolic and cardiovascular diseases, thereby facilitating personalized interventions targeting organokine pathways.

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.