BackgroundThe causative relationship between chronic rhinosinusitis (CRS) and depression remains unclear. Herein we employed Mendelian randomization (MR) coupled with single-cell analysis to investigate the causality between CRS and depression.MethodsData pertaining to CRS and depression were mined from the genome-wide association study database, and a single-cell dataset was sourced from the literature. To explore causality, we conducted bidirectional MR analysis using MR-Egger, weighted median, inverse variance weighted (IVW), simple mode, and weighted mode, with IVW representing the most important method. Further, sensitivity analysis was performed to evaluate the robustness of MR analysis results. Candidate genes were analyzed via single-cell combined MR analysis.ResultsForward MR analysis indicated depression as a risk factor for CRS when depression was the exposure factor and CRS was the outcome (OR = 1.425, P < 0.001). Reverse MR analysis revealed the same positive relationship between CRS and depression when CRS was the exposure factor and depression was the outcome (OR = 1.012, P = 0.038). Sensitivity analysis validated the robustness of bidirectional MR analysis results. Ten cell types (endothelial, ciliated, basal, myeloid, mast, apical, plasma, glandular, fibroblast, and T cells) were identified in the single-cell dataset. The network of receptor–ligand pairs showed that in normal samples, cell–cell interactions were present among various cell types, such as epithelial, mast, myeloid, and endothelial cells. In contrast, CRS samples featured only one specific receptor–ligand pair, confined to myeloid cells. TCF4 and MEF2C emerged as potentially crucial for CRS-associated depression development.ConclusionsOur findings suggest a bidirectional causal relationship between CRS and depression, offering a new perspective on the association between CRS and depression.

Background:Terpinen-4-ol (T4O), a key constituent of tea tree essential oil and various aromatic plants, has shown promising antiproliferative and pro-apoptotic effects in melanoma and other cancer types. However, its efficacy against cutaneous squamous cell carcinoma (cSCC) remains unclear. Thus, in this study, we investigated the in vivo and in vitro effects of T4O on cSCC cell lines and preliminarily explored its impacting pathways. Methods:Using CCK8 and assay colony formation, we assessed the viability of cSCC A431, SCL-1, and COLO-16 cells treated with T40 at varying concentrations (0, 1, 2, and 4 μM). Flow cytometry was employed to evaluate T4O's effect on cSCC cell's cycle progression and apoptosis induction. Additionally, western blotting was utilized to examine the expression intensities of N-cadherin and E-cadherin, two indicative markers of the epithelial-mesenchymal transition (EMT) pathway. T4O's in vivo effect on inhibiting tumor progression was evaluated on an established xenograft tumor model. Then, the molecular mechanisms of T4O's antitumor effect were explored by an integrated genome-wide transcriptomics and proteomics study on cSCC A431c cells. Finally, calpain-2's potential mediator role in T4O's anti-tumor mechanism was investigated in calpain-2 knockdown cell lines prepared via siRNA transfection. Result:It's demonstrated that T4O treatment inhibited cSCC proliferation, clonogenicity, migration, and invasion while inducing apoptosis and suppressing the EMT pathway. T4O administration also inhibited cSCC tumorigenesis in the xenograft tumor model. RNA-sequencing and iTRAQ analysis detected significant upregulation of calpain-2 expression in T4O-treated cSCC cells. Western blotting confirmed that T4O significantly increased calpain-2 expression and promoted proteolytic cleavage of β-catenin and caspase-12, two calpain-2 target proteins. Importantly, siRNA-mediated calpain-2 knockdown relieved T4O's suppressive effect on cSCC cell proliferation and motility. Mechanistically, T4O upregulates calpain-2 expression and promotes the cleavage of β-catenin and caspase-12, with siRNA-mediated calpain-2 knockdown mitigating T4O's suppressive effects. Conclusion:These findings suggest that T4O's antitumor activity in cSCC is mediated through the upregulation of calpain-2 expression and subsequent modulation of β-catenin and caspase-12.

BackgroundSkin Cutaneous Melanoma (SKCM) incidence is continually increasing, with chemotherapy and immunotherapy being among the most common cancer treatment modalities. This study aims to identify novel biomarkers for chemotherapy and immunotherapy response in SKCM and explore their association with oxidative stress.MethodsUtilizing TCGA-SKCM RNA-seq data, we employed Weighted Gene Co-expression Network Analysis (WGCNA) and Protein-Protein Interaction (PPI) networks to identify six core genes. Gene co-expression analysis and immune-related analysis were conducted, and specific markers associated with oxidative stress were identified using Gene Set Variation Analysis (GSVA). Single-cell analysis revealed the expression patterns of Oxidative Stress-Associated Genes (OSAG) in the tumor microenvironment. TIDE analysis was employed to explore the association between immune therapy response and OSAG, while CIBERSORT was used to analyze the tumor immune microenvironment. The BEST database demonstrated the impact of the Oxidative Stress signaling pathway on chemotherapy drug resistance. Immunohistochemical staining and ROC curve evaluation were performed to assess the protein expression levels of core genes in SKCM and normal samples, with survival analysis utilized to determine their diagnostic value.ResultsWe identified six central genes associated with SKCM metastasis, among which the expression of DSC2 and DSC3 involved in the oxidative stress pathway was closely related to immune cell infiltration. DSC2 influenced drug resistance in SKMC patients. Furthermore, downregulation of DSC2 and DSC3 expression enhanced the response of SKCM patients to immunotherapy.ConclusionThis study identified two Oxidative Stress-Associated genes as novel biomarkers for SKCM. Additionally, targeting the oxidative stress pathway may serve as a new strategy in clinical practice to enhance SKCM chemotherapy and sensitivity.

Background: Colon cancer, a prevalent and deadly malignancy worldwide, ranks as the third leading cause of cancer-related mortality. Disulfidptosis stress triggers a unique form of programmed cell death known as disulfidoptosis, characterized by excessive intracellular cystine accumulation. This study aimed to establish reliable bioindicators based on long non-coding RNAs (LncRNAs) associated with disulfidptosis-induced cell death, providing novel insights into immunotherapeutic response and prognostic assessment in patients with colon adenocarcinoma (COAD).Methods: Univariate Cox proportional hazard analysis and Lasso regression analysis were performed to identify differentially expressed genes strongly associated with prognosis. Subsequently, a multifactorial model for prognostic risk assessment was developed using multiple Cox proportional hazard regression. Furthermore, we conducted comprehensive evaluations of the characteristics of disulfidptosis response-related LncRNAs, considering clinicopathological features, tumor microenvironment, and chemotherapy sensitivity. The expression levels of prognosis-related genes in COAD patients were validated using quantitative real-time fluorescence PCR (qRT-PCR). Additionally, the role of ZEB1-SA1 in colon cancer was investigated through CCK8 assays, wound healing experiment and transwell experiments.Results: disulfidptosis response-related LncRNAs were identified as robust predictors of COAD prognosis. Multifactorial analysis revealed that the risk score derived from these LncRNAs served as an independent prognostic factor for COAD. Patients in the low-risk group exhibited superior overall survival (OS) compared to those in the high-risk group. Accordingly, our developed Nomogram prediction model, integrating clinical characteristics and risk scores, demonstrated excellent prognostic efficacy. In vitro experiments demonstrated that ZEB1-SA1 promoted the proliferation and migration of COAD cells.Conclusion: Leveraging medical big data and artificial intelligence, we constructed a prediction model for disulfidptosis response-related LncRNAs based on the TCGA-COAD cohort, enabling accurate prognostic prediction in colon cancer patients. The implementation of this model in clinical practice can facilitate precise classification of COAD patients, identification of specific subgroups more likely to respond favorably to immunotherapy and chemotherapy, and inform the development of personalized treatment strategies for COAD patients based on scientific evidence.

Sinapine thiocyanate (ST), an alkaloid existed extensively in seeds of cruciferous plants, exhibits a number of pharmacological effects, including anti-inflammatory and anti-malignancy properties. However, it is still unknown what effects and molecular mechanisms ST has on colorectal cancer (CRC). In the current study, it was indicated that ST inhibited proliferation, colony formation, and apoptosis in vitro, as well as arrested the G1 phase of CRC cells. There was a significant repressive effects of ST on invasion and migration of CRC cells in vitro. RNA-sequencing indicated that 750 differentially expressed genes existed in CRC cells after ST treatment, and enrichment analysis demonstrated that ST obviously decreased the activation of keratinization pathways. Among DEGs enriched in keratinization, keratin 6A (KRT6A) was decreased the most significant, as well as its target gene S100 calcium-binding protein A2 (S100A2). Low expression of KRT6A and S100A2 signatures indicated a favorable prognosis in CRC patients. Moreover, we found overexpression of KRT6A relieved the inhibitory effects of ST in CRC cells. Furthermore, ST inhibited the CRC cell proliferation in vivo, and reduced KRT6A and KI67 expression in xenograft tumor. Taken together, we demonstrated that ST exhibited anti-CRC properties by inhibiting KRT6A/S100A2 axis. It is possible that ST can be used as a treatment for CRC.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

A range of novel 1-phenyl-benzopyrrolizidin-3-one derivatives were synthesized and evaluated for neuroprotective effects against N-methyl-D-aspartate (NMDA)-induced injury in PC12 cells. Interestingly, derivatives that 1-phenyl moiety bearing electron-donating group, especially benzyloxy, and the trans-forms exhibited better protective activity against NMDA-induced neurotoxicity. Compound 11 m demonstrated the best neuroprotective potency and shown a dose-dependent prevention. The increased intracellular calcium (Ca2+) influx caused by NMDA in PC12 cells was reversed in the case of compound 11 m pretreatment at 15 mu M. These results suggested that the synthesized 1-phenyl-benzopyrrolizidin-3-one derivatives exerted neuroprotective effect on NMDA-induced excitotoxicity in PC12 cells associated with inhibition of Ca2+ overload and can be further optimized for the development of neuroprotective agents.

Dysregulation of immune cell infiltration in the tumor microenvironment contributes to the progression of osteosarcoma (OS). In the present study, we explored genes related to immune cell infiltration and constructed a risk model to predict the prognosis of and guide therapeutic strategies for OS. The gene expression profile of OS was obtained from TARGET and Gene Expression Omnibus, which were set as the discovery and verification cohorts. CIBERSORT and Kaplan survival analyses were used to analyze the effects of immune cells on the overall survival rates of OS in the discovery cohort. Differentially expressed gene (DEG) analysis and protein–protein interaction (PPI) networks were used to analyze genes associated with immune cell infiltration. Cox regression analysis was used to select key genes to construct a risk model that classified OS tissues into high- and low-risk groups. The prognostic value of the risk model for survival and metastasis was analyzed by Kaplan–Meier survival analyses, receiver operating characteristic curves, and immunohistochemical experiments. Immunological characteristics and response effects of immune checkpoint blockade (ICB) therapy in OS tissues were analyzed using the ESTIMATE and Tumor Immune Dysfunction and Exclusion algorithms, while sensitivity for both targeted and chemotherapy drugs was analyzed using the OncoPredict algorithm. It was demonstrated that the high infiltration of resting dendritic cells in OS tissues was associated with poor prognosis. A total of 225 DEGs were found between the high- and low-infiltration groups of OS tissues, while 94 genes interacted with others. Through COX analyses, among these 94 genes, four genes (including AOC3, CDK6, COL22A1, and RNASE6) were used to construct a risk model. This risk model showed a remarkable prognostic value for survival rates and metastasis in both the discovery and verification cohorts. Even though a high microsatellite instability score was observed in the high-risk group, the ICB response in the high-risk group was poor. Furthermore, using OncoPredict, we found that the high-risk group OS tissues were resistant to seven drugs and sensitive to 25 drugs. Therefore, our study indicates that the resting dendritic cell signature constructed by AOC3, CDK6, COL22A1, and RNASE6 may contribute to predicting osteosarcoma prognosis and thus therapy guidance.

The liver, an organ with robust regenerative capacity, is involved in many physiological functions, such as detoxification and modulation of optimal brain function. Exosomes are secreted by almost all cell types and mediate intercellular communication, as well as, they are involved in neuroinflammatory process. In this study, we found that fetal liver cell-derived exosomes (FLC-EXOs) administration to lipopolysaccharide (LPS)-induced microglia, which are brain resident immune cells responsible for neuroinflammation, decreased the expression of pro-inflammatory cytokines, such as interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha), in the LPS-activated microglia. We also examined the different signaling pathways that may be involved in this process to determine the anti-inflammatory mechanism of FLC-EXOs. The results showed that activation of the p38 pathway was attenuated after FLC-EXOs administration, which may be related to the anti-inflammatory effects of FLC-EXOs.

Objective: Radiation-induced heart disease (RIHD) is a concern during radiation therapy (RT). In past decades, recombinant human endostatin (rE) has widely been used for the treatment of non-small cell lung cancer. However, the incidence of rE-associated cardiovascular toxicity is substantial and previously under-recognised. Materials and methods: Sprague-Dawley rats were placed into the following experimental groups: RT (25Gy), rE (6mg/kg), rE (12mg/kg), RT (25Gy)+ rE (6mg/kg), RT (25Gy)+ rE (12mg/kg) and blank control groups. Hematoxylin and eosin staining (HE), Masson trichrome staining, Western blotting (TGF-beta 1, Smad2/3, collagen-I) and real-time PCR (TGF-beta 1, Smad2, Smad3, collagen-I) were performed to. Result: During autopsy, interstitial fibrosis could reliably be detected and quantified following irradiation and irradiation combined with recombinant endostatin hearts after follow-up times of 3 and 6 months. Based on Western blotting results, TGF-beta 1 and collagen-I was increased 3 and 6 months after irradiation and irradiation combined with recombinant endostatin on cardiac tissue. Real-time PCR results indicate that TGF-beta 1, Smad2, Smad3 and collagen-I increased 3 and 6 months after irradiation and irradiation combined with recombinant endostatin on cardiac tissue. Conclusion: The studied parameters could be used in future experiments for testing protective agents for the prevention of radiation heart injury and the toxicity of recombinant human endostatin.

Objective: To investigate Small breast epithelial mucin(SBEM) expression difference in mammary tissues and relationship with survival in thetriple-negative breast cancer(TNBC) patients in Han, Buyi and Miao ethnic. Methods : In our study, SBEM protein expressions were detected by means of immunohistochemistry in 297 patients diagnosed from 2014 to 2015,including 99 normal breast tissue specimens, 99 cases of breast benign tumor tissue specimens and 99 tissues specimens from TNBC patients.Each set of tissue specimens contains 33 samples from Han,Miao and Buyi ethnics, respectively.We analyze the expression of SBEM in different mammary tissues in different ethnics and the association of different SBEM expression levels in tissue of TNBC patients with clinical- pathological features, DFS and OS in Han,Miao and Buyi ethnics,respectively. Results: SBEM expression in breast cancer tumor cells were related to the ki67 in the Han, Miao and Buyi ethnic ( P =0.034、0.027、0.047), respectively. There was a marked associations between the SBEM expression level and lymphatic metastasis ( P = 0.042、0.039) in the Han and Miao ethnic, while the same results were not found in the Buyi people ( P =0.072).There was significant difference in DFS ( P =0.028、0.013)and OS ( P =0.09、0.037) between the high expression group and low expression group in the Han and Miao ethnic.But there was no significant difference in DFS ( P = 0.053 ) and OS ( P = 0.088 )in the Buyi people. Conclusion: The SBEM positive detection rate was no significant difference in the han, miao and buyi ethnic groups. SBEM was associated with DFS and OS in the Han and Miao ethnic, while no correlation in the Buyi ethnic.

Background and purpose: To investigate the SPARC expression and relationship with survival in Colorectal cancer (CRC) patients in Han, Buyi and Miao race. Methods: In our study, SPARC protein expression was detected in 90 available formalin-fixed paraffin-embedded (FFPE) tissues specimens from CRC patients in Han, Buyi and Miao race from the Third Affiliated Hospital of Guizhou Medical University by means of immunohistochemistry. According to the different expression of SPARC, the patients were divided into low expression group (SPARC score of 0+and 1+) and high expression group (SPARC score of 2+ and 3+). The correlations between the two groups in DFS and OS were analyzed, respectively. Results: SPARC was mainly expressed in tumor cell cytoplasm and the positive rates of SPARC was 52.2% (47/90). There was no difference in the positive expression rate in the Han, Buyi and Miao race (P =0.87). SPARC expression was related to the pathological type (Adenocarcinoma). There was a marked associations in DFS between the low expression of SPARC group and high expression group (P=0.048, 0.047) in the Han and Miao ethnic. While the same result was no found in the Buyi race (P=0.176). There was no statistical significance in OS between the low expression of SPARC group and high expression group in the Buyi, Miao and Han race, respectively(P= 0.338, 0.424, 0.282). Conclusion: SPARC was related with DFS in the Miao and Han race, while no correlation in the Buyi race.