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Low accumulation and penetration of nanomedicines in tumor severely reduce therapeutic efficacy. Herein, a pH-responsive gold nanoassembly is designed to overcome these problems. Polyethylene glycol linked raltitrexed (RTX, target ligand and chemotherapy drug) and two tertiary amine molecules (1-(2-aminoethyl) pyrrolidine and N,N-dibutylethylenediamine) are modified on the surface of the 6-nm gold nanoparticles by lipoic acid to form gold nanoassembly defined as Au-NNP(RTX). The Au-NNP (RTX) nanoassembly could remain at about 160 nm at the blood circulation (pH 7.4), while split into 6-nm gold nanoparticles due to tertiary amine protonation at tumor extracellular pH (pH 6.8). This pH-responsive disassembly behavior endows Au-NNP(RTX) better tumor tissue permeability through the better diffusion brought by the size reduction. Meanwhile, after disassembly, more RTXs on the surface of gold nanoparticles are exposed from the shielded state of assembly along with 2.25-fold augment of cellular uptake capability. Most importantly, the results show that Au-NNP(RTX) possesses of high tumor accumulation and effective tumor penetration, thereby enhancing the tumor chemo-radiotherapy efficiency., Graphical abstract Image 1, Highlights • A pH-responsive self-targeting & splitting gold nanoassembly is fabricated. • The nanoassembly holds better tumor tissue permeability by the size reduction. • The nanoassembly enhances targeting capability by ligand shielding and exposure. • Clever design endows the system synergistic effect of chemo-radiotherapy.

This study aims to evaluate the effects of dietary α-lipoic acid (α-LA) on bioaccumulation, oxidative stress, apoptosis, and inflammation in Channa argus after 28 d of lead (Pb) exposure. A total of 300 fish were divided into five groups: the first group was the control group and the other four groups were exposed to waterborne Pb (800 ppb) and fed α-LA diets supplemented with 0, 300, 600, and 900 mg/kg. The results demonstrated that dietary α-LA effectively reduced the Pb accumulation in the liver, kidney, gill, intestine, and muscle of C. argus after exposure to Pb. Meanwhile, dietary α-LA reversed alterations in the biochemical parameters (Alanine aminotransferase (ALT), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), blood urea nitrogen (BUN), cortisol (COR), and creatinine (CRE)) and immunity parameters (myeloperoxidase (MPO), complement 3 (C3), lysozyme (LYS), complement 4 (C4), C-reactive protein (CRP), and immunoglobulin M (IgM)) in the serum of fish caused by Pb. Pb-induced reduction of antioxidant enzyme activities (Catalase (CAT), glutathione reductase (GR), superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GSH-Px)) was inhibited by dietary α-LA. And malondialdehyde (MDA) and protein carbonyl (PC) content exhibited an opposite trend. Meanwhile, dietary supplemented with α-LA was found to relieve Pb-induced oxidative stress by downregulating Keap1 mRNA expression levels and upregulating the expression levels of CAT, nuclear factor erythroid 2-related factor 2 (Nrf2), GSH-Px, and Cu/Zn SOD. Furthermore, α-LA supplementation reversed Pb-induced upregulation of pro-inflammatory genes (interleukin (IL)-6, IL-1β, tumor necrosis factor α (TNF-α), and nuclear factor kappa B (NF-κB)), Pro-apoptotic genes (Bcl-2-associated X (Bax), caspase (Cas)-3, and tumor protein p53 (p53)) and Hsp70, and downregulation of anti-inflammatory genes (IL-10, inhibitor of κBα (IκBα), and transforming growth factor β (TGF-β)) and anti-apoptosis gene (B-cell lymphoma-2 (Bcl-2)). Overall, dietary α-LA supplementation could enhance the innate immunity and antioxidant capacity of fish, attenuating the Pb accumulation, and cell apoptosis after being exposed to Pb. Furthermore, dietary α-LA could relieve Pb-induced inflammatory response and oxidative stress of fish via regulating NF-κB and Nrf2 signaling, respectively.

A membrane-lytic mechanism-based nanodrug is developed for drug-resistant tumor therapy by anchoring the small-molecule quaternary ammonium salt (QAS) on cross-linked (R)-(+)-lipoic acid nanoparticles (cLANs). The anchoring of QAS on the nanoparticle avoids the direct attack of long alkyl chains to the cell membrane under physiological conditions, while after entering tumor cells, the QAS is released from the dissociated cLANs, migrates to the phospholipid bilayer via electrostatic interaction, and destroys the cell membrane by the puncture of long alkyl chains. Since the QAS is designed to finally be hydrolyzed to amino acid betaine and food additive cetanol and the cLANs degrade to dihydrolipoic acid (DHLA, reduced form of dietary antioxidant lipoic acid in cells), the QAS@cLANs hold superior biosafety. In addition to the drug-resistant tumors, the QAS@cLANs demonstrate significant inhibition of metastatic tumors. This work provides not only a general and clinic-promising treatment for the refractory tumors but also opens a door for the medicinal use of QAS.

Purpose: To investigate the effect of lipoic acid on nerve cell apoptosis in rats with Parkinson's disease via the extracellular signal-regulated kinase (ERK) signaling pathway.Methods: A total of 36 rats were randomly divided into normal group (n = 12), Parkinson's disease model group (n = 12) and lipoic acid group (n = 12). The neuronal morphology was examined by means of Nissl staining, while cell apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay.Results: The neurons were severely damaged in model group, while neuronal morphology and structure were ameliorated in lipoic acid group when compared with those in model group. The p-ERK was lowered significantly (p < 0.05) in model group and lipoic acid group compared with that in normal group. Levels of mRNA, caspase-3 and Bax increased significantly, while Bcl-2 decreased in model group and lipoic acid group when compared with those in normal group (p < 0.05). Lipoic acid treatment significantly reduced mRNA expression of caspase-3 and Bax, but increased Bcl-2 compared with model group. Furthermore, ELISA results indicate that model and lipoic acid groups exhibited raised caspase-3 and Bax but significantly reduced Bcl-2 levels, compared with normal group. The results also showed that the apoptosis was higher in the other two groups than in normal group; on the other hand, it was significantly lower in lipoic acid group than in model group (p < 0.05).Conclusion: Lipoic acid inhibits nerve cell apoptosis in rats with Parkinson's disease by up-regulating ERK signaling pathway. Therefore, lipoic acid is a potential neuroprotective agent for the management of Parkinson’s disease.

Objective: The aim of the study was to evaluate the possible protective effects of alpha-lipoic acid (α-LA), donepezil and memantine combined therapy in the scopolamine-induced amnesia rat model. Objective: The aim of the study was to evaluate the possible protective effect of donepezil, memantine and alpha-lipoic acid (α-LA) combined therapy in the scopolamine-induced amnesia rat model. Methods: In this study, the effect of combined therapy used in the treatment of scopolamine-induced amnesia on behavioural parameters was evaluated using Y-maze and new object recognition (NOR) test. In addition, muscarinic acetylcholine receptor subtype M1, N-methyl-D-aspartate receptor NR2B subunit, brain-derived neurotrophic factor (BDNF) and mitochondrial apoptosis-related proteins [B-cell lymphoma-2 (Bcl-2) / Bcl-2 associated X (Bax) ratio, caspase (casp) -3, and -9] expression levels were evaluated using the western blot method in the frontal cortex and hippocampus regions. Results: The main findings of this study demonstrated that in scopolamine-induced amnesia rats, cognitive dysfunction determined by both the Y-maze and the NOR test were reversed with the combined treatment of memantine, donepezil and α-LA. According to immunoblotting results in both brain regions, scopolamine-induced decreased M1, BDNF, Bcl-2 / Bax ratio and increased NR2B, casp-3 and -9 expression levels were found to be reversed to almost control values with combined treatment. Conclusion: Consistent with the literature, our study results suggest that the positive contribution of α-LA to the combined treatment of donepezil and memantine, which is used in the routine treatment of neurodegenerative diseases, may be a treatment option in the future. Results: The main findings of this study demonstrated that in scopolamine-induced amnesia rats, cognitive dysfunction determined by both the Y-maze and the NORT test were reversed with the combined treatment of memantine, donepezil and α-LA. In addition, decreased BDNF, M1, bcl-2/bax ratio and increased NR2B, caspase-3 and caspase-9 expression levels due to scopolamine in both regions were improved with α-LA, donepezil and memantine combined therapy. Conclusion: The results of our study and other study results in the literature suggest that α-LA may be a future treatment option due to its positive contribution to the effects of other drugs used in the routine treatment of neurodegenerative diseases.

α-Lipoic acid as an antioxidant is used in the treatment of many diseases, such as diabetes, cardiovascular diseases, cancer, and AIDS. The objective of this study was to investigate the capability of human serum albumin (HSA) as a potential carrier for α-lipoic acid (α-LA). Molecular interactions between HSA and α-LA were monitored via fluorescence and circular dichroism spectroscopies as well as molecular docking and molecular dynamics simulations studies. The results revealed that α-LA binds to HSA with binding stoichiometry of 1:1 through hydrogen bonding and van der Waals interactions. The overall binding affinity was estimated to be of the order 105 M−1. α-LA induced partial folding in the tertiary structure and subtle alterations in the secondary structure of HSA, which was accompanied by increased thermal stability. The results also demonstrated that the complex formation between α-LA and HSA enhanced photostability under UV irradiation. The improved antioxidant activity of α-LA in electron donation was amongst the positive influences observed through the association of α-LA with HSA. Thus, their complexes can successfully be employed in the food and pharmaceutical industries.

Primary hypothyroidism occurs in the general population with an incidence of 0.5–1 %, and includes congenital and acquired (due to autoimmune thyroiditis, after surgical removal of the thyroid gland or treatment with radioactive iodine) forms. The basic treatment of primary hypothyroidism is replacement therapy with L-thyroxine. Combined administration of L-thyroxine and α-lipoic acid resulted in more marked decrease of oxidative stress, hyperlipidemia, hyperactivity of the immune system, endothelial dysfunction and neurological disorders, observed in patients with primary hypothyroidism, as compared to monotherapy with L-thyroxine. α-lipoic acid use was effective in adults and children, in case of parenteral and/or oral administration., Первичный гипотиреоз встречается в общей популяции с частотой 0,5–1 % и включает в себя врожденные и приобретенные (вследствие аутоиммунного тиреоидита, после оперативного удаления щитовидной железы либо лечения ее радиоактивным йодом) формы. Базовой терапией первичного гипотиреоза является назначение заместительной терапии L-тироксином. При этом сочетанное назначение L-тироксина и α-липоевой кислоты позволяет более эффективно бороться с окислительным стрессом, гиперлипидемией, гиперреактивностью иммунной системы, эндотелиальной дисфункцией и неврологическими нарушениями, наблюдаемыми у больных с первичным гипотиреозом, по сравнению с монотерапией L-тироксином. Применение α-липоевой кислоты было эффективно у взрослых и детей, при парентеральном и/или пероральном введении., Первинний гіпотиреоз трапляється в загальній популяції з частотою 0,5–1 % і містить уроджені та набуті (унаслідок автоімунного тиреоїдиту, після оперативного видалення щитоподібної залози або лікування її радіоактивним йодом) форми. Базовою терапією первинного гіпотиреозу є призначення замісної терапії L-тироксином. При цьому поєднане призначення L-тироксину і α-ліпоєвої кислоти дозволяє більш ефективно боротися з окислювальним стресом, гіперліпідемією, гіперреактивністю імунної системи, ендотеліальною дисфункцією і неврологічними порушеннями, які спостерігаються у хворих на первинний гіпотиреоз, порівняно з монотерапією L-тироксином. Призначення α-ліпоєвої кислоти було ефективне у дорослих і дітей, при парентеральному та/або пероральному введенні.

Ferroptosis, a new type of programmed cell death discovered in recent years, plays an important role in many neurodegenerative diseases. N2L is a novel lipoic acid-niacin dimer regulating lipid metabolism with multifunction, including antioxidant effect. It also exerts neuroprotective effects against glutamate- or β-amyloid (Aβ) -induced cell death. Because reactive oxygen species (ROS) play an essential role in ferroptosis, we hypothesize that N2L might protect cells from ferroptosis. Here, we investigated the protective effect of N2L and the underlying mechanism(s) under RAS-selective lethality 3 (RSL3) treatment in HT22 cells. RSL3 decreased the cell viability and induced excessive accumulation of ROS in HT22 cells. N2L pretreatment effectively protected HT22 cells against lipid peroxidation. What's more, N2L recovered glutathione peroxidase 4 (GPX4) expression and blocked the increase of Cyclooxygenase-2 (cox-2) and acyl-CoA synthetase long-chain family member 4 (ACSL4) protein expressions. Moreover, N2L also significantly prevented Ferritin Heavy Chain 1 (FTH1) from downregulation and maintained iron homeostasis. Finally, N2L pretreatment could decrease c-Jun N-terminal kinase (JNK) / extracellular regulated protein kinases (ERK) activation induced by RSL3. Taken together, our results showed that N2L could protect HT22 cells from RSL3-induced ferroptosis through decreasing lipid peroxidation and JNK/ERK activation. And N2L could be a ferroptosis inhibitor for the therapy of ferroptosis-related diseases, such as Alzheimer's disease.

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

AIMS Alpha-lipoic acid (ALA) is a unique antioxidant that can eradicate different kinds of free radicals. The current trial was designed to investigate the effects of ALA supplementation on some oxidative stress biomarkers in women with GDM. MATERIALS AND METHODS Sixty women with GDM at 24-28 weeks of pregnancy were selected and then they were divided into the drug (n = 30) received ALA 300 mg/day for 8 weeks and the placebo (n = 30) groups. Serum values of fasting blood sugar (FBS), thiol groups, glutathione, catalase, total antioxidant capacity (TAC), total oxidant status (TOS) and malondialdehyde (MDA) were measured. Values of the oxidative stress index (OSI), the MDA/TAC ratio and total antioxidant gap (TAG) were calculated. RESULTS After the intervention values of FBS (p = .001), TAC (p

A simple, highly sensitive, and selective differential pulse voltammetry method for the determination of α-lipoic acid (LA) in pharmaceutical preparations was developed and validated. The method is based on a quasi-reversible, diffusion-controlled, one-electron anodic oxidation of LA on a boron-doped diamond electrode (BDDE) in a McIlvaine (citrate-phosphate, C-PB) buffer solution at pH 3.0. For the first time, this environment was used for LA determination. A linear calibration curve was obtained within the concentration range 5.82 × 10−8 to 4.00 × 10−4 mol L−1 with a correlation coefficient of 0.9999. The limits of detection was estimated to be 1.94 × 10−8 mol L−1, which is one of the lowest values characteristic of voltammetric and chromatographic methods of LA determination. The proposed procedure is sensitive, accurate, and precise. Its utility was demonstrated in the determination of LA in pharmaceuticals without the need for its separation from the matrices. The results were comparable to those obtained by high performance liquid chromatography reference method and were in good accordance with the once declared by manufacturers. Thus, our method can be considered as an alternative to the dominant chromatographic determinations of α-LA in real samples.

New indoline spiropyran was synthesized by the cyclocondensation of 5-chlorine-substituted Fischer base with 2,7-dihydroxy-1-naphthaldehyde. This spiropyran was used to prepare a new derivative of α-lipoic acid with potential biological activity, which can be considered as a promising photopharmacological agent. The structures of the synthesized compounds were determined by NMR and IR spectroscopy and mass spectrometry and were confirmed by X-ray diffraction. Biological assays using HeLa cells showed that the spirocyclic compounds possess low cytotoxicity even at relatively high concentrations.

The prevalence of psoriasis poses a considerable public health burden and requires the elaboration of new treatment approaches. Despite the high prevalence and incidence of the disease and large amounts of reports on this problem, there has not been established an integral vision on the pathogenesis of this dermatosis. Risk factors for psoriasis can be divided into two groups, first of all, external and internal ones. Special attention is paid to smoking and alcohol consumption. The aim of our study was to determine the role of alpha - lipoic acid as a component of the complex therapy for psoriatic patients with alcohol and smoking abuse. The study has demonstrated that alpha-lipoic acid increases the reserves of intracellular glutathione, prevents the damage of mitochondria during lipid peroxidation. This enables to restore the balance of redox processes in hepatocytes and reduces the damaging effects of toxic substances. The effectiveness of the psoriasis therapy including alpha-lipoic acid was evaluated by comparing the biochemical blood parameters of the patients who took the therapy with alpha-lipoic acid (I group) and who did not (II group). The obtained results show the patients of the I group the have indicators of total cholesterol improved by 73.7%, the indicators of total and direct bilirubin improved by 25.7% and 32.4%; infiltration and erythema has considerably diminished by 92.9% of the patients that is 2.3 times higher compared with patients of the II group (control). We consider that this study has supported higher therapeutic efficacy of the proposed method of complex therapy for psoriatic patients of the I group that includes the addition of 600 mg of alpha-lipoic acid as a single dose taken in 30 minutes before the first meal for a month.

As an antioxidant, α-lipoic acid (LA) has attracted much attention to cancer research. However, the exact mechanism of LA in cancer progression control and prevention remains to be unclear. In this study, we demonstrated that α-lipoic acid has inhibitory effects on the proliferation, migration, and proapoptotic effects of non-small-cell lung cancer (NSCLC) cell lines A549 and PC9. LA-induced NSCLC cell apoptosis was mediated by elevated mitochondrial reactive oxygen species (ROS). Further study confirmed that it is by downregulating the expression of PDK1 (the PDH kinase), resulted in less phospho-PDH phenotype which could interact with Keap1, the negative controller of NRF2, directly leading to NRF2 decrease. Thus, by downregulating the NRF2 antioxidant system, LA plays a role in promoting apoptosis through the ROS signaling pathway. Moreover, LA could enhance other PDK inhibitors with the proapoptosis effect. In summary, our study shows that LA promotes apoptosis and exerts its antitumor activity against lung cancer by regulating mitochondrial energy metabolism enzyme-related antioxidative stress system. Administration of LA to the tumor-bearing animal model further supported the antitumor effect of LA. These findings provided new ideas for the clinical application of LA in the field of cancer therapy.

This study aimed to evaluate the effect of dietary supplementation of α-lipoic acid (LA) in the growth, blood chemistry, and liver antioxidant status of African catfish Clarias gariepinus. This study applied a completely randomised experimental design consisting of five experimental diets (30% protein and 4% lipid) with graded levels of LA, i.e. LA0.0 as the control (0.0 g LA kg−1 feed), LA0.5 (0.5g LA kg−1 feed), LA1.0 (1.0 g LA kg−1 feed), LA1.5 (1.5 g LA kg−1 feed), and LA2.0 (2.0 g kg−1 feed) with three replications. An orthogonal polynomial regression analysis was used to determine the optimum dose of LA for fish growth. Seventy-five catfish juveniles (14.65±0.05 g) were randomly distributed into each fibre tank (600 L in capacity) and maintained in zero water exchange condition for 60 days. The fish were fed twice a day to apparent satiation at 08.00 AM and 05.00 PM (GMT+7). Fish survival was at a range of 93.78–97.78% and was not significantly different amongst the treatments (P>0.05). The final body weight, biomass and specific growth rate of the fish fed with LA supplemented diets were generally higher than those of the control. Higher feed intake and feed protein retention were also higher in LA treatment groups compared to that of the control, but there were no significant differences in the feed conversion ratio. In the present study, visual observation on the liver colour was used to indicate the liver condition. Abnormal coloured fish liver (pale coloured) was found to be higher in lipid and malondialdehyde, and lower in superoxide dismutase (SOD) activity than those of normal coloured (red coloured) liver. The percentage of normal coloured liver (red coloured liver) in the control (28.8 %) was lower than that of the LA treatment groups (46.7–70 %). Antioxidant status of the fish in LA treatment groups was superior than that of the control as indicated by the lower levels of MDA and the higher SOD activities. Regardless of the dose of LA, all fish fed on LA supplemented diets demonstrated significantly lower plasma alanine aminotransferase and aspartate aminotransferase levels than those of the control (P

This work deals with the study of two derivatives of spiropyrans of indoline series and α-lipoic acid, which are considered as potential photopharmacological agents with controllable biological activity. The structure of the compounds has been studied in detail by X-ray diffraction analysis that revealed high lability of lipoic acid fragments. To assess potential biological activity, molecular docking for the possibility of spiropyran molecule to bind to amylin protein in order to inhibit its aggregation has been performed. The results of molecular docking showed a potential increase in the affinity of spirocyclic derivatives toward this protein as compared with α-lipoic acid.

Activation of various isoforms of NADPH oxidase contributes to the pathogenesis of asthma at multiple levels: promoting hypercontractility, hypertrophy, and proliferation of airway smooth muscle; enabling lung influx of eosinophils via VCAM-1; and mediating allergen-induced mast cell activation. Free bilirubin, which functions physiologically within cells as a feedback inhibitor of NADPH oxidase complexes, has been shown to have a favorable impact on each of these phases of asthma pathogenesis. The spirulina chromophore phycocyanobilin (PhyCB), a homolog of bilirubin’s precursor biliverdin, can mimic the inhibitory impact of biliverdin/bilirubin on NADPH oxidase activity, and spirulina’s versatile and profound anti-inflammatory activity in rodent studies suggests that PhyCB may have potential as a clinical inhibitor of NADPH oxidase. Hence, spirulina or PhyCB-enriched spirulina extracts merit clinical evaluation in asthma. Promoting biosynthesis of glutathione and increasing the expression and activity of various antioxidant enzymes – as by supplementing with N-acetylcysteine, Phase 2 inducers (eg, lipoic acid), selenium, and zinc – may also blunt the contribution of oxidative stress to asthma pathogenesis. Nitric oxide (NO) and hydrogen sulfide (H2S) work in various ways to oppose pathogenic mechanisms in asthma; supplemental citrulline and high-dose folate may aid NO synthesis, high-dose biotin may mimic and possibly potentiate NO’s activating impact on soluble guanylate cyclase, and NAC and taurine may boost H2S synthesis. The amino acid glycine has a hyperpolarizing effect on airway smooth muscle that is bronchodilatory. Insuring optimal intracellular levels of magnesium may modestly blunt the stimulatory impact of intracellular free calcium on bronchoconstriction. Nutraceutical regimens or functional foods incorporating at least several of these agents may have utility as nutraceutical adjuvants to standard clinical management of asthma.

Introduction. Thioctic (α-lipoic) acid is an endogenous antioxidant and is used for liver diseases, poisoning with salts of heavy metals, hyperlipidemia, atherosclerotic heart disease, neuropathy, insulin-resistant forms of diabetes mellitus, etc. technologies for producing tableted medicinal preparations of thioctic acid, necessary for the pharmaceutical development of thioctic acid tablets at pharmaceutical industry enterprises.Text. The review considers the physicochemical properties of the pharmaceutical substance thioctic acid, the features of its pharmaceutical and technological properties, and compatibility with excipients. In the technology of thioctic acid tablets, methods of direct compression and compression with preliminary wet granulation, including those using organic solvents, are used. To increase photostability, thioctic acid tablets are coated. Information on excipients in the composition of core tablets and film coat of thioctic acid tablets registered in Russia is presented. The problems of tabletting thioctic acid are described: sintering of the granulate during the drying process, adhesion of the tabletting mass to the pressing tool and the resulting unevenness of the tablet surface. The ways of optimizing the tabletting process of thioctic acid using various compositions of excipients, improving the flowability of a pharmaceutical substance both during its synthesis and as a result of technological processing, choosing the optimal modes of granulation, drying, pressing are considered.Conclusion. As a result of the analysis of the literature data, the features of the technology for producing thioctic acid tablets were revealed, which are due to the high content of the pharmaceutical substance in tablets (up to 600 mg), the need to use a minimum amount of excipients (from 27 to 51 %), poor flowability, and low melting point of the pharmaceutical substance. Improvement of compressibility and prevention of adhesion can be achieved by using the pharmaceutical substance thioctic acid of a certain granulometric composition, auxiliary substances of the basic nature and a high content of glidants (up to 6 %). The identified manufacturing features should be taken into account in the pharmaceutical development of thioctic acid tablets.

This study evaluated the effect of adding alpha lipoic acid (ALA) to the vitrification solution of sheep ovarian tissue on 7 days of in vitro culture or 15 days of xenotransplantion. ALA was used at two different concentrations (100 μM: ALA100 and 150 μM: ALA150). Ovarian tissue was evaluated by classical histology (follicular morphology, development, and stromal cell density); immunohistochemistry for forkhead box O3a (FOXO3a); Ki67 (cell proliferation); cluster of differentiation 31 (CD31); and alpha smooth muscle actin (α-SMA). Reactive oxygen species (ROS) levels in ovarian tissue, as well as malondialdehyde (MDA) and nitrite levels in the culture medium, were assessed. Similar percentage of morphologically normal follicles was found in the vitrified ovarian tissue in the presence of ALA100 or ALA150 after in vitro culture or xenotransplantation. Follicular development from all treatments was higher (P0.05) than the control group. Moreover, an activation of primordial follicles was observed by FOXO3a. Stromal cell density and immunostaining for Ki67 and CD31 were significantly higher (P0.05) in ALA150 vitrified tissue. No difference (P0.05) was found in α-SMA between ALA concentrations after in vitro culture or xenograft. ROS levels in the ovarian tissue were similar (P0.05) in all treatments, as well as MDA and nitrite levels after 7 days of culture. We concluded that the addition of ALA 150 is able to better preserve the stromal cell density favoring granulosa cell proliferation and neovascularization.

The glycine cleavage system H protein (GCSH) is an integral part of the glycine cleavage system with its additional involvement in the synthesis and transport of lipoic acid. We hypothesize that pathogenic variants in GCSH can cause variant nonketotic hyperglycinemia (NKH), a heterogeneous group of disorders with findings resembling a combination of severe NKH (elevated levels of glycine in plasma and CSF, progressive lethargy, seizures, severe hypotonia, no developmental progress, early death) and mitochondriopathies (lactic acidosis, leukoencephalopathy and Leigh-like lesions on MRI). We herein report three individuals from two unrelated Indian families with clinical, biochemical, and radiological findings of variant NKH, harboring a biallelic start loss variant, c.1A G in GCSH.

The aim of the study is an experimental confirmation of the use of a new combination of biologically active substances with tonic and antioxidant effects. This combination contains acetylcysteine in its composition to reduce the severity of psychoneurological consequences of alcohol intoxication.Materials and methods. The study was conducted on male Wistar rats. The post-intoxication state was simulated by a single injection of ethanol (3 g/kg, intraperitoneally). Half an hour after awakening, the rats were divided into groups, which were injected with saline, acetylcysteine (1 g/kg), taurine (20 mg/kg), caffeine ( 20 mg/kg), succinic acid (100 mg/kg), lipoic acid (100 mg/kg), pyridoxine (400 mg/kg), or a combination of acetylcysteine with all these substances taken in a twice lower dose (except taurine). Before the treatment and 3 hours after it, the degree of neurological disorders was fixed according to the Combs and D'Alecy scale, in the Open Field test and the Adhesion test. Then the animals were euthanized to assess the level of glutathione, triglycerides and malondialdehyde (MDA) in liver homogenates, to determine the activity of enzymatic antioxidant systems and serum aminotransferases.Results. In the animals injected with alcohol, there were evident signs of neuropsychiatric disorders, manifested in a low motor activity and a decrease in fine motor skills. This state did not change after an oral administration of saline. After the administration of acetylcysteine, taurine, caffeine, succinic and lipoic acids, pyridoxine and, to a greater extent, their compositions, the compensation of neuropsychiatric disorders and improvement of fine motor skills were notified. In the liver of these animals, the levels of glutathione, MDA, triglycerides, and the activity of antioxidant defense enzymes corresponded to the physiological norm.Conclusion. The introduction of a combination of acetylcysteine with taurine, caffeine, pyridoxine, lipoic and succinic acids after an acute alcohol intoxication, to a greater extent than each of the substances separately, contributes to the function retention of the antioxidant system of hepatocytes. Besides, it reduces the level of their dystrophic changes and leads to a decrease in the severity of psychoneurological disturbances in the experimental animals.

The paper presents an analysis of current literature data on the use of the R-enantiomer of α-lipoic acid as an antihypertensive treatment in patients with hypertension and metabolic syndrome. An analysis of the literature was carried out on its use as an antiinflammatory agent in inflammatory diseases. Currently, a very important aspect of researches is the possibility of using R-α-lipoic acid as a micronutrient and therapeutic agent for the treatment of diabetic polyneuropathy and neurodegenerative di­seases, especially Alzheimer’s disease, carbohydrate metabolism disorders and metabolic syndrome. Lipoic acid has now become an important ingredient in multivitamin formulas, anti-aging supplements. R-α-lipoic acid is a metabolic antioxidant, its molecule contains a dithiolane ring in oxidized form, this ring has the ability to cleave with formation of dihydrolipoic acid. And since α-lipoic acid, a physiological form of thioctic acid, is a strong antioxidant that relieves the symptoms of diabetic neuropathy, the literature review analyzed data from various authors on the antioxidant effects of the R-enantiomer of α-lipoic acid and found that it had strong antioxidant effects, and its dose of 300 mg is bioequivalent to 600 mg of racemic α-lipoic acid. As presented in a sufficient number of analyzed sources, the biological role of lipoic acid is quite diverse. It is important to determine the exact causal relationship between lipoic acid and its immediate cellular targets. Lipoic acid can have a number of important and diverse physiological effects on the stimulation of neurohormonal function and, thus, indirectly affect multiple cellular signaling pathways in peripheral tissues.

This study investigates the hepatoprotective effect of bone marrow mononuclear cells (BM-MNCs) transplantation, N-acetylcysteine (NAC) and α-lipoic acid (ALA). Rats were administrated carbon tetrachloride (CCl4) (1 mg/kg, i.p.) twice/week for 8 weeks for the induction of hepatotoxicity. 7 groups of rats were used as follows: Normal control, CCl4, CCl4 co-administered with BM-MNCs (1 × 106 in 0.1 ml PBS, i.v.), or NAC (300 mg/kg, p.o) or ALA (100 mg/kg, p.o) single or combination. Liver function was tested by measuring serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and albumin as well as interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α), malondialdehyde (MDA), total antioxidant capacity (TAC), glutathione peroxidase (Gpx), superoxide dismutase (SOD) and catalase (CAT) activities in liver homogenates. Besides that, estimation of DNA damage was performed. In addition to Micronucleus test and histopathological investigation. CCl4 treated rats showed elevation in ALT, AST, TNF-α, IL-6 and MDA accompanied by reduction in ALB, IL-10, SOD, CAT, GPx and TAC and increased the number of DNA breaks in liver tissue, showed many micronucleated polychromatic erythrocytes (MnPCEs) in bone marrow. NAC, ALA, BM-MNCs and their combination caused a reduction of ALT, AST, while, increase albumin, CAT, TAC, GPx, SOD as compared to CCl4 treated groups. Also decrease in MDA, IL-6 and TNF-α concurrently with an increase in IL-10. Moreover, BM-MNCs, NAC, ALA, and their combination decreased DNA tail %, and the count of MnPCEs. BM-MNCs combination with NAC or ALA exerted significant antioxidant, anti-inflammatory and anti-cytogenetical aberrations effect compared to each of them alone.HighlightsCCl4 elevated ALT, AST, TNF-α, IL-6 and MDACCl4 reduced ALB, IL-10, SOD, CAT, GPx and TACCCl4 increased the number of DNA breaks in liverNAC, ALA and BM-MNCs reduced ALT, AST, while, increase albumin, CAT, TAC, GPx, SODNAC, ALA and BM-MNCs decreased in MDA, IL-6 and TNF-α and increased IL-10 [Figure: see text].

Aim: Oxidative stress and inflammation are important for development of nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). High fat diet (HFD) acts as promoter and induces cancer formation by diethylnitrosamine (DEN)-initiated carcinogenesis. DEN+HFD experimental model may be suitable to investigate the relationship between diet, cirrhosis and cancer.Methods: Rats were injected with DEN (50 mg/kg/once a week; i.p.) for 4 weeks. After 15 days, rats received HFD with/without supplementations of α-lipoic acid (ALA; 2 g/kg chow), N-acetylcysteine (NAC; 1% w/v drinking water) and their combination for 12 weeks. Results: DEN+HFD-treatment resulted in increase of serum hepatic damage markers, hepatic oxidative stress parameters (lipid/protein oxidation products) and fibrotic changes. However, no HCC nodule was detected. Hepatic GST-pi and Ki-67 expressions also increased. Accordingly, DEN+HFD-treatment resulted in precancerous lesions and high rate of proliferation in the liver. NAC supplementation decreased hepatic oxidative stress and formation of fibrotic and preneoplastic lesions of DEN+HFD-treated rats. However, ALA supplementation did not have a curative effect on these lesions. No synergistic effect was seen with co-administration of ALA and NAC.Conclusions: According to present results NAC, acting as an antioxidant, has ameliorating effect on DEN+HFD-induced oxidative stress and the formation of preneoplastic lesions in liver., Amaç: Oksidatif stres ve inflamasyon steatohepatit (NASH), siroz ve hepatoselüler karsinom (HCC) gelişimi için önemlidir. Yüksek yağlı diyet (HFD) promotör görevi görür ve dietilnitrosamin (DEN) ile başlatılan karsinogenez modelinde kanser oluşumunu indükler. DEN + HFD uygulaması diyet, siroz ve kanser arasındaki ilişkiyi araştırmak için uygun bir deneysel model olabilir.Yöntemler: Sıçanlara 4 hafta boyunca DEN (haftada bir kez 50 mg / kg / i.p.) enjekte edildi. 15 gün sonra, sıçanlara HFD tek başına veya α -lipoik asit (ALA; 2 g / kg yem), N-asetilsistein (NAC; içme suyunda % 1 w/v) takviyeleri 12 hafta süreyle verildi.Bulgular: DEN + HFD uygulaması serum hepatik hasar belirteçleri ve hepatik oksidatif stres parametrelerinin (lipit/protein oksidasyon ürünleri) armasına ve fibrotik değişikliklere neden oldu. Ancak, HCC nodülü tespit edilmedi. Hepatik GST-pi ve Ki-67 ekspresyonları de artmış olarak bulunduğundan dolayı, DEN + HFD uygulaması, prekanseröz lezyonlara ve karaciğerde yüksek proliferasyon oranlarına neden oldu. NAC takviyesi, DEN + HFD ile muamele edilen sıçanların karaciğerinde oksidatif stresi ve fibrotik ve preneoplastik lezyonların oluşumunu azalttı. Bununla birlikte, ALA takviyesinin bu lezyonlar üzerinde iyileştirici bir etkisi olmamıştır. ALA ve NAC'nin birlikte uygulanmasıyla hiçbir sinerjistik etki görülmedi.Sonuçlar: Sonuçlarımıza göre, bir antioksidan olan NAC, karaciğerde DEN + HFD'nin neden olduğu artmış oksidatif stresi azaltmada ve preneoplastik lezyonların oluşumu üzerine iyileştirici etkiye sahiptir.

To investigate the effects of lipoic acid (LA) supplementation during adulthood combined with supplementation later in life or LA administration only at old age on age-induced cognitive dysfunction, mitochondrial DNA deletions, caspase 3 and antioxidant response enzymes expression in iron-treated rats. Male rats were submitted to iron treatment (30 mg/kg body wt of Carbonyl iron) from 12 to 14th post-natal days. Iron-treated rats received LA supplementation (50 mg/kg, daily) in adulthood and old age or at old age only for 21 days. Memory, mitochondrial DNA (mtDNA) complex I deletions, caspase 3 mRNA expression and antioxidant response enzymes mRNA expression were analyzed in the hippocampus. LA administration in adulthood combined with treatment later in life was able to reverse age-induced effects on object recognition and inhibitory avoidance memory, as well as on mtDNA deletions, nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression, and antioxidant enzymes disruption induced by iron in aged rats. LA treatment only at old age reversed iron-induced effects to a lesser extent when compared to the combined treatment. The present findings support the view that LA supplementation may be considered as an adjuvant against mitochondrial damage and cognitive decline related to aging and neurodegenerative disorders.

α-Lipoic acid (ALA) is widely used as a nutritional supplement and therapeutic agent in diabetes management. Well-established antioxidant and hypoglycemic effects of ALA were considered to be particularly important in combating diabetic complications including renal injury. The present study evaluated the potential of ALA to affect profibrotic events in kidney that could alter its structure and functioning. ALA was administered intraperitoneally (10 mg/kg) to nondiabetic and streptozotocin-induced diabetic male Wistar rats for 4 and 8 weeks. The effects of ALA were assessed starting from structural/morphological alterations through changes that characterize profibrotic processes, to regulation of collagen gene expression in kidney. Here, we demonstrated that ALA improved systemic glucose and urea level, reduced formation of renal advanced glycation end products (AGEs), and maintained renal structural integrity in diabetic rats. However, profibrotic events provoked in diabetes were not alleviated by ALA since collagen synthesis/deposition and expression of transforming growth factor-β1 (TGF-β1) and α-smooth muscle actin (α-SMA) remained elevated in ALA-treated diabetic rats, especially after 8 weeks of diabetes onset. Moreover, 8 weeks treatment of nondiabetic rats with ALA led to the development of profibrotic features reflected in increased collagen synthesis/deposition. Besides the TGF-β1 downstream signaling, the additional mechanism underlying the upregulation of collagen IV in nondiabetic rats treated with ALA involves decreased DNA methylation of its promoter that could arise from increased Tet1 expression. These findings emphasize the therapeutic caution in the use of ALA, especially in patients with renal diabetic complication.