OBJECTIVETo explore arsenic-induced oxidative stress and the protective efficacy of α-lipoic acid and vitamin c.

METHODS50 male SD rats were randomly divided into 5 groups. Ten rats (the control group) were exposed to deionized water for 6 weeks, and the others were alone exposed to sodium arsenite (50 mg/L water) for 6 weeks, at the same time, three group rats were administered intragastrically (i.g.) with α-lipoic acid 10 mg×kg(-1)×d(-1) and vitamin C 25 mg×kg(-1)×d(-1) either alone or in combination. At the end of experiment, blood was drawn from abdominal aorta, and then the blood, brain and liver of rats were used for biochemical assays, including blood glutathione (GSH), δ-aminolevulinic acid dehydratase (δ-ALAD ), reactive oxygen species (ROS) and oxidized glutathione (GSSG) level. At the same time, the super oxide dismutase (SOD) activity, glutathione peroxidase (GSH-Px) activity, catalase (CAT) activity, ATPase activity of brain and liver were determined. The caspase activity of brain were also determined.

RESULTSThere were a significant increase in ROS level (P < 0.05), but a significant decrease in δ-ALAD activity (P < 0.01) in the chronic arsenic toxicity model group compared with the control group. These alterations were marginally restored by co-administration of vitamin C and α-lipoic acid individually, while significant recovery was observed in the animals supplemented with both the antioxidants together with arsenite in rat (P < 0.05). At the same time, there was a significant increase in the ROS and TBARS level of the brain and liver (P < 0.05), and caspase activity of the brain (P < 0.05), while there was a significant decrease in antioxidant enzymes and ATPase activity on arsenite exposure in rats (P < 0.05). These alterations were also marginally restored by co-administration of vitamin C and α-lipoic acid individually, while significant recovery was observed in the animals supplemented with both the antioxidants together with arsenite in rat (P < 0.05).

CONCLUSIONSArsenite-induced oxidative stress can be significantly protected by co-administration of α-lipoic acid and vitamin C individually, but the best effects could be observed with combined administration of two antioxidants during arsenite exposure in animals. The dietary intervention of or supplementation with natural dietary nutrients is possible to prevent the effects of arsenic in populations of risk.

Animals ; Arsenic Poisoning ; metabolism ; Ascorbic Acid ; pharmacology ; Male ; Oxidative Stress ; drug effects ; Rats ; Rats, Sprague-Dawley ; Thioctic Acid ; pharmacology

Sulfur is an essential element for the entire biological kingdom because of its incorporation into amino acids, proteins and other biomolecules. Sulfur atoms are also important in the iron-containing flavoenzymes. Unlike humans, plants can use inorganic sulfur to synthesize sulfur-containing amino acids. Therefore, plants are an important source of sulfur for humans. Sulfur-containing compounds are found in all body cells and are indispensable for life. Some of sulfur-containing antioxidant compounds are, cysteine, methionine, taurine, glutathione, lipoic acid, mercaptopropionylglycine, N-acetylcysteine, and the three major organosulfur compounds of garlic oil, diallylsulfide, diallyldisulfide and diallyltrisulfide. In a comparison of the structure-function relationship among these sulfur-containing antioxidant compounds, dihydrolipoic acid (the reduced form of LA) is the most effective antioxidant. Dihydrolipoic acid contains two sulfhydryl groups and can undergo further oxidation reaction to form lipoic acid. The antioxidative activities of sulfur-containing compounds follow a general trend, the more highly reduced forms are stronger antioxidants and the number of sulfur atoms determine, at least in part, their modulatory activites on the glutathione related antioxidant enzymes. In this article, the antioxidant effects and the antioxidative activities, of sulfur-containing amino acids, are reviewed. In addition, the general antioxidant effects and the structure-function relationship of some sulfur-containing compounds are also reviewed.
Acetylcysteine/pharmacology ; Amino Acids, Sulfur/*pharmacology ; Antioxidants/*pharmacology ; Cysteine/pharmacology ; Glutathione/pharmacology ; Methionine/pharmacology ; Structure-Activity Relationship ; Taurine/pharmacology ; Thioctic Acid/pharmacology ; Thiopronine/pharmacology

OBJECTIVETo evaluate the effect of sustained-release alpha-lipoic acid tablets (SRLA) on blood lipid, glucose and insulin levels in hyperlipidemic New Zealand rabbits.

METHODSTwenty-four New Zealand rabbits were randomized into normal diet group, high-fat diet group, and high-fat diet + SRLA (300 mg/tablet) group with corresponding feed. At the beginning and 4 weeks after the feeding, the serum levels of total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), blood glucose, and serum insulin were measured, and insulin sensitivity index (ISI) was calculated.

RESULTSFour weeks after feeding with high-fat diet, the insulin levels was elevated and the ISI lowered in the New Zealand rabbits, indicating successful establishment of the animal model of hyperlipidemia. Compared with the high-fat diet group, the serum levels of TG, TC, LDL-C and insulin were significantly reduced (P<0.05), and the ISI was significantly increased (P<0.05) in high fat diet + SRLA group. But no statistically significant difference was found in the blood glucose among the 3 groups.

CONCLUSIONSRLA can significantly correct blood lipid and insulin disorders in hyperlipidemic New Zealand rabbits and prevent the occurrence of insulin resistance and hyperlipidemia.

Animals ; Blood Glucose ; metabolism ; Delayed-Action Preparations ; Hyperlipidemias ; blood ; drug therapy ; metabolism ; Insulin ; metabolism ; Lipids ; blood ; Male ; Rabbits ; Tablets ; Thioctic Acid ; administration & dosage ; pharmacology ; therapeutic use

OBJECTIVETo investigate the accumulation of advanced glycation end products (AGEs) and expression of receptor for AGEs (RAGE) in streptozocin (STZ)-induced diabetic nephropathy in rats, and the role of antioxidants on the AGEs-RAGE signaling.

METHODSDiabetic rats were induced by once intraperitoneal injection of STZ at the dose of 60 mg/kg, and randomly divided into the DN group (n=12, treated with normal saline by intraperitoneal injection, once daily), the extract of Ginkgo biloba (EGb) group (n=14, treated with EGb 300 mg/kg by oral administration, once every other day), and the alpha-lipoic acid (ALA) group (n=12, treated with ALA at the dose of 35 mg/kg by intraperitoneal injection, once every other day). Rats of the normal control group (n=10) were given vehicle citrate buffer at the dose of 60 mg/kg. Rats were sacrificed at the 12th week and the 20th week of this study. The four groups were compared in terms of body weight, blood glucose, renal function, 24-h urine protein. Renal pathological changes were observed by PAS staining. Oxidative stress indices were detected using spectrophotometry. The concentrations of AGEs were measured using fluoro spectrophotometry, and the expressions of RAGE were detected by Real-time PCR and Western blot.

RESULTSCompared with the normal control group, the 24-h urine protein quantitation was higher and the glomerular filtration rate increased in rats at the 12th week and the 20th week. The pathological tissue staining showed dilated glomerular mesangium, proliferated glomerular matrix, vacuolar degeneration of the renal tubular epithelium. Malonaldehyde (MDA) levels and 8-hydroxide radical guanine deoxyriboside (8-OHdG) levels increased, and catalase (CAT) and reduced glutathione hormone (GSH) levels decreased. The AGEs contents in serum and renal tissue homogenate increased. The expressions of RAGE mRNA and protein increased in the DN group at the 12th and the 20th week. The 24-h urine protein quantitation was reduced in the EGb group and the ALA group, with alleviated pathological changes, lowered MDA and 8-OHdG levels, increased CAT and GSH levels, decreased AGEs contents, and down-regulated RAGE expressions.

CONCLUSIONSAGEs contents increased and RAGE expression up-regulated in the circulation and local renal tissues in DN rats. EGb and ALA could inhibit AGEs production and down-regulate RAGE expressions by reducing oxidative stress, thus further improving the renal tissue structure and renal functions of DN rats. It had better application prospect in treatment and prevention of DN.

Animals ; Antioxidants ; pharmacology ; Diabetes Mellitus, Experimental ; metabolism ; Diabetic Nephropathies ; metabolism ; Ginkgo biloba ; Glycation End Products, Advanced ; metabolism ; Kidney ; metabolism ; Male ; Rats ; Rats, Wistar ; Receptor for Advanced Glycation End Products ; Receptors, Immunologic ; metabolism ; Thioctic Acid ; pharmacology

The study was aimed at exploring the effect of noise on total antioxidant capacity (TAC) in serum, nitric oxide (NO) level in the cochlea and the protective action of alpha-lipoic acid against noise-induced hearing loss (NIHL). Sixty guinea pigs (350-400 g) were divided randomly into three groups (control group, noise+saline group and noise+alpha-lipoic acid group). Serum and cochlear tissue were treated immediately after noise exposure (4-kHz octave band, 115 dB SPL 5 h) to determine the level of TAC and NO, respectively. Auditory brainstem responses (ABRs) were measured before and immediately after exposure. The threshold of hearing in the control group was relatively stable, while the hearing threshold in the noise+saline group was significantly higher than those in the noise+alpha-lipoic acid group (P<0.05). TAC level of the noise+saline group was significantly lower than that of the control group P<0.05 . TAC level of the noise+alpha-lipoic acid group was significantly higher than that of the noise+saline group P<0.05 , while there was no significant difference in the levels between the noise+alpha-lipoic acid group and the control group (P>0.05). The NO level of the cochlear tissue in the noise+saline group was significantly higher than that of the control group (P<0.05). Cochlear NO level in the noise+alpha-lipoic acid group was significantly lower than that of the noise+saline group (P<0.05), while there was no significant difference in cochlear NO levels between the noise+alpha-lipoic acid group and the control group (P>0.05). The results obtained indicate that noise exposure causes a decrease in serum TAC and an increase in NO in cochlea. alpha-Lipoid acid exerts a protective effect against hearing loss in acoustic trauma through its antioxidant effects.
Animals ; Antioxidants ; pharmacology ; therapeutic use ; Cochlea ; metabolism ; Evoked Potentials, Auditory, Brain Stem ; Guinea Pigs ; Hearing Loss, Noise-Induced ; metabolism ; prevention & control ; Male ; Nitric Oxide ; metabolism ; Noise ; adverse effects ; Random Allocation ; Reactive Oxygen Species ; blood ; Thioctic Acid ; pharmacology ; therapeutic use

The migration of vascular smooth muscle cells (VSMCs) into the intima, an important step in injury-induced neointimal hyperplasia, requires the activation of nuclear factor-kappaB (NF-kappaB) and the consequent up-regulation of matrix metalloproteinase-9 (MMP-9). This study was undertaken to test for a possible effect of alpha-lipoic acid (ALA), a potent inhibitor of NF-kappaB, on MMP-9 expression. ALA inhibited high-glucose- and TNF-alpha-stimulated VSMC migrations in vitro. It also inhibited high-glucose- and TNF-alpha-induced increases in MMP-9 expression. The activity of MMP-9-promoter constructs with mutations in the NF-kappaB binding site was not inhibited by ALA, indicating an involvement of the NF-kappaB signaling pathway in the ALA-specific inhibition of MMP-9. These data suggest the possibility that ALA may be useful for the prevention of neointimal hyperplasia after angioplasty, by inhibiting the NF-kappaB/ MMP-9 pathway, especially with hyperglycemia.
Thioctic Acid/*pharmacology ; Rats, Sprague-Dawley ; Rats ; Promoter Regions (Genetics)/genetics ; NF-kappa B/*metabolism ; Muscle, Smooth, Vascular/cytology/drug effects/metabolism ; Matrix Metalloproteinase 9/genetics/*metabolism ; Male ; Gene Expression/*drug effects/*genetics ; Cells, Cultured ; Cell Movement/drug effects ; Animals

OBJECTIVETo study the functional and ultramicrostructural effects of alpha lipoic acid on hypothalamus-pituitary-adrenal (HPA) axis in normal and diabetic rats.

METHODSUsing radioimmunoassay we observed the effects of three doses (1, 20, and 100 mg/kg) of alpha lipoic acid injected intraperitoneally for 3 weeks on the plasma levels of CRH, ACTH and COR in normal and diabetic rats. The ultramicrostructural changes of the hypophysis and pituitary gland after alpha lipoic acid treatment were observed under transmission electron microscope.

RESULTSCompared with the control group, CRH level in lipoicin-treated normal and diabetic rats was significantly reduced (P<0.05). ACTH level of the 3 lipoicin doses groups of normal rats decreased, and a significant reduction occurred in medium-dose lipoicin group of diabetic rats (P<0.05). COR level showed the same changes as CRH level in normal rats, but decreased significantly in high- and medium-dose lipoicin groups of diabetic rats. Lipoicin treatment produced no apparent effect on the ultramicrostructures of the hypophysis and pituitary gland cells, which were the targets of diabetic lesions with low metabolism functions. Lipoicin treatment obviously enhanced the hypophysis and pituitary gland cell metabolism function to resist diabetic oxidative stress.

CONCLUSIONLipoicin can inhibit the HPA axis directly or indirectly in normal and diabetic rats.

Animals ; Diabetes Mellitus, Experimental ; pathology ; physiopathology ; Hypothalamo-Hypophyseal System ; drug effects ; physiology ; ultrastructure ; Male ; Pituitary-Adrenal System ; diagnostic imaging ; drug effects ; physiology ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Thioctic Acid ; pharmacology ; Ultrasonography

OBJECTIVETo investigate the alterations in auditory brainstem evoked responses (ABRs) and the changes of carboplatin-induced ototoxicity in the cochlear oxidant/antioxidant systems and otoprotection by an antioxidant lipoate.

METHODSMale wistar rats were divided into four groups and treated as follows: 1) vehicle (saline) control, 2) carboplatin (256 mg/kg, i.p.), 3) lipoate (100 mg/kg, i.p.), 4) lipoate + carboplatin. Post-treatment ABRs were performed after four days and rats were sacrificed with their cochleae harvested and analyzed.

RESULTSCarboplatin significantly elevated ABR threshold above the pretreatment thresholds. Lipoate+carboplatin treated rats showed decreased elevation of hearing threshold. Carboplatin significantly depleted cochlear reduced to oxizized glutathione (GSH/GSSG) ratio, whereas lipoate+carboplatin treatment increased GSH/GSSG ratio. Carboplatin significantly decreased cochlear copper zinc-superoxide dismutase (CuZn-SOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione reductase (GR) and glutathione-S-transferase (GST) activities and enzyme protein expressions and a significant increase in Mn-SOD activity, protein expression and malondialdehyde (MDA) level. Cochlear antioxidant enzyme activities, enzyme protein expressions and MDA level were partially restored in lipoate+carboplatin treated rats, compared to carboplatin alone.

CONCLUSIONCarboplatin-induced ototoxicity is related to impairment of cochlear antioxidant system and otoprotection conferred by lipoate is associated with partial sparing of the cochlear antioxidant defense system.

Animals ; Antioxidants ; pharmacology ; Auditory Threshold ; drug effects ; Carboplatin ; Catalase ; metabolism ; Cochlea ; drug effects ; enzymology ; metabolism ; Evoked Potentials, Auditory, Brain Stem ; drug effects ; Glutathione ; metabolism ; Glutathione Disulfide ; metabolism ; Glutathione Peroxidase ; metabolism ; Glutathione Reductase ; metabolism ; Glutathione Transferase ; metabolism ; Hearing Loss, Sensorineural ; chemically induced ; Lipid Peroxidation ; Male ; Malondialdehyde ; metabolism ; Protective Agents ; pharmacology ; Rats ; Rats, Wistar ; Superoxide Dismutase ; metabolism ; Thioctic Acid ; pharmacology

OBJECTIVETo investigate the mechanism of diabetic erectile dysfunction (ED) and find new methods for its treatment by detecting the changes in nitric oxide synthase (NOS) isoforms and erectile function of diabetic rats and observing the effects of insulin and alpha-lipoic acid (LA) on it.

METHODSFifty male Sprague-Dawley rats were divided into Groups A (normal control, n=10), B (non-intervention diabetes mellitus, n=13), C (insulin intervention diabetes mellitus, n=12), and D (insulin + LA intervention, n=15). And the diabetic models were made by intraperitoneal injection of streptozocin (STZ). Eight weeks later, the erectile function of the rats was assessed following apomorphine injection and the contents of NOS isoforms in the erectile tissues measured by immunohistochemical staining.

RESULTSAll the rats of Group A showed a normal erectile function (100%). In comparison, those in Groups B, C and D exhibited a significantly decreased rate, 28.6% in Group B, 62.5% in Group C and 80.9% in Group D. The numbers of positive nNOS fibers and eNOS in the penile tissues per visual field were 86.7 and 9.6 in Group A, but only 36.5 and 3.3 in Group B, 52.7 and 5.7 in Group C, and 71.4 and 7.4 in Group D (P < 0.05). However, the expression of iNOS was significantly lower in Group A (6.9) than in Groups B (43.6), C (36.2) and D (19.3) (P < 0.05). Compared with Groups B and C, the erectile function and the expressions of nNOS and eNOS were markedly increased, while the expression of iNOS significantly decreased in Group D (P < 0.05).

CONCLUSIONDiabetes mellitus severely affects penile erectile function and the expressions of NOS isoforms in the cavernous tissues, for which hyperglycemia is mainly responsible. LA is proved obviously efficacious for diabetic ED, which might be related to its antioxidant effect.

Animals ; Diabetes Mellitus, Experimental ; metabolism ; physiopathology ; Erectile Dysfunction ; metabolism ; physiopathology ; Insulin ; pharmacology ; Male ; Nitric Oxide Synthase ; metabolism ; Nitric Oxide Synthase Type I ; Nitric Oxide Synthase Type III ; metabolism ; Penile Erection ; Penis ; metabolism ; physiopathology ; Protein Isoforms ; Rats ; Rats, Sprague-Dawley ; Thioctic Acid ; pharmacology

OBJECTIVETo investigate the role of oxidative stress in impaired intermediate-conductance Ca(2+)-activated potassium channels (IKCa)- and small-conductance Ca(2+)-activated potassium channels (SKCa)-mediated relaxation in diabetic resistance arteries.

METHODSRat diabetic model was induced by a high fat and high glucose diet and streptozotocin (STZ) injection. Endothelial function of mesenteric arteries was assessed with the use of wire myography. The expression levels of IKCa and SKCa in cultured human umbilical vein endothelial cells (HUVECs) treated with H2O2 and/or antioxidant alpha lipoic acid (ALA) were measured using Western blotting.

RESULTSIKCa- and SKCa-mediated vasodilatation in response to acetylcholine was impaired in the third-order mesenteric arterioles of diabetic rats. In cultured HUVECs, H2O2 significantly decreased the protein expression of IKCa and SKCa. ALA alleviated the impairment of both vasodilatation function of the mesenteric arterioles ex vivo and enhanced the expression of IKCa and SKCa challenged with H2O2 in cultured HUVECs.

CONCLUSIONOur data demonstrated for the first time that impaired IKCa- and SKCa-mediated vasodilatation in diabetes was induced, at least in part, by oxidative stress via down-regulation of IKCa and SKCa channels.

Animals ; Cells, Cultured ; Diabetes Mellitus, Experimental ; metabolism ; physiopathology ; Human Umbilical Vein Endothelial Cells ; drug effects ; pathology ; Humans ; Hydrogen Peroxide ; pharmacology ; Intermediate-Conductance Calcium-Activated Potassium Channels ; metabolism ; Male ; Mesenteric Arteries ; physiopathology ; Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; Small-Conductance Calcium-Activated Potassium Channels ; metabolism ; Thioctic Acid ; pharmacology ; Vasodilation