Development and validation of a tumor immune cell infiltration-related gene signature for recurrence prediction by weighted gene co-expression network analysis in prostate cancer.

Introduction: Prostate cancer (PCa) is the second most common malignancy in men. Despite multidisciplinary treatments, patients with PCa continue to experience poor prognoses and high rates of tumor recurrence. Recent studies have shown that tumor-infiltrating immune cells (TIICs) are associated with PCa tumorigenesis. Methods: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were used to derive multi-omics data for prostate adenocarcinoma (PRAD) samples. The CIBERSORT algorithm was used to calculate the landscape of TIICs. Weighted gene co-expression network analysis (WGCNA) was performed to determine the candidate module most significantly associated with TIICs. LASSO Cox regression was applied to screen a minimal set of genes and construct a TIIC-related prognostic gene signature for PCa. Then, 78 PCa samples with CIBERSORT output p-values of less than 0.05 were selected for analysis. WGCNA identified 13 modules, and the MEblue module with the most significant enrichment result was selected. A total of 1143 candidate genes were cross-examined between the MEblue module and active dendritic cell-related genes. Results: According to LASSO Cox regression analysis, a risk model was constructed with six genes (STX4, UBE2S, EMC6, EMD, NUCB1 and GCAT), which exhibited strong correlations with clinicopathological variables, tumor microenvironment context, antitumor therapies, and tumor mutation burden (TMB) in TCGA-PRAD. Further validation showed that the UBE2S had the highest expression level among the six genes in five different PCa cell lines. Discussion: In conclusion, our risk-score model contributes to better predicting PCa patient prognosis and understanding the underlying mechanisms of immune responses and antitumor therapies in PCa.

Targeting CDCP1 gene transcription coactivated by BRD4 and CBP/p300 in castration-resistant prostate cancer.

CUB domain-containing protein 1 (CDCP1), a transmembrane protein with tumor pro-metastatic activity, is highly expressed in late-stage and castrate-resistant prostate cancer (CRPC). However, the molecular mechanism driving CDCP1 overexpression in CRPC progress remains elusive. Here we report that transcription cofactors BRD4 and CBP/p300 co-regulate transcriptional expression of CDCP1 in CRPC tumorigenesis. In contrast to androgen receptor (AR) in CRPC, increased expression of BRD4 and CBP/p300 is strongly correlated with CDCP1 gene amplification. Combined knockdown or dual-inhibition of BRD4 and CBP/p300 down-regulated CDCP1 transcription and downstream PI3K/AKT and/or SRC/MAPK signaling pathways in CRPC cells much more so than single-protein perturbation. Our biochemical and structural analyses further showed that NEO2734, a dual-inhibitor targeting BRD4 and p300 bromodomains exhibits greater efficacy than single inhibitors for BRD4 or CBP/p300 in suppressing CDCP1 transcriptional expression and its downstream signaling pathways in CRPC cell proliferation and metastasis. Our study illustrates that targeting CDCP1 through dual-inhibition of BRD4 and CBP/p300 represents a synergistic therapeutic strategy for new treatment of CRPC.

The evaluation of hepatoprotective effects of flavonoids from Scorzonera austriaca Wild against CCl4-induced acute liver injury in vitro and in vivo.

Scorzonera austriaca Wild is a traditional herbal medicine; however, little is known with regard to the effect of flavonoids from S. austriaca (FSA) on liver injury induced by Carbon tetrachloride (CCl4), especially the mechanism remains unknown. Therefore, our paper was designed to investigate the hepatoprotective effect of FSA against CCl4-induced acute liver injury in vitro and in vivo, with focus on its potential mechanism. The purity of FSA prepared by using polyporous resin column chromatography could reach 94.5%, and seven flavonoid compounds in FSA were identified by using LC-ESI-MS analysis. In vivo results showed that FSA markedly decreased the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and malonaldehyde (MDA) and increased the contents of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Furthermore, in vivo and in vitro results confirmed that FSA could inhibit inflammatory response, as evidenced by decreasing the levels of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) through inactivating toll-like receptor-4/nuclear factor-κB (TLR4/NF-κB) signaling pathway. FSA activated autophagy by increasing the ratio of LC3B-II/I and decreasing the protein level of p62 so as to exert its hepatoprotective effect. In general, these evidences suggested that FSA is likely to serve as a potential material for the drugs against chemical hepatic injury.

Characterization and Evaluation of the Pro-Coagulant and Immunomodulatory Activities of Polysaccharides from Bletilla striata.

Bletilla striata is widely used for stanching bleeding. In this study, polysaccharides from B. striata (BSP) were extracted by hot water. Four polysaccharides named BSP-1-BSP-4 were fractionated using DEAE-52 cellulose. BSP fractions contained sulfate, and the degrees of substitution of BSP-3 and BSP-4 were 1.59 and 1.70, respectively. Analysis of monosaccharide composition showed that four polysaccharides were mainly composed of mannan and glucose. The in vitro results showed that BSP-1-BSP-4 elicited pro-coagulant capacities by shortening the activating partial thromboplastin time, prothrombin time, and thrombin time and elevating the fibrinogen content. Immunomodulatory activity was evaluated by MTT assay, the pinocytic capacity and NO production. Although BSP fractions did not affect RAW 264.7 cell viability, they, especially BSP-2, enhanced the immunomodulatory activity by increasing the pinocytic capacity and NO production. Overall, BSP may be developed as a potential coagulant with immunomodulatory effects.

Microwave-assisted extraction releases the antioxidant polysaccharides from seabuckthorn (Hippophae rhamnoides L.) berries.

Seabuckthorn berries are rich in various bioactive components and used as a traditional medicine for a long time. Until now, little information is available for the extraction of polysaccharides from seabuckthorn berries (PSB) by linking antioxidant activity and microwave power. In this study, microwave-assisted extraction, characterization, in vitro and in vivo antioxidant activities of PSB were explored. The maximum PSB extraction yield of 0.264±0.005% was obtained under the optimal conditions as follows: microwave power 600W, extraction time 6min, liquid to material ratio 10: 1mL/g, and extraction temperature 85°C. Meanwhile, effects of microwave power on antioxidant activity of PSB was investigated and found that microwave at power of 600W can facilitate the release of antioxidant PSB in a high yield. The main monosaccharides of PSB were Rha, Man, Glu, and Gal at a molar ratio of 1.00: 6.89: 1.62: 13.52, UV and FT-IR analysis coupled with molecular weight determination further indicated that PSB is a polydisperse polysaccharide. Moreover, PSB obtained under the optimal conditions equally exerted in vivo antioxidant activity through decreasing malonaldehyde and protein carbonyls and increasing superoxide dismutase and glutathione.