Alpha Lipoic Acid

The effectiveness of any cosmetic product containing a functional ingredient is determined by the skin delivery of the active molecule, which is influenced by the type of carrier and the molecule itself. Furthermore, the functional ingredient should be stable in the formulation. The purpose of this paper is to study the stability of lipoic acid in the presence of vitamins A (as palmitate) and E (as acetate) in semisolids for cosmetic use. The systems formulated were studied in regard to their aspect, pH, stability under centrifugation, and rheological behavior. The chemical analyses of lipoic acid and vitamins A and E were carried out by HPLC after studying the specificity of the method employed in each case. The quantitation of the active principles was performed by HPLC with C18 (5 microm) columns. The mobile phase was methanol for the vitamins, with spectrophotometric detection at 325 nm for vitamin A and 230 nm for vitamin E. The mobile phase for lipoic acid was methanol:water (...

and suggests that a larger fragment of PDC-E2 is sequestered at the site of immune-mediated destruction in PBC livers. These findings question the presence of a molecular mimic of PDC-E2 localized to the apical surface of BEC and further substantiate the theory that disease-specific apical staining is due to PDC-E2, or a fragment thereof, that is present at the apical surface of BEC.

Clinical studies have shown that the antioxidant vitamin E can slow the progression of Alzheimer's disease (AD). Other antioxidants reported to affect cognitive function include ginkgo biloba, vitamin C, and lipoic acid. To examine the effects of combination antioxidant therapy (CAT) on longevity and neuropathology in mice, we supplemented the diet of ApoE-deficient mice with vitamin E, ginkgo biloba, pycnogenol, and ascorbyl palmitate. ApoEdeficient mice normally exhibit increased numbers of PAS-positive inclusion bodies with aging. However, supplementation with CAT resulted in a significant increase in life span and a marked reduction of inclusion body histopathology in the hippocampus. In addition, while untreated apoE-deficient mice exhibited increased levels of TUNEL staining, a marker of DNA fragmentation, supplementation with CAT resulted in a significant reduction in the levels of TUNEL staining. These findings suggest that oxidative mechanisms, perhaps related to neuronal apoptosis, are integral to inclusion body formation in aging mice. The association between the reduced number of apoptotic cells and the reduction in inclusion bodies may explain in part the increased longevity of mice fed CAT, and supports the contention that the combined actions of selected antioxidants may be therapeutically effective against neurodegenerative diseases.

The effectiveness of any cosmetic product containing a functional ingredient is determined by the skin delivery of the active molecule, which is influenced by the type of carrier and the molecule itself. Furthermore, the functional ingredient should be stable in the formulation.

Alpha Lipoic Acid (ALA, thioctic acid, pyruvate oxidation factor) was first discovered by bacteriologis t Irwin C. Gunsalus in 1948 when he observed that aerobic (oxygen-requiring) bacteria could not grow without it. Later, Gunsalus and Lester Reed determined the true structure and named it ALA (1951). ALA is a natural substance, produced in every higher-type cell, and it has many functions. Probably most importantly, ALA is the rate-limiting factor for the production of energy from carbohydrates (pyruvate). Without ALA, you could not obtain energy from the food you eat, and you could not stay alive.

The stability of ascorbyl palmitate, sodium ascorbyl phosphate and magnesium ascorbyl phosphate in topical formulations was investigated by direct reverse phase high performance liquid chromatography after sample dilution with a suitable buffer – organic solvent mixture. Ascorbyl palmitate, sodium ascorbyl phosphate and magnesium ascorbyl phosphate are derivatives of ascorbic acid which differ in hydrolipophilic properties. They are widely used in cosmetic and pharmaceutical preparations. According to the results, ascorbyl esters showed significant differences: sodium ascorbyl phosphate and magnesium ascorbyl phosphate are more stable derivatives of vitamin C than ascorbyl palmitate and may be easily used in cosmetic products.On recherche la stabilité du palmitate d’ ascorbyl et phosphate de magnésium dans des formulations topiques par RP-HPLC directe après dilution de l’échantillon avec une mélange approprié tampon-dissolvant organique. Les propriétés hydro-lipophiles du palmitate d’ascorbyl, du phosphate d’ascorbyl et sodium et du phosphate d’ascorbyl et magnésium, dérivés du acide ascorbique, sont différentes. Ils sont utilisés vastement dans des préparations cosmétiques et pharmaceutiques. Selon les résultats, ils montrent différences significatives: le phosphate d’ascorbyl et sodium et le phosphate d’ascorbyl et magnésium, sont les dérivés plus stables de la vitamine C, et peuvent être utilisés facilement dans des produits cosmétiques.

Altered metabolism of cancer first highlighted by Otto Warburg has a long history. Although ignored for a considerable amount of time, it is now receiving substantial attention. We recently published results obtained with a combination of two drugs, lipoic acid and hydroxycitrate, targeting metabolic enzymes particularly affected in cancer: ATP citrate lyase and pyruvate dehydrogenase kinase. This treatment was as efficient as chemotherapy in the three mouse cancer models that were tested. In this work, we asked if our drug combination could be used in conjunction with standard cytotoxic chemotherapy, in particular cisplatin, to improve basic protocol efficacy. A combination of lipoic acid and hydroxycitrate was administered to mice implanted with syngeneic cancer cells, LL/2 lung carcino-ma and MBT-2 bladder carcinoma, concommitantly with classical chemotherapy (cisplatin or methotrexate). We demonstrate that the triple combination lipoic acid + hydroxycitrate + cisplatin or methotrexate is more efficient than cisplatin or methotrexate used individually or the combination of lipoic acid and hydroxycitrate administered alone. Of particular note are the results obtained in the treatment of an 80 year-old female who presented with ductal adenocarcinoma of the pancreas accompanied by liver metastases. A treatment course using gemcitabine plus αlipoic acid and hydroxycitrate gave highly promising results. The in vivo data, coupled with the case study results, suggest a possible advantage in using a treatment targeted at cancer metabolism in association with classical chemotherapy.

Oxygen-free radicals, more generally known as reactive oxygen species (ROS) along with reactive nitrogen species (RNS) are well recognised for playing a dual role as both deleterious and beneficial species. The "two-faced" character of ROS is substantiated by growing body of evidence that ROS within cells act as secondary messengers in intracellular signalling cascades, which induce and maintain the oncogenic phenotype of cancer cells, however, ROS can also induce cellular senescence and apoptosis and can therefore function as anti-tumourigenic species. The cumulative production of ROS/RNS through either endogenous or exogenous insults is termed oxidative stress and is common for many types of cancer cell that are linked with altered redox regulation of cellular signalling pathways. Oxidative stress induces a cellular redox imbalance which has been found to be present in various cancer cells compared with normal cells; the redox imbalance thus may be related to oncogenic stimulation. DNA mutation is a critical step in carcinogenesis and elevated levels of oxidative DNA lesions (8-OH-G) have been noted in various tumours, strongly implicating such damage in the etiology of cancer. It appears that the DNA damage is predominantly linked with the initiation process. This review examines the evidence for involvement of the oxidative stress in the carcinogenesis process. Attention is focused on structural, chemical and biochemical aspects of free radicals, the endogenous and exogenous sources of their generation, the metal (iron, copper, chromium, cobalt, vanadium, cadmium, arsenic, nickel)-mediated formation of free radicals (e.g. Fenton chemistry), the DNA damage (both mitochondrial and nuclear), the damage to lipids and proteins by free radicals, the phenomenon of oxidative stress, cancer and the redox environment of a cell, the mechanisms of carcinogenesis and the role of signalling cascades by ROS; in particular, ROS activation of AP-1 (activator protein) and NF-B (nuclear factor kappa B) signal transduction pathways, which in turn lead to the transcription of genes involved in cell growth regulatory pathways. The role of enzymatic (superoxide dismutase (Cu, Zn-SOD, Mn-SOD), catalase, glutathione peroxidase) and non-enzymatic antioxidants (Vitamin C, Vitamin E, carotenoids, thiol antioxidants (glutathione, thioredoxin and lipoic acid), flavonoids, selenium and others) in the process of carcinogenesis as well as the antioxidant interactions with various regulatory factors, including Ref-1, NF-B, AP-1 are also reviewed.

In this case report, we describe the treatment of a 64-year-old male patient diagnosed with metastatic renal cell carcinoma
(RCC) in June of 2008. In spite of a left nephrectomy and the standard oncological protocols, the patient developed a solitary
left lung metastasis that continued to grow. He was informed that given his diagnosis and poor response to conventional
therapy, any further treatment would, at best, be palliative. The patient arrived at the Integrative Medical Center of New
Mexico in August of 2010. He was in very poor health, weak, and cachectic. An integrative program—developed by one of
the authors using intravenous (IV) α-lipoic acid, IV vitamin C, low-dose naltrexone, and hydroxycitrate, and a healthy life
style program—was initiated. From August 2010 to August 2015, the patient’s RCC with left lung metastasis was followed
closely using computed tomography and positron emission tomography/computed tomography imaging. His most recent
positron emission tomography scan demonstrated no residual increased glucose uptake in his left lung. After only a few
treatments of IV α-lipoic acid and IV vitamin C, his symptoms began to improve, and the patient regained his baseline
weight. His energy and outlook improved, and he returned to work. The patient had stable disease with disappearance
of the signs and symptoms of stage IV RCC, a full 9 years following diagnosis, with a gentle integrative program, which is
essentially free of side effects. As of November 2017 the patient feels well and is working at his full-time job.

Vitamin C, also known as ascorbic acid, is a water-soluble antioxidant. Today we meet our requirements of vitamin C through consumption of fruits and vegetables or by supplementation. Homo sapiens cannot produce vitamin C like many other species that can convert glucose to vitamin C. The gene for enzyme production is dormant in humans. The gene, GULO, that we all carry converts glucose to Vitamin C. in other species but not in humans and primates. The open-label study showed Metadichol ® raised levels of vitamin C by 3 fold, endogenously without supplementation of Vitamin C. Possible mechanisms for the increased Vitamin C levels through antioxidant pathways are presented. Metadichol ® [1] is a nano-formulation of long chain alcohols derived from sugar cane. In addition to increased Vitamin C levels reduction in Potassium and uric acid, and decreased blood pressure and improvement in quality of life issues were also observed.

Age-related decline in the capacity to withstand stress, such as ischemia and reperfusion, results in congestive heart failure. Though the mechanisms underlying cardiac decay are not clear, age dependent somatic damages to mitochondrial DNA (mtDNA), loss of mitochondrial function, and a resultant increase in oxidative stress in heart muscle cells may be responsible for the increased risk for cardiovascular diseases. The effect of a safe nutritional supplement, POLY-MVA, containing the active ingredient palladium a-lipoic acid complex, was evaluated on the activities of the Krebs cycle enzymes such as isocitrate dehydrogenase, a-ketoglutarate dehydrogenase, succinate dehydrogenase, and malate dehydrogenase as well as mitochondrial complexes I, II, III, and IV in heart mitochondria of aged male albino rats of Wistar strain.

Background: YKL-40 − a chitinase-like protein − was increased in patients with severe asthma and chronic obstructive pulmonary disease (COPD). Neutrophils secrete YKL-40. We hypothesized that increased YKL-40 levels in lung diseases reflect neutrophilic inflammation and that YKL-40 accumulates in the airways of cystic fibrosis patients (CF), a prototypic neutrophilic airway disease. We aimed to analyze YKL-40 levels in human and murine CF lung disease compared to COPD, asthma and control subjects. Methods: YKL-40 protein levels were measured in serum and sputum samples of CF, asthma, COPD and healthy individuals. Protein levels of the murine homologue BRP-39 were quantified in airway fluids from CF-like bENaC-Tg mice. Results: YKL-40 levels were significantly increased in human and murine CF airway fluids compared to asthma, COPD and healthy individuals. In both CF patients and bENaC-Tg mice, YKL-40/BRP-39 airway levels correlated with severity of obstructive lung disease. Conclusion: YKL-40 is increased in CF airway fluids and is negatively associated with pulmonary function. These findings suggest YKL-40 as potential biomarker and therapeutic target in CF lung disease.

Type 2 diabetes is a growing health concern. The use of nutritional supplements by patients with type 2 diabetes is estimated at somewhere between 8% to 49%. The objective of this review was to search the scientific literature for advances in the treatment and prevention of type 2 diabetes with nutritional supplements. Twelve databases were searched with a focus on extracting studies published in the past 3 years. The following nutritional supplements were identified as potentially beneficial for type 2 diabetes treatment or prevention: vitamins C and E, α-lipoic acid, melatonin, red mold, emodin from Aloe vera and Rheum officinale, astragalus, and cassia cinnamon. Beta-carotene was shown to be ineffective in the prevention of type 2 diabetes. Ranging from preclinical to clinical, there is evidence that nutritional supplements may be beneficial in the treatment or prevention of type 2 diabetes. Health providers should investigate drug-nutritional supplement interactions prior to treatment.

Palladium a-lipoic acid formulation -'POLY-MVA' is found to enhance the activities of Krebs cycle dehydrogenases and respiratory complexes in the heart of aged rat. In this study, we aimed to evaluate the effect of POLY-MVA on the activities of antioxidant status in the heart mitochondria of aged rat. We determined the activities of manganese-superoxide dismutase (Mn SOD), catalase (CAT), glutathione peroxidase (GPx), and level of reduced GSH and lipid peroxidation in the heart mitochondria of aged rats, after administering POLY-MVA (0.05 ml/kg; equivalent to 0.38 mg complexed a-lipoic acid/kg) orally once daily for 30 days. DL-a-lipoic acid (0.38 mg/kg, p.o) treated for 30 days was kept as the positive control. We found that the antioxidant in the aged control was declined significantly than the young control. The formulation significantly (p < 0.05) enhanced the activity of CAT and GPx compared to the aged control. The level of GSH was also significantly improved and the level of lipid peroxidation was decreased significantly (p < 0.05) by POLY-MVA. The results indicate that POLY-MVA is effective to protect the agelinked decline of myocardial mitochondrial antioxidant status. The findings suggest the use of this formulation against myocardial aging.

OBJECTIVE: The effects of dimethyl phthalate, diethyl phthalate, diisobutyl phthalate, din -butyl phthalate, benzylbutyl phthalate, di-2-ethylhexyl phthalate were investigated on human prostate cancer cell lines DU145 and PC3 in vitro. MATERIALS AND METHODS: Standards of dimethyl phthalate, diethyl phthalate, di-isobutyl phthalate, dibutyl phthalate, benzyl butyl phthalate, and di-ethyl hexyl phthalate were used. Alpha lipoic acid was used as antioxidant compound. DU145 and PC3 human prostate carcinoma cells were used. MTT assay were used for cytotoxicity assay. RESULTS: A low dose proliferative effect of phthalates in vitro was observed. With the hypothesis of the inhibition of aerobic glycolysis activity in cancer treatment, α-lipoic acid was applied to cells; where as a contrary to previous studies, no change in the cell proliferation was observed. In combination with ALA, at IC50 and lower doses, an increase of the cytotoxic effect was found for DIBP, DBP and BBP; while for DMP, DEP and DEHP, a decrease was observed for DU145 cells. In PC3 cells, a decrease was observed for DMP, DEP and DBPs; while no signifi cant difference were observed for DEHP, DIBP and BBP. CONCLUSSION: The present study demonstrates preliminary information regarding the low dose proliferative effects of phthalates in prostate cancer in vitro (Tab. 2, Fig. 2, Ref. 65).

Regrowth of plants after cryopreservation varies, and resulting regrowth ranges from poor to excellent. Oxidative stress is a potential cause of damage in plant tissues. Antioxidants and anti-stress compounds may improve regrowth by preventing or repairing the damage. Lipoic acid (LA), glutathione (GSH), glycine betaine (GB), and polyvinylpyrrolidone (PVP) were tested during cryopreservation of shoot tips using the plant vitrification solution 2 (PVS2) protocol. Two in vitro-grown blackberry cultivars were cold acclimated and then cryopreserved in liquid nitrogen (LN). The antioxidant and anti-stress compounds were added at four critical steps of the protocol: pretreatment, loading, rinsing, and regrowth. Three out of the four compounds significantly improved regrowth of cryopreserved shoot tips. Regrowth ranged from 40% to 50% for controls to >80% for treated shoot tips. LA (4-8 mM) produced high regrowth at pretreatment, loading, and rinsing for ‘Chehalem’ and at all steps for ‘Hull Thornless’. Recovery improved at all steps with GSH (0.16 mM) and GB (10 mM). PVP had a neutral or negative impact on regrowth. Overall addition of LA, GSH, and GB improved regrowth by ∼25% over the shoot tips cryopreserved using the regular PVS2 protocol (control). This study shows that adding non-vitamin antioxidants and anti-stress compounds during the PVS2-vitrification protocol improves regrowth of shoot cultures following cryopreservation. We recommend inclusion of antioxidants as part of standard cryopreservation protocols.

Impaired antioxidant defense mechanisms and oxidative stress are implicated in the pathogenesis of arsenic toxicity. Our study was designed to determine whether ␣-lipoic acid, which has been shown to have substantial antioxidant properties, when administered (70 mg/kg body weight) once daily for 60 days along with arsenic (100 ppm sodium arsenite mixed in drinking water) would prevent arsenic-induced changes in antioxidant defense system, superoxide dismutase (SOD-total SOD, Mn SOD, Cu/Zn SOD), catalase (CAT) and glutathione peroxidase (GSH-PX) in rat brain regions such as cortex, hypothalamus, striatum, cerebellum and hippocampus. The present study also examined the effect of ␣-lipoic acid over arsenic-induced oxidant production and lipid peroxidation level (LPO) in discrete brain regions of rats. The cortex, striatum and hippocampus showed greater decreases in GSH-Px enzyme activity than cerebellum and hypothalamus with arsenic exposure. Striatum had the greatest percentage of decreased activities of total SOD and Mn SOD, whereas cortex had the greatest percentage decrease in the activity of Cu/Zn SOD in arsenic-alone treated rats. Hypothalamus and cerebellum exhibited the lowest catalase activity among all tested regions in arsenic-only treated rats. Rate of dichlorofluorescin oxidation, an indication of reactive oxygen species and other intracellular oxidants production was increased with arsenic exposure in all brain regions studied. Cortex, hippocampus and striatum exhibited greater increase of LPO levels than cerebellum and hypothalamus. SOD, CAT, GSH-Px activities were upregulated in arsenic plus lipoic acid treated versus arsenic-only treated rats. Also, simultaneous lipoic acid treatment along with arsenic proved to be sufficient in reducing oxidant production and LPO level in all rat brain regions. Our results demonstrate that arsenic-induced deficits in antioxidant enzyme activities and increase in oxidant production and lipid peroxidation level in brain regions can be overcome through simultaneous treatment with lipoic acid.

To evaluate the role of ALA treatment on the healing of acetic acid-induced gastric ulcer, rats were given ALA (35 mg/kg/day) or saline for 3 days before the induction of ulcer and the treatment was continued twice daily for 2 days (early) or 10 days (late) until they were decapitated. Gastric ulcer index, microscopic score, elevated DNA fragmentation and chemiluminescence levels of the saline-treated ulcer groups were all reduced by ALA treatment. Likewise, ALA treatment inhibited chemiluminescence levels in both early and late ulcer groups. Marked reduction in glutathione levels of the saline-treated early ulcer group was reversed by ALA treatment, while ALA treatment was effective in depressing gastric myeloperoxidase activity in the late ulcer group. In conclusion, ALA treatment shows protective role in the healing of acetic acid-induced gastric injury in rats via the suppression of neutrophil accumulation, preservation of endogenous glutathione, inhibition of reactive oxidant generation and apoptosis.

Background: Alpha lipoic acid is a potent antioxidant
that plays numerous roles in human health. This study
examined the effect of ALA on rat sciatic nerve ischemia
reperfusion damage.
Aims: Protective effect of alpha lipoic acid (ALA) on
sciatic nerve following ischemia-reperfusion in rats
was investigated by using light microscopy and biochemical
methods. Provided that the protective effect
of ALA on sciatic nerve is proven, we think the damage
to the sciatic nerve that has already occurred or might
occur in patients for various reasons maybe prevented
or stopped by giving ALA in convenient doses.
Study Design: Animal experiment.
Methods: Forty-two adult male Sprague-Dawley rats
(250-300 grams) were used in this study. Rats were
randomly divided into six groups including one control
(Group 1), one sham (Group 2), two ischemia-reperfusion
(Groups 3 and 4) and two treatment groups
(Groups5 and 6). Doses of 60 and 100 mg/kg ALA were
given (Group 5 and 6) intra peritoneally twice, 1 and
24 hours before the ischemia to each treatment group.
Ischemia was carried out the abdominal aorta starting
from the distal part of the renal vein for two hours followed
by reperfusion for three hours. In immunohistochemical
methods, fibronectin immunoreactivity was
analyzed. For biochemical analyses, the tissues were
taken in eppendorf microtubes and superoxide dismutase
(SOD) and glutathione peroxidase (GSHPx)
enzyme activities as well as malondialdehyde (MDA)
and nitricoxide (NO) levels were measured.
Results: Fibronectin was observed to have increased
significantly in the ischemia group; on the other hand,
it was observed to have decreased in parallel to the doses
in the ALA groups. Biochemical studies showed that
SOD and GSHPx declined with ischemia-reperfusion,
but the activities of these enzymes were increased in
the treatment groups in parallel with the dose. It was
found that increased MDA levels with ischemia-reperfusion
were decreased in parallel with ALA dose. There
were no statistically significant changes in NO.
Conclusion: Increased fibronectin observed after ischemia/
reperfusion of rat sciatic nerve is reduced after
the administration of ALA. This indicates that the function
of fibronectin, to reconnect cut nerve segments and
regenerate nerves, is more prominent than its function
in tissue healing after ischemia. ALA administered before
ischemia decreases MDA and increases SOD and
GSHPx. We think that ALA may protect against the
pathological changes in ischemic nerve and may be
used to devise more efficient treatments.
Keywords: Alpha lipoic acid, ischemia-reperfusion,
sciatic nerve, rat

2-(2-Acetoxyethyl)cyclohexanone (4) was converted into the lactone (-)-(5) re io and enantioselectively using g -2-oxo-ti-4,5,5-trimethylcyclopentenyl acetyl-CoA monooxygenase, an NADPH-dependent Baeyer-Villiger monooxygenase from camphor grown Pseudomonas putidu NCIMB 10007. The lactone (-)-(5) was converted into (R)-( + )-lipoic acid in six steps. In contrast cyclopentanone monooxygenase, an NADPH-dependent Baeyer-Villiger monooxygenase from cyclopentanol-grown Pseudomonas sp. NCIMB 9872 selectively oxidized the (S)-enantiomer of the ketone (4) giving better access to optically enriched, naturally occurring lipoic acid. 0 1997, Elsevier Science Ltd. All rights reserved.

Alpha lipoic acid (ALA, thioctic acid), among other actions, is an essential coenzyme in the conversion of pyruvate to acetyl co-enzyme A. Therefore, it is necessary for the production of energy for aerobic organisms. Scientists have found that it can be used medically to help regenerate liver tissue, reverse the complications of diabetes mellitus, slow or stop the growth of cancer cells, and chelate heavy metals, among other actions. In this article, the authors describe the cellular mitochondrial damage from excessively high doses of this beneficial agent.

In this paper we describe the treatment of a 71-year-old female registered nurse (JA) diagnosed with Hepatocellular Carcinoma (HCC) in early October 2006. The patient was a heavy smoker and drank alcohol on weekends. She contracted hepatitis C following a finger sticks from a patient with the disease. Several years later she developed HCC. Her doctor at a large medical center, after viewing her CT scans, told her that with so many tumors in her liver, only a liver transplant would offer some hope of survival. She was informed that, given her diagnosis, that without liver transplant surgery any further treatment would, at best, be palliative. Mrs. JA refused liver transplant surgery. The patient arrived at the Integrative Medical Center of New Mexico (IMCNM) in late October 2006 she appeared to be in very poor health, weak, and fatigued. An integrative program developed by one of the authors using intravenous alpha-lipoic acid, oral low dose naltrexone and a healthy lifestyle program...

fluidity at 4 nmol/mg and increasingly less active up to 20 nmol/mg protein. By contrast the R-form of lipoic Human red cell membranes (ghosts) were treated by acid was moderately efficient in increasing fluidity 5 min of incubation with fasting or hypo-and hyperglythrough a larger concentration range between 4 and cemic concentrations of D-glucose. This simulation of 80 nmol/mg protein. ᭧ 1995 Academic Press, Inc. nondiabetic or diabetic conditions revealed an influ-Key Words: erythrocyte (human); D-glucose; memence on membrane fluidity and on protein-SH reactivbrane fluidity;-SH groups; lipoic acid; 2-mercaptoity. Protein-SH groups, measured with Ellman's repropionylglycine; membrane protein; hyperglycemia; agent, generally behave in the same way as membrane hypoglycemia; dialysis; GluT1; glycophorin A. fluidity determined with diphenylhexatriene. Maximal values were obtained with 5 mM D-glucose, whereas decrease was observed above 10 mM D-glucose. Addition of a-lipoic acid (4 nmol/mg protein) resulted in a significant increase in membrane fluidity Long term diabetes mellitus results in multiple comand titratable-SH groups at glucose concentrations of plications. These are particularly dependent on vascu-10 mM and above. Dithiothreitol diminished titrablelar developments which depend on hyperglycemia, hy-SH groups and did not restore membrane fluidity. perlipidemia, concomitant with arteriosclerotic compli-2-Mercaptopropionylglycine was only effective in rescations. toration of-SH groups. By contrast to D-glucose, other Red cell membrane structure and function is altered sugars such as L-glucose, D-fructose, or sucrose reby hyperglycemia. Rigidity of the membrane systems vealed no comparable changes on membrane fluidity contributes and is reflected in increasing viscosity of and titratable membrane-SH groups between concenthe red cell membrane (1-4), not allowing red cells trations of 5 and 10 mM. The hyperglycemic effects of to traffic through the capillary systems without being D-glucose were corroborated with isolated, reconstitudeformed. Increased viscosity of membrane probably ted membrane proteins and erythrocyte glucose cardoes not concern only the red cells, but concerns in rier, indicating that, in general, the observed diveraddition other membranes (5-7) or vascular systems. gent biochemical/biophysical changes of the red cell Concomitantly, the ratio of cholesterol/phospholipid is membrane are influenced by the glucose transport increased (8). In diabetics the percentages of acidic protein GluT1. The natural R-form and the S-form of phospholipids and of sphingomyelin were found ina-lipoic acid were compared with racemic R-/S-forms creased (9). These changes decrease membrane fluidity: for their efficiencies in alterations of red cell memanisotropy values of isolated red cells in diabetic pabrane fluidity. Decreased fluidities in presence of 10 tients were found increased. mM glucose were found to be influenced in differenti-There also are changes in the membrane proteins. ated ways: the S-form was highly active in increasing Glycosylation comprises the Amadori reaction (10) and consequences of glucose autoxidation (10, 11

OBJECTIVE— Because α-lipoic acid (ALA), a potent antioxidant, prevents or improves nerve conduction attributes, endoneurial blood flow, and nerve (Na(+) K(+) ATPase activity in experimental diabetes and in humans and may improve positive neuropathic sensory symptoms, in this report we further assess the safety and efficacy of ALA on the Total Symptom Score (TSS), a measure of positive neuropathic sensory symptoms. RESEARCH DESIGN AND METHODS— Metabolically stable diabetic patients with symptomatic (stage 2) diabetic sensorimotor polyneuropathy (DSPN) were randomized to a parallel, double-blind study of ALA (600 mg) (n = 60) or placebo (n = 60) infused daily intravenously for 5 days/week for 14 treatments. The primary end point was change of the sum score of daily assessments of severity and duration of TSS. Secondary end points were sum scores of neuropathy signs (NIS), symptoms (NSC), attributes of nerve conduction, quantitative sensation tests (QSTs), and an autonomic test. RESULT...

Mercury exposure is the second-most common cause of toxic metal poisoning. Public health concern over mercury exposure, due to contamination of fish with methylmercury and the elemental mercury content of dental amalgams, has long been a topic of political and medical debate. Although the toxicology of mercury is complex, there is evidence for antioxidant protection in the prevention of neurological

Novel thiazolidinedione derivatives of the potent antioxidant, a-lipoic (thioctic, 1,2-dithiolane) acid, were prepared. The prototype N-(2-{4-[2,4-dioxo(1,3-thiazolidin-5-yl)methyl]phenoxy}ethyl)-5-(1,2-dithiolan-3yl)-N-methylpentanamide (designated BP-1003), and dithioester derivatives thereof were shown to be potent activators of peroxisome proliferator-activated receptor gamma (PPARg) (EC 50 range 15-101 nM) and modest activators of PPARa (EC 50 5 mM). Both the relatively hydrophobic dithiolane prototype, BP-1003, and its watersoluble dithioglycinate derivative, BP-1017, were shown to inhibit the proliferation of human keratinocytes and suppress the production of interleukin-2 by human peripheral lymphocytes to a greater extent than the antidiabetic thiazolidinedione, rosiglitazone. Both oral and topical administration of BP-1017 showed significant antiinflammatory effects in the oxazolone-sensitized mouse model of allergic contact dermatitis (ACD). These findings suggest that water-soluble lipoic acid-based thiazolidinediones may be efficacious as oral and topical agents for treating inflammatory skin conditions such as contact dermatitis, atopic dermatitis, and psoriasis.

Gallium arsenide (GaAs), an inter-metallic semiconductor, known to exhibit superior optical and electronic properties compared to silicon, promotes its use in semiconductor industries. Extensive use of GaAs will inevitably lead to an increase in the exposure of workers manufacturing these products. Antioxidants are exogenous or endogenous compounds acting in several ways, including scavenging reactive oxygen species (ROS) or their precursors, inhibiting ROS formation, and binding metal ions needed for the catalysis of ROS generation. In the present study we investigated the protective efficacy of ␣-lipoic acid, quercetin and captopril individually against gallium arsenide exposure. Co-administration of ␣-lipoic acid with GaAs was most effective in reducing GaAs induced inhibition of blood ␦-aminolevulinic acid dehydratase (ALAD) activity, liver, kidney and brain reduced glutathione (GSH) level and elevation of oxidized glutathione (GSSG). Captopril, on the other hand was effective in reducing thiobarbituric acid reactive substance (TBARS) levels, while quercetin reduced ROS in liver and kidney. The results suggest comparatively better preventive efficacy of concomitant ␣-lipoic acid administration during Gallium arsenide exposure compared to quercetin and captopril in preventing GaAs induced oxidative stress.

Aims-Alpha-lipoic acid (LA) is a commonly used dietary supplement that exerts anti-oxidant and anti-inflammatory effects in vivo and in vitro. We investigated the mechanisms by which LA may confer protection in models of established atherosclerosis.

Recent studies have shown that lead causes oxidative stress by inducing the generation of reactive oxygen species, reducing the antioxidant defense system of cells via depleting glutathione, inhibiting sulfhydryl-dependent enzymes, interfering with some essential metals needed for antioxidant enzyme activities, and/or increasing susceptibility of cells to oxidative attack by altering the membrane integrity and fatty acid composition. Consequently, it is plausible that impaired oxidant/antioxidant balance can be partially responsible for the toxic effects of lead. Where enhanced oxidative stress contributes to lead-induced toxicity, restoration of a cell's antioxidant capacity appears to provide a partial remedy. Several studies are underway to determine the effect of antioxidant supplementation following lead exposure. Data suggest that antioxidants may play an important role in abating some hazards of lead. To explain the importance of using antioxidants in treating lead poisoning the following topics are addressed: (i) Oxidative damage caused by lead poisoning; (ii) conventional treatment of lead poisoning and its side effects; and (iii) possible protective effects of antioxidants in lead toxicity.

Purpose. Reactive oxygen species (ROS) and reactive nitrogen species (RNS), generated during tissue reperfusion, are characteristic of ischemia/reperfusion (I/R) injury. We conducted this study to evaluate the protective effect of α-lipoic acid (α-LA) and ebselen against intestinal I/R injury. Methods. Forty Sprague-Dawley rats were divided into fi ve groups: a sham-operated group; an I/R group, subjected to intestinal ischemia for 45 min and reperfusion for 3 days; an I/R+α-LA group; an I/R+ebselen group; and an I/R+α-LA+ebselen group. We collected ileal specimens, to measure the tissue levels of malondialdehyde (MDA), protein carbonyl content (PCC), superoxide dismutase (SOD), and glutathione peroxidase (GPx), and to evaluate the histologic changes. Results. There was a signifi cant decrease in SOD and GPx levels, with an increase in MDA and PCC levels and intestinal mucosal injury in the intestinal I/R group (P < 0.05). Superoxide dismutase and GPx levels were signifi cantly higher, MDA and PCC levels were significantly lower, and intestinal injury was signifi cantly less severe in the I/R+α-LA+ebselen group than in the I/R group (P < 0.05). Although shortened villi and epithelial lifting were seen in the I/R group, only slight mucosal injury was seen in the treatment groups. Conclusion. α-Lipoic acid and ebselen played an important role in attenuating I/R injury of the intestine by scavenging ROS and RNS.

Two-dimensional 15 N-heteronuclear single-quantum coherence (HSQC) NMR studies with a di-domain (lipoyl domain+ linker+ peripheral subunitbinding domain) of the dihydrolipoyl acetyltransferase (E2) component of the pyruvate dehydrogenase complex of Bacillus stearothermophilus allowed a molecular comparison of the need for lipoic acid to be covalently attached to the lipoyl domain in order to undergo reductive acetylation by the pyruvate decarboxylase (E1) component, in contrast with the ability of free lipoic acid to serve as substrate for the dihydrolipoyl dehydrogenase (E3) component. Tethering the lipoyl domain to the peripheral subunit-binding domain in a complex with E1 or E3 rendered the system more like the native enzyme complex, compared with the use of a free lipoyl domain, yet of a size still amenable to investigation by NMR spectroscopy. Recognition of the tethered lipoyl domain by E1 was found to be ensured by intensive interaction with the lipoyl-lysine-containing β-turn and with residues in the protruding loop close to the β-turn. The size and sequence of this loop varies significantly between species and dictates the lipoylated lipoyl domain as the true substrate for E1. In contrast, with E3 the main interaction sites on the tethered lipoyl domain were revealed as residues Asp41 and Ala43, which form a conserved sequence motif, DKA, around the lipoyllysine residue. No domain specificity is observed at this step and substrate channelling in the complex thus rests on the recognition of the lipoyl domain by the first enzyme, E1. The cofactor, thiamine diphosphate, and substrate, pyruvate, had distinct but contrasting effects on the E1/didomain interaction, whereas NAD + and NADH had negligible effect on the E3/di-domain interaction. Tethering the lipoyl domain did not significantly change the nature of its interaction with E1 compared with a free lipoyl domain, indicative of the conformational freedom allowed by the linker in the movement of the lipoyl domain between active sites.

In the present work a series of novel coumarin-3-carboxamides and their hybrids with the alpha-lipoic acid were designed, synthesized and tested as potent antioxidant and anti-inflammatory agents. The new compounds were evaluated for their antioxidant activity, their activity to inhibit in vitro lipoxygenase and their in vivo anti-inflammatory activity. In general, the derivatives were generally found to present antioxidant and anti-inflammatory activities. Discussion is made based on the results for the structureactivity relationships in order to define the structural features required for activity. diamine. Yield: 71%; 1 H NMR (CDCl 3 /CF 3 COOD): d ¼ 1.24-1.45 (m, 8H, (CH 2 ) 2 (CH 2 ) 4 (CH 2 ) 2 ), 1.67-1.72 (m, 4H, CH 2 (CH 2 ) 4 CH 2 ), 3.14 (t, J ¼ 6.7 Hz, 2H, CH 2 NH 2 ), 3.46 (t, J ¼ 6.9 Hz, 2H, NHCH 2 ), 7.37 (dd,

A growing body of interest on the possible beneficial role of chromium, magnesium, and antioxidant supplements in the treatment of diabetes has contributed to debate about their value for reaching metabolic control and to prevent chronic complications in diabetic ...

A highly sensitive method for the determination of α-lipoic acid (LA) and dihydrolipoic acid (DHLA) in human plasma and urine has been developed. Samples were acidified and extracted with organic solvent, and the free sulfhydryls of DHLA protected as the dicarboxyethylate by treatment with ethylchloroformate. The free carboxylic function of LA and the SH-protected DHLA were converted into their amide derivatives with the strong fluorophore 2-(4-aminophenyl)-6-methylbenzothiazole in the presence of a coupling agent and a base catalyst. The resulting fluorescent amides of both LA and DHLA were separated on a reversed-phase column (Ultrasphere C8) using simple isocratic elution with acetonitrile–water (80:20) and detected fluorimetrically (excitation 343, emission 423 nm). The method is highly sensitive, reproducible, and is easily applied for the simultaneous determination of LA and DHLA in biological samples.

The interaction of lipoic acid with β-cyclodextrin (β-CD) has been studied by capillary electrophoresis in aqueous phosphate buffer (20 mM, pH = 9.0) at 20°C. The results allowed us to detect the formation of an inclusion complex with a 1:1 lipoic acid/β-CD stoichiometry and an association constant of 1645 M −1 . The geometry of the inclusion complex in D 2 O was investigated by means of 2D-ROESY (Rotating-frame Overhauser Enhancement Spectroscopy) NMR experiments, [a]

Current evidences support the hypothesis that non-steroidal anti-inflammatory drugs (NSAIDs) and antioxidant therapy might protect against the development of Alzheimer's disease (AD). In the present work, our attention was focused on ibuprofen (IBU) used in clinical trails to prevent Alzheimer's disease, and (R)-a-lipoic acid (LA) considered as a potential neuroprotective agent in AD therapy. In particular, we investigated a series of lipophilic molecular combinations obtained by joining (R)-a-lipoic acid and ibuprofen via an amide bond. These new entities might allow targeted delivery of the parent drugs to neurons, where cellular oxidative stress and inflammation seem related to Alzheimer's disease. Our study included the synthesis of conjugates 1-3 and the evaluation of their physicochemical and in-vitro antioxidant properties. The new compounds are extremely stable in aqueous buffer solutions (pH = 1.3 and 7.4), and in rat and human plasma they showed a slow bioconversion to ibuprofen and (R)-a-lipoic acid. Codrugs 1-3 displayed in vitro free radical scavenging activity and were hydrolyzed more rapidly in brain tissue than in rat serum indicating that these new entities might allow targeted delivery of the parent drugs to neurons. The immunohistochemical analysis of Ab (1-40) protein showed that Ab-injected cerebral cortices treated with ibuprofen or compound 1 showed few plaques within capillary vessels and, in particular, Ab (1-40) protein was less expressed in codrug-1treated than in ibuprofen-treated cerebral cortex.

Alterations in metabolic pathways are known to characterize cancer. In order to suppress cancer growth, however, multiple proteins involved in these pathways have to be targeted simultaneously. We have developed a screening method to assess the best drug combination for cancer treatment based on targeting several factors implicated in tumor specific metabolism. Following a review of the literature, we identified those enzymes known to be deregulated in cancer and established a list of sixty-two drugs targeting them. These molecules are used routinely in clinical settings for diseases other than cancer. We screened a first library in vitro against four cell lines and then evaluated the most promising binary combinations in vivo against three murine syngeneic cancer models, (LL/2, Lewis lung carcinoma; B16-F10, melanoma; and MBT-2, bladder cancer). The optimum result was obtained using a combination of α-lipoic acid and hydroxycitrate (METABLOCTM). In this study, a third agent was added by in vivo evaluation of a large number of combinations. The addition of octreotide strongly reduced tumor development (T/C% value of 30.2 to 34.5%; P < 0.001) in the same models and prolonged animal survival (P < 0.001) as compared to cisplatin. These results were confirmed in a different laboratory setting using a human xenograft model (NCI-H69, small cell lung cancer). None of these three molecules are known to target DNA. The effectiveness of this combination in several animal models, as well as the low toxicity of these inexpensive drugs, emphasizes the necessity of rapidly setting up a clinical trial.

Future environmental conditions will include elevated concentrations of salt in the soil and an elevated concentration of CO 2 in the atmosphere. Because these environmental changes will likely affect reactive oxygen species (ROS) formation and cellular antioxidant metabolism in opposite ways, we analyzed changes in cellular H 2 O 2 and non-enzymatic antioxidant metabolite [lipoic acid (LA), ascorbate (ASA), glutathione (GSH)] content induced by salt stress (0, 80, 160 or 240 mM NaCl) under ambient (350 μmol mol −1 ) or elevated (700 μmol mol −1 ) CO 2 concentrations in two barley cultivars (Hordeum vulgare L.) that differ in sensitivity to salinity (cv. Alpha is more sensitive than cv. Iranis). Under non-salinized conditions, elevated CO 2 increased LA content, while ASA and GSH content decreased. Under salinized conditions and ambient CO 2 , ASA increased, while GSH and LA decreased. At 240 mM NaCl, H 2 O 2 increased in Alpha and decreased in Iranis. When salt stress was imposed at elevated CO 2 , less oxidative stress and lower increases in ASA were detected, while LA was constitutively higher. The decrease in oxidative stress could have been because of less ROS formation or to a higher constitutive LA level, which might have improved regulation of ASA and GSH reductions. Iranis had a greater capacity to synthesize ASA de novo and had higher constitutive LA content than did Alpha. Therefore, we conclude that elevated CO 2 protects barley cultivars against oxidative damage. However, the magnitude of the positive effect is cultivar specific.

In this paper we describe the treatment of a 71-year-old female registered nurse (JA) diagnosed with Hepatocellular Carcinoma (HCC) in early October 2006. The patient was a heavy smoker and drank alcohol on weekends. She contracted hepatitis C following a finger sticks from a patient with the disease. Several years later she developed HCC. Her doctor at a large medical center, after viewing her CT scans, told her that with so many tumors in her liver, only a liver transplant would offer some hope of survival. She was informed that, given her diagnosis, that without liver transplant surgery any further treatment would, at best, be palliative. Mrs. JA refused liver transplant surgery. The patient arrived at the Integrative Medical Center of New Mexico (IMCNM) in late October 2006 she appeared to be in very poor health, weak, and fatigued. An integrative program developed by one of the authors using intravenous alpha-lipoic acid, oral low dose naltrexone and a healthy lifestyle program...