Molecules

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15 pages, 3969 KiB

Open AccessArticle

Contribution of TGF-β1 and Effects of Gene Silencer Pyrrole-Imidazole Polyamides Targeting TGF-β1 in Diabetic Nephropathy

by Shu Horikoshi, Noboru Fukuda, Akiko Tsunemi, Makiyo Okamura, Masari Otsuki, Morito Endo and Masanori Abe

Molecules 2020, 25(4), 950; https://doi.org/10.3390/molecules25040950 - 20 Feb 2020

Cited by 21 | Viewed by 3063

Abstract

TGF-β1 has been known to induce diabetic nephropathy with renal fibrosis and glomerulosclerosis. DNA-recognized peptide compound pyrrole-imidazole (PI) polyamides as novel biomedicines can strongly bind promoter lesions of target genes to inhibit its transcription. We have developed PI polyamide targeting TGF-β1 for progressive [...] Read more.

TGF-β1 has been known to induce diabetic nephropathy with renal fibrosis and glomerulosclerosis. DNA-recognized peptide compound pyrrole-imidazole (PI) polyamides as novel biomedicines can strongly bind promoter lesions of target genes to inhibit its transcription. We have developed PI polyamide targeting TGF-β1 for progressive renal diseases. In the present study, we evaluated the contribution of TGF-β1 in the pathogenesis of diabetic nephropathy, and examined the effects of PI polyamide targeting TGF-β1 on the progression of diabetic nephropathy in rats. For in vitro experiments, rat renal mesangial cells were incubated with a high (25 mM) glucose concentration. Diabetic nephropathy was established in vivo in eight-week-old Wistar rats by intravenously administering 60 mg/kg streptozotocin (STZ). We examined the effects of PI polyamide targeting TGF-β1 on phenotype and the growth of mesangial cells, in vitro, and the pathogenesis of diabetic nephropathy in vivo. High glucose significantly increased expression of TGF-β1 mRNA, changed the phenotype to synthetic, and increased growth of mesangial cells. STZ diabetic rats showed increases in urinary excretions of protein and albumin, glomerular and interstitial degenerations, and podocyte injury. Treatment with PI polyamide targeting TGF-β1 twice weekly for three months improved the glomerular and interstitial degenerations by histological evaluation. Treatment with PI polyamide improved podocyte injury by electron microscopy evaluation. These findings suggest that TGF-β1 may be a pivotal factor in the progression of diabetic nephropathy, and PI polyamide targeting TGF-β1 as a practical medicine may improve nephropathy. Full article

(This article belongs to the Special Issue Bioactive Compounds for Metabolic Syndrome and Type 2 Diabetes-II)

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24 pages, 3070 KiB

Open AccessArticle

Pleiotropic Activity of Metformin and Its Sulfonamide Derivatives on Vascular and Platelet Haemostasis

by Magdalena Markowicz-Piasecka, Kristiina M. Huttunen, Adrianna Sadkowska and Joanna Sikora

Molecules 2020, 25(1), 125; https://doi.org/10.3390/molecules25010125 - 28 Dec 2019

Cited by 15 | Viewed by 4620

Abstract

As type 2 diabetes mellitus (T2DM) predisposes patients to endothelial cell injury and dysfunction, improvement of vascular function should be an important target for therapy. The aim of this study was to evaluate the effects of metformin, its sulfenamide and sulfonamide derivatives on [...] Read more.

As type 2 diabetes mellitus (T2DM) predisposes patients to endothelial cell injury and dysfunction, improvement of vascular function should be an important target for therapy. The aim of this study was to evaluate the effects of metformin, its sulfenamide and sulfonamide derivatives on selected parameters of endothelial and smooth muscle cell function, and platelet activity. Metformin was not found to significantly affect the viability of human umbilical vein endothelial cells (HUVECs) or aortal smooth muscle cells (AoSMC); however, it decreased cell migration by approximately 21.8% in wound healing assays after 24 h stimulation (wound closure 32.5 µm versus 41.5 µm for control). Metformin reduced platelet aggregation manifested by 19.0% decrease in maximum of aggregation (A_max), and 20% reduction in initial platelet aggregation velocity (v₀). Furthermore, metformin decreased spontaneous platelet adhesion by 27.7% and ADP-induced adhesion to fibrinogen by 29.6% in comparison to control. Metformin sulfenamide with an n-butyl alkyl chain (compound 1) appeared to exert the most unfavourable effects on AoSMC cell viability (IC₅₀ = 0.902 ± 0.015 μmol/mL), while 4-nitrobenzenesulfonamide (compound 3) and 2-nitrobenzenesulfonamide (compound 4) derivatives of metformin did not affect AoSMC and HUVEC viability at concentrations up to 2.0 μmol/mL. These compounds were also found to significantly reduce migration of smooth muscle cells by approximately 81.0%. Furthermore, sulfonamides 3 and 4 decreased the initial velocity of platelet aggregation by 11.8% and 20.6%, respectively, and ADP-induced platelet adhesion to fibrinogen by 76.3% and 65.6%. Metformin and its p- and o-nitro-benzenesulfonamide derivatives 3, 4 appear to exert beneficial effects on some parameters of vascular and platelet haemostasis. Full article

(This article belongs to the Special Issue Bioactive Compounds for Metabolic Syndrome and Type 2 Diabetes-II)

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19 pages, 3779 KiB

Open AccessArticle

Deficiency of Urokinase Plasminogen Activator May Impair β Cells Regeneration and Insulin Secretion in Type 2 Diabetes Mellitus

by Chung-Ze Wu, Shih-Hsiang Ou, Li-Chien Chang, Yuh-Feng Lin, Dee Pei and Jin-Shuen Chen

Molecules 2019, 24(23), 4208; https://doi.org/10.3390/molecules24234208 - 20 Nov 2019

Cited by 6 | Viewed by 2847

Abstract

Background: The relationship between urokinase-type plasminogen activator (uPA) and the development of type 2 diabetes mellitus (T2DM) was investigated in the study by using mice and cell models, as well as patients with T2DM. Methods: In mice models, wild-type and uPA knockout (uPA-/-) [...] Read more.

Background: The relationship between urokinase-type plasminogen activator (uPA) and the development of type 2 diabetes mellitus (T2DM) was investigated in the study by using mice and cell models, as well as patients with T2DM. Methods: In mice models, wild-type and uPA knockout (uPA-/-) BALB/c mice were used for induction of T2DM. In cell models, insulin secretion rate and β cell proliferation were assessed in normal and high glucose after treating uPA siRNA, uPA, or anti-uPA antibody. In our clinical study, patients with T2DM received an oral glucose-tolerance test, and the relationship between uPA and insulin secretion was assessed. Results: Insulin particles and insulin secretion were mildly restored one month after induction in wild-type mice, but not in uPA-/- mice. In cell models, insulin secretion rate and cell proliferation declined in high glucose after uPA silencing either by siRNA or by anti-uPA antibody. After treatment with uPA, β cell proliferation increased in normal glucose. In clinical study, patients with T2DM and higher uPA levels had better ability of insulin secretion than those with lower uPA levels. Conclusion: uPA may play a substantial role in insulin secretion, β cell regeneration, and progressive development of T2DM. Supplementation of uPA might be a novel approach for prevention and treatment of T2DM in the future. Full article

(This article belongs to the Special Issue Bioactive Compounds for Metabolic Syndrome and Type 2 Diabetes-II)

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14 pages, 1570 KiB

Open AccessArticle

Biological Evaluation of Natural and Synthesized Homovanillic Acid Esters as Inhibitors of Intestinal Fatty Acid Uptake in Differentiated Caco-2 Cells

by Barbara Lieder, Joachim Hans, Fabia Hentschel, Katrin Geissler and Jakob Ley

Molecules 2019, 24(19), 3599; https://doi.org/10.3390/molecules24193599 - 7 Oct 2019

Cited by 8 | Viewed by 4280

Abstract

With raising prevalence of obesity, the regulation of human body fat is increasingly relevant. The modulation of fatty acid uptake by enterocytes represents a promising target for body weight maintenance. Recent results demonstrated that the trigeminal active compounds capsaicin, nonivamide, and trans-pellitorine [...] Read more.

With raising prevalence of obesity, the regulation of human body fat is increasingly relevant. The modulation of fatty acid uptake by enterocytes represents a promising target for body weight maintenance. Recent results demonstrated that the trigeminal active compounds capsaicin, nonivamide, and trans-pellitorine dose-dependently reduce fatty acid uptake in differentiated Caco-2 cells as a model for the intestinal barrier. However, non-pungent alternatives have not been investigated and structural determinants for the modulation of intestinal fatty acid uptake have not been identified so far. Thus, based on the previous results, we synthesized 23 homovanillic acid esters in addition to the naturally occurring capsiate and screened them for their potential to reduce intestinal fatty acid uptake using the fluorescent fatty acid analog Bodipy-C12 in differentiated Caco‑2 cells as an enterocyte model. Whereas pre-incubation with 100 µM capsiate did not change fatty acid uptake by Caco-2 enterocytes, a maximum inhibition of −47% was reached using 100 µM 1‑methylpentyl-2-(4-hydroxy-3-methoxy-phenyl)acetate. Structural analysis of the 24 structural analogues tested in the present study revealed that a branched fatty acid side chain, independent of the chain length, is one of the most important structural motifs associated with inhibition of fatty acid uptake in Caco-2 enterocytes. The results of the present study may serve as an important basis for designing potent dietary inhibitors of fatty acid uptake. Full article

(This article belongs to the Special Issue Bioactive Compounds for Metabolic Syndrome and Type 2 Diabetes-II)

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17 pages, 5754 KiB

Open AccessArticle

Design, Synthesis, and Activity Evaluation of Novel N-benzyl Deoxynojirimycin Derivatives for Use as α-Glucosidase Inhibitors

by Fanxin Zeng, Zhongping Yin, Jiguang Chen, Xuliang Nie, Ping Lin, Tao Lu, Meng Wang and Dayong Peng

Molecules 2019, 24(18), 3309; https://doi.org/10.3390/molecules24183309 - 11 Sep 2019

Cited by 9 | Viewed by 3218

Abstract

To obtain α-glucosidase inhibitors with high activity, 19 NB-DNJDs (N-benzyl-deoxynojirimycin derivatives) were designed and synthesized. The results indicated that the 19 NB-DNJDs displayed different inhibitory activities towards α-glucosidase in vitro. Compound 18a (1-(4-hydroxy-3-methoxybenzyl)-2-(hydroxymethyl) piperidine-3,4,5-triol) showed the highest activity, with an IC [...] Read more.

To obtain α-glucosidase inhibitors with high activity, 19 NB-DNJDs (N-benzyl-deoxynojirimycin derivatives) were designed and synthesized. The results indicated that the 19 NB-DNJDs displayed different inhibitory activities towards α-glucosidase in vitro. Compound 18a (1-(4-hydroxy-3-methoxybenzyl)-2-(hydroxymethyl) piperidine-3,4,5-triol) showed the highest activity, with an IC₅₀ value of 0.207 ± 0.11 mM, followed by 18b (1-(3-bromo-4-hydroxy-5-methoxybenzyl)-2-(hydroxymethyl) piperidine-3,4,5-triol, IC₅₀: 0.276 ± 0.13 mM). Both IC₅₀ values of 18a and 18b were significantly lower than that of acarbose (IC₅₀: 0.353 ± 0.09 mM). According to the structure-activity analysis, substitution of the benzyl and bromine groups on the benzene ring decreased the inhibition activity, while methoxy and hydroxyl group substitution increased the activity, especially with the hydroxyl group substitution. Molecular docking results showed that three hydrogen bonds were formed between compound 18a and amino acids in the active site of α-glucosidase. Additionally, an arene–arene interaction was also modelled between the phenyl ring of compound 18a and Arg 315. The three hydrogen bonds and the arene–arene interaction resulted in a low binding energy (−5.8 kcal/mol) and gave 18a a higher inhibition activity. Consequently, compound 18a is a promising candidate as a new α-glucosidase inhibitor for the treatment of type Ⅱ diabetes. Full article

(This article belongs to the Special Issue Bioactive Compounds for Metabolic Syndrome and Type 2 Diabetes-II)

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19 pages, 2216 KiB

Open AccessArticle

Aspalathin-Rich Green Rooibos Extract Lowers LDL-Cholesterol and Oxidative Status in High-Fat Diet-Induced Diabetic Vervet Monkeys

by Patrick Orlando, Nireshni Chellan, Johan Louw, Luca Tiano, Ilenia Cirilli, Phiwayinkosi Dludla, Elizabeth Joubert and Christo J.F. Muller

Molecules 2019, 24(9), 1713; https://doi.org/10.3390/molecules24091713 - 2 May 2019

Cited by 25 | Viewed by 4935

Abstract

Type 2 diabetic patients possess a two to four-fold-increased risk for cardiovascular diseases (CVD). Hyperglycemia, oxidative stress associated with endothelial dysfunction and dyslipidemia are regarded as pro-atherogenic mechanisms of CVD. In this study, high-fat diet-induced diabetic and non-diabetic vervet monkeys were treated with [...] Read more.

Type 2 diabetic patients possess a two to four-fold-increased risk for cardiovascular diseases (CVD). Hyperglycemia, oxidative stress associated with endothelial dysfunction and dyslipidemia are regarded as pro-atherogenic mechanisms of CVD. In this study, high-fat diet-induced diabetic and non-diabetic vervet monkeys were treated with 90 mg/kg of aspalathin-rich green rooibos extract (Afriplex GRT) for 28 days, followed by a 1-month wash-out period. Supplementation showed improvements in both the intravenous glucose tolerance test (IVGTT) glycemic area under curve (AUC) and total cholesterol (due to a decrease of the low-density lipoprotein [LDL]) values in diabetics, while non-diabetic monkeys benefited from an increase in high-density lipoprotein (HDL) levels. No variation of plasma coenzyme Q10 (CoQ₁₀) were found, suggesting that the LDL-lowering effect of Afriplex GRT could be related to its ability to modulate the mevalonate pathway differently from statins. Concerning the plasma oxidative status, a decrease in percentage of oxidized CoQ₁₀ and circulating oxidized LDL (ox-LDL) levels after supplementation was observed in diabetics. Finally, the direct correlation between the amount of oxidized LDL and total LDL concentration, and the inverse correlation between ox-LDL and plasma CoQ₁₀ levels, detected in the diabetic monkeys highlighted the potential cardiovascular protective role of green rooibos extract. Taken together, these findings suggest that Afriplex GRT could counteract hyperglycemia, oxidative stress and dyslipidemia, thereby lowering fundamental cardiovascular risk factors associated with diabetes. Full article

(This article belongs to the Special Issue Bioactive Compounds for Metabolic Syndrome and Type 2 Diabetes-II)

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8 pages, 1693 KiB

Open AccessArticle

New Metabolic Influencer on Oxytocin Release: The Ghrelin

by Renáta Szabó, Rudolf Ménesi, Andor H. Molnár, Zita Szalai, Lejla Daruka, Gábor Tóth, János Gardi, Márta Gálfi, Denise Börzsei, Krisztina Kupai, Anna Juhász, Marianna Radács, Ferenc A. László, Csaba Varga and Anikó Pósa

Molecules 2019, 24(4), 735; https://doi.org/10.3390/molecules24040735 - 18 Feb 2019

Cited by 10 | Viewed by 4114

Abstract

Background: The hypothalamic–pituitary axis by secreting neuropeptides plays a key role in metabolic homeostasis. In light of the metabolic regulation, oxytocin is a potential neuropeptide for therapies against obesity and related disorders. The aim of our study is to measure ghrelin-induced oxytocin secretion [...] Read more.

Background: The hypothalamic–pituitary axis by secreting neuropeptides plays a key role in metabolic homeostasis. In light of the metabolic regulation, oxytocin is a potential neuropeptide for therapies against obesity and related disorders. The aim of our study is to measure ghrelin-induced oxytocin secretion in rats and to detect the changes after administration of ghrelin antagonist. Methods: Ghrelin was administrated centrally (intracerebroventricular, i.c.v., 1.0, 10.0, and 100.0 pmol) or systemically (intravenous, i.v., 1.0, and 10.0 nmol). [d-Lys³]-GHRP-6 ghrelin antagonist was injected 15 min before ghrelin injection in a dose of 10.0 pmol i.c.v. and 10.0 nmol i.v. Results: Either i.c.v. or i.v. administration of ghrelin dose-dependently increased the plasma oxytocin concentration. Following pretreatment with the ghrelin antagonist [d-Lys³]-GHRP-6, the high plasma oxytocin level induced by ghrelin was significantly reduced. Conclusion: The results indicate that the release of oxytocin is influenced directly by the ghrelin system. Examination of the mechanism of ghrelin-induced oxytocin secretion is a new horizon for potential therapeutic options. Full article

(This article belongs to the Special Issue Bioactive Compounds for Metabolic Syndrome and Type 2 Diabetes-II)

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18 pages, 2559 KiB

Open AccessFeature PaperArticle

The Drug Candidate BGP-15 Delays the Onset of Diastolic Dysfunction in the Goto-Kakizaki Rat Model of Diabetic Cardiomyopathy

by Mariann Bombicz, Daniel Priksz, Rudolf Gesztelyi, Rita Kiss, Nora Hollos, Balazs Varga, Jozsef Nemeth, Attila Toth, Zoltan Papp, Zoltan Szilvassy and Bela Juhasz

Molecules 2019, 24(3), 586; https://doi.org/10.3390/molecules24030586 - 7 Feb 2019

Cited by 17 | Viewed by 4788

Abstract

Background and Aims: Diabetic cardiomyopathy (DCM) is an emerging problem worldwide due to an increase in the incidence of type 2 diabetes. Animal studies have indicated that metformin and pioglitazone can prevent DCM partly by normalizing insulin resistance, and partly by other, [...] Read more.

Background and Aims: Diabetic cardiomyopathy (DCM) is an emerging problem worldwide due to an increase in the incidence of type 2 diabetes. Animal studies have indicated that metformin and pioglitazone can prevent DCM partly by normalizing insulin resistance, and partly by other, pleiotropic mechanisms. One clinical study has evidenced the insulin-senzitizing effect of the drug candidate BGP-15, along with additional animal studies that have confirmed its beneficial effects in models of diabetes, muscular dystrophy and heart failure, with the drug affecting chaperones, contractile proteins and mitochondria. Our aim was to investigate whether the inzulin-senzitizer BGP-15 exert any additive cardiovascular effects compared to metformin or pioglitazone, using Goto-Kakizaki (GotoK) rats. Methods: Rats were divided into five groups: (I) healthy control (Wistar), (II) diseased (GotoK), and GotoK rats treated with: (III) BGP-15, (IV) metformin, and (V) pioglitazone, respectively, for 12 weeks. Metabolic parameters and insulin levels were determined at the endpoint. Doppler echocardiography was carried out to estimate diabetes-associated cardiac dysfunction. Thoracotomy was performed after the vascular status of rats was evaluated using an isolated aortic ring method. Furthermore, western blot assays were carried out to determine expression or phosphorylation levels of selected proteins that take part in myocyte relaxation. Results: BGP-15 restored diastolic parameters (e′/a′, E/e′, LAP, E and A wave) and improved Tei-index compared to untreated GotoK rats. Vascular status was unaffected by BGP-15. Expression of sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA2a) and phosphodiesterase 9A (PDE9A) were unchanged by the treatments, but the phosphorylation level of vasodilator-stimulated phosphoprotein (VASP) and phospholamban (PLB) increased in BGP-15-treated rats, in comparison to GotoK. Conclusions: Even though the BGP-15-treatment did not interfere significantly with glucose homeostasis and vascular status, it considerably enhanced diastolic function, by affecting the SERCA/phospholamban pathway in GotoK rats. Although it requires further investigation, BGP-15 may offer a new therapeutic approach in DCM. Full article

(This article belongs to the Special Issue Bioactive Compounds for Metabolic Syndrome and Type 2 Diabetes-II)

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9 pages, 1975 KiB

Open AccessArticle

Preparation and Evaluation of Antidiabetic Agents of Berberine Organic Acid Salts for Enhancing the Bioavailability

by Hong-Xin Cui, Ya-Nan Hu, Jing-Wan Li, Ke Yuan and Ying Guo

Molecules 2019, 24(1), 103; https://doi.org/10.3390/molecules24010103 - 28 Dec 2018

Cited by 43 | Viewed by 6732

Abstract

Berberine has many pharmacological effects, such as antidiabetic, antimicrobial, anti-inflammatory, and antioxidant, but the question remains on how its low oral bioavailability has greatly limited its clinical application. As a safer hypoglycemic agent, we must evaluate the bioavailability of berberine organic acid salts [...] Read more.

Berberine has many pharmacological effects, such as antidiabetic, antimicrobial, anti-inflammatory, and antioxidant, but the question remains on how its low oral bioavailability has greatly limited its clinical application. As a safer hypoglycemic agent, we must evaluate the bioavailability of berberine organic acid salts (BOAs) to ensure that the bioavailability of berberine is not negatively affected. It has been proven that the bioavailability of BOAs is higher than that of BH (berberine hydrochloride); especially BF (berberine fumarate) and BS (berberine succinate), which are improved by 1.278-fold and 1.313-fold, respectively. After 1 h of oral administration, berberine mainly acted on the stomach of mice, it also influenced the liver, kidney, lungs, and intestines after 4 h. The accumulation of BF in the lung is more evident than BH. Our analysis shows that these results are closely related to the regulation of organic acids and berberine in the intestinal tract, they also indicate the influence of intestinal flora on berberine metabolism. Full article

(This article belongs to the Special Issue Bioactive Compounds for Metabolic Syndrome and Type 2 Diabetes-II)

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15 pages, 1436 KiB

Open AccessArticle

Insulin Mimetic Properties of Extracts Prepared from Bellis perennis

by Renate Haselgrübler, Verena Stadlbauer, Flora Stübl, Bettina Schwarzinger, Ieva Rudzionyte, Markus Himmelsbach, Marcus Iken and Julian Weghuber

Molecules 2018, 23(10), 2605; https://doi.org/10.3390/molecules23102605 - 11 Oct 2018

Cited by 26 | Viewed by 6491

Abstract

Diabetes mellitus (DM) and consequential cardiovascular diseases lead to millions of deaths worldwide each year; 90% of all people suffering from DM are classified as Type 2 DM (T2DM) patients. T2DM is linked to insulin resistance and a loss of insulin sensitivity. It [...] Read more.

Diabetes mellitus (DM) and consequential cardiovascular diseases lead to millions of deaths worldwide each year; 90% of all people suffering from DM are classified as Type 2 DM (T2DM) patients. T2DM is linked to insulin resistance and a loss of insulin sensitivity. It leads to a reduced uptake of glucose mediated by glucose transporter 4 (GLUT4) in muscle and adipose tissue, and finally hyperglycemia. Using a fluorescence microscopy-based screening assay we searched for herbal extracts that induce GLUT4 translocation in the absence of insulin, and confirmed their activity in chick embryos. We found that extracts prepared from Bellis perennis (common daisy) are efficient inducers of GLUT4 translocation in the applied in vitro cell system. In addition, these extracts also led to reduced blood glucose levels in chicken embryos (in ovo), confirming their activity in a living organism. Using high-performance liquid chromtaography (HPLC) analysis, we identified and quantified numerous polyphenolic compounds including apigenin glycosides, quercitrin and chlorogenic acid, which potentially contribute to the induction of GLUT4 translocation. In conclusion, Bellis perennis extracts reduce blood glucose levels and are therefore suitable candidates for application in food supplements for the prevention and accompanying therapy of T2DM. Full article

(This article belongs to the Special Issue Bioactive Compounds for Metabolic Syndrome and Type 2 Diabetes-II)

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16 pages, 2102 KiB

Open AccessArticle

Hexanoic, Octanoic and Decanoic Acids Promote Basal and Insulin-Induced Phosphorylation of the Akt-mTOR Axis and a Balanced Lipid Metabolism in the HepG2 Hepatoma Cell Line

by Sabri Ahmed Rial, Gaetan Ravaut, Tommy B. Malaret, Karl-F. Bergeron and Catherine Mounier

Molecules 2018, 23(9), 2315; https://doi.org/10.3390/molecules23092315 - 11 Sep 2018

Cited by 25 | Viewed by 7104

Abstract

Metabolic illnesses such as non-alcoholic fatty liver disease (NAFLD) are in constant increase worldwide. Highly consumed long chain fatty acids (LCFA) are among the most obesogenic and steatogenic nutrients. Hepatic steatosis is associated with several complications such as insulin resistance. Growing evidence points [...] Read more.

Metabolic illnesses such as non-alcoholic fatty liver disease (NAFLD) are in constant increase worldwide. Highly consumed long chain fatty acids (LCFA) are among the most obesogenic and steatogenic nutrients. Hepatic steatosis is associated with several complications such as insulin resistance. Growing evidence points to medium chain fatty acids (MCFA), more efficiently oxidized than LCFA, as a promising dietary alternative against NAFLD. However, reports on the hepatic effects of MCFA are sometimes conflicting. In this study we exposed HepG2 cells, a human hepatocellular model, to 0.25 mM of hexanoic (C6), or octanoic (C8), and decanoic (C10) acids separately or in a C8 + C10 equimolar mix reflecting commercially available MCFA-rich oils. We found that C6, a poorly studied MCFA, as well as C8 and C10 did not provoke the deleterious lipid anabolism runaway typically induced by LCFA palmitate. MCFA tended, instead, to promote a balanced metabolic profile and were generally non-cytotoxic. Accordingly, mitochondrial integrity was mostly preserved following MCFA treatment. However, treatments with C8 induced a mitochondrial membrane potential decrease, suggesting prolonged exposure to this lipid could be problematic. Finally, MCFA treatments maintained optimal insulin sensitivity and even fostered basal and insulin-dependent phosphorylation of the Akt-mTOR pathway. Overall, MCFA could constitute an effective nutritional tool to manage liver steatosis and hepatic insulin resistance. Full article

(This article belongs to the Special Issue Bioactive Compounds for Metabolic Syndrome and Type 2 Diabetes-II)

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Review

Jump to: Research, Other

13 pages, 734 KiB

Open AccessReview

Pharmacological Overview of the BGP-15 Chemical Agent as a New Drug Candidate for the Treatment of Symptoms of Metabolic Syndrome

by Ágota Pető, Dóra Kósa, Pálma Fehér, Zoltán Ujhelyi, Dávid Sinka, Miklós Vecsernyés, Zoltán Szilvássy, Béla Juhász, Zoltán Csanádi, László Vígh and Ildikó Bácskay

Molecules 2020, 25(2), 429; https://doi.org/10.3390/molecules25020429 - 20 Jan 2020

Cited by 28 | Viewed by 6712

Abstract

BGP-15 is a new insulin sensitizer drug candidate, which was developed by Hungarian researchers. In recent years, numerous research groups have studied its beneficial effects. It is effective in the treatment of insulin resistance and it has protective effects in Duchenne muscular dystrophy, [...] Read more.

BGP-15 is a new insulin sensitizer drug candidate, which was developed by Hungarian researchers. In recent years, numerous research groups have studied its beneficial effects. It is effective in the treatment of insulin resistance and it has protective effects in Duchenne muscular dystrophy, diastolic dysfunction, tachycardia, heart failure, and atrial fibrillation, and it can alleviate cardiotoxicity. BGP-15 exhibits chemoprotective properties in different cytostatic therapies, and has also proven to be photoprotective. It can additionally have advantageous effects in mitochondrial-stress-related diseases. Although the precise mechanism of the effect is still unknown to us, we know that the molecule is a PARP inhibitor, chaperone co-inducer, reduces ROS production, and is able to remodel the organization of cholesterol-rich membrane domains. In the following review, our aim was to summarize the investigated molecular mechanisms and pharmacological effects of this potential API. The main objective was to present the wide pharmacological potentials of this chemical agent. Full article

(This article belongs to the Special Issue Bioactive Compounds for Metabolic Syndrome and Type 2 Diabetes-II)

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4 pages, 179 KiB

Open AccessCommentary

The Modulatory Action of Vitamin D on the Renin–Angiotensin System and the Determination of Hepatic Insulin Resistance

by Po Sing Leung

Molecules 2019, 24(13), 2479; https://doi.org/10.3390/molecules24132479 - 5 Jul 2019

Cited by 20 | Viewed by 4241

Abstract

Vitamin D deficiency or hypovitaminosis D is associated with increased risks of insulin resistance, type 2 diabetes mellitus (T2DM) and its related non-alcoholic fatty liver disease (NAFLD). Meanwhile, inappropriate over-activation of the renin–angiotensin system (RAS) in the liver leads to the hepatic dysfunction [...] Read more.

Vitamin D deficiency or hypovitaminosis D is associated with increased risks of insulin resistance, type 2 diabetes mellitus (T2DM) and its related non-alcoholic fatty liver disease (NAFLD). Meanwhile, inappropriate over-activation of the renin–angiotensin system (RAS) in the liver leads to the hepatic dysfunction and increased risk of T2DM, such as abnormalities in lipid and glucose metabolism. Our previous findings have shown that calcitriol, an active metabolite of vitamin D, reduces hepatic triglyceride accumulation and glucose output in diabetic db/db mice and human hepatocellular cell HepG2 cells under insulin-resistant conditions. Notwithstanding the existence of this evidence, the protective action of vitamin D in the modulation of overexpressed RAS-induced metabolic abnormalities in the liver under insulin resistance remains to be elusive and investigated. Herein, we have reported the potential interaction between vitamin D and RAS; and its beneficial effects on the expression and function of the RAS components in HepG2 cells and primary hepatocytes under insulin-resistance states. Our study findings suggest that hormonal vitamin D (calcitriol) has modulatory action on the inappropriate upregulation of the hepatic RAS under insulin-resistant conditions. If confirmed, vitamin D supplementation might provide a nutraceutical potential as a cost-effective approach for the management of hepatic metabolic dysfunction as observed in T2DM and related NAFLD. Full article

(This article belongs to the Special Issue Bioactive Compounds for Metabolic Syndrome and Type 2 Diabetes-II)

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