Lipoic acid. Kinetics and pluripotent biological properties and derivatives.

Lipoic acid (LA) is globally known and its supplements are widely used. Despite its importance for the organism it is not considered a vitamin any more. The multiple metabolic forms and the differences in kinetics (absorption, distribution and excretion), as well as the actions of its enantiomers are analysed in the present article together with its biosynthetic path. The proteins involved in the transfer, biotransformation and activity of LA are mentioned. Furthermore, the safety and the toxicological profile of the compound are commented, together with its stability issues. Mechanisms of lipoic acid intervention in the human body are analysed considering the antioxidant and non-antioxidant characteristics of the compound. The chelating properties, the regenerative ability of other antioxidants, the co-enzyme activity and the signal transduction by the implication in various pathways will be discussed in order to be elucidated the pleiotropic effects of LA. Finally, lipoic acid integrating analogues are mentioned under the scope of the multiple pharmacological actions they acquire towards degenerative conditions.

In-vitro activity of lipoic acid against Ureaplasma urealyticum and Ureaplasma parvum isolated from women with infections of the urogenital tract. A pilot study.

Several species of Ureaplasma bacteria are known to be present in the urogenital tract of humans, in both healthy individuals and symptomatic patients. These pathogens are associated with urogenital tract infections, infertility problems and spontaneous abortion in humans. The present study involved 77 strains of Ureaplasma species (Ureaplasma spp.), including 21 Ureaplasma urealyticum (U. urealyticum) strains and 56 Ureaplasma parvum (U. parvum) strains. Lipoic acid (LA) and its reduced form dihydrolipoic acid (DHLA) are synthesized in all prokaryotic and eukaryotic cells. Research of recent years increasingly points to therapeutic properties of exogenously supplemented LA. In our study, we examined for the first time the effect of LA on the bacteria multiplication and its bactericidal activity against U. urealyticum and U. parvum. The LA concentrations used were: 1200 µg/ml, 120 µg/ml, and 12 µg/ml. The titer for each strain of Ureaplasma spp. was estimated using the color changing units (CCU) assay. For CCU measurements, a series of 10-fold dilutions of each cell culture in 0.9% NaCl (titration) was prepared and 1 CCU/ml was defined as the highest dilution of cells at which color change was detected. The strongest bacteriostatic and bactericidal effect of LA was observed at a concentration of 1200 µg/ml. In contrast, at lower LA concentrations, stimulation of the bacteria multiplication was noted for 14% of the total number of strains tested. Taken together, the current data provide novel findings about potential beneficial antimicrobial effects of LA.

The first method for determination of lipoyllysine in human urine after oral lipoic acid supplementation.

Aim: The first method on urinary excreted amounts of lipoyllysine (LLys) after lipoic acid (LA) supplementation was developed and validated. The suggested procedure allowed simultaneous determination of LLys and LA. Methodology & results: After the conversion of analytes into their reduced forms with tris(2-carboxyethyl)phosphine and derivatization via thiol group with 1-benzyl-2-chloropyridinium bromide, separation of analytes derivatives was performed on C18 column using a gradient mobile phase consisting of acetic acid and acetonitrile. The calibration curves for LA and LLys were linear (R2 > 0.999) in the range of 0.4-12 µM concentration and all validation results were acceptable, according to the US FDA bioanalytical method guidelines. Conclusion: This method was effectively applied for LA and LLys quantification in human urine after oral LA supplementation.

The utility of DHL-HisZnNa, a novel antioxidant, against anticancer agent-induced alopecia in breast cancer patients: a multicenter phase II clinical trial.

PURPOSE: Chemotherapy-induced alopecia (CIA) is a distressing adverse effect of anticancer drugs; however, there are currently no mechanisms to completely prevent CIA. In this study, we performed a clinical trial to examine whether sodium N-(dihydrolipoyl)-l-histidinate zinc complex (DHL-HisZnNa), an alpha-lipoic acid derivative, prevents CIA in patients with breast cancer. METHODS: Between July 2014 and May 2015, we performed a multi-center, single arm, clinical trial involving 103 breast cancer patients who received adjuvant chemotherapy at three medical institutions in Japan. During chemotherapy, a lotion containing 1% DHL-HisZnNa was applied daily to the patients' scalps. The primary endpoint was the incidence of grade 2 alopecia; the secondary endpoints were the duration of grade 2 alopecia, alopecia-related symptoms, and drug-related adverse events. Alopecia was evaluated by three independent reviewers using head photographs taken from four angles. RESULTS: Safety analysis was performed for 101 patients who started the protocol therapy. After excluding one patient who experienced disease progression during treatment, 100 patients who received at least two courses of chemotherapy underwent efficacy analysis. All original 101 patients developed grade 2 alopecia, the median durations of which were 119 days (112-133 days) and 203 days (196-212 days) in the groups treated with four and eight courses of chemotherapy, respectively. Mild or moderate adverse events potentially related to DHL-HisZnNa were observed in 11 patients. Alopecia-related symptoms were observed in 53 patients (52%). CONCLUSIONS: The application of 1% DHL-HisZnNa to the scalp did not prevent CIA. However, this drug may promote recovery from CIA. TRIAL REGISTRATION NUMBER: UMIN000014840.

Ex-vivo absorption study of lysine R-lipoate salt, a new pharmaceutical form of R-ALA.

Alpha-lipoic acid (ALA) oral supplements were used in many pathologies associated with increased oxidative stress. Although only R-ALA is considered the biologically active form, R,S-ALA is used in therapeutic applications even showing poor water solubility. The aim of this work was to study the absorption and transport mechanism across the intestinal barrier of new R-ALA stable and water soluble form, consisting in the lysine R-ALA salt, in presence and absence of specific inhibitors of Na+/multivitamin (SMVT) and monocarboxylic acids (MCT). The absorption of a new ALA form was investigated at rat everted sacs in comparison with R-ALA, S-ALA, and R,S-ALA. Results showed that duodenum is the best portion of intestine for ALA forms absorption. The absorption percentage of R-ALA, S-ALA, R,S-ALA, and lysine R-ALA salt was 66%, 43%, 55%, and 70%, respectively. The modest effect of the SMVT inhibitor biotin demonstrated that this transporter system is not principally involved in the absorption of lysine R-lipoate salt across the rat intestinal barrier. On the contrary, the MCT inhibitor octanoic acid significantly reduced the transport of this salt, whit an absorption decrease of R-ALA and lysine R-lipoate salt of 28% and 24%, respectively. Since the highest concentration of these inhibitors did not completely inhibit the absorption of lysine R-lipoate salt, other transport mechanisms probably operate for its intracellular delivery. The new form of ALA, lysine R-lipoate salt, was the most absorbed respect to the other ALA forms demonstrating that this compound is more suitable for oral administration. This new salt could represent a promising candidate for ALA oral supplementation.

Safety of oral alpha-lipoic acid treatment in pregnant women: a retrospective observational study.

OBJECTIVE: Alpha-lipoic acid is a natural molecule, which directly or by means of its reduced form, dihydrolipoic acid, exerts antioxidant, anti-inflammatory and immunomodulatory activities, very helpful also in preventing miscarriage and preterm delivery. Used as dietary supplement alpha-lipoic acid was demonstrated to be safe for living organisms even when administered at high doses. However, no study was made so far to verify the safety of its continuous administration on a substantial number of pregnant women. The present investigation was performed to answer this issue. PATIENTS AND METHODS: An observational retrospective study was carried out analyzing 610 expectant mothers. They had been treated daily by oral route with 600 mg alpha-lipoic acid, for at least 7 weeks during gestation. The primary outcome was to verify alpha-lipoic acid safety in the mother and infant. Maternal safety was assessed by monitoring for adverse reactions, physical and clinical examination, including a morbidity assessment. Laboratory and clinical examinations were performed monthly. Neonatal safety was assessed by the evaluation of birth weight, gestational age, Apgar scores, neonatal death with the related cause of death. Data collected from the Birth Registry of Campania Region were used as control. RESULTS: This study provided a very clear and reassuring picture about the safety of alpha-lipoic acid oral treatment during pregnancy. No adverse effect was noticed in mothers or newborns. The two sets of monitored data, from treated and controls, were completely superimposable or, in some cases, better in alpha-lipoic acid group. CONCLUSIONS: Our results open a reassuring scenario regarding the administration of alpha-lipoic acid during pregnancy.

Nitric oxide induces monosaccharide accumulation through enzyme S-nitrosylation.

Nitric oxide (NO) is extensively involved in various growth processes and stress responses in plants; however, the regulatory mechanism of NO-modulated cellular sugar metabolism is still largely unknown. Here, we report that NO significantly inhibited monosaccharide catabolism by modulating sugar metabolic enzymes through S-nitrosylation (mainly by oxidizing dihydrolipoamide, a cofactor of pyruvate dehydrogenase). These S-nitrosylation modifications led to a decrease in cellular glycolysis enzymes and ATP synthase activities as well as declines in the content of acetyl coenzyme A, ATP, ADP-glucose and UDP-glucose, which eventually caused polysaccharide-biosynthesis inhibition and monosaccharide accumulation. Plant developmental defects that were caused by high levels of NO included delayed flowering time, retarded root growth and reduced starch granule formation. These phenotypic defects could be mediated by sucrose supplementation, suggesting an essential role of NO-sugar cross-talks in plant growth and development. Our findings suggest that molecular manipulations could be used to improve fruit and vegetable sweetness.

Novel Synthetic PEGylated Conjugate of α-Lipoic Acid and Tempol Reduces Cell Death in a Neuronal PC12 Clonal Line Subjected to Ischemia.

α-Lipoic acid (α-LA), a natural thiol antioxidant, and Tempol, a synthetic free radical scavenger, are known to confer neuroprotection following ischemic insults in both in vivo and in vitro models. The aim of this study was to synthesize and characterize a conjugate of α-LA and Tempol linked by polyethylene glycol (PEG) in order to generate a more efficacious neuroprotectant molecule. AD3 (α-Tempol ester-ω-lipo ester PEG) was synthesized, purified, and characterized by flash chromatography and reverse phase high pressure liquid chromatography and by 1H nuclear magnetic resonance, infrared spectroscopy, and mass spectrometry. AD3 conferred neuroprotection in a PC12 pheochromocytoma cell line of dopaminergic origin, exposed to oxygen and glucose deprivation (OGD) insult measured by LDH release. AD3 exhibited EC50 at 10 µM and showed a 2-3-fold higher efficacy compared to the precursor moieties, indicating an intrinsic potent neuroprotective activity. AD3 attenuated by 25% the intracellular redox potential, by 54% lipid peroxidation and prevented phosphorylation of ERK, JNK, and p38 by 57%, 22%, and 21%, respectively. Cumulatively, these findings indicate that AD3 is a novel conjugate that confers neuroprotection by attenuation of MAPK phosphorylation and by modulation of the redox potential of the cells.

The disulfide compound α-lipoic acid and its derivatives: A novel class of anticancer agents targeting mitochondria.

The endogenous disulfide α-lipoic acid (LA) is an essential mitochondrial co-factor. In addition, LA and its reduced counterpart dihydro lipoic acid form a potent redox couple with antioxidative functions, for which it is used as dietary supplement and therapeutic. Recently, it has gained attention due to its cytotoxic effects in cancer cells, which is the key aspect of this review. We initially recapitulate the dietary occurrence, gastrointestinal absorption and pharmacokinetics of LA, illustrating its diverse antioxidative mechanisms. We then focus on its mode of action in cancer cells, in which it triggers primarily the mitochondrial pathway of apoptosis, whereas non-transformed primary cells are hardly affected. Furthermore, LA impairs oncogenic signaling and displays anti-metastatic potential. Novel LA derivatives such as CPI-613, which target mitochondrial energy metabolism, are described and recent pre-clinical studies are presented, which demonstrate that LA and its derivatives exert antitumor activity in vivo. Finally, we highlight clinical studies currently performed with the LA analog CPI-613. In summary, LA and its derivatives are promising candidates to complement the arsenal of established anticancer drugs due to their mitochondria-targeted mode of action and non-genotoxic properties.

Lipoic acid inhibits the DNA repair protein O 6-methylguanine-DNA methyltransferase (MGMT) and triggers its depletion in colorectal cancer cells with concomitant autophagy induction.

Alkylating agents are present in food and tobacco smoke, but are also used in cancer chemotherapy, inducing the DNA lesion O (6)-methylguanine. This critical adduct is repaired by O (6)-methylguanine-DNA methyltransferase (MGMT), resulting in MGMT inactivation and degradation. In the present study, we analyzed the effects of the natural disulfide compound lipoic acid (LA) on MGMT in vitro and in colorectal cancer cells. We show that LA, but not its reduced form dihydrolipoic acid, potently inhibits the activity of recombinant MGMT by interfering with its catalytic Cys-145 residue, which was partially reversible by N-acetyl cysteine. Incubation of HCT116 colorectal cancer cells with LA altered their glutathione pool and caused a decline in MGMT activity. This was mirrored by LA-induced depletion of MGMT protein, which was not attributable to changes in MGMT messenger RNA levels. Loss of MGMT protein coincided with LA-induced autophagy, a process resulting in lysosomal degradation of proteins, including presumably MGMT. LA-stimulated autophagy in a p53-independent manner as revealed by the response of isogenic HCT116 cell lines. Knockdown of the crucial autophagy component beclin-1 and chemical inhibitors blocked LA-induced autophagy, but did not abrogate LA-triggered MGMT degradation. Concomitant with MGMT depletion, LA pretreatment resulted in enhanced O (6)-methylguanine levels in DNA. It also increased the cytotoxicity of the alkylating anticancer drug temozolomide in temozolomide-resistant colorectal cancer cells. Taken together, our study showed that the natural compound LA inhibits MGMT and induces autophagy. Furthermore, LA enhanced the cytotoxic effects of temozolomide, which makes it a candidate for a supplement in cancer therapy.

Lipoamide channel-binding sulfonamides selectively inhibit mycobacterial lipoamide dehydrogenase.

Tuberculosis remains a global health emergency that calls for treatment regimens directed at new targets. Here we explored lipoamide dehydrogenase (Lpd), a metabolic and detoxifying enzyme in Mycobacterium tuberculosis (Mtb) whose deletion drastically impairs Mtb's ability to establish infection in the mouse. Upon screening more than 1.6 million compounds, we identified N-methylpyridine 3-sulfonamides as potent and species-selective inhibitors of Mtb Lpd affording >1000-fold selectivity versus the human homologue. The sulfonamides demonstrated low nanomolar affinity and bound at the lipoamide channel in an Lpd-inhibitor cocrystal. Their selectivity could be attributed, at least partially, to hydrogen bonding of the sulfonamide amide oxygen with the species variant Arg93 in the lipoamide channel. Although potent and selective, the sulfonamides did not enter mycobacteria, as determined by their inability to accumulate in Mtb to effective levels or to produce changes in intracellular metabolites. This work demonstrates that high potency and selectivity can be achieved at the lipoamide-binding site of Mtb Lpd, a site different from the NAD⁺/NADH pocket targeted by previously reported species-selective triazaspirodimethoxybenzoyl inhibitors.

Direct and indirect antioxidant properties of α-lipoic acid and therapeutic potential.

Diabetes has emerged as a major threat to worldwide health. The exact mechanisms underlying the disease are unknown; however, there is growing evidence that the excess generation of reactive oxygen species (ROS) associated with hyperglycemia, causes oxidative stress in a variety of tissues. In this context, various natural compounds with pleiotropic actions like α-lipoic acid (LA) are of interest, especially in metabolic diseases such as diabetes. LA, either as a dietary supplement or a therapeutic agent, modulates redox potential because of its ability to match the redox status between different subcellular compartments as well as extracellularly. Both the oxidized (disulfide) and reduced (di-thiol: dihydro-lipoic acid, DHLA) forms of LA show antioxidant properties. LA exerts antioxidant effects in biological systems through ROS quenching but also via an action on transition metal chelation. Dietary supplementation with LA has been successfully employed in a variety of in vivo models of disease associated with an imbalance of redox status: diabetes and cardiovascular diseases. The complex and intimate association between increased oxidative stress and increased inflammation in related disorders such as diabetes, makes it difficult to establish the temporal sequence of the relationship.

Prevention of free fatty acid-induced hepatic lipotoxicity by carnitine via reversal of mitochondrial dysfunction.

BACKGROUND: Mitochondria are the main sites for fatty acid oxidation and play a central role in lipotoxicity and nonalcoholic steatohepatitis. AIMS: We investigated whether carnitine prevents free fatty acid (FFA)-induced lipotoxicity in vitro and in vivo. METHODS: HepG2 cells were incubated with FFA, along with carnitine and carnitine complexes. Mitochondrial ß-oxidation, transmembrane potential, intracellular ATP levels and changes in mitochondrial copy number and morphology were analysed. Otsuka Long-Evans Tokushima Fatty and Long-Evans Tokushima Otsuka rats were segregated into three experimental groups and fed for 8 weeks with (i) normal chow, (ii) a methionine choline-deficient (MCD) diet or (iii) an L-carnitine-supplemented MCD diet. RESULTS: Carnitine prevented FFA-induced apoptosis (16% vs. 3%, P < 0.05). FFA treatment resulted in swollen mitochondria with increased inner matrix density and loss of cristae. However, mitochondria co-treated with carnitine had normal ultrastructure. The mitochondrial DNA copy number was higher in the carnitine treatment group than in the palmitic acid treatment group (375 vs. 221 copies, P < 0.05). The carnitine group showed higher mitochondrial ß-oxidation than did the control and palmitic acid treatment groups (597 vs. 432 and 395 ccpm, P < 0.05). Carnitine treatment increased the mRNA expression of carnitine palmitoyltransferase 1A and peroxisome proliferator-activated receptor-γ, and carnitine-lipoic acid further augmented the mRNA expression. In the in vivo model, carnitine-treated rats showed lower alanine transaminase levels and lesser lobular inflammation than did the MCD-treated rats. CONCLUSIONS: Carnitine and carnitine-lipoic acid prevent lipotoxicity by increasing mitochondrial ß-oxidation and reducing intracellular oxidative stress.

Lipoic acid - biological activity and therapeutic potential.

α-Lipoic acid (LA; 5-(1,2-dithiolan-3-yl)pentanoic acid) was originally isolated from bovine liver by Reed et al. in 1951. LA was once considered a vitamin. Subsequently, it was found that LA is not a vitamin and is synthesized by plants and animals. LA is covalently bound to the ε-amino group of lysine residues and functions as a cofactor for mitochondrial enzymes by catalyzing the oxidative decarboxylation of pyruvate, α-ketoglutarate and branched-chain α-keto acids. LA and its reduced form - dihydrolipoic acid (DHLA), meet all the criteria for an ideal antioxidant because they can easily quench radicals, can chelate metals, have an amphiphlic character and they do not exhibit any serious side effects. They interact with other antioxidants and can regenerate them. For this reason, LA is called an antioxidant of antioxidants. LA has an influence on the second messenger nuclear factor κB (NF-κB) and attenuates the release of free radicals and cytotoxic cytokines. The therapeutic action of LA is based on its antioxidant properties. Current studies support its use in the ancillary treatment of many diseases, such as diabetes, cardiovascular, neurodegenerative, autoimmune diseases, cancer and AIDS. This review was undertaken to gather the most recent information regarding the therapeutic properties of LA and its possible utility in disease treatment.

Simple HPLC evaluation of lipoamidase activity in tissue using a newly synthesized fluorescent substrate, dansyl-α-lipoyllysine.

α-Lipoic acid (LA) is a naturally occurring disulfide-containing compound used as an antioxidant supplement which also has been used as a medicine for diabetic neuropathy in Europe. Physiologically LA acts as a coenzyme of mitochondrial multienzyme complex in its protein bound form but it is not yet clear how the externally administrated LA is incorporated into other proteins in the same protein-bound form or why the bound form is active as an antioxidant. The binding and cleavage of LA to or from the protein is mediated by lipoamidase and thus determines LA distribution in tissues. We have developed a simple sensitive assay for lipoamidase using a fluorescent substrate, dansyl-α-lipoyllysine (DLL). Lipoamidase in tissues cleaves the amide bond between LA and the ε-amino-lysine moiety to release dansylated lysine (DL). A HPLC comparison of the fluorescence intensity between DLL and DL was used to quantify the enzyme activity. The hydrolytic reaction did not occur when the tissue was heat-treated before incubation with DLL and was inhibited by free LA, especially by the R-enantiomer of LA (physiologically active form). N(ε)-Acetyl-L-lysine did not compete with DLL in the cleavage reaction. The method was applied for the determination of lipoamidase activity levels in various rat tissues. It was revealed the spleen had the highest activity followed by the kidney, heart, lung and liver. The activity in the brain was below the detection limit of the assay.

New lipoic acid derivative drug sodium zinc dihydrolipoylhistidinate prevents cardiac dysfunction in an isolated perfused rat heart model.

OBJECTIVE: Myocardial ischemia/reperfusion injury is a life-limiting condition. Reactive oxygen species are released upon reperfusion, resulting in damage to myocardial cells. Accordingly, antioxidant drugs have been shown to protect the myocardium against ischemia/reperfusion injury. The purpose of the present study was to determine the cardioprotective effects of the new lipoic acid-derivative drug sodium zinc dihydrolipoylhistidinate in a global ischemia isolated perfused rat heart model. DESIGN: Animals were randomly divided into five groups: 1) normal group, 2) control ischemia/reperfusion group, 3) high-dose sodium zinc dihydrolipoylhistidinate (1 ng/mL) plus ischemia/reperfusion group, 4) medium-dose sodium zinc dihydrolipoylhistidinate (0.1 ng/mL) plus ischemia/reperfusion group, or 5) low-dose sodium zinc dihydrolipoylhistidinate (0.01 ng/mL) plus ischemia/reperfusion group. SETTING: University medical center research laboratory. SUBJECTS: Male Sprague-Dawley rats weighing 250-300 g. MEASUREMENTS AND MAIN RESULTS: Hearts underwent ischemia/reperfusion after isolation with or without sodium zinc dihydrolipoylhistidinate treatment. We then conducted cardiac histopathology and transmission electron microscopy analyses and assessed cardiac function. In addition, we examined the effects of sodium zinc dihydrolipoylhistidinate on ischemia/reperfusion-induced mitochondrial dysfunction. We found that cardiac dysfunction and mitochondrial damage were significantly reduced after reperfusion by sodium zinc dihydrolipoylhistidinate treatment. However, only rats treated with high-dose sodium zinc dihydrolipoylhistidinate showed improved cardiac function. Furthermore, treatment with sodium zinc dihydrolipoylhistidinate significantly improved mitochondrial function in vitro. CONCLUSIONS: These findings suggest that sodium zinc dihydrolipoylhistidinate attenuates ischemia/reperfusion-induced myocardial dysfunction in rats. Furthermore, sodium zinc dihydrolipoylhistidinate exerted cardioprotective effects via preservation of mitochondrial function. Taken together, our results strongly support the potential therapeutic role of sodium zinc dihydrolipoylhistidinate in the treatment of ischemia/reperfusion injury.

Is it time to reassess alpha lipoic acid and niacinamide therapy in schizophrenia?

As sulfur containing thiols, alpha lipoic acid (ALA) and its reduced form dihydrolipoic acid (DHLA) are powerful antioxidants and free radical scavengers capable of performing many of the same functions as glutathione (GSH). ALA supplementation may help protect mitochondria from oxidative stress, a possible mechanism contributing to certain forms of brain diseases called schizophrenia. Shortly before the advent of antipsychotic medications, two small studies found ALA relieved psychiatric symptoms in schizophrenia. More recently, animal studies have shown ALA augmentation improves mitochondrial function. At pharmaceutical levels, niacinamide helps preserve mitochondrial membrane integrity and acts as an antioxidant. ALA is a precursor for lipoamide, an essential mitochondrial coenzyme and niacinamide is a component of niacinamide adenine dinucleotide (NAD). NADH, the reduced form of NAD, is involved in the reduction of ALA to DHLA within the mitochondria. This is relevant to contemporary research because DHLA increases GSH and low GSH levels contribute to mitochondrial dysfunction and oxidative stress which have been implicated in the pathophysiology of schizophrenia.

Dihydrolipoamide dehydrogenase (DLD) deficiency in a Spanish patient with myopathic presentation due to a new mutation in the interface domain.

We present a 32-year-old patient who, from age 7 months, developed photophobia, left-eye ptosis and progressive muscular weakness. At age 7 years, she showed normal psychomotor development, bilateral ptosis and exercise-induced weakness with severe acidosis. Basal blood and urine lactate were normal, increasing dramatically after effort. PDHc deficiency was demonstrated in muscle and fibroblasts without detectable PDHA1 mutations. Ketogenic diet was ineffective, however thiamine gave good response although bilateral ptosis and weakness with acidosis on exercise persisted. Recently, DLD gene analysis revealed a homozygous missense mutation, c.1440 A>G (p.I480M), in the interface domain. Both parents are heterozygous and DLD activity in the patient's fibroblasts is undetectable. The five patients that have been reported with DLD-interface mutations suffered fatal deteriorations. Our patient's disease is milder, only myopathic, more similar to that due to mutation p.G229C in the NAD(+)-binding domain. Two of the five patients presented mutations (p.D479V and p.R482G) very close to the present case (p.I480M). Despite differing degrees of clinical severity, all three had minimal clues to DLD deficiency, with occasional minor increases in α-ketoglutarate and branched-chain amino acids. In the two other patients, hypertrophic cardiomyopathy was a significant feature that has been attributed to moonlighting proteolytic activity of monomeric DLD, which can degrade other mitochondrial proteins, such as frataxin. Our patient does not have cardiomyopathy, suggesting that p.I480M may not affect the DLD ability to dimerize to the same extent as p.D479V and p.R482G. Our patient, with a novel mutation in the DLD interface and mild clinical symptoms, further broadens the spectrum of this enzyme defect.

Synthesis and anticancer evaluation of alpha-lipoic acid derivatives.

alpha-Lipoic acid derivatives were synthesized and evaluated for their in vitro anticancer activities against NCI-460, HO-8910, KB, BEL-7402, and PC-3 cell lines. The results, for most compounds exhibited dose-dependent inhibitory property and several compounds had good inhibitions at the dose of 100 microg/mL. Compound 17 m was further selected for in vivo evaluation against S180 xenograft in ICR mice, which had 24.7% tumor-weight inhibition through intragastric administration of 200mg/kg of body weight. Moreover, the LD(50) in mice for 17 m through ig exceeded 1000 mg/kg of body weight.

Alpha-lipoic acid supplementation: a tool for obesity therapy?

Lipid peroxidation has supposed as the major biochemical alteration underling oxidant-induced cell injury in stress including numerous diseases. One of the natural molecules know to prevent or retard oxidation is alpha-lipoic acid (LA) and, therefore, the lipoic acid/dihydrolipoic acid (LA/DHLA) redox couple has received considerable attention. Recent studies have highlighted the potential of free LA and DHLA as powerful metabolic antioxidants that are able to scavenge the reactive oxygen species, to recycle other antioxidants. Our aim was to investigate the beneficial effects of LA in the treatment of Italian pre-obese and obese subjects. We screened 1612 subjects for enrollment; of these, 1127 subjects (445 men and 682 women, 18-60 age) met enrolment criteria and were enrolled in the study. According to body mass index (BMI) the 53% was obese and the 43% was pre-obese. The subjects were treated for 4 month with 800 mg/day of LA. In pre-obese subject significant reduction (p<0.001) of weight (8%, both gender), BMI (2 points), blood pressure, and abdominal circumference (female 6 cm, male 7 cm) were observed. In obese subjects significant reductions (p<0.001) of weight (9%, both gender), BMI (female 3 point, male 4 point), blood pressure and abdominal circumference (female 9 cm, male 11 cm) were observed. Our study indicated that LA is an ideal antioxidant candidate for the therapy of obesity related diseases. Further clinical studies should be considered to highlight the role and efficacy of LA treatment.