Strong antineoplastic effects of metformin in preclinical models of liver carcinogenesis

2016 ◽  
Vol 131 (1) ◽  
pp. 27-36 ◽  
Author(s):  
François Cauchy ◽  
Mouniya Mebarki ◽  
Benjamin Leporq ◽  
Samira Laouirem ◽  
Miguel Albuquerque ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Visceral Fat ◽  
Tumour Growth ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Hepatoma Cell ◽  
Preclinical Models ◽  
Subcutaneous Tumour ◽  
Fat Composition ◽  
The Impact

Studies suggest that metformin, widely used for treating Type 2 diabetes, possesses innate antineoplastic properties. For metabolic syndrome patients with hepatocellular carcinoma (HCC), metformin may provide antitumoral effects. We evaluated the impact of metformin on tumour growth and visceral fat composition using relevant preclinical models of metabolic syndrome. Studies were performed in three hepatoma cell lines, in HepG2 xenograft mice fed with standard chow (SC) diet, 60% high-fat diet (HFD) or 30% fructose diet (FR), and an ex vivo model of human cultured HCC slices. Visceral fatty acid composition was analysed by magnetic resonance imaging (MRI). Metformin had a dose-dependent inhibitory effect on cell proliferation and apoptosis in vitro through the deregulation of mTOR/AMPK, AKT and extracellular signal regulated kinase (ERK) signalling pathways. Tumour engraftment rates were higher in HFD mice than SC mice (hepatic: 79% compared with 25%, P=0.02) and FR mice (subcutaneous: 86% compared with 50%, P=0.04). Subcutaneous tumour volume was increased in HFD mice (+64% compared with FR and SC, P=0.03). Metformin significantly decreased subcutaneous tumour growth via cell-cycle block and mammalian target of rapamycin (mTOR) pathway inhibition, and also induced hypoxia and decreased angiogenesis. In ex vivo tumour slices, metformin treatment led to increased necrosis, decreased cyclin D1 and increased carbonic anhydrase-9 (CA-9). Metformin caused qualitative changes in visceral fat composition of HFD mice, with decreased proportions of polyunsaturated fatty acids (14.6% ± 2.3% compared with 17.9% ± 3.0%, P=0.04). The potent antitumoral effects of metformin in multiple preclinical models implicating several molecular mechanisms provide a strong rationale for clinical trials including combination studies in HCC patients.

scholarly journals Cell–cell coupling and DNA methylation abnormal phenotypes in the after-hours mice

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Federico Tinarelli ◽  
Elena Ivanova ◽  
Ilaria Colombi ◽  
Erica Barini ◽  
Edoardo Balzani ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Neuronal Networks ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Neuronal Cultures ◽  
Functional Impairments ◽  
After Hours ◽  
The Impact

Abstract Background DNA methylation has emerged as an important epigenetic regulator of brain processes, including circadian rhythms. However, how DNA methylation intervenes between environmental signals, such as light entrainment, and the transcriptional and translational molecular mechanisms of the cellular clock is currently unknown. Here, we studied the after-hours mice, which have a point mutation in the Fbxl3 gene and a lengthened circadian period. Methods In this study, we used a combination of in vivo, ex vivo and in vitro approaches. We measured retinal responses in Afh animals and we have run reduced representation bisulphite sequencing (RRBS), pyrosequencing and gene expression analysis in a variety of brain tissues ex vivo. In vitro, we used primary neuronal cultures combined to micro electrode array (MEA) technology and gene expression. Results We observed functional impairments in mutant neuronal networks, and a reduction in the retinal responses to light-dependent stimuli. We detected abnormalities in the expression of photoreceptive melanopsin (OPN4). Furthermore, we identified alterations in the DNA methylation pathways throughout the retinohypothalamic tract terminals and links between the transcription factor Rev-Erbα and Fbxl3. Conclusions The results of this study, primarily represent a contribution towards an understanding of electrophysiological and molecular phenotypic responses to external stimuli in the Afh model. Moreover, as DNA methylation has recently emerged as a new regulator of neuronal networks with important consequences for circadian behaviour, we discuss the impact of the Afh mutation on the epigenetic landscape of circadian biology.

scholarly journals Sex Hormone Binding Globulin (SHBG) Mitigates ER Stress in Hepatocytes In Vitro and Ex Vivo

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 755
Author(s):  
Katarzyna Kornicka-Garbowska ◽  
Lynda Bourebaba ◽  
Michael Röcken ◽  
Krzysztof Marycz
Keyword(s):  
Metabolic Syndrome ◽  
Er Stress ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Sex Hormone ◽  
Sex Hormone Binding Globulin ◽  
Large Animal Model ◽  
Large Animal ◽  
Hormone Binding

Despite multiple research studies regarding metabolic syndrome and diabetes, the full picture of their molecular background and pathogenies remains elusive. The latest studies revealed that sex hormone-binding globulin (SHBG)—a serum protein released mainly by the liver—may participate in metabolic dysregulation, as its low serum level correlates with a risk for obesity, metabolic syndrome, and diabetes. Yet, the molecular phenomenon linking SHBG with these disorders remains unclear. In the presented study, we investigate how exogenous SHBG affects metabolically impaired hepatocytes with special attention to endoplasmic reticulum stress (ER stress) and lipid metabolism both in vitro and ex vivo. For that reason, palmitate-treated HepG2 cells and liver tissue samples collected post mortem were cultured in the presence of 50 nM and 100 nM SHBG. We found that SHBG protects against ER stress development and its progression. We have found that SHBG decreased the expression levels of inositol-requiring enzyme 1 (IRE1α), activating transcription factor 6 (ATF6), DNA damage-inducible transcript 3 (CHOP), and immunoglobulin heavy chain-binding protein (BIP). Furthermore, we have shown that it regulates lipolytic gene expression ex vivo. Additionally, herein, we deliver a novel large-animal model to study SHBG in translational research. Our data provide new insights into the cellular and molecular mechanisms by which SHBG modulates hepatocyte metabolism and offer a new experimental approach to study SHBG in human diseases.

Overexpression of Par-4 Increases TRAIL-Induced Apoptosis in Neoplastic Lymphocytes by Diminishing Expression of Inhibitors-of-Apoptosis-Proteins and by Enforcing Activation of Initiator- and Executionercaspases.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4329-4329
Author(s):  
Simone Boehrer ◽  
Daniel Nowak ◽  
Dieter Hoelzer ◽  
Paris S. Mitrou ◽  
Kai Uwe Chow
Keyword(s):  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Jurkat Cells ◽  
Extrinsic Pathway ◽  
Neoplastic Lymphocytes ◽  
Executioner Caspases ◽  
Induced Apoptosis ◽  
Gene 4 ◽  
The Impact ◽  
Apoptosis Proteins

Abstract Acknowledging the previously demonstrated deregulated expression of the prostate-apoptosis-response-gene-4 (par-4) in ex vivo cells of patients suffering from acute and chronic lymphatic leukemias, we hypothesized that expression of par-4 determines sensitivity of neoplastic lymphocytes towards TRAIL-induced apoptosis. Evaluating this hypothesis we thus demonstrate, that par-4-transfected Jurkat cells incubated with the agonistic TRAIL-antibody CH11 exhibit a considerably increased rate of apoptosis as compared to their par-4-negative counterparts. Outlining the underlying molecular mechanisms we provide evidence, that par-4 promotes activation of the initiator caspase-8. Despite upregulating Bcl-2, overexpression of par-4 enhances cleavage of Bid and activation of caspase-9, resulting in an enforced activation of the executioner caspases-6 and -7, whereas caspase-3 remains unaltered. These effects are observed with a concomittant down-regulation of the inhibitor-of-apoptosis proteins cIAP-1 and XIAP. In conclusion, we here provide first evidence that expression of par-4 augments sensitivity of neoplastic lymphocytes to TRAIL-induced cell death, and describe the impact of par-4-expression on key molecules considered crucial in the induction of apoptosis via the extrinsic pathway.

scholarly journals Advanced Molecular Imaging (MRI/MRS/1H NMR) for Metabolic Information in Young Adults with Health Risk Obesity

Life ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1035
Author(s):  
Khin Thandar Htun ◽  
Jie Pan ◽  
Duanghathai Pasanta ◽  
Montree Tungjai ◽  
Chatchanok Udomtanakunchai ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Young Adults ◽  
Molecular Imaging ◽  
Body Fat ◽  
Visceral Fat ◽  
Fat Distribution ◽  
Fat Depots ◽  
The Metabolic Syndrome ◽  
Fat Depot ◽  
The Impact

Background: Obesity or being overweight is a medical condition of abnormal body fat accumulation which is associated with a higher risk of developing metabolic syndrome. The distinct body fat depots on specific parts of the anatomy have unique metabolic properties and different types of regional excessive fat distribution can be a disease hazard. The aim of this study was to identify the metabolome and molecular imaging phenotypes among a young adult population. Methods: The amount and distribution of fat and lipid metabolites profile in the abdomen, liver, and calf muscles of 46 normal weight, 17 overweight, and 13 obese participants were acquired using MRI and MR spectroscopy (MRS), respectively. The serum metabolic profile was obtained using proton NMR spectroscopy. NMR spectra were integrated into seven integration regions, which reflect relative metabolites. Results: A significant metabolic disorder symptom appeared in the overweight and obese group, and increased lipid deposition occurred in the abdomen, hepatocytes, and muscles that were statistically significant. Overall, the visceral fat depots had a marked influence on dyslipidemia biomarkers, blood triglyceride (r = 0.592, p < 0.001), and high-density lipoprotein cholesterol (r = −0.484, p < 0.001). Intrahepatocellular lipid was associated with diabetes predictors for hemoglobin (HbA1c%; r = 0.379, p < 0.001) and for fasting blood sugar (r = 0.333, p < 0.05). The lipid signals in serum triglyceride and glucose signals gave similar correspondence to biochemical lipid profiles. Conclusions: This study proves the association between alteration in metabolome in young adults, which is the key population for early prevention of obesity and metabolic syndrome. This study suggests that dyslipidemia prevalence is influenced mainly by the visceral fat depot, and liver fat depot is a key determinant for glucose metabolism and hyperglycemia. Moreover, noninvasive advanced molecular imaging completely elucidated the impact of fat distribution on the anthropometric and laboratory parameters, especially indices of the metabolic syndrome biomarkers in young adults.

scholarly journals Garlic Derived Diallyl Trisulfide in Experimental Metabolic Syndrome: Metabolic Effects and Cardioprotective Role

2020 ◽  
Vol 21 (23) ◽  
pp. 9100
Author(s):  
Jovana N. Jeremic ◽  
Vladimir Lj. Jakovljevic ◽  
Vladimir I. Zivkovic ◽  
Ivan M. Srejovic ◽  
Jovana V. Bradic ◽  
...  
Keyword(s):  
Gene Expression ◽  
Metabolic Syndrome ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Metabolic Effects ◽  
Albino Rats ◽  
Diallyl Trisulfide ◽  
Relative Gene Expression ◽  
The Impact ◽  
Relative Gene

This study aimed to examine the effects of diallyl trisulfide (DATS), the most potent polysulfide derived from garlic, on metabolic syndrome and myocardial function in rats with metabolic syndrome (MetS). For that purpose, we used 36 male Wistar albino rats divided into control rats, rats with MetS and MetS rats treated with 40 mg/kg of DATS every second day for 3 weeks. In the first part, we studied the impact of DATS on MetS control and found that DATS significantly raised H2S, decreased homocysteine and glucose levels and enhanced lipid and antioxidative, while reducing prooxidative parameters. Additionally, this polysulfide improved cardiac function. In the second part, we investigated the impact of DATS on ex vivo induced ischemia/reperfusion (I/R) heart injury and found that DATS consumption significantly improved cardiodynamic parameters and prevented oxidative and histo-architectural variation in the heart. In addition, DATS significantly increased relative gene expression of eNOS, SOD-1 and -2, Bcl-2 and decreased relative gene expression of NF-κB, IL-17A, Bax, and caspases-3 and -9. Taken together, the data show that DATS can effectively mitigate MetS and have protective effects against ex vivo induced myocardial I/R injury in MetS rat.

scholarly journals Molecular Mechanisms of Leonurus Cardiaca L. Extract Activity in Prevention of Staphylococcal Endocarditis—Study on in Vitro and ex Vivo Models

Molecules ◽  
2019 ◽  
Vol 24 (18) ◽  
pp. 3318
Author(s):  
Beata Sadowska ◽  
Dariusz Laskowski ◽  
Przemysław Bernat ◽  
Bartłomiej Micota ◽  
Marzena Więckowska-Szakiel ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Blood Platelets ◽  
Adhesion Forces ◽  
Herbal Products ◽  
Bacterial Membranes ◽  
Invasive Infections ◽  
Leonurus Cardiaca ◽  
The Impact

Better understanding the mechanisms of Leonurus cardiaca L. extract (LCE) activity is necessary to prepare recommendations for the use of LCE-based herbal products for preventive/supportive purposes in case of infective endocarditis (IE) and other staphylococcal invasive infections. The aim of the study was to analyze molecular mechanisms of LCE effect on Staphylococcus aureus and blood platelets in the context of their interactions playing a pivotal role in such disorders. Using atomic force microscopy, we demonstrated that adhesion forces of S. aureus were markedly reduced after exposure to LCE at subinhibitory concentrations. The effect resulted from the impact of LCE on S. aureus cell morphology and the composition of phospholipids and fatty acids in bacterial membranes (assessed by HPLC), which modulated their stabilization, hydrophobicity, and charge. Moreover, using FACS we showed also that LCE significantly reduced GP IIb/IIIa expression on blood platelets, thus the disruption of platelet-fibrinogen interactions seems to explain antiplatelet effect of LCE. The obtained results prove the usefulness of LCE in the prevention of S. aureus adhesion, platelet activation, and vegetations development, however, also pointed out the necessity of excluding the cationic antibiotics from the treatment of S. aureus-associated IE and other invasive diseases, when motherwort herb is used simultaneously as an addition to the daily diet.

THE IMPACT OF SLEEP DISORDERS ON THE STATE OF PSYCHOEMOTIONAL SPHERE IN METABOLIC SYNDROME

2017 ◽  
Vol 19 (2) ◽  
pp. 11-14
Author(s):  
N.S. Alekseeva ◽  
◽  
O.I. Salmina-Khvostova ◽  
E.V. Beloborodova ◽  
◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Sleep Disorders ◽  
The State ◽  
The Impact
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