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Garcinia indica (Kokum) and Ilex aquifolium (European Holly)
Published in Azamal Husen, Herbs, Shrubs, and Trees of Potential Medicinal Benefits, 2022
Dicson Sheeja Malar, Mani Iyer Prasanth, Tewin Tencomnao, James Michael Brimson, Anchalee Prasansuklab
Garcinol exhibited morphological changes and inhibited the proliferation of human non-small cell lung carcinoma (NSCLC) cells. Garcinol induced G1 cell cycle arrest was mediated through the upregulation of CDK inhibitors p21Waf1/Cip1 and p27KIP1. Moreover, cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase 4 (CDK4), cyclin D1, and cyclin D3 were decreased, whereas cyclin E and cyclin-dependent kinase 6 (CDK6) were increased along with inhibition of ERK and p38-MAPK (Yu et al., 2014). In A549 cells, garcinol enriched DNA damage-inducible transcript 3 (DDIT3), altered DDIT3-CCAAT-enhancer-binding proteins beta (C/EBPβ) interaction resulting in the attenuation of the prognostic cancer cell marker Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1) expression (Wang et al., 2017a). In addition, garcinol significantly diminished the ability of the NSCLC cells to form spheres and form colonies, by impairing phosphorylation of LRP6, a co-receptor of Wnt and STAT3, downregulating β-catenin, Dvl2, Axin2, and cyclin D1 expressions, suggesting its ability to regulate the Wnt/β-catenin signaling pathway (Huang et al., 2018). Garcinol induced the sensitivity of A549 cells toward TRAIL and induced apoptosis mediated through upregulation of DR5 and downregulation c-FLIP (Kim et al., 2018).
Toxic Effects and Biodistribution of Ultrasmall Gold Nanoparticles *
Published in Valerio Voliani, Nanomaterials and Neoplasms, 2021
Gunter Schmid, Wolfgang G. Kreyling, Ulrich Simon
Following the initial growth response, heat shock and stress-related genes were upregulated after 6 h and strongly upregulated after 12 h in Au1.4MS-treated but not in Au15MS-treated or untreated HeLa cells. This group of genes (HSPA1A, DNAJA4, CHAC1, HSPA1A, DDIT3, GEM, LOC387763, PGF, HSPA6, SESN2, LOC284561, PPP1R15A, HMOX1, C16orf81, LOC344887, NGF, OSGIN1, FOSL1, CXCL2, IL8) suggested that a robust stress response had occurred in the Au1.4MS-treated cells. Highly elevated expression of heat shock proteins has been demonstrated to inhibit apoptosis at several stages including blocking of cytochrome c release from mitochondria, thus preventing the formation of an apoptosome and the activation of caspase-3, ultimately forcing cells into necrosis instead of apoptosis.
Regulation of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Jiang et al. (2013) have developed a novel mediation analysis approach to identify new expression quantitative trait loci (eQTLs) driving CYP2D6 activity by combining genotype, gene expression, and enzyme activity data. The authors have found 389,573 and 1,214,416 SNP–transcript–CYP2D6 activity trios that are strongly associated for two different genotype platforms, namely, Affymetrix and Illumina, respectively. In the Affymetrix data set, 295 SNPs correlate with at least 20 genes, which are used to check for overlapping with the results of mediation analysis. A total of 289 eQTL hotspots are found to correlate with 1542 gene expression profiles. The Illumina data set has found that 724 SNPs correlate with at least 20 genes, and 719 of the hotspots are significantly correlated with 2444 genes in mediation analysis. Nine hundred thirty-nine and 1420 genes are successfully mapped in the Ingenuity database for two platforms. The majority of eQTLs are trans-SNPs. Five (CCL16, CCL20, CMTM5, IL-6, and SPP1) and 7 (CCL16, CCL20, CKLF, CKLFSF5, EPO, FAM3C, and SPP1) cytokines, 5 (AR, NR1I2/PXR, NR1I3/CAR, NR2F6, and PPARα) and 7 (AR, ESR1, NR1I2/PXR, NR1I3/CAR, PPARα, RORα/NR1F1, and RORγ) nuclear receptors, and 80 and 113 transcription regulators are found to mediate the relationship between genetic variant and CYP2D6 activity for Affymetrix and Illumina data sets. Overlapped eQTL hotspots with the mediators lead to the identification of 64 transcription factors that can regulate CYP2D6 (Jiang et al. 2013). These transcription factors include AATF, ALYREF, ARHGAP35, ASB8, ATF4, CBX4, CEBPG, CSDA, DDIT3, E2F5, ETV7, FOXN3, FOXN3, FUBP1, GPS2, HDAC10, HMGN1, ID1, INVS, IRF9, KANK1, KAT2B, KHDRBS1, KLF12, MAF, MAML2, MEIS2, MLXIPL, MXD4, MYBBP1A, MYCL1, NCOA7, NCOR1, NFIA, NFKB2, NFYA, NOLC1, NPM1, PEX14, PYCARD, SAP18, SATB1, SIM2, SLC2A4RG, SMARCC1, SNAI3, SNW1, SOX5, TCERG1, TCF7L2, TEAD3, TEAD4, TFDP2, TFEB, TOB1, p53, YWHAB, YY1, ZGPAT, ZHX3, ZKSCAN1, ZNF132, ZNF256, and ZNF263 (Jiang et al. 2013). Among them, YY1 has been reported to putatively bind to human CYP2D6 or rat Cyp2d4 promoter and regulate the expression of CYP2D6 (Gong et al. 2013) and Cyp2d4 (Mizuno et al. 2003). This study has provided new insights into the complex regulatory network for hepatic CYP2D6. Addition of the p53 inhibitor cyclic PFT-α in HepG2 cells dose-dependently enhances CYP2D6 and 3A4 activity, whereas addition of the p53 activator NSC 66811 dose-dependently inhibits CYP2D6 and 3A4 activity (Xiao et al. 2015). Further functional and validation studies are certainly needed to verify the regulation of CYP2D6 by these genes.
The endoplasmic reticulum chaperone BiP: a target for immunogenic cell death inducers?
Published in OncoImmunology, 2022
Oliver Kepp, Lucillia Bezu, Guido Kroemer
The unfolded protein response (UPR) is a type of ER stress that is activated in response to the accumulation of unfolded or misfolded proteins in the ER lumen. In this context, the ER chaperone heat shock protein family A member 5 (HSPA5, better known as binding immunoglobulin protein, BiP) acts as an ER stress sensor. Misfolded proteins present in the ER lumen interact with BiP, thus causing its dissociation from several effectors of the UPR: ER to nucleus signaling 1 (ERN, best known as IRE1α), eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3, best known as PERK) and activating transcription factor 6 (ATF6). This then triggers the alternative splicing of X-box binding protein 1 (XBP1) mRNA by IRE1α, the phosphorylation of eukaryotic initiation factor a (eIF2α) by PERK (with downstream expression of ATF4), and the nuclear translocation of ATF6. ATF4, ATF6 and the short form of XBP1 (XBP1s) act as transcription factors that, in combination with the phospho-eIF2α-mediated suppression of cap-dependent protein translation, activate a transcriptional and translational response altering the cellular proteome for homeostatic adaptation and cellular survival4,5 (Figure 1a). Of note, in the case of failure of the adaptive responses, the prolongation of ER stress in time results in the transactivation of DNA damage inducible transcript 3 (DDIT3, better known as C/EBP homologous protein, CHOP), thus leading to the induction of apoptotic cell death.6
High variability in toxicity of welding fume nanoparticles from stainless steel in lung cells and reporter cell lines: the role of particle reactivity and solubility
Published in Nanotoxicology, 2019
Sarah McCarrick, Zheng Wei, Nynke Moelijker, Remco Derr, Kjell-Arne Persson, Giel Hendriks, Inger Odnevall Wallinder, Yolanda Hedberg, Hanna L. Karlsson
The results from the reporter cell activation are clearly in line with the data from the lung cells suggesting genotoxicity caused by the welding fume particles generated using FCWs tested in this study (F3) but not when using solid wires (S1). The reporter cells are considered activated when the fluorescence is at least doubled when compared to non-exposed cells. For the F3 particles, a clear induction was observed for one of the oxidative stress reporters (Srxn1 reporter) where, interestingly, the Rtkn reporter related to DNA double-strand breaks was activated already at an exposure dose of 3.1µg/mL. No effect was observed for the DNA damage reporter related to the formation of bulky DNA adducts and subsequent inhibition of DNA replication (Bscl2 reporter). The F3 particles also caused an induction of pathways related to p53-signaling (Btg2 reporter), indicating general stress, whereas the reporter for protein unfolding (Ddit3) was not activated.
IFN-γ-induced ER stress impairs autophagy and triggers apoptosis in lung cancer cells
Published in OncoImmunology, 2021
Can Fang, Tao Weng, Shaojie Hu, Zhiwei Yuan, Hui Xiong, Bing Huang, Yixin Cai, Lequn Li, Xiangning Fu
To further confirm the effect of IFN-γ on ER conditions, we cultured human-derived lung adenocarcinoma cells from seven patients ex vivo. We found that IFN-γ induced DDIT3 transcription in four out of seven tumor specimens (Figure S1d). Upregulation of ATF-4 expression was also observed (Figure S1e). The data reflect heterogeneity in tumors in response to IFN-γ treatment. Our data show that IFN-γ can induce UPR in some of the human adenocarcinomas.