SmMYB98b positive regulation to tanshinones in Salvia miltiorrhiza Bunge hairy roots

Plant Cell, Tissue and Organ Culture (PCTOC) - Tanshinones are major secondary metabolites in Salvia miltiorrhiza Bunge, the traditional Chinese medicinal plant Danshen. Increasing the production...     

Transforming growth factor-β promotes the function of HIV-specific CXCR5+CD8 T cells

HIV replication can be inhibited by CXCR5⁺CD8 T cells (follicular cytotoxic T cell [TFC]) which transfer into B-cell follicles where latent HIV infection persists. However, how cytokines affect TFC remain unclear. Understanding which cytokines show the ability to affect TFC could be a key strategy toward curing HIV. Similar mechanisms could be used for the growth and transfer of TFCs and follicular helper T (TFH) cells; as a result, we hypothesized that cytokines IL-6, IL-21, and transforming growth factor-β (TGF-β), which are necessary for the differentiation of TFH cells, could also dictate the development of TFCs. In this work, lymph node mononuclear cells and peripheral blood mononuclear cells from HIV-infected individuals were cocultured with IL-6, IL-21, and TGF-β. We then carried out T-cell receptor (TCR) repertoire analysis to compare the differences between CXCR5^– and CXCR5⁺CD8 T cells. Our results showed that the percentage and function of TFC can be enhanced by stimulation with TGF-β. Besides, TGF-β stimulation enhanced the diversity of TCR and complementarity-determining region 3 sequences. HIV DNA showed a negative correlation with TFC. The use of TGF-β to promote the expression of CXCR5⁺CD8 T cells could become a new treatment approach for curing HIV.     

A prognostic eight-gene expression signature for patients with breast cancer receiving adjuvant chemotherapy

Breast cancer is a popularly diagnosed malignant tumor. Genomic profiling studies suggest that breast cancer is a disease with heterogeneity. Chemotherapy is one of the chief means to treat breast cancer, while its responses and clinical outcomes vary largely due to the conventional clinicopathological factors and inherent chemosensitivity of breast cancer. Using the least absolute shrinkage and selection operator (LASSO) Cox regression model, our study established a multi-mRNA-based signature model and constructed a relative nomogram in predicting distant-recurrence-free survival for patients receiving surgery and following chemotherapy. We constructed a signature of eight mRNAs (IPCEF1, SYNDIG1, TIGIT, SPESP1, C2CD4A, CLCA2, RLN2, and CCL19) with the LASSO model, which was employed to separate subjects into groups with high- and low-risk scores. Obvious differences of distant-recurrence-free survival were found between these two groups. This eight-mRNA-based signature was independently associated with the prognosis and had better prognostic value than classical clinicopathologic factors according to multivariate Cox regression results. Receiver operating characteristic results demonstrated excellent performance in diagnosing 3-year distant-recurrence by the eight-mRNA signature. A nomogram that combined both the eight-mRNA-based signature and clinicopathological risk factors was constructed. Comparing with an ideal model, the nomograms worked well both in the training and validation sets. Through the results that the eight-mRNA signature effectively classified patients into low- and high-risk of distant recurrence, we concluded that this eight-mRNA-based signature played a promising predictive role in prognosis and could be clinically applied in breast cancer patients receiving adjuvant chemotherapy.     

An in situ collagen-HA hydrogel system promotes survival and preserves the proangiogenic secretion of hiPSC-derived vascular smooth muscle cells

Human-induced pluripotent stem cell-derived vascular smooth muscle cells (hiPSC-VSMCs) with proangiogenic properties have huge therapeutic potential. While hiPSC-VSMCs have already been utilized for wound healing using a biomimetic collagen scaffold, an in situ forming hydrogel mimicking the native environment of skin offers the promise of hiPSC-VSMC mediated repair and regeneration. Herein, the impact of a collagen type-I-hyaluronic acid (HA) in situ hydrogel cross-linked using a polyethylene glycol-based cross-linker on hiPSC-VSMCs viability and proangiogenic paracrine secretion was investigated. Our study demonstrated increases in cell viability, maintenance of phenotype and proangiogenic growth factor secretion, and proangiogenic activity in response to the conditioned medium. The optimally cross-linked and functionalized collagen type-I/HA hydrogel system developed in this study shows promise as an in situ hiPSC-VSMC carrier system for wound regeneration.     

Deregulation of UCA1 expression may be involved in the development of chemoresistance to cisplatin in the treatment of non-small-cell lung cancer via regulating the signaling pathway of microRNA-495/NRF2

Non-small-cell lung cancer (NSCLC) remains the leading cause of cancer death worldwide. As a platinum-based chemotherapeutic drug, cisplatin has been used for over 30 years in NSCLC treatment while its effects are diminished by drug resistance. Therefore, we aimed to study the potential role of UCA1 in the development of chemoresistance against cisplatin. Real-time polymerase chain reaction, western-blot analysis, and immunofluorescence were used to study the involvement of UCA1, miR-495, and NRF2 in chemoresistance against cisplatin. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed to determine the effect of cisplatin on cell proliferation. Computational analysis and luciferase assay were carried out to explore the interaction among UCA1, miR-495, and NRF2. The cisplatin-R group exhibited lower levels of UCA1 and NRF2 expression but a higher level of miR-495 expression than the cisplatin-S group. The growth rate and half-maximal inhibitory concentration of cellular dipeptidyl peptidase (cisplatinum) of the cisplatin-R group were much higher than those in the cisplatin-S group. MiR-495 contained a complementary binding site of UCA1, and the luciferase activity of wild-type UCA1 was significantly reduced after the transfection of miR-495 mimics. MiR-495 directly targeted the 3′-untranslated region (3′-UTR) of NRF2, and the luciferase activity of wild-type NRF2 3′-UTR was evidently inhibited by miR-495 mimics. Finally, UCA1 and NRF2 expressions in the effective group were much lower than that in the ineffective group, along with a much higher level of miR-495 expression. We suggested for the first time that high expression of UCA1 contributed to the development of chemoresistance to cisplatin through the UCA1/miR-495/NRF2 signaling pathway.     

Expression scoring of a small-nucleolar-RNA signature identified by machine learning serves as a prognostic predictor for head and neck cancer

Head and neck squamous cell carcinoma (HNSCC) is a common malignancy with high mortality and poor prognosis due to a lack of predictive markers. Increasing evidence has demonstrated small nucleolar RNAs (snoRNAs) play an important role in tumorigenesis. The aim of this study was to identify a prognostic snoRNA signature of HNSCC. Survival-related snoRNAs were screened by Cox regression analysis (univariate, least absolute shrinkage and selection operator, and multivariate). The predictive value was validated in different subgroups. The biological functions were explored by coexpression analysis and gene set enrichment analysis (GSEA). One hundred and thirteen survival-related snoRNAs were identified, and a five-snoRNA signature predicted prognosis with high sensitivity and specificity. Furthermore, the signature was applicable to patients of different sexes, ages, stages, grades, and anatomic subdivisions. Coexpression analysis and GSEA revealed the five-snoRNA are involved in regulating malignant phenotype and DNA/RNA editing. This five-snoRNA signature is not only a promising predictor of prognosis and survival but also a potential biomarker for patient stratification management.     

Pak2 inhibition promotes resveratrol-mediated glioblastoma A172 cell apoptosis via modulating the AMPK-YAP signaling pathway

As a polyphenolic compound, resveratrol (Res) is widely present in a variety of plants. Previous studies have shown that Res can inhibit various tumors. However, its role in c remains largely unexplored. In the present study, we first demonstrated that Res inhibited cell viability and induced apoptosis of glioblastoma A172 cell. Further experiments showed that Res induced mitochondrial dysfunction and activated the activity of caspase-9. Functional studies have found that Res treatment is associated with an increase in the expression of Pak2. Interestingly, inhibition of Pak2 could further augment the proapoptotic effect of Res. Mechanistically, Pak2 inhibition induced reactive oxygen species overproduction, mitochondria-JNK pathway activation, and AMPK-YAP axis suppression. However, overexpression of YAP could abolish the anticancer effects of Res and Pak2 inhibition, suggesting a necessary role played by the AMPK-YAP pathway in regulating cancer-suppressive actions of Res and Pak2 inhibition. Altogether, our results indicated that Res in combination with Pak2 inhibition could further enhance the anticancer property of Res and this effect is mediated via the AMPK-YAP pathway.