Fullerenol/iron nanocomposite diminishes doxorubicin-induced toxicity Seke, Mariana; Petrovic, Danijela; Labudovic Borovic, Milica ...
Journal of nanoparticle research : an interdisciplinary forum for nanoscale science and technology,
11/2019, Letnik:
21, Številka:
11
Journal Article
Fullerenol C
60
(OH)
24
with its spherical shape, symmetrical structure, 1 nm size and the ability to form polyionic nanoparticles in water solution, was used to synthesise a novel nanocomposite made ...of fullerenol nanoparticles (FNP) and iron ions (Fe
2+
). The FNP/Fe
2+
nanocomposite was characterised by DLS and TEM-EDS analyses which have shown that the size distribution of FNP/Fe
2+
stayed in the same scope as the size distribution of FNP, ranging from 11 to 60 nm. However, Fe
2+
did affect the change of FNP’s zeta potential (− 49.2 mV), shifting it to more positive values (− 30.8 mV). In this study, it was assumed that FNP/Fe
2+
could reduce the toxic effects of doxorubicin (Dox). Male Wistar rats were treated
i.p
. with FNP/Fe
2+
nanocomposite 1 h prior to Dox treatment. At the subcellular level, the ultrastructural analysis revealed minor alterations sporadically displayed within the heart and liver tissues. Moreover, at the molecular level, the gene expressions analysis of mRNAs for catalase (heart and liver) and MnSOD (only liver) were significantly downregulated, indicating reduction in oxidative stress. Overall, the pretreatment with FNP/Fe
2+
nanocomposite, followed by Dox application, significantly diminished harmful effects of the applied drug on the heart and liver, suggesting the potential protective effect of the nanocomposite on the healthy tissues.
The aim of our study was to examine the effects of different dietary strategies, high-fat (HFd) or standard diet (Sd) alone or in combination with standardized oral supplementation (0.45 mL/kg/day) ...of Aronia melanocarpa extract (SAE) in rats with metabolic syndrome (MetS). SAE is an official product of pharmaceutical company Pharmanova (Belgrade, Serbia); however, the procedure for extraction was done by EU-Chem company (Belgrade, Serbia). Rats were divided randomly into six groups: control with Sd, control with Sd and SAE, MetS with HFd, MetS with HFd and SAE, MetS with Sd and MetS with Sd and SAE during 4 weeks. At the end of the 4-week protocol, cardiac function and liver morphology were assessed, while in the blood samples glucose, insulin, iron levels and systemic redox state were determined. Our results demonstrated that SAE had the ability to lower blood pressure and exert benefits on in vivo and ex vivo heart function. Moreover, SAE improved glucose tolerance, attenuated pathological liver alterations and oxidative stress present in MetS. Obtained beneficial effects of SAE were more prominent in combination with changing dietary habits. Promising potential of SAE supplementation alone or in combination with different dietary protocols in triggering cardioprotection should be further examined in future.
We examined the effects of betaine, an endogenous and dietary methyl donor essential for the methionine-homocysteine cycle, on oxidative stress, inflammation, apoptosis, and autophagy in ...methionine-choline deficient diet (MCD)-induced non-alcoholic fatty liver disease (NAFLD). Male C57BL/6 mice received standard chow (control), standard chow and betaine (1.5% w/v in drinking water), MCD, or MCD and betaine. After six weeks, serum and liver samples were collected for analysis. Betaine reduced MCD-induced increase in liver transaminases and inflammatory infiltration, as well as hepatosteatosis and serum levels of low-density lipoprotein, while it increased that of high-density lipoprotein. MCD-induced hepatic production of reactive oxygen and nitrogen species was significantly reduced by betaine, which also improved liver antioxidative defense by increasing glutathione content and superoxide-dismutase, catalase, glutathione peroxidase, and paraoxonase activity. Betaine reduced the liver expression of proinflammatory cytokines tumor necrosis factor and interleukin-6, as well as that of proapoptotic mediator Bax, while increasing the levels of anti-inflammatory cytokine interleukin-10 and antiapoptotic Bcl-2 in MCD-fed mice. In addition, betaine increased the expression of autophagy activators beclin 1, autophagy-related (Atg)4 and Atg5, as well as the presence of autophagic vesicles and degradation of autophagic target sequestosome 1/p62 in the liver of NAFLD mice. The observed effects of betaine coincided with the increase in the hepatic phosphorylation of mammalian target of rapamycin (mTOR) and its activator Akt. In conclusion, the beneficial effect of betaine in MCD-induced NAFLD is associated with the reduction of liver oxidative stress, inflammation, and apoptosis, and the increase in cytoprotective Akt/mTOR signaling and autophagy.
The aim of this study was to examine the effects of folic acid administration on the antioxidant enzyme (superoxide dismutase (SOD) and catalase (CAT)) activities, lactate and malate dehydrogenase ...(LDH and MDH) activities, and certain LDH and MDH isoform distribution in the cardiac tissue of diabetic Wistar male rats. Diabetes mellitus (DM) was induced by streptozotocin (STZ). There were five groups: C1—control (physiological saline 1 ml/kg, i.p. one day), C2—control with daily physiological saline treatment (1 ml/kg, i.p. 28 days), DM—diabetes mellitus (STZ 100 mg/kg in physiological saline, i.p. one day), FA—folic acid (5 mg/kg in physiological saline, i.p. 28 days), and DM+FA—diabetes mellitus and folic acid group (STZ 100 mg/kg in physiological saline, i.p. one day, and folic acid 5 mg/kg in physiological saline, i.p. 28 days). After four weeks, animal hearts were isolated for measurement of enzyme activities, as well as for histomorphometry analyses. An elevated glucose level and a decreased insulin level were obtained in the DM group. SOD, CAT, and MDH activities were elevated in the DM group, while there was no difference in LDH activity among the groups. In all tested groups, four LDH and three MDH isoforms were detected in the heart tissue, but with differences in their relative activities among the groups. Left ventricular cardiomyocyte transversal diameters were significantly smaller in both diabetic groups. Folic acid treatment of diabetic rats induced a reduced glucose level and reduced CAT, SOD, and MDH activities and alleviated the decrease in cardiomyocyte diameters. In conclusion, increased activities of antioxidant enzymes and MDH may be the consequence of oxidative stress caused by DM. Administration of the folic acid has a protective effect since it leads to reduction in glycemia and activities of the certain examined enzymes in the rats with experimentally induced DM.
Macrophage inhibitory factor (MIF) is a multipotent cytokine, involved in the inflammatory response to infections or injuries. This study investigates the role of MIF in liver fibrosis and the ...modulating effect of betaine on MIF in thioacetamide (TAA)-induced liver fibrosis. The wild-type and knockout MIF−/− C57BL/6 mice were divided into the following groups: control; Bet group, which received betaine; MIF−/−; MIF−/−+Bet; TAA group, which received TAA; TAA+Bet; MIF−/−+TAA; and MIF−/−+TAA+Bet group. After eight weeks of treatment, liver tissue was collected for further analysis. The results revealed that TAA-treated MIF-deficient mice had elevated levels of hepatic TGF-β1 and PDGF-BB, as well as MMP-2, MMP-9, and TIMP-1 compared to TAA-treated wild-type mice. However, the administration of betaine to TAA-treated MIF-deficient mice reduced hepatic TGF-β1 and PDGF-BB levels and also the relative activities of MMP-2, MMP-9 and TIMP-1, albeit less effectively than in TAA-treated mice without MIF deficiency. Furthermore, the antifibrogenic effect of MIF was demonstrated by an increase in MMP2/TIMP1 and MMP9/TIMP1 ratios. The changes in the hepatic levels of fibrogenic factors were confirmed by a histological examination of liver tissue. Overall, the dual nature of MIF highlights its involvement in the progression of liver fibrosis. Its prooxidant and proinflammatory effects may exacerbate tissue damage and inflammation initially, but its antifibrogenic activity suggests a potential protective role against fibrosis development. The study showed that betaine modulates the antifibrogenic effects of MIF in TAA-induced liver fibrosis, by decreasing TGF-β1, PDGF-BB, MMP-2, MMP-9, TIMP-1, and the deposition of ECM (Coll1 and Coll3) in the liver.
The aims of this study were to examine the effects of pyridoxine administration on the activities of cardiac antioxidant stress enzymes superoxide dismutase (SOD) and catalase (CAT) and enzyme ...indicators of cardiometabolic status, lactate and malate dehydrogenase (LDH, MDH), as well as LDH and MDH isoforms’ distribution in the cardiac tissue of healthy and diabetic Wistar male rats. Experimental animals were divided into five groups: C1—control (0.9% sodium chloride—NaCl—1 mL/kg, intraperitoneally (i.p.), 1 day); C2—second control (0.9% NaCl 1 mL/kg, i.p., 28 days); DM—diabetes mellitus (streptozotocin 100 mg/kg in 0.9% NaCl, i.p., 1 day); P—pyridoxine (7 mg/kg, i.p., 28 days); and DM + P—diabetes mellitus and pyridoxine (streptozotocin 100 mg/kg, i.p., 1 day and pyridoxine 7 mg/kg, i.p., 28 days). Pyridoxine treatment reduced CAT and MDH activity in diabetic rats. In diabetic rats, the administration of pyridoxine increased LDH1 and decreased LDH4 isoform activities, as well as decreased peroxisomal MDH and increased mitochondrial MDH activities. Our findings highlight the positive effects of pyridoxine administration on the complex interplay between oxidative stress, antioxidant enzymes, and metabolic changes in diabetic cardiomyopathy.
Diabetes mellitus (DM) is a metabolic disorder that causes severe complications. Thus, the aims of this study were to investigate the influence of DM and folic acid treatment on liver and renal ...biomarkers, and heart remodeling through evaluation of cardiac matrix metalloproteinase (MMP) activity. There were 4 groups: control (physiological saline 1 mL/kg, i.p., 28 days), DM (streptozotocin STZ 100 mg/kg in physiological saline, i.p., 1 day), folic acid (FA; 5 mg/kg, i.p., 28 days), and DM+FA (STZ 100 mg/kg, i.p., 1 day and folic acid 5 mg/kg, i.p., 28 days). Our results demonstrated increased aminotransferase and alkaline phosphatase activity, urea and creatinine concentration, and decreased albumin and fibrinogen concentration in the DM group. MMP-2 relative activity was elevated in the DM and FA groups; MMP-9 was decreased in the DM and increased in the FA group. The folic acid treatment of diabetic rats did not change aminotransferase activity; it alleviated the increase in alkaline phosphatase and the decrease in albumin and fibrinogen concentration, and reduced MMP-2 activity; however, it increased urea and creatinine concentration. In conclusion, folic acid treatment of diabetic rats has cardio- and hepato-protective effects. However, its dosing should be carefully considered because of possible renal damage.
Heart failure (HF) is one of the major cardiovascular causes of death worldwide. In this study, we explored the effects of folic acid (FA) on cardiometabolic, oxidative stress biomarker changes, and ...the activity of proliferation marker Ki67 in monocrotaline-induced HF. The research was conducted during a 4 week period using five experimental groups (eight animals per group): blank solution exposed controls (C1: 1 mL/kg physiological saline, 1 day; C2: 1 mL/kg physiological saline, 28 days), monocrotaline (MCT) induced HF (50 mg/kg MCT), FA (5 mg·kg
−1
·day
−1
FA), and MCT+FA (50 mg/kg MCT, 5 mg·kg
−1
·day
−1
FA). Superoxide dismutase and glutathione peroxidase activities together with total glutathione and parameters of oxidative damage of proteins were determined in cardiac tissue as well as cardiometabolic parameters in plasma or serum. The total glutathionylation was determined by Western blot and proliferation marker Ki67 was assessed by immunohistochemistry. The right ventricular (RV) wall hypertrophy and Ki67 positivity, accompanied by a significant increase of troponin T, has been shown in MCT-induced HF. The antioxidant effect of FA was reflected through superoxide dismutase activity, reduced Ki67 positivity in the RV wall, and a slightly decreased total glutathionylation level.
Oestradiol is an important regulatory factor with several positive effects on the cardiovascular (CV) system. We evaluated the molecular mechanism of the in vivo effects of oestradiol on the ...regulation of cardiac inducible nitric oxide (NO) synthase (iNOS) expression and activity.
Male Wistar rats were treated with oestradiol (40 mg/kg, intraperitoneally) and after 24 h the animals were sacrificed. The concentrations of NO and L-Arginine (L-Arg) were determined spectrophotometrically. For protein expressions of iNOS, p65 subunit of nuclear factor-κB (NFκB-p65), Ras homolog gene family-member A (RhoA), angiotensin II receptor type 1 (AT1R), insulin receptor substrate 1 (IRS-1), p85, p110 and protein kinase B (Akt), Western blot method was used. Coimmunoprecipitation was used for measuring the association of IRS-1 with the p85 subunit of phosphatidylinositol- 3-kinase (PI3K). The expression of iNOS messenger ribonucleic acid (mRNA) was measured with the quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemical analysis of the tissue was used to detect localization and expression of iNOS in heart tissue.
Oestradiol treatment reduced L-Arg concentration (p<0.01), iNOS mRNA (p<0.01) and protein (p<0.001) expression, level of RhoA (p<0.05) and AT1R (p<0.001) protein. In contrast, plasma NO (p<0.05), Akt phosphorylation at Thr308 (p<0.05) and protein level of p85 (p<0.001) increased after oestradiol treatment.
Our results suggest that oestradiol in vivo regulates cardiac iNOS expression via the PI3K/Akt signaling pathway, through attenuation of RhoA and AT1R.
This study investigated different dietary strategies, high-fat (HFd), or standard diet (Sd) alone or in combination with standardized
Aronia melanocarpa
extract (SAE), as a polyphenol-rich diet, and ...their effects on lipids and fatty acids (FA) in rats with metabolic syndrome (MetS).
Wistar albino
rats were randomly divided into two groups: healthy and rats with MetS, and then depending on dietary patterns on six groups: healthy rats fed with Sd, healthy rats fed with Sd and SAE, rats with MetS fed with HFd, rats with MetS fed with HFd and SAE, rats with MetS fed with Sd, and rats with MetS fed with Sd and SAE. 4 weeks later, after an overnight fast (12–14 h), blood for determination of total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), index of lipid peroxidation (measured as TBARS), and FA was collected. Increased FA and lipid concentration found in MetS rats were reduced when changing dietary habits from HFd to Sd with or without SAE consumption. Consumption of SAE slightly affects the FA profiles, mostly palmitoleic acid in healthy rats and PUFA in MetS + HFd rats. Nevertheless, in a high-fat diet, SAE supplementation significantly decreases
n
-6/
n
-3 ratio, thereby decreasing systemic inflammation. Further researches are warranted to confirm these effects in humans.
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