Lipoic acid metabolism in the rat

dl-[1,6-¹⁴C]Lipoic acid was administered by intraperitoneal injection to rats at the level of 0.5 mg/100 g body weight. Approximately 56% of the radioactivity was recovered in the urine. When acidified and extracted with benzene, 92% of the radioactivity remained in the aqueous phase. Gel-filtration and paper chromatography were used to identify three of the compounds in the benzene extract as lipoic, bisnorlipoic and tetranorlipoic acids. In addition, a keto compound appears to be present. The aqueous phase contained several radioactive components separable by ion-exchange and paper chromatographies. Two of these compounds were identified as lipoate and β-hydroxybisnorlipoate. No evidence for oxidation of the dithiolane ring of lipoic acid was observed. dl-[7,8-¹⁴C]Lipoic acid was administered to rats under the same conditions. The urine contained 81% of the radioactivity, 72% of which remained in the aqueous phase and 28% was extracted into benzene. In contrast to over 30% of the label from dl-(1,6-¹⁴C] lipoate being expired as ¹⁴CO₂, a negligible amount of ¹⁴CO₂ was produced by rats injected with dl-[7,8-¹⁴C]lipoate. The catabolites identified were the same as those found using the 1,6-labeled lipoate. Another dithiolane-intact compound was also isolated. It appears that the rat, similar to Pseudomonas putida LP, metabolizes lipoate mainly via β-oxidation of the valeric acid side chain.     

Lipoic acid analogs with enhanced pharmacological activity

Lipoic acid (1,2-dithiolane-3-pentanoic acid) is a pharmacophore with unique antioxidant and cytoprotective properties. We synthesized a library based upon the condensation of natural and unnatural amino acids with the carboxylic acid moiety of lipoic acid. SAR studies were conducted using a cardiac ischemia-reperfusion animal model. Cytoprotective efficacy was associated with the R-enantiomer of the dithiolane. Potency of library compounds was dictated by the acidic strength of the adduct. α-N-[(R)-1,2-dithiolane-3-pentanoyl]-l-glutamyl-l-alanine, designated CMX-2043, was chosen for further pharmacologic evaluation.     

Lipoic acid inhibition of mitochondrial malate dehydrogenase

Porcine heart mitochondrial malate dehydrogenase (L-malate:NAD⁺ oxidoreductase, EC 1.1.1.37) has been shown to be inhibited by extremely low concentrations of lipoic acid. The actual inhibitor was found to be a high molecular weight substance, which can be separated by gel permeation from the non-inhibitory monomeric form of lipoic acid. This inhibitor has been identified as a polymeric form of lipoic acid.     

Lipoic acid a multi-level molecular inhibitor of tumorigenesis

We discuss how lipoic acid (LA), a natural antioxidant, induces apoptosis and inhibits proliferation, EMT, metastasis and stemness of cancer cells. Furthermore, owing to its ability to reduce chemotherapy-induced side effects and chemoresistance, LA appears to be a promising compound for cancer treatment.     

Lipoic acid and diabetes II: Mode of action of lipoic acid

Intraperitoneal administration of lipoic acid (10 mg/100 g) does not effect changes in serum insulin levels in normal and alloxan diabetic rats, while normalising increased serum pyruvate, and impaired liver pyruvic dehydrogenase characteristic of the diabetic state. Dihydrolipoic acid has been shown to participate in activation of fatty acids with equal facility as coenzyme A. Fatty acyl dihydrolipoic acid however is sparsely thiolyzed to yield acetyl dihydrolipoic acid. Also acetyl dihydrolipoic acid does not activate pyruvate carboxylase unlike acetyl coenzyme A. The reduced thiolysis of Β-keto fatty acyl dihydrolipoic acid esters and the lack of activation of pyruvic carboxylase by acetyl dihydrolipoic acid could account for the antiketotic and antigluconeogenic effects of lipoic acid     

Lipoic acid modified antimicrobial peptide with enhanced antimicrobial properties

RIWVIWRR-NH₂ (Bac8c) is a natural antimicrobial peptide (AMP) exhibiting great antibacterial activity against Gram-negative and Gram-positive bacteria. In this work, lipoic acid was used as a fatty acid hydrophobic ligand to modify Bac8c (LA-Bac8c) to further improve its antimicrobial properties. Minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) assays showed that LA-Bac8c exhibited lower MIC (MBC) values against Staphylococcus aureus (S. aureus) and methicillin-resistant Staphylococcus aureus (MRSA) than Bac8c. Similar results were reflected in the antibiofilm activity towards S. aureus and MRSA, and LA-Bac8c showed better activity to the biofilm which has been formed or is being formed. In addition to this, the obvious interaction between bacteria/biofilm and LA-Bac8c was observed by microscopy. LA-Bac8c displayed strong membrane depolarization and outer membrane permeabilizing ability, and the cell membrane treated with LA-Bac8c was destroyed to the leakage of bacteria cellular components. All these data indicated LA-Bac8c could be used as a useful antimicrobial peptide with wide application prospect.     

Trace element status in Saudi patients with established atherosclerosis

BACKGROUND: Traditional coronary risk factors do not fully explain variations in the incidence of cardiovascular disease (CVD). Epidemiological studies have implicated perturbations in selenium, copper, and zinc metabolism in the aetiology of CVD. However, these studies have been principally undertaken in Caucasian populations, in whom trace element intake is generally sufficient. METHOD: We have measured serum and urine selenium, copper, and zinc; and superoxide dismutase, glutathione peroxidase, and lipid peroxide concentrations in 130 Saudi male subjects with established CVD, and 130 age-matched controls. RESULTS: Diabetes mellitus, positive smoking habit (p<0.0001 for both), and hypertension (p<0.05) were more prevalent among CVD patients. Urinary copper (p<0.0001) and zinc (p<0.05) were higher among controls. Serum selenium concentrations were lower among CVD patients (p<0.001), and a high proportion (52%) had selenium levels below 79mug/L compared to controls (22%) (p<0.0001). Conditional logistic regression analysis, showed the characteristics differentiating CVD patients from controls were serum zinc (odds ratio (OR) 0.92, confidence interval (CI) 0.85-0.99, p<0.05), serum copper/zinc ratio (OR 0.31, CI 0.10-0.96), serum selenium (OR 0.07, CI 0.02-0.31, p<0.0001), and urine selenium (OR 3.34, CI 1.40-7.99, p<0.01). CONCLUSION: Measures of trace metals status appear to be associated with the risk of atherosclerosis in a Saudi male population.     

神经节苷脂联合α-硫辛酸治疗糖尿病神经源性膀胱临床观察

目的：观察α-硫辛酸、神经节苷脂联合治疗糖尿病神经源性膀胱的临床疗效。方法：60例2型糖尿病神经源性膀胱患者,随机分为α-硫辛酸治疗对照组、神经节苷脂治疗对照组,联合治疗组,疗程30d,观察症状体征及治疗前后B超膀胱残余尿量症状的变化,比较不同方案的疗效。结果：α-硫辛酸治疗对照组有效率90％,神经节苷脂治疗对照组有效率90％,联合治疗组有效率95％两组间无统计学差异（P〉0．05）,但3组的治愈率分别为90．0％、50．0％、60．0%,治疗组的治愈率高于两个对照组,有统计学差异（P〈0．05）。结论：α-硫辛酸和神经节苷脂联合治疗糖尿病神经源性膀胱有较好的临床疗效,值得临床推广。     

Lipoic acid content of Escherichia coli and other microorganisms

A mutant strain of Escherichia coli K12 requiring lipoic acid, W1485 lip 2 (ATCC 25645), was used to develop a turbidimetric assay for lipoic acid and a polarographic assay based on the oxidation of pyruvate by suspensions of lipoic acid-deficient organisms. The turbidimetric assay was more sensitive with a working range equivalent to 0.2–2.0 ng of dl-α-lipoic acid compared with 5–50 ng for the polarographic method. The mutant responded equally to racemic mixtures of α-lipoic acid, β-lipoic acid and dihydrolipoic acid but gave little response to lipoamide, and other derivatives without prior hydrolysis; 8-methyllipoic acid was a competitive inhibitor of the response to lipoic acid. A high specificity of the mutant for the natural stereoisomer was indicated by the fact that (+)-α-lipoic acid had twice the activity of the racemic mixture. Escherichia coli K12 contained less than 0.05 ng of free (+)-α-lipoic acid per mg dry weight but, depending on the growth substrate, the equivalent of between 13 and 47 ng of (+)-α-lipoic acid per mg dry weight after acid extraction. There was a strong correlation between the lipoic acid content and the sum of the specific activities for the pyruvate and α-ketoglutarate dehydrogenase complexes. Experiments with washed suspensions of Escherichia coli showed only small increases in lipoic acid content (18%) when incubated with pyruvate, cysteine and methionine. When supplied with exogenous lipoic acid the mutant, W1485 lip 2, accumulated very little more than was demanded by its metabolism. The lipoic acid contents of several organisms were measured and correlated with their metabolism.     

神经节苷脂联合α-硫辛酸治疗糖尿病神经源性膀胱临床观察

目的:观察α-硫辛酸、神经节苷脂联合治疗糖尿病神经源性膀胱的临床疗效。方法:60例2型糖尿病神经源性膀胱患者,随机分为α-硫辛酸治疗对照组、神经节苷脂治疗对照组,联合治疗组,疗程30d,观察症状体征及治疗前后B超膀胱残余尿量症状的变化,比较不同方案的疗效。结果:α-硫辛酸治疗对照组有效率90%,神经节苷脂治疗对照组有效率90%,联合治疗组有效率95%两组间无统计学差异(P>0.05),但3组的治愈率分别为90.0%、50.0%、60.0%,治疗组的治愈率高于两个对照组,有统计学差异(P<0.05)。结论:α-硫辛酸和神经节苷脂联合治疗糖尿病神经源性膀胱有较好的临床疗效,值得临床推广。     

Lipoic acid and acetyl-carnitine reverse iron-induced oxidative stress in human fibroblasts

Iron overload occurs frequently in thalassemia and other disorders that require regular blood transfusions. Excess iron is toxic owing to the generation of free radicals that lead to oxidation of biomolecules and tissue damage. In order to identify compounds that reduce oxidative injury from iron, we evaluated alpha-lipoic acid (LA), a multifunctional antioxidant, in iron-overloaded primary human fibroblasts (IMR-90). Oxidant stress was measured using dichlorodihydrofluorescein diacetate that is converted to the fluorescent dichlorofluorescein (DCF) upon oxidation. Exposure to ferric ammonium citrate (FAC) increased the iron-content of IMR-90 cells and caused a rise in oxidant appearance. The addition of LA improved the cellular redox status and attenuated the iron-mediated rise in oxidants in a dose-dependent manner. The R- and RS-enantiomers of LA demonstrated similar antioxidant activity. N-tert-butyl hydroxylamine (NtBHA) treated cells also exhibited a decrease in DCF fluorescence, but at a much higher concentration compared with LA. The combination acetyl-L-carnitine (ALCAR) and LA exhibited superior antioxidant effect at all dose levels. We conclude that LA is highly effective in reversing oxidative stress arising from iron overload and that its antioxidant efficacy is further enhanced in combination with ALCAR.     

Lipoic acid and diabetes: Effect of dihydrolipoic acid administration in diabetic rats and rabbits

Relative α-lipoic acid content of diabetic livers was considerably less than that of normal livers as determined by gas chromatography. It was not possible to detect any dihydrolipoic acid in the livers. Biochemical abnormalities such as hyperglycaemia, ketonemia, reduction in liver glycogen and impaired incorporation of [2-¹⁴C] -acetate into fatty acids in alloxan diabetic rats were brought to near normal levels by the oral or intraperitoneal administration of dihydrolipoic acid. The effect of α-lipoic acid was comparable to that of dihydrolipoic acid in reducing the blood sugar levels of diabetic rabbits during a glucose tolerance test. The results suggest that the mode of action of lipoic acid was through stimulation of pyruvate dehydrogenase.     

Lipoic acid stimulates cAMP production in T lymphocytes and NK cells

The anti-oxidant lipoic acid (LA) potently suppresses clinical and pathologic disease in the animal model of multiple sclerosis, experimental autoimmune encephalomyelitis, by inhibiting the migration of pathogenic T cells to the spinal cord. The mechanism by which this occurs is largely unknown. In this report we demonstrate that LA induces increases in cyclic AMP, a known immunosuppressant, in human T cells. The increase in cAMP is associated with increased adenylyl cyclase activity and is partially blocked by prostanoid receptor antagonists. We present evidence that LA also stimulates cAMP production in natural killer (NK) cells. This novel mechanism of action is highly relevant to the immunomodulatory effects of LA and provides further support for the study of LA as a therapeutic agent for multiple sclerosis and other autoimmune diseases.     

Lipoic acid protects efficiently only against a specific form of peroxynitrite-induced damage

The ability of the sulfur-containing compounds glutathione (GSH), glutathione disulphide (GSSG), S-methylglutathione (GSMe), lipoic acid (LA), and dihydrolipoic acid (DHLA) to protect against hypochlorous acid (HOCl)-mediated damage and peroxynitrite (ONOOH)-induced damage has been compared. Protective activity was assessed in competition assays by monitoring several detectors, i.e. dihydrorhodamine-123 (DHR-123) oxidation, alpha(1)-antiproteinase (alpha(1)-AP) inactivation, and glutathione S-transferase P1-1 (GST-P1-1) inactivation. In addition, nitration of tyrosine was measured to assess protection of the sulfur-containing compounds against ONOOH. For protection against HOCl, the efficacy of the antioxidant was controlled by the ratio of the reaction rates of the antioxidant and the detector molecule with the oxidant. The rank order of the activity of the antioxidants (GSH > DHLA approximately LA approximately GSMe > GSSG) appeared to be independent of the detector used. However, the rank order of the antioxidants against ONOOH-induced damage is strongly dependent on the detector. LA was 40 times less active than GSH in the inhibition of ONOOH-induced DHR-123 oxidation, whereas LA was 20 times more active than GSH in preventing the inhibition of GST-P1-1 by ONOOH. This points to different molecular mechanisms of ONOOH damage to DHR-123 compared with ONOOH damage to GST-P1-1. LA is a poor antioxidant in protecting against the form of ONOOH damage involved in DHR-123 oxidation. In the form of ONOOH toxicity involved in GST-P1-1 inhibition, LA is the most potent sulfur-containing antioxidant in our series. It is proposed that an intermediate product in which both sulfur atoms of LA have reacted is involved in the reaction of ONOOH with LA. The high potency of LA to protect GST-P1-1 against ONOOH might be of therapeutic interest.     

Lysosomal acid lipase and atherosclerosis

PURPOSE OF REVIEW: Atherosclerosis remains the leading cause of death in the developed countries. In addition to lipid-lowering drugs - statins, dietary control, and exercise, new approaches are needed for the treatment and prevention of atherosclerosis. This review will focus on the role(s) of lysosomal acid lipase and its use as an enzyme therapy to reduce atherosclerotic lesions in a mouse model and to examine the molecular basis supporting this novel strategy and its mechanism of effect. RECENT FINDINGS: Administration of human lysosomal acid lipase via tail vein into mice with atherosclerosis eliminates early aortic and coronary ostial lesions and reduces lesional size in advanced disease. The reduction of advanced lesional area is related to decreases in foamy macrophages, collagen positive areas, and necrotic areas. Compared with sham-treated mice, the human lysosomal acid lipase-treated mice also have reduced levels of plasma cholesteryl esters, and reduced levels of hepatic cholesterol and triglycerides. SUMMARY: These studies indicate that administrated lysosomal acid lipase affects the atherogenesis by at least two mechanisms: (1) direct targeting of lesional macrophages with resultant decreases in cholesteryl esters and triglyceride in the lysosomes of macrophages in the lesions; (2) systemic effects that mediate the liver to reduce the hepatic cholesteryl ester and triglyceride release, possibly leading to reduced production of VLDL and LDL.