Modulation of lipid profile by secretory phospholipase A2 group IIA: Verification with a transgenic mouse model.

We previously demonstrated a positive relation of secretory phospholipase A2 group IIA (sPLA2-IIA) with circulating high-density lipoprotein cholesterol (HDL-C) in patients with coronary artery disease, and sPLA2-IIA increased cholesterol efflux in THP-1 cells through peroxisome proliferator-activated receptor-γ (PPAR-γ)/liver X receptor α/ATP-binding cassette transporter A1 (ABCA1) signaling pathway. The aim of the present study was to examine the role of sPLA2-IIA over-expression on lipid profile in a transgenic mouse model. Fifteen apoE-/- and C57BL/7 female mice received bone marrow transplantation from transgenic SPLA2-IIA mice, and treated with specific PPAR-γ inhibitor GW9662. High fat diet was given after one week of bone marrow transplantation, and animals were sacrificed after twelve weeks. Immunohistochemical staining showed over-expression of sPLA2-IIA protein in the lung and spleen. The circulating level of HDL-C, but not that of low-density lipoprotein cholesterol (LDL-C), total cholesterol, or total triglyceride, was increased by sPLA2-IIA over-expression, and was subsequently reversed by GW9662 treatment. Over-expression of sPLA2-IIA resulted in augmented expression of cholesterol transporter ABCA1 at mRNA level in the aortas, and at protein level in macrophages, co-localized with macrophage specific antigen CD68. GW9662 exerted potent inhibitory effects on sPLA2-IIA-induced ABCA1 expression. Conclusively, we demonstrated the effects of sPLA2-IIA on circulating HDL-C level and the expression of ABCA1, possibly through regulation of PPAR-γ signaling in transgenic mouse model, that is in concert with the conditions in patients with coronary artery disease.

DPY30 promotes colorectal carcinoma metastasis by upregulating ZEB1 transcriptional expression.

DPY30 belongs to the core subunit of components of the histone lysine methyltransferase complex, which is implicated in tumorigenesis, cell senescence, and other biological events. However, its contribution to colorectal carcinoma (CRC) progression and metastasis has yet to be elucidated. Therefore, this study aimed to investigate the biological function of DPY30 in CRC metastasis both in vitro and in vivo. Herein, our results revealed that DPY30 overexpression is significantly positively correlated with positive lymph nodes, epithelial-mesenchymal transition (EMT), and CRC metastasis. Moreover, DPY30 knockdown in HT29 and SW480 cells markedly decreased EMT progression, as well as the migratory and invasive abilities of CRC cells in vitro and lung tumor metastasis in vivo. Mechanistically, DPY30 increased histone H3K4me3 level and promoted EMT and CRC metastasis by upregulating the transcriptional expression of ZEB1. Taken together, our findings indicate that DPY30 may serve as a therapeutic target and prognostic marker for CRC.

DPY30 Promotes Proliferation and Cell Cycle Progression of Colorectal Cancer Cells via Mediating H3K4 Trimethylation.

DPY30, a core subunit of the SET1/MLL histone H3K4 methyltransferase complexes, plays an important role in diverse biological functions through the epigenetic regulation of gene transcription, especially in cancer development. However, its involvement in human colorectal carcinoma (CRC) has not been elucidated yet. Here we demonstrated that DPY30 was overexpressed in CRC tissues, and significantly associated with pathological grading, tumor size, TNM stage, and tumor location. Furthermore, DPY30 knockdown remarkably suppressed the CRC cell proliferation through downregulation of PCNA and Ki67 in vitro and in vivo, simultaneously induced cell cycle arrest at S phase by downregulating Cyclin A2. In the mechanistic study, RNA-Seq analysis revealed that enriched gene ontology of cell proliferation and cell growth was significantly affected. And ChIP result indicated that DPY30 knockdown inhibited H3 lysine 4 trimethylation (H3K4me3) and attenuated interactions between H3K4me3 with PCNA, Ki67 and cyclin A2 respectively, which led to the decrease of H3K4me3 establishment on their promoter regions. Taken together, our results demonstrate overexpression of DPY30 promotes CRC cell proliferation and cell cycle progression by facilitating the transcription of PCNA, Ki67 and cyclin A2 via mediating H3K4me3. It suggests that DPY30 may serve as a potential therapeutic molecular target for CRC.

Retinoic Acid Receptor Gamma (RARγ) Promotes Cartilage Destruction through Positive Feedback Activation of NF-κB Pathway in Human Osteoarthritis.

Osteoarthritis (OA) is a severe inflammation-related disease which leads to cartilage destruction. The retinoic acid receptor gamma (RARγ) has been indicated to be involved in many inflammation processes. However, the role and mechanism of RARγ in cartilage destruction caused by inflammation in OA are still unknown. Here, we demonstrated that the RARγ was highly expressed in chondrocytes of OA patients compared with healthy people and was positively correlated with the damage degree of cartilage in OA. Cytokine TNF-α promoted the transcription and expression of RARγ through activating the NF-κB pathway in OA cartilage. In addition, the overexpression of RARγ resulted in the upregulation of matrix degradation and inflammation associated genes and downregulation of differentiation and collagen production genes in human normal chondrocyte C28/I2 cells. Mechanistically, overexpression of RARγ could increase the level of p-IκBα and p-P65 to regulate the expression of downstream genes. RARγ and IκBα also could interact with each other and had the same localization in C28/I2 cells. Moreover, the SD rats OA model induced by monosodium iodoacetate indicated that CD437 (RARγ agonist) and TNF-α accelerated the OA progression, including more severe cartilage layer destruction, larger knee joint diameter, and higher serum ALP levels, while LY2955303 (RARγ inhibitor) showed the opposite result. RARγ was also highly expressed in OA group and even higher in TNF-α group. In conclusion, RARγ/NF-κB positive feedback loop was activated by TNF-α in chondrocyte to promote cartilage destruction. Our data not only propose a novel and precise molecular mechanism for OA disease but also provide a prospective strategy for the treatment.

Trilobolide-6-O-isobutyrate suppresses hepatocellular carcinoma tumorigenesis through inhibition of IL-6/STAT3 signaling pathway.

Currently available therapies for hepatocellular carcinoma (HCC), with a high morbidity and high mortality, are only marginally effective and with sharp adverse side effects, which makes it compulsory to explore novel and more effective anticancer molecules. Chinese medicinal herbs exhibited prominent anticancer effects and were applied to supplement clinical cancer treatment. Here, we reported a compound, trilobolide-6-O-isobutyrate (TBB), isolated from the flowers of Wedelia trilobata with a markedly cytotoxic effect on HCC cells. We found that TBB time- and dose-dependently inhibited HCC cells' growth and colony formation in vitro. Moreover, TBB induced cell cycle arrest at the G2/M phase, mitochondrial caspase-dependent apoptosis, and suppressed migration and invasion, as well as the glycolysis of HCC cells. Mechanistically, our data indicated that TBB inhibited the STAT3 pathway activation by directly interacting with the TYR 640/657 sites of the STAT3 protein and decreasing the level of p-STAT3. TBB also regulated the expression of PCNA, Ki67, Cyclin B1, Cyclin E, Bax, Bcl2, MMP2/9, and PGK1 through the inhibition of the IL-6/STAT3 signaling pathway. Lastly, we confirmed that TBB effectively eliminated tumor growth without causing overt toxicity to healthy tissues in the xenograft tumor model. The exploration of anticancer activity and the underlying mechanism of TBB suggested its usage as a promising chemotherapeutic agent for HCC.

Plasma levels of Interleukin 18 but not amyloid-ß or Tau are elevated in female depressive patients.

BACKGROUND: Depression is associated with inflammation and Alzheimer's disease (AD). However, detailed molecular mechanisms linking mood, neuroinflammation and AD remain unclear. Although changes in peripheral inflammatory factors such as Interleukin 18 (IL18), and AD-associated amyloid-ß (Aß) peptides have been linked to depression, a solid relationship between these factors in depressive disorder has yet to be established. This study aims to further determine whether plasma IL18, Aß40, Aß42, and the AD-associated tangle component Tau, as well as IL18 single nucleotide polymorphisms (SNPs) may be biomarkers for depression. METHODS: We measured plasma IL18, Aß40, Aß42, and Tau in 64 depressive patients and 75 healthy controls, and characterized genotypes of three IL18 SNPs (rs187238, rs1946518 and rs1946519) in these subjects. Comparisons between depressive patients and controls were carried out in males, in females or in combination. Regression analyses were conducted to examine the correlation between these parameters. RESULTS: We found that none of the plasma levels of IL18, Aß40, Aß42, and Tau, the ratio of Aß42/Aß40, and the genotypes of IL18 SNPs were significantly different between combined depressive patients and combined healthy controls, or between male depressive patients and male controls. However, IL18 levels were less in females than in males in healthy people and were significantly increased in female depressive patients compared to female controls. Moreover, IL18 and standardized IL18 were correlated with standardized Aß42/Aß40 ratio and standardized Tau in depressive patients. CONCLUSIONS: Plasma IL18 may be a potential biomarker for depression in women.

Association between IL-1B gene polymorphisms and Helicobacter pylori infection: A meta-analysis.

BACKGROUND: To clarify the impact of IL-1B gene polymorphisms (IL-1B-511C/T, IL-1B-31C/T, IL-1B+3954C/T) in Helicobacter pylori (H. pylori) infection by mean of a meta-analysis. METHODS: The relevant studies were retrieved from PubMed, Web of Science, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure (CNKI) and Wanfang databases until September 9, 2018. Odds ratio (OR) and its 95% confidence intervals (CIs) were used to assess the associations. Statistical analyses of this meta-analysis were conducted by using STATA 12 software. RESULTS: Totally, 45 articles including 9606 cases and 5654 controls were enrolled in this meta-analysis. Our results indicated that IL-1B-511C/T polymorphism was significantly related to an increased the risk of H. pylori infection under recessive model (OR = 1.13, 95% CI: 1.00-1.27, P = 0.048). However, no significant associations were obtained between H. pylori infection and IL-1B-31C/T as well as IL-1B+3954C/T polymorphisms under all models. In addition, subgroup analyses were also performed by country, study design, and detection methods of H. pylori. CONCLUSIONS: This meta-analysis suggested that IL-1B-511C/T polymorphism was related to the risk of H. pylori infection. Further larger studies with high quality are needed to conform these findings.

Mechanistic Insights into Cyclic Voltammograms on Pt(111): Kinetics Simulations.

A detailed understanding of the electrochemistry of platinum electrodes is of great importance for the electrochemical oxidation of fuels and electrochemical reduction of dioxygen in fuel cells. The Pt(111) facet is the most representative model mimicking Pt nanoparticles and polycrystals for fundamental studies. Herein, we propose a site-specific model accompanied with the typical elementary steps of the electrochemistry of Pt(111) in non-adsorbing electrolyte within the potential range between 0.05 and 1.15 V versus reversible hydrogen electrode. Simulations were conducted at different scanning rates based on the kinetics models. We reproduce all the anodic and cathodic peaks observed in the reported experimental curves. These results demonstrate the underlying mechanisms of the peak formation in different potential regions.

miR-9-5p Suppresses Malignant Biological Behaviors of Human Gastric Cancer Cells by Negative Regulation of TNFAIP8L3.

BACKGROUND: MicroRNA is essential for the malignant progression of human gastric cancer (GC), which is a leading cause of cancer deaths. However, the mechanism is still not so clear. AIMS: In our present research, we investigated the effect of miR-9-5p in GC. METHODS: We detected miR-9-5p expression in human gastric epithelial cell (GES-1) and GC cells (AGS, BGC-823, MKN-45, and MGC-803), plasma of normal or GC patients, as well as orthotopic xenograft mouse models by real-time PCR. The migration ability was detected by Transwell assays after miR-9-5p mimic or inhibitor transfection in GC cells. RESULTS: Our results showed that miR-9-5p expression in GC cells and plasma was significantly decreased. miR-9-5p inhibited migration of GC cells by regulating TNFAIP8L3 directly. Low expression of miR-9-5p in GC patients hardly suppressed the migration mediated by TNFAIP8L3. CONCLUSIONS: miR-9-5p, as a potential tumor suppressor gene, is closely related to the malignant progression of GC. Exploring the regulation between miR-9-5p and TNFAIP8L3 may provide a novel strategy for GC treatment.

Knockdown of TIPE2 increases the proliferation in lipopolysaccharide-stimulated gastric cancer cells.

BACKGROUND: Gastric cancer (GC) is one of the most common malignant diseases with high morbidity and mortality, especially in Asian countries. During the GC developing progress, TIPE2, a member of TNF-alpha induced protein 8-like (TNFAIP8L) family, may play important roles. However, the molecular mechanisms of TIPE2 contributing to cell proliferation and tumor growth are poorly understood in GC. We performed flow cytometry to detect the cell cycle of TIPE2-knockdown GC cells under lipopolysaccharide (LPS) stimulation. METHODS: We measured TIPE2 expression in tumor samples from 46 human GC patients at mRNA level by Realtime PCR and in 68 pairs of GC tissues at protein level by immunohistochemistry. We established stable TIPE2 knockdown SGC7901 and BGC823 cell lines and performed CCK-8 and EdU proliferation assays under the stimulation of LPS. And then we analyzed AKT, IκBα and ERK phosphorylation levels, as well as cycle related proteins CDK4 and CyclinD3 in the stable TIPE2 knockdown SGC7901 and BGC823 cells. RESULTS: Our present studies indicated that the expression of TIPE2 was significantly decreased in tumor tissues compared to distant mucosa tissues in human GC patients. TIPE2 inhibited proliferation stimulated by LPS in SGC7901 and BGC823 cells. Silencing of TIPE2 significantly decreased cell G0/G1 phase ratio and increased G2/M phase. TIPE2 knockdown SGC7901 and BGC823 cells declined AKT and IκBα phosphorylation. TIPE2's action on GC cell cycle was. CONCLUSIONS: Our results demonstrated that TIPE2 is a novel tumor suppressor gene that inhibits GC growth may mediated via AKT and IκBα phosphorylated activation. We revealed that TIPE2 may effectively interdict neoplasm development, which has potential clinical application values for GC targeted therapies.

Retinoic Acid Receptor α Knockdown Suppresses the Tumorigenicity of Esophageal Carcinoma via Wnt/ß-catenin Pathway.

BACKGROUND: Aberrant expression of retinoic acid receptor α (RARα) was correlated with diverse carcinomas such as acute promyelocytic leukemia and colorectal carcinoma. Nevertheless, the function and mechanism of RARα in esophageal carcinoma (EC) remain unclear. AIM: To investigate the expression of RARα in EC and its effect in the tumorigenesis of EC. METHODS AND RESULTS: In immunohistochemistry study, RARα was overexpressed in human EC tissues, and its overexpression was closely related to the pathological differentiation, lymph node metastasis, and clinical stages in EC patients. Functionally, RARα knockdown suppressed the proliferation and metastasis of EC cells through downregulating the expression of PCNA, Ki67, MMP7, and MMP9, as well as enhanced drug susceptibility of EC cells to 5-fluorouracil and cisplatin. Mechanistically, RARα knockdown inhibited the activity of Wnt/ß-catenin pathway through reducing the phosphorylation level of GSK3ß at Ser-9 and inducing phosphorylation level at Tyr-216, which resulted in downregulation of its downstream targets such as MMP7, MMP9, and P-gP. CONCLUSIONS: Our results demonstrated that RARα knockdown suppressed the tumorigenicity of EC via Wnt/ß-catenin pathway. RARα might be a potential molecular target for EC clinical therapy.

Retinoid X receptor α enhances human cholangiocarcinoma growth through simultaneous activation of Wnt/ß-catenin and nuclear factor-κB pathways.

Retinoid X receptor α (RXRα) plays important roles in the malignancy of several cancers such as human prostate tumor, breast cancer, and thyroid tumor. However, its exact functions and molecular mechanisms in cholangiocarcinoma (CCA), a chemoresistant carcinoma with poor prognosis, remain unclear. In this study we found that RXRα was frequently overexpressed in human CCA tissues and CCA cell lines. Downregulation of RXRα led to decreased expression of mitosis-promoting factors including cyclin D1and cyclin E, and the proliferating cell nuclear antigen, as well as increased expression of cell cycle inhibitor p21, resulting in inhibition of CCA cell proliferation. Furthermore, RXRα knockdown attenuated the expression of cyclin D1 through suppression of Wnt/ß-catenin signaling. Retinoid X receptor α upregulated proliferating cell nuclear antigen expression through nuclear factor-κB (NF-κB) pathways, paralleled with downregulation of p21. Thus, the Wnt/ß-catenin and NF-κB pathways account for the inhibition of CCA cell growth induced by RXRα downregulation. Retinoid X receptor α plays an important role in proliferation of CCA through simultaneous activation of Wnt/ß-catenin and NF-κB pathways, indicating that RXRα might serve as a potential molecular target for CCA treatment.

Exploring SLC16A1 as an Oncogenic Regulator and Therapeutic Target in Cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a primary malignant tumor of the liver, typically diagnosed in advanced stages. Surgical resection remains the principal treatment method in clinical practice. Regrettably, the majority of patients receive their diagnosis at an advanced stage, making surgical intervention unfeasible. While chemotherapy serves as the main palliative treatment for advanced CCA, its effectiveness is significantly limited due to the rapid development of chemoresistance. Studying the pathogenesis of CCA and new resistance targets is crucial for improving clinical outcomes. In our current study, we first identified the expression of SLC16A1 in the transcriptome and proteome of human tumors and found abnormal expression of SLC16A1 in various human cancers. Subsequently, we focused our attention on the role of SLC16A1 in CCA. Utilizing bioinformatics analysis, we pioneered the identification of the clinical significance of SLC16A1 in this type of cancer. Specifically, higher expression levels of SLC16A1 were observed in CCA patients with venous invasion and higher T and M stages. Additionally, patients with higher SLC16A1 expression had poorer prognoses. These results suggest the oncogenic role of SLC16A1 in CCA. Further immune infiltration analysis revealed a significant correlation between SLC16A1 and the infiltration levels of cells like neutrophils and macrophages in the tumor microenvironment, indicating SLC16A1's potential involvement in regulating the tumor immune microenvironment of CCA. Moreover, results from functional and pathway enrichment analyses revealed that SLC16A1 might affect clinical outcomes in CCA patients by participating in drug metabolism processes. Finally, through further in vitro and in vivo experiments, we confirmed that SLC16A1, as an oncogene in CCA, promotes the growth of CCA cells and chemoresistance. Knocking down SLC16A1 inhibited the growth of CCA cells and enhanced their sensitivity to 5-Fluorouracil (5-FU). Overall, this study reveals the key role of SLC16A1 in the development of CCA and highlights its significance as a potential target for improving treatment efficacy and chemotherapy sensitivity.

KHDRBS1 as a novel prognostic signaling biomarker influencing hepatocellular carcinoma cell proliferation, migration, immune microenvironment, and drug sensitivity.

Background: Human tumors pose significant challenges, with targeted therapy against specific molecular targets or signaling pathways being a mainstay alongside surgical resection. Previous studies have implicated KHDRBS1 in the oncogenesis of certain human tumors such as colorectal and prostate cancers, underscoring its potential as a therapeutic target. However, the comprehensive expression pattern of KHDRBS1 in hepatocellular carcinoma (HCC) warrants further exploration. Methods: Integrating and analyzing multi-omics, multi-cohort data from public databases, coupled with clinical samples and molecular biology validation, we elucidate the oncogenic role of KHDRBS1 in HCC progression. Additionally, leveraging HCC single-cell sequencing data, we segregate malignant cells into KHDRBS1-positive and negative subsets, uncovering significant differences in their expression profiles and functional roles. Results: Our study identifies KHDRBS1 as a tumor-promoting factor in HCC, with its positivity correlating with tumor progression. Furthermore, we highlight the clinical significance of KHDRBS1-positive malignant cells, aiming to further propel its clinical utility. Conclusion: KHDRBS1 plays a key role in HCC development. This study provides crucial insights for further investigation into KHDRBS1 as a therapeutic target in HCC.

Downregulation of dermatopontin in cholangiocarcinoma cells suppresses CCL19 secretion of macrophages and immune infiltration.

OBJECTIVE: The tumor microenvironment (TME) in cholangiocarcinoma (CHOL) is typically characterized by a low level of immune infiltration, which accounts for the dismal prognosis of this patient population. This study sought to investigate the mechanisms underlying the reduced infiltration of immune cells into the CHOL TME. METHODS: We constructed a Least Absolute Shrinkage and Selection Operator (LASSO) regression model to identify prognosis-related differentially expressed genes (DEGs). The 'Corrplot' package was employed to analyze the correlation between dermatopontin (DPT) and immune infiltration in CHOL. The Tumor and Immune System Interaction Database (TISIDB) was used to evaluate the association between DPT and immunology. Single-cell analysis was conducted to localize CCL19 secretions. Western blot and qPCR were utilized to detect DPT expression, while immunofluorescence was performed to investigate the cellular localization of DPT. Additionally, ELISA analysis was employed to assess the alteration in CCL19 secretion in cancer-associated fibroblasts (CAFs) and macrophages. RESULTS: Our findings revealed that CHOL patients with low DPT expression had a poorer prognosis. Enrichment analysis demonstrated a positive correlation between DPT levels and the infiltration of immunomodulators and immune cells. Moreover, high DPT levels were associated with enhanced anti-PD-1/PD-L1 immunotherapeutic responses. Furthermore, DPT expression impacted the landscape of gene mutations, showing a negative association with tumor grade, stage, and lymph node metastasis. Based on the results of protein peptides analysis and cell experiments, it was inferred that the downregulation of DPT in CHOL cells effectively suppressed the secretion of CCL19 in macrophages. CONCLUSIONS: DPT is a novel prognosis-related biomarker for CHOL patients, and this study provides preliminary insights into the mechanism by which DPT promotes the infiltration of immune cells into the CHOL TME.

DPY30 knockdown suppresses colorectal carcinoma progression via inducing Raf1/MST2-mediated apoptosis.

Colorectal Carcinoma (CRC) is one of the most common malignant tumors of the digestive tract, with a high mortality rate. DPY30 is one of the core subunits of the histone methyltransferase complex, which was involved in many cancer processes. However, the role of DPY30 in the occurrence and progression of CRC remains unclear. In this study, we sought to evaluate the role and mechanism of DPY30 in CRC cells apoptosis. Here, we identified that knockdown of DPY30 significantly inhibited the HT29 and HCT116 cells proliferation in vitro. Moreover, the knockdown of DPY30 significantly increased the apoptosis rate and promoted the expression of apoptosis-related proteins in CRC cells. Meanwhile, DPY30 knockdown promoted CRC cells apoptosis through endogenous programmed death and in a caspase activation-dependent manner. Furthermore, RNA-seq analysis revealed that the action of DPY30 is closely related to the apoptosis biological processes, and screened its potential effectors Raf1. Mechanistically, DPY30 downregulation promotes MST2-induced apoptosis by inhibiting Raf1 transcriptional activity through histone H3 lysine 4 trimethylation (H3K4me3). In vivo experiments showed that DPY30 was correlated with Raf1 in nude mouse subcutaneous xenografts tissues significantly. Clinical colorectal specimens further confirmed that overexpression of DPY30 in malignant tissues was significantly correlated with Raf1 level. The vital role of the DPY30/Raf1/MST2 signaling axis in the cell death and survival rate of CRC cells was disclosed, which provides potential new targets for early diagnosis and clinical treatment of CRC.

Trilobolide-6-O-isobutyrate exerts anti-tumor effects on cholangiocarcinoma cells through inhibiting JAK/STAT3 signaling pathway.

Trilobolide-6-O-isobutyrate exhibits significant antitumor effects on cholangiocarcinoma (CCA) cells by effectively inhibiting the JAK/STAT3 signaling pathway. This study aims to investigate the mechanisms underlying the antitumor properties of trilobolide-6-O-isobutyrate, and to explore its potential as a therapeutic agent for CCA. This study illustrates that trilobolide-6-O-isobutyrate efficiently suppresses CCA cell proliferation in a dose- and time-dependent manner. Furthermore, trilobolide-6-O-isobutyrate stimulates the production of reactive oxygen species, leading to oxidative stress and initiation of apoptosis via the activation of the mitochondrial pathway. Data from xenograft tumor assays in nude mice confirms that TBB inhibits tumor growth, and that there are no obvious toxic effects or side effects in vivo. Mechanistically, trilobolide-6-O-isobutyrate exerts antitumor effects by inhibiting STAT3 transcriptional activation, reducing PCNA and Bcl-2 expression, and increasing P21 expression. These findings emphasizes the potential of trilobolide-6-O-isobutyrate as a promising therapeutic candidate for the treatment of CCA.

Inhibition of Wnt/ß-catenin signaling downregulates P-glycoprotein and reverses multi-drug resistance of cholangiocarcinoma.

The development of multi-drug resistance (MDR) represents a major obstacle in the successful treatment of cancers. However, the factors and mechanisms that lead to MDR in cholangiocarcinoma (CCA), a chemoresistant bile duct carcinoma with a poor prognosis, remain unclear. In this study, we established a human MDR CCA cell line QBC939/5-FU. Compared with QBC939 cells, a rounder shape, a higher nuclear-cytoplasmic ratio, a shorter cell cycle, faster growth and resistance to chemotherapeutics are major characteristics of QBC939/5-FU cells. P-glycoprotein (P-gp) and ß-catenin were upregulated in QBC939/5-FU cells. Furthermore, the drug susceptibility of QBC939 cells to common chemotherapeutics was significantly decreased after Wnt3a treatment, whereas inhibition of Wnt/ß-catenin pathway by ß-catenin siRNA reversed the MDR of QBC939/5-FU cells to chemotherapeutics. Molecular study revealed that activation of Wnt/ß-catenin pathway resulted in upregulation of P-gp and contributed to MDR of QBC939/5-FU cells. Extraction of Siamese Crocodile 3 (ESC-3) bile enhanced the drug sensitivity of QBC939/5-FU cells to 5-FU, paralleled with downregulation of ß-catenin and P-gp. The association of Wnt/ß-catenin pathway and P-gp was further confirmed by the clinical data for CCA tissues. Our study represents the first implication of Wnt/ß-catenin activation in the MDR of CCA, which may be a beneficial target for the clinical treatment of CCA.

Oncogenic potential of cyclin kinase subunit-2 in cholangiocarcinoma.

BACKGROUND: Cyclin kinase subunit-2 (Cks2), a member of the human Cks family, plays an important role in the regulation of meiosis and mitosis; and its abnormal expression is usually associated with carcinogenesis. However, its exact functions and molecular mechanisms remain unclear. AIMS: To observe Cks2 expression in cholangiocarcinoma and explore its role in the carcinogenesis of cholangiocarcinoma and possible mechanism. METHODS: Cks2 expression in cholangiocarcinoma was detected with immunostaining and RT-PCR. MTT, colony formation, immunofluorescence, flow cytometry and Western blotting were performed to explore the role of Cks2 in cholangiocarcinoma and possible mechanism. RESULTS: Cks2 was significantly elevated in cholangiocarcinoma tissues and its over-expression was associated with poor differentiation, CA19-9 and poor prognosis. Furthermore, Cks2 down-regulation inhibited cholangiocarcinoma cell proliferation and colony formation in vitro, and the growth of cholangiocarcinoma xenografts in animals; especially, enhanced the sensitivity of cholangiocarcinoma cells to chemotherapy. We further found that Cks2 knockdown induced cholangiocarcinoma cell cycle arrest in G2/M phase through down-regulation of Cyclin A and Cyclin B1 and Bax up-regulation and activation, mitochondrial membrane permeabilization and caspase-3 activation, which resulted in facilitating cholangiocarcinoma apoptosis. CONCLUSIONS: These findings suggest that Cks2 may serve as an independent prognostic factor in patients with cholangiocarcinoma, and play an important role in the carcinogenesis of cholangiocarcinoma by facilitating cell cycle progression and Bax-mediated mitochondrial caspase-dependent apoptosis.

Different nursing interventions on sleep quality among critically ill patients: A systematic review and network meta-analysis.

BACKGROUND: Critically ill patients in intensive care often struggle with disrupted sleep, a prevalent issue in this population. However, the question of which non-pharmacological intervention is most effective in enhancing sleep quality remains unanswered. This study was conducted to comprehensively evaluate and compare the efficacy of various non-pharmacological interventions aimed at improving sleep quality among critically ill individuals. METHODS: We conducted a search of PubMed, Embase, and the Cochrane Library (Cochrane Central Register of Controlled Trials) without language restrictions to identify articles published until July 15, 2023. Randomized controlled trials (RCTs) that investigated various nursing interventions designed to improve sleep quality in critically ill patients were included in this network meta-analysis. All analyses were performed using R software (version 3.4.3) with the "gemtc" package. RESULTS: A total of 2036 patients from 31 RCTs were included in the network meta-analysis, involving 11 different nursing interventions (routine care, relaxation combined with imagery (RI), nursel, music + earplugs + eye masks, music, eye masks, earplugs + eye masks, earplugs, aromatherapy, Warm footbath combined with acupoint exercise (WFA), Virtual reality meditation (VR)). Eye masks and earplugs + eye masks were associated with improved sleep quality compared to routine care intervention (P < .05). CONCLUSIONS: In summary, eye masks and earplugs + eye masks stand out as the most effective interventions for enhancing sleep quality in critically ill patients. Therefore, critical care nurses should consider incorporating the use of eye masks alone or combining music with eye masks into the sleep care regimen for critically ill patients.