Keratin gene signature expression drives epithelial-mesenchymal transition through enhanced TGF-ß signaling pathway activation and correlates with adverse prognosis in lung adenocarcinoma.

Background: Lung adenocarcinoma (LUAD) stands as the foremost histological subtype of non-small-cell lung cancer, accounting for approximately 40% of all lung cancer diagnoses. However, there remains a critical unmet need to enhance the prediction of clinical outcomes and therapy responses in LUAD patients. Keratins (KRTs), serving as the structural components of the intermediate filament cytoskeleton in epithelial cells, play a crucial role in the advancement of tumor progression. This study investigated the prognostic significance of the KRT family gene and developed a KRT gene signature (KGS) for prognostic assessment and treatment guidance in LUAD. Methods: Transcriptome profiles and associated clinical details of LUAD patients were meticulously gathered from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The KGS score was developed based on the expression of five prognostic KRT genes (KRT7, KRT8, KRT17, KRT18, and KRT80), and the upper quartile of the KGS score was chosen as the cutoff. The Kaplan-Meier method was evaluated to compare survival outcomes between KGS-high and KGS-low groups. The underlying mechanism was further investigated by GSEA, GSVA, and other bioinformatic algorithms. Results: High expression of the KGS signature exhibited a robust association with poorer overall survival (OS) in the TCGA-LUAD dataset (HR: 1.81; 95% CI: 1.35-2.42, P = 0.00011). The association was further corroborated in three external GEO cohorts, including GSE31210 (HR: 3.31; 95% CI: 1.7-6.47, P = 0.00017), GSE72094 (HR: 1.95; 95% CI: 1.34-2.85, P = 0.00057) and GSE26939 (HR: 3.19; 95% CI: 1.74-5.84, P < 0.0001). Interestingly, KGS-high tumors revealed enrichments in TGF-ß and WNT-ß catenin signaling pathways, exhibited heightened activation of the epithelial-mesenchymal transition (EMT) pathway and proved intensified tumor stemness compared to their KGS-low counterparts. Additionally, KGS-high tumor cells exhibited increased sensitivity to several targeted agents, including gefitinib, erlotinib, lapatinib, and trametinib, in comparison to KGS-low cells. Conclusion: This study developed a KGS score that independently predicts the prognosis in LUAD. High expression of KGS score, accompanied by upregulation of TGF-ß and WNT-ß catenin signaling pathways, confers more aggressive EMT and tumor progression.

Dealuminated Beta zeolite reverses Ostwald ripening for durable copper nanoparticle catalysts.

Copper nanoparticle-based catalysts have been extensively applied in industry, but the nanoparticles tend to sinter into larger ones in the chemical atmospheres, which is detrimental to catalyst performance. In this work, we used dealuminated Beta zeolite to support copper nanoparticles (Cu/Beta-deAl) and showed that these particles become smaller in methanol vapor at 200°C, decreasing from ~5.6 to ~2.4 nanometers in diameter, which is opposite to the general sintering phenomenon. A reverse ripening process was discovered, whereby migratable copper sites activated by methanol were trapped by silanol nests and the copper species in the nests acted as new nucleation sites for the formation of small nanoparticles. This feature reversed the general sintering channel, resulting in robust catalysts for dimethyl oxalate hydrogenation performed with supported copper nanoparticles for use in industry.

Deep learning reveals cuproptosis features assist in predict prognosis and guide immunotherapy in lung adenocarcinoma.

Background: Cuproptosis is a recently found non-apoptotic cell death type that holds promise as an emerging therapeutic modality in lung adenocarcinoma (LUAD) patients who develop resistance to radiotherapy and chemotherapy. However, the Cuproptosis' role in the onset and progression of LUAD remains unclear. Methods: Cuproptosis-related genes (CRGs) were identified by a co-expression network approach based on LUAD cell line data from radiotherapy, and a robust risk model was developed using deep learning techniques based on prognostic CRGs and explored the value of deep learning models systematically for clinical applications, functional enrichment analysis, immune infiltration analysis, and genomic variation analysis. Results: A three-layer artificial neural network risk model was constructed based on 15 independent prognostic radiotherapy-related CRGs. The risk model was observed as a robust independent prognostic factor for LUAD in the training as well as three external validation cohorts. The patients present in the low-risk group were found to have immune "hot" tumors exhibiting anticancer activity, whereas the high-risk group patients had immune "cold" tumors with active metabolism and proliferation. The high-risk group patients were more sensitive to chemotherapy whereas the low-risk group patients were more sensitive to immunotherapy. Genomic variants did not vary considerably among both groups of patients. Conclusion: Our findings advance the understanding of cuproptosis and offer fresh perspectives on the clinical management and precision therapy of LUAD.

Alloyed PdCu Nanoparticles within Siliceous Zeolite Crystals for Catalytic Semihydrogenation.

Selective hydrogenation of acetylene to ethylene is an industrially important process to purify the raw ethylene stream for producing high-grade polyethylene. The supported Pd catalyst exhibits superior activity for acetylene hydrogenation but suffers from poor ethylene selectivity because of the easy overhydrogenation to produce ethane. Here, we report that the PdCu alloy nanoparticles within siliceous zeolite crystals effectively tuned Pd-catalyzed overhydrogenation into semihydrogenation. This catalyst displayed an ethylene selectivity of 92.9% with a full conversion of acetylene. Mechanism studies reveal that the zeolite fixation stabilized the alloyed structure, where the electron-enriched Pd surface benefits the rapid ethylene desorption to hinder the deep hydrogenation. This work provides an efficient strategy for a rational design of bimetallic metal catalysts for selective hydrogenations.

Inferior pulmonary ligament approach and/or interlobar fissure approach for posterior and/or lateral basal segment resection: a case-series of 31 patients.

Background: Thoracoscopic posterior and/ or lateral basal segment resection is a major difficult segmentectomy for thoracic surgeons, because of its high surgical difficulty and high incidence of postoperative complications. Here we describe the surgical procedure and techniques of the transpulmonary ligament approach and/or interlobar fissure approach for the thoracoscopic posterior and/or lateral basal segment resection. Methods: The clinical data of 31 patients who underwent thoracoscopic posterior and/or lateral basal segment resection from January 2020 to June 2022 were included. All patients underwent posterior and/or lateral basal segment resection via the inferior pulmonary ligament and/or interlobar fissure approach. Follow-up was continued to September 2022. Results: All patients including 7 males and 24 females, with a median age of 51 [31-62] years, completed the operation successfully. One patient was converted to lobectomy due to insufficient margins intraoperatively. Two patients were treated using the interlobar fissure approach, 25 patients were treated via the inferior pulmonary ligament approach, and four patients were treated by employing both methods. Also, 20 patients had a single lesion and 1 patient had two lesions. Eleven patients underwent surgical resections on other lesions when posterior and/or lateral basal segment lesions resected. The median operation time was 120 [50-290] minutes, the median intraoperative blood loss was 50 [10-100] mL, the median postoperative drainage time was 4 [2-10] days, and the median postoperative hospital stay was 4 [2-13] days. There was no perioperative death. Postoperative complications included five cases of persistent air leakage longer than 5 days (7, 7, 8, 9, and 10 days), and one patient developed a pulmonary infection and abnormal liver function after the operation. The median maximum diameter of the lesion was 0.8 [0.2-1.5] cm, lymph nodes were resected in a median of 8 [4-15] case. Conclusions: The approach of the inferior pulmonary ligament to resect posterior and/or the lateral basal segment can optimize the surgical procedure. The surgical trauma and postoperative complications are reduced, which is worthy of popularization and application.

Effects of ruxolitinib on infection in patients with myeloproliferative neoplasm: a meta-analysis.

OBJECTIVE: Infections in ruxolitinib-treated myeloproliferative neoplasm (MPN) patients were reported frequently. This work aimed to systematically estimate the risk of infection associated with ruxolitinib in MPN patients. METHODS: The PUBMED, CNKI, EMBASE, Cochrane and CBM databases were searched to identify all related studies. Odds ratio (OR) and 95% confidence interval (CI) were used to express the difference between groups. I2 was calculated to evaluate heterogeneity. Revman software was used to conduct the analysis. RESULTS: Eleven randomized control trials were included in this analysis. The risk of overall infections was not different at the early stage of ruxolitinib use (OR, 95%CI: 1.23, [0.91, 1.67]). In the extension phase, overall infection was significantly lower in patients receiving ruxolitinib (OR, 95%CI: 0.53, [0.36, 0.79]). Herpes zoster infection was at higher risk both at early stage and in the extension phase (OR, 95%CI: 7.39, [1.33, 41.07]), (OR, 95%CI: 5.23, [1.46, 18.79]), respectively. CONCLUSION: Our study suggested that ruxolitinib increased the risk of herpes zoster infection. However, current studies were not enough to estimate the effects of ruxolitinib on the risk of overall infection in patients with myeloproliferative neoplasm.

The methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism is associated with breast cancer subtype susceptibility in southwestern China.

Methylenetetrahydrofolate reductase (MTHFR), a folate-dependent enzyme, is reportedly involved in several cancer types. The MTHFR C677T polymorphism influences many biological processes, including tumorigenesis. However, the association between the MTHFR C677T polymorphism and breast cancer (BC) subtypes is not fully understood. In this study, the MTHFR C677T polymorphism was genotyped in 490 individuals with or without BC from southwestern China. Analysis of the association between the MTHFR C677T polymorphism and BC revealed that there was a significant association between the MTHFR C677T polymorphism and triple-negative breast cancer (TNBC) (OR = 2.83, 95% CI: 1.12-9.51, P = 0.0401). Furthermore, the MTHFR C677T polymorphism can also serve as a protective factor in luminal A breast cancer (OR = 0.57, 95% CI: 0.34-0.94, P = 0.0258). Evaluation of the association between the MTHFR C677T polymorphism and clinical characteristics indicated that people who suffered from hypertension had an increased risk for BC (OR = 2.27; 95% CI: 1.08-4.6; P = 0.0264), especially TNBC (OR = 215.38; 95% CI: 2.45-84430.3; P = 0.0317). Our results suggest that the MTHFR C677T polymorphism is significantly associated with susceptibility to luminal B breast cancer and TNBC.

The global COVID-19 pandemic at a crossroads: relevant countermeasures and ways ahead.

BACKGROUND: Since the outbreak of novel coronavirus disease (COVID-19) in Wuhan, China at the beginning of December 2019, there have been over 11,200,000 confirmed cases in the world as of the 3rd July 2020, affecting over 213 countries and regions with nearly 530,000 deaths. The pandemic has been sweeping all continents, North America, Latin America, Europe, Middle East and South Asia among others at an alarming rapidity. Here, we provide an estimate of the scale of the pandemic spread under different scenarios of variation in key influencing parameters with a hybrid model. METHODS: We developed a new hybrid model of infectious disease transmission based on Cellular Automata (CA)-configured SEIR to analyse the COVID-19 outbreak and estimate its transmission pattern. A probabilistic contamination network is embedded in the pandemic transmission model to capture the randomness feature of person-to-person spread of the novel virus. We used the improved SEIR model to quantify the population contact state with isolation measures under different continuous time series contact probability via CA. We adjusted the modelling parameters to verify the model performance in accordance to the data from the reports published by the Chinese Center for Disease Control and Prevention. We simulated several scenarios by varying such key parameters as number of isolation rate, average contact times of the population, number of infected people before taking prevention and control measures, medical level and number of imported cases. RESULTS: In the baseline model, we identified that the isolation control as the most influencing factor that had the largest impact on decreasing the speed of the reproductive number, accelerating the arrival of the "inflection point" of pandemic prevention and control, and the death rate reduction. We estimated that the probability of people contacts and the number of the onset infected cases before prevention measures also had significant effect on the infection rate reduction with appropriate prevention measures adoption, which partly reflects the impact of timely measure on the severity of the outbreak. We found that imported cases will risk the domestic prevention. CONCLUSIONS: Our modelling results clearly indicate that early-stage preventive measures are the most effective way to contain the pandemic spread and a strong interventionist approach needs to be adopted by policymakers vis-à-vis of the highly contagious nature of the COVID-19. Human resources, intensified isolation and confinement as well as special hospital buildings should be prioritised in countries with large number of infections to constrain the global transmission of the virulent infection. To do so, internationally coordinated actions require to be taken to replicate good practices to less infected countries and regions immediately.

Mannose Suppresses the Proliferation and Metastasis of Lung Cancer by Targeting the ERK/GSK-3ß/ß-Catenin/SNAIL Axis.

INTRODUCTION: It has been found that mannose exerts antitumoural properties in vitro and in animal models. Whether mannose has potential anti-proliferative and anti-metastatic properties against non-small-cell lung cancer (NSCLC) is still unclear. METHODS: Here, we performed ex vivo experiments and established a nude mouse model to evaluate the anticancer effects of mannose on NSCLC cells and its effects on the ERK/GSK-3ß/ß-catenin/SNAIL axis. A CCK-8 assay was conducted to evaluate the effects of mannose on lung cancer cells (A549 and HCC827) and normal lung cells (HPAEpiC). Transwells were used to examine the motility of cancer cells. qRT-PCR was used to evaluate the effects of mannose on the mRNA expression of ß-catenin. Western blotting was conducted to explore the effects of mannose on the ERK/GSK-3ß/ß-catenin/SNAIL axis and nuclear accumulation of ß-catenin. An animal model was established to evaluate the antitumoural effect of mannose on hepatic metastasis in vivo. RESULTS: In this study, we found that mannose inhibited the proliferation of A549 and HCC827 cells in vitro both time- and dose-dependently. However, it exerted only a slight influence on the viability of normal lung cells in vitro. Moreover, mannose also inhibited the migrating and invading capacity of NSCLC cells in vitro. Using Western blotting, we observed that mannose reduced SNAIL and ß-catenin expression and ERK activation and promoted phospho-GSK-3ß expression. The ERK agonist LM22B-10 promoted the metastatic ability of NSCLC cells and increased SNAIL and ß-catenin expression in cancer cells, which could be reversed by mannose. Furthermore, ERK-mediated phosphorylation of the ß-catenin-Tyr654 residue might participate in the nuclear accumulation of ß-catenin and its transcriptional function. The results from animal experiments showed that mannose effectively reduced hepatic metastasis of A549 cells in vivo. Furthermore, mannose inhibited ERK/GSK-3ß/ß-catenin/SNAIL in tumour tissues obtained from nude mice. DISCUSSION: Collectively, these findings suggest that mannose exerts anti-metastatic activity against NSCLC by inhibiting the activation of the ERK/GSK-3ß/ß-catenin/SNAIL axis, which indicates the potential anticancer effects of mannose.

Superelastic Carbon Aerogel with Ultrahigh and Wide-Range Linear Sensitivity.

Compressible and elastic carbon materials offer many advantages and have promising applications in various electronic devices. However, fabricating carbon materials with super elasticity, fatigue resistance, and high and wide-range linear sensitivity for pressure or strain remains a great challenge. Herein, a facile and sustainable route is developed to fabricate a carbon aerogel with not only superior mechanical performances but also exceptionally high and wide-range linear sensitivity by using chitosan as a renewable carbon source and cellulose nanocrystal as a nanoreinforcement or support. The as-prepared carbon aerogel with wave-shaped layers shows high compressibility, super elasticity, stable strain-current response, and excellent fatigue resistance (94% height retention after 50 000 cycles). More importantly, it demonstrates both an ultrahigh sensitivity of 103.5 kPa-1 and a very wide linear range of 0-18 kPa. In addition, the carbon aerogel has a very low detection limit (1.0 Pa for pressure and 0.05% for strain). The carbon aerogel also can be bended to detect a small angle change. These superiorities render its applications in various wearable devices.

Ars2 promotes cell proliferation and tumorigenicity in glioblastoma through regulating miR-6798-3p.

Arsenic resistance protein 2 (Ars2) is a component of the nuclear RNA cap-binding complex (CBC) that is important for some microRNA biogenesis and it is critical for cell proliferation and tumorigenicity. However, mechanism of Ars2-regulated cellular proliferation and tumorigenicity in glioblastoma has not been fully understood. Western blotting was used to detect the expressions of Ars2, p53, p21, and cleavage/activation of caspases-3 (C-Caspase 3). Microarray and Quantitative Real-time PCR (qRT-PCR) were performed to identify the Ars2-regulated microRNAs. Apoptosis assessed by flow cytometry analysis was used to evaluate the role of Ars2 in cells proliferation. The lentivirus-mediated gene knockdown approach was conducted to determine the function of Ars2. The orthotopic glioblastoma xenograft was used to demonstrate the role of Ars2 in glioblastoma growth in vivo. The high expression of Ars2 was observed in several glioblastoma cell lines and was significantly associated with poorer overall survival. Importantly, the overexpression of Ars2 promoted cell proliferation and colony formation in glioblastoma cells, whereas the depletion of Ars2 inhibited cell proliferation, colony formation, and tumor growth. Mechanistic study revealed that knockdown of Ars2 reduced the expression levels of miR-6798-3p, which was responsible for the up-regulation of p53 and p21, leading to apoptosis. Furthermore, the knockdown of Ars2 suppressed tumor growth in orthotopic glioblastoma xenograft model and significantly prolonged the survival time of the tumor-bearing mice. These findings identify a critical role for Ars2 in regulation of proliferation and tumorigenicity in glioblastoma and suggest that Ars2 could be a critical therapeutic target for glioblastoma intervention.

Flavonoids inhibit cell proliferation and induce apoptosis and autophagy through downregulation of PI3Kγ mediated PI3K/AKT/mTOR/p70S6K/ULK signaling pathway in human breast cancer cells.

Anticancer activities of flavonoids derived from Tephroseris kirilowii (Turcz.) Holub. were evaluated in human cancer cells. We isolated and identified, for the first time, eight flavonoids from T. kirilowii and found that three of them (IH: isorhamnetin, GN: genkwanin, and Aca: acacetin) inhibited cell proliferation in a variety of human cancer cell lines. These active flavonoids caused cell cycle arrest at G2/M phase and induced apoptosis and autophagy in human breast cancer cells. Molecular docking revealed that these flavonoids dock in the ATP binding pocket of PI3Kγ. Importantly, treatment with these flavonoids decreased the levels of PI3Kγ-p110, phospho-PI3K, phospho-AKT, phospho-mTOR, phospho-p70S6K, and phospho-ULK. Pretreatment with PI3Kγ specific inhibitor AS605240 potentiated flavonoids-mediated inactivation of AKT, mTOR, p70S6K, ULK, and apoptosis. Taken together, these findings represent a novel mechanism by which downregulation of PI3Kγ-p110 and consequent interruption of PI3K/AKT/mTOR/p70S6K/ULK signaling pathway might play a critical functional role in these flavonoids-induced cell cycle arrest at G2/M phase, apoptosis, and autophagy. Our studies provide novel insights into the anticancer activities of selected flavonoids and their potential uses in anticancer therapy.

Identification of crucial genes associated with esophageal squamous cell carcinoma by gene expression profile analysis.

To uncover the genes associated with the development of esophageal squamous cell carcinoma (ESCC), an ESCC microarray dataset was used to identify genes differentially expressed between ESCC and normal control tissues. The dataset GSE17351 was downloaded from the Gene Expression Omnibus, containing 5 tumor esophageal mucosa samples and 5 adjacent normal esophageal mucosa samples from 5 male patients with ESCC. The differentially expressed genes (DEGs) were identified using the Linear Models for Microarray Data R package. Then, a co-expression network was constructed using the Weighted Correlation Network Analysis (WGCNA) package, and co-expression network modules were obtained with a hierarchical clustering algorithm. Additionally, functional enrichment analyses for DEGs in the top 2 modules with the highest significance were respectively conducted using the WGCNA package and the cluster Profiler package. In total, 487 upregulated and 468 downregulated DEGs were identified. A total of 24 modules were obtained from the co-expression network, and the top 2 modules with the highest significance, designated as 'blue4' and 'magenta', were further analyzed. In the module blue4, DEGs were significantly enriched in a number of Gene Ontology terms, including 'spindle organization' [e.g., ubiquitin conjugating enzyme E2 C (UBE2C) and SAC3 domain containing 1] and 'cell cycle process' [e.g., UBE2C, minichromosome maintenance complex component 6 (MCM6) and cell division cycle 20 (CDC20)]. Furthermore, a number of DEGs (e.g., UBE2C, CDC20 and MCM6) were enriched in the 'cell cycle' and 'ubiquitin mediated proteolysis' pathways. In the module 'magenta', a number of DEGs [e.g., transferrin receptor (TFRC) and TEA domain transcription factor 4 (TEAD4)] were enriched in the primary metabolic process and intracellular membrane-bounded organelle. Additionally, 308 upregulated genes and 215 downregulated genes were differentially expressed in the same pattern in another dataset, GSE20347, including UBE2C, CDC20, MCM6, TFRC, TEAD4, protein phosphatase 1 regulatory subunit 3C and MAL, T-cell differentiation protein. These DEGs may function in the development of ESCC.

Identification of key genes and long non­coding RNAs in celecoxib­treated lung squamous cell carcinoma cell line by RNA­sequencing.

Celecoxib is an inhibitor of cyclooxygenase-2, a gene that is often aberrantly expressed in the lung squamous cell carcinoma (LSQCC). The present study aims to provide novel insight into chemoprevention by celecoxib treatment. The human LSQCC cell line SK­MES­1 was treated with or without celecoxib and RNA­sequencing (RNA­seq) was performed on the Illumina HiSeq 2000 platform. Expression levels of genes or long non­coding RNAs (lncRNAs) were calculated by Cufflinks software. Subsequently, differentially expressed genes (DEGs) and differentially expressed lncRNAs (DE­LNRs) between the two groups were selected using the limma package and LNCipedia 3.0, respectively; followed by co­expression analysis based on their expression correlation coefficient (CC). Enrichment analysis for the DEGs and co­expressed DE­LNRs were performed. Protein­protein interaction (PPI) network analysis for DEGs was performed using STRING database. A set of 317 DEGs and 25 DE­LNRs were identified between celecoxib­treated and non­treated cell lines. A total of 12 pathways were enriched by the DEGs, including 'protein processing in endoplasmic reticulum' for activating transcription factor 4 (ATF4), 'mammalian target of rapamycin (mTOR) signaling pathway' for vascular endothelial growth factor A (VEGFA) and 'ECM­receptor interaction' for fibronectin 1 (FN1). Genes such as VEGFA, ATF4 and FN1 were highlighted in the PPI network. VEGFA was linked with lnc­AP000769.1­2:10 (CC= ­0.99227), whereas ATF4 and FN1 were closely correlated with lnc­HFE2­2:1 (CC=0.996159 and ­0.98714, respectively). lncRNAs were also enriched in pathways such as 'mTOR signaling pathway' for lnc­HFE2­2:1. Several important molecules were identified in celecoxib­treated LSQCC cell lines, such as VEGFA, ATF4, FN1, lnc­AP000769.1­2:10 and lnc­HFE2­2:1, which may enhance the anti­cancer effects of celecoxib on LSQCC.

Integrated TCGA analysis implicates lncRNA CTB-193M12.5 as a prognostic factor in lung adenocarcinoma.

BACKGROUND: Lung cancer is a malignant tumor with the highest incidence and mortality around the world. Recent advances in RNA sequencing technology have enabled insights into long non-coding RNAs (lncRNAs), a previously largely overlooked species in dissecting lung cancer pathology. METHODS: In this study, we used a comprehensive bioinformatics analysis strategy to identify lncRNAs closely associated with lung adenocarcinoma, using the RNA sequencing datasets collected from more than 500 lung adenocarcinoma patients and deposited at The Cancer Genome Atlas (TCGA) database. RESULTS: Differential expression analysis highlighted lncRNAs CTD-2510F5.4 and CTB-193M12.5, both of which were significantly upregulated in cancerous specimens. Moreover, network analyses showed highly correlated expression levels of both lncRNAs with those of differentially expressed protein-coding genes, and suggested central regulatory roles of both lncRNAs in the gene co-expression network. Importantly, expression of CTB-193M12.5 showed strong negative correlation with patient survival. CONCLUSIONS: Our study mined existing TCGA datasets for novel factors associated with lung adenocarcinoma, and identified a largely unknown lncRNA as a potential prognostic factor. Further investigation is warranted to characterize the roles and significance of CTB-193M12.5 in lung adenocarcinoma biology.

A novel autophagy inhibitor berbamine blocks SNARE-mediated autophagosome-lysosome fusion through upregulation of BNIP3.

Increasing evidences reveal that autophagy inhibitor could enhance the effect of chemotherapy to cancer. However, few autophagy inhibitors are currently approved for clinical application in humans. Berbamine (BBM) is a natural compound extracted from traditional Chinese medicine that is widely used for treatment of a variety of diseases without any obvious side effects. Here we found that BBM is a novel auophagy inhibitor, which potently induced the accumulation of autophagosomes by inhibiting autophagosome-lysosome fusion in human breast cancer cells. Mechanistically, we found that BBM blocked autophagosome-lysosome fusion by inhibiting the interaction of SNAP29 and VAMP8. Furthermore, BBM induced upregulation of BNIP3 and the interaction between SNAP29 and BNIP3. BNIP3 depletion or SNAP29 overexpression abrogated BBM-mediated blockade of autophagosome-lysosome fusion through the interaction between SNAP29 and VAMP8, whereas BNIP3 overexpression blocked autophagosome-lysosome fusion through inhibition of the interaction between SNAP29 and VAMP8. These findings suggest that upregulation of BNIP3 and interaction between BNIP3 and SNAP29 could be involved in BBM-mediated blockade of autophagosome-lysosome fusion through inhibition of the interaction between SNAP29 and VAMP8. Our findings identify the critical role of BNIP3 in blockade of autophagosome-lysosome fusion mediated by BBM, and suggest that BBM could potentially be further developed as a novel autophagy inhibitor, which could enhance the effect of chemotherapy to cancer.

Mitochondrial fission and mitophagy depend on cofilin-mediated actin depolymerization activity at the mitochondrial fission site.

Mitochondria fission and mitophagy are fundamentally crucial to cellular physiology and play important roles in cancer progression. Developing a comprehensive understanding of the molecular mechanism underlying mitochondrial fission and mitophagy will provide novel strategies for cancer prevention and treatment. Actin has been shown to participate in mitochondrial fission and mitophagy regulation. Cofilin is best known as an actin-depolymerizing factor. However, the molecular mechanism by which cofilin regulates mitochondrial fission and mitophagy remains largely unknown. Here we report that knockdown of cofilin attenuates and overexpression of cofilin potentiates mitochondrial fission as well as PINK1/PARK2-dependent mitophagy induced by staurosporine (STS), etoposide (ETO), and carbonyl cyanide 3-chlorophenylhydrazone (CCCP). Cofilin-mediated-PINK1 (PTEN-induced putative kinase 1) accumulation mainly depends on its regulation of mitochondrial proteases, including peptidase mitochondrial processing beta (MPPß), presenilin-associated rhomboid-like protease (PARL), and ATPase family gene 3-like 2 (AFG3L2), via mitochondrial membrane potential activity. We also found that the interaction and colocalization of G-actin/F-actin with cofilin at mitochondrial fission sites undergo constriction after CCCP treatment. Pretreatment with the actin polymerization inhibitor latrunculin B (LatB) increased and actin-depolymerization inhibitor jasplakinolide (Jas) decreased mitochondrial translocation of actin induced by STS, ETO, and CCCP. Both LatB and Jas abrogated CCCP-mediated mitochondrial fission and mitophagy. Our data suggest that G-actin is the actin form that is translocated to mitochondria, and the actin-depolymerization activity regulated by cofilin at the mitochondrial fission site is crucial for inducing mitochondrial fission and mitophagy.

miR-339-5p downregulation contributes to Taxol resistance in small-cell lung cancer by targeting α1,2-fucosyltransferase 1.

Lung cancer is a leading cause of cancer-related mortality, and non-small-cell lung carcinoma is responsible for almost 80% of lung cancer-related deaths. In recent years, lung cancer has shown increasing incidence but poor prognosis, and many studies have demonstrated that microRNAs play crucial roles in the development of lung carcinoma and chemoresistance. This study investigated the role of miR-339-5p involvement in lung carcinoma cell lines and chemoresistance to Taxol. We observed that miR-339-5p was significantly downregulated in Taxol-A549 cells compared with A549 cells. In vitro studies further indicated that miR-339-5p could promote colony formation and attenuate apoptosis of lung carcinoma cell lines through targeting α1,2-fucosyltransferase 1 and regulation of the downstream protein Lewis y. Furthermore, miR-339-5p was found to enhance the proliferation inhibition ability of Taxol in lung carcinoma cell lines as well as in the Taxol-A549 subclone. An in vivo study indicated that both miR-339-5p and Taxol could attenuate the growth of lung carcinoma; moreover, miR-339-5p could synergistically promote this inhibitory function of Taxol. In summary, our results suggest a miR-339-5p molecular network that is involved in controlling lung carcinoma progression. © 2017 The Authors IUBMB Life published by Wiley Periodicals, Inc. on behalf of International Union of Biochemistry and Molecular Biology, 69(11):841-849, 2017.

Apamin-mediated actively targeted drug delivery for treatment of spinal cord injury: more than just a concept.

Faced with the complex medical challenge presented by spinal cord injuries (SCI) and considering the lack of any available curative therapy, the development of a novel method of delivering existing drugs or candidate agents can be perceived to be as important as the development of new therapeutic molecules. By combining three ingredients currently in clinical use or undergoing testing, we have designed a central nervous system targeted delivery system based on apamin-modified polymeric micelles (APM). Apamin, one of the major components of honey bee venom, serves as the targeting moiety, poly(ethylene glycol) (PEG) distearoylphosphatidylethanolamine (DSPE) serves as the drug-loaded material, and curcumin is used as the therapeutic agent. Apamin was conjugated with NHS (N-hydroxysuccinimide)-PEG-DSPE in a site-specific manner, and APM were prepared by a thin-film hydration method. A formulation comprising 0.5 mol % targeting ligand with 50 nm particle size showed strong targeting efficiency in vivo and was evaluated in pharmacodynamic assays. A 7-day treatment by daily intravenous administration of low doses of APM (corresponding to 5 mg/kg of curcumin) was performed. Significantly enhanced recovery and prolonged survival was found in the SCI mouse model, as compared to sham-treated groups, with no apparent toxicity. A single dose of apamin-conjugated polymers was about 700-fold lower than the LD50 amount, suggesting that APM and apamin have potential for clinical applications as spinal cord targeting ligand for delivery of agents in treatment of diseases of the central nervous system.