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HTLV-1 is an oncogenic human retrovirus and the etiologic agent of the highly aggressive ATL malignancy. Two viral genes, Tax and Hbz, are individually linked to oncogenic transformation and play an important role in the pathogenic process. Consequently, regulation of HTLV-1 gene expression is a central feature in the viral lifecycle and directly contributes to its pathogenic potential. Herein, we identified the cellular transcription factor YBX1 as a binding partner for HBZ. We found YBX1 activated transcription and enhanced Tax-mediated transcription from the viral 5′ LTR promoter. Interestingly, YBX1 also interacted with Tax. shRNA-mediated loss of YBX1 decreased transcript and protein abundance of both Tax and HBZ in HTLV-1-transformed T-cell lines, as well as Tax association with the 5′ LTR. Conversely, YBX1 transcriptional activation of the 5′ LTR promoter was increased in the absence of HBZ. YBX1 was found to be associated with both the 5′ and 3′ LTRs in HTLV-1-transformed and ATL-derived T-cell lines. Together, these data suggest that YBX1 positively influences transcription from both the 5′ and 3′ promoter elements. YBX1 is able to interact with Tax and help recruit Tax to the 5′ LTR. However, through interactions with HBZ, YBX1 transcriptional activation of the 5′ LTR is repressed. [ABSTRACT FROM AUTHOR]

In this study, electroactive poly (amic acid) (EPAA) and corresponding polyimide (EPI) without or with a sulfonated group (i.e., S-EPAA, and S-EPI) were prepared and applied in electrochemical sensing of ascorbic acid (AA). The electroactive polymers (EAPs) containing EPAA/EPI and S-EPAA/S-EPI were synthesized by using an amine-capped aniline trimer (ACAT) and sulfonated amine-capped aniline trimer (S-ACAT) as an electroactive segment that controlled the redox capability and influenced the degree of sensitivity of the EAPs towards AA. Characterization of the as-prepared EAPs was identified by FTIR spectra. The redox capability of the EAPs was investigated by electrochemical cyclic voltammetric studies. It should be noted that the redox capability of the EAPs was found to show the following trend: S-EPAA > S-EPI > EPAA > EPI. For the electrochemical sensing studies, a sensor constructed from an S-EPAA-modified carbon paste electrode (CPE) demonstrated 2-fold, 1.27-fold, and 1.35-fold higher electro-catalytic activity towards the oxidation of AA, compared to those constructed using a bare CPE, S-EPI-, and EPI/EPAA-modified CPE, respectively. The higher redox capability of S-EPAA-modified CPE exhibited a good electrochemical response towards AA at a low oxidative potential, with good stability and selectivity. Moreover, an electrochemical sensor constructed from S-EPAA-modified CPE was found to reveal better selectivity for a tertiary mixture of AA/DA/UA, as compared to that of EPI-modified, EPAA-modified and S-EPI-modified CPE, based on a series of differential pulse voltammograms. [ABSTRACT FROM AUTHOR]

Three new secoiridoid constituents, goncarin A−C (1–3), and a new derivative, goncarin A monoacetate (4), along with two known lignins, pinoresinol (5) and paulownin (6), were isolated from the seed of Gonocaryum calleryanum (Baill.) Becc. The structures of the new metabolites were determined on the basis of extensive spectroscopic analysis, particularly mass spectroscopy and 2D NMR (1H–1H COSY, HMQC, HMBC, and NOESY) spectroscopy. The aim of this study was to identify the anti-inflammatory effects of compounds 1–6 on lipopolysaccharide (LPS)-stimulated murine macrophage cell lines (RAW 264.7). Following stimulation with LPS, elevated levels of nitric oxide (NO) production were detected in RAW 264.7 cells; however, pretreatment with compounds 1–6 significantly inhibited the production of NO (around 40–80%, p < 0.01–0.05), by suppressing the expression of inducible NO synthase (iNOS). In addition, LPS-stimulated tumor necrosis factor-α (TNF-α) production was significantly reduced by compounds 1–3 (25–40%, p < 0.01–0.05). These results suggested that compounds 1–3 may exert anti-inflammatory activity, and that compounds 1–3 may be considered a potential therapeutic for the treatment of inflammatory diseases associated with macrophage activation. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is thought to be caused by amyloid-β (Aβ) accumulation in the central nervous system due to deficient clearance. The aim of the present study was to investigate the effect of ganoderic acid A (GAA) on Aβ clearance in microglia and its anti-AD activity. Aβ degradation in BV2 microglial cells was determined using an intracellular Aβ clearance assay. GAA stimulated autophagosome formation via the Axl receptor tyrosine kinase (Axl)/RAC/CDC42-activated kinase 1 (Pak1) pathway was determined by Western blot analyses, and fluorescence-labeled Aβ42 was localized in lysosomes in confocal laser microscopy images. The in vivo anti-AD activity of GAA was evaluated by object recognition and Morris water maze (MWM) tests in an AD mouse model following intracerebroventricular injection of aggregated Aβ42. The autophagy level in the hippocampus was assayed by immunohistochemical assessment against microtubule-associated proteins 1A/1B light-chain 3B (LC3B). Intracellular Aβ42 levels were significantly reduced by GAA treatment in microglial cells. Additionally, GAA activated autophagy according to increased LC3B-II levels, with this increased autophagy stimulated by upregulating Axl and Pak1 phosphorylation. The effect of eliminating Aβ by GAA through autophagy was reversed by R428, an Axl inhibitor, or IPA-3, a Pak1 inhibitor. Consistent with the cell-based assay, GAA ameliorated cognitive deficiency and reduced Aβ42 levels in an AD mouse model. Furthermore, LC3B expression in the hippocampus was up-regulated by GAA treatment, with these GAA-specific effects abolished by R428. GAA promoted Aβ clearance by enhancing autophagy via the Axl/Pak1 signaling pathway in microglial cells and ameliorated cognitive deficiency in an AD mouse model. [ABSTRACT FROM AUTHOR]

Simple Summary: Visfatin is an adipocytokine highly expressed in breast tumor tissues and circulation, and is positively associated with breast cancer progression and poorer clinical prognosis. In this study, we explored the role of adipocytokine in the breast tumor microenvironment with the focus on the interactions between visfatin and macrophages in breast cancer development by using in vitro, in vivo, and clinical studies. Visfatin promoted M2 differentiation in monocytic cells through ERK/CXCL1 induction and enhanced breast cancer cell viability, migration, tumorsphere formation, EMT, and stemness. Our study adds new insights to the growing body of evidence supporting the role of tumor-stromal interactions in breast cancer and also provides a potential therapeutic target. Visfatin, an adipocytokine highly expressed in breast tumor tissues, is associated with breast cancer progression. Recent studies showed that adipocytokines mediate tumor development through adipocytokine tumor-stromal interactions in the tumor microenvironment. This study focused on the interaction between one key stromal constituent—tumor-associated macrophages—and visfatin. Pretreatment of THP-1 and peripheral blood mononuclear cells (PBMCs) with recombinant visfatin resulted in M2-polarization determined by CD163 and CD206 expression. Indirect co-culture with visfatin-treated THP-1 (V-THP-1) promoted the viability, migration, tumorsphere formation, EMT, and stemness of breast cancer cells. Cytokine array identified an increased CXCL1 secretion in V-THP-1 conditioned medium and recombinant CXCL1 enhanced cell migration and invasion, which were abrogated by the CXCL1-neutralizing antibody. Additionally, visfatin induced pERK in THP-1 cells and clinical samples confirmed a positive CXCL1/pERK correlation. In an orthotopic mouse model, the tumor bioluminescent signal of luciferase-expressing MDA-MB-231 (Luc-MDA-MB-231) cells co-cultured with V-THP-1 and the expression of proliferation marker Ki67 were significantly higher than that co-cultured with THP-1. Furthermore, tail vein-injected Luc-MDA-MB-231 pretreated with V-PBMCs conditioned medium metastasized to lungs more frequently compared to control, and this was reversed by CXCL1 blocking antibody. In summary, this study demonstrated that visfatin enhanced breast cancer progression via pERK/CXCL1 induction in macrophages. [ABSTRACT FROM AUTHOR]

Presently, natural sources and herbs are being sought for the treatment of human oral squamous cell carcinoma (OSCC) in order to alleviate the side effects of chemotherapy. This study investigates the effect of sandensolide, a cembrane isolated from Sinularia flexibilis , to inhibit human OSCC cell growth with the aim of developing a new drug for the treatment of oral cancer. In vitro cultured human OSCC models (Ca9.22, SCC9 and HSC-3 cell lines) and oral normal cells (HGF-1), as well as a zebrafish xenograft model, were used to test the cytotoxicity of sandensolide (MTT assay), as well as to perform cell cycle analysis and Western blotting. Both the in vitro bioassay and the zebrafish xenograft model demonstrated the anti-oral cancer effect of sandensolide. Moreover, sandensolide was able to significantly suppress colony formation and induce apoptosis, as well as cell cycle arrest, in OSCC by regulating multiple key proteins. Induction of reactive oxygen species (ROS) was observed in sandensolide-treated oral cancer cells. However, these apoptotic changes were rescued by NAC pretreatment. These findings contribute to the knowledge of the model of action of sandensolide, which may induce oxidative stress-mediated cell death pathways as a potential agent in oral cancer therapeutics.

Three new secoiridoid constituents, goncarin A−C ( 1 ⁻ 3 ), and a new derivative, goncarin A monoacetate ( 4 ), along with two known lignins, pinoresinol ( 5 ) and paulownin ( 6 ), were isolated from the seed of Gonocaryum calleryanum (Baill.) Becc. The structures of the new metabolites were determined on the basis of extensive spectroscopic analysis, particularly mass spectroscopy and 2D NMR (¹H⁻¹H COSY, HMQC, HMBC, and NOESY) spectroscopy. The aim of this study was to identify the anti-inflammatory effects of compounds 1 ⁻ 6 on lipopolysaccharide (LPS)-stimulated murine macrophage cell lines (RAW 264.7). Following stimulation with LPS, elevated levels of nitric oxide (NO) production were detected in RAW 264.7 cells; however, pretreatment with compounds 1 ⁻ 6 significantly inhibited the production of NO (around 40⁻80%, p < 0.01⁻0.05), by suppressing the expression of inducible NO synthase (iNOS). In addition, LPS-stimulated tumor necrosis factor-α (TNF-α) production was significantly reduced by compounds 1 ⁻ 3 (25⁻40%, p < 0.01⁻0.05). These results suggested that compounds 1 ⁻ 3 may exert anti-inflammatory activity, and that compounds 1 ⁻ 3 may be considered a potential therapeutic for the treatment of inflammatory diseases associated with macrophage activation.