Effect of dietary zinc deficiency on hematological and biochemical parameters and concentrations of zinc, copper, and iron in growing rats

Zinc has a wide spectrum of biological activities and its deficiency has been related to various dysfunctions and alterations of normal cell metabolism. The effects of adequate Zn level (38 mg/kg diet, control) and two low levels that create Zn deficiencies (19 mg/kg diet, 1/2 of control and 3.8 mg/kg diet, 1/10 of control) were investigated in growing male and female rats for 10 weeks. This allowed for evaluation of the effects these Zn levels may have on body weight gain, specific organ weights, blood parameters, and serum concentrations of Zn, Cu and Fe. Rats fed Zn-deficient diets gained less (P<0.05) than the control groups. There was increase (P<0.05) in liver and spleen weights, and a decrease (P<0.05) in testes weight. However, brain, kidney, heart, and lung weights were not affected (P<0.05). Hematological parameters that were decreased (P<0.05) by Zn deficiency included hemoglobin (Hb), total erythrocyte count (TEC) and packed cell volume (PCV) with the magnitude being dose-dependent. Serum concentrations of total protein, globulin, glucose, and high density lipoprotein (HDL) also decreased (P<0.05) in a dose-dependent manner. Zn deficiency increased (P<0.05) total leukocyte count (TLC) and concentrations of serum albumin, total lipids, cholesterol, triglycerides and low density lipoprotein (LDL) in a dose-dependent manner. Serum concentrations of urea and creatinine were, however, not affected (P<0.05) by zinc deficiency. Zn-deficient rats had lower serum concentrations of Zn, Cu and Fe. These results showed that Zn deficiency has negative effects on growth rate, specific organ weights, hematological parameters, and serum levels of Zn, Cu and Fe, especially in rats fed the lowest Zn level.     

Developmental toxicity of dietary zinc deficiency in New Zealand white rabbits

Chemically induced maternal Zn deficiency has been shown previously to cause terata and increase embryonic loss in rodents. To examine the potential effects of Zn deficiency in the rabbit, a major developmental toxicity test species, rabbit dams were fed an ethylenediamine-tetraacetic acid-washed alfalfa-based Zn-deficient diet (−Zn) or the same diet replete with 80 ppm Zn (control) from Gestation Day (GD) 0 through 20. A third group of animals was pair fed to match the mean daily feed consumption levels of the <2 ppm Zn group. By GD 7, maternal serum Zn levels of the − Zn dams were decreased 56% and reached a nadir with a 75% decrease of serum Zn by GD 14. Zinc concentrations in the visceral yolk sac and visceral yolk sac-exoceolomic fluid were decreased 30% and 50%, respectively, by GD 11. Although GD 11 embryonic Zn levels were not affected, the embryos from Zn-deficient dams exhibited decreased head length, somite number, and total protein. On GD 28, a significant increase in resorptions/litter was noted in the − Zn group, and the incidence of totally resorbed litters of the −Zn group was greater than laboratory historical control values. No terata were observed in GD 28 fetuses. This study indicates that Zn deficiency occurring during the standard dosing period of guideline rabbit developmental toxicity studies may be associated with a modest increase in resorption rate and a transient inhibition of embryonic growth, but in contrast to rodent species, does not appear to be teratogenic.     

大蒜素对高脂饮食诱发大鼠非酒精性脂肪肝的保护作用

目的：观察大蒜素对大鼠非酒精性脂肪肝（NAFLD）的保护作用,并初步探讨相关机制。方法：SD大鼠50只,随机平均分成5组,每组10只：正常组、模型组、大蒜素高、中、低剂量组（30、20、10 mg/kg）。实验12周后观察各组大鼠肝功能酶学、血浆内毒素的含量、肝组织中血清丙二醛（MDA）含量、过氧化物歧化酶（SOD）活性、肝组织谷胱甘肽（GSH）含量、脂质代谢、血清游离脂肪酸（FFA）等水平,以及病理组织学的特点。结果：大蒜素高、中、低剂量组大鼠血脂和血浆内毒素水平与模型组相比差异均有统计学意义（P〈0.01或P〈0.05） ,各用药组大鼠血清SOD活性、MDA含量和FFA水平,以及肝组织SOD活性、MDA含量、GSH含量与模型组相比差异均有统计学意义（P〈0.01或P〈0.05） ,组织学观察表明高、中剂量大蒜素均能明显减轻肝细胞脂肪变性（P〈0.05）。结论：大蒜素对大鼠NAFLD具有很好的保护作用,并有一定的量效关系,其机制可能与对抗脂质过氧化反应和降低血浆内毒素水平有关。     

Long-term intake of a high zinc diet causes iron deficiency anemia accompanied by reticulocytosis and extra-medullary erythropoiesis

To elucidate the pathophysiology of zinc (Zn)-induced iron (Fe) deficiency anemia (IDA), we examined hemoglobin (Hb) concentrations, hematocrit (Ht) levels, numbers of circulating red blood cells (RBC) and reticulocytes, values of mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC), serum Zn, Fe and erythropoietin (EPO) concentrations and histopathological changes in the bone marrow, spleen and liver using rats fed with a standard or high Zn diet for 20 weeks. Rats fed with the high Zn diet exhibited a significant decrease in Hb concentrations, Ht levels and MCV, MCH and MCHC values, indicating microcytic hypochromic anemia characterized by Fe deficiency. Also, a marked decrease in serum Fe concentrations was seen in rats fed with the high Zn diet relative to rats fed with the standard diet. Interestingly, the number of RBC was comparable in both groups of rats, although a decrease in the number of RBC is ordinarily seen in IDA. There were reticulocytosis and extra-medullary erythropoiesis in the spleen and an increase in serum EPO concentrations in rats fed with the high Zn diet vs. those on the standard diet. These observations suggest that both reticulocytosis and extra-medullary erythropoiesis in the spleen played a role in maintaining the number of RBC in rats fed with the high Zn diet, preventing further progression of anemia. Further, increased production of EPO may be involved in the induction of reticulocytosis and extra-medullary erythropoiesis in the spleen.     

The induced synthesis of metallothionein in various tissues of rats in response to metals. II. Influence of zinc status and specific effect on pancreatic metallothionein

Metallothionein (MT) of various tissues contains bound zinc (Zn) and any change in Zn status can alter its synthesis and tissue deposition. The changes in MT levels and its inducibility in Zn-injected and Zn-deficient (Zn-D) rats were studied. MT levels in 11 tissues (brain, lung, heart, liver, kidney, stomach, small intestine, pancreas, spleen, testes and muscle) of control and rats injected with different doses of ZnSO₄ (20 mg Zn/kg for 2, 4 or 7 times) were measured by the cadmium-hemolysate (Cd-hem) method. A dose dependent increase in MT levels was observed only in the pancreas, liver, small intestine and kidney after ZnSO₄ injection — the highest level being in the pancreas. A positive correlation was found between Zn and MT concentrations and also the relative inducibility of MT was similar in these 4 tissues (slopes of regression equations were 12.6–15.5). In order to study the effect of Zn-D in MT induction, rats were fed a diet containing 1 ppm Zn for 18 days and CdCl₂ (1 mg Cd/kg) was injected subcutaneously 3 times at 48-h intervals to control and Zn-D rats. Although the tissue distribution of Cd was similar in both the groups, MT concentrations in pancreas and kidney were significantly decreased in Zn-D. The plasma and tissue levels of Zn were also decreased in Zn-D rats injected with CdCl₂. The decrease in both Zn and MT levels was more prominent in pancreas than other organs of Zn-D rats. The results suggest that of all the organs studied, the induction of pancreatic MT is sensitive to Zn status and Zn may be a primary inducer of MT.     

Cadmium-induced testes oxidative damage in rats can be influenced by dietary zinc intake.

We tested the hypothesis that zinc deficient animals would be characterized by an increased sensitivity to cadmium-induced oxidative damage to the testes. Weanling male rats were given free access to either a control (25 microg Zn/g) or a zinc deficient (0.5 microg Zn/g) diet; or restricted access to the 25 microg Zn/g diet at a level of intake similar to that of rats fed the 0.5 microg Zn/g diet. After 14 days on the diets, animals were injected s.c. with either saline or CdCl2 (2 mg Cd/kg body weight) solutions, and killed 24 h later. In the zinc-deficient group, testes weight and testes/body weight were higher in the cadmium-injected rats than in the saline-injected rats. The extent of hemorrhages, as indicated by high hemoglobin and testes iron concentrations was higher in the cadmium-treated zinc deficient group than in the cadmium-injected controls. In the zinc-deficient group, cadmium injection was associated with higher levels of lipid peroxidation (33% higher TBARS content) and protein oxidation (17% lower glutamine synthetase activity). Cadmium injection did not influence these parameters in the zinc-adequate groups. Extracellular superoxide dismutase activity was lower in the zinc-deficient group than in the zinc-sufficient groups; there was a trend (P < 0.06) for a lower activity in the cadmium- versus the saline-injected rats. These results support the concept that zinc deficiency increases the susceptibility of testes to cadmium-mediated free radical damage.     

Protein deficiency and muscle damage in carbon tetrachloride induced liver cirrhosis

Protein undernutrition, alterations of hormones such as IGF-1, testosterone and cortisol, and increased lipid peroxidation—which may be related with deranged metabolism of some elements such as iron (Fe), zinc (Zn), manganese (Mn), selenium (Se) or copper (Cu)—may contribute to muscle damage in non alcoholic cirrhosis. Here, we analyse the effect of protein deficiency on muscle Cu, Fe, Zn, Mn and Se in carbon-tetrachloride (CCl₄) induced liver cirrhosis. We also study the association between protein undernutrition and these trace elements with the activity of glutathione peroxidase (GPX), superoxide dismutase (SOD) and lipid peroxidation products, and how all these are related with muscle morphological changes in 40 male adult Sprague-Dawley rats. Liver cirrhosis was induced by intraperitoneal injection of CCl₄ to 10 rats fed a 2% protein diet, and to another 10 fed a 18% protein control diet. Two further groups included rats without cirrhosis fed the 2% protein and the 18% protein diets. After sacrifice (6 weeks later), we found type IIa fibre atrophy in the cirrhotic animals, especially in the low-protein fed ones and this was due to protein deficiency. Muscle Fe increased in low protein fed cirrhotic rats. No relationship was found between muscle changes and any of the hormones, enzymes and trace elements analysed, or with liver fibrosis. These results suggest that muscle atrophy observed in CCl₄-induced cirrhosis is related with protein deficiency, but not with cirrhosis itself.     

肥胖大鼠非酒精性脂肪肝与血清脂联素和肿瘤坏死因子α的关系及吡格列酮干预

目的观察营养性肥胖大鼠非酒精性脂肪肝(NAFLD)与血清脂联素和肿瘤坏死因子α(TNF-α)的关系,以及吡格列酮干预后的变化。方法45只SD♂大鼠随机分为3组:吡格列酮组(P)、高脂对照组(HF)和普通饮食组(NC),各15只。P、HF组给予高脂饮食,NC组给予普通饲料;12wk后,P组行吡格列酮10mg·kg-1.d-1灌胃,HF组和NC组用相应溶剂灌胃,均灌胃4wk。检测血清脂联素、TNF-α、游离脂肪酸(FFA)水平和其他生化指标等,计算Lee′s指数、HOMA-IR指数和肝脏指数,行肝脏病理切片和HE染色。结果与NC组相比,HF组大鼠体重、肝脏指数、FPG、FINS、ALT、HOMA-IR和血清TNF-α水平均明显增高,血清脂联素水平降低(P<0.05),肝细胞出现脂肪变性。与HF组比较,P组大鼠肝脏指数、HOMA-IR、FFA、TNF-α均降低,脂联素水平升高(P<0.05),肝细胞脂肪变性明显改善。HF组大鼠血清FFA、TNF-α与HOMA-IR、肝脏指数正相关,脂联素与之负相关(P<0.05)。结论高脂饮食可引起大鼠营养性肥胖、胰岛素抵抗和NAFLD;吡格列酮能提高胰岛素敏感性,改善脂肪细胞变性,可能与降低TNF-α、升高脂联素有关。     

A chronic toxicity study of josamycin in F344 rats.

The chronic toxicity of josamycin was examined in Fischer 344 (F344) rats. Groups of 10 males and 10 females were given the test compound in the diet at concentrations of 0 (control), 0.02, 0.1, 0.5 or 2.5% for 52 weeks. Daily intake of josamycin was 0, 10, 50, 260 and 1310 mg/kg body weight in males and 0, 10, 60, 290 and 1460 mg/kg body weight in females, respectively. Body weight gain was significantly (P<0.05) reduced in the male 2.5% group but no noticeable changes were found in food intake. In hematological examination, the platelet count was significantly (P<0.01) lower in the male groups given 0.02% or more of josamycin and in the 2.5% female group as compared with the control group values in a dose-dependent manner. In serum biochemical examination, blood urea nitrogen was significantly (P<0.05 and P<0.01, respectively) higher in males given 0.5 and 2.5% and total bilirubin was significantly (P<0.05) higher in females receiving 2.5% as compared with those of the control group. No death occurred at any dose levels during the dosing period. At necropsy, with the exception of cecal enlargement in the groups given more than 0.1% josamysin and a significant (P<0.01) increase in the relative liver weight of females in the 2.5% group, no particular findings related to the administration were observed. Histopathologically, the incidence and severity of liver bile duct proliferation in female 2.5% group were significantly (P<0.01) greater than those of the control group. Other histological changes found in the treated and control groups were similar to the spontaneous lesions in this strain of rats in terms of the incidence and severity. Interestingly, the josamycin treatment reduced the development of altered liver cell foci in females in a dose-dependent manner. Thus, it is concluded that, under the present experimental conditions, josamycin induces bile duct proliferation in female F344 rats at a high dose of 1460 mg/kg body weight. Based on the decrease of platelet count found in males given 10 mg/kg body weight or more, the no-observed-adverse-effect level (NOAEL) was estimated to be less than 10 mg/kg body weight.     

Excessive dietary selenium decreases the vitamin A storage and the enzymatic antioxidant defence in the liver of rats

This study investigated the influence of selenium intake, over 8 weeks, on vitamin A level and on enzymatic antioxidant defence in the liver of young rats. Deficient animals were fed a well-balanced diet but without selenite addition; the Se content of this diet which originated from natural Se content of ingredients was 0.05 mg/kg. Controls were fed the same diet with 0.40 mg/kg added Se. The two other groups received high levels of Se, 2.05 or 4.05 mg/kg. Excessive Se intake decreased the concentrations of retinol and retinyl palmitate in the liver. The linear regression analysis indicated a significant (P < 0.001) dose-dependent vitamin A decline. As expected, Se deficit lowered glutathione peroxidase activity. The highest Se excess decreased the enzymatic antioxidation: Zn,Cu Superoxide dismutase, catalase, glutathione peroxidase activities. Data showed that high dietary Se can sometimes enhance carcinogenesis and our results suggest that it is best to be cautious in administrating Se to humans with the aim of preventing diseases.     

Role of Oxidative Stress in the Selective Toxicity of Dieldrin in the Mouse Liver

Dieldrin, an organochlorine insecticide, induces hepatic tumors in mice but not in rats. Although the mechanism(s) responsible for this species specificity is not fully understood, accumulating evidence indicates that oxidative stress may be involved. This study examined the association of dieldrin-induced hepatic DNA synthesis with the modulation of biomarkers of oxidative damage to lipids (malondialdehyde [MDA]) and DNA (8-hydroxy-2-deoxyguanosine [oh8dG]), in male B6C3F1 mice and F344 rats fed dieldrin (0.1, 1.0, or 10 mg/kg diet) for 7, 14, 28, and 90 days. The nonenzymatic components of the antioxidant defense system (ascorbic acid, glutathione, and α-tocopherol) were also examined. Increased urinary MDA was observed in mice fed 0.1, 1.0, or 10 mg dieldrin/kg diet for 7, 14, 28, and 90 days; while increased hepatic MDA was seen only after 7 days in mice fed 0.1, 1.0, or 10 mg dieldrin/kg diet and after 14 days in mice fed 10 mg/kg diet. In rats, dieldrin had no effect on either hepatic MDA or urine MDA levels after 7, 14, and 28 days of treatment. A dose-dependent increase in urinary MDA was observed in rats at the 90-day sampling time. The only significant elevation in urinary or hepatic oh8dG content was limited to urinary oh8dG in mice fed 10 mg/kg dieldrin diet for 14 days. Dietary dieldrin produced sustained decreases in hepatic and serum α-tocopherol and sustained elevations in hepatic ascorbic acid in both mice and rats. Rats, however, possessed a three- to four-fold higher content of endogenous or basal (control) hepatic α-tocopherol; and, even when fed 10 mg dieldrin/kg diet, the levels of hepatic α-tocopherol were maintained at higher levels than those of mice fed control diet. In both rats and mice fed dieldrin, transient (14 and 28 days on diet) elevations in hepatic glutathione were observed. These data support the hypothesis that the species specificity of dieldrin-induced hepatotoxicity may be related to dieldrin's ability to induce oxidative stress in the liver of mice, but not in rats. Only in mice fed dieldrin was a temporal association of increases in hepatic MDA content and hepatic DNA synthesis seen, suggesting that oxidative damage (shown by increased lipid peroxidation) may be involved in early events in dieldrin-induced hepatocarcinogenesis. Rats may be protected from dieldrin-induced oxidative stress by a more effective antioxidant defense system, characterized by higher basal levels of hepatic α-tocopherol and ascorbic acid than that seen in the mouse.     

橙皮苷对辛伐他汀调脂作用及细胞色素P4503A mRNA表达的影响

目的　研究橙皮苷对辛伐他汀 (simvastatingroup ,SV)调脂作用及CYP450 3AmRNA表达的影响。方法　将Wistar大鼠随机分为 :对照组 (controlgroup)、高脂血症模型组 (modelgroup)、辛伐他汀组 (simvastatingroup ,SVgroup)、低剂量橙皮苷 +辛伐他汀组 (lowdosehesperidin +SV group ,LDHS)、高剂量橙皮苷 +辛伐他汀组 (highdosehesperidin +SV group ,HDHS)。除对照组外 ,余组均饲喂高脂饮食 ,各实验组按 5mg·kg- 1SV灌胃 ,并分别加用不同剂量的橙皮苷。实验 8wk后 ,检测各组大鼠血脂水平 ,肝脏及小肠CYP450 3A基因表达水平。结果　高脂饲养 8wk后 ,模型组TC、TG和LDL C均升高 (P <0 0 1) ;SV组TC、TG和LDL C较模型组降低 (P <0 0 1或P <0 0 5) ;加用橙皮苷后 ,TC和TG均较SV组呈剂量依赖性降低。模型组肝脏CYP450 3AmRNA表达量与对照组比较无统计学意义 (P >0 0 5) ,小肠CYP450 3AmRNA表达量较对照组升高 (P <0 0 5)。使用SV后 ,肝脏CYP450 3AmRNA表达量较模型组有增加趋势 ,小肠表达量增加 (P <0 0 5)。SV与橙皮苷合用后 ,随橙皮苷剂量的加大 ,肝脏及小肠CYP450 3AmR NA的表达呈下降趋势 ,以HDHS组明显 (P <0 0 5)。结论　橙皮苷能增加SV的调脂作用 ,其机制可能与橙皮苷抑制了CYP450 3A基因表达?     

Effects on growth and cadmium residues from feeding cadmium-added diets with and without montmorillonite nanocomposite to growing pigs

One hundred and ninety-two crossbred pigs (barrows, Duroc x Landrace x Yorkshine, initial weight 27.6 kg) were used to evaluate the effects of montmorillonite nanocomposite (MNC) on cadmium (Cd) retention in tissues of growing pigs. The animals were randomly assigned to 2 supplementations of Cd (0 or 10 mg/kg) and 2 levels of MNC (0 or 0.5%) in a 2x2 factorial arrangement. Each group was fed corn-soybean basal diets and consisted of 3 replications of 16 pigs. The feeding experiment lasted 83 d. Pig growth performances decreased significantly by addition of 10 mg Cd/kg (p<0.05) and improved with supplementation of MNC (p<0.05). Addition of MNC with Cd decreased Cd retentions in muscle, liver, kidney, spleen, thymus and lymphaden of pigs (p<0.05). MNC also decreased tissue Cd residues of pigs fed the diet without added Cd (p>0.05). There were decreased iron levels and increased copper levels in serum and liver of 10 mg Cd/kg treatment (p<0.05). Zinc content in serum and liver was not affected by the addition of Cd (p>0.05). Serum and liver iron, copper and zinc concentrations of pigs fed MNC without added Cd were unaffected by MNC (p>0.05).     

Role of Zn(2+) in oxidative stress caused by endotoxin challenge

The role of Zn(2+) in oxidative stress during endotoxemia was investigated. In rats fed a Zn(2+)-deficient diet (Zn(2+) concentration of less than 1.5 mg/kg) for 8 weeks, the Zn(2+) level in the serum was about 62% lower than that in rats fed a Zn(2+)-adequate diet (Zn(2+) concentration, 50 mg/kg). The Zn(2+) level in serum 18 h after administration of endotoxin (6 mg/kg, i.p.) to Zn(2+)-deficient diet rats was markedly lower than that of the endotoxin/Zn(2+)-adequate diet group. Lipid peroxide formation in the liver of Zn(2+)-deficient diet rats was markedly increased 18 h after endotoxin injection compared with that in the endotoxin/Zn(2+)-adequate diet group. Metallothionein in the liver of endotoxin/Zn(2+)-adequate diet rats was increased more than 17-fold by endotoxin administration, while a markedly lower level of metallothionein was observed in the endotoxin/Zn(2+)-deficient diet group. On the other hand, treatment with ZnSO(4) (100 microM) significantly increased endotoxin (1 microg/ml)-induced tumor necrosis factor-alpha (TNF-alpha) production in J774A.1 cells. Our results clearly demonstrated that treatment with ZnSO(4) significantly inhibited the endotoxin-induced increase in intracellular Ca(2+) level in J774A.1 cells. However, a cell membrane-permeable Zn(2+) chelator, N,N,N',N'-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN, 1 microM), did not affect the endotoxin-induced TNF-alpha production or Ca(2+) level in J774A.1 cells. In addition, we investigated whether Zn(2+) can suppress nitric oxide (NO) generation and cytotoxicity in endotoxin-treated cells. Treatment with ZnSO(4) (50 microM) significantly inhibited endotoxin-induced NO production in J774A.1 cells, but did not affect endotoxin-induced cytotoxicity. These findings suggest that zinc may play an important role, at least in part, in the oxidative stress during endotoxemia.     

Zinc deficiency induces behavioral alterations in the tail suspension test in mice. Effect of antidepressants

BackgroundRecently, experimental zinc deficiency has been correlated with depression-like alterations in rodents.MethodsIn the first part of present study, the time course of zinc deficient diet induced alterations in the tail suspension test (TST) in mice was investigated. In the second part, the effect of imipramine and escitalopram in control and zinc-deprived for 3 weeks mice was examined in the TST.ResultsA 4- and 10-week administration of a Zn-deficient diet enhanced the immobility time in the TST (by 20% and 57%, respectively). By contrast, a 2-week period of a zinc deficient diet effected the reduction (by 24%) of the immobility time. Moreover, a 2- and 4-week (but not 10-week) of a Zn-deficient diet resulted in the reduction of the body weight (by 37% and 18%, respectively). These results indicate the developing response to zinc deficiency induced by a zinc-deficient diet. The antidepressant-like effect (reduction in the immobility time) of both drugs was significantly reduced in zinc-deprived mice, which suggests treatment-resistance induced by zinc deprivation.ConclusionsZinc deprivation induces “pro-depressive” behavior and alters antidepressant efficacy.     

Dietary iron lowers the intestinal uptake of cadmium-metallothionein in rats.

It has been shown that addition of extra calcium/phosphorus (Ca/P), zinc (Zn) and iron (Fe2+) to the diet results in a significant protection against cadmium (Cd) accumulation and toxicity in rats fed inorganic Cd salt. However, it is not clear whether the presence of these mineral supplements in the diet also protects against the Cd uptake from cadmium-metallothionein. The present study examines the influence of Ca/P, Zn and Fe2+ on the Cd disposition in rats fed diets containing either 1.5 and 8 mg Cd/kg diet as cadmium-metallothionein (CdMt) or as cadmium chloride (CdCl2) for 4 weeks. The feeding of Cd resulted in a dose-dependent increase of Cd in intestine, liver and kidneys. The total Cd uptake in liver and kidneys after exposure to CdMt was lower than after exposure to CdCl2. At the low dietary Cd level and after addition of the mineral supplement, the kidney/liver concentration ratio increased. However, this ratio was always higher with CdMt than with CdCl2, suggesting a selective renal disposition of dietary CdMt. The uptake of Cd from CdCl2 as well as from CdMt was significantly decreased by the presence of a combined mineral supplement of Ca/P, Zn and Fe2+. The protection which could be achieved was 72 and 75% for CdMt and 85 and 92% for CdCl2 after doses of 1.5 mg/kg and 8 mg/kg respectively. In a following experiment it was shown that the protective effect of the mineral mixture against CdMt was mainly due to the presence of Fe2+. It seems clear that Cd speciation and the mineral status of the diet have a considerable impact on the extent of Cd uptake in rats.     

Effects of hesperidin on the progression of hypercholesterolemia and fatty liver induced by high-cholesterol diet in rats

The protective effects of hesperidin against hypercholesterolemia and fatty liver were examined in male Wistar rats fed a high-cholesterol diet for 12 weeks. Compared with a standard diet, a high-cholesterol diet not only increased body weights, liver weights, and serum concentration of cholesterol, but also induced the fatty degeneration (steatosis) of liver. Hesperidin (0.08%) reduced levels of hepatic steatosis, adipose tissue and liver weights (P < 0.05), serum total cholesterol and retinol binding protein (RBP) 4 concentrations (P < 0.05) in rats fed with high-cholesterol diet, while reduction in low-density lipoprotein cholesterol levels and triglyceride concentrations was not significant. It also attenuated the marked changes in mRNA expression of lipid metabolism-related proteins: RBP, heart fatty acid-binding protein (H-FABP), and cutaneous fatty acid-binding protein (C-FABP), in liver and adipose tissue. According to the results of gas chromatography, serum concentrations of total cholesterol and biomarkers of cholesterol synthesis (lathosterol) and absorption (campesterol, β-sitosterol) were lower, and concentrations of cholesterol in feces were higher in the rats given hesperidin (P < 0.05). Hesperidin may improve hypercholesterolemia and fatty liver by inhibiting both the synthesis and absorption of cholesterol and regulating the expression of mRNA for RBP, C-FABP, and H-FABP.     

Chronic toxicity of diethyl phthalate in male Wistar rats--a dose-response study

Diethyl phthalate (DEP) is widely used in personal care products, plastics and medical devices at various concentrations, but its information is limited on its toxicity associated with exposure at high as well as low doses for a prolonged period. Therefore, a study was undertaken to understand the dose-response toxic effect of DEP in male Wistar rats. Control rats were fed on normal diet and water ad libitum. Rats were given DEP dissolved individually in corn oil mixed with the diet at 10, 25 and 50 mg/kg of the diet/day, which is equal to 0.57, 1.425 and 2.85 mg/kg body wt/day. After 5 months of treatment animals were sacrificed, enzymes and other biochemical parameters in the serum and liver were assessed. Liver weight to body weight ratio showed a significant increase only in 10 ppm DEP treated rats. A significant increase was observed in the serum ACP, LDH, ALT enzyme levels of 10 mg/kg treated rats as compared to control, 25 and 50 mg/kg treated rats. Other biochemical parameters like glycogen, total cholesterol, total triglycerides and lipid peroxidation were also increased in the liver of all the three treated groups. In the 10 and 50 mg/kg diet/day treated rats, there was a significant decrease in liver total GSH as compared to controls and 25 mg/kg treated rats. Histology of liver showed severe vacuolations, fatty degeneration and loss of hepatic architecture in the 10mg/kg treated rats, whereas in the 25 and 50 mg/kg treated rats only loss of hepatic architecture and granular deposits in the hepatocytes was predominant. Histology of liver by electron micrographs showed a significant dose-dependent proliferation of mitochondria in the hepatocytes, while the 10mg/kg treated rats showed increased number of peroxisomes in the hepatocytes. It is evident from this study that treatment with higher concentrations of DEP results in mitochondrial proliferation as well as accumulation of glycogen, cholesterol and triglycerides within the liver, but exposure to lower concentrations for longer periods results in increase in peroxisome numbers leading to severe hepatocellular changes which can be confirmed by significantly increased liver weights, elevated enzyme levels in the serum and liver and impaired metabolism of glycogen, cholesterol and triglyceride as well as altered liver histology.     

藏药三果汤调节Nrf2/HO-1信号通路干预高脂血症大鼠的作用机制研究

目的：基于Nrf2/HO-1信号通路探讨藏药三果汤对高脂血症大鼠保护作用及相关作用机制。方法：雄性SD大鼠48只,随机分为6组,即正常对照组、模型对照组、辛伐他汀组（3.5 mg/kg）,藏药三果汤低、中、高剂量组（0.43 g/kg、0.86 g/kg、1.72 g/kg）,每组8只。正常组给予基础饲料喂养,其余各组给予H00016高脂饲料喂养,制备高脂血症大鼠模型,造模的同时,各给药组每天一次给予相应药物灌胃,正常对照组、模型对照组给予等体积的生理盐水（1次/d）,连续灌胃6周。实验期间每周固定时间称取各组大鼠体重一次,6周后试剂盒检测血清中血脂（TC、TG、LDL与HDL）及氧化指标（MAD、SOD与GSH）的水平。Western Blot法测定肝组织中Nrf2、HO-1、Keap1、NQO1蛋白表达,采用person相关性分析分析血脂与氧化指标之间的相关性。结果：与正常对照组比较,模型对照组的体重明显增加,血清中的TC、TG、LDL、MDA含量明显升高,而血清中HDL含量明显减低,SOD、GSH活力明显减低（P<0.05或P<0.01）;与模型对照组比较,各给药组的体重减轻,血清中的TC、TG、LDL、MDA含量明显减低,血清中的HDL含量明显升高,SOD、GSH活力明显升高（P<0.05或P<0.01）。与空白对照组比较,模型对照组Keap1蛋白水平表达明显上调,Nrf2、HO-1与NQO1蛋白水平表达明显下调（P<0.05或P<0.01）,与模型对照组比较,三果汤低、高剂量肝组织中的Keap1蛋白水平表达明显下调,Nrf2、HO-1与NQO1蛋白水平表达明显上调（P<0.05或P<0.01）。相关性分析可见TG与SOD、HO-1及NQO1呈负相关,与Keap1呈正相关,TC与SOD、HO-1、GSH及Nrf2呈负相关,与Keap1及MDA呈正相关。结论：藏药三果汤可改善高脂血症大鼠体重及血脂水平,其机制可能与调节Nrf2/HO-1信号通路,改善氧化应激有关。