A novel mechanism underlying alcohol dehydrogenase expression: hsa-miR-148a-3p promotes ADH4 expression via an AGO1-dependent manner in control and ethanol-exposed hepatic cells

2021 ◽  
pp. 114458
Author(s):  
Jiao Luo ◽  
Yufei Hou ◽  
Wanli Ma ◽  
Mengyue Xie ◽  
Yuan Jin ◽  
...  
2017 ◽  
Vol 33 (8) ◽  
pp. 611-622 ◽  
Author(s):  
Imen Ghorbel ◽  
Awatef Elwej ◽  
Mariem Chaabene ◽  
Ons Boudawara ◽  
Rim marrakchi ◽  
...  

The present study investigates the toxic effects of acrylamide (ACR) administered to rats at two doses on (i) oxidative stress and disruption of pro-oxidant/antioxidant balance in hepatic cells and (ii) its correlation with metallothioneins (MTs) genes expression, DNA damage and histomorphological changes. Treated rats with 20 and 40 mg/kg body weight of ACR led to an increase in malondialdehyde, hydrogen peroxide, advanced oxidation protein products, protein carbonyl levels as well as an alteration in the antioxidant status. Total MT content in the liver and MT I and MT II genes induction were increased. Plasma transaminases activities, albumin, total protein and glucose levels were also increased, while alkaline phosphatase activity was decreased. Moreover, total cholesterol (TC), triglyceride, low-density lipoprotein cholesterol (LDL-C) levels, TC/high-density lipoprotein cholesterol (HDL-C) and LDL-C/HDL-C ratios were increased, while HDL-C decreased in a dose-dependent manner. A random DNA degradation was observed only in the liver of ACR-treated rats with the highest dose. These changes were confirmed by histopathological observations.


1999 ◽  
Vol 112 (9) ◽  
pp. 1353-1364
Author(s):  
T. Nakadai ◽  
T. Kishimoto ◽  
Y. Miyazawa ◽  
N. Okada ◽  
Y. Makino ◽  
...  

Using a new subtraction method and chemically induced rat hepatocellular carcinomas, we identified a hepatocellular carcinogenesis and hepatocyte proliferation-related gene designated hp33 that encoded a 33-kDa protein. The predicted protein was similar to the bovine aralkyl N-acyltransferase and arylacetyl N-acyltransferase. HP33 was restrictively expressed in the liver and kidney, and its gene expression was stimulated in the regenerating liver as well as in hepatocellular carcinoma. Interestingly, it was demonstrated in various hepatic cells that HP33 was localized in regions surrounding the centrosome, where mitochondria were not concentrated. Moreover, its centrosomal localization was evident in the interphase but not in the mitotic phase of the cell cycle. The centrosomal localization of HP33 was dependent on microtubules, and ectopically expressed HP33 was seen at centrosomes even in fibroblasts, which do not exhibit a typical staining pattern of HP33. The centrosomal localization of HP33 became invisible by nocodazole treatment, whereas the mitochondrial staining pattern was not affected by it. In vitro cosedimentation experiments using purified microtubules indicated that HP33 bound to MTs directly and that its MT-binding ability was dependent on the C-terminal basic domain of the protein. These results suggest that, different from early predictions based on its primary structure, HP33 has a growth- and carcinogenesis-related function that may be independent of mitochondrial function.


2021 ◽  
Author(s):  
Avis D. W. Nugroho ◽  
Berdien van Olst ◽  
Sjef Boeren ◽  
Michiel Kleerebezem ◽  
Herwig Bachmann

Manganese (Mn) is an essential trace element that is supplemented in microbial media with varying benefits across species and growth conditions. We found that growth of Lactococcus cremoris was unaffected by manganese omission from the growth medium. The main proteome adaptation to manganese omission involved increased manganese transporter production (up to 2000-fold), while the remaining 10 significant proteome changes were between 1.4 and 4 fold. Further investigation in translationally-blocked (TB), non-growing cells showed that Mn supplementation (20 µM) led to approximately 1.5X faster acidification compared to Mn-free conditions. However, this faster acidification stagnated within 24 hours, likely due to draining of intracellular NADH that coincides with substantial loss of culturability. Conversely, without manganese, non-growing cells persisted to acidify for weeks, albeit at a reduced rate, but maintaining redox balance and culturability. Strikingly, despite being unculturable, α-keto acid-derived aldehydes continued to accumulate in cells incubated in the presence of manganese, whereas without manganese cells predominantly formed the corresponding alcohols. This is most likely reflecting NADH availability for the alcohol dehydrogenase-catalyzed conversion. Overall, manganese influences the lactococcal acidification rate, and flavor formation capacity in a redox dependent manner. These are important industrial traits especially during cheese ripening, where cells are in a non-growing, often unculturable state.


2019 ◽  
Author(s):  
Robert P. Sparks ◽  
Andres S. Arango ◽  
Zachary L. Aboff ◽  
Jermaine L. Jenkins ◽  
Wayne C. Guida ◽  
...  

ABSTRACTSortilin regulates hepatic exocytosis and endocytosis of ApoB containing lipoproteins (ApoB-Lp) and mediates the secretion of the subtilase PCSK9. To elucidate connections between these pathways, we previously identified a small molecule (cpd984) that binds to a non-canonical site on Sortilin. In hepatic cells cpd984 augments ApoB-Lp secretion, increases cellular PCSK9 levels, and reduces LDLR expression indicative of reduced secretion of PCSK9. We have shown that insulin-induced ApoB-Lp degradation occurs through Vps34-dependent autophagy. Here we show that the specific Vps34 inhibitor PIK-III enhances ApoB-100 secretion, reducing cellular levels of PCSK9 and Sortilin resulting in reduced LDLR expression, which implicates a role for autophagy in PCSK9 secretion. Results suggest that Sortilin is central to both PCSK9 and ApoB-100 secretion. Finally, we found that cpd984 in yeast blocks CPY secretion while increasing vacuolar homotypic fusion in a Vps10-dependent manner, indicating an evolutionarily conserved mechanism required for lysosomal protease trafficking.


Nutrients ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 4238
Author(s):  
Václav Tvrdý ◽  
Marcel Hrubša ◽  
Eduard Jirkovský ◽  
David Biedermann ◽  
Michal Kutý ◽  
...  

Silymarin is known for its hepatoprotective effects. Although there is solid evidence for its protective effects against Amanita phalloides intoxication, only inconclusive data are available for alcoholic liver damage. Since silymarin flavonolignans have metal-chelating activity, we hypothesized that silymarin may influence alcoholic liver damage by inhibiting zinc-containing alcohol dehydrogenase (ADH). Therefore, we tested the zinc-chelating activity of pure silymarin flavonolignans and their effect on yeast and equine ADH. The most active compounds were also tested on bovine glutamate dehydrogenase, an enzyme blocked by zinc ions. Of the six flavonolignans tested, only 2,3-dehydroderivatives (2,3-dehydrosilybin and 2,3-dehydrosilychristin) significantly chelated zinc ions. Their effect on yeast ADH was modest but stronger than that of the clinically used ADH inhibitor fomepizole. In contrast, fomepizole strongly blocked mammalian (equine) ADH. 2,3-Dehydrosilybin at low micromolar concentrations also partially inhibited this enzyme. These results were confirmed by in silico docking of active dehydroflavonolignans with equine ADH. Glutamate dehydrogenase activity was decreased by zinc ions in a concentration-dependent manner, and this inhibition was abolished by a standard zinc chelating agent. In contrast, 2,3-dehydroflavonolignans blocked the enzyme both in the absence and presence of zinc ions. Therefore, 2,3-dehydrosilybin might have a biologically relevant inhibitory effect on ADH and glutamate dehydrogenase.


2021 ◽  
pp. jcs.253914
Author(s):  
Bartika Ghoshal ◽  
Edouard Bertrand ◽  
Suvendra N. Bhattacharyya

MicroRNAs, the tiny regulators of gene expression, can be transferred between neighbouring cells via Extracellular Vesicles (EV) to control the expression of genes in both donor and recipient cells. How the EV-derived miRNAs get internalized and become functional in target cells is an unresolved question. We have expressed liver specific microRNA, miR-122, in non-hepatic cells for packaging in the released EVs. With these EVs, we have followed the trafficking of miR-122 to recipient HeLa cells that otherwise don't express this miRNA. We found that EV-associated miR-122 are primarily single stranded and, to become functional, get loaded onto the recipient cell Ago proteins without requiring host Dicer1. Following endocytosis, EV-associated miR-122 get loaded onto the host cell Ago on the endosomal membrane where the release of internalized miRNAs occurs in a pH-dependent manner facilitating the formation of the exogenous miRNP pool in the recipient cells. Endosome maturation defect affects EV-mediated entry of exogeneous miRNAs in mammalian cells.


2014 ◽  
Vol 66 (1) ◽  
pp. 317-321 ◽  
Author(s):  
Lingjiao Wu ◽  
Shaohua Chen ◽  
Yu Zhang ◽  
Hongming Pan

Chronic alcohol consumption has been identified as a significant risk factor for cancer in humans. The aim of the study was to analyze the influence of low concentrations of ethanol on gastric adenocarcinoma cell viability, apoptosis, and changes in the expression of alcohol dehydrogenase with ethanol treatment. Gastric adenocarcinoma cell lines (MGC803, MGC823 and SGC7901) were treated with different concentrations of ethanol (0.03125%, 0.0625%, 0.125%, 0.25%, 0.5%, 1%, 2%, and 4%). An MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and flow cytometry were used to analyze the effect of ethanol treatment on cell viability and apoptosis. Western blotting was used to analyze the expression of alcohol dehydrogenase in gastric carcinoma cells. Ethanol treatment inhibited cell proliferation in gastric adenocarcinoma cell lines in a significant dose-dependent manner. Ethanol was also able to induce the apoptosis of gastric adenocarcinoma cells in a dose-dependent manner. Alcohol dehydrogenase activity of gastric adenocarcinoma cells increased with the increase in the concentration of ethanol. Ethanol inhibited cell viability and growth of gastric adenocarcinoma cell lines. Low concentrations of ethanol also induced apoptosis and increased the expression of alcohol dehydrogenase of the gastric adenocarcinoma cell lines.


2015 ◽  
Vol 65 (4) ◽  
pp. 463-471 ◽  
Author(s):  
Zhiwei Huang ◽  
Lianqiu Wang ◽  
Lifeng Chen ◽  
Yifei Zhang ◽  
Ping Shi

Abstract Clioquinol has been shown to have anticancer activity in several carcinoma cells. In this study, we preliminarily examined the effect of clioquinol in human SMMC-7721 hepatoma and QSG-7701 normal hepatic cells. Our results indicated that clioquinol did not significantly affect survival of QSG-7701 cells, whereas it reduced cell viability in a concentration- and time-dependent manner in SMMC-7721 cells. Clioquinol did not trigger autophagy and apoptosis, while it induced cell cycle arrest in the S-phase in SMMC- 7721 cells. Additionally, down-regulation of cyclin D1, A2, E1, Cdk2 and up-regulation of p21, p27 were detected after the treatment with clioquinol. The results demonstrated for the first time that clioquinol suppressed cell cycle progression in the S-phase in SMMC-7721 cells via the p21, p27-cyclin E,A/Cdk2 pathway. This suggests that clioquinol may have a therapeutic potential as an anticancer drug for certain malignances.


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