Prostate cancer is a major health issue in western countries and is the second leading cause of cancer death in American men. Prostate cancer depends on the androgen receptor (AR), a transcriptional ...factor critical for prostate cancer growth and progression. Castration by surgery or medical treatment reduces androgen levels, resulting in prostatic atrophy and prostate cancer regression. Thus, metastatic prostate cancers are initially managed with androgen deprivation therapy. Unfortunately, prostate cancers rapidly relapse after castration therapy and progress to a disease stage called castration-resistant prostate cancer (CRPC). Currently, clinical treatment for CRPCs is focused on suppressing AR activity with antagonists like Enzalutamide or by reducing androgen production with Abiraterone. In clinical practice, these treatments fail to yield a curative benefit in CRPC patients in part due to AR gene mutations or splicing variations, resulting in AR reactivation. It is conceivable that eliminating the AR protein in prostate cancer cells is a promising solution to provide a potential curative outcome. Multiple strategies have emerged, and several potent agents that reduce AR protein levels were reported to eliminate xenograft tumor growth in preclinical models
distinct mechanisms, including proteasome-mediated degradation, heat-shock protein inhibition, AR splicing suppression, blockage of AR nuclear localization, AR N-terminal suppression. A few small chemical compounds are undergoing clinical trials combined with existing AR antagonists. AR protein elimination by enhanced protein or mRNA degradation is a realistic solution for avoiding AR reactivation during androgen deprivation therapy in prostate cancers.
Background
Membrane protein TMEM158 was initially reported as a Ras-induced gene during senescence and has been implicated as either an oncogenic factor or tumor suppressor, depending on tumor types. ...It is unknown if TMEM158 expression is altered in prostate cancers.
Methods
Multiple public gene expression datasets from RNA-seq and cDNA microarray assays were utilized to analyze candidate gene expression profiles. TMEM158 protein expression was assessed using an immunohistochemistry approach on a tissue section array from benign and malignant prostate tissues. Comparisons of gene expression profiles were conducted using the bioinformatics software R package.
Results
COX regression-based screening identified the membrane protein TMEM158 gene as negatively associated with disease-specific and progression-free survival in prostate cancer patients. Gene expression at the mRNA and protein levels revealed that TMEM158 expression was significantly reduced in malignant tissues compared to benign compartments. Meanwhile, TMEM158 downregulation was strongly correlated with advanced clinicopathological features, including late-stage diseases, lymph node invasion, higher PSA levels, residual tumors after surgery, and adverse Gleason scores. In castration-resistant prostate cancers, TMEM158 expression was negatively correlated with AR signaling activity but positively correlated with neuroendocrinal progression index. Consistently, in cell culture models, androgen treatment reduced TMEM158 expression, while androgen deprivation led to upregulation of TMEM158 expression. Correlation analysis showed a tight correlation of TMEM158 expression with the level of R-Ras gene expression, which was also significantly downregulated in prostate cancers. Tumor immune infiltration profiling analysis discovered a strong association of TMEM158 expression with NK cell and Mast cell enrichment.
Conclusion
The membrane protein TMEM158 is significantly downregulated in prostate cancer and is tightly associated with disease progression, anti-tumor immune infiltration, and patient survival outcome.
Galangin, a flavonol derived from Alpinia officinarum Hance and used as food additives in southern China, induces apoptosis and autophagy to suppress the proliferation of HepG2 cells. In this study, ...we demonstrated that galangin induced autophagy by increasing the ratio of AMP/TAN in HepG2 cells. It stimulated the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and LKB1, but inhibited the phosphorylation of AKT and mTOR. Inhibition of AMPK activation suppressed the dephosphorylation of mTOR to block galangin-induced autophagy. AMPK activation by galangin appeared to be independent of the LKB1 signaling pathway because the down-regulation of LKB1 by its siRNA failed to affect galangin-induced autophagy. Collectively, the findings demonstrated a novel mechanism of how galangin induces autophagy via activating AMPK in a LKB1- independent manner. The induction of autophagy can thus reflect the anti-proliferation effect of galangin in HCC cells.
•Prolonged ER stress induces by galangin may be a possible way for enhancing cancer therapy.•CHOP and MAPKs play critical roles in ER stress induced by galangin.•Galangin suppresses the growth of HCC ...with novel pathways.
Prolonged endoplasmic reticulum (ER) stress may activate apoptotic pathways in cancer cells. It is suggested that ER stress has the potential of enhancing tumor death in cancer therapy. Galangin, a flavonol derived from Alpinia officinarum Hance, has been shown to suppress the proliferation of hepatocellular carcinoma cells (HCC). The aim of this study was to determine whether galangin was able to induce ER stress in HepG2, Hep3B and PLC/PRF/5 cells. The proliferation of HCC was tested by MTT method. Intracellular Ca2+ levels were measured with Fluo3-AM.The proteins levels of GRP94, GRP78 and CHOP were detected by Western blot. To further understand the anti-HCC mechanism of galangin, mitogen-activated protein kinases (MAPKs) were detected. The results showed that galangin treatment induced ER stress was evidenced by increased protein levels of GRP94, GRP78 and CHOP, as well as increased free cytosolic Ca2+ concentration. ER stress inhibitor 4-PBA and CHOP siRNA blocked significantly galangin-induced ER in all three cell lines. Furtherexperiments showed that MAPKs involved in ER stress induced by galangin. In summary, galangin is identified as a stimulator of ER stress to suppress the proliferation of HCC, and may be used as a potential anti-cancer agent.
Triple-negative breast cancer (TNBC) is the most heterogenous and aggressive subtype of breast cancer. Chemotherapy remains the standard treatment option for patients with TNBC owing to the ...unavailability of acceptable targets and biomarkers in clinical practice. Novel biomarkers and targets for patient stratification and treatment of TNBC are urgently needed. It has been reported that the overexpression of DNA damage-inducible transcript 4 gene (DDIT4) is associated with resistance to neoadjuvant chemotherapy and poor prognosis in patients with TNBC. In this study, we aimed to identify novel biomarkers and therapeutic targets using RNA sequencing (RNA-seq) and data mining using data from public databases.
RNA sequencing (RNA-Seq) was performed to detect the different gene expression patterns in the human TNBC cell line HS578T treated with docetaxel or doxorubicin. Sequencing data were further analyzed by the R package "edgeR" and "clusterProfiler" to identify the profile of differentially expressed genes (DEGs) and annotate gene functions. The prognostic and predictive value of DDIT4 expression in patients with TNBC was further validated by published online data resources, including TIMER, UALCAN, Kaplan-Meier plotter, and LinkedOmics, and GeneMANIA and GSCALite were used to investigate the functional networks and hub genes related to DDIT4, respectively.
Through the integrative analyses of RNA-Seq data and public datasets, we observed the overexpression of DDIT4 in TNBC tissues and found that patients with DDIT4 overexpression showed poor survival outcomes. Notably, immune infiltration analysis showed that the levels of DDIT4 expression correlated negatively with the abundance of tumor-infiltrating immune cells and immune biomarker expression, but correlated positively with immune checkpoint molecules. Furthermore, DDIT4 and its hub genes (ADM, ENO1, PLOD1, and CEBPB) involved in the activation of apoptosis, cell cycle, and EMT pathways. Eventually, we found ADM, ENO1, PLOD1, and CEBPB showed poor overall survival in BC patients.
In this study, we found that DDIT4 expression is associated with the progression, therapeutic efficacy, and immune microenvironment of patients with TNBC, and DDIT4 would be as a potential prognostic biomarker and therapeutic target. These findings will help to identify potential molecular targets and improve therapeutic strategies against TNBC.
Subcellular distributions and chemical forms of cadmium (Cd) in the leaves, stems and roots were investigated in low-Cd accumulation cultivars and high-Cd accumulation cultivars of pakchoi (Brassica ...chinensis L.). Root cell wall played a key role in limiting soil Cd from entering the protoplast, especially in the low-Cd cultivars. The high-Cd cultivars had significantly higher leaf and stem Cd concentrations than the low-Cd cultivars in cell wall fraction, chloroplast/trophoplast fraction, organelle fraction and soluble fraction. In low-Cd cultivars, which were more sensitive and thus had greater physiological needs of Cd detoxification than high-Cd cultivars, leaf vacuole sequestrated higher proportions of Cd. Cd in the form of pectate/protein complexes (extracted by 1 mol·L⁻¹ NaCl) played a decisive role in Cd translocation from root to shoot, which might be one of the mechanisms that led to the differences in shoot Cd accumulation between the two types of cultivars. Furthermore, the formation of Cdphosphate complexes (extracted by 2% HAc) was also involved in Cd detoxification within the roots of pakchoi under high Cd stress, suggesting that the mechanisms of Cd detoxification might be different between low- and high-Cd cultivars.
Response of castor (Ricinus communis L.) to cadmium (Cd) was assessed by a seed-suspending seedbed approach. Length of total radicle was the most sensitive indicator of Cd tolerance among the tested ...germination and growth characters. The ED
50
value for Cd was 11.87 mg L
−1
, indicating high Cd tolerance in castor. A pot experiment was conducted by growing 46 varieties of castor under CK (without Cd) and Cd1 (10 mg kg
−1
of Cd) and Cd2 (50 mg kg
−1
of Cd) treatments to investigate genotype variations in growth response and Cd accumulation of castor under different Cd exposures. Castor possessed high Cd accumulation ability; average shoot and root Cd concentrations of the 46 tested varieties were 21.83 and 185.43 mg kg
−1
, and 174.99 and 1181.96 mg kg
−1
under Cd1 and Cd2, respectively. Great variation in Cd accumulation was observed among varieties, and Cd concentration of castor was genotype dependent. The correlation between biomass and Cd accumulation was significantly positive, while no significant correlation was observed between Cd concentration and Cd accumulation, which indicated that biomass performance is the dominant factor in determining Cd accumulation ability.
In recent years, self-supervised representation learning for skeleton-based action recognition has achieved remarkable results using skeleton sequences with the advance of contrastive learning ...methods. However, existing methods often overlook the local information within the skeleton data, so as to not efficiently learn fine-grained features. To leverage local features to enhance representation capacity and capture discriminative representations, we design an adaptive self-supervised contrastive learning framework for action recognition called AdaSCLR. In AdaSCLR, we introduce an adaptive spatiotemporal graph convolutional network to learn the topology of different samples and hierarchical levels and apply an attention mask module to extract salient and non-salient local features from the global features, emphasizing their significance and facilitating similarity-based learning. In addition, AdaSCLR extracts information from the upper and lower limbs as local features to assist the model in learning more discriminative representation. Experimental results show that our approach is better than the state-of-the-art methods on NTURGB+D, NTU120-RGB+D, and PKU-MMD datasets.
A novel core/shell C-TiO2/CoTiO3 type II heterojunction was successfully synthesized via a direct calcination method by using MIL-125/Co core-shell nanocakes as a sacrificial template and precursor. ...In the calcination process, the organic ligand in MIL-125 acts as an in-situ carbon doping source to form a carbon-doped TiO2 core (C-TiO2). At the same time, CoTiO3 nanoparticles are formed on the surface of C-TiO2 by an in-situ solid-state reaction between the C-TiO2 and Co2+ shell of MIL-125/Co. Due to such delicate core/shell structural features, carbon doping and type II heterojunctions, C-TiO2/CoTiO3 core/shell composites can effectively harvest visible light, facilitate the interfacial separation and suppress the recombination of photogenerated electron-hole pairs, leading to the remarkable photocatalytic activity for removal of ciprofloxacin (CIP). In particular, C-TiO2/CoTiO3-3 exhibits the best photocatalytic degradation activity of CIP with a degradation efficiency of 99.6% and a total carbon content removal percentage of 76% under visible-light illumination for 120 min. In addition, the proposed photocatalytic mechanism study illustrated that the main radical species in the photocatalytic degradation of CIP using C-TiO2/CoTiO3 as the photocatalyst is •OH. This work provides a new approach and insight for synthesizing core/shell heterojunction-based photocatalysts for various applications.
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•Core/shell C-TiO2/CoTiO3 type II heterojunction was synthesized by MOF-derived method.•C-TiO2/CoTiO3 shows excellent photocatalytic degradation and TOC removal of CIP.•The •OH is the main radical species in the photocatalytic degradation of CIP.•A new approach and insight for the synthesis of core/shell heterojunction was proposed.
Imbalance in the microbiota has been identified in Crohn's disease (CD). We explored the difference of the microbiota in fecal and intestinal mucosa (including ileocecal junction, terminal ileum and ...transverse colon) in pediatric patients with active CD, CD patients in remission, nonspecific enteritis (NE) and the healthy children. Seven children had active CD, 5 cases of patients achieve remission (CDR), 19 were NE patients, and 11 were healthy controls (Col). A total of 168 samples were collected. Microbiota compositions were analyzed using 16 S rRNA sequencing. The results showed that, in fecal samples, Clostridium_sensu_stricto, Enterobacter and Akkermansia had a higher relative abundance in the CD group than that in CDR, Col and NE groups. Fusobacterium and Streptococcus showed a higher abundance in both CD and CDR than that in Col group. In intestinal mucosa samples, the bacterial communities of the three sampling sites were extremely similar. Escherichia-Shigella was the most abundant mucosal bacteria in the CD group, and the abundance of Bacillus, Ruminococcus_torques_group, Streptococcus, Faecalibacterium and Blautia was lower in the CD group than in other groups. In conclusion, as a very characteristic bacteria, the abundance of Escherichia-Shigella in the intestinal mucosa can be used as a diagnostic criterion for CD patients. Also, the Bacilus and Blautia, which were not as prominent as Escherichia-Shigella could still be used as a diagnostic candidate due to their neatness in CD patients. Mucosal samples may be better than stool samples when assessing the community and diversity of patients' intestinal microbes.
•Intestinal microbiota has a significant correlation with Crohn's disease.•The difference of the microbiota in fecal and intestinal mucosa in Chinese children.•Microbiota compositions were analysed using 16S rRNA sequencing.•Escherichia-Shigella was the most abundant mucosal bacteria in the CD group.•The intestinal mucosal samples may have better stability than fecal samples.
