Diphenyl diselenide protects against metabolic disorders induced by acephate acute exposure in rats

The present study investigated the effect of diphenyl diselenide [(PhSe)₂] on metabolic disorders induced by acephate acute exposure in rats. We also investigated a possible mechanism of action of (PhSe)₂ against hyperglycemia induced by acephate. (PhSe)₂ was administered to rats at a dose of 10 or 30 mg/kg by oral gavage (p.o.) 1 hour prior to acephate administration (140 mg/kg; p.o.). Glucose and corticosterone levels as well as the lipid status were determined in plasma of rats. Cardiovascular risk factors and the atherogenic index were calculated. Glycogen levels as well as tyrosine aminotransferase (TAT) and glucose‐6‐phosphatase (G6Pase) activities were determined in livers of rats. Cerebral acetylcholinesterase (AChE) activity was assayed. Acephate induced an increase in glucose and corticosterone levels as well as in TAT and G6Pase activities. AChE activity was inhibited by acephate. Triglyceride (TG) levels and the cardiovascular risk factor TG/high‐density lipoprotein‐cholesterol (HDL) were increased by acephate. (PhSe)₂ was effective against the metabolic disorders induced by acephate acute exposure in rats. © 2012 Wiley Periodicals, Inc. Environ Toxicol 29: 665–671, 2014.     

Protective effects of vitamin E and selenium against dimethoate‐induced cardiotoxicity in vivo: Biochemical and histological studies

There is considerable interest in the study of free radical‐mediated damage to biological systems due to pesticide exposure. However, there is a lack of consensus as to which determinations are best used to quantify future risks arising from xenobiotic exposure and natural antioxidant interventions. Our study investigated the potential ability of selenium and/or vitamin E, used as nutritional supplements, to alleviate cardiotoxicity induced by dimethoate. Female Wistar rats were exposed for 30 days either to dimethoate (0.2 g L^?1 of drinking water), dimethoate+selenium (0.5 mg kg^?1 of diet), dimethoate+vitamin E (100 mg kg^?1 of diet), or dimethoate+selenium+vitamin E. The exposure of rats to dimethoate promoted oxidative stress with a rise in malondialdehyde, advanced protein oxidation, and protein carbonyl levels. An increase of glutathione peroxidase, superoxide dismutase, and catalase activities was also noted. A fall in acetylcholinesterase and Na⁺K⁺‐ATPase activities, glutathione, nonprotein thiols, vitamins C and E levels was observed. Plasma levels of cholesterol, triglycerides, and low density lipoprotein‐cholesterol increased and those of high density lipoprotein‐cholesterol decreased. Coadministration of selenium or vitamin E to the diet of dimethoate‐treated rats ameliorated the biochemical parameters cited above. The histopathological findings confirmed the biochemical results and the potential protective effects of selenium and vitamin E against cardiotoxicity induced by dimethoate. © 2011 Wiley Periodicals, Inc. Environ Toxicol 28:630–643, 2013.     

Effects of barium graded doses on redox status,membrane bound ATPases and histomorphological aspect of the liver in adult rats

Nowadays, liver diseases constitute a major health problem in the world. The objective of the present study was to elucidate the hepatotoxicity induced by barium chloride (BaCl₂) administered at graded doses in order to evaluate redox state and membrane-bound ATPases in the liver of adult rats. Our results showed, after 21 days of treatment with barium at doses 67 150 and 300?ppm, an increase in hepatic biomarkers such as AST, ALT and GGT activities and in bilirubin and albumin levels. A significant increase in MDA, LOOHs, H₂O₂, AOPP and PCO levels in liver of treated rats with graded doses of BaCl₂ was also observed suggesting the implication of oxidative stress with a significant relation between dose and response. Moreover, LDH activity increased in plasma and decreased in liver of all treated groups. Antioxidant activities of glutathione peroxidase and catalase decreased, especially with the highest dose of barium, indicating a failure of antioxidant system defense. Additionally, the activities of Na⁺K⁺-ATPase and Mg²⁺-ATPase significantly decreased in all treated groups. Our biochemical findings were supported by histological observations. These results highlight the subchronic hepatotoxicity of barium.     

Oestrogen compromises the facilitatory effect of chronic nicotine on adenosine A2B receptor–K+ channel‐mediated renal vasodilation

We have shown previously that the renal vasodilatory action of the adenosine analogue 5′‐N‐ethylcarboxamidoadenosine (NECA) in female rats is mediated via preferential activation of adenosine A_2B receptor (A_2BR)–K⁺ channel signalling. In the present study, we tested the hypothesis that the renal vasodilatory effect of NECA and its A_2BR/K⁺ channel specificities are altered by chronic nicotine administration. The oestrogenic modulation of the nicotine–NECA renovascular interaction was also evaluated by determining the effect of ovariectomy (OVX) and oestrogen replacement (OVXE2) on the evoked responses. In isolated phenylephrine‐preconstricted perfused kidneys obtained from sham‐operated rats, vasodilation in response to cumulative bolus injections of NECA (1.6–50 nmol) or papaverine (1–243 nmol) were not affected by nicotine (1–8 mg/kg per day, i.p., 2 weeks). However, vasodilator responses to NECA, but not papaverine, were reduced in kidneys of OVX rats and restored to near‐sham values after E₂ replacement. Further, nicotine increased NECA‐induced vasodilation in perfused kidneys from OVX rats, but failed to do so in OVXE2 preparations. The enhanced NECA responsiveness in nicotine‐treated OVX preparations was abolished after infusion (into isolated kidneys) of 10 μmol/L alloxazine (A_2BR antagonist) or BaCl₂ plus glibenclamide (blockers of inward rectifier and ATP‐sensitive K⁺ channels, respectively). Vasodilator responses to 0.05–1.6 μmol minoxidil (a K⁺ channel opener) were increased by nicotine in OVX, but not OVXE2, preparations and this increase was abolished after infusion of BaCl₂ + glibenclamide. Together, the data suggest that chronic nicotine enhances A_2BR/K⁺ channel‐mediated renal vasodilation in oestrogen‐depleted rats.     

Lung sulfhydryl changes in rats following chlorine inhalation

Respiratory tract irritation by chlorine (Cl₂) may be associated with tissue sulfhydryl (-SH) oxidation. This study examined the effects of Cl₂ on lung -SH content and on the enzymes which maintain non-protein -SH levels, glucose-6-phosphate dehydrogenase (G-6PD) and glutathione reductase (GSSG-RED). Male Fischer-344 rats were exposed to 12 ppm Cl₂, 6 hr/day for 1,5, or 10 days. Following Cl₂ exposure, rats were sacrificed immediately or after a 3- to 17-day recovery period. A study using pair-fed nonexposed rats was carried out to clarify possible nonspecific malnutrition effects. No alterations in lung protein -SH, nonprotein -SH, G-6PD, or GSSG-RED were observed in rats sacrificed immediately following 1, 5, or 10 days of Cl₂ exposure. Rats allowed to recover 3 days following 10 days of Cl₂ treatment had a 20% increase in lung -SH above the values for controls fed ad libitum while G-6PD and GSSG-RED activities increased 98 and 39% above controls, respectively. Similar increases in lung -SH, G-6PD, and GSSG-RED were observed after 6 days recovery. Biochemical alterations returned to control values by 10 days recovery. The observed increases in pulmonary -SH, G-6PD, and GSSG-RED were not the result of decreased food consumption. In conclusion, oxidation of lung -SH content immediately following Cl₂ exposure was not observed. An increase in lung -SH and enzyme activities during recovery periods may reflect reparative processes subsequent to Cl₂-induced lung damage.     

Ajuga iva aqueous extract improves reverse cholesterol transport in streptozotocin-induced diabetic rat

Objectives The aim of this study was to determine the effects of Ajuga iva aqueous extract on lecithin : cholesterol acyltransferase (LCAT) activity and amount and composition of high‐density lipoprotein (HDL)₂ and (HDL)₃, in streptozotocin (STZ)‐induced diabetic rats. Methods Diabetes was induced in male Wistar rats by intraperitoneal injection of STZ (60 mg/kg body weight). Diabetic rats (n = 12) were divided into two groups. The diabetic control group (D) received a 20% casein diet and the diabetic treated group received the same diet supplemented with A. iva aqueous extract (0.5 g/100 g diet) (DAi), for 4 weeks. Key findings Total cholesterol and HDL₃‐C were respectively decreased by 32% and 55% in the DAi group compared with the D group, whereas HDL₂‐C was increased by 30%. The amounts of HDL₂ and HDL₃, which were the sum of apolipoproteins, unesterified cholesterol (UC), cholesteryl esters (CEs), triacylglycerols (TGs) and phospholipids (PLs), showed no significant difference. A. iva treatment increased LCAT by 33% and its cofactor‐activator, apolipoprotein A‐I, by 58%. HDL₃‐PL (enzyme substrate) and HDL₃‐UC (acyl group acceptor) were respectively decreased by 70% and 57%, whereas HDL₂‐CE (product of LCAT reaction) was enhanced by 30%. Conclusions In STZ‐induced diabetic rats, A. iva improves reverse cholesterol transport by enhancing LCAT activity, leading to anti‐atherogenic effects.     

某些药物对大鼠血浆和肝脏脂蛋白脂酶活性及血浆胆固醇的影响

Lipoprotein lipase (LPL) is one of the most important factors in lipoprotein metabolism. The plasma and liver LPL activities (indicaded by fatty acid release), the ratio of LPL activity to total lipase activity and theoplasma cholesterol levels in rats treated with drugs were determined so as to study the relationship between LPL and lipoprotein metabolism.Plasma LPL activity is negatively related to the total cholesterol and high density lipoprotein cholesterol levels. As the liver LPL activity, increased, the plasma LPL activity also increased. When rats were treated with insulin, phenytoin or Radix Polygonum multiflorum, the plasma and liver LPL activities and the ratio of LPL activity to total lipase activity increased, whereas the plasma total cholesterol and high density lipoprotein cholesterol levels decreased. No significant effect of phenytoin on the total cholesterol level was observed, When large doses of phenytoin were used, the plasma very low density lipoprotein and low density lipoprotein cholesterol level increased and the ratio of high density lipoprotein cholesterol to total cholesterol decreased.     

Antihyperlipidaemic Effect of Gymnema montanum: A Study on Lipid Profile and Fatty Acid Composition in Experimental Diabetes

Abstract: In the present study, the antihyperlipidaemic efficacy of ethanol extract of Gymnema montanum leaves was investigated in alloxan‐induced diabetic rats and the effect was compared to standard hypoglycaemic drug, glibenclamide. Male adult albino Wistar rats were injected with freshly prepared solution of alloxan monohydrate (150 mg/kg body weight) to induce diabetes. After 2 weeks, the rats with moderate diabetes were administered G. montanum leaves (200 mg/kg body weight) for 21 days by gastric lavage, after which serum, liver and kidney samples were analysed for lipid profile, lipoprotein changes and fatty acid composition. While the alloxan‐induced diabetic rats showed a significant increase in the levels of cholesterol, triglycerides and free fatty acids, the levels in the animals treated with G. montanum leaves were considerably reduced and restored to near normal values. Antihyperlipidaemic effects of G. montanum leaves were found to be comparable with that of glibenclamide. Similarly, G. montanum leaves treatment resulted in reversal of alterations observed in the plasma lipoproteins (high‐density lipoprotein, low‐density lipoprotein and very high‐density lipoprotein‐cholesterol) and fatty acid composition in serum, liver and kidney of alloxan‐induced rats. Our study suggests that phytochemicals present in G. montanum may play an important role in suppressing the elevated lipid profile in diabetes and may be useful for the prevention and/or early treatment of diabetes‐associated hyperlipidaemia.     

Role of Oxidative Stress in Reproductive Toxicity Induced by Co‐administration of Chloramphenicol and Multivitamin–Haematinics Complex in Rats

Abstract: Concurrent administration of chloramphenicol (CAP) with multivitamin–haematinics complex (MHC) is a common practice to cushioning anticipated anaemic effect of CAP in most developing countries. This study investigated the mechanism involved in CAP‐induced reproductive toxicity as well as the effects of its co‐administration with MHC in male rats. CAP and MHC were administered orally at therapeutic doses of 28 mg/kg body‐weight and 0.08 ml/kg body‐weight, respectively, every 6 hr for 10 days. After exposure, while there was body‐weight loss in CAP, MHC and CAP plus MHC‐treated animals, there were no treatment‐related changes in the absolute and relative weights of the testes in all treated groups. Alone, MHC treatment markedly decreased catalase (CAT), glutathione S‐transferase (GST), and 5′ nucleotidase (5′ NTD) activities whereas it resulted in significant increase in superoxide dismutase (SOD) activity. Activities of SOD, CAT and GST as well as H₂O₂ levels were not significantly affected in CAP and CAP plus MHC‐treated rats whereas GSH level and 5′ NTD activity were markedly decreased in CAP plus MHC‐treated rats. Significant increase in testicular alkaline phosphatase activity, lipid peroxidation and sperm abnormalities were accompanied by reduction in epididymal sperm number, sperm motility and live–dead ratio in all treatment groups whereas aminotransferase activities were unaffected. Treatment‐related degeneration of the testes was evident in all treated animals. In summary, while MHC‐induced testicular toxicity via oxidative stress, CAP did not and their combination is implicated in reproductive dysfunction within the time course of our investigation.     

Influence of atorvastatin on fractional and subfractional composition of serum lipoproteins and MMP activity in mice with Triton WR 1339-induced lipaemia

Objectives The effects of atorvastatin on the atherogenic and anti‐atherogenic lipoprotein‐cholesterol (C‐LP) and lipoprotein‐triglyceride (TG‐LP) fractions and subfractions at the early stage of murine acute hyperlipidaemia, and its pleiotropic anti‐inflammatory effects via the activity of matrix metalloproteinases (MMPs) were studied. Methods Atorvastatin (75 mg/kg) was administered to ICR mice with acute lipaemia induced by a single injection of Triton WR 1339 (500 mg/kg). A novel small‐angle X‐ray scattering (SAXS) method was used for the determination of the fractional and subfractional composition of C‐LP and TG‐LP. Key finding In Triton WR 1339‐treated mice, there was a drastic increase in the atherogenic low‐density C‐LP (C‐LDL) fraction, intermediate density lipoprotein‐cholesterol (C‐IDL) subfraction, and very low‐density C‐LP (C‐VLDL) fractions (C‐VLDL_3–5 subfraction). Additionally, there was an increase in the C‐HDL₃ subfraction. Treatment of lipaemia with atorvastatin resulted in the normalization of the atherogenic C‐LDL fraction and the C‐IDL subfraction. A decrease in C‐VLDL (C‐VLDL_3–5 subfraction), total cholesterol and, especially, triglyceride (TG) concentrations was also demonstrated. Similar results were obtained with the TG‐LP fractions and subfractions. Additionally, atorvastatin treatment resulted in an increase in the serum and liver MMP activity. Conclusion High‐dose atorvastatin therapy exerts its rapid lipid‐lowering and pleiotropic effect(s) in the early stages of acute lipaemia induced with Triton WR‐1339.     

Subchronic Toxicity of Barium Chloride Dihydrate Administered to Rats and Mice in the Drinking Water

Barium Chloride dihydrate (BaCl₂ 2H²O was given for 92 daysto B⁶C³F¹ mice and Fischer 344/N rats in their drinking waterat levels of 0, 125, 500, 1000, 2000, and 4000 ppm. The no-effectlevel for this study was 2000 ppm BaCl₂ 2H²O in the drinkingwater. At 4000 ppm, daily consumption for mice was 436 to 562mg/kg barium, up to four times more chemical than rats. Mortalityranged from 60 to 70% in mice and from 10 to 30% in rats inthe 4000 ppm groups. Deaths in mice were associated with a treatment-relatedrenal toxicity. Renal lesions in rats were much less severethan in mice and did not contribute to the treatment-relateddeaths seen in the high dose group. Body weights of both speciesand sexes in the 4000 ppm groups were lower than controls at92 days. Male and female rats in treated groups exhibited higherserum phosphorus than controls. Serum sodium, potassium, andcalcium levels in rats were unchanged by barium treatment, aswere hematological values. In both species at 4000 ppm, motoractivity, grip strength, and thermal sensitivity were marginallyaffected. These effects were probably secondary changes resultingfrom BaCl₂ toxicity observed at this dose level. In a matingtrial, no anatomical effects on offspring of rats or mice wereseen. Rats receiving 4000 ppm exhibited marginal reductionsin pup weights. No effects were seen on reproductive indices.     

Rat lung response to ozone and fine particulate matter (PM2.5) exposures

Exposure to different ambient pollutants maybe more toxic to lung than exposure to a single pollutant. In this study, we discussed the inflammation and oxidative stress responses of rat lung caused by ozone and PM_2.5 versus that of rats exposed to saline, ozone, or single PM_2.5. Wistar rats inhaled 0.8 ppm ozone or air for 4 h and then placed in air for 3 h following intratracheal instillation with 0, 0.2 (low dose), 0.8 (medium dose), 3.2 (high dose) mg/rat PM_2.5 dissolved in sterile saline (0.25 mL/rat), repeated twice per week for 3 weeks, the cumulative doses of PM_2.5 in animals were 1.2, 4.8, and 19.2 mg. Rats were sacrificed 24 h after the last (sixth) exposure. The collected bronchoalveolar lavage fluid (BALF) was analyzed for inflammatory cells and cytokines. Lung tissues were processed for light microscopic and transmission electron microscopic (TEM) examinations. Results showed that total cell number in BALF of PM_2.5‐exposed groups were higher than control (p < 0.05). PM_2.5 instillation caused dose‐trend increase in tumor necrosis factor alpha (TNF‐α), interleukin‐6, lactate dehydrogenase, and total protein of BALF. Exposure to ozone alone only caused TNF‐α significant change in above‐mentioned indicators of lung injury. On the other hand, ozone could enhance PM_2.5‐induced inflammatory changes and pathological characters in rat lungs. SOD and GSH‐Px activities in lung were reduced in PM_2.5‐exposed rats with and without prior ozone exposure compared to control. To determine whether the PM_2.5 and ozone affect endothelium system, iNOS, eNOS, and ICAM‐1 mRNA levels in lung were analyzed by real‐time PCR. These data demonstrated that inflammation and oxidative stress were involved in toxicology mechanisms of PM_2.5 in rat lung and ozone potentiated these effects induced by PM_2.5. These results have implications for understanding the pulmonary effects induced by ozone and PM_2.5. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 343–356, 2015.     

Lipoprotein lipids and apoproteins during beta-blocker administration: Comparison of penbutolol and atenolol

Summary Serum lipoprotein lipid and apoprotein concentrations were determined in 21 hypertensive men during administration of two beta-blockers, penbutolol or atenolol, for 6 months preceded by a 4 week placebo period. Post-heparin plasma lipoprotein lipase and hepatic lipase activities were also measured.There was a trend to an increase of triglyceride and VLDL triglyceride concentrations during penbutolol administration, but the changes were not significant. Penbutolol also increased the total cholesterol by 11% at 3 months (mainly due to increase of VLDL cholesterol), but this effect diminished at 6 months.Atenolol did not cause any significant change in the total cholesterol but increased HDL cholesterol by 7% at 1 month, the change being due to rise of the HDL₃. The HDL₃ accounted also for a significant decrease of HDL cholesterol seen in the men receiving penbutolol at 6 months. HDL₂ cholesterol as well as the LDL/HDL₂ cholesterol ratio remained unchanged in both groups.Neither drug consistently influenced the post-heparin plasma lipase activities or the serum apoprotein A or B concentrations.In contrast to an earlier study the results suggest that the clinically most important HDL subfraction, the HDL₂, remains unaffected during treatment with beta-blockers.     

(TTA)n Polymorphism in 3‐Hydroxy‐3‐Methylglutaryl‐Coenzyme A and Response to Atorvastatin in Coronary Artery Disease Patients

Abstract: 3‐Hydroxy‐3‐methylglutaryl‐coenzyme A reductase inhibitors have been used clinically for lowering total and low‐density lipoprotein cholesterol. Interindividual pharmacological differences observed with this treatment have been attributed to genetic differences. The aim of this study was to assess the association in the low‐density lipoprotein cholesterol reduction by atorvastatin and (TTA)n polymorphism in the 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase gene in patients with coronary artery disease. Changes in total cholesterol levels, triglycerides, high‐sensitivity C‐reactive protein and free F₂‐isoprostanes were also evaluated. In an open study, patients received 40 mg atorvastatin daily for 8 weeks. Genotyping was done through polymerase chain reaction. The genotype distribution of the 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase (TTA)n polymorphism was: >10/>10 in 22 out of 64 patients (34%), >10/10 in 14 out of 64 patients (22%) and 10/10 in 28 out of 64 patients (44%). The reduction of low‐density lipoprotein cholesterol levels by atorvastatin was not different between allelic variants (TTA)n repeat polymorphism. Reductions in high‐sensitivity C‐reactive protein were observed in atorvastatin‐treated patients with alleles >10/>10 and 10/10. Free F₂‐isoprostanes and total cholesterol were also significantly lower after treatment for all alleles, irrespective of type of polymorphism. In conclusion, the changes induced by atorvastatin treatment on low‐density lipoprotein cholesterol, total cholesterol, triglycerides, high‐sensitivity C‐reactive protein and free F₂‐isoprostane concentrations were not related to the presence of 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase polymorphism (TTA)n.     

Investigation of 3,5-Isoxazolidinediones as Hypolipidemic Agents in Rodents

A series of 2-benzoyl-4,4-dialkyl-3,5-isoxazolidinediones proved to have potent hypolipidemic activity, lowering both serum cholesterol and triglyceride levels at 10 or 20 mg/kg/day, IP and orally in rodents. 2-(3,4,5-Trimethoxybenzoyl)-4,4-diethyl-3,5-isoxazolidinedione (4) afforded the best hypolipidemic activity lowering normolipidemic CF_l mouse serum cholesterol levels 49% and serum triglyceride levels 34% at 20 mg/kg/day, IP. Compound 4 was selected as a typical derivative of the chemical class for further detailed studies. Serum cholesterol levels in normolipidemic Sprague Dawley male rats were reduced 45% after 8 weeks at 10 and 20 mg/kg/day of compound, orally. Serum triglyceride levels were reduced 38–49% at 10 and 20 mg/kg/day, orally. In vitro liver enzyme activities studies in normolipidemic CF_l mice showed the compound inhibited mitochondrial citrate exchange, acetyl CoA synthetase, HMG CoA reductase, acyl CoA cholesterol acyl transferase, acetyl CoA carboxylase, sn-glycerol-3-phosphate acyl transferase, phosphatidylate phosphohydrolase and heparin-induced lipoprotein lipase activities with increases in the activities of cholesterol ester hydrolase and ATP-dependent citrate lyase. Similar enzyme activities were inhibited in vivo except HMG CoA reductase activity was not inhibited in rat liver or small intestinal mucosa after 8 weeks drug administration. Cholesterol levels were reduced in tissues after 8 weeks administration of compound 4 in normolipidemic rats. Bile cholesterol and triglyceride levels were elevated after two weeks administration to rats at 20 mg/kg/day. Serum lipoprotein levels in normolipidemic and hyperlipidemic rats showed the cholesterol levels in VLDL and LDL fractions after 4, 6 and 8 weeks at 10 and 20 mg/kg/day were reduced whereas HDL-cholesterol levels were significantly elevated. Studies demonstrated that ³H-cholesterol and ¹⁴C-palmitic acid incorporation into lipids of the lipoprotein fraction was reduced by the drug but ³²P-incorporation was generally elevated. The agent demonstrated no observable toxicity in rats after 8 weeks administration, orally. The acute toxicity study in normolipidemic mice at 20, 40 and 100 mg/ kg/day, IP, demonstrated no observable harmful effects of the drug.     

Effects of oleanolic acid and maslinic acid on hyperlipidemia

In the present study, we examined the therapeutic effects of pentacyclic triterpenes, oleanolic acid (OA) and maslinic acid (MA), on hyperlipidemia in a high‐cholesterol diet model. Hyperlipidemia was induced in male Sprague‐Dawley rats by feeding with a high‐cholesterol diet (HCD) for 30 days. MA and OA were supplemented (100 mg/kg body wt/day) during the last 15 days. The levels of serum total cholesterol (TC), triglyceride (TG), high‐density lipoprotein‐cholesterol (HDL‐C), and low‐density lipoprotein‐cholesterol (LDL‐C) increased in hyperlipidemic rats. An apparent increase in the expression of Acyl‐CoA cholesterol acyltransferase (ACAT) mRNA was seen in HCD‐fed rats. The activities of hepatic marker enzymes that serve as indices of cellular injury were also altered in HCD‐fed rats. Treatment with triterpenes modulated the abnormalities induced by hyperlipidimia. Lipid accumulation was decreased in histological findings. Elevated hepatic glycogen content (P<0.05) in triterpene groups was observed compared with HCD‐fed groups. Furthermore, ACAT gene expression was suppressed compared with hyperlipidemia‐induced groups without triterpenes. It can be concluded that triterpene treatment possesses therapeutic effects on diet‐induced hyperlipidemia by inhibiting the intestinal absorption and storage of cholesterol. Drug Dev Res 68:261–266, 2007. © 2007 Wiley‐Liss, Inc.     

Resveratrol relieves particulate matter (mean diameter < 2.5 μm)‐induced oxidative injury of lung cells through attenuation of autophagy deregulation

Oxidative stress and inflammation are critically implicated in ambient fine particulate matter (mean diameter < 2.5 μm; PM_2.5)‐induced lung injury. Autophagy, playing a crucial role in various physiopathological conditions, modulates cellular homeostasis and stress adaptation. Resveratrol is a phytoalexin that exerts potent antioxidant effects on cardiopulmonary diseases. To date, the mechanisms by which resveratrol protects against PM_2.5 remain to be elucidated. In the present study, we investigated the effect of resveratrol on PM_2.5‐induced oxidative injury. The potential role of nuclear factor erythroid‐2‐related factor 2 and autophagy in this progress was explored. Human bronchial epithelial cells were treated with PM_2.5 and the cytotoxicity and oxidative stress markers were determined. The results showed that PM_2.5 decreased cell viability and elevated the level of lactate dehydrogenase. The levels of malondialdehyde and reactive oxygen species were increased by PM_2.5 exposure. PM_2.5 also induced a significant increase of the inflammatory cytokines including interleukin (IL)‐6, IL‐8, IL‐1β and tumor necrosis factor α. Meanwhile, PM_2.5 triggered autophagy formation and alteration of the nuclear factor erythroid‐2‐related factor 2 pathway. Furthermore, human bronchial epithelial cells were co‐treated with PM_2.5 and resveratrol in the presence or absence of 3‐methylamphetamine, an inhibitor of autophagic formation. It was revealed that resveratrol intervention abolished PM_2.5‐induced oxidative injury partially through the suppression of autophagy deregulation. Findings from this study could provide new insights into the molecular mechanisms of pulmonary intervention during PM_2.5 exposure.     

Cytotoxic,genotoxic, and neurotoxic effects of Mg,Pb, and Fe on pheochromocytoma (PC‐12) cells

Metals such as lead (Pb), magnesium (Mg), and iron (Fe) are ubiquitous in the environment as a result of natural occurrence and anthropogenic activities. Although Mg, Fe, and others are considered essential elements, high level of exposure has been associated with severe adverse health effects including cardiovascular, hematological, nephrotoxic, hepatotoxic, and neurologic abnormalities in humans. In the present study we hypothesized that Mg, Pb, and Fe are cytotoxic, genotoxic and neurotoxic, and their toxicity is mediated through oxidative stress and alteration in protein expression. To test the hypothesis, we used the pheochromocytoma (PC‐12) cell line as a neuro cell model and performed the LDH assay for cell viability, Comet assay for DNA damage, Western blot for oxidative stress, and HPLC‐MS to assess the concentration levels of neurological biomarkers such as glutamate, dopamine (DA), and 3‐methoxytyramine (3‐MT). The results of this study clearly show that Mg, Pb, and Fe, respectively in the form of MgSO₄, Pb(NO₃)₂, FeCl₂, and FeCl₃ induce cytotoxicity, oxidative stress, and genotoxicity in PC‐12 cells. In addition, exposure to these metallic compounds caused significant changes in the concentration levels of glutamate, dopamine, and 3‐MT in PC‐12 cells. Taken together the findings suggest that MgSO₄, Pb(NO₃)₂, FeCl₂, and FeCl₃ have the potential to induce substantial toxicity to PC‐12 cells. © 2014 Wiley Periodicals, Inc. Environ Toxicol 30: 1445–1458, 2015.     

Two-day inhalation toxicity study of methyl iodide in the rat

The effects of inhaled methyl iodide (MeI) on clinical pathology parameters, glutathione (GSH) tissue levels, serum thyroid hormone and inorganic iodide concentrations, S-methylcysteine hemoglobin concentrations, and liver UDP-glucuronyltransferase activity were studied in the rat. Male rats were exposed by whole-body inhalation to 0, 25, or 100 ppm MeI, 6 h/day for up to 2 days. Serum cholesterol concentrations (both high-density lipoprotein [HDL] and low-density lipoprotein [LDL] fractions) were increased and triglycerides were decreased at both exposure levels. Serum thyroid-stimulating hormone (TSH) concentrations were increased at 25 and 100 ppm, and serum triiodothyronine (T₃) and thyroxine (T₄) concentrations were decreased at 100 ppm. There was no change in either reverse triiodothyronine (rT₃) or UDP-glucuronyltransferase activity at either exposure level. A dose- and time-dependent reduction in GSH levels in blood, kidney, liver, and nasal tissue was observed, with the greatest reduction in nasal tissue (olfactory and respiratory epithelium). MeI exposure also resulted in a substantial dose- and time-dependent increase in both serum inorganic iodide and red blood cell S-methylcysteine hemoglobin adducts. These results indicate that following inhalation exposure, MeI is rapidly metabolized in blood and tissue of rats, resulting in methylation products and release of inorganic iodide.