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The present study investigated the protective effects and mechanism of action of cyanidin-3-O-glucoside (C3G) and its major metabolite protocatechuic acid (PCA) against 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induced cytotoxicity in HepG2 cells. The results demonstrated that C3G and PCA dose-dependently suppressed PhIP-induced mutation in Salmonella typhimurium TA98, and inhibited PhIP-induced cytotoxicity and apoptosis in HepG2 cells. Western blot analysis indicated that C3G and PCA minimized PhIP-induced cell damage by reversing the abnormal expression of Bax/Bcl-2, Cytochrome c, cleaved Caspase-3, XIAP, Nrf2, HO-1, LC3 and p62 involved in intrinsic apoptotic and Nrf2/p62 pathways. Molecular docking results revealed that C3G and PCA were able to interfere with Nrf2 signaling and apoptotic cascade through binding to Keap1 and Bcl-2. Moreover, the protective effect of C3G was stronger than that of PCA. These findings suggested that dietary consumption of food sources rich in C3G can fight against the health risks of heterocyclic aromatic amines., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The aim of this study was to investigate the mechanism of action of cyanidin-3-O-glucoside (C3G) and its metabolite protocatechuic acid (PCA) mediated protection against 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)-induced cytotoxicity in HepG2 cells. The effects of C3G and PCA on cell viability, LDH release and apoptosis in IQ-induced HepG2 cells were evaluated using CCK-8, LDH release and flow cytometry assays, respectively. TMT-based proteomics was utilized to characterize the proteins and pathways associated with the improvement after C3G and PCA treatment. Results showed that exposure to IQ significantly increased cytotoxicity and apoptosis in HepG2 cells, which were alleviated by C3G and PCA. C3G was more effective than PCA in protecting HepG2 cells against IQ-induced cytotoxicity and regulating the related signaling pathways. Proteomics and bioinformatics analyses and Western blot validation revealed that apoptosis-related signaling pathways played pivotal roles in protecting against the cytotoxicity of IQ by C3G, and XIAP was identified as the target protein. Molecular docking proved that C3G had strong binding affinity to XIAP and hindered the binding of IQ to the BIR3 domain of XIAP, resulting in the inhibition of apoptosis. Our findings suggested that C3G has potential as a preventive food ingredient to prevent carcinogenic risk of heterocyclic aromatic amines., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Osimertinib, a third-generation irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), provides marked clinical benefit for patients with EGFR-activating mutations. Unfortunately, limited treatments exist for patients who acquire osimertinib resistance. We observed two 'special' patients who regained an antitumor response with osimertinib plus aspirin treatment. As previous data indicate that aspirin induces antiproliferative effects in tumor cells, we designed a preclinical study to explore whether aspirin combined with osimertinib could synergistically sensitize osimertinib-resistant non-small-cell lung cancer (NSCLC) cells. The effects of combined treatment with osimertinib and aspirin on osimertinib-resistant NSCLC cell lines were examined in vitro and in vivo. The combination of osimertinib and aspirin induced strong antiproliferative and proapoptotic effects in osimertinib-resistant NSCLC cells through inhibition of Akt/FoxO3a signaling component phosphorylation and increased Bim expression. Furthermore, Bim knockdown by siRNA significantly attenuated osimertinib resensitization by aspirin. In vivo, combination of aspirin and osimertinib significantly decreased tumor growth of PC-9GROR cell xenografts. Data of patients with NSCLC who received osimertinib treatment at Daping Hospital between January 2015 and January 2019 were reviewed retrospectively. According to clinical data for 45 patients with NSCLC, retrospective analysis showed that the median progression-free survival was significantly longer in the osimertinib plus aspirin group than in the osimertinib group. In summary, aspirin synergistically enhances the antitumor activity of osimertinib in osimertinib-resistant lung cancer cells through promoting Bim-dependent apoptosis. This combination therapy may be effective in overcoming acquired resistance to osimertinib and prolonging survival in patients with NSCLC., (© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Objective: Lobaplatin shows antitumor activity against a wide range of tumors, including metastatic breast cancer (BCa). The overexpression of metadherin (MTDH) is associated with poor prognosis of BCa patients. This study was designed to investigate the effect of lobaplatin on MCF-7 cell proliferation and its association with MTDH expression., Patients and Methods: Clinical treatment for BCa using lobaplatin, in combination with other general chemotherapy drugs, was administered to 32 BCa patients. The safety, effectiveness, and prognosis in lobaplatin-treated BCa patients were compared with those in controls (n=32). In vitro experiments were performed in MCF-7 cells to investigate the effect of lobaplatin on cell proliferation, apoptosis, and MTDH expression., Results: We found the intraoperative local chemotherapy using lobaplatin was safe and effective for BCa treatment, in comparison with the patients administered general chemotherapy drugs. Treatment of MCF-7 cell cultures with lobaplatin significantly reduced cell proliferation and increased cell apoptotic percentage. The expression of MTDH and Bcl-2 was inhibited by lobaplatin and that of Bax was increased by lobaplatin. Moreover, we observed the inhibition of MTDH by shRNA reduced cell proliferation and enhanced cell apoptosis., Conclusion: Lobaplatin was a safe and effective adjuvant chemotherapy for BCa. The effect of lobaplatin on inhibiting MCF-7 cell proliferation and inducing cell apoptosis might be, as least in part, mediated by suppressing the expression of oncogene MTDH., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

The objective of this study was to evaluate the role of apoptosis in the development of the newborn cochlear structures and hearing loss caused by prenatal cis-diaminedichloroplatinum (cisplatin) exposure. Pregnant albino guinea pigs were intraperitoneally injected with 1.5 mg/kg body weight cisplatin once a day for seven consecutive days at gestational day (GD) 51 to GD 57. At postnatal day (PND) 14, pups were examined in the distortion product otoacoustic emission (DPOAE) task. The temporal bones were then removed and immunohistochemically stained for caspase 3, using the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) method. Cisplatin used during pregnancy could induce hearing loss in newborn and cochlear hair cell apoptosis. In conclusion, apoptosis may play an important role in the development of hearing impairment, caused by perinatal cisplatin exposure.

Highlights: [•] We use a mild maternal iron deficiency anemia model to induce hearing impairment in young guinea pigs. [•] Mild iron deficiency anemia induces hair cell apoptosis and caspase-3/9 activation. [•] Apoptosis may play a key role for inhibition of hair cell development caused by mild iron deficiency anemia. [ABSTRACT FROM AUTHOR]

Abstract: d-Galactose could give rise to free radical damage by disturbing the some maternal antioxidants. The oxidative stress induced by d-galactose is a potent inducer of apoptosis, which is accompanied by the activation of protein-splitting enzymes called caspases. Apoptosis is a crucial physiological determinant of embryonic and neonatal development, and play an essential role in the development of the inner ear structures. Recently the increasing of d-galactose exposure is due to high consumption of dairy foods or reduced galactose metabolism. An overwhelming presence of d-galactose is known to become highly ototoxicity to humans. The purpose of this study was to investigate whether supplementation of pregnant and lactational mothers with β-carotene could attenuate cochlear function damage and hair cells apoptosis induced by d-galactose in newborn rats. Pregnant rats were supplemented with d-galactose, or d-galactose and β-carotene from gestational day (GD) 7 until postnatal day (PND) 21. On PND 22, offspring were examined in the distortion product otoacoustic emission (DPOAE) task, cochleae were then harvested for assessment of apoptosis by immunohistochemical stain for cysteine–aspartic acid proteases 3 (caspase-3) and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay. Maternal and offspring blood samples were then collected by direct cardiac puncture in heparin tubes, blood levels of d-galactose and β-carotene were measured, plasma was separated for malondialdehyde (MDA) analysis, erythrocytes were left for superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and glutathione (GSH). d-Galactose could significantly disturb the balance between maternal antioxidants and free radicals, and induce hearing loss in the offspring and cochlear hair cell apoptosis. In contrast, β-carotene supplementation, coincidentally with d-galactose exposure, ameliorated these changes. Our data offer a conceptual framework for designing clinical trials using a safe micronutrient, β-carotene, as a simple preventive strategy for d-galactose-induced ototoxicity. [Copyright &y& Elsevier]

Phycocyanin, a type of functional food colorant, is shown to have a potent anti-cancer property. Non-small cell lung cancer (NSCLC) is one of the most aggressive form of cancers with few effective therapeutic options. Previous studies have demonstrated that phycocyanin exerts a growth inhibitory effect on NSCLC A549 cells. However, its biological function and underlying regulatory mechanism on other cells still remain unknown. Here, we investigated the in vitro function of phycocyanin on three typical NSCLC cell lines, NCI-H1299, NCI-H460, and LTEP-A2, for the first time. The results showed that phycocyanin could significantly induce apoptosis, cell cycle arrest, as well as suppress cell migration, proliferation, and the colony formation ability of NSCLC cells through regulating multiple key genes. Strikingly, phycocyanin was discovered to affect the cell phenotype through regulating the NF-κB signaling of NSCLC cells. Our findings demonstrated the anti-neoplastic function of phycocyanin and provided valuable information for the regulation of phycocyanin in NSCLC cells. [ABSTRACT FROM AUTHOR]