Alpha Lipoic Acid

α-Lipoic acid is a sulfur-containing nutrient endowed with pleiotropic actions and a safe biological profile selected to replace the unsaturated alkyl acid of capsaicin with the aim of obtaining lipoic amides potentially active as a TRPV1 ligand and with significant antioxidant properties. Thus, nine compounds were obtained in good yields following a simple synthetic procedure and tested for their functional TRPV1 activity and radical-scavenger activity. The safe biological profile together with the protective effect against hypoxia damage as well as the in vitro antioxidant properties were also evaluated. Although less potent than capsaicin, almost all lipoic amides were found to be TRPV1 agonists and, specifically, compound 4, the lipoic analogue of capsaicin, proved to be the best ligand in terms of efficacy and potency. EPR experiments and in vitro biological assays suggested the potential protective role against oxidative stress of the tested compounds and their safe biological...

A double-blind randomized controlled trial was performed to compare the safety and efficacy of α-lipoic acid(ALA) in liver transplantation. The grafts were randomized to receive ALA or placebo before the cold ischemia time. Furthermore, patients transplanted with the ALA-perfused graft received 600mg of intravenous ALA, while patients with the non-perfused graft received the placebo just before graft reperfusion. Hepatic biopsy was performed 2 hours post-reperfusion. Blood samples were collected before, during and 1 and 2 days after reperfusion. qPCR analysis was performed on biopsies to assess genes involved in the response to hypoxia, apoptosis, cell growth, survival and proliferation, cytokine production and tissue damage protection. Nine of 40 patients developed post-reperfusion syndrome(PRS),

Background: Recent evidence indicates that insulin resistance in skeletal muscle may be related to reduce mitochondrial number and oxidation capacity. However, it is not known whether increasing mitochondrial number and function improves insulin resistance. In the present study, we investigated the effects of a combination of nutrients on insulin resistance and mitochondrial biogenesis/function in skeletal muscle of type 2 diabetic Goto-Kakizaki rats. Methodology/Principal Findings: We demonstrated that defect of glucose and lipid metabolism is associated with low mitochondrial content and reduced mitochondrial enzyme activity in skeletal muscle of the diabetic Goto-Kakizaki rats. The treatment of combination of R-a-lipoic acid, acetyl-L-carnitine, nicotinamide, and biotin effectively improved glucose tolerance, decreased the basal insulin secretion and the level of circulating free fatty acid (FFA), and prevented the reduction of mitochondrial biogenesis in skeletal muscle. The nutrients treatment also significantly increased mRNA levels of genes involved in lipid metabolism, including peroxisome proliferator-activated receptor-a (Ppara), peroxisome proliferatoractivated receptor-d (Ppard), and carnitine palmitoyl transferase-1 (Mcpt-1) and activity of mitochondrial complex I and II in skeletal muscle. All of these effects of mitochondrial nutrients are comparable to that of the antidiabetic drug, pioglitazone. In addition, the treatment with nutrients, unlike pioglitazone, did not cause body weight gain. Conclusions/Significance: These data suggest that a combination of mitochondrial targeting nutrients may improve skeletal mitochondrial dysfunction and exert hypoglycemic effects, without causing weight gain.

The aim of the study was to address the importance of mitochondrial function in insulin resistance and type 2 diabetes, and also to identify effective agents for ameliorating insulin resistance in type 2 diabetes. We examined the effect of two mitochondrial nutrients, R-αlipoic acid (LA) and acetyl-L-carnitine (ALC), as well as their combined effect, on mitochondrial biogenesis in 3T3-L1 adipocytes. Methods Mitochondrial mass and oxygen consumption were determined in 3T3-L1 adipocytes cultured in the presence of LA and/or ALC for 24 h. Mitochondrial DNA and mRNA from peroxisome proliferator-activated receptor gamma and alpha (Pparg and Ppara) and carnitine palmitoyl transferase 1a (Cpt1a), as well as several tran-scription factors involved in mitochondrial biogenesis, were evaluated by real-time PCR or electrophoretic mobility shift (EMSA) assay. Mitochondrial complexes proteins were measured by western blot and fatty acid oxidation was measured by quantifying CO 2 production from [1-14 C] palmitate. Results Treatments with the combination of LA and ALC at concentrations of 0.1, 1 and 10 μmol/l for 24 h significantly increased mitochondrial mass, expression of mitochondrial DNA, mitochondrial complexes, oxygen consumption and fatty acid oxidation in 3T3L1 adipocytes. These changes were accompanied by an increase in expression of Pparg, Ppara and Cpt1a mRNA, as well as increased expression of peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1 alpha (Ppargc1a), mitochondrial transcription factor A (Tfam) and nuclear respiratory factors 1 and 2 (Nrf1 and Nrf2). However, the treatments with LA or ALC alone at the same concentrations showed little effect on mitochondrial function and biogenesis. Conclusions/interpretation We conclude that the combination of LA and ALC may act as PPARG/A dual ligands to complementarily promote mitochondrial synthesis and adipocyte metabolism. Keywords Mitochondrial complex . Mitochondrial transcription factor A . Nuclear respiratory factor 1 . Nuclear respiratory factor 2 . Peroxisome proliferatoractivated receptor gamma . Peroxisome proliferator-activated receptor alpha . Peroxisome proliferator-activated receptor . Gamma coactivator 1 alpha Abbreviations ALC acetyl-L-carnitine EMSA electrophoretic mobility shift

Background: Recent evidence indicates that insulin resistance in skeletal muscle may be related to reduce mitochondrial number and oxidation capacity. However, it is not known whether increasing mitochondrial number and function improves insulin resistance. In the present study, we investigated the effects of a combination of nutrients on insulin resistance and mitochondrial biogenesis/function in skeletal muscle of type 2 diabetic Goto-Kakizaki rats. Methodology/Principal Findings: We demonstrated that defect of glucose and lipid metabolism is associated with low mitochondrial content and reduced mitochondrial enzyme activity in skeletal muscle of the diabetic Goto-Kakizaki rats. The treatment of combination of R-a-lipoic acid, acetyl-L-carnitine, nicotinamide, and biotin effectively improved glucose tolerance, decreased the basal insulin secretion and the level of circulating free fatty acid (FFA), and prevented the reduction of mitochondrial biogenesis in skeletal muscle. The nutrients treatment also significantly increased mRNA levels of genes involved in lipid metabolism, including peroxisome proliferator-activated receptor-a (Ppara), peroxisome proliferatoractivated receptor-d (Ppard), and carnitine palmitoyl transferase-1 (Mcpt-1) and activity of mitochondrial complex I and II in skeletal muscle. All of these effects of mitochondrial nutrients are comparable to that of the antidiabetic drug, pioglitazone. In addition, the treatment with nutrients, unlike pioglitazone, did not cause body weight gain. Conclusions/Significance: These data suggest that a combination of mitochondrial targeting nutrients may improve skeletal mitochondrial dysfunction and exert hypoglycemic effects, without causing weight gain.

The aim of the study was to address the importance of mitochondrial function in insulin resistance and type 2 diabetes, and also to identify effective agents for ameliorating insulin resistance in type 2 diabetes. We examined the effect of two mitochondrial nutrients, R-αlipoic acid (LA) and acetyl-L-carnitine (ALC), as well as their combined effect, on mitochondrial biogenesis in 3T3-L1 adipocytes. Methods Mitochondrial mass and oxygen consumption were determined in 3T3-L1 adipocytes cultured in the presence of LA and/or ALC for 24 h. Mitochondrial DNA and mRNA from peroxisome proliferator-activated receptor gamma and alpha (Pparg and Ppara) and carnitine palmitoyl transferase 1a (Cpt1a), as well as several tran-scription factors involved in mitochondrial biogenesis, were evaluated by real-time PCR or electrophoretic mobility shift (EMSA) assay. Mitochondrial complexes proteins were measured by western blot and fatty acid oxidation was measured by quantifying CO 2 production from [1-14 C] palmitate. Results Treatments with the combination of LA and ALC at concentrations of 0.1, 1 and 10 μmol/l for 24 h significantly increased mitochondrial mass, expression of mitochondrial DNA, mitochondrial complexes, oxygen consumption and fatty acid oxidation in 3T3L1 adipocytes. These changes were accompanied by an increase in expression of Pparg, Ppara and Cpt1a mRNA, as well as increased expression of peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1 alpha (Ppargc1a), mitochondrial transcription factor A (Tfam) and nuclear respiratory factors 1 and 2 (Nrf1 and Nrf2). However, the treatments with LA or ALC alone at the same concentrations showed little effect on mitochondrial function and biogenesis. Conclusions/interpretation We conclude that the combination of LA and ALC may act as PPARG/A dual ligands to complementarily promote mitochondrial synthesis and adipocyte metabolism. Keywords Mitochondrial complex . Mitochondrial transcription factor A . Nuclear respiratory factor 1 . Nuclear respiratory factor 2 . Peroxisome proliferatoractivated receptor gamma . Peroxisome proliferator-activated receptor alpha . Peroxisome proliferator-activated receptor . Gamma coactivator 1 alpha Abbreviations ALC acetyl-L-carnitine EMSA electrophoretic mobility shift

Lung cancer is the leading cause of mortality in the world. However, the urgent demand of new drugs for the treatment of lung cancer and the rapidly rising costs of drug development support efforts to explore methodology addressing these issues. Here we designed various gene signature selection methods via expression datasets generated from human lung adenocarcinoma tumor and adjacent non-tumor tissues to query the Connectivity Map (CMap), which hosts 6,100 drug-mediated expression profiles. We hypothesized that if a drug signature could reverse, at least in part, the gene expression signature of lung adenocarcinoma, it might have the potential to inhibit dysregulated pathways and thereby treat lung cancer. To test this hypothesis, 62 out of the 95 examined drugs with anti-tumor activities were validated via MTT and/or clonogenic assays using lung cancer cell lines and through a PubMed search. Subsequently, 9 functional categories, such as DNA demethylating agents, anti-psychotic and antiinflammation, were selected to classify 62 in vitro validated drugs. A subset of gene signatures embedded in these 62 drug-mediated expression profiles from the CMap was uncovered, suggesting the possible reversal connection between drug and patient gene signatures. There were 89 differentially expressed probesets that produced a reverse signature, including 12.5% that follow the up-regulated (patient) to down-regulated (CMap) pattern and 16.6% with the reverse down-regulated (patient) to up-regulated (CMap) pattern. Such bioinformatics analysis makes functional connections among disease, genetic perturbation, and drug action, resulting in the systematic identification of potential therapeutic drugs for clinical use.

Nephroprotective effect of aqueous thyme extract was investigated in rabbits with acute renal injury induced by a single i.p. injection of cisplatin (6.5 mg/kg). Aqueous thyme extract treatment (500 mg/kg/day, orally) was applied for 7 consecutive days, starting 4 days before cisplatin administration. Aqueous thyme extract significantly reduced serum urea and serum creatinine levels and increased serum albumin levels which were altered by cisplatin. Aqueous thyme extract significantly compensated deficits in kidney tissue glutathione level, suppressed lipid peroxidation, and decreased the elevations of serum tumor necrosis factor-alpha resulted from cisplatin administration. Also, histopathological renal tissue damage mediated by cisplatin as well as inflammatory cells infiltration was greatly ameliorated by aqueous thyme extract treatment. It was concluded that aqueous thyme extract represents a potential therapeutic option to protect against acute cisplatin nephrotoxicity commonly encountered in clinical practice.

Diabetes Mellitus (DM) encompasses a range of metabolic disorders marked by persistent high blood glucose levels. Type 2 Diabetes Mellitus (T2DM), the more common form of the disease is characterized by insulin resistance and partial insulin deficiency. The primary contributors to mortality and morbidity in diabetes are its vascular complications. Alpha-Lipoic Acid (ALA) is an antioxidant derived from caprylic acid and synthesized within the mitochondria. Extensive research shows that ALA aids in preventing and treating Diabetic Neuropathy (DN), lowers the risk of diabetes in atrisk individuals and is also beneficial for those with impaired glucose tolerance. Therefore, this review article aims to explore the different aspects of ALA and its beneficial effects on individuals with T2DM. A range of articles from databases such as Springer, Wiley, Web of Science, PubMed, Google Scholar, SCOPUS, Embase and Cochrane were examined. References from these articles were also analysed to broaden the search for pertinent reviews. Administering ALA in T2DM was found to have beneficial effects like anti-oxidant, anti-inflammatory, enhance glucose uptake, prevents diabetic neuropathy, neuroprotective, anti-obesity, cardio-protective, reno-protective, prevent diabetic retinopathy, anti-aging and improve metabolic parameters in Polycystic Ovary Syndrome (PCOS). Incorporating ALA into a comprehensive treatment plan, combined with lifestyle changes and standard therapies could improve patient outcome and enhance the quality of life for those managing T2DM and related conditions.

This study was designed to evaluate the possible protective effect of pentoxifylline against doxorubicin-induced nephrotoxicity in rabbits. The animals groups were divided into a control group received 5 ml of normal saline intraperitoneally for 5 days, doxorubicin group that received (25mg/kg) intraperitoneally at day 3 and then the animals were sacrificed at day 5 and pentoxifylline + doxorubicin group (80mg/kg/day) intraperitoneally administered for 3 days before and two days after doxorubicin (25mg/kg) intraperitoneally administered at day 3 and then the animals were sacrificed at day 5. All animal were anasthesized by ether and sacrificed, after 48 hour after doxorubicin administered, at day 5. The spectrophotometry measuring of kidney function parameters such as serum urea and creatinine level. In addition, the oxidative stress parameters that included malondialdehyde and reduced glutathione in the renal tissue homogenate. The results obtained by analysis of data, by using ind...

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Background Evidence shows the vital role of sleep in the modulation of cognitive functions. Sleep deprivation (SD) can disrupt learning and memory processes. SD also affects pain perception and locomotor activity. Furthermore, alpha lipoic acid (ALA) may induce antioxidant and neuroprotective effects. ALA affects memory processes, pain subthreshold, and locomotor activity. The goal of the present study was to investigate the effect of REM (rapid-eye movement) SD and ALA on social and passive avoidance memory, locomotor activity, and pain perception. Methods Multiple-platform apparatus was used to induce REM SD for 24 h. Three-chamber paradigm test, the shuttle box, locomotion apparatus, and hot plate were used to assess social interaction memory, passive avoidance memory, locomotor activity, and pain perception, respectively. ALA was injected intraperitoneally at the doses of 35 and 70 mg/kg. Results 24 h REM SD impaired both types of memory. In addition, ALA (35 mg/kg) reversed REM SD-induced memory impairments. However, ALA (70 mg/kg) impaired social memory with no effect on REM SD-induced memory impairments. ALA (70 mg/kg) also decreased pain subthreshold in REM SD rats. Conclusion REM SD impairs social interaction and passive avoidance memory. Furthermore, ALA may exhibit a dosedependent manner in some cognitive tasks. ALA can induce a therapeutic effect at one dose, and an impairment effect at another dose (lower or higher), while the cognitive task and the conditions are equal.

A simple and sensitive electrochemical method was developed for the determination of N‐Acetylcysteine (NAC) and Glutathione (GSH), on glassy carbon electrode. The results indicate that α‐lipoic acid (LipS2) is oxidized at the electrode, but is regenerated by thiols, suggesting a redox catalytic effect. Under optimized conditions, the analytical curves for NAC and GSH were obtained in the range of 1 up to 10 µM and 1 up to 60 µM, respectively. The quantification can be performed in a single assay with high sensitivity, reproducibility and low detection limit of 0.27 and 0.67 µM for NAC and GSH, respectively. This method was successfully applied to the determination of NAC and GSH in artificial saliva and human urine samples, with excellent recovery results.

The objective of the present work was to evaluate the toxic effects of sodium arsenite, As(III), in mice and the protective effect of 2 antioxidants, hesperidin and lipoic acid, against the observed As(III)-induced toxicity. In each study, mice were assigned to 1 of 4 groups: control, antioxidant, antioxidant + arsenite, and arsenite. Animals were first injected with the vehicle or 25 mg antioxidant/kg BW. After 30 minutes they received an injection of 10 mg arsenite/kg BW or 0.9% NaCl. Two hours after the first injection, the liver, kidney, and testis were collected for histological evaluation. Liver samples were also taken for quantification of arsenic. In mice exposed only to As(III), various histopathological effects were observed in the liver, kidneys, and testes. In mice pretreated with either hesperidin or lipoic acid, a reduction of histopathologic effects on the liver and kidneys was observed. No protective effects were observed in the testes for either of the 2 studied ant...

Primary biliary cirrhosis is an enigmatic autoimmune disease of women characterized by antimitochondrial antibodies and destruction of intrahepatic bile ducts. The etiology of PBC is unknown, but we present data herein that the disease may be induced by xenobiotic (i.e. chemicals) exposure. In particular, we postulate that halogenated compounds will bind to the autoantigen, break tolerance, and lead to an intense mucosal response.

Lipoic acid plays a crucial role as antioxidant and metabolic component of enzymes involved in glucose metabolism of different cell types. Choline alphoscerate (a-glyceryl-phosphoryl-choline [aGPC]) is a semisynthetic derivative of phosphatidylcholines representing, among acetilcholine precursors, a cholinergic drug. In the present study, we evaluated the expression of some proliferation and differentiation markers in 15 or 21 DIV astrocyte cultures treated with 50 lM (1)lipoic acid or (1/2)lipoic acid and/or 10 mM aGPC for 24 hr. In addition, we evaluated the possible genoprotective effect by analysis of DNA status detected by alkaline comet assay. The addition of single drugs [(1)lipoic acid, (1/2)lipoic acid, or aGPC] induced an "upward modulation" of the expression of biomarkers used in our study. On the contrary, the cotreatment with either (1)lipoic acid 1 aGPC or (1/2)lipoic 1 aGPC surprisingly showed no significant modification or even a downregulation of the above-mentioned biomarkers. This latter finding demonstrated no additional effect after the cotreatment with both drugs with respect to the single treatments alone. Further studies are necessary to clarify the specific mechanism evoked by the processing of these neuroprotective agents in our in vitro models. Finally, these preliminary findings may represent a good tool with which to clarify the antioxidant and metabolic roles played by lipoic acid in proliferating and differentiating astroglial cell cultures, during an interactive cross-talk between glial and neuronal cells, after brain lesions or damage correlated with oxidative stress that may occur in some degenerative diseases.

Background: One of the widely abused anabolic-androgenic steroids worldwide is nandrolone decanoate (ND). Objectives: This work aimed to study whether alpha lipoic acid (ALA) treatment could modulate ND-induced renal dysfunction. Materials & methods: forty adult albino rats were divided into four groups. 1st group served as negative control; 2nd group received ALA (100 mg/kg orally by gastric gavage daily); 3rd group received ND in 28 mg/kg BW intra-peritoneal injection once weekly; 4th group received the dose of ND along with ALA (in the previous doses); all for eight weeks. Results: administration of nandrolone decanoate induced significant increase in serum urea and creatinine. Significant increase in lipid peroxidation malondialdehyde (MDA) and pro-inflammatory cytokines (TNFα) together with significant reduction of the antioxidant Glutathione peroxidase (GPx) activities and the anti-inflammatory interleukin (IL-4) in kidney tissues were also recorded. Histopathological evidence of renal tissue injury was detected. Co-administration of ALA along with ND ameliorated the effects mentioned above. Conclusion: According to this study, the administration of ALA can provide a protective role, through its anti-inflammatory and antioxidant effects, against ND-induced renal toxicity.

OBJECTIVE: Neuropathic pain during pregnancy is a common condition due to the physical changes and compression around pregnancy and childbirth that make pregnant women more prone to develop several medical conditions such as carpal tunnel syndrome, sciatica, meralgia paraesthetica and other nerve entrapment syndromes. Most of the treatments usually performed to counteract neuropathic pain are contraindicated in pregnancy so that, the management of these highly invalidating conditions remains an issue in the clinical practice. We aimed to review the efficacy and safety of alpha lipoic acid supplementation in the treatment of neuropathic pain. DISCUSSION: Lipoic acid is a co-factor essential in the regulation of mitochondrial energy. It has been demonstrated that lipoic acid supplementation is involved in several biochemical processes and actions, exerting important antioxidant and anti-inflammatory activity and significantly improving pain and paraesthesia in patients with sciatica, carpal tunnel syndrome and diabetic neuropathy. CONCLUSIONS: Efficacy of lipoic acid is combined with a high safety profile, making this molecule a novel candidate for the management of several diseases. Data reported so far are promising and dietary supplementation with lipoic acid seems a useful tool to contrast neuropathic pain during pregnancy.

Neuropathic pain is a frequent condition caused by a lesion or disease of the central or peripheral somatosensory nervous system. A frequent cause of peripheral neuropathic pain is diabetic neuropathy. Its complex pathophysiology is not yet fully elucidated, which contributes to underassessment and undertreatment. A mechanism-based treatment of painful diabetic neuropathy is challenging but phenotype-based stratification might be a way to develop individualized therapeutic concepts. Our goal is to review current knowledge of the pathophysiology of peripheral neuropathic pain, particularly painful diabetic neuropathy. We discuss state-of-the-art clinical assessment, validity of diagnostic and screening tools, and recommendations for the management of diabetic neuropathic pain including approaches towards personalized pain management. We also propose a research agenda for translational research including patient stratification for clinical trials and improved preclinical models in rel...

The influence of initial BW of the pullets and beak trimming on growth performance and BW uniformity was studied in Lohmann Brown pullets fed diets supplemented or not with Na-butyrate (Butirex C4; Novation 2002 S. L.) from hatching to 42 d of age

Objectives: The nuclear factor κB regulates the expression of genes involved in many processes that play a key role in the development and progression of cancer. The aim of this study was to examine the infl uence of the alpha lipoic acid in the chemoprevention of colon and cervix carcinoma in vitro. Background: In recent years, special attention has been paid to the potential chemopreventive properties of antioxidants. There are no published data on the impact of alpha lipoc acid of chemoprevention of cervix and colon cancer. Methods: We examined the effect of alpha lipoic acid alone or in combination with cisplatin and 5-fl uorouracil on proliferation of the two cell lines, HeLa (human cervical carcinoma cells) and Caco-2 (human colon cancer cells) by MTT test. The measurement of the level of transcription factor NF-κB was also performed in the cells of both cell lines. Results: At least one of the mechanisms of the antiproliferative and/or cytotoxic effect of alpha lipoic acid on Caco-2 and HeLa cells at high concentrations, the transcription factor NF-κB, may be involved, as well as the products of transcription of genes that are under its control. The alpha lipoic acid has proven to be a promising candidate in the combat arena against cancer (Tab. 4, Ref. 31). Text in PDF www.elis.sk.

In recent years, special attention has been paid to the correlation between oxidation–reduction mechanisms and human health. The free radicals produced via physiological cellular biochemical processes are major contributors to oxidation phenomena. Their instability is the major cause of cellular damage. Free radical reactive oxygen species containing oxygen are the best-known ones. The body neutralises the harmful effects of free radicals via the production of endogenous antioxidants (superoxide dismutase, catalase, glutathione, and melatonin). The field of study of nutraucetics has found antioxidant capacity in substances such as vitamins A, B, C, E, coenzyme Q-10, selenium, flavonoids, lipoic acid, carotenoids, and lycopene contained in some foods. There are several areas of investigation that aim to research the interaction between reactive oxygen species, exogenous antioxidants, and the microbiota to promote increased protection via the peroxidation of macromolecules (proteins, ...

Background: Oxidative stress is a mediator of secondary injury to the spinal cord following trauma. Objective: To investigate the putative neuroprotective effect of a-lipoic acid (LA), a powerful antioxidant, in a rat model of spinal cord injury (SCI). Methods: Wistar albino rats were divided as control, vehicle-treated SCI, and LA-treated SCI groups. To induce SCI, a standard weight-drop method that induced a moderately severe injury (100 g/cm force) at T10 was used. Injured animals were given either 50 mg/kg LA or saline at 30 minutes postinjury by intraperitoneal injection. At 7 days postinjury, neurologic examination was performed, and rats were decapitated. Spinal cord samples were taken for histologic examination or determination of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity, and DNA fragmentation. Formation of reactive oxygen species in spinal cord tissue samples was monitored by using a chemiluminescence (CL) technique. Results: SCI caused a significant decrease in spinal cord GSH content, which was accompanied with significant increases in luminol CL and MDA levels, MPO activity, and DNA damage. Furthermore, LA treatment reversed all these biochemical parameters as well as SCI-induced histopathologic alterations. Conversely, impairment of the neurologic function caused by SCI remained unchanged. Conclusion: The present study suggests that LA reduces SCI-induced oxidative stress and exerts neuroprotection by inhibiting lipid peroxidation, glutathione depletion, and DNA fragmentation.

The white skeletal muscle of very long‐chain acyl‐CoA‐dehydrogenase‐deficient (VLCAD−/−) mice undergoes metabolic modification to compensate for defective β‐oxidation in a progressive and time‐dependent manner by upregulating glucose oxidation. This metabolic regulation seems to be accompanied by morphologic adaptation of muscle fibers toward the glycolytic fiber type II with the concomitant upregulation of mitochondrial fatty acid biosynthesis (mFASII) and lipoic acid biosynthesis. Dietary supplementation of VLCAD−/− mice with different medium‐chain triglycerides over 1 year revealed that odd‐chain species has no effect on muscle fiber switch, whereas even‐chain species inhibit progressive metabolic adaptation. Our study shows that muscle may undergo adaptive mechanisms that are modulated by dietary supplementation. We describe for the first time a concomitant change of mFASII in this muscular adaptation process.

The aim of this study was to assess the skin penetration, stability, and antioxidant effects of a α-tocopherol-lipoic acid codrug. To enhance penetration, we evaluated three microemulsions varying in water content and composition of the oil phase (isopropyl myristate with either monocaprylin or oleic acid). The codrug was incorporated at 1% (w/w). Codrug hydrolysis in the microemulsion increased with increases in time (up to 48 h) and formulation water content (10%-30%, w/w). Microemulsions increased the codrug delivery into viable layers of porcine ear skin by 2.9-7.8-fold compared with a control formulation (20% monocaprylin in isopropyl myristate) after 24 h. Penetration enhancement was influenced by the oil phase, with the formulation containing monocaprylin displaying the most pronounced effect. Antioxidant activity, assessed in skin bioequivalents using the thiobarbituric acid-reactive substances (TBARS) assay, demonstrated that TBARS levels decreased by 39% after treatment wi...

Quantum-chemical computations were used to investigate the structure-antioxidant parameter relationships of α-lipoic acid and its natural metabolites bisnorlipoic acid and tetranorlipoic acid in their oxidized and reduced forms. The enantiomers of lipoic and dihydrolipoic acid were optimized using the B3LYP/6-311+G(3df,2p), B3LYP/aug-cc-pVDZ and MP2(full)/6-31+G(d,p) levels of theory as isolated molecules and in the presence of water. The geometries of the metabolites and the values of their antioxidant parameters (proton affinity, bond dissociation enthalpy, adiabatic ionization potential, spin density, and the highest occupied molecular orbital energy) were calculated at the B3LYP/6-311+G(3df,2p) level of theory. The results obtained reveal similarities between these structures: a pentatomic, nonaromatic ring is present in the oxidized forms, while an unbranched aliphatic chain (as found in saturated fatty acids) is present in both the oxidized and the reduced forms. Analysis of the spin density and the highest occupied molecular orbital energy revealed that the SH groups exhibited the greatest electrondonating activities. The values obtained for the proton affinity, bond dissociation enthalpy and adiabatic ionization potential indicate that the preferred antioxidant mechanisms for α-lipoic acid and its metabolites are sequential proton loss electron transfer in polar media and hydrogen atom transfer in vacuum. Keywords α-Lipoic acid. Antioxidant. Metabolites. DFT method. MP2 method. C-PCM model Electronic supplementary material The online version of this article

Background and aim of work: metabolic hepatosteatosis is a common serious prevalent condition in KSA. The current study investigated alpha lipoic acid (ALA) effects on hepatic lipid accumulation in severely fatty rats and secondarily on blood lipid profile. Materials and methods: sixty male Zucker rats were selectively used half of which (Lean) weighed 200±25g & others weighed 375±30g. Fatty animals were allowed free access to food and water for one week before experiment. The animals were divided into lean untreated (group I), lean ALAmanaged (group II), fatty untreated (group III) and fatty ALAmanaged (group IV) (fifteen animals per each group). ALA was taken orally (20 mg/kg/day) for six months. Animals were sacrificed and weighed (BW). Their liver was weighed (LW) and its portion was sliced to study its lipid content. Right tibia length (TL) was measured and LW: TL ratio was calculated. Results: ZF ALA-untreated rats showed high LW: TL ratio. ALA therapy significantly reduced BW, TL, LW and LW: TL ratio in managed ZF rats compared to untreated ones while it didn't affect these parameters significantly in lean (ZL) rats. ZF rats exhibited significant hepatosteatosis evidenced by excessive liver triglyceride (TG) and total cholesterol (TC) contents and microscopically by large cytoplasmic vacuoles. Interestingly, 6-months' ALA therapy in ZF caused significantly diminished serum triglycerides and cholesterol levels as well as diminished hepatic triglycerides and TC component in addition to decreased its lipid vacuoles compared to untreated ZF rats. The results were insignificantly changed between managed and untreated lean groups. Conclusion: our findings support effectiveness of ALA therapy in excessive hepatosteatosis and in hyperlipidemia via improving abnormal lipid metabolism.

Background and Objective: There is growing evidence that excess generation of highly reactive free radicals, largely due to hyperglycemia, causes oxidative stress, which followed by further exacerbating the development and progression of diabetes and its complications. The ...

To examine the effects of alpha-lipoic acid (ALA) treatment over a period of 2 months on fasting blood glucose (FBG), insulin resistance (IR), and glutathione peroxidase (GH-Px) activity in type 2 diabetes (T2DM) patients. This study took place in Motahari Clinic, Shiraz, Iran, which is affiliated to Shiraz University of Medical Sciences from May to October 2006. Type 2 DM patients (n=57) were divided into 2 groups to receive either ALA (300 mg daily) or placebo by systematic randomization, and were followed-up for 8 weeks. After an overnight fasting and 2 hours after breakfast, patients' blood samples were drawn and tested for FBG, 2 hours PPG, serum insulin level, and GH-Px activity. The result of the study showed a significant decrease in FBG and PPG levels, IR-Homeostasis Model Assessment (IR-HOMA index) and GH-Px level in the ALA group. The comparison of differences between FBG and IR at the beginning and at the end of study in the ALA treated group and the placebo group we...

Ethinyl estradiol (EO) is the most commonly used as a component of oral contraceptive and hormonal replacement therapy (HRT) in women. However, its excessive and prolonged use may cause cytotoxicity, including cancer of many organs. Hence, the present study was performed to produce the experimental hepatotoxicity in female albino rats. EO was administered to different groups of rats, respectively @ 250, 500 and 750 μg/kg body weight, orally, weekly for 16 and 20 weeks. One group of rats was administered with saline alone to serve as control. The rats were sacrificed after their respective experimental periods, and the livers were collected and preserved in 10% buffered formalin. Later on, the histopathological study of liver tissues was done. On the 17 th week, the hepatic tissues showed severe congestion, focal areas of hemorrhage, extreme vacuolation of cytoplasm, distended sinusoids with dilated central veins. Degeneration and necrosis of hepatocytes as evidenced by increased cytoplasmic granularity, and dissolution of nuclear materials were seen. On the 21 st weeks, these changes were extremely severe and quite conspicuous. Distinct fibrosis was also noticed. EO caused hepatotoxicity, the extent and severity of which were dose and time dependent, indicating that this drug at higher dose after prolonged duration (500 or 750 μg/kg, orally, weekly for 20 weeks) may cause the standard experimental hepatotoxicity in rats.

The pyruvate dehydrogenase complex of Escherichia coli contains two lipoic acid residues per dihydrolipoamide acetyltransferase chain, and these are known to engage in the part-reactions of the enzyme. The enzyme complex was treated with trypsin at pH 7.0, and a partly proteolysed complex was obtained that had lost almost 60% of its lipoic acid residues although it retained 80% of its pyruvate dehydrogenase-complex activity. When this complex was treated with N-ethylmaleimide in the presence of pyruvate and the absence of CoASH, the rate of modification of the remaining S-acetyldihydrolipoic acid residues was appoximately equal to the accompanying rate of loss of enzymic activity. This is in contrast with the native pyruvate dehydrogenase complex, where under the same conditions modification proceeds appreciably faster than the loss of enzymic activity. The native pyruvate dehydrogenase complex was also treated with lipoamidase prepared from Streptococcusfaecalis. The release of lipoic acid from the complex followed zero-order kinetics for most of the reaction, whereas the accompanying loss of pyruvate dehydrogenase-complex activity lagged substantially behind. These results eliminate a model for the enzyme mechanism in which specifically one of the two lipoic acid residues on each dihydrolipoamide acetyltransferase chain is essential for the reaction. They are consistent with a model in which the di- hydrolipoamide acetyltransferase component contains more lipoic acid residues than are required to serve the pyruvate decarboxylase subunits under conditions of saturating substrates, enabling the function of an excised or inactivated lipoic acid residue to be taken over by another one. Unusual structural properties of the enzyme complex might permit this novel feature of the enzyme mechanism. The pyruvate dehydrogenase multienzyme com- plex of Escherichia coli catalyses the following reaction:

The pyruvate dehydrogenase multienzyme complex was isolated from Escherichia coli grown in the presence of [35S]sulphate. The three component enzymes were separated by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis and the molar ratios of the three polypeptide chains were determined by measurement of the radioactivity in each band. The chain ratio of lipoamide dehydrogenase to lipoate acetyltransferase approached unity, but there was a molar excess of chains of the pyruvate decarboxylase component. The 35S-labelled complex was also used in a new determination of the total lipoic acid content. It was found that each polypeptide chain of the lipoate acetyltransferase component appears to bear at least three lipoyl groups.

Two lipoic acid residues on each dihydrolipoamide acetyltransferase (E2) chain of the pyruvate dehydrogenase multienzyme complex of Escherichia coli were found to undergo oxidoreduction reactions with NAD+ catalysed by the lipoamide dehydrogenase component. It was observed that: (a) 2 mol of reagent/mol of E2 chain was incorporated when the complex was incubated with N-ethylmaleimide in the presence of acetyl-SCoA and NADH; (b) 4 mol of reagent/mol of E2 chain was incorporated when the complex was incubated with N-ethylmaleimide in the presence of NADH; (c) between 1 and 2 mol of acetyl groups/mol of E2 chain was incorporated when the complex was incubated with acetyl-SCoA plus NADH; (d) 2 mol of acetyl groups/mol of E2 chain was incorporated when the complex was incubated with pyruvate either before or after many catalytic turnovers through the overall reaction. There was no evidence to support the view that only half of the dihydrolipoic acid residues can be reoxidized by NAD+. Ho...

Amino-acid sequences around two lipoic acid residues in the lipoate acetyltransferase component of the pyruvate dehydrogenase complex of Escherichia coli were investigated. A single amino acid sequence of 13 residues was found. A repeated amino acid sequence in the lipoate acetyltransferase chain might explain this result.

The catalytic roles of the two reductively acetylatable lipoic acid residues on each lipoate acetyltransferase chain of the pyruvate dehydrogenase complex of Escherichia coli were investigated. Both lipoyl groups are reductively acetylated from pyruvate at the same apparent rate and both can transfer their acetyl groups to CoASH, part-reactions of the overall complex reaction. The complex was treated with N-ethylmaleimide in the presence of pyruvate and the absence of CoASH, conditions that lead to the modification and inactivation of the S-acetyldihydrolipoic acid residues. Modification was found to proceed appreciably faster than the accompanying loss of enzymic activity. The kinetics of the modification were fitted best by supposing that the two lipoyl groups react with the maleimide at different rates, one being modified at approximately 3.5 times the rate of the other. The loss of complex activity took place at a rate approximately equal to that calculated for the modification ...

α-Lipoic acid is a sulfur-containing nutrient endowed with pleiotropic actions and a safe biological profile selected to replace the unsaturated alkyl acid of capsaicin with the aim of obtaining lipoic amides potentially active as a TRPV1 ligand and with significant antioxidant properties. Thus, nine compounds were obtained in good yields following a simple synthetic procedure and tested for their functional TRPV1 activity and radical-scavenger activity. The safe biological profile together with the protective effect against hypoxia damage as well as the in vitro antioxidant properties were also evaluated. Although less potent than capsaicin, almost all lipoic amides were found to be TRPV1 agonists and, specifically, compound 4, the lipoic analogue of capsaicin, proved to be the best ligand in terms of efficacy and potency. EPR experiments and in vitro biological assays suggested the potential protective role against oxidative stress of the tested compounds and their safe biological...

Background: There is accumulating evidence that Juglans regia L. (GRL) leaf extract has hypoglycemic and antioxidative properties. The present study aimed to investigate the protective effects of GRL leaf extract against diabetic nephropathy (DN). Methods: In total, 28 male adult Sprague-Dawley rats were used. The DN rat model was generated by intraperitoneal injection of a single 55 mg/kg dose of streptozotocin (STZ). A subset of the STZ-induced diabetic rats received intragastric administration of GRL leaf extract (200 mg/kg/day) starting 1 week (preventive group) and 4 weeks (curative group) after the onset of hyperglycemia up to the end of the 8 th week, whereas other diabetic rats received only isotonic saline (diabetic group) as the same volume of GRL leaf extract. To evaluate the effects of GRL leaf extract on the diabetic nephropathy, various parameters of apoptosis and inflammation were assessed. Statistical analysis was performed using the SPSS software, version 15.0. The data were compared between the groups using the Tukey's multiple comparison test and the analysis of the variance. P values ˂0.05 were considered statistically significant. Results: Fasting blood sugar (FBS) levels (P=0.001) and histopathological changes in the kidney of diabetic rats attenuated after GRL leaf extract consumption. Greater caspase-3 (P=0.004), COX-2 (P=0.008), PARP (P=0.007), and iNOS (P=0.005) expression could be detected in the STZ-diabetic rats, which were significantly (P=0.009) attenuated after GRL leaf extract consumption. In addition, attenuation of lipid peroxidation in the diabetic rats was detected after GRL consumption (P=0.01). Conclusion: GRL leaf extract exerts preventive and curative effects against diabetic nephropathy.

Lipoic acid is powerful antioxidant which is used as a dietary supplement to treat a lot of disorders associated with the oxidative stress and was found to be useful in patients with diabetes and cardiovascular diseases. The article deals with analytical methods used for the determination of lipoic acid in various samples.

The present experiment was carried out to investigate the effectivness of -lipoic acid in allevating the toxicity of aluminium phosphide on biochemical parameters, free radicals and enzyme activities in plasma, liver and kidney of male rats. Animals were orally treated with aluminium phosphide, -lipoic acid and their combination for 30 consecutive days. Treatment with aluminium phosphide led to significant decrease in plasma total protein and glucose and increase in transaminases, phosphatases, urea, creatinine and bilirubin. Treatment with aluminium phosphide significantly decreased glutathione S-transferase (GST), catalase (CAT) and reduced glutathione (GSH) in plasma, liver and kidney. While, thiobarbituric acid reactive substances (TBARS; as an index of lipid peroxidation) and superoxide dismutase (SOD) were increased in plasma, liver and kidney of rats treated with aluminium phosphide. Administration of -lipoic acid in combination with aluminium phosphide minimized and alleviated its toxic effects on most of the measured parameters. In conclusion, lipoic acid has beneficial effects and could be able to attenuate aluminium phosphide toxicity.

Free fatty acids (FFA), hyperglycemia, and inflammatory cytokines are major mediators of β-cell toxicity in type 2 diabetes mellitus, impairing mitochondrial metabolism. Glutaredoxin 5 (Glrx5) is a mitochondrial protein involved in the assembly of iron–sulfur clusters required for complexes of the respiratory chain. We have provided evidence that islet cells are deprived of Glrx5, correlating with impaired insulin secretion during diabetes in genetically obese mice. In this study, we induced diabesity in C57BL/6J mice in vivo by feeding the mice a high-fat diet (HFD) and modelled the diabetic metabolism in MIN6 cells through exposure to FFA, glucose, or inflammatory cytokines in vitro. qRT-PCR, ELISA, immunohisto-/cytochemistry, bioluminescence, and respirometry were employed to study Glrx5, insulin secretion, and mitochondrial biomarkers. The HFD induced a depletion of islet Glrx5 concomitant with an obese phenotype, elevated FFA in serum and reactive oxygen species in islets, and ...

S117 Results: TFN-:, alone did not induce apoptosis of hepatocytes below a dose of IOOOU/ml. However, as little as IOU/ml TFN-:, increased the rate of cisplatin induced apoptosis from 20.5% to 40. I % (p 0.005) after 48h. TFN-:, induced the accumulation of p53 in a dose-and timedependent way. This accumulation was independent of MAPK signalling, as blocking p38 or JNK with specific inhibitors did not interfere with p53 accumulation. Additional DNA-damage by cisplatin activated p53, as indicated by induction of p21 expression. The promotion of apoptosis by IFN-:, was verified by increased PARP and caspase-3 cleavage in cisplatin and IFN-y treated cells compared to cisplatin treatment alone. Conclusion: In primary hepatocytes, the pro-inflammatory cytokine TFN-:, did not induce apoptosis by itself, but rather promoted apoptosis induced by DNA damage. This is explained by an accumulation ofp53 induced by TFN-:,. Since chronic inflammation is known to promote carcinogenesis, further studies are warranted to test for the role of other inflammatory cytokines in DNA-damage induced apoptosis. markers of apoptosis, such as DNA fragmentation, caspase activation, expression of pro-apoptic genes, phosphorylation of p53. Results: the results showed that a-LA inhibits the growth ofboth cell lines as indicated by the reduction in cell number, the reduced expression of cyclin A and the increased levels of the cyclin/CDKs inhibitors, p27Kipl and p21Cipl. Cell cycle arrest was associated with cell loss, and DNA laddering indicative of apoptosis. Apoptosis was preceded by increased generation of reactive oxygen species, and associated with p53 activation, increased expression of Bax, release of cytochrome c from mitochondria, caspases activation, decreased levels of survivin, induction of proapoptotic signaling (i.e .JNK) and inhibition of anti-apoptotic signaling (i.e. PKBIAkt) pathways. Conclusions: this study provides evidence that a-LA induces apoptosis in hepatoma cells and describes a possible sequence of molecular events underlying its lethal effect. In vivo studies of the effect of a-LA on liver tumor development are warranted.

Conflict of interest: MJF and ENO are coinventors on International Patent Application No. PCT/US19/39631 based on US Serial Nos. 62/690,718 and 62/830,850, filed in the name of Children's Hospital of Philadelphia. MJF is a scientific advisory board member with equity interest in RiboNova and scientific board member as paid consultant with Khondrion and Larimar Therapeutics. MJF has previous or current engagements with companies involved in mitochondrial disease therapeutic preclinical and/or clinical stage development as paid consultant

The aim of the present study was to analyze the involvement of oxidative stress and inflammation in the modulation of glucocorticoid production in the adrenal cortex of diabetic rats. Male Wistar rats were treated with or without streptozotocin (STZ, an insulinopenic model of diabetes) and either α-lipoic (90 mg/kg ip.), α-tocopherol (200 mg/kg po.) or with STZ and supplemented with insulin (STZ + INS: 2.5U/day) for 4 weeks. Oxidative/nitrosative stress parameters and antioxidant enzymes were determined in adrenocortical tissues. Apoptosis and macrophage activation were evaluated by immunohistochemistry (TUNEL and ED1). Basal and ACTH-stimulated corticosterone production were assessed by RIA and plasma ACTH levels were determined by an immunometric assay. Diabetic rats showed a diminished response to exogenous ACTH stimulation along with higher basal corticosterone and lower plasma ACTH levels. In the adrenal cortex we determined an increase in the levels of lipoperoxides, S-nitroso...

Hemoglobin and iron overload is considered the major contributor to intracerebral hemorrhage (ICH)-induced brain injury. Accumulation of iron in the brain leads to microglia activation, inflammation and cell loss. Current available treatments for iron overload-mediated disorders are characterized by severe adverse effects, making such conditions an unmet clinical need. We assessed the potential of α-lipoic acid (ALA) as an iron chelator, antioxidant and anti-inflammatory agent in both in vitro and in vivo models of iron overload. ALA was found to revert iron-overload-induced toxicity in HMC3 microglia cell line, preventing cell apoptosis, reactive oxygen species generation and reducing glutathione depletion. Furthermore, ALA regulated gene expression of iron-related markers and inflammatory cytokines, such as IL-6, IL-1β and TNF. Iron toxicity also affects mitochondria fitness and biogenesis, impairments which were prevented by ALA pre-treatment in vitro. Immunocytochemistry assay s...

Background: Palladium a-lipoic acid (Pd-LA) complex has unique electronic and redox properties that appear to be the key to its physiological effectiveness. A proprietary liquid blend containing Pd-LA as the major component was demonstrated to be effective in improving the activities of mitochondrial enzymes in aged rats. Methods: The Pd-LA complex was evaluated for its hypoglycemic effect against the alloxan-induced diabetic model, as well as in the oral glucose tolerance test in rats. The in vitro free radical scavenging activity of Pd-LA was also determined. Results: Administration of Pd-LA (0.5 mL ⁄ kg; equivalent to 3.8 mg complexed a-lipoic acid ⁄ kg, p.o.) daily for 5 days to alloxan-induced diabetic animals significantly reduced the blood glucose level (P < 0.05). The blood antioxidant status in the diabetic animals was significantly improved by the treatment of Pd-LA (P < 0.05). Similarly, Pd-LA showed significant in vitro antioxidant activity in a concentration-dependent manner. Conclusions: Results of the study conclude that the Pd-LA complex is effective in lowering the blood glucose level and enhancing the declined antioxidant status in diabetic animals. Significant finding(s) of the study include: (i) Pd-LA significantly increased the tolerance of glucose and was also effective in ameliorating hyperglycemia induced by alloxan; (ii) Pd-LA significantly enhanced the activities of blood superoxide dismutase, catalase, glutathione peroxidase and level of glutathione in diabetic animals; and (iii) Pd-LA showed significant in vitro antioxidant activity. This study adds: The therapeutic efficiency of Pd-LA is demonstrated against declined antioxidant status as well as hyperglycemia associated with diabetes.

Objective(s): To investigate the effect of topical administration of alpha-lipoic acid into chitosan conduit on peripheral nerve regeneration using a rat sciatic nerve transection model. Materials and Methods: Forty five Wistar rats were divided into three experimental groups randomly. A 10-mm gap of sciatic nerve was bridged with a chitosan conduit following surgical preparation and anesthesia. In treatment group, the conduit was filled with 30 µl alpha-lipoic acid (10 mg/kg/bw).It was filled with 30 µl phosphate buffered saline solution in control group. In Sham group sciatic nerve was just exposed. Results: The recovery of nerve function was faster in treatment group than in control, at 4 and 8 weeks after surgery (P-value&lt;0.05). Conduction velocity was better in treatment group than in control group at 4 and 12 weeks (P-value&lt;0.05). Recovery index was higher in treatment group than the control group, 8 weeks after surgery (P-value &lt;0.05). Greater nerve fiber diameter, a...

Objective: Oxidative stress is one of the major causes of methotrexate induced lung injury (MILI). Alpha-lipoic acid (ALA), which occurs naturally in human food, has antioxidative and anti-inflammatory activities. The aim of this study was to research the potential protective role of ALA on MILI in rats. Methods: Twenty one rats were randomly subdivided into three groups: control (group I), methotrexate (MTX) treated (group II), and MTX+ALA treated (group III). Lung injury was performed with a single dose of MTX (20 mg/kg) to groups 2 and 3. On the sixth day, animals in all groups were sacrificed by decapitation and lung tissue and blood samples were removed for histological examination and also measurement the levels of interleukin-1-beta (IL-1β), malondialdehyde (MDA), glutathione (GSH), tumour necrosis factor-alpha (TNF-α), myeloperoxidase (MPO), and sodium potassium-adenosine triphosphatase (Na+/K+ATPase). Results: In MTX group tissue GSH, Na+/K+ATPase activities were lower, tissue MDA, MPO and plasma IL-1?, TNF-? were significantly higher than the other groups. Histopathological examination showed that lung injury was less severe in group 2 according to group 3. Conclusions: Oxidative damage of MTX in rat lung is partially reduced when combined with ALA.