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Cisplatin has strong broad-spectrum anticancer activity and is one of the most effective anticancer drugs currently used. The clinical application of cisplatin has led to the resistance of cancer cells to cisplatin. Tachyplesin is an active, natural marine peptide with antitumour activity. In the present study, we investigated whether tachyplesin can be used in non-small cell lung cancer (NSCLC) A549 and H460 cells as well as the cisplatin-resistant human A549/DDP NSCLC cell line. The results revealed that tachyplesin treatment significantly inhibited proliferation and induced apoptosis in A549 and H460 cells and the combination of tachyplesin and cisplatin significantly suppressed migration and improved sensitivity to cisplatin in A549/DDP cells. Further mechanistic examination revealed that tachyplesin induced apoptosis in A549/DDP cells by increasing Fas, FasL and p-RIPK1 levels. These results indicated that tachyplesin induces lung cancer death by activating the Fas, mitochondrial and necroptosis pathways. Tachyplesin could be developed as a candidate drug for cisplatin-resistant NSCLC., (© 2020 John Wiley & Sons A/S.)

Introduction: Malignant gliomas are the most common and deadly primary brain tumors in adults. Increasing evidence has indicated that microRNAs (miRNAs) have an influence on the regulation of apoptotic cell signaling. Downregulation of miRNA 218 (miR-218) has been indicated in human glioma specimens. Here, we investigate the function of miR-218 in apoptosis and tumor growth of glioma cells., Methods: The expression of miR-218 was detected by real-time quantitative reverse transcriptase PCR. The effects of miR-218 on glioma cell proliferation and tumorigenicity were investigated by in vitro clonogenicity and in vivo xenograft assay. Apoptosis was evaluated by flow cytometric analysis and assay by terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling. The downstream targets of miR-218 were identified by bioinformatics analysis and further validated by Western blot and luciferase reporter assay., Results: Overexpression of miR-218 induces glioma cell apoptosis and inhibits glioma cell viability, proliferation, and tumorigenicity. Epidermal growth factor receptor-coamplified and overexpressed protein (ECOP) was identified as a functional downstream target of miR-218, which can regulate transcriptional activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and associated with apoptotic response. Ectopic expression of ECOP rescued the glioma cells from miR-218-induced apoptosis and increased NF-κB activity., Conclusion: These results suggest that miR-218 sensitizes glioma cells to apoptosis by regulating ECOP-mediated suppression of NF-κB activity, which may provide novel opportunities for glioma therapy.

Apoptosis occurs by distinct pathways that involve the cell surface, mitochondria or the endoplasmic reticulum. Previous studies had shown that deoxyadenosine-resistant L1210 cells (Y8) proceeded to apoptosis under conditions in which the parental L1210 cell line (WT) did not undergo an apoptotic response. Combinations of drugs, acting at different molecular targets, markedly potentiated the apoptotic response in the Y8 cells without inducing apoptosis in the WT cells. In the present study, induction of apoptosis by parthenolide and BAY 11-7085, drugs that targeted nuclear factor kappa B activation, was blocked by the presence of N-acetylcysteine (NAC). On the other hand, the levels of apoptosis induced by parthenolide or BAY 11-7085 were increased by pre-treatment of the cells with glutathione lowering L-buthionine-(S,R)-sulfoximine (BSO). Western blot analyses showed that the levels of the stress proteins, Grp 78 and Gadd 153 were reduced in the parthenolide-treated Y8 cells, but not in those co-treated with NAC. Protection of the cells from apoptosis induced by parthenolide or BAY 11-7085 by NAC was relatively specific as the induction of apoptosis in the Y8 cells by MG-132, flavopiridol, Gemcitabine or PRIMA-1 was not decreased by NAC. These data suggest that multiple pathways, one of which is ER-stress induced, may ultimately be involved and interactive in the induction of apoptosis in specific cell lines.

Intervertebral disc degeneration (IDD) is a chronic progressive condition mainly caused by excessive inflammatory cytokines. Berberine (BBR) exerts anti-inflammatory effect on diseases and protective effect against IDD. However, the mechanism is not uncertain. This study is aimed at investigating the molecular mechanism of BBR on IDD. Nucleus pulposus (NP) cells were treated with BBR at different concentrations. The IDD rat model was established by acupuncture. The effect of BBR on interleukin- (IL-) 1β-induced cell proliferation was measured by CCK-8 assay and BrdU staining. The role of BBR in IL-1β-induced apoptosis, autophagy repression, and extracellular matrix (ECM) degradation was measured by Annexin/PI staining, immunofluorescence, and immunoblot. The effect of BBR on IDD was investigated in rat. Our findings showed that BBR restored cell growth and attenuated apoptosis in IL-1β-induced NP cells. BBR also prevented the IL-1β-induced ECM degradation through regulating ECM-related enzymes and factors. Additionally, BBR significantly activated autophagy repressed by IL-1β. Autophagy stimulated by BBR was diminished by the inhibition of the AMPK/mTOR/Ulk1 signaling pathway. In vivo study also showed BBR attenuated intervertebral disc degeneration. BBR could attenuate NP cells apoptosis and ECM degradation induced by IL-1β through autophagy by the AMPK/mTOR/Ulk1 pathway. This study suggests BBR might function as an AMPK activator to alleviate IDD progression. [ABSTRACT FROM AUTHOR]

Sepsis-induced acute lung injury (ALI) is associated with considerable morbidity and mortality in critically ill patients. S100A9, a key endothelial injury factor, is markedly upregulated in sepsis-induced ALI; however, its specific mechanism of action has not been fully elucidated. The Gene Expression Omnibus database transcriptome data for sepsis-induced ALI were used to screen for key differentially expressed genes (DEGs). Using bioinformatics analysis methods such as Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and protein-protein interaction network analyses, the pathogenesis of sepsis-induced ALI was revealed. Intratracheal infusion of lipopolysaccharide (LPS, 10 mg/kg) induced ALI in wild-type (WT) and S100A9 knockout mice. Multiomics analyses (transcriptomics and proteomics) were performed to investigate the potential mechanisms by which S100A9 exacerbates acute lung damage. Hematoxylin-eosin, Giemsa, and TUNEL staining were used to evaluate lung injury and cell apoptosis. LPS (10 μg/mL)-induced murine lung epithelial MLE-12 cells were utilized to mimic ALI and were modulated by S100A9 lentiviral transfection. The impact of S100A9 on cell apoptosis and inflammatory responses were identified using flow cytometry and PCR. The expression of interleukin (IL)-17–nuclear factor kappa B (NFκB)–caspase-3 signaling components was identified using western blotting. Six common DEGs (S100A9, S100A8, IFITM6, SAA3, CD177, and MMP9) were identified in the six datasets related to ALI in sepsis. Compared to WT sepsis mice, S100A9 knockout significantly alleviated LPS-induced ALI in mice, with reduced lung structural damage and inflammatory exudation, decreased exfoliated cell and protein content in the lung lavage fluid, and reduced apoptosis and necrosis of pulmonary epithelial cells. Transcriptomic analysis revealed that knocking out S100A9 significantly affected 123 DEGs, which were enriched in immune responses, defense responses against bacteria or lipopolysaccharides, cytokine-cytokine receptor interactions, and the IL-17 signaling pathway. Proteomic analysis revealed that S100A9 knockout alleviated muscle contraction dysfunction and structural remodeling in sepsis-induced ALI. Multiomics analysis revealed that S100A9 may be closely related to interferon-induced proteins with tetratricopeptide repeats and oligoadenylate synthase-like proteins. LPS decreased MLE12 cell activity, accompanied by high expression of S100A9. The expression of IL-17RA, pNFκB, and cleaved-caspase-3 were increased by S100A9 overexpression and reduced by S100A9 knockdown in LPS-stimulated MLE12 cells. S100A9 knockdown decreases transcription of apoptosis-related markers Bax, Bcl and caspase-3, alleviating LPS-induced apoptosis. S100A9 as a key biomarker of sepsis-induced acute lung injury, and exacerbates lung damage and epithelial cell apoptosis induced by LPS via the IL-17–NFκB–caspase-3 signaling pathway. • Six genes were excessively expressed in sepsis-induced acute lung injury, including S100A9, S100A8, IFITM6, SAA3, CD177, and MMP9. • Both bioinformatics analysis of GEO datasets, Transcriptomic and proteomic analysis of lung injury data all suggest the key role of S100A9 in sepsis induced ALI. • Knocking out S100A9 significantly alleviates lung injury in septic mice, characterized by reduced structural damage and inflammatory exudation, decreased content of exfoliated cells and proteins in BALF, and reduced apoptosis of pulmonary epithelial cells. [ABSTRACT FROM AUTHOR]

Retinoids, natural and synthetic derivatives of vitamin A, induce cellular changes by activating nuclear retinoic acid receptors ( RAR) and retinoid X receptors ( RXR). Although the ability of retinoids to govern gene expression is exploited clinically for cancer therapeutics, the full benefit of retinoid-based strategies is unrealized due to detrimental side effects. Delineating the receptors that prompt cellular outcomes is critical to advancing retinoid-based approaches. Here, we identify the receptors that evoke multiple responses in cutaneous T-cell lymphoma ( CTCL). The data demonstrate that RARα drives integrin β7-dependent adhesion and CCR9-mediated chemotaxis in CTCL cells. Of note, concomitant activation of RARα and RXR nuclear receptors yielded synergistic increases in adhesion and migration at concentrations where single agents were ineffective. As the established paradigm of retinoid action in CTCL is apoptosis and growth arrest, the role of RARα/ RXR in these events was studied. As with adhesion and migration, RARα/ RXR synergism prompted apoptosis and dampened CTCL cell proliferation. Strikingly, RARα/ RXR synergism induced responses from CTCL cell lines previously reported to be unresponsive to retinoids. These data provide a novel framework that may further refine a proven CTCL therapy. [ABSTRACT FROM AUTHOR]

The paired box 6 (Pax6) gene encodes a transcription factor essential for eye development in a wide range of animal lineages. Here we describe the cloning and characterization of Pax6 gene from the blind hydrothermal vent tubeworm Ridgeia piscesae (RpPax6). The deduced RpPax6 protein shares extensive sequence identity with Pax6 proteins from other species and contains both the paired domain and a complete homeodomain. Phylogenetic analysis indicates that it clusters with the corresponding sequence from the closely related species Platynereis dumerilii (P. dumerilii) of Annelida. Luciferase reporter assay indicate that RpPax6 protein suppresses the transcription of sine oculis (so) in D. melanogaster, interfering with the C-terminal of RpPax6. Taking advantage of Drosophila model, we show that RpPax6 expression is not able to rescue small eye phenotype of ey2 mutant, only to cause a more severe headless phenotype. In addition, RpPax6 expression induced apoptosis and inhibition of apoptosis can partially rescue RpPax6-induced headless phenotype. We provide evidence RpPax6 plays at least two roles: it blocks the expression of later-acting transcription factors in the eye development cascade, and it promotes cell apoptosis. Our results indicate alternation of the Pax6 function may be one of the possible causes that lead the eye absence in vestimentiferan tubeworms. [ABSTRACT FROM AUTHOR]

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of malignancies characterized by accumulation of malignant T-cells within the skin. Retinoids, metabolic derivatives, and synthetic analogs of vitamin A embody an effective CTCL therapy with over three decades of clinical use. The established mechanism of action is induction of growth arrest and apoptosis. However, the natural role of retinoids in T-cell biology is imprinting gut-homing properties by inducing integrin α4β7 expression. How the natural role of retinoids relates to therapeutic effectiveness in CTCL has not been addressed and merits investigation. Here we provide evidence that retinoids, including Bexarotene, selectively induce CTCL lineages to increase integrin β7 expression and function prior to growth arrest and apoptosis. Interestingly, augmented CTCL cell adhesion obtained with retinoid exposure was potently attenuated by 1,25-dihydroxyvitamin D3, a metabolic vitamin derivative involved in prompting immune cell skin homing. The integrin-dependent adhesion changes in CTCL cells occurred through synergistic activation of RAR and RXR nuclear receptors. These data explore the early cellular changes induced by retinoids that may be pivotal to sensitizing CTCL cells to growth arrest and apoptosis. [ABSTRACT FROM AUTHOR]

Abstract: This paper reports synthesis and photobiological properties of a novel chlorin photosensitizer BCPD-18MA. Cytotoxicity, cellular uptake, subcellular location, biodistribution, photodynamic therapy (PDT) efficiency, cell apoptosis as well as histological analysis of the liposomal-delivered BCPD-18MA (L-BCPD-18MA) was studied using mammary adenocarcinoma MDA-MB-231 cells and Lewis lung carcinoma (LLC) implanted in C57BL/6 mice as experimental models. The results showed that L-BCPD-18 was incorporated rapidly into MDA-MB-231 cells and localized partially in mitochondria. L-BCPD-18 induced cell apoptosis by PDT. In addition, biodistribution of L-BCPD-18MA in LLC-bearing mice demonstrated a fast clearance rate of the drug and good skin-related tumor selectivity. Finally, entrapment of BCPD-18 into liposomes resulted in a dramatic impairment of dark toxicity and a notable improvement of PDT antitumor efficacy in vitro. Compared with liposomal-delivered BPDMA (L-BPDMA), L-BCPD-18MA exhibited low dark toxicity and high PDT efficiency on MDA-MB-231 cells. The photodynamic efficacy of L-BCPD-18MA on LLC-bearing mice is comparable to that of L-BPDMA, implying that L-BCPD-18MA is a potential antitumor candidate for PDT. [Copyright &y& Elsevier]

Following genotoxic stress, transcriptional activation of target genes by p53 tumor suppressor is critical in cell fate determination. Here we report that the restoration of p53 function in human cancer cell lines that are deficient in p53 function upregulated the expression of Notch1. Interestingly, the expression of wild-type p53 in human prostate and breast cancer cell lines correlated well with increased expression of Notch1. Furthermore, knockdown of p53 expression in cancer cells that express wild-type p53 resulted in reduced expression of Notch1. Importantly, genotoxic stress to cancer cells that resulted in activation of p53 also upregulated the expression of Notch1. Moreover, p53-mediated induction of Notch1 expression was associated with stimulation of the activity of Notch-responsive reporters. Notably, p53 differentially regulated the expression of Notch family members: expression of Notch2 and Notch4 was not induced by p53. Significantly, treatment of cells with gamma secretase inhibitor, an inhibitor of Notch signaling, increased susceptibility to apoptosis in response to genotoxic stress. Together, our observations suggest that p53-mediated upregulation of Notch1 expression in human cancer cell lines contributes to cell fate determination after genotoxic stress. Neoplasia (2007) 9, 427-434. [ABSTRACT FROM AUTHOR]