LINC00665 target let-7i/HMGA1 promotes the proliferation and invasion of hepatoma cells.

OBJECTIVES: Our group previously found that LINC00665 was upregulated in hepatocellular carcinoma (HCC) tissues through database analysis; however, the potential molecular mechanism of LINC00665 in HCC progression still needs further study. METHODS: qRTPCR was performed to determine the differential expression of LINC00665 and let-7i in HCC cells. Dual-luciferase reporter assays were performed to analyze the interaction of LINC00665 and let-7i. CCK-8 assays, scratch assays, Transwell invasion assays, qRTPCR and western blotting were performed to determine the regulatory mechanism of LINC00665/let-7i/HMGA1 in HCC cells. RESULTS: LINC00665 was upregulated in HCC cells compared with normal hepatocytes. A potential binding site between LINC00665 and let-7i was confirmed by dual-luciferase reporter assay. In HCC cells, inhibition of LINC00665 significantly reduced cell proliferation, migration and invasion ability via the let-7i/HMGA1 signaling axis. CONCLUSION: LINC00665 promotes the proliferation and invasion of HCC cells via the let-7i/HMGA1 signaling axis.

Therapeutic Effects of Human Pluripotent Stem Cell-Derived Mesenchymal Stem Cells on a Murine Model of Acute Type-2-Dominated Airway Inflammation.

Allergic rhinitis and allergic asthma are the most common type-2 inflammatory diseases, which are hardly curable and cause heavy burden to general well-being. Mesenchymal stem cells (MSCs) are multipotent nonhematopoietic cells with potential immunomodulatory effects that have been showning to have a therapeutic effect on allergic diseases. Here, we investigated the effects of human induced pluripotent stem cell (iPSC)-derived MSCs on airway hyperresponsiveness and acute type-2-dominated inflammation throughout the upper and lower airways. In this study, human MSCs, MSC cell culture supernatant, and culture medium (control) was injected into the acute airway inflammatory model via the tail vein. Mouse behavioristics were recorded immediately and mouse lung function was measured 24 hours after the last ovalbumin (OVA) challenge. Histological staining, Luminex, Elisa and flow cytometry were employed to evaluate the effects on the production of total/OVA-specific IgG1 and IgE, cytokines expression in lung tissues, and inflammatory cells infiltration in the lung and spleen of the experimental mice. Expressions of eotaxin, IL-4, IL-5, IL-13, IL-33 in nasal and lung lavage were evaluated by Luminex and Elisa. We found that for this acute inflammatory mouse model, human MSC transplantation significantly mitigated the decreased motoring time and the increased lung function Rrs caused by OVA challenge. Serum OVA-IgG1, OVA-IgE, and eosinophil percentages in the splenocytes were significantly decreased. Injection of the MSC supernatant also showed the same trend, but not significantly changed. After treatment, IL-4 and IL-13 were significantly decreased in the lung tissue, and IL-5 and IL-13 were significantly decreased in lung lavage. In conclusion, both human MSC culture supernatant and cell transplantation could alleviate AHR and inflammation in acute inflammatory experimental animals, which demonstrated their potential for clinical therapeutics. Human iPSC-MSCs, MSC cell culture supernatant, or culture medium (control) was injected into the OVA-induced acute airway inflammatory model via the tail vein. Behavioral changes, AHR, serum OVA-specific IgG1 and IgE concentrations, and type-2 inflammations were alleviated.

Tumor necrosis factor receptor-associated protein 1 regulates hypoxia-induced apoptosis through a mitochondria-dependent pathway mediated by cytochrome c oxidase subunit II.

BACKGROUND: Tumor necrosis factor receptor-associated protein 1 (TRAP1) plays a protective effect in hypoxic cardiomyocytes, but the precise mechanisms are not well clarified. The study is aimed to identify the mechanism of TRAP1 on hypoxic damage in cardiomyocytes. METHODS: In this study, the effects of TRAP1 and cytochrome c oxidase subunit II (COXII) on apoptosis in hypoxia-induced cardiomyocytes were explored using overexpression and knockdown methods separately. RESULTS: Hypoxia induced cardiomyocyte apoptosis, and TRAP1 overexpression notably inhibited apoptosis induced by hypoxia. Conversely, TRAP1 silencing promoted apoptosis in hypoxic cardiomyocytes. Further investigation revealed that the proapoptotic effects caused by the silencing of TRAP1 were prevented by COXII overexpression, whereas COXII knockdown reduced the antiapoptotic function induced by TRAP1 overexpression. Additionally, changes in the release of cytochrome c from mitochondria into the cytosol and the caspase-3 activity in the cytoplasm, as well as reactive oxygen species production, were found to be correlated with the changes in apoptosis. CONCLUSIONS: The current study uncovered that TRAP1 regulates hypoxia-induced cardiomyocyte apoptosis through a mitochondria-dependent apoptotic pathway mediated by COXII, in which reactive oxygen species presents as an important component.

Two New Chromone Glycosides from the Roots of Saposhnikovia divaricata.

Five chromone glycosides were isolated from the water-soluble portions of 70% EtOH extract of the roots of Saposhnikovia divaricata, including two new chromone glycosides 1 and 2. The structures of the chromone glycosides were identified as (3'S)-3'-O-ß-d-apiofuranosyl-(1 → 6)-ß-d-glucopyranosylhamaudol (1), (2'S)-4'-O-ß-d-apiofuranosyl-(1 → 6)-ß-d-glucopyranosylvisamminol (2), 3'-O-glucopyranosylhamaudol (3), 4'-O-ß-d-glucopyranosylvisamminol (4), and 4'-O-ß-d-glucopyranosyl-5-O-methylvisamminol (5) on the basis of extensive spectroscopic methods, and the absolute configurations of the new compounds were elucidated by the electronic circular dichroism (ECD) calculation and acid hydrolysis. The cytotoxic activities of the glycosides 1 - 5 against three human cancer cell lines (PC-3, SK-OV-3, and H460) were evaluated. The result showed that compounds 1 - 5 had weak cytotoxic activities against the human cancer cell lines with IC50 values in the range of 48.54 ± 0.80 - 94.25 ± 1.45 µm.

Cytotoxic Triterpenoids from Roots of Actinidia chinensis.

Phytochmical investigation of roots of Actinidia chinensisPlanch. led to the isolation triterpenoids 1 - 16, including a new compound 2α,3α,23,24-tetrahydroxyursa-12,20(30)-dien-28-oic acid (1). Their structures were identified on the basis of spectroscopic analysis, including 1D- and 2D-NMR, HR-ESI mass spectrometry, and by comparison with the literatures. The cytotoxicities of triterpenoids 1 - 16 against a panel of cultured human cancer cell lines (HepG2, A549, MCF-7, SK-OV-3, and HeLa) were evaluated. The new compound 1 exhibited moderate antitumor activities with IC50 values of 19.62 ± 0.81, 18.86 ± 1.56, 45.94 ± 3.62, 62.41 ± 2.29, and 28.74 ± 1.07 µm, respectively. The experiment data might be available to explain the use of roots of A. chinensis to treat various cancers in traditional Chinese medicine.

[Chemical constituents from roots of Actinidia rufa and their cytotoxicity].

To investigate the chemical compounds from the roots of Actinidia rufa, nine compounds were isolated by various column chromatography on silica gel and Sephadex LH-20, and high performance liquid chromatography (HPLC). Their structures were elucidated as 2α, 3ß, 19α, 23, 24-pentahydroxyurs-12-en-28-oic acid-28-O-ß-D-glucopyranoside (1), 2α, 3α, 19α, 24-tetrahydroxyurs-12-en-28-oic acid-28-O-ß-D-glucopyranoside (2), 2α, 3α, 24-trihydroxyurs-12-en-28-oic acid (3), 2α, 3α, 24-trihydroxyolean-12-en-28-oic acid (4), 2α, 3α, 23, 24-tetrahydroxyurs -12-en-28-oic acid (5), 2α, 3ß, 23, 24-tetrah-ydroxyurs-12-en-28-oic acid (6), 2α, 3ß, 23-trihydroxy-12-en-28-oic acid (7), 2α, 3ß, 23-trihydroxyurs-12, 20(30)-dien-28-oic acid (8), and 2α, 3α, 23-trihydroxyurs-12, 20(30)-dien-28-oic acid (9). Compounds 1 and 2 were isolated from the Actinidia genus for the first time. Compounds 2, 3, and 4 showed cytotoxic activity against human SKVO3 and TPC-1 cancer cell lines with IC50 values ranging from 10.99 to 16.41 µmol•L⁻¹, compounds 3 and 4 have cytotoxic activity against human HeLa cancer cell line with IC50 values of 15.53 and 13.07 µmol•L⁻¹, respectively.

Tumor necrosis factor receptor-associated protein 1 improves hypoxia-impaired energy production in cardiomyocytes through increasing activity of cytochrome c oxidase subunit II.

Tumor necrosis factor receptor-associated protein 1 protects cardiomyocytes against hypoxia, but the underlying mechanisms are not completely understood. In the present study, we used gain- and loss-of-function approaches to explore the effects of tumor necrosis factor receptor-associated protein 1 and cytochrome c oxidase subunit II on energy production in hypoxic cardiomyocytes. Hypoxia repressed ATP production in cultured cardiomyocytes, whereas overexpression of tumor necrosis factor receptor-associated protein 1 significantly improved ATP production. Conversely, knockdown of tumor necrosis factor receptor-associated protein 1 facilitated the hypoxia-induced decrease in ATP synthesis. Further investigation revealed that tumor necrosis factor receptor-associated protein 1 induced the expression and activity of cytochrome c oxidase subunit II, a component of cytochrome c oxidase that is important in mitochondrial respiratory chain function. Moreover, lentiviral-mediated overexpression of cytochrome c oxidase subunit II antagonized the decrease in ATP synthesis caused by knockdown of tumor necrosis factor receptor-associated protein 1, whereas knockdown of cytochrome c oxidase subunit II attenuated the increase in ATP synthesis caused by overexpression of tumor necrosis factor receptor-associated protein 1. In addition, inhibition of cytochrome c oxidase subunit II by a specific inhibitor sodium azide suppressed the ATP sy nthesis induced by overexpressed tumor necrosis factor receptor-associated protein 1. Hence, tumor necrosis factor receptor-associated protein 1 protects cardiomyocytes from hypoxia at least partly via potentiation of energy generation, and cytochrome c oxidase subunit II is one of the downstream effectors that mediates the tumor necrosis factor receptor-associated protein 1-mediated energy generation program.