Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 4 de 4
Filter
Add more filters










Database
Language
Publication year range
1.
Cells ; 12(19)2023 09 27.
Article in English | MEDLINE | ID: mdl-37830582

ABSTRACT

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. In metabolic dysfunction-associated steatohepatitis (MASH)-related HCC, cellular redox imbalance from metabolic disturbances leads to dysregulation of the α1-subunit of the Na/K-ATPase (ATP1A1) signalosome. We have recently reported that the normalization of this pathway exhibited tumor suppressor activity in MASH-HCC. We hypothesized that dysregulated signaling from the ATP1A1, mediated by cellular metabolic stress, promotes aberrant epigenetic modifications including abnormal post-translational histone modifications and dysfunctional autophagic activity, leading to HCC development and progression. Increased H3K9 acetylation (H3K9ac) and H3K9 tri-methylation (H3K9me3) were observed in human HCC cell lines, HCC-xenograft and MASH-HCC mouse models, and epigenetic changes were associated with decreased cell autophagy in HCC cell lines. Inhibition of the pro-autophagic transcription factor FoxO1 was associated with elevated protein carbonylation and decreased levels of reduced glutathione (GSH). In contrast, normalization of the ATP1A1 signaling significantly decreased H3K9ac and H3K9me3, in vitro and in vivo, with concomitant nuclear localization of FoxO1, heightening cell autophagy and cancer-cell apoptotic activities in treated HCC cell lines. Our results showed the critical role of the ATP1A1 signalosome in HCC development and progression through epigenetic modifications and impaired cell autophagy activity, highlighting the importance of the ATP1A1 pathway as a potential therapeutic target for HCC.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Mice , Animals , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/pathology , Epigenesis, Genetic , Genes, Tumor Suppressor , Autophagy/genetics , Sodium-Potassium-Exchanging ATPase/metabolism
2.
Int J Mol Sci ; 23(13)2022 Jul 01.
Article in English | MEDLINE | ID: mdl-35806364

ABSTRACT

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide, with an estimate of 0.84 million cases every year. In Western countries, because of the obesity epidemic, non-alcoholic steatohepatitis (NASH) has become the major cause of HCC. Intriguingly, the molecular mechanisms underlying tumorigenesis of HCC from NASH are largely unknown. We hypothesized that the growing uncoupled metabolism during NASH progression to HCC, manifested by lower cell redox status and an apoptotic 'switch' activity, follows a dysregulation of α1-Na/K-ATPase (NKA)/Src signalosome. Our results suggested that in NASH-related malignancy, α1-NKA signaling causes upregulation of the anti-apoptotic protein survivin and downregulation of the pro-apoptotic protein Smac/DIABLO via the activation of the PI3K → Akt pro-survival pathway with concomitant inhibition of the FoxO3 circuit, favoring cell division and primary liver carcinogenesis. Signalosome normalization using an inhibitory peptide resets apoptotic activity in malignant cells, with a significant decrease in tumor burden in vivo. Therefore, α1-NKA signalosome exercises in HCC the characteristic of a tumor suppressor, suggesting α1-NKA as a putative target for clinical therapy.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Non-alcoholic Fatty Liver Disease , Sodium-Potassium-Exchanging ATPase , Carcinogenesis/metabolism , Carcinoma, Hepatocellular/metabolism , Humans , Liver Neoplasms/metabolism , Non-alcoholic Fatty Liver Disease/metabolism , Sodium-Potassium-Exchanging ATPase/metabolism
3.
Int J Mol Sci ; 23(14)2022 Jul 13.
Article in English | MEDLINE | ID: mdl-35887082

ABSTRACT

Autophagy, a cellular self-digestion process, involves the degradation of targeted cell components such as damaged organelles, unfolded proteins, and intracellular pathogens by lysosomes. It is a major quality control system of the cell and plays an important role in cell differentiation, survival, development, and homeostasis. Alterations in the cell autophagic machinery have been implicated in several disease conditions, including neurodegeneration, autoimmunity, cancer, infection, inflammatory diseases, and aging. In non-alcoholic fatty liver disease, including its inflammatory form, non-alcoholic steatohepatitis (NASH), a decrease in cell autophagic activity, has been implicated in the initial development and progression of steatosis to NASH and hepatocellular carcinoma (HCC). We present an overview of autophagy as it occurs in mammalian cells with an insight into the emerging understanding of the role of autophagy in NASH and NASH-related HCC.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Non-alcoholic Fatty Liver Disease , Animals , Autophagy , Carcinoma, Hepatocellular/metabolism , Humans , Liver/metabolism , Liver Neoplasms/metabolism , Mammals , Non-alcoholic Fatty Liver Disease/metabolism
4.
J Hum Reprod Sci ; 5(1): 37-42, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22870013

ABSTRACT

AIMS: This study was carried out to investigate the effect of Allium cepa crude extract on cadmium-induced testicular toxicity in rats. MATERIALS AND METHODS: Adult male Sprague-Dawley rats were randomized into 4 groups (n = 6). Group 1 was used as control, group 2 was administered 0.3 mg/kgBW of cadmium sulfate (CdSO(4)) intraperitoneally for 3 days, group 3 was pretreated with 1 ml/100 g BW of Allium cepa (AcE) for 8 weeks followed by intraperitoneal administration of 0.3 mg/kgBW of CdSO(4) in the last 3 days of experiment, and group 4 was administered 1 ml/100 g BW of AcE throughout the experiment. Testicular weight and semen analysis revealing the sperm count, sperm motility, and sperm morphology was carried out. Superoxide dismutase (SOD), catalase activities, and lipid peroxidation status were also carried out in testes. RESULTS: The study demonstrated that Allium cepa ameliorated CdSO(4)-induced alteration in testicular weight, sperm count, sperm motility, and sperm morphology. It also showed that Allium cepa attenuated the derangement of lipid peroxidation profile in testicular tissues caused by CdSO(4) exposure. CONCLUSIONS: The findings in the study showed that pre-treatment of rat model with Allium cepa extract prevented CdSO(4)-induced reproductive toxicity by improving sperm quality and enhancing testicular lipid peroxidation status.

SELECTION OF CITATIONS
SEARCH DETAIL
...