Antagonist Effect of Triptolide on AKT Activation by Truncated Retinoid X Receptor-alpha

Background: Retinoid X receptor-alpha (RXR alpha) is a key member of the nuclear receptor superfamily. We recently demonstrated that proteolytic cleavage of RXR alpha resulted in production of a truncated product, tRXR alpha, which promotes cancer cell survival by activating phosphatidylinositol-3-OH kinase (PI3K)/AKT pathway. However, how the tRXR alpha-mediated signaling pathway in cancer cells is regulated remains elusive. Methodology/Principal Findings: We screened a natural product library for tRXR alpha targeting leads and identified that triptolide, an active component isolated from traditional Chinese herb Trypterygium wilfordii Hook F, could modulate tRXR alpha-mediated cancer cell survival pathway in vitro and in animals. Our results reveal that triptolide strongly induces cancer cell apoptosis dependent on intracellular tRXR alpha expression levels, demonstrating that tRXR alpha serves as an important intracellular target of triptolide. We show that triptolide selectively induces tRXR alpha degradation and inhibits tRXR alpha-dependent AKT activity without affecting the full-length RXR alpha. Interestingly, such effects of triptolide are due to its activation of p38. Although triptolide also activates Erk1/2 and MAPK pathways, the effects of triptolide on tRXR alpha degradation and AKT activity are only reversed by p38 siRNA and p38 inhibitor. In addition, the p38 inhibitor potently inhibits tRXR alpha interaction with p85 alpha leading to AKT inactivation. Our results demonstrate an interesting novel signaling interplay between p38 and AKT through tRXR alpha mediation. We finally show that targeting tRXR alpha by triptolide strongly activates TNF alpha death signaling and enhances the anticancer activity of other chemotherapies Conclusions/Significance: Our results identify triptolide as a new xenobiotic regulator of the tRXR alpha-dependent survival pathway and provide new insight into the mechanism by which triptolide acts to induce apoptosis of cancer cells. Triptolide represents one of the most promising therapeutic leads of natural products of traditional Chinese medicine with unfortunate side-effects. Our findings will offer new strategies to develop improved triptolide analogs for cancer therapy.National Natural Science Foundation of China [NSFC: 30971445, 90913015, 91129302]; NSFC/Hong Kong Research Grants Council [NSFC/RGC: 30931160431/N_HKU 735/09]; Natural Science Foundation of Fujian Province [2009J01198

Validation of rapid and economic colorimetric nanoparticle assay for SARS-CoV-2 RNA detection in saliva and nasopharyngeal swabs

This article belongs to the Special Issue Advances in Molecular Biosensors.Even with the widespread uptake of vaccines, the SARS-CoV-2-induced COVID-19 pandemic continues to overwhelm many healthcare systems worldwide. Consequently, massive scale molecular diagnostic testing remains a key strategy to control the ongoing pandemic, and the need for instrument-free, economic and easy-to-use molecular diagnostic alternatives to PCR remains a goal of many healthcare providers, including WHO. We developed a test (Repvit) based on gold nanoparticles that can detect SARS-CoV-2 RNA directly from nasopharyngeal swab or saliva samples with a limit of detection (LOD) of 2.1 × 105 copies mL−1 by the naked eye (or 8 × 104 copies mL−1 by spectrophotometer) in less than 20 min, without the need for any instrumentation, and with a manufacturing price of <$1. We tested this technology on 1143 clinical samples from RNA extracted from nasopharyngeal swabs (n = 188), directly from saliva samples (n = 635; assayed by spectrophotometer) and nasopharyngeal swabs (n = 320) from multiple centers and obtained sensitivity values of 92.86%, 93.75% and 94.57% and specificities of 93.22%, 97.96% and 94.76%, respectively. To our knowledge, this is the first description of a colloidal nanoparticle assay that allows for rapid nucleic acid detection at clinically relevant sensitivity without the need for external instrumentation that could be used in resource-limited settings or for self-testing.This research was funded by EITB Maratoia (BIO21/COV/032/BD) and Iniciativa Medtech (BIO21/COV/032/BD) grants. C.H.L. and his research were supported by grants from the IKERBASQUE Foundation for Science, the Starmer–Smith Memorial Fund, Ministerio de Economía y Competitividad (MINECO) of the Spanish Central Government, the ISCIII and FEDER funds (PI12/00663, PIE13/00048, DTS14/00109, PI15/00275, PI18/01710), Departamento de Desarrollo Económico y Competitividad y Departamento de Sanidad of the Basque government, Asociación Española Contra el Cancer (AECC), Diputación Foral de Guipuzcoa (DFG) and Gobierno Vasco, Departamento de Industria (ELKARTEK project code: KK-2018/00038). The involvement of B.K. in this project was supported by Project EVAgoEAST, funded by the European Regional Development Fund, Operational program Integrated Infrastructure, ITMS code: 313011ASU8.Peer reviewe

Molecular cloning and mRNA expression profile of Sucrose Transporter Gene <i style="mso-bidi-font-style:normal">BnSUT1C</i> from <i style="mso-bidi-font-style: normal">Brassica napus</i> L.

1130-1136The genomic and cDNA sequences of BnSUT1C were isolated from B. napus. Combination of cDNA and genomic DNA sequences revealed that the BnSUT1C gene contained three exons and two introns. The cDNA encodes a protein of 513 amino acids with a calculated molecular mass of 54.7 kDa and an isoelectric point of 9.12. It exhibits typical features of sucrose transporter with 12 trans-membranes spanning domains. BnSUT1C showed highly homologous with AtSUC1 and AtSUC5. A histidine residue, which is conserved across all functional sucrose transporter proteins in higher plants, is located at position 66 of the BnSUT1C. Two putative pollen-specific cis-elements, AGAAA and GTGA motifs, are located in 5<span style="mso-bidi-font-family: " times="" new="" roman""="" lang="EN-GB">′-upstream of <i style="mso-bidi-font-style: normal">BnSUT1C. The spatial and temporal expression patterns carried out by semi-quantitative RT-PCR and Real-Time PCR, which indicated that <i style="mso-bidi-font-style: normal">BnSUT1C predominantly expressed in later developmental stages of anther, as tapetal cells began&nbsp;to shrink and collapse. BnSUT1C could mediate the uptake of sucrose in the pollen and retrieval of tapetal degenerated products during pollen maturation. </span

An Automatic Identification Method of Crested Ibis (<i>Nipponia nippon</i>) Habitat Based on Spatiotemporal Density Detection

To address the current challenges of the heavy workload, time-consuming nature and labor-intensiveness involved in existing crested ibis’s (Nipponia nipponTemminck, 1835) habitat identification approaches, this paper proposes an automatic habitat identification method based on spatiotemporal density detection. With consideration of the characteristics of the crested ibis’s trajectory data, such as aggregation, repeatability, and uncertainty, this method achieves detecting the crested ibis’s stopping points by using the spatial characteristics of the trajectory data. On this basis, an improved spatiotemporal clustering-based DBSCAN method is proposed in this paper, incorporating temporal characteristics of the trajectory data. By combining the spatial and temporal features, the proposed method is able to accurately identify the roosting and foraging sites among the crested ibis’s stopping points. Supported by remote sensing images and field investigations, it was found that the method proposed in this paper has a good clustering effect and can effectively identify the crested ibis’s foraging sites and overnight roosting areas. Specifically, the woodland, farmland, and river areas are the common foraging sites for the crested ibis, while the woodland with large trees is their common overnight site. Therefore, the method proposed in this paper can provide technical support for identifying and protecting the crested ibis’s habitats

Withaferin A Exerts Preventive Effect on Liver Fibrosis through Oxidative Stress Inhibition in a Sirtuin 3-Dependent Manner

Sirtuin 3 (SIRT3) is a deacetylase involved in the development of many inflammation-related diseases including liver fibrosis. Withaferin A (WFA) is a bioactive constituent derived from the Withania somnifera plant, which has extensive pharmacological activities; however, little is known about the regulatory role of SIRT3 in the WFA-induced antifibrogenic effect. The current study is aimed at investigating the role of SIRT3 in WFA-induced antioxidant effects in liver fibrosis. Our study verified that WFA attenuated platelet-derived growth factor BB- (PDGF-BB-) induced liver fibrosis and promoted PDGF-BB-induced SIRT3 activity and expression in JS1 cells. SIRT3 silencing attenuated the antifibrogenic and antioxidant effects of WFA in activated JS1 cells. Moreover, WFA inhibited carbon tetrachloride- (CCl4-) induced liver injury, collagen deposition, and fibrosis; increased the SIRT3 expression; and suppressed the CCl4-induced oxidative stress in fibrotic livers of C57/BL6 mice. Furthermore, the antifibrogenic and antioxidant effects of WFA could be available in CCl4-induced WT (129S1/SvImJ) mice but were unavailable in CCl4-induced SIRT3 knockout (KO) mice. Our study suggested that WFA inhibited liver fibrosis through the inhibition of oxidative stress in a SIRT3-dependent manner. WFA could be a potential compound for the treatment of liver fibrosis

Geochronology, geochemistry, Sr–Nd–Hf isotopic composition of the late Permian adakite in West Ujimqin, Inner Mongolia: petrogenesis and tectonic implications

We report new zircon U–Pb ages, whole-rock major and trace elements, and the Sr–Nd–Hf isotope composition for adakitic intrusives collected from the West Ujimqin district in the Southeast region of the Central Asian Orogenic Belt (CAOB). These data provide important constraints on the petrogenetic evolution and geodynamic setting of late Permian magmatism in the Southeast CAOB. The U–Pb dating of zircon shows that the ages of Seerbeng pluton and Nuhetingshala pluton in West Ujimqin are 255.3 0.71 Ma and 254.4 1.2 Ma, respectively, which signifies that these are products of magmatic activity in the late Permian. The adakitic intrusives are characterized by high Sr (Sr ≥ 741 ppm), low Y, low Yb, as well as high Sr/Y ratios, and strongly fractionated rare earth elements (10.3The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Inhibition of Ribosomal RNA Processing 15 Homolog (RRP15) Suppressed Tumor Growth, Invasion and Epithelial to Mesenchymal Transition (EMT) of Colon Cancer

Although ribosomal RNA processing 15 Homolog (RRP15) has been implicated in the occurrence of various cancers and is considered a potential target for cancer treatment, its significance in colon cancer (CC) is unclear. Thus, this present study aims to determine RRP15 expression and biological function in CC. The results demonstrated a strong expression of RRP15 in CC compared to normal colon specimens, which was correlated with poorer overall survival (OS) and disease-free survival (DFS) of the patients. Among the nine investigated CC cell lines, RRP15 demonstrated the highest and lowest expression in HCT15 and HCT116 cells, respectively. In vitro assays demonstrated that the knockdown of RRP15 inhibited the growth, colony-forming ability and invasive ability of the CC cells whereas its overexpression enhanced the above oncogenic function. Moreover, subcutaneous tumors in nude mice showed that RRP15 knockdown inhibited the CC growth while its overexpression enhanced their growth. Additionally, the knockdown of RRP15 inhibited the epithelial–mesenchymal transition (EMT), whereas overexpression of RRP15 promoted the EMT process in CC. Collectively, inhibition of RRP15 suppressed tumor growth, invasion and EMT of CC, and might be considered a promising therapeutic target for treating CC