Hereditas最新文献

Background: Patients with severe acute pancreatitis (SAP) often experience systemic inflammatory responses and microcirculatory disturbances, for which existing treatments have limited intervention effects.

Objectives: It aimed to investigate the impact of early blood purification on serum inflammatory mediators, hemorheological parameters, and clinical prognosis in patients with SAP.

Methods: 120 patients with SAP were randomly grouped: observation group (OG) (routine treatment + early continuous veno-venous hemodiafiltration) and control group (CG) (routine treatment). The time to clinical symptom improvement, hemorheological parameters [whole blood viscosity (WBV), plasma viscosity (PV), hematocrit, and platelet adhesion rate], and inflammatory mediators were compared. Multivariate logistic regression analysis (MLRA) was used to identify prognostic factors.

Results: The OG had markedly shorter times to symptom relief for fever, abdominal pain, and abdominal distension (all P < 0.001) and a higher cure rate (P = 0.012); The levels of C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), as well as WBV and PV, were more markedly improved (all P < 0.01). Multivariate analysis suggested that peak CRP (OR = 1.01, P < 0.001) and peak TNF-α (OR = 1.02, P = 0.003) maintained independent predictive value, and all hemorheological parameters were confirmed as independent prognostic factors.

Conclusion: Early blood purification can effectively improve the inflammatory response and hemodynamics in patients with SAP, with its efficacy influenced by multiple factors, including disease severity, intensity of inflammatory response, and hemorheological status.

Clinical trial number: Not applicable.

Context: Hyperuricemia (HUA) is a known factor contributing to testicular spermatogenic dysfunction. Shenling Baizhu San (SLBZS), a traditional Chinese medicine compound, has demonstrated efficacy in reducing uric acid levels. However, its specific impact on testicular spermatogenic function in mice with HUA remains unclear.

Objective: To investigate the impact and mechanism of SLBZS on testicular spermatogenic function in HUA mice.

Materials and methods: A hyperuricemia-induced spermatogenic dysfunction model was created by administering intraperitoneal injections of potassium oxonate (600 mg/kg/d) for seven days. Following model establishment, 48 Balb/c mice were randomly divided into six groups: control, model, low-dose SLBZS (5.04 g/kg/d), medium-dose SLBZS (10.07 g/kg/d), high-dose SLBZS (20.14 g/kg/d), and febuxostat (10 mg/kg/d). All groups, except the control, underwent model induction, followed by specific interventions. Subsequent analyses included serum uric acid levels, testicular and epididymal indices, histopathological assessments, sperm quality, oxidative stress and inflammation markers, and the expression of proteins related to apoptosis and inflammation signaling pathways.

Results: SLBZS markedly enhanced sperm quality, testicular and epididymal indices, and serum uric acid levels in mice, while ameliorating histopathological lesions in testicular tissue. Additionally, SLBZS significantly reduced oxidative stress, serum inflammation markers, and testicular cell apoptosis, with the high-dose group showing superior effects compared to the febuxostat group. Further investigation revealed that SLBZS inhibited the expression and phosphorylation of proteins in the MAPK/NF-κB pathway and suppressed the expression of proteins in the NLRP3 inflammasome pathway.

Discussion and conclusions: SLBZS potentially modulates the MAPK/NF-κB and NLRP3 inflammasome signaling pathways, thereby suppressing inflammatory responses and enhancing spermatogenesis in the testes of HUA mice.

Purpose: HOXB13 has been shown to act as a tumor promoter in various malignancies; however, its role in nasopharyngeal carcinoma (NPC) remains unexplored. This study aimed to investigate the function of HOXB13 in NPC and elucidate its underlying mechanism to identify novel targets for NPC diagnosis and therapy.

Methods: HOXB13 expression in NPC was examined through bioinformatic analyses of the TCGA and GEO databases, and the findings were validated using molecular biology techniques. After the transfection of NPC cell lines with siRNA targeting HOXB13 (si-HOXB13), the effects of HOXB13 knockdown on cell proliferation, migration, invasion, and stemness were evaluated. Expression levels of Wnt/β-catenin/SOX2 pathway-related proteins were assessed. In vivo, NPC cells transfected with sh-HOXB13 were injected into nude mice, after which tumor volume and mass were measured, and lung metastases were analyzed using hematoxylin and eosin (H&E) staining.

Results: HOXB13 knockdown significantly reduced NPC cell viability, suppressed clonogenicity and invasiveness, increased scratch width in wound healing assays, and decreased sphere formation and the proportion of CD133⁺ cells. Additionally, si-HOXB13 significantly downregulated the protein expression of β-catenin, c-Myc, and SOX2. In vivo, the sh-HOXB13 group exhibited reduced tumor mass, volume and lung metastatic nodules compared to the sh-NC group.

Conclusion: This study demonstrates that HOXB13 facilitates the malignant progression of NPC by regulating the Wnt/β-catenin/SOX2 signaling pathway, suggesting HOXB13 as a potential therapeutic and diagnostic target for NPC, thereby offering a new strategy to improve patient prognosis.

Background: Adult pneumonia is an infectious lung disease caused by bacteria, viruses, or other microorganisms and exhibits some degree of contagion. Tenuigenin, a bioactive compound derived from Polygala tenuifolia, possesses broad pharmacological effects, but its role in adult pneumonia remains incompletely understood.

Methods: Bioinformatics and database analysis were employed to screen and analyze the Tenuigenin target genes relevant to adult pneumonia. Cell functions were assessed using cell counting kit-8 (CCK8), 5-ethynyl-2'-deoxyuridine (EdU) staining, transwell, tube formation, Fluo-4 calcium assay, and transepithelial electrical resistance (TER) assays. Protein levels were measured by western blot. Network pharmacology and molecular docking were employed to screen core target genes and verify binding interactions.

Results: Tenuigenin targets in adult pneumonia were enriched in the pathways related to vascular permeability and calcium signaling. Tenuigenin mitigated lipopolysaccharide (LPS)-induced impairment of human pulmonary microvascular endothelial cell (HPMEC) viability, proliferation, migration, and angiogenesis, while attenuating LPS-induced increases in apoptosis, calcium ion, and reactive oxygen species (ROS) levels. Besides, Tenuigenin also attenuated the TER decrease and permeability increase caused by LPS exposure in HPMECs. Network pharmacology and molecular docking identified steroid receptor coactivator (SRC) as a core target of Tenuigenin, demonstrating binding to specific SRC amino acid residues. Tenuigenin also reduced LPS-induced increase in phosphor-SRC (p-SRC) expression. Crucially, after inhibition of SRC kinase activity, Tenuigenin no longer exerted significant protective effects against LPS-induced HPMEC injury and dysfunction.

Conclusion: Tenuigenin alleviates LPS-induced injury and dysfunction of HPMECs by targeting the SRC pathway, providing a target for managing adult pneumonia.

In this comprehensive study, we explored the molecular landscape C-X-C chemokine receptor (CXCR) family genes (CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, and CXCR7) in osteosarcoma (OS) by scrutinizing the expression profiles and functional implications using Bioinformatics analyses and molecular experiments. We found significant up-regulation of these genes in OS cell lines compared to control cell lines, as assessed by RT-qPCR, with high diagnostic potential demonstrated by receiver operating characteristic (ROC) curve analysis. Cross-validation using the GSE12865 dataset revealed consistent up-regulation of CXCR family genes in OS samples, alongside decreased promoter methylation in tumor samples compared to normal tissues, as confirmed by the UALCAN database. Mutational analysis, conducted using data from 237 OS samples from the cBioPortal database, revealed minimal mutations in CXCR1 and CXCR2, with no alterations in CXCR3, CXCR4, CXCR5, and CXCR7. Copy number variation (CNV) analysis showed some level of amplification in CXCR1 and CXCR2, but no significant alterations in the copy numbers of the other genes. Survival analysis using meta-analysis across multiple independent studies showed that the expression of some CXCR genes were significantly associated with poor patient survival. Further exploration of the transcriptional regulation of CXCR genes using the ENCORI database revealed an intricate miRNA-mRNA network involving miR-130a, miR-146a, miR-155, miR-21, and miR-7, which regulate the expression of these genes. Elevated expression of these miRNAs in OS samples was validated by RT-qPCR, with promising diagnostic potential highlighted by ROC analysis. Additionally, the immunological analysis revealed a positive correlation between the expressions of CXCR genes and immune cell types, including macrophages and T cells, and CXCR genes were found to enhance drug responsiveness in OS patients. Gene enrichment analysis identified critical biological processes and pathways, such as chemokine-mediated signaling and immune response, linked to the CXCR family. Knockdown of CXCR1 in HOS and MG-63 cells confirmed that CXCR1 plays a crucial role in cell proliferation, colony formation, and migration. CXCR1 knockdown significantly reduced cell proliferation and colony formation, while enhancing cell migration, underscoring its functional importance in OS progression. Overall, our findings suggest that the CXCR family genes are potential diagnostic and prognostic markers in OS, with implications for therapeutic targeting and further investigation into their role in OS pathogenesis.

Background: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is characterized by hepatic lipid accumulation and metabolic disturbances. Caspase-2 cleaves site-1 protease (S1P), leading to the persistent activation of sterol regulatory element-binding proteins (SREBPs), which subsequently promote the progression of MASLD. Previous studies have demonstrated that the Qushi Huayu Decoction (QHD) significantly alleviates MASLD, particularly inhibiting the expression of SREBP-1 in hepatocytes of MASLD mouse models. However, its regulatory effect on the Caspase-2/SREBP-1 pathway and the dose-dependent nature of these effects remain unclear.

Objective: The regulatory effects of high, medium, and low doses of Qushi Huayu Decoction (QHD) on the Caspase-2/SREBP-1 pathway and their potential dose-dependent impacts was investigated.

Method: A MASLD model was induced in 28-week-old C57BL/6J mice using a high-fat diet (HFD). Mice were treated with QHD granules at high (3.466 g/kg), medium (1.733 g/kg), and low doses (0.867 g/kg), as well as a Caspase-2 inhibitor for a duration of 5 weeks. Pharmacodynamic indicators, including triglycerides (TG) and free fatty acids (FFA) in liver tissue, hepatic histopathology, and serum biochemical markers, were assessed. The expression of genes in the Caspase-2/SREBP-1 signaling pathway and its downstream targets was also analyzed.

Results: QHD at all doses effectively improved hepatic steatosis. The low-dose group significantly reduced hepatic TG levels (p < 0.01) and the insulin resistance index (p < 0.05). The high-dose group significantly inhibited the expression of Caspase-2 protein (p < 0.01) and nuclear SREBP-1 protein (p < 0.05), with a dose-dependent decrease in Caspase-2 activity.

Conclusion: QHD exhibits dose-dependent, complementary effects in MASLD, with low doses improving lipid metabolism and insulin sensitivity, and high doses more effectively suppressing Caspase-2/SREBP-1 and inflammatory signaling. This dual action underscores its broad regulation of ER stress and supports stage-specific, hierarchical dosing strategies aligned with traditional Chinese medicine principles.

Background: Renal cell carcinoma is characterized by immune and metabolic alterations. These metabolic reprogramming processes enhance tumor cell proliferation and infiltration. The purpose of this study was to investigate the characteristics of metabolism-related molecules and to identify potential prognostic biomarkers in kidney renal papillary renal cell carcinoma (KIRP).

Methods: We conducted a comprehensive analysis of metabolism-related genes using weighted gene co-expression network analysis and differential expression analysis. Subsequently, we constructed a metabolism-related signature (MRS) by integrating 90 machine learning algorithms. Based on Cox regression analyses, we developed a predictive nomogram. Functional enrichment analysis, genomic variant analysis, chemotherapy response evaluation, and immune cell infiltration profiling were then performed among the MRS subtypes. Finally, the MRS was further examined at the single-cell level, and quantitative PCR and immunohistochemical staining were conducted to validate the key genes.

Results: We identified 16 differentially expressed metabolic genes. The random survival forest (RSF) emerged as the optimal machine learning model in the TCGA-KIRP and GSE2748 cohorts. The MRS demonstrated robust predictive performance, with an AUC of 0.989 for 5-year survival predictions. The risk score was significantly correlated with T stage and pathological stage and was identified as an independent prognostic factor. Patients in the high-risk group exhibited higher tumor mutation burdens and derived greater benefits from sunitinib, pazopanib, lenvatinib, and temsirolimus. A four-genes nomogram was then constructed to predict overall survival. PYCR1, INMT, and KIF20A were highly expressed in KIRP according to scRNA-seq analysis and were validated in vitro.

Conclusion: This study revealed the heterogeneity of metabolic molecules in KIRP and established a prognostic machine learning model that enhances risk stratification and may optimize chemotherapy strategies in the management of KIRP.

Resistance to targeted cancer therapies is a significant barrier to favorable treatment outcomes. Malignant cells can tolerate and resist drug treatments due to their biological flexibility. Specifically, slow-cycling drug-resistant cells may achieve permanent resistance to the treatment or restore sensitivity upon cessation of therapy. Enhancing cancer treatment methodologies necessitates a deeper understanding of the adaptability of tumor cells. Drug resistance and cellular heterogeneity are closely associated with cancer cell adaptability. Alterations in cellular signaling, interactions with the tumor microenvironment, and genetic and epigenetic alterations are all implicated. Analyzing these pathways will enhance our understanding of how cancer cells evolve and evade treatment. Two effective strategies to address cancer cell adaptability are to target specific biological pathways and to employ combination therapies. The progression of cancer therapy methodologies relies on comprehending and exploring the concept of cancer cell adaptability. Understanding tumor heterogeneity and drug resistance necessitates identifying the cellular, molecular, and genetic processes that govern cancer cell plasticity. This understanding enables the development of more personalized and effective cancer therapies, leading to improved treatment outcomes. CLINICAL TRIAL NUMBER: Not applicable.

Background: This study examines the causal relationship between spermidine levels and coronary artery disease (CHD) risk using a bidirectional Mendelian Randomization (MR) approach.

Methods: We employed genetic variants as instrumental variables to assess the influence of genetically predicted spermidine levels on CHD risk and vice versa. Data for the MR analysis were sourced from the UK Biobank and genome-wide association study datasets, focusing on single nucleotide polymorphisms (SNPs) associated with spermidine levels and CHD. The study also utilized liquid chromatography-tandem mass spectrometry (LC-MS/MS) for accurate quantification of spermidine in plasma samples.

Results: Our analysis identified a significant association between lower genetically predicted spermidine levels and increased CHD risk. The LC-MS/MS results supported the accurate measurement of spermidine, highlighting its feasibility as a clinical biomarker.

Conclusions: The findings suggest that reduced spermidine levels may be a significant risk factor for CHD. This study supports the potential of spermidine as a biomarker for CHD risk assessment and its development as a therapeutic target. The integration of genetic and biochemical methodologies enhances our understanding of the role of spermidine in cardiovascular health and its utility in managing CHD risk.