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Eight Novel chalcones were synthesized and their structures were confirmed by different spectral tools. All the prepared compounds were subjected to SRB cytotoxic screening against several cancer cell lines. Compound 5c exerted the most promising effect against MCF7 and HEP2 cells with IC50 values of 9.5 and 12 µg/mL, respectively. Real-time PCR demonstrated the inhibitory effect of compound 5c on the expression level of Antigen kiel 67 (KI-67), Survivin, Interleukin-1beta (IL-1B), Interleukin-6 (IL-6), Cyclooxygenase-2 (COX-2) and Protein kinase B (AKT1) genes. Flow-cytometric analysis of the cell cycle indicated that compound 5c stopped the cell cycle at the G0/G1 and G2/M phases in MCF7 and HEP2 treated cells, respectively. ELISA assay showed that Caspase 8, Caspase 9, P53, BAX, and Glutathione (GSH) were extremely activated and Matrix metalloproteinase 2 (MMP2), Matrix metalloproteinase 9 (MMP9), BCL2, Malondialdehyde (MDA), and IL-6 were deactivated in 5c treated MCF7 and HEP2 cells. Wound healing revealed that chalcone 5c reduced the ability to close the scrape wound and decreased the number of migrating MCF7 and HEP2 cells compared to the untreated cells after 48 h. Theoretical molecular modeling against P53 cancer mutant Y220C and Bcl2 showed binding energies of -22.8 and -24.2 Kcal/mole, respectively, which confirmed our ELISA results. [ABSTRACT FROM AUTHOR]

Abstract Cervical cancer is reported as one of the most lethal types of cancer among female. However, extensive studies of the molecular mechanisms that regulate the progression of cervical cancer are still required. B-cell associated protein (BAP)-31 is a 28-kDa integral membrane protein in the endoplasmic reticulum (ER), playing essential role in modulating various physiological processes. The present study indicated that BAP31 was a novel gene associated with cervical cancer development. Here, we demonstrated that BAP31 was significantly increased in human cervical cancer specimens, which was positively correlated to histological grade of the cancer. BAP31 knockdown suppressed cell proliferation, clonogenic ability and metastasis-associated traits in vitro, as well as carcinogenesis and pulmonary metastasis in vivo. Further studies indicated that the expression levels of transforming growth factor (TGF)-β1, matrix metalloproteinase (MMP)-2, MMP-9, Rho-associated protein kinase 1 (ROCK1), α-smooth muscle actin (α-SMA), Vimentin and N-cadherin were markedly reduced by BAP31 knockdown in cervical cancer cells. In addition, intrinsic and extrinsic apoptosis was significantly induced in BAP31 knockdown cells, as evidenced by the increased expression of cleaved Caspase-8/-9/-3 and poly (ADP-ribose) polymerases (PARP). Notably, suppressing the activities of Caspase-8/-9 and −3 obviously diminished BAP31 silence-triggered apoptosis. Together, these findings highlighted an essential role for BAP31 in the modulation of tumorigenesis and metastatic potential of cervical cancer, and demonstrated a promising application of BAP31 in cancer prevention. Highlights • BAP31 knockdown reduces proliferation, migration and invasion of cervical cancer cells. • BAP31 knockdown induces apoptosis in cervical cancer cells. • BAP31 knockdown reduces tumor growth and metastasis in vivo. [ABSTRACT FROM AUTHOR]

Retinal ganglion cell (RGC) death is the principal consequence of injury to the optic nerve. For several decades, we have understood that the RGC death process was executed by apoptosis, suggesting that there may be ways to therapeutically intervene in this cell death program and provide a more direct treatment to the cells and tissues affected in diseases like glaucoma. A major part of this endeavor has been to elucidate the molecular biological pathways active in RGCs from the point of axonal injury to the point of irreversible cell death. A major component of this process is the complex interaction of members of the BCL2 gene family. Three distinct family members of proteins orchestrate the most critical junction in the apoptotic program of RGCs, culminating in the activation of pro-apoptotic BAX. Once active, BAX causes irreparable damage to mitochondria, while precipitating downstream events that finish off a dying ganglion cell. This review is divided into two major parts. First, we summarize the extent of knowledge of how BCL2 gene family proteins interact to facilitate the activation and function of BAX. This area of investigation has rapidly changed over the last few years and has yielded a dramatically different mechanistic understanding of how the intrinsic apoptotic program is run in mammalian cells. Second, we provided a comprehensive analysis of nearly two decades of investigation of the role of BAX in the process of RGC death, much of which has provided many important insights into the overall pathophysiology of diseases like glaucoma. [ABSTRACT FROM AUTHOR]

The objective of this research is to investigate the regulation of apoptotic associated-genes and proteins expression of aloe emodin on oestrogen receptor (ER)-positive (MCF-7). Oestrogen receptor (E x positive (MCF-7) cells were cultured in complete RPMI media. Cells were treated with aloe emodin at its IC50 of 80uM. Maximum treatment time was set for 72 hours in all assays. Both genes and proteins involved in the regulation of apoptosis (Fas, FADD, Caspase-3, Caspase-8, Caspase-9, Bax, Bcl-2, and Cytochrome c) in aloe emodin-treated MCF-7 were determined using Quantigene 2.0 Plex and protein ELISA assays respectively. Aloe emodin, previously reported as anti-cancer agent, was found to act as an apoptotic inducer on MCF-7 cells. In intrinsic apoptosis signalling, Bax, Cytochrome c and Caspase-9 proteins were upregulated (54.11% ± 4.51, 25.17% ± 4.13 and 36.05% ±11.75); while no change was observed in Bcl-2 protein. Except for Caspase-9, these results are in accordance with gene expression. In extrinsic apoptosis, Fas and Caspase-8 were upregulated (133.82% ±2.85 and 26.44%±2.48), contrary to gene expression. These findings indicate that aloe emodin activates both extrinsic and intrinsic apoptosis pathways. The data suggests (i) aloe emodin has the potential to be a selective apoptotic inducer in ER+-breast cancer management; and (ii) the present study could be used as a basis for in vivo experiment. [ABSTRACT FROM AUTHOR]

Background: Due to the aggressive clinical behavior, poor outcome, and lack of effective specific targeted therapies, triple-negative breast cancer (TNBC) has currently been recognized as one of the most malignant types of tumors. In the present study, we investigated the cytotoxic effect of ziyuglycoside I, one of the major components extracted from Chinese anti-tumor herbal Radix Sanguisorbae, on the TNBC cell line MDA-MB-231. Methods: The underlying molecular mechanism of the cytotoxic effect ziyuglycoside I on MDA-MB-231 cells was investigated with cell viability assay, flow cytometric analysis andWestern blot. Results: Compared to normal mammary gland Hs 578Bst cells, treatment of ziyuglycoside I resulted in a significant growth inhibitory effect on MDA-MB-231 cells. Ziyuglycoside I induced the G2/M phase arrest and apoptosis of MDA-MB-231 cells in a dose-dependent manner. These effects were found to be partially mediated through the up-regulation of p53 and p21WAF1, elevated Bax/Bcl-2 ratio, and the activation of both intrinsic (mitochondrial-initiated) and extrinsic (Fas/FasL-initiated) apoptotic pathways. Furthermore, the p53 specific siRNA attenuated these effects. Conclusion: Our study suggested that ziyuglycoside I-triggered MDA-MB-231 cell cycle arrest and apoptosis were probably mediated by p53. This suggests that ziyuglycoside I might be a potential drug candidate for treating TNBC. [ABSTRACT FROM AUTHOR]

Erectile dysfunction (ED) is a common and debilitating condition with high impact on quality of life. An underlying cause of ED is apoptosis of penile smooth muscle, which occurs with cavernous nerve injury, in prostatectomy, diabetic and aging patients. We are developing peptide amphiphile (PA) nanofiber hydrogels as an in vivo delivery vehicle for Sonic hedgehog protein to the penis and cavernous nerve to prevent the apoptotic response. We examine two important aspects required for clinical application of the biomaterials: if SHH PA suppresses intrinsic (caspase 9) and extrinsic (caspase 8) apoptotic mechanisms, and if suppressing one apoptotic mechanism forces apoptosis to occur via a different mechanism. We show that SHH PA suppresses both caspase 9 and 8 apoptotic mechanisms, and suppressing caspase 9 did not shift signaling to caspase 8. SHH PA has significant clinical potential as a preventative ED therapy, by management of intrinsic and extrinsic apoptotic mechanisms. Erectile dysfunction (ED) is a common and debilitating condition with high impact on quality of life. An underlying cause of ED is apoptosis of penile smooth muscle, which occurs with cavernous nerve injury, in prostatectomy, diabetic and aging patients. We are developing peptide amphiphile (PA) nanofiber hydrogels as an in vivo delivery vehicle for Sonic hedgehog protein to the penis and cavernous nerve to prevent the apoptotic response and ED. We examine two important aspects required for clinical application of the biomaterials: if SHH PA suppresses intrinsic (caspase 9) and extrinsic (caspase 8) apoptotic mechanisms, and if suppressing one apoptotic mechanism forces apoptosis to occur via a different mechanism. We show that SHH PA suppresses both caspase 9 and 8 apoptotic mechanisms, and suppressing caspase 9 did not shift signaling to caspase 8. SHH PA has significant clinical potential as a preventative ED therapy, by management of intrinsic and extrinsic apoptotic mechanisms. [Display omitted] [ABSTRACT FROM AUTHOR]

Erectile dysfunction (ED) is a common and debilitating condition with high impact on quality of life. An underlying cause of ED is apoptosis of penile smooth muscle, which occurs with cavernous nerve injury, in prostatectomy, diabetic and aging patients. We are developing peptide amphiphile (PA) nanofiber hydrogels as an in vivo delivery vehicle for Sonic hedgehog protein to the penis and cavernous nerve to prevent the apoptotic response. We examine two important aspects required for clinical application of the biomaterials: if SHH PA suppresses intrinsic (caspase 9) and extrinsic (caspase 8) apoptotic mechanisms, and if suppressing one apoptotic mechanism forces apoptosis to occur via a different mechanism. We show that SHH PA suppresses both caspase 9 and 8 apoptotic mechanisms, and suppressing caspase 9 did not shift signaling to caspase 8. SHH PA has significant clinical potential as a preventative ED therapy, by management of intrinsic and extrinsic apoptotic mechanisms., (Published by Elsevier Inc.)