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Oxidative stress is the leading cause of most liver diseases, such as drug-induced liver injury, viral hepatitis, and alcoholic hepatitis caused by drugs, viruses, and ethanol. The Kelch-like ECH-associated protein 1-NFE2-related factor 2 (Keap1-Nrf2) system is a critical defense mechanism of cells and organisms in response to oxidative stress. Accelerating studies have clarified that the Keap1-Nrf2 axis are involved in the prevention and attenuation of liver injury. Nrf2 up-regulation could alleviate drug-induced liver injury in mice. Moreover, many natural Nrf2 activators can regulate lipid metabolism and oxidative stress of liver cells to alleviate fatty liver disease in mice. In virus hepatitis, the increased Nrf2 can inhibit hepatitis C viral replication by up-regulating hemeoxygenase-1. In autoimmune liver diseases, the increased Nrf2 is essential for mice to resist liver injury. In liver cirrhosis, the enhanced Nrf2 reduces the activation of hepatic stellate cells by reducing reactive oxygen species levels to prevent liver fibrosis. Nrf2 plays a dual function in liver cancer progression. At present, a Nrf2 agonist has received clinical approval. Therefore, activating the Nrf2 pathway to induce the expression of cytoprotective genes is a potential option for treating liver diseases. In this review, we comprehensively summarized the relationships between oxidative stress and liver injury, and the critical role of the Nrf2 pathway in multiple liver diseases.

Ossification of the ligamentum flavum (OLF) is characterized by ligamentum flavum thickening and subsequent thoracic canal stenosis. Emerging evidence has demonstrated the involvement of N6-methyladenosine (m6A) methylation in OLF pathogenesis. This study investigates the regulatory role of METTL3-mediated m6A methylation of BMP2 in OLF progression. Clinical ligamentum flavum tissues were analyzed for m6A levels using dot blot analysis. Osteogenic differentiation was assessed through quantitative real-time PCR (qPCR), alkaline phosphatase staining, alizarin red S staining, and western blot analysis. Mechanistic insights were obtained through methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP), and luciferase reporter assays. The regulatory role of histone lactylation on METTL3 expression was examined using LDHA knockdown, sodium lactate (Nala) treatment, and 2-deoxy-D-glucose (2-DG) administration in OLF cells. Our findings revealed significant upregulation of METTL3 expression and m6A levels in OLF patients. METTL3 was shown to enhance osteogenic differentiation and m6A methylation of BMP2, which was specifically recognized by IGF2BP1. Furthermore, increased histone lactylation was observed in OLF patients, with enrichment in the METTL3 promoter region facilitating its transcriptional activation. LDHA knockdown-mediated inhibition of endogenous lactylation suppressed osteogenic differentiation, a phenotype that was rescued by METTL3 overexpression. In conclusion, this study elucidates that histone lactylation-mediated upregulation of METTL3 promotes OLF progression through IGF2BP1-dependent m6A methylation of BMP2, providing novel insights into potential therapeutic strategies for OLF management.

Background Machine learning (ML) has been widely applied to predict the outcomes of numerous diseases. The current study aimed to develop a prognostic prediction model using machine learning algorithms and identify risk factors associated with residual back pain in patients with osteoporotic vertebrae compression fracture (OVCF) following percutaneous vertebroplasty (PVP). Methods A total of 863 OVCF patients who underwent PVP surgery were enrolled and analyzed. One month following surgery, a Visual Analog Scale (VAS) score of ≥ 4 was deemed to signify residual low back pain following the operation and patients were grouped into a residual pain group and pain-free group. The optimal feature set for both machine learning and statistical models was adjusted based on a 2000-resample bootstrap-based internal validation via an exhaustive search. The area under the curve (AUC), classification accuracy, sensitivity, and specificity of each model were then calculated to evaluate the predictive performance of each model. Results In our current study, two main findings were observed: (1) Compared with statistical models, ML models exhibited superior predictive performance, with SVM demonstrating the highest prediction accuracy; (2) several variables were identified as the most predictive factors by both the machine learning and statistical models, including bone cement volume, number of fractured vertebrae, facet joint violation, paraspinal muscle degeneration, and intravertebral vacuum cleft. Conclusion Overall, the study demonstrated that machine learning classifiers such as SVM can effectively predict residual back pain for patients with OVCF following PVP while identifying associated predictors in a multivariate manner.

Background CT examination for lung cancer has been carried out for more than 20 years and great achievements have been made in the early detection of lung cancer. However, in the clinical work, a large number of advanced central lung squamous cell carcinoma are still detected through bronchoscopy. Meanwhile, a part of CT-occult central lung squamous cell carcinoma and squamous epithelial precancerous lesions are also accidentally detected through bronchoscopy. Methods This study retrospectively collects the medical records of patients in the bronchoscopy room of the Endoscopy Department of Zhejiang Cancer Hospital from January 2014 to December 2018. The inclusion criteria for patients includes: 1.Patient medical records completed, 2.Without history of lung cancer before the diagnosis and first pathological diagnosis of primary lung cancer, 3.Have the lung CT data of the same period, 4.Have the bronchoscopy records and related pathological diagnosis, 5.The patients undergoing radical surgical treatment must have a complete postoperative pathological diagnosis. Finally, a total of 10,851 patients with primary lung cancer are included in the study, including 7175 males and 3676 females, aged 22–98 years. Firstly, 130 patients with CT-occult lesions are extracted and their clinical features are analyzed. Then, 604 cases of single central squamous cell carcinoma and 3569 cases of peripheral adenocarcinoma are extracted and compares in postoperative tumor diameter and lymph node metastasis. Results 115 cases of CT-occult central lung squamous cell carcinoma and 15 cases of squamous epithelial precancerous lesions are found. In the total lung cancer, the proportion of CT-occult lesions is 130/10,851 (1.20%). Meanwhile, all these patients are middle-aged and elderly men with a history of heavy smoking. There are statistically significant differences in postoperative median tumor diameter (3.65 cm vs.1.70 cm, P  < 0.0001) and lymph node metastasis rate (50.99% vs.13.06%, P  < 0.0001) between 604 patients with operable single central lung squamous cell carcinoma and 3569 patients with operable peripheral lung adenocarcinoma. Of the 604 patients with squamous cell carcinoma, 96.52% (583/604) are male with a history of heavy smoking and aged 40–82 years with a median age of 64 years. Conclusions This study indicates that the current lung CT examination of lung cancer is indeed insufficiency for the early diagnosis of central squamous cell carcinoma and squamous epithelial precancerous lesions. Further bronchoscopy in middle-aged and elderly men with a history of heavy smoking can make up for the lack of routine lung CT examination.

Retinitis pigmentosa (RP) is an inherited disorder that results in vision impairment but general and mutation-independent therapeutic strategies are not available. However, it is widely regarded that the cGMP system, including cGMP and its interactor cGMP-dependent protein kinase (PKG), acts as a crucial effector during retinal degeneration. We have previously identified a list of cGMP-PKG-dependent genes in the context of RP, and in this study, we further validated one of these, namely pyruvate kinase 2 (PKM2), and investigated the potential role of PKM2 for the photoreceptors’ well-being during RP. With the aid of organotypic retinal explant cultures, we pharmacologically manipulated the PKM2 activities in two different RP mouse models (rd2 and rd10) via the addition of TEPP-46 (a PKM2 activator) and found that activation of PKM2 alleviates the progress of photoreceptor death in the rd10 mouse model. We also noted that the expression of both PKM2 and one of its targets, glucose transporter-1 (Glut1), showed alterations depending on the degeneration state. The observations provide supportive evidence that PKM2 may serve as a novel potential molecular target in RP.

Background Epigenetic alterations contribute greatly to metastasis and dissemination in hepatocellular carcinoma (HCC). SMARCC1, as a SWI/SNF chromatin remodeling factor, has been reported to play important roles in many cancers. For the first time, with the bioinformatics analysis and wet-bench experiments, we explored the biological significance of SMARCC1 and its potential as putative therapeutic target in HCC. Methods The mRNA expression profiles and prognostic value of SMARCC1 were analyzed in the Oncomine, UALCAN and Kaplan–Meier Plotter databases. The expression of SMARCC1 and associated clinicopathological factors were further evaluated using a tissue microarray. Differentially expressed genes associated with SMARCC1 in HCC were obtained and analyzed via the LinkedOmics and GEPIA databases and Cytoscape software. To verify the important role of SMARCC1 in HCC, we knocked down and overexpressed SMARCC1 in different hepatic cell lines and conducted several functional experiments. Then, we evaluated the mutation profiles and transcriptional regulators of SMARCC1 using the cBioPortal, COSMIC, CistromeDB and TCGA databases. Finally, we addressed the relationship of SMARCC1 expression with immune cell infiltration via TIMER database analysis. Results Through data mining and tissue microarray verification, we found that the protein and mRNA levels of SMARCC1 are high in tumor tissues, which has remarkable diagnostic value in HCC patients. SMARCC1 and its hub genes showed prognostic value in HCC. Furthermore, we confirmed that SMARCC1 influenced the proliferation, migration, and invasion of HCC cells. Moreover, correlation analyses revealed that SMARCC1 expression was positively correlated with ZBTB40 transcription factors and negatively correlated with the DNA methylation level. Overall, we found that SMARCC1 affects immune infiltration and plays a tumor-promoting role in HCC. Conclusions SMARCC1 is overexpressed and is a putative prognostic predictor in HCC. Due to the tumor-promoting role of SMARCC1, treatments inhibiting DNA methyltransferases and transcription factors or weakening the role of SMARCC1 in immune infiltration might improve the survival of HCC patients.

Background The plate-to-disc distance (PDD) is an important factor affecting the degeneration of adjacent segments after anterior cervical discectomy and fusion (ACDF). However, the most suitable PDD is controversial. This study examined the adjacent intervertebral disc stress, bone graft stress, titanium plate stress and screw stress to evaluate the biomechanical effect of different PDD on surgical segment and adjacent segment following C5/C6 ACDF. Methods We constructed 10 preoperative finite element models of intact C4–C7 segments and validated them in the present study. We simulated ACDF surgery based on the 10 intact models in software. We designed three different distance of plate-to-disc titanium plates: long PDD (10 mm), medium PDD (5 mm) and short PDD (0 mm). The changes in C4/C5 and C6/C7 intervertebral disc stress, bone graft stress, titanium plate stress and screw stress were analyzed. Results The von Mises stress of C4/C5 and C6/C7 intervertebral discs had no significant differences ( P  > 0.05) in three different PDD groups. Titanium plate stress increased as the PDD decreased. The bone graft stress and screws stress decreased as the PDD decreased. The maximum stress of each part occurred was mostly in the conditions of rotation and lateral bending. Conclusions The PDD has no effect on adjacent intervertebral disc stress, but it is an important factor that affecting the bone graft stress, titanium plate stress and screws stress after ACDF. Shorter PDD plate can provide better stability to reduce stress on screws and bone graft, which may be helpful to prevent cage subsidence, pseudarthrosis and instrument failure. This can serve as a reference for clinical choice of plate.

Background Due to the fact that the CT-occult central lung squamous cell carcinoma and squamous epithelial precancerous lesions. (CT-occult CLSCC and SEPL) cannot be detected by lung CT screening, early and timely diagnosis of central lung cancer becomes very difficult, which directly affects the prognosis of patients. Methods We retrospectively review medical records of patients at the Zhejiang Cancer Hospital and enrolled 41 patients with the CT-occult CLSCC and SEPL and 48 patients without the CT-occult CLSCC and SEPL. We compare the clinical characteristics, imaging features and Changes in the number of pixels under different CT value intervals of patients with and without the CT-occult CLSCC and SEPL and we perform univariate and multivariate logistic regression analysis to explore independent factors for the CT-occult CLSCC and SEPL in the patients. Results We demonstrate that pack-years ≥ 20 (OR: 3.848, 95% CI: 1.086 ~ 13.633), the number of pixels change of CT value in interval [-850 ~ -750HU] (OR: 5.302, 95% CI: 1.122 ~ 25.057) and in interval [-900 ~ -850HU] (OR: 3.478, 95% CI: 1.167 ~ 10.365) are independently associated with the CT-occult CLSCC and SEPL in the patients. Ultimately, the logistic model obtained is statistically significant ( p  < 0.05) and an area under the ROC curve is 0.776 (95% CI: 0.682–0.870). The sensitivity of this model is 90.2% and the specificity is 52.1%. Conclusion The results of this study indicate that in the CT value range [-950 ~ -750HU], when the total number of lung pixels tend to increase towards the region with high CT value, the probability of the occurrence of CT-occult CLSCC and SEPL lesions also increases. Meanwhile, these results have guiding significance for the further study of radiomic.

Abstract Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn’s disease, is a chronic inflammation of the gastrointestinal tract with unknown etiology. The cause of IBD is widely considered multifactorial, with prevailing hypotheses suggesting that the microbiome and various environmental factors contribute to inappropriate activation of the mucosal immune system in genetically susceptible individuals. Although the incidence of IBD has stabilized in Western countries, it is rapidly increasing in newly industrialized countries, particularly China, making IBD a global disease. Significant changes in multiple biomarkers before IBD diagnosis during the preclinical phase provide opportunities for earlier diagnosis and intervention. Advances in technology have driven the development of telemonitoring tools, such as home-testing kits for fecal calprotectin, serum cytokines, and therapeutic drug concentrations, as well as wearable devices for testing sweat cytokines and heart rate variability. These tools enable real-time disease activity assessment and timely treatment strategy adjustments. A wide range of novel drugs for IBD, including interleukin-23 inhibitors (mirikizumab, risankizumab, and guselkumab) and small-molecule drugs (etrasimod and upadacitinib), have been introduced in the past few years. Despite these advancements, approximately one-third of patients remain primary non-responders to the initial treatment, and half eventually lose response over time. Precision medicine integrating multi-omics data, advanced combination therapy, and complementary approaches, including stem cell transplantation, psychological therapies, neuromodulation, and gut microbiome modulation therapy, may offer solutions to break through the therapeutic ceiling.

Despite advancements in melanoma therapy, the prognosis remains unfavorable for many patients. The proteasome inhibitor MG132 has shown therapeutic potential through pathway regulation, yet its precise mechanisms in melanoma require systematic elucidation. Using A375 melanoma cells, we conducted multi-modal investigations combining cytotoxicity assessment (CCK8), migration analysis (wound healing), apoptosis quantification (flow cytometry), and proteomic profiling (western blot) to dissect MG132’s molecular mechanisms. Our findings revealed MG132’s potent anti-tumor activity with an IC 50 of 1.258 ± 0.06 µM, significantly suppressing cellular migration at therapeutic concentrations. Apoptosis assays demonstrated concentration-dependent effects, with 2 µM treatment inducing early apoptosis in 46.5% and total apoptotic response in 85.5% of cells within 24 h. Mechanistic studies uncovered MG132’s dual regulatory capacity: (1) Through MDM2 inhibition, it activated p53/p21/caspase-3 axis while suppressing CDK2/Bcl2, triggering cell cycle arrest and DNA damage cascades; (2) MAPK pathway activation emerged as a critical apoptosis driver. Notably, western blot analysis established dose-responsive modulation of these molecular targets, confirming pathway specificity. Our results position MG132 as a multi-target agent capable of simultaneously disrupting proliferative signaling and activating apoptotic machinery. The observed MAPK-mediated apoptosis mechanism provides novel insights for melanoma therapeutics, suggesting that combinatorial targeting of proteasomal and MAPK pathways may enhance treatment efficacy.