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Lymph node metastasis of tumors is a crucial early step in the metastatic process. Tumor lymphangiogenesis plays an important role in promoting tumor metastasis to regional lymph nodes. Norcantharidin (NCTD) has been reported to possess potent anti-angiogenesis and antitumor properties in several cell lines and xenograft tumor models. However, its role in tumor-associated lymphangiogenesis and lymphatic metastasis remains unclear. Here, we investigated the effect of NCTD on proliferation, apoptosis, migration, invasion and the lymphatic tube formation, lymphangiogenesis, of human lymphatic endothelial cells (HLECs) in vitro by MTT, proliferation assay, Hoechst staining and flow cytometry, scraping line method, Matrigel invasion assay, inverted or fluorescence microscope and transmission electron microscope. Moreover, the underlying mechanisms, such as VEGF-C, VEGF-D, VEGFR-3 at protein and mRNA levels in lymphangiogenesis using 3-dimensional (3-D) culture of HLECs were measured by immunohistochemistry, western blotting and real-time polymerase chain reaction (RT-PCR). It was shown that NCTD inhibited proliferation, migration, invasion and lymphatic tube formation (forming-lymphatic and/or formed-lymphatic) of HLECs, induced HLEC apoptosis (all P<0.01) significantly, in a dose- and time-dependent manner (IC50 6.8 μg/ml); and downregulated the expression of VEGF-C, VEGF-D and VEGFR-3 at protein or/and mRNA levels (P<0.01) in HLEC lymphatic tube formation. Thus, we identified for the first time that NCTD inhibited HLEC lymphangiogenesis by simultaneously blocking VEGF-C and VEGF-D/VEGFR-3 in vitro. The present findings may be of importance to explore the therapeutical target or strategy of NCTD for tumor lymphangiogenesis and lymphatic metastasis.

Ocean anoxia has been widely implicated in the Permian-Triassic extinction. However, the duration and distribution of the ocean anoxia remains controversial. In this study, the detailed redox changes across the Permian-Triassic boundary （PTB） in the shallow platform interior at Great Bank of Guizhou （GBG） has been reconstructed based on the high-resolution microfossil composition and multiple paleo-redox proxies. The shallow platform is characterized by low sulfur （total sulfur （TS） and pyrite sulfur （Spy）） concentrations, low Spy/TOC ratios, and low DOP values before the mass extinction, representing oxic conditions well. Following the mass extinction, the shift of multiple geochemical proxies, including high Spy/TOC ratios and DOP values, indicates dysoxic-anoxic conditions in shallow ocean. Furthermore, we reconstruct the transition of the redox conditions of Nanpanjiang Basin： the intense volcanic eruptions, which release huge COz and SO2 before the mass extinction, provoke the temperature rising and the collapse of terrestrial ecosystem. As a result, the increased weathering influx causes the carbon iso- topic negative excursion and the expansion of the ocean oxygen minimum zone （OMZ）. When the OMZ expanded into the photic zone, the episodic H2S release events enhance the pyrite burial at Dajiang section. Thus, intense volcanic eruptions, temperature increase, and oceanic hypoxia together lead to the PTB extinction. Recent studies show high temperature might be the key mechanism of the PTB extinction. In addition, this study confirms that the microbialites were formed in the dysoxic- anoxic shallow water.

Colon cancer stem cells (CSCs) have been shown to be responsible for the recurrence and metastasis of colorectal cancer (CRC). As a crucial microenvironmental factor, extracellular matrix (ECM) stiffness is known to affect the stemness of CSCs. Recently, fibrin deposition in the stroma of CRC was demonstrated to be responsible for tumor development. In this study, we used salmon fibrin gel to provide a 3D ECM for colon cancer cells and investigated its effects on cell growth as well as the underlying mechanisms. Compared with stiff 420 Pascal (Pa) and 1 050 Pa gels, 90 Pa soft fibrin gel was most efficient at isolating and enriching tumor colonies. The size and number of colony formation negatively correlated with gel stiffness. Specifically, these tumor colonies exhibited efficient tumorigenicity, upregulated stem cell markers, and had anti-chemotherapeutic properties and were thus named tumor-repopulating cells (TRCs). More importantly, the self-renewal molecule Nanog was sharply induced in 3D-cultured colon TRCs; further, Nanog siRNA significantly inhibited colony formation, suggesting the indispensable role of Nanog in TRC growth. A subsequent mechanistic study illustrated that Nanog expression could be modulated through fibrin gel stiffness-induced DAB2IP/PI3K/FOXA1 signaling in colon TRCs.

Background Cognitive impairment is one of the main complications after a stroke and seriously affects the quality of life and survival time of patients, thereby causing a heavy burden on the social economy and public health. Although exercise is an effective non‐pharmacological strategy for prevention and treatment of cognitive impairment, the mechanism(s) of this effect remain unclear. Methods The current study investigated the effects of irisin treatment on the behavioral characteristics of mice with post‐stroke cognitive impairment (PSCI). The expression levels of platelet endothelial cell adhesion molecule 1 (PECAM, PECAM‐1, CD31), glial fibrillary acidic protein (GFAP), vascular endothelial growth factor (VEGF), and molecules in the adenosine 5‐monophosphate (AMP)‐activated protein kinase (AMPK)–endothelial nitric oxide synthase (eNOS) signaling cascade in the hippocampus were then measured. Results Irisin significantly enhances learning and memory functions in cases of PSCI. This improvement correlates with a reduction in cerebral infarction size and decreased neuronal death. Additionally, irisin treatment resulted in a marked decrease in the levels of astrocytic scar formation in the cortex. Furthermore, irisin activates the AMPK‐eNOS signaling pathway, which promotes the expression of VEGF. The irisin compounds are involved in the process of brain angiogenesis and play a critical role in endothelial and reactive astrocytes function. Conclusion The study revealed a potential mechanism by which exercise‐induced irisin secretion may attenuate PSCI. Irisin improved endothelial dysfunction and neuroinflammation, suggesting it may be a promising target for PSCI therapy. Irisin/FNDC5 is a crucial regulator of the cognitive benefits of exercise in post‐stroke cognitive impairment. The following schematic diagram shows that increasing the irisin/FNDC5 level can activate the AMPK‐eNOS pathway, promoting lower infraction volume and learning and memory cognitive functions.

Background Due to the high morbidity and poor clinical outcomes, early predictive and prognostic biomarker identification is desiderated in colorectal cancer (CRC). As a homologue of the Deleted in Colorectal Cancer (DCC) gene, the role of Neogenin-1 (NEO1) in CRC remained unveiled. This study was designed to probe into the effects and potential function of NEO1 in CRC. Methods Online databases, Gene Set Enrichment Analysis (GSEA), quantitative real-time PCR and western blotting were used to evaluate NEO1 expression in colorectal cancer tissues. Survival analysis was performed to predict the prognosis of CRC patients based on NEO1 expression level. Then, cell proliferation was detected by colony formation and Cell Counting Kit 8 (CCK-8) assays. CRC cell migration and invasion were examined by transwell assays. Finally, we utilized the Gene Set Variation Analysis (GSVA) and GSEA to dig the potential mechanisms of NEO1 in CRC. Results Oncomine database and The Cancer Genome Atlas (TCGA) database showed that NEO1 was down-regulated in CRC. Further results validated that NEO1 mRNA and protein expression were both significantly lower in CRC tumor tissues than in the adjacent tissues in our clinical samples. NEO1 expression was decreased with the progression of CRC. Survival and other clinical characteristic analyses exhibited that low NEO1 expression was related with poor prognosis. A gain-of-function study showed that overexpression of NEO1 restrained proliferation, migration and invasion of CRC cells while a loss-of-function showed the opposite effects. Finally, functional pathway enrichment analysis revealed that NEO1 low expression samples were enriched in inflammation-related signaling pathways, EMT and angiogenesis. Conclusion A tumor suppressor gene NEO1 was identified and verified to be correlated with the prognosis and progression of CRC, which could serve as a prognostic biomarker for CRC patients.

Background Transposable elements (TEs) are common and often present with high copy numbers in cellular genomes. Unlike in cellular organisms, TEs were previously thought to be either rare or absent in viruses. Almost all reported TEs display only one or two copies per viral genome. In addition, the discovery of pandoraviruses with genomes up to 2.5-Mb emphasizes the need for biologists to rethink the fundamental nature of the relationship between viruses and cellular life. Results Herein, we performed the first comprehensive analysis of miniature inverted-repeat transposable elements (MITEs) in the 5170 viral genomes for which sequences are currently available. Four hundred and fifty one copies of ten miniature inverted-repeat transposable elements (MITEs) were found and each MITE had reached relatively large copy numbers (some up to 90) in viruses. Eight MITEs belonging to two DNA superfamilies ( hobo/Activator/Tam3 and Chapaev–Mirage–CACTA ) were for the first time identified in viruses, further expanding the organismal range of these two superfamilies. TEs may play important roles in shaping the evolution of pandoravirus genomes, which were here found to be very rich in MITEs. We also show that putative autonomous partners of seven MITEs are present in the genomes of viral hosts, suggesting that viruses may borrow the transpositional machinery of their cellular hosts’ autonomous elements to spread MITEs and colonize their own genomes. The presence of seven similar MITEs in viral hosts, suggesting horizontal transfers (HTs) as the major mechanism for MITEs propagation. Conclusions Our discovery highlights that TEs contribute to shape genome evolution of pandoraviruses. We concluded that as for cellular organisms, TEs are part of the pandoraviruses’ diverse mobilome.