Intracellular Exposure Dose-Associated Susceptibility of Steatotic Hepatocytes to Metallic Nanoparticles

Non-alcoholic fatty liver disease (NAFLD), mainly characterized by the accumulation of excess fat in hepatocytes, is the most prevalent liver disorder afflicting ~25% of adults worldwide. In vivo studies have shown that adult rodents with NAFLD were more sensitive to metallic nanoparticles (MNPs) than healthy MNPs. However, due to the complex interactions between various cell types in a fatty liver, it has become a major challenge to reveal the toxic effects of MNPs to specific types of liver cells such as steatotic hepatocytes. In this study, we reported the susceptibility of steatotic hepatocytes in cytotoxicity and the induction of oxidative stress to direct exposures to MNPs with different components (silver, ZrO2, and TiO2 NPs) and sizes (20–30 nm and 125 nm) in an oleic acid (OA) -induced steatotic HepG2 (sHepG2) cell model. Furthermore, the inhibitory potential of MNPs against the process of fatty acid oxidation (FAO) were obvious in sHepG2 cells, even at extremely low doses of 2 or 4 μg/mL, which was not observed in non-steatotic HepG2 (nHepG2) cells. Further experiments on the differential cell uptake of MNPs in nHepG2 and sHepG2 cells demonstrated that the susceptibility of steatotic hepatocytes to MNP exposures was in association with the higher cellular accumulation of MNPs. Overall, our study demonstrated that it is necessary and urgent to take the intracellular exposure dose into consideration when assessing the potential toxicity of environmentally exposed MNPs.

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Activation of TAF9 via Danshensu-Induced Upregulation of HDAC1 Expression Alleviates Non-alcoholic Fatty Liver Disease

Frontiers in Pharmacology ◽

10.3389/fphar.2021.775528 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ruiwen Wang ◽

Zhecheng Wang ◽

Ruimin Sun ◽

Rong Fu ◽

Yu Sun ◽

...

Keyword(s):

Fatty Acid ◽

Liver Disease ◽

Fatty Liver ◽

Protective Effect ◽

Fatty Liver Disease ◽

Cell Model ◽

Signaling Mechanism ◽

Alcoholic Fatty Liver

Fatty acid β-oxidation is an essential pathogenic mechanism in nonalcoholic fatty liver disease (NAFLD), and TATA-box binding protein associated factor 9 (TAF9) has been reported to be involved in the regulation of fatty acid β-oxidation. However, the function of TAF9 in NAFLD, as well as the mechanism by which TAF9 is regulated, remains unclear. In this study, we aimed to investigate the signaling mechanism underlying the involvement of TAF9 in NAFLD and the protective effect of the natural phenolic compound Danshensu (DSS) against NAFLD via the HDAC1/TAF9 pathway. An in vivo model of high-fat diet (HFD)-induced NAFLD and a palmitic acid (PA)-treated AML-12 cell model were developed. Pharmacological treatment with DSS significantly increased fatty acid β-oxidation and reduced lipid droplet (LD) accumulation in NAFLD. TAF9 overexpression had the same effects on these processes both in vivo and in vitro. Interestingly, the protective effect of DSS was markedly blocked by TAF9 knockdown. Mechanistically, TAF9 was shown to be deacetylated by HDAC1, which regulates the capacity of TAF9 to mediate fatty acid β-oxidation and LD accumulation during NAFLD. In conclusion, TAF9 is a key regulator in the treatment of NAFLD that acts by increasing fatty acid β-oxidation and reducing LD accumulation, and DSS confers protection against NAFLD through the HDAC1/TAF9 pathway.

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Hepatoprotective effects of herbal medicines against non-alcoholic fatty liver disease; A systematic review of clinical and in vivo studies

Current Traditional Medicine ◽

10.2174/2215083807666211007094102 ◽

2021 ◽

Vol 07 ◽

Author(s):

Alireza Moayyedkazemi ◽

Morteza Amraei ◽

Efran Babaei Nejad ◽

Ali Moghaddam ◽

Kimia Karami ◽

...

Keyword(s):

Systematic Review ◽

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Herbal Medicines ◽

In Vivo Studies ◽

Alcoholic Fatty Liver ◽

Hepatoprotective Effects ◽

Alcoholic Fatty Liver Disease

Background: In this systematic review, we mainly emphasis on the current advances on the hepatoprotective effects of medicinal herbs in the non-alcoholic fatty liver diseases (NAFLD) treatment. Methods: This review was done based on the 06- PRISMA guideline (Moher, Liberati Tetzlaff, & Altman, 2009) and registered in the CAMARADES-NC3Rs Preclinical Systematic Review and Meta-Analysis Facility (SyRF) database. We did all the research in scientific databases in some English language databases, such as Web of Science, PubMed, Scopus, Google Scholar, and EMBASE, with no limitation in time to find the in vivo and clinical investigations on hepatoprotective effects of herbal medicines on non-alcoholic fatty liver disease. The selected words and terms for our search were: “fatty liver”, “extract”, “essential oil”, “clinical trial”, “herbal medicine”, “medicinal plants”, and “non-alcoholic fatty liver”. Results: Out of 21230 papers, 28 papers including 21 in vivo (75.0%), and 7 clinical trials (25.0%) up to 2020, met the inclusion criteria for discussion in this systematic review. The most part used of plants were leaves (14, 50.0%), rhizome (4, 14.3%), seeds (3, 10.3%), respectively. The most formulations of medicinal herbs were extracts essential oil (9, 35.7%) followed by ethanolic extract (5, 17.8%). The most animals used in vivo studies were rats (12, 42.8%) followed by mice (9, 32.1%). The obtained results also showed that the most period of administrated by these plants were 12 weeks (6, 21.4%), 2 months (6, 21.4%), and 30 days (3, 10.7%), respectively. Conclusion: The obtained findings of the present review demonstrated that medicinal plants due to high availability, high efficacy, and low or minimal toxicity are considered as a valuable and proper alternative to chemical synthetic drugs to treat and prevent of NAFLD. However, further studies especially on the toxicity of these agents are required to approve these recommendations.

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Natural Aldose Reductase Inhibitor: A Potential Therapeutic Agent for Non-alcoholic Fatty Liver Disease

Current Drug Targets ◽

10.2174/1389450120666191007111712 ◽

2020 ◽

Vol 21 (6) ◽

pp. 599-609 ◽

Cited By ~ 3

Author(s):

Longxin Qiu ◽

Chang Guo

Keyword(s):

Oxidative Stress ◽

Liver Disease ◽

Fatty Liver ◽

Aldose Reductase ◽

Fatty Liver Disease ◽

Acid Oxidation ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Alcoholic Fatty Liver ◽

Nonalcoholic Fatty Liver

Aldose reductase (AR) has been reported to be involved in the development of nonalcoholic fatty liver disease (NAFLD). Hepatic AR is induced under hyperglycemia condition and converts excess glucose to lipogenic fructose, which contributes in part to the accumulation of fat in the liver cells of diabetes rodents. In addition, the hyperglycemia-induced AR or nutrition-induced AR causes suppression of the transcriptional activity of peroxisome proliferator-activated receptor (PPAR) α and reduced lipolysis in the liver, which also contribute to the development of NAFLD. Moreover, AR induction in non-alcoholic steatohepatitis (NASH) may aggravate oxidative stress and the expression of inflammatory cytokines in the liver. Here, we summarize the knowledge on AR inhibitors of plant origin and review the effect of some plant-derived AR inhibitors on NAFLD/NASH in rodents. Natural AR inhibitors may improve NAFLD at least in part through attenuating oxidative stress and inflammatory cytokine expression. Some of the natural AR inhibitors have been reported to attenuate hepatic steatosis through the regulation of PPARα-mediated fatty acid oxidation. In this review, we propose that the natural AR inhibitors are potential therapeutic agents for NAFLD.

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Adipocyte PHLPP2 inhibition prevents obesity-induced fatty liver

Nature Communications ◽

10.1038/s41467-021-22106-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

KyeongJin Kim ◽

Jin Ku Kang ◽

Young Hoon Jung ◽

Sang Bae Lee ◽

Raffaela Rametta ◽

...

Keyword(s):

Fatty Liver ◽

Whole Body ◽

Acid Oxidation ◽

Chow Diet ◽

Peroxisome Proliferator ◽

Obese Mice ◽

Ph Domain ◽

Peroxisome Proliferator Activated Receptor

AbstractIncreased adiposity confers risk for systemic insulin resistance and type 2 diabetes (T2D), but mechanisms underlying this pathogenic inter-organ crosstalk are incompletely understood. We find PHLPP2 (PH domain and leucine rich repeat protein phosphatase 2), recently identified as the Akt Ser473 phosphatase, to be increased in adipocytes from obese mice. To identify the functional consequence of increased adipocyte PHLPP2 in obese mice, we generated adipocyte-specific PHLPP2 knockout (A-PHLPP2) mice. A-PHLPP2 mice show normal adiposity and glucose metabolism when fed a normal chow diet, but reduced adiposity and improved whole-body glucose tolerance as compared to Cre- controls with high-fat diet (HFD) feeding. Notably, HFD-fed A-PHLPP2 mice show increased HSL phosphorylation, leading to increased lipolysis in vitro and in vivo. Mobilized adipocyte fatty acids are oxidized, leading to increased peroxisome proliferator-activated receptor alpha (PPARα)-dependent adiponectin secretion, which in turn increases hepatic fatty acid oxidation to ameliorate obesity-induced fatty liver. Consistently, adipose PHLPP2 expression is negatively correlated with serum adiponectin levels in obese humans. Overall, these data implicate an adipocyte PHLPP2-HSL-PPARα signaling axis to regulate systemic glucose and lipid homeostasis, and suggest that excess adipocyte PHLPP2 explains decreased adiponectin secretion and downstream metabolic consequence in obesity.

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A self-assembled Ru–Pt metallacage as a lysosome-targeting photosensitizer for 2-photon photodynamic therapy

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1912549116 ◽

2019 ◽

Vol 116 (41) ◽

pp. 20296-20302 ◽

Cited By ~ 21

Author(s):

Zhixuan Zhou ◽

Jiangping Liu ◽

Juanjuan Huang ◽

Thomas W. Rees ◽

Yiliang Wang ◽

...

Keyword(s):

Photodynamic Therapy ◽

Near Infrared ◽

Building Blocks ◽

Cell Uptake ◽

Photon Absorption ◽

In Vivo Studies ◽

Infrared Light ◽

Ros Generation ◽

Multicellular Spheroids

Photodynamic therapy (PDT) is a treatment procedure that relies on cytotoxic reactive oxygen species (ROS) generated by the light activation of a photosensitizer. The photophysical and biological properties of photosensitizers are vital for the therapeutic outcome of PDT. In this work a 2D rhomboidal metallacycle and a 3D octahedral metallacage were designed and synthesized via the coordination-driven self-assembly of a Ru(II)-based photosensitizer and complementary Pt(II)-based building blocks. The metallacage showed deep-red luminescence, a large 2-photon absorption cross-section, and highly efficient ROS generation. The metallacage was encapsulated into an amphiphilic block copolymer to form nanoparticles to encourage cell uptake and localization. Upon internalization into cells, the nanoparticles selectively accumulate in the lysosomes, a favorable location for PDT. The nanoparticles are almost nontoxic in the dark, and can efficiently destroy tumor cells via the generation of ROS in the lysosomes under 2-photon near-infrared light irradiation. The superb PDT efficacy of the metallacage-containing nanoparticles was further validated by studies on 3D multicellular spheroids (MCS) and in vivo studies on A549 tumor-bearing mice.

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In vitro neuroprotective activities of two distinct probiotic consortia

Beneficial Microbes ◽

10.3920/bm2018.0105 ◽

2019 ◽

Vol 10 (4) ◽

pp. 437-447 ◽

Cited By ~ 2

Author(s):

D.R. Michael ◽

T.S. Davies ◽

K.E. Loxley ◽

M.D. Allen ◽

M.A. Good ◽

...

Keyword(s):

Cell Model ◽

Neuronal Cell ◽

In Vivo Studies ◽

Intact Cells ◽

Bacterial Consortia ◽

Differentiated Cells ◽

Genes Encoding ◽

Induced Apoptosis

Neurodegeneration has been linked to changes in the gut microbiota and this study compares the neuroprotective capability of two bacterial consortia, known as Lab4 and Lab4b, using the established SH-SY5Y neuronal cell model. Firstly, varying total antioxidant capacities (TAC) were identified in the intact cells from each consortia and their secreted metabolites, referred to as conditioned media (CM). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Crystal Violet (CV) assays of cell viability revealed that Lab4 CM and Lab4b CM could induce similar levels of proliferation in SH-SY5Y cells and, despite divergent TAC, possessed a comparable ability to protect undifferentiated and retinoic acid-differentiated cells from the cytotoxic actions of rotenone and undifferentiated cells from the cytotoxic actions of 1-methyl-4-phenylpyridinium iodide (MPP+). Lab4 CM and Lab4b CM also had the ability to attenuate rotenone-induced apoptosis and necrosis with Lab4b inducing the greater effect. Both consortia showed an analogous ability to attenuate intracellular reactive oxygen species accumulation in SH-SY5Y cells although the differential upregulation of genes encoding glutathione reductase and superoxide dismutase by Lab4 CM and Lab4b CM, respectively, implicates the involvement of consortia-specific antioxidative mechanisms of action. This study implicates Lab4 and Lab4b as potential neuroprotective agents and justifies their inclusion in further in vivo studies.

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Adiponectin: A Key Adipokine in Alcoholic Fatty Liver

Experimental Biology and Medicine ◽

10.3181/0902-mr-61 ◽

2009 ◽

Vol 234 (8) ◽

pp. 850-859 ◽

Cited By ~ 74

Author(s):

Min You ◽

Christopher Q. Rogers

Keyword(s):

Fatty Liver ◽

De Novo ◽

Regulatory System ◽

Receptor Expression ◽

Sirtuin 1 ◽

De Novo Lipogenesis ◽

Lipid Lowering ◽

Acid Oxidation ◽

Alcoholic Fatty Liver ◽

Central Target

Alcoholic fatty liver is a major risk factor for advanced liver injuries such as steatohepatitis, fibrosis, and cirrhosis. While the underlying mechanisms are multiple, the development of alcoholic fatty liver has been attributed to a combined increase in the rate of de novo lipogenesis and a decrease in the rate of fatty acid oxidation in animal liver. Among various transcriptional regulators, the hepatic SIRT1 (sirtuin 1)-AMPK (AMPK-activated kinase) signaling system represents a central target for the action of ethanol in the liver. Adiponectin is one of the adipocyte-derived adipokines with potent lipid-lowering properties. Growing evidence has demonstrated that the development of alcoholic fatty liver is associated with reduced circulating adiponectin levels, decreased hepatic adiponectin receptor expression, and impaired hepatic adiponectin signaling. Adiponectin confers protection against alcoholic fatty liver via modulation of complex hepatic signaling pathways largely controlled by the central regulatory system, SIRT1-AMPK axis. This review aims to integrate the current research findings of ethanol-mediated dysregulation of adiponectin and its receptors and to provide a comprehensive point of view for understanding the role of adiponectin signaling in the development of alcoholic fatty liver.

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