Photochemical stability of lipoic acid and its impact on skin ageing

Abstract

It is well known that α-lipoic acid (LA) functions as an essential co-factor of the mitochondrial multi-enzyme complex and thus plays an important role in energy metabolism. Currently, it is attracting attention as a nutritional supplement because of its unique antioxidant properties and broad spectra of cellular functions. Skin protection from photodamage and ageing is one of the functional applications of LA. Medical and cosmetic application has been widely realized in the world. However, LA has a unique structure bearing a distorted five membered 1, 2-dithiolane ring, making it quite vulnerable to UV radiation. The present article briefly reviews skin ageing from the viewpoint of oxidative stress and sun exposure and analyses the photochemical properties of LA. It also discusses the effect of LA to cellular signalling and its adequate applications to treat skin ageing caused by oxidation. Data presented in this review suggest that LA is a powerful anti-ageing agent under the appropriate usage.     

Photochemical stability of lipoic acid and its impact on skin ageing

It is well known that α-lipoic acid (LA) functions as an essential co-factor of the mitochondrial multi-enzyme complex and thus plays an important role in energy metabolism. Currently, it is attracting attention as a nutritional supplement because of its unique antioxidant properties and broad spectra of cellular functions. Skin protection from photodamage and ageing is one of the functional applications of LA. Medical and cosmetic application has been widely realized in the world. However, LA has a unique structure bearing a distorted five membered 1, 2-dithiolane ring, making it quite vulnerable to UV radiation. The present article briefly reviews skin ageing from the viewpoint of oxidative stress and sun exposure and analyses the photochemical properties of LA. It also discusses the effect of LA to cellular signalling and its adequate applications to treat skin ageing caused by oxidation. Data presented in this review suggest that LA is a powerful anti-ageing agent under the appropriate usage.     

Is alpha-lipoic acid a scavenger of reactive oxygen species in vivo? Evidence for its initiation of stress signaling pathways that promote endogenous antioxidant capacity

The chemical reduction and oxidation (redox) properties of alpha-lipoic acid (LA) suggest that it may have potent antioxidant potential. A significant number of studies now show that LA and its reduced form, dihydrolipoic acid (DHLA), directly scavenge reactive oxygen species (ROS) and reactive nitrogen species (RNS) species and protect cells against a host of insults where oxidative stress is part of the underlying etiology. However, owing to its limited and transient accumulation in tissues following oral intake, the efficacy of nonprotein-bound LA to function as a physiological antioxidant has been questioned. Herein, we review the evidence that the micronutrient functions of LA may be more as an effector of important cellular stress response pathways that ultimately influence endogenous cellular antioxidant levels and reduce proinflammatory mechanisms. This would promote a sustained improvement in cellular resistance to pathologies where oxidative stress is involved, which would not be forthcoming if LA solely acted as a transient ROS scavenger.     

Lipoic acid inhibits adiponectin production in 3T3-L1 adipocytes

Lipoic acid (LA) is a naturally occurring compound with antioxidant properties. Recent attention has been focused on the potential beneficial effects of LA on obesity and related metabolic disorders. Dietary supplementation with LA prevents insulin resistance and upregulates adiponectin, an insulin-sensitizing adipokine, in obese rodents. The aim of this study was to investigate the direct effects of LA on adiponectin production in cultured adipocytes, as well as the potential signaling pathways involved. For this purpose, fully differentiated 3T3-L1 adipocytes were treated with LA (1–500 μM) during 24 h. The amount of adiponectin secreted to media was detected by ELISA, while adiponectin mRNA expression was determined by RT-PCR. Treatment with LA induced a dose-dependent inhibition on adiponectin gene expression and protein secretion. Pretreatment with the PI3K inhibitor LY294002 inhibited adiponectin secretion and mRNA levels, and significantly potentiated the inhibitory effect of LA on adiponectin secretion. The AMPK activator AICAR also reduced adiponectin production, but surprisingly, it was able to reverse the LA-induced inhibition of adiponectin. The JNK inhibitor SP600125 and the MAPK inhibitor PD98059 did not modify the inhibitory effect of LA on adiponectin. In conclusion, our results revealed that LA reduces adiponectin secretion in 3T3-L1 adipocytes, which contrasts with the stimulation of adiponectin described after in vivo supplementation with LA, suggesting that an indirect mechanism or some in vivo metabolic processing is involved.     

-Lipoic acid and -lipoamide prevent oxidant-induced lysosomal rupture and apoptosis

Abstract

-Lipoic acid (LA) and its corresponding derivative, -lipoamide (LM), have been described as antioxidants, but the mechanisms of their putative antioxidant effects remain largely uncharacterised. The vicinal thiols present in the reduced forms of these compounds suggest that they might possess metal chelating properties. We have shown previously that cell death caused by oxidants may be initiated by lysosomal rupture and that this latter event may involve intralysosomal iron which catalyzes Fenton-type chemistry and resultant peroxidative damage to lysosomal membranes. Here, using cultured J774 cells as a model, we show that both LA and LM stabilize lysosomes against oxidative stress, probably by chelating intralysosomal iron and, consequently, preventing intralysosomal Fenton reactions. In preventing oxidant-mediated apoptosis, LM is significantly more effective than LA, as would be expected from their differing capacities to enter cells and concentrate within the acidic lysosomal compartment. As previously reported, the powerful iron-chelator, desferrioxamine (Des) (which also locates within the lysosomal compartment), also provides protection against oxidant-mediated cell death. Interestingly, although Des enhances the partial protection afforded by LA, it confers no additional protection when added with LM. Therefore, the antioxidant actions of LA and LM may arise from intralysosomal iron chelation, with LM being more effective in this regard.     

Lipoamide Acts as an Indirect Antioxidant by Simultaneously Stimulating Mitochondrial Biogenesis and Phase II Antioxidant Enzyme Systems in ARPE-19 Cells

In our previous study, we found that pretreatment with lipoamide (LM) more effectively than alpha-lipoic acid (LA) protected retinal pigment epithelial (RPE) cells from the acrolein-induced damage. However, the reasons and mechanisms for the greater effect of LM than LA are unclear. We hypothesize that LM, rather than the more direct antioxidant LA, may act more as an indirect antioxidant. In the present study, we treated ARPE-19 cells with LA and LM and compared their effects on activation of mitochondrial biogenesis and induction of phase II enzyme systems. It is found that LM is more effective than LA on increasing mitochondrial biogenesis and inducing the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its translocation to the nucleus, leading to an increase in expression or activity of phase II antioxidant enzymes (NQO-1, GST, GCL, catalase and Cu/Zn SOD). Further study demonstrated that mitochondrial biogenesis and phase II enzyme induction are closely coupled via energy requirements. These results suggest that LM, compared with the direct antioxidant LA, plays its protective effect on oxidative damage more as an indirect antioxidant to simultaneously stimulate mitochondrial biogenesis and induction of phase II antioxidant enzymes.     

Lipoamide protects retinal pigment epithelial cells from oxidative stress and mitochondrial dysfunction

alpha-Lipoic acid (LA) has been widely studied as an agent for preventing and treating various diseases associated with oxidative disruption of mitochondrial functions. To investigate a related mitochondrial antioxidant, we compared the effects of lipoamide (LM), the neutral amide of LA, with LA for measures of oxidative damage and mitochondrial dysfunction in a human retinal pigment epithelial (RPE) cell line. Acrolein, a major component of cigarette smoke and a product of lipid peroxidation, was used to induce oxidative mitochondrial damage in RPE cells. Overall, using comparable concentrations, LM was more effective than LA at preventing acrolein-induced mitochondrial dysfunction and oxidative stress. Relative to LA, LM improved ATP levels, membrane potentials, and activities of mitochondrial complexes I, II, and V and dehydrogenases that had been decreased by acrolein exposure. LM reduced acrolein-induced oxidant generation, calcium levels, protein oxidation, and DNA damage to a greater degree than LA. And, total antioxidant capacity, glutathione content, glutathione S-transferase, and superoxide dismutase activities and expression of nuclear factor-E2-related factor 2 were increased by LM relative to LA. These results suggest that LM is a more potent mitochondrial-protective agent and antioxidant than LA in protecting RPE from oxidative damage.     

Antioxidant Activity of Diethyldithiocarbamate

Diethyldithiocarbamate (DDC), a potent copper chelating agent, has long been used for the treatment of oxygen toxicity to the central nervous system, as an immunomodulator to treat cancer, and in HIV-infected patients. We evaluated the antioxidant properties of DDC, including its scavenging of reactive oxygen species, its reducing properties, its iron-chelating properties, and its protective effects on oxidant-induced damage to brain tissue, protein, human LDL, and DNA. It is found that DDC is a powerful reductant and antioxidant since it scavenges hypochlorous acid, hydroxyl radical and peroxynitrite; it chelates, then oxidizes ferrous ions; it blocks the generation of hydroxyl radicals and inhibits oxidative damage to deoxyribose, protein, DNA, and human LDL. These findings may provide an explanation for the apparent beneficial effects of DDC against oxidative stress-related diseases that have been observed in experimental and clinical studies.     

Altered gene and protein expression by Nm23-H1 in metastasis suppression

The aim of our work was to study (1) the antioxidant properties of lipoic acid (LA) and its reduced metabolite dihydrolipoic acid (DHLA) formed by reduction of LA and (2) the effects of treatment with LA and DHLA on (a) K(+) efflux from human red blood cells and (b) post-ischemic recovery and oxidative stress in isolated perfused rat hearts challenged with an ischemia-reperfusion (IR) sequence. In vitro, we used xanthine and xanthine oxidase to generate superoxide anion, which is not directly measurable by electron paramagnetic resonance (EPR), but specifically oxidizes the spin probe CPH into an EPR-detectable long lasting CP(*) nitroxide radical. While 5 mM of LA was ineffective in reducing the kinetics of CP(*) nitroxide formation, DHLA was shown to lessen this rate in a dose-dependent manner and at 30 mM was even more efficient than 300 UI/ml SOD. These results are in agreement with the fact that DHLA is able to directly scavenge superoxide anion. Red cells are a good model to investigate oxidative damage in biological membranes; hence, we used a suspension of erythrocytes incubated with 2,2(')-azobis(2-amidinopropane) hydrochloride (AAPH) which generates in vitro free radicals. DHLA provided more effective protection of red cells membranes than LA; DHLA was comparable to Trolox for its antioxidant potency. In vivo, treatment of rats (50 mg/kg/day i.p. for 7 days) with LA induced a slight increase in coronary flow (CF) in isolated perfused hearts, after 30 min of global total ischemia. This effect was not associated with an improvement in contractile function and reduction of myocardial oxidative stress. In conclusion, because of their ability to scavenge free radicals, LA and to an even greater degree DHLA were able to protect the membranes of red blood cells. This finding suggests that LA and DHLA might be useful in the treatment of diseases associated with oxidative stress such as diabetes.     

Polylactic acid: synthesis and biomedical applications

Social and economic development has driven considerable scientific and engineering efforts on the discovery, development and utilization of polymers. Polylactic acid (PLA) is one of the most promising biopolymers as it can be produced from nontoxic renewable feedstock. PLA has emerged as an important polymeric material for biomedical applications on account of its properties such as biocompatibility, biodegradability, mechanical strength and process ability. Lactic acid (LA) can be obtained by fermentation of sugars derived from renewable resources such as corn and sugarcane. PLA is thus an eco-friendly nontoxic polymer with features that permit use in the human body. Although PLA has a wide spectrum of applications, there are certain limitations such as slow degradation rate, hydrophobicity and low impact toughness associated with its use. Blending PLA with other polymers offers convenient options to improve associated properties or to generate novel PLA polymers/blends for target applications. A variety of PLA blends have been explored for various biomedical applications such as drug delivery, implants, sutures and tissue engineering. PLA and their copolymers are becoming widely used in tissue engineering for function restoration of impaired tissues due to their excellent biocompatibility and mechanical properties. The relationship between PLA material properties, manufacturing processes and development of products with desirable characteristics is described in this article. LA production, PLA synthesis and their applications in the biomedical field are also discussed.     

Dihydrolipoic acid inhibits 15-lipoxygenase-dependent lipid peroxidation

The potential antioxidant effects of the hydrophobic therapeutic agent lipoic acid (LA) and of its reduced form dihydrolipoic acid (DHLA) on the peroxidation of either linoleic acid or human non-HDL fraction catalyzed by soybean 15-lipoxygenase (SLO) and rabbit reticulocyte 15-lipoxygenase (RR15-LOX) were investigated. DHLA, but not LA, did inhibit SLO-dependent lipid peroxidation, showing an IC(50) of 15 microM with linoleic acid and 5 microM with the non-HDL fraction. In specific experiments performed with linoleic acid, inhibition of SLO activity by DHLA was irreversible and of a complete, noncompetitive type. In comparison with DHLA, the well-known lipoxygenase inhibitor nordihydroguaiaretic acid and the nonspecific iron reductant sodium dithionite inhibited SLO-dependent linoleic acid peroxidation with an IC(50) of 4 and 100 microM, respectively, while the hydrophilic thiol N-acetylcysteine, albeit possessing iron-reducing and radical-scavenging properties, was ineffective. Remarkably, DHLA, but not LA, was also able to inhibit the peroxidation of linoleic acid and of the non-HDL fraction catalyzed by RR15-LOX with an IC(50) of, respectively, 10 and 5 microM. Finally, DHLA, but once again not LA, could readily reduce simple ferric ions and scavenge efficiently the stable free radical 1,1-diphenyl-2-pycrylhydrazyl in ethanol; DHLA was considerably less effective against 2,2'-azobis(2-amidinopropane) dihydrochloride-mediated, peroxyl radical-induced non-HDL peroxidation, showing an IC(50) of 850 microM. Thus, DHLA, at therapeutically relevant concentrations, can counteract 15-lipoxygenase-dependent lipid peroxidation; this antioxidant effect may stem primarily from reduction of the active ferric 15-lipoxygenase form to the inactive ferrous state after DHLA-enzyme hydrophobic interaction and, possibly, from scavenging of fatty acid peroxyl radicals formed during lipoperoxidative processes. Inhibition of 15-lipoxygenase oxidative activity by DHLA could occur in the clinical setting, eventually resulting in specific antioxidant and antiatherogenic effects.     

Arjunolic acid: a novel phytomedicine with multifunctional therapeutic applications

Herbal plants with antioxidant activities are widely used in Ayurvedic medicine for cardiac and other problems. Arjunolic acid is one such novel phytomedicine with multifunctional therapeutic applications. It is a triterpenoid saponin, isolated earlier from Terminalia arjuna and later from Combretum nelsonii, Leandra chaeton etc. Arjunolic acid is a potent antioxidant and free radical scavenger. The scientific basis for the use of arjunolic acid as cardiotonic in Ayurvedic medicine is proven by its vibrant functions such as prevention of myocardial necrosis, platelet aggregation and coagulation and lowering of blood pressure, heart rate and cholesterol levels. Its antioxidant property combined with metal chelating property protects organs from metal and drug induced toxicity. It also plays an effective role in exerting protection against both type I and type II diabetes and also ameliorates diabetic renal dysfunctions. Its therapeutic multifunctionality is shown by its wound healing, antimutagenic and antimicrobial activity. The mechanism of cytoprotection conferred by arjunolic acid can be explained by its property to reduce the oxidative stress by enhancing the antioxidant levels. Apart from its pathophysiological functions, it possesses dynamic insecticidal property and it is used as a structural molecular framework in supramolecular chemistry and nanoscience. Esters of ajunolic acid function as gelators of a wide variety of organic liquids. Experimental studies demonstrate the versatile effects of arjunolic acid, but still, further investigations are necessary to identify the functional groups responsible for its multivarious effects and to study the molecular mechanisms as well as the probable side effects/toxicity owing to its long-term use. Though the beneficial role of this triterpenoid has been assessed from various angles, a comprehensive review of its effects on biochemistry and organ pathophysiology is lacking and this forms the rationale of this review.     

Lipoic acid prevents body weight gain induced by a high fat diet in rats: Effects on intestinal sugar transport

Several studies have suggested that oxidative stress might cause and aggravate the inflammatory state associated with obesity and could be the link between excessive weight gain and its related disorders such as insulin resistance and cardiovascular diseases. Thus, antioxidant treatment has been proposed as a therapy to prevent and manage obesity and associated complications. Therefore, the aim of the present study was to investigate the effects of supplementation of a standard or high fat diet with the antioxidant lipoic acid (LA) during 56 days, on body weight gain, adiposity, feed efficiency and intestinal sugar absorption, in male Wistar rats. LA supplementation induced a lower body weight gain and adipose tissue size in both control or high fat fed rats accompanied by a reduction in food intake. The group fed on a high fat diet and treated with LA (OLIP group) showed a lower body weight gain than its corresponding Pair-Fed (PF) group (P<0.05), which received the same amount of food than LA-treated animals but with no LA. In fact, LA induced a reduction on feed efficiency and also significantly decreased intestinal α-methylglucoside (α-MG) absorption both in lean and obese rats. These results suggest that the beneficial effects of dietary supplementation with LA on body weight gain are mediated, at least in part, by the reduction observed in food intake and feed efficiency. Furthemore, the inhibitory action of LA on intestinal sugar transport could explain in part the lower feed efficiency observed in LA-treated animals and therefore, highlighting the beneficial effects of LA on obesity.     

Omega-3 fatty acids and antioxidants in edible wild plants

Human beings evolved on a diet that was balanced in the omega-6 and omega-3 polyunsaturated fatty acids (PUFA), and was high in antioxidants. Edible wild plants provide alpha-linolenic acid (ALA) and higher amounts of vitamin E and vitamin C than cultivated plants. In addition to the antioxidant vitamins, edible wild plants are rich in phenols and other compounds that increase their antioxidant capacity. It is therefore important to systematically analyze the total antioxidant capacity of wild plants and promote their commercialization in both developed and developing countries. The diets of Western countries have contained increasingly larger amounts of linoleic acid (LA), which has been promoted for its cholesterol-lowering effect. It is now recognized that dietary LA favors oxidative modification of low density lipoprotein (LDL) cholesterol and increases platelet response to aggregation. In contrast, ALA intake is associated with inhibitory effects on the clotting activity of platelets, on their response to thrombin, and on the regulation of arachidonic acid (AA) metabolism. In clinical studies, ALA contributed to lowering of blood pressure, and a prospective epidemiological study showed that ALA is inversely related to the risk of coronary heart disease in men. Dietary amounts of LA as well as the ratio of LA to ALA appear to be important for the metabolism of ALA to longer-chain omega-3 PUFAs. Relatively large reserves of LA in body fat. as are found in vegans or in the diet of omnivores in Western societies, would tend to slow down the formation of long-chain omega-3 fatty acids from ALA. Therefore, the role of ALA in human nutrition becomes important in terms of long-term dietary intake. One advantage of the consumption of ALA over omega-3 fatty acids from fish is that the problem of insufficient vitamin E intake does not exist with high intake of ALA from plant sources.     

Effects of lipoic acid on apelin in 3T3-L1 adipocytes and in high-fat fed rats

Lipoic acid (LA) is an antioxidant with therapeutic properties on several diseases like diabetes and obesity. Apelin is a novel adipokine with potential beneficial actions on glucose metabolism and insulin resistance. The aim of this study was to examine in 3T3-L1 adipocytes the effects of LA on apelin gene expression and secretion, as well as elucidate the signaling pathways involved. We also tested the regulation of adipose apelin gene expression by LA supplementation in a model of high-fat diet-induced obesity. LA increased apelin secretion but not apelin gene expression in 3T3-L1 adipocytes. The AMPK inhibitor Compound C induced an increase in LA-stimulated apelin production, and, on the contrary, the AMPK activator AICAR completely reversed the LA stimulatory effects on apelin secretion, also inducing a significant reduction in apelin mRNA levels in this in vitro model. Apelin mRNA levels were increased in those animals fed with the high-fat diet, while the caloric restriction decreased apelin mRNA to control levels. However, apelin gene expression was not significantly modified in rats treated with LA compared with the obese group. The current data suggest the ability of LA to modulate apelin secretion by adipocytes. However the insulin-sensitizing effect of LA in vivo is not related to changes in apelin gene expression in our model of diet-induced obesity.     

Targeting lipoic acid to mitochondria: synthesis and characterization of a triphenylphosphonium-conjugated alpha-lipoyl derivative

Lipoic acid (LA) is a widely used antioxidant that protects mitochondria from oxidative damage in vivo. Much of this protection is thought to be due to the reduction of LA to dihydrolipoic acid (LAH(2)). This reduction is catalyzed in vivo by thioredoxin, thioredoxin reductase (TrxR), and lipoamide dehydrogenase. We hypothesized that specifically targeting LA to mitochondria, the site of most cellular reactive oxygen species production, would make it a more effective antioxidant. To do this, we made a novel molecule, MitoLipoic acid, by attaching lipoic acid to the lipophilic triphenylphosphonium cation. MitoL was accumulated rapidly within mitochondria several-hundred fold driven by the membrane potential. MitoL was reduced to the active antioxidant dihydroMitoLipoic acid by thioredoxin and by lipoamide dehydrogenase but not by TrxR. In isolated mitochondria or cells MitoL was only slightly reduced (5-10%), while, in contrast, LA was extensively reduced. This difference was largely due to the reaction of LA with TrxR, which did not occur for MitoL. Furthermore, in cells MitoL was quantitatively converted to an S-methylated product. As a consequence of its lack of reduction, MitoL was not protective for mitochondria or cells against a range of oxidative stresses. These results suggest that the protective action of LA in vivo may require its reduction to LAH(2) and that this reduction is largely mediated by TrxR.     

Intake assessment of L-ergothioneine in some European countries and in the United States

L-ergothioneine is an amino acid synthetized by fungi and mycobacteria that cannot be synthesized by other species. It has been detected in plants, animals, and the human body. In the last few years, it has been recognized as a good antioxidant and, recently, it has also been related to other properties besides antioxidant properties. Even though few studies on the toxicity of L-ergothioneine have been carried out, evidence suggests that L-ergothioneine is not harmful to health. Considering that L-ergothioneine has increasingly been linked to positive effects on human health, coupled with the fact that it seems to be safe for human consumption, this molecule may be suitable for use as an ingredient in foods. On the other hand, despite the positive effects reported for this molecule, no estimate of L-ergothioneine intake has been carried out until now. Thus, the aim of this work is to estimate the intake of L-ergothioneine through food consumption of several European countries and the United States. Values were estimated by using the deterministic and probabilistic approach. Results show that the populations with the highest intake of L-ergothioneine correspond to Italian population, both for children and adults.     

Lipoic acid: a unique antioxidant in the detoxification of activated oxygen species

Lipoic acid (1,2-dithiolane-pentanoic acid) is a dithiol which is effective in affording protection against oxidative stress by virtue of its two sulphydryl moieties. It is present in all kinds of eukaryotic and prokaryotic cells. As lipoamide, it functions as a cofactor in the multienzyme complexes that catalyse the oxidative decarboxylation of α-keto acids such as pyruvate, α-ketoglutarate, and branched-chain α-keto acids. The complete enzyme pathway responsible for the de novo synthesis of lipoic acid has not yet been elucidated. Octanoic acid appears to be the precursor for the eight-carbon fatty acid chain, and cysteine the source of sulfur. Lipoic acid is unique, among antioxidants, because it retains powerful antioxidant properties in both its reduced (dihydrolipoic acid) and oxidised (lipoic acid) forms. Both lipoic and dihydrolipoic acids have metal-chelating ability and quench activated oxygen species either in the cytosol or in the hydrophobic domains. Dihydrolipoic acid has more antioxidant properties than lipoic acid, and it plays an important role in the recycling of other oxidised radical scavengers such as glutathione, ascorbate and tocopherol. However, dihydrolipoic acid can also exert pro-oxidant properties both by its iron-reducing ability and by its ability to generate sulfur-containing radicals that can damage proteins. There are few quantitative data on lipoic acid contents in vegetables. It has been found in asparagus, wheat and potatoes, and recently, the presence of both lipoic and dihydrolipoic acids in roots, leaves and in the stroma of wheat has been demonstrated.