scholarly journals The Hepatotoxicity of Alantolactone and Germacrone: Their Influence on Cholesterol and Lipid Metabolism in Differentiated HepaRG Cells

Nutrients ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1720
Author(s):  
Tomáš Zárybnický ◽  
Petra Matoušková ◽  
Lenka Skálová ◽  
Iva Boušová
Keyword(s):  
Lipid Metabolism ◽  
Mrna Expression ◽  
Anticancer Agents ◽  
Regulatory Element ◽  
Intercellular Adhesion Molecule ◽  
Functional Markers ◽  
Intercellular Adhesion Molecule 1 ◽  
Element Binding Protein ◽  
Coa Reductase ◽  
Toxic Concentrations

The sesquiterpenes alantolactone (ATL) and germacrone (GER) are potential anticancer agents of natural origin. Their toxicity and biological activity have been evaluated using the differentiated HepaRG (dHepaRG) cells, a hepatocyte-like model. The half-maximal inhibitory concentrations of cell viability after 24-h treatment of dHepaRG cells are approximately 60 M for ATL and 250 M for GER. However, both sesquiterpenes induce reactive oxygen species (ROS) formation in non-toxic concentrations and significantly dysregulate the mRNA expression of several functional markers of mature hepatocytes. They similarly decrease the protein level of signal transducer and activator of transcription 3 (STAT3), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-B) and their transcription target, intercellular adhesion molecule 1 (ICAM-1). Based on the results of a BATMAN-TCM analysis, the effects of sesquiterpenes on cholesterol and lipid metabolism were studied. Sesquiterpene-mediated dysregulation of both cholesterol and lipid metabolism was observed, during which these compounds influenced the protein expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and sterol regulatory element-binding protein 2 (SREBP-2), as well as the mRNA expression of HMGCR, CYP19A1, PLIN2, FASN, SCD, ACACB, and GPAM genes. In conclusion, the two sesquiterpenes caused ROS induction at non-toxic concentrations and alterations in cholesterol and lipid metabolism at slightly toxic and toxic concentrations, suggesting a risk of liver damage if administered to humans.

Diet-induced obesity and hepatic gene expression alterations in C57BL/6J and ICAM-1-deficient mice

2002 ◽  
Vol 282 (3) ◽  
pp. E703-E713 ◽  
Author(s):  
Francine M. Gregoire ◽  
Qin Zhang ◽  
Steven J. Smith ◽  
Carmen Tong ◽  
David Ross ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Fat Diet ◽  
Regulatory Element ◽  
Intercellular Adhesion Molecule ◽  
High Fat ◽  
Intercellular Adhesion Molecule 1 ◽  
Affymetrix Genechips ◽  
Element Binding Protein ◽  
Liver Gene ◽  
Deficient Mice

The effects of high-fat feeding on the development of obesity were evaluated in intercellular adhesion molecule-1 (ICAM-1) knockout and C57BL/6J (B6) male mice fed a high-fat diet for ≤50 days. Serum and tissues were collected at baseline and after 1, 11, and 50 days on the diet. After 11 days on the diet, ICAM-1-deficient, but not B6, mice developed fatty livers and showed a significant increase in inguinal fat pad weight. At day 50, ICAM-1-deficient mice weighed less, and their adiposity index and circulating leptin levels were significantly lower than those of B6 controls. To better understand the early differential response to the diet, liver gene expression was analyzed at three time points by use of Affymetrix GeneChips. In both strains, a similar pattern of gene expression was detected in response to the high-fat diet. However, sterol regulatory element-binding protein-1, apolipoprotein A4, and adipsin mRNAs were significantly induced in ICAM-1-deficient livers, suggesting that these genes and their associated pathways may be involved in the acute diet response observed in the knockout mice.

Thrombosis and Altered expression of Intercellular Adhesion Molecule-1 (Icam-1) after Avulsion Injury in Rat Vessels

2004 ◽  
Vol 29 (3) ◽  
pp. 228-232 ◽  
Author(s):  
N. ISOGAI ◽  
H. TANAKA ◽  
S. ASAMURA
Keyword(s):  
Mrna Expression ◽  
Adhesion Molecule ◽  
Microscopic Analysis ◽  
Intercellular Adhesion ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Post Injury ◽  
Electron Microscopic ◽  
Altered Expression ◽  
Avulsion Injury

This study was undertaken to characterize the relative degrees of arterial and venous trauma after graded avulsion injuries. Rat femoral arteries and veins were subjected to reproducible avulsion injuries using forces of between 60 and 220 g. Thrombotic occlusion occurred at lower avulsion forces in veins than in arteries. Histologic and scanning electron microscopic analysis indicated increased endothelial disruption and exposed elastic lamina with increasing avulsion force in both vessels, but more prominently in arteries. Intercellular adhesion molecule-1 (ICAM-1) mRNA expression was evident at 3 and 6 hours after avulsion injury in veins, but only with higher avulsion force injuries in arteries. ICAM-1 mRNA expression was not found in either vessel before or after this 3 to 6 hour post-injury interval. These results indicate that the amount of avulsion force to which traumatized extremity vessels are subjected has a direct effect on the degree of intimal injury and subsequent thrombosis.

scholarly journals Pengaruh Simvastatin Terhadap Kadar Proliferasi Limfosit Mencit Balb/C yang Diinduce Sepsis dengan LPS

2013 ◽  
Vol 5 (3) ◽  
pp. 193
Author(s):  
Made Ryan Kharmayani ◽  
Haris Lutfi ◽  
Danu Soesilowati
Keyword(s):  
Interferon Gamma ◽  
Adhesion Molecule ◽  
Intercellular Adhesion Molecule ◽  
T Helper ◽  
Intercellular Adhesion Molecule 1 ◽  
T Helper 1 ◽  
Mhc Ii ◽  
Leukocyte Function ◽  
Post Test ◽  
Coa Reductase

Latar Belakang : Statin, inhibitor 3-hidroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase merupakan agen yang paling efektif dalam menurunkan lipid dan mempunyai efek pleiotrofik yaitu anti inflamatori dan immunomodulatori. Statin juga memodifikasi interaksi interseluler dan kemotaksis seluler pada sistem imun serta berpotensi mempengaruhi limfosit T dengan cara menghambat iinteraksi antara adhesi molekul seluler leukocyte function-associated antigen-1 (LFA-1) dan intercellular adhesion molecule-1 (ICAM-1), juga menurunkan interferon gamma (IFN -ɣ) yang berperan dalam ekspresi class II major histocompatibilty complex (MHC II) pada antigen precenting cells (APC) dan merupakan proses penting dalam aktivasi sel T. Penurunan ekspresi MHC II berakibat pada inhibisi aktivasi CD 4 limfosit, sehingga mengakibatkan penurunan diferensiasi T helper-1 (Th1) dan pelepasan sitokin proinflamasi juga menurun.Tujuan : Membuktikan efek simvastatin dosis bertingkat peroral pada mencit yang diberi LPS intraperitoneal terhadap penurunan kadar proliferasi limfosit.Metode : Penelitian eksperimental laboratorik dengan desain randomized post test only controlled group pada 20 ekor mencit Balb/c yang disuntik lipopolisakarida 10 mg/KgBB intraperitoneal dan simvastatin dosis 0,03 mg, 0,06 mg dan 0,12 mg peroral. Mencit dibagi menjadi 4 kelompok secara random, yaitu K1 sebagai control,  K2 yang mendapat simvastatin 0,03 mg, K3 yang mendapat simvastatin 0,06 mg dan K4 yang mendapat simvastatin 0,12 mg. Pemeriksaan limfosit diambil dari kultur limpa setelah 72 jam pemberian simvastatin. Uji statistik yang digunakan adalah parametrik ANOVA dan dilanjutkan PosterioriHasil : Kadar rerata limfosit kelompok K1 (1,546 ± 0,106), K2 (0,541 ± 0,046), K3 (0,471 ± 0,013) dan K4 (0,553 ± 0,02). Terdapat penurunan kadar limfosit secara signifikan pada kelompok K2, K3 dan K4 dibanding K1 dengan p <0,05. Tidak terdapat perbedaan bermakna antara kadar limfosit kelompok K2 dengan kelompok K3 dan K4 ( p>0,05) tetapi didapatkan perbedaan bermakna antara kelompok K3 dibandingkan kelompok K4 ( p<0,05).Simpulan : Simvastatin secara signifikan menurunkan kadar proliferasi limfosit pada mencit yang diberi LPS intraperitoneal. Dosis 0,06 mg memiliki efek menekan kadar proliferasi limfosit paling besar.

scholarly journals Tissue-Specific Effects of Central Leptin on the Expression of Genes Involved in Lipid Metabolism in Liver and White Adipose Tissue

Endocrinology ◽  
2007 ◽  
Vol 148 (12) ◽  
pp. 5604-5610 ◽  
Author(s):  
Nilda Gallardo ◽  
Elena Bonzón-Kulichenko ◽  
Teresa Fernández-Agulló ◽  
Eduardo Moltó ◽  
Sergio Gómez-Alonso ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Lipid Metabolism ◽  
White Adipose Tissue ◽  
Binding Protein ◽  
Regulatory Element ◽  
Epididymal Adipose Tissue ◽  
Key Enzymes ◽  
Specific Effects ◽  
Element Binding Protein ◽  
Sterol Regulatory Element

Leptin reduces adiposity and exerts antisteatotic effects on nonadipose tissues. However, the mechanisms underlying leptin effects on lipid metabolism in liver and white adipose tissue have not been fully clarified. Here, we have studied the effects of central leptin administration on key enzymes and transcription factors involved in lipid metabolism in liver and epididymal adipose tissue. Intracerebroventricular leptin infusion for 7 d did not change leptin plasma levels but decreased triacylglyceride content in liver, epididymal adipose tissue, and plasma. In both tissues this treatment markedly decreased the expression of key enzymes of the de novo fatty acid (FA) synthesis such as acetyl-coenzyme A-carboxylase, FA synthase, and stearoyl-coenzyme A desaturase-1, in parallel with a reduction in mRNA expression of sterol regulatory element binding protein-1c in liver and carbohydrate regulatory element binding protein in adipose tissue. In addition, leptin also decreased phosphoenol-pyruvate carboxykinase-C expression in adipose tissue, an enzyme involved in glyceroneogenesis in this tissue. Central leptin administration down-regulates delta-6-desaturase expression in liver and adipose tissue, in parallel with the decrease of the expression of sterol regulatory element binding protein-1c in liver and peroxisome proliferator activated receptor α in adipose tissue. Finally, leptin treatment, by regulating adipose triglyceride lipase/hormone sensitive lipase/diacylglycerol transferase 1 expression, also established a new partitioning in the FA-triacylglyceride cycling in adipose tissue, increasing lipolysis and probably the FA efflux from this tissue, and favoring in parallel the FA uptake and oxidation in the liver. These results suggest that leptin, acting at central level, exerts tissue-specific effects in limiting fat tissue mass and lipid accumulation in nonadipose tissues, preventing the development of obesity and type 2 diabetes.

scholarly journals Associations between the ICAM1 gene polymorphisms and atherosclerotic cardiovascular disease risk, including hypercholesterolemia, in rural Thais

2021 ◽  
Author(s):  
Naruemon Wechjakwen ◽  
Amornrat Aroonnual ◽  
Pattaneeya Prangthip ◽  
Ngamphol Soonthornworasiri ◽  
Pornpimol Panprathip Phienluphon ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Mrna Expression ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Intercellular Adhesion Molecule ◽  
Atherosclerotic Cardiovascular Disease ◽  
Nucleotide Polymorphisms ◽  
Intercellular Adhesion Molecule 1 ◽  
Single Nucleotide ◽  
Atherosclerotic Cardiovascular Disease Risk

Abstract We determine the relationships between single nucleotide polymorphisms (SNPs), including rs5498 and rs287432 on Intercellular adhesion molecule 1 gene (ICAM1) and atherosclerotic cardiovascular disease (ASCVD) susceptibility in patients with hypercholesterolemia (HCL). The clinical characteristics of 278 participants were assessed, classified to group having HCL and without HCL. ICAM1 SNPs Genotyping was performed by DNA sequencing and ICAM1 expression was measured using real-time PCR. Positive dominant model rs5498 subjects had twice the risk of HCL (P = 0.005). Participants with the rs5498 AG or GG variants and high ICAM1 mRNA expression (≥ 3.12) had 2.68 times the risk (P = 0.000), and those with a high LDL-C concentration (≥ 3.36 mmol/L) had 1.99 times the risk (P = 0.014) of developing ASCVD compared with those with low ICAM1 mRNA and LDL-C levels. Interestingly, participants carrying the rs5498 AG or GG variants who had tachycardia (resting heart rates (RHRs) > 100 beats/min) had a 5.40-times higher risk than those with a lower RHR (P = 0.010). It may consider the G allele in ICAM1 rs5498 is associated with a higher risk of ASCVD in Thai people with HCL, and is also positively associated with ICAM1 mRNA expression, LDL-C concentration, and RHR.

Modulation of human Niemann-Pick C1-like 1 gene expression by sterol: role of sterol regulatory element binding protein 2

2007 ◽  
Vol 292 (1) ◽  
pp. G369-G376 ◽  
Author(s):  
Waddah A. Alrefai ◽  
Fadi Annaba ◽  
Zaheer Sarwar ◽  
Alka Dwivedi ◽  
Seema Saksena ◽  
...  
Keyword(s):  
Promoter Activity ◽  
Binding Protein ◽  
Regulatory Element ◽  
Cholesterol Absorption ◽  
Cholesterol Depletion ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Niemann Pick ◽  
Coa Reductase

Niemann-Pick C1-like 1 (NPC1L1) is an essential intestinal component of cholesterol absorption. However, little is known about the molecular regulation of intestinal NPC1L1 expression and promoter activity. We demonstrated that human NPC1L1 mRNA expression was significantly decreased by 25-hydroxycholesterol but increased in response to cellular cholesterol depletion achieved by incubation with Mevinolin (an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase) in human intestinal Caco-2 cells. We also showed that a −1741/+56 fragment of the NPC1L1 gene demonstrated high promoter activity in Caco-2 cells that was reduced by 25-hydroxycholesterol and stimulated by cholesterol depletion. Interestingly, we showed that the NPC1L1 promoter is remarkably transactivated by the overexpression of sterol regulatory element (SRE) binding protein (SREBP)-2, suggesting its involvement in the sterol-induced alteration in NPC1L1 promoter activity. Finally, we identified two putative SREs in the human NPC1L1 promoter and established their essential roles in mediating the effects of cholesterol on promoter activity. Our study demonstrated the modulation of human NPC1L1 expression and promoter activity by cholesterol in a SREBP-2-dependent mechanism.

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