Search

The widespread occurrence of perfluorooctane sulfonate (PFOS) and the mass production and application of graphene oxide (GO) lead to their inevitable release and interaction in the environment, which may enhance associated toxic impacts on aquatic organisms. This study elucidates the induction of apoptosis by 60-day chronic single and mixture exposures to environmentally relevant levels of PFOS (0.5 μg/L and 5 μg/L) and GO (1 mg/L) in adult marine medaka Oryzias melastigma. Results showed a significant increase (p < 0.05) in reactive oxygen species (ROS) levels, the apoptotic positive rate in livers, and activities of caspases 3, 8, and 9 in all treated groups compared to the control. PFOS individual and PFOS-GO combined exposures significantly impacted fish growth, upregulated expressions of six apoptosis-related genes including p53, apaf1, il1b, tnfa, bcl2l1, bax, as well as enriched cell cycle and p53 signaling pathways (transcriptomic analysis) related to apoptosis compared to control group. Besides higher ROS production, GO also had a higher binding affinity to proteins than PFOS, especially to caspase 8 as revealed by molecular docking. Overall, PFOS induced ROS-p53-caspase apoptosis pathway through multi-gene regulation during single or mixture exposure, while GO single exposure induced apoptosis through tissue damage and ROS-caspase pathway activation and direct docking with caspase 8 to activate the caspase cascade. Under co-exposure, the PFOS-induced apoptotic pathway overshadowed the GO-induced pathway, due to competition for limited active sites on caspases. These findings will contribute to a better understanding of the apoptosis mechanism and ecological risks of nanomaterials and per- and polyfluoroalkyl substances in marine ecosystems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Prostate cancer (PCa) cells exploit cellular metabolic reprogramming as their survival advantage, especially aberrant lipid signaling and metabolism. Although recent studies deemed that PCa tends to rely on lipid fuel in comparison with aerobic glycolysis, the relationship between lipid metabolism and cancer growth remains unknown. We demonstrated that wogonin, a naturally occurring mono-flavonoid, could induce apoptosis of PCa cells in vivo and in vitro. Mechanistically, 100 μM wogonin significantly increased the expression of proteins related to the fatty acid synthesis and accumulation as a result of stimulation of AKT phosphorylation and nuclear accumulation of sterol regulatory element-binding protein 1 (SREBP1). The wogonin-induced up-regulation of fatty acid synthase (FASN) promoted fatty acid synthesis and storage, while increased oxidation in mitochondria driven by carnitine palmitoyl-transferase 1A (CPT1A) resulted in the loss of mitochondrial membrane potential and reactive oxygen species (ROS) accumulation, ultimately inducing apoptosis in DU145 and 22Rv1 cells. In vivo, 100 mg/kg of wogonin (i.v.) significantly repressed tumor growth without any obvious toxicity in the PCa xenograft model. In short, we proved that wogonin regulated the fatty acid metabolism and induced apoptosis by activating the AKT-SREBP1-FASN signaling network in human PCa cells, and it exhibited potent anti-tumor effects both in vivo and vitro. Thus it might be a promising candidate for the development of anti-cancer drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Prostate cancer (PCa) depends on androgen receptor (AR) signaling to regulate cell metabolism, including glycolysis, and thereby promotes tumor growth. Glycolysis is overactive in PCa and associated with poor prognosis, but the therapeutic efficacy of glycolysis inhibitors has thus far been limited by their inability to induce cell death. FV-429, a flavonoid derivative of Wogonin, is a glycolysis inhibitor that has shown anti-cancer promise. In this study, we used FV-429 as an anti-PCa agent and investigated its mechanisms of action. In vitro, both the glycolytic ability and the viability of PCa cells were inhibited by FV-429. We found that FV-429 could induce mitochondrial dysfunction and apoptosis, with AKT-HK2 signaling pathway playing a key role. In addition, FV-429 had a pro-apoptotic effect on human prostate cancer cells that relied on the inhibition of AR expression and activity. In vivo, FV-429 exerted significant tumor-repressing activity with high safety in the xenograft model using LNCaP cells. In summary, we demonstrated that FV-429 induced glycolysis inhibition and apoptosis in human prostate cancer cells by downregulating the AR-AKT-HK2 signaling network, making FV-429 a promising candidate as one therapeutic agent for advanced PCa., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Bupivacaine (BP) is commonly used as a local anaesthetic(LA) in the clinic, but it can also cause neurotoxicity, especially in patients with diabetes. Previous studies have found that high-glucose environments can aggravate BP-induced DNA damage in nerve cells. Ku70 is subunit of the DNA damage repair enzyme DNA-PK. This study was designed to determine whether high-glucose conditions enhance BP neurotoxicity and DNA damage by inhibiting Ku70 expression., Methods: We examined the effect of BP on apoptosis and DNA damage in murine dorsal root ganglion (DRG) neurons under hyperglycaemic conditions. Untreated DRG cells and DRG cells pretreated with NU7441, a DNA-PK inhibitor, were cultured for 3 days under normal culture conditions or with 50 mM glucose, and the cells were then treated with BP for 3 h. DNA damage was investigated via comet assays, the ratio of early to late apoptotic cells was assessed by Annexin V-FITC/PI staining, and cell viability was measured by CCK-8 assays. The protein expression levels of DNA-PK, Ku70, Bax, Bcl-2 and γH2ax were measured by immunofluorescence or Western blotting., Results: Compared to its effect under normal culture conditions, BP treatment led to decreased cell viability and increased DNA damage in DRG cells grown under high-glucose conditions. The rate of DRG cell apoptosis and the expression of γH2ax, the ratio of Bax to Bcl-2 also increased under the high-glucose conditions. Furthermore, Ku70 expression was inhibited. The DNA-PK inhibitor, NU7441, could significantly inhibit DNA-PK and Ku70 expression, simultaneously further aggravating BP-induced apoptosis and DNA damage under high-glucose conditions., Conclusion: These data indicate that hyperglycaemia may enhance BP-induced neurotoxicity and DNA damage by inhibiting the DNA repair protein Ku70., (Copyright © 2019 Elsevier B.V. All rights reserved.)

CTCF plays key roles in gene regulation, chromatin insulation, imprinting, X chromosome inactivation and organizing the higher-order chromatin architecture of mammalian genomes. Previous studies have mainly focused on the roles of the canonical CTCF isoform. Here, we explore the functions of an alternatively spliced human CTCF isoform in which exons 3 and 4 are skipped, producing a shorter isoform (CTCF-s). Functionally, we find that CTCF-s competes with the genome binding of canonical CTCF and binds a similar DNA sequence. CTCF-s binding disrupts CTCF/cohesin binding, alters CTCF-mediated chromatin looping and promotes the activation of IFI6 that leads to apoptosis. This effect is caused by an abnormal long-range interaction at the IFI6 enhancer and promoter. Taken together, this study reveals a non-canonical function for CTCF-s that antagonizes the genomic binding of canonical CTCF and cohesin, and that modulates chromatin looping and causes apoptosis by stimulating IFI6 expression.

An alkaline extractable and water-soluble polysaccharide (ADAPW), with an average molecular weight of 16kDa, was purified from the alkaline extraction of the roots of Dipsacus asperoides. Monosaccharide component analysis indicated that ADAPW was composed of glucose, rhamnose, arabinose and mannose in a molar ratio of 8.54:1.83:1.04:0.42. This study aimed to investigate the effect of ADAPW on the viability of human osteosarcoma cell line HOS cells, and explore the possible mechanisms. The results revealed that ADAPW inhibited the proliferation of HOS cells in a dose-dependent manner by inducing apoptosis. Furthermore, treatment with ADAPW caused a loss of mitochondrial membrane potential and accumulation of reactive oxygen species (ROS). In addition, Western blot analysis demonstrated that ADAPW down-regulated the protein expressions of PI3K and phosphorylated Akt (pAkt) in HOS cells. Taken together, induction of apoptosis on HOS cells by ADAPW was mainly associated with ROS production, mitochondrial dysfunction, and inhibition of PI3K/Akt signaling pathway. So this finding suggests that ADAPW may be potentially effective in cancer prevention against human osteosarcoma., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Four new quassinoids (1 – 4) and twenty known analogues (5 – 24) were isolated from the seeds of Brucea javanica. All the compounds belong to tetracyclic quassinoids. The structures of the new compounds were elucidated by comprehensive spectroscopic analysis, including HRESIMS and 1D, 2D NMR. In in vitro bioassays, (5 – 9 , 17 – 19 and 23) showed inhibitory activities for nitric oxide (NO) release in LPS-activated MH-S macrophages and IC 50 values of 0.11–45.56 μM. Among them, bruceoside B significantly decreased LPS-induced NO, secretion of inflammatory factor cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β). Western Blot was used to verify the expression of p-IκB-α, IκB-α, p-NF-κB, NF-κB, Bax, Bcl-2, Caspase-3, p-PI3K, PI3K, p-Akt, and Akt proteins in PI3K/Akt/NF-κB signal pathway. Bruceoside B inhibited the activity of Akt and its downstream pathways and reduced the activation of apoptotic. In vivo , it was found that bruceoside B had obvious therapeutic effect on LPS-induced acute lung injury (ALI) in mice, and the effect of tissue section was obvious. The regulatory signal pathway of bruceoside B on inflammation was consistent with the anti-inflammatory pathway in vitro. Therefore, the results implied that bruceoside B has a certain therapeutic effect on inflammation and has a certainly effect on acute lung injury. [Display omitted] [ABSTRACT FROM AUTHOR]