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Studies on lipoate effects on blood redox state in human immunodeficiency virus infected patients
Abstract
Several investigators have implicated that human immunodeficiency virus (HIV) infected patients have a compromised antioxidant defense system. Blood antioxidants are decreased and peroxidation products of lipids and proteins are increased in the patients. This may have pathophysiological implications, because antioxidants, such as glutathione, and reactive oxidants are involved in the regulation of the human immunodeficiency virus. Consequently it was suggested that HIV infected patients may benefit from antioxidant supplementation therapy. In a open and unblinded pilot study the short term effect of the natural antioxidant lipoate (Thioctacid) on blood antioxidants and peroxidation products was investigated in HIV positive patients (CDC IV). In the majority of the patients, lipoate increased plasma ascorbate (9 of 10 patients) total glutathione (7 of 7 patients), total plasma thiol groups (8 of 9 patients); T helper lymphocytes and T helper/suppressor cell ratio (6 of 10 patients), while the lipid peroxidation products malondialdehyde (8 of 9 patients) and 4-hydroxynonenal (7 of 9 patients) were decreased. The results of this pilot study indicate that lipoate supplementation changes the blood redox state of HIV infected patients. A prospective and longitudinal therapy study is warranted to investigate the long term effects of lipoate therapy on blood redox state, disease progression and incidence of opportunistic infections in HIV infected patients.
... AIDS (Fuchs et al., 1993) Renal lithiasis ...
... Vitamin C regeneration has also been studied in organisms subjected to oxidative stress. In plasma of HIV-positive patients, Lipoic acid increased vitamin C levels (Fuchs et al., 1993). In the eye lenses of newborn rats (Maitra et al., 1995), lipoic acid prevented a decrease in vitamin C levels induced by BSO treatment. ...
1. Lipoic acid is an example of an existing drug whose therapeutic effect has been related to its antioxidant activity. 2. Antioxidant activity is a relative concept: it depends on the kind of oxidative stress and the kind of oxidizable substrate (e.g., DNA, lipid, protein). 3. In vitro, the final antioxidant activity of lipoic acid is determined by its concentration and by its antioxidant properties. Four antioxidant properties of lipoic acid have been studied: its metal chelating capacity, its ability to scavenge reactive oxygen species (ROS), its ability to regenerate endogenous antioxidants and its ability to repair oxidative damage. 4. Dihydrolipoic acid (DHLA), formed by reduction of lipoic acid, has more antioxidant properties than does lipoic acid. Both DHLA and lipoic acid have metal chelating capacity and scavenge ROS, whereas only DHLA is able to regenerate endogenous antioxidants and to repair oxidative damage. 5. As a metal chelator, lipoic acid was shown to provide antioxidant activity by chelating Fe2+ and CU2+; DHLA can do so by chelating Cd2+. 6. As scavengers of ROS, lipoic acid and DHLA display antioxidant activity in most experiments, whereas, in particular cases, pro oxidant activity has been observed. However, lipoic acid can act as an antioxidant against the pro oxidant activity produced by DHLA. 7. DHLA has the capacity to regenerate the endogenous antioxidants vitamin E, vitamin C and glutathione. 8. DHLA can provide peptide methionine sulfoxide reductase with reducing equivalents. This enhances the repair of oxidatively damaged proteins such as α-1 antiprotease. 9. Through the lipoamide dehydrogenase-dependent reduction of lipoic acid, the cell can draw on its NADH pool for antioxidant activity additionally to its NADPH pool, which is usually consumed during oxidative stress. 10. Within drug-related antioxidant pharmacology, lipoic acid is a model compound that enhances understanding of the mode of action of antioxidants in drug therapy.
... 27 Many studies have shown that oxidative stress and free oxygen radicals play an important role in the pathogenesis of viral infection, especially in hepatitis, influenza, and acquired immune deficiency syndrome. 20,25,30,31 However, there are very few studies in the literature that have examined oxidative stress in patients with measles. Although there is a limited number of studies that have explained oxidative stress in measles by different mechanisms, no study has evaluated thiol/disulfide, TAS, TOS, and OSI parameters altogether. ...
Objective:
Measles is an infectious disease, in which oxidative stress increases. Thiols are an antioxidant substance which play a critical role in programmed cell death, detoxification, and regulation of cellular enzymatic activity, and the thiol-disulfide balance is associated with some diseases. The purpose of this study was to evaluate the thiol-disulfide balance in children with measles.
Materials and methods:
This descriptive study included case and control groups. The plasma total oxidant status level was measured using the Erel method, and the groups were compared. Before the study, informed consent was obtained from patients and Ethics Committee approval was provided (No:17/Session:05, Date: May 2019). The Pearson's and Fisher's chi-square tests were applied in the comparisons of categorical data, and independent t-test/Mann-Whitney U tests were used to compare the patient and the control groups.
Results:
There were no significant differences between the patient-control groups in terms of age and gender (P > .05). The total antioxidant status value was significantly lower, and the total oxidant status and oxidative stress index values were significantly higher (P < .05) in the patient group compared to the control group. Native thiol, total thiol, and native thiol/total thiol percentage values were significantly lower, and the disulfide, disulfide/native thiol, and disulfide/total thiol percentage values were significantly higher (P < .05) in the patients compared to the controls.
Conclusions:
The detection of oxidative stress in patients with measles is important, and these results show the possibility of using the thiol/disulfide homeostasis and oxidative stress index values as biomarkers of oxidative stress in patients with measles.
... But it is imperative to have an augmented cellular antioxidant status to prolong the HSP action because both enzymatic and nonenzymatic antioxidants function in cohesion with HSPs to confer cellular thermo tolerance (Hall et al. 2001). ALA is known to modulate the redox status of the cell and often called as "universal antioxidant" (Liu et al. 2017), possessing both hydrophilic and lipophilic antioxidant properties (Fuchs et al. 1993;Packer 1998). Thus it can be stated that ALA favorably modulates HSP responses through improving cellular antioxidant and redox status (Abadi et al. 2013). ...
Ectoparasitism has a damaging impact on the economy of goat production in India, but the factors influencing its distribution and dynamics are less explored. The present study was designed to investigate the influence of environmental factors like weather and air quality parameters on the occurrence of different types of ectoparasites in goats of two agro-climatic regions of India, viz. the Upper Gangetic Plain (UGP) and the Western Himalayas (WH). The prevalence survey for ectoparasitism among goats was conducted during the four distinct climatic seasons (winter, summer, monsoon, autumn) in both the regions. The season-wise data of weather parameters (maximum & minimum temperature, relative humidity in morning & evening, sunrise & sunset time, mean daily temperature & relative humidity, daily variation in temperature & relative humidity and day length) and air quality parameters (Air Quality Index-AQI, Particulate Matter 2.5μm-PM2.5, Particulate Matter 10μm-PM10) of both the regions were analyzed in relation with the ectoparasitic prevalence pattern of corresponding regions. The results depict a noticeable correlation between the studied parameters and seasonal variation in the occurrence of each type of ectoparasites. This outcome on the interaction of studied parameters and ectoparasitism is intriguing and it opens a huge scope for future studies on the biometeorological aspects of host-parasite ecological interplay and evolutionary biology. The better understanding of climatological aspects of ectoparasite occurrences helps goat farmers in formulating appropriate timely intervention strategies for the economic control of ectoparasites, which in turn tackles ectoparasiticidal drug resistance and reduces threat of vector-borne diseases.
... But it is imperative to have an augmented cellular antioxidant status to prolong the HSP action because both enzymatic and nonenzymatic antioxidants function in cohesion with HSPs to confer cellular thermo tolerance (Hall et al. 2001). ALA is known to modulate the redox status of the cell and often called as "universal antioxidant" (Liu et al. 2017), possessing both hydrophilic and lipophilic antioxidant properties (Fuchs et al. 1993;Packer 1998). Thus it can be stated that ALA favorably modulates HSP responses through improving cellular antioxidant and redox status (Abadi et al. 2013). ...
A supplement which ameliorates temperature-humidity menace in food producing livestock is a prerequisite to develop climate smart agricultural packages. A study was conducted to investigate the heat stress ameliorative efficacy of alpha lipoic acid (ALA) in male Murrah water buffaloes (Bubalus bubalis). Eighteen animals (293.61 ± 4.66Kg Bwt) were randomly allocated into three groups (n = 6); NHSC (non-heat-stressed control), HS (heat-stressed) and HSLA (heat-stressed-supplemented with ALA@32 mg/kg Bwt orally) based on the temperature humidity index (THI) and ALA supplementation. HS and HSLA were exposed to simulated heat challenge in a climatically controlled chamber (40 °C) for 21 consecutive days, 6 h daily. Physiological responses viz. Respiration rate (RR), Pulse rate (PR) and Rectal temperature (RT) were recorded daily before and after heat exposure. Blood samples were collected at the end of heat exposure on days 1, 6, 11, 16, and 21 and on day 28 (7th day post exposure which is considered as recovery) for peripheral blood mononuclear cells (PBMCs) separation, followed by RNA and Protein extraction for Real time quantitative PCR and Western blot analysis respectively, of heat shock proteins (HSPs). Two-way repeated measure ANOVA was performed between groups at different experimental periods. RR (post exposure) in HS and HSLA was significantly higher (P < 0.05) than NHSC from day 1 onwards but HSLA varied significantly from the HS 8th day onwards. Post exposure RT and PR in both HS and HSLA varied (P < 0.05) from NHSC throughout the study; but between HS and HSLA, RT significantly varied on initial 2 days and last 6 days (from days 16 to 21). HSP70 mRNA expression significantly up regulated in high THI groups with respect to the low THI group throughout the experimental period. During chronic stress (days 16 and 21) HSP70 significantly (P < 0.05) increased in HS but not in HSLA (P > 0.05) with respect to NHSC. ALA supplementation up-regulates and sustains (P < 0.05) the expression of HSP90 in HSLA in comparison to the HS and NHSC. HSP105 expression was significantly up-regulated (P < 0.05) in HS on days 16 and 21 (during long-term exposure) but only on day 21 (P < 0.05) in HSLA. HSP70, HSP90, and HSP105 protein expression dynamics were akin to the mRNA transcript data between the study groups. In conclusion, supplementing ALA ameliorates the deleterious effect of heat stress as reflected by improved physiological and cellular responses. ALA supplementation improved cellular antioxidant status and sustained otherwise easily decaying heat shock responses which concertedly hasten the baton change from a limited window of thermo tolerance to long run acclimatization.
... These results are nearly similar to those reported by [25] who reported that, serum vitamin C and erythrocyte reduced glutathione levels reached values that were significantly higher than the untreated diabetic model after treatment with ALA. In addition, αlipoic acid can reduces oxidative stress in the body and indirectly spares or recycles or regenerates the other major antioxidants, raising their levels in the blood stream [23]. Vitamin C can be regenerated through reaction with alpha-lipoic acid [51]. ...
In the present study, the effects of alpha lipoic acid (ALA) supplementation on glycemic control, lipid
profile, vitamin C, lipid peroxidation and antioxidant enzymes in streptozotocin (STZ)-induced
diabetic rats have been evaluated. This study was carried out on 80 male rats. The rats were divided
into four equal groups of 20 rats each. Group Ι :( Control group): Injected with citrate buffer only.
Group Π: (Diabetic group): Injected with a single intraperetinoel (i.p) dose of 50 mg/kg of
streptozotocin for diabetes induction. Group III :( diabetic alpha lipoic acid treated group) and Group
IV: (control alpha lipoic acid treated group). ALA was injected intrperetinoel in a daily dose of 54
mg/kg bw. Blood samples for serum separation and liver and kidney tissues were collected from all
animal groups two times at 4 and 6 weeks from the onset of treatment with α-lipoic acid which begin
after five weeks of diabetes induction. All sera were processed directly for determination of glucose,
total cholesterol, triacylglycerols, HDL–C, LDL-C, VLDL-C and vitamin C in addition to liver and
kidney L- malondialdehyde (L- MDA) and antioxidant enzymes were also determined. The obtained
results revealed that, a significant increase in serum glucose, total cholesterol, triacylglycerols, LDLC,
VLDL-C, HDL-C, vitamin C and L-MDA concentrations in liver and kidney as well as marked
reduction in CAT, SOD and GpX activites of liver and kidney were observed in STZ-induced diabetic
rats. Treatment with ALA to STZ-induced diabetic rats lowered serum glucose, total cholesterol,
triacylglycerols, LDL-C, HDL-C concentration and lipid peroxidation of liver and kidney as well as
significantly increased serum vitamin C and liver catalase activity. These results suggest that, ALA
may be effective in controlling glycemic status and improving dyslipidemia and has the potential in
reducing cardiovascular complications due to diabetes mellitus. In addition, treatment with ALA
improved significantly the diabetes-induced deterioration of vitamin C and attenuates the status of
antioxidant enzymes and biomarkers of oxidative stress produced by diabetes mellitus.
... The results of this study show that alpha lipoic acid changes the blood redox state of HIV infected individuals. 175 Alpha lipoic acid has been found to be an effective inhibitor of HIV-1 virus replication. In cultured lymphoid T-cells, alpha lipoic acid was able to inhibit replication of the HIV virus and caused a 90% reduction in reverse transcriptase activity. ...
... 64 HNE plasma content further increased, in a statistically significant way, in patients actually suffering from AIDS, reaching values two times higher than in controls. 64,379 ...
A comprehensive focus on 4-hydroxynonenal (HNE) as candidate molecule in a variety of pathophysiological conditions occurring in humans is here provided. Despite an active, now well characterized, metabolism in most cells and tissues, HNE can be easily detected and quantified by means of several methods, although with different sensitivity. Measurements of HNE and/or stable metabolites in biological fluids are already applied as lipid peroxidation/oxidative stress markers in a huge number of human disease processes, often sustained by inflammatory reactions. A primary involvement of this aldehydic product of membrane lipid oxidation in inflammation-related events, as well as in regulation of cell proliferation and growth, in necrotic or apoptotic cell death, appears supported by its marked ability to modulate several major pathways of cell signaling and, consequently, gene expression. The actual knowledge of HNE reactivity, metabolism, signaling and modulatory effect in the various human organs should provide a solid background to the investigation of the aldehyde's contribution to the pathogenesis of human major chronic diseases and would likely promote advanced and oriented applications not only in diagnosis and prevention but also in molecular treatment of human diseases.
... [20] ...
Endometrial osseous metaplasia is a rare clinical entity. It causes infertility and occurs in more than 80% of cases after an abortion. Various theories have been proposed and the most accepted theory is metaplasia of the stromal cells into osteoblastic cells that produce bone. This disease may be misdiagnosed. However once diagnosed, the complete removal of bone spicules by hysteroscopy allows, in most cases, fertility to be restored. We present the case of a 36-year-old patient nulliparous with a history of abortion for eight years who consulted May 5, 2008 to become pregnant. Detailed examination showed chronic endometritis with bone metaplasia as a possible cause of her infertility. Seven months after complete removal of bone fragments by hysteroscopy, the patient had a spontaneous pregnancy with normal development. She gave birth to a male infant weighing 3,000 g with an Apgar score of 9 at 1 and 5 min. Delivery and postpartum were normal.
... [20] ...
Leimyomatosis peritonealis disseminata (LPD) is a benign tumor of smooth muscle tissue. It is rare and is characterized by the development of multiple peritoneal nodules mimicking peritoneal carcinomatosis. We report a case of LPD diagnosed in a 35-year-old patient, G4/P1, without any major gynecological history. The patient underwent an elective cesarean section at 42 weeks, during which numerous peritoneal nodules ranging in size from 0.1 to 0.5 cm were found. Microscopic examination showed a proliferation of smooth-muscle cells without mitosis or atypia or necrosis.
... These compounds can easily pass through the blood-brain barrier [23] and are considered potent antioxidants capable of scavenging free radicals, inducing antioxidant enzyme expression and chelating metals [22]. They have been shown to prevent oxidative stress in experimental models of a variety of disorders, such as Alzheimer and Parkinson diseases [22], ischemia-reperfusion injury [24], diabetes [25], AIDS [26], and in aging [27]. Some studies have shown an improvement on intellectual and motor performance of patients with disorders of pyruvate metabolism daily supplemented with lipoic acid [28][29][30]. ...
Phenylketonuria (PKU) is a recessive autosomal disorder caused by a severe deficiency of phenylalanine-4-hydroxilase activity which leads to the accumulation of L-phenylalanine (Phe) in the tissues and plasma of patients. The main clinical features are retarded development and intellectual impairment. Recent studies have shown that oxidative stress may be involved in neuropathology of hyperphenylalaninemia. Lipoic acid (LA) is considered a potent antioxidant which is well absorbed from diet and can easily cross the blood-brain barrier. We investigated the neuroprotective effects of lipoic acid against oxidative stress caused by Phe in vivo and in vitro. Lipoic acid prevented the inhibition provoked by Phe on the activities of catalase, superoxide dismutase, glutathione peroxidase, and glucose-6-phosphate dehydrogenase. It also prevented Phe alterations on total radical-trapping antioxidant potential, thiobarbituric acid-reactive substances, glutathione concentration and on production of reactive species. It is concluded that lipoic acid may be an efficient antioxidant in the CNS against oxidative stress induced by hyperphenylalaninemia. If the present results are confirmed in PKU patients, it is possible that supplementation of lipoic acid may contribute to the treatment of PKU as an adjuvant therapeutic approach to Phe-restricted dietary treatment and amino acid mixture.
... 11 Studies from our laboratory have shown that a -lipoic acid has a protective role against calcium oxalate stone formation in rats, 12 heavy metals-induced toxicities 13 and gentamicin-induced nephrotoxicity. 14 Other distinct features of lipoic acid includes pharmacological effectiveness in pathologies like cerebral ischemia, 15 HIV infection 16 and oxidant stress in ageing rat heart. 17 a -Lipoic acid is depicted both as a potent antioxidant and a protective agent against membraneinduced damage produced as a consequence of decreased level of glutathione. ...
The cytoprotective activity of alpha-lipoic acid against free radical toxicity manifested during adriamycin (ADR)-induced cardiotoxicity has been investigated. ADR is a potent antitumour drug known to cause severe cardiotoxicity. Although ADR generates free radicals, the role of these radicals in the development of cardiac toxicity is still not well understood. In the present study, we evaluated the influence of chronic ADR treatment on the cellular defence mechanism against free radicals and the effect of alpha-lipoic acid supplementation on ADR-induced cardiotoxicity in male Wistar rats. The increase in lipid peroxidation (LPO) and activities of serum myocardial enzymes, namely lactate dehydrogenase (LDH) and creatinephosphokinase, associated with the decrease in activities of enzymatic (SOD, CAT, GPx, G6PD and GR) and non-enzymatic (GSH, Vit C and Vit E) antioxidants levels were the salient features observed in ADR-induced cardiotoxicity. Lipoic acid pretreated groups showed significant increase in activities of both enzymatic and non-enzymatic antioxidant levels. These observations highlight the antioxidant property of alpha-lipoic acid and its cytoprotective action against ADR-induced cardiotoxicity.
... ␣-Lipoic acid (␣-LA) and its reduced form, dihydrolipoic acid (DHLA), have received considerable attention because of their activities as biological thiol antioxidants. (27) ␣-LA is widely used clinically, including in ischemiareperfusion injury, (28) diabetic neuropathy, (29) HIV infection, (30) and neurodegenerative diseases. (31) In this study, we tested whether TNF-␣-induced apoptosis of human bone marrow stromal cells (hBMSCs) is mediated by excessive ROS generation and whether ␣-LA can protect hBMSCs against TNF-␣-induced apoptosis. ...
TNF-α is an important mediator of bone loss. In the HS-5 hBMSC, TNF-α and H2O2 increased intracellular ROS levels and induced cell apoptosis through activation of caspases, JNK and NF-κB. α-Lipoic acid prevented these changes induced by TNF-α and H2O2, suggesting its potential therapeutic applications in attenuating bone loss.
Introduction: Oxidative stress is an important mediator of bone loss. TNF-α, which plays a critical role in the bone loss after menopause, has been shown to increase intracellular oxidative stress. Because oxidative stress is associated with cell death, we analyzed the apoptotic effects of TNF-α and H2O2 on human bone marrow stromal cells (hBMSCs). We also examined the protective effects of an important biological thiol antioxidant, α-lipoic acid (α-LA), against TNF-α- and H2O2-induced apoptosis.
Materials and Methods: Using the HS-5 hBMSC cell line, we tested whether TNF-α-induced apoptosis was mediated by the generation of excessive reactive oxygen species (ROS). Apoptosis was determined by 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT) assay, trypan blue exclusion assay, quantitation of histone-associated DNA fragments in cytosol, and the activation of caspases. The mechanisms mediating these apoptotic effects were determined by Western blotting and enzyme immunoassay.
Results: Both TNF-α and H2O2 increased intracellular ROS levels, reduced total cellular glutathione levels, activated caspases-3, -9, and -8, and enhanced hBMSC apoptosis. The activation of c-jun N-terminal kinase (JNK) and NF-κB mediated these apoptotic effects. Pretreatment of cells with α-LA prevented these changes induced by TNF-α and H2O2.
Conclusions: Our data show that TNF-α increases intracellular ROS in hBMSC and that TNF-α and H2O2 induce apoptosis in hBMSC through the activation of JNK and NF-κB. Our findings also suggest that α-LA may have therapeutic applications in halting or attenuating bone loss associated with increased oxidative stress.
... 374 In patients suffering from AIDS increased HNE plasma levels were found, too -with about double of normal levels. 375 ...
A comprehensive focus on 4-hydroxynonenal (HNE) as candidate molecule in a variety of pathophysiological conditions occurring in humans is here provided. Despite an active, now well characterized, metabolism in most cells and tissues, HNE can be easily detected and quantified by means of several methods, although with different sensitivity. Measurements of HNE and/or stable metabolites in biological fluids are already applied as lipid peroxidation/oxidative stress markers in a huge number of human disease processes, often sustained by inflammatory reactions. A primary involvement of this aldehydic product of membrane lipid oxidation in inflammation-related events, as well as in regulation of cell proliferation and growth, in necrotic or apoptotic cell death, appears supported by its marked ability to modulate several major pathways of cell signaling and, consequently, gene expression. The actual knowledge of HNE reactivity, metabolism, signaling and modulatory effect in the various human organs should provide a solid background to the investigation of the aldehyde's contribution to the pathogenesis of human major chronic diseases and would likely promote advanced and oriented applications not only in diagnosis and prevention but also in molecular treatment of human diseases.
... In addition, the LA/DHLA redox couple has a low potential of Ϫ320 mV, making it a powerful reductant. This reducing capacity allows DHLA to nonenzymatically regenerate GSH and vitamin C (3,15). Thus, the capacity of the LA/DHLA couple to scavenge radicals and regenerate endogenous antioxidants suggests potential benefit for treatment of IPF. ...
Lipoic acid (LA) and its reduced product dihydrolipoic acid (DHLA) are potent antioxidants with capacity to scavenge reactive oxygen species (ROS) and recycle endogenous antioxidants. LA may increase cellular glutathione (GSH), an antioxidant lacking in the lung's epithelial lining fluid in lung disorders such as idiopathic pulmonary fibrosis (IPF). Neutrophils (PMN) are key innate responders and are pivotal in clearing bacterial infection, therefore it is crucial to understand the impact LA may have on their function. Circulating neutrophils were isolated from healthy volunteers and pretreated with LA or diluent. Cells were subsequently activated with phorbol 12-myristate 13-acetate (PMA, 100 ng/ml) to induce ROS production. SOD-inhibitable reduction of acetylated cytochrome c demonstrated the PMA-dependent respiratory burst was suppressed by LA. Oxygen consumption also was diminished when PMA-stimulated cells were pretreated with LA. PMN respiratory burst was partially restored by addition of NADPH but not other pyridine nucleotides. LA did not inhibit glucose-6-phosphate dehydrogenase activity of PMN. These data together suggest that the reduction of LA to DHLA using cellular NADPH may limit the capacity of the PMN NADPH oxidase to produce superoxide. Further studies will be required to determine if LA can diminish excessive superoxide produced by PMN and/or alveolar macrophages in IPF or relevant disease models in vivo.
Oxidative stress (OS), resulting from a disrupted balance between reactive oxygen species (ROS) and protective antioxidants, is thought to play an important pathogenetic role in several diseases, including viral infections. Alpha-lipoic acid (LA) is one of the most-studied and used natural compounds, as it is endowed with a well-defined antioxidant and immunomodulatory profile. Owing to these properties, LA has been tested in several chronic immunoinflammatory conditions, such as diabetic neuropathy and metabolic syndrome. In addition, a pharmacological antiviral profile of LA is emerging, that has attracted attention on the possible use of this compound for the cotreatment of several viral infections. Here, we will review the emerging literature on the potential use of LA in viral infections, including COVID-19.
We investigated the effects of α-lipoic acid (AL) and α-tocopherol (AT) on renal histopathology in a streptozotocin (STZ) induced diabetic rat model. Adult male rats were divided into six groups: group 1, saline only; group 2, AL only; group 3, AT only; group 4, STZ only; group 5, STZ + AL; group 6 STZ + AT. Experimental diabetes was induced by STZ. AL and AT were administered for 15 days. Kidney sections were examined using a light microscope after hematoxylin and eosin (H & E), periodic acid-Schiff (PAS) and caspase-3 staining. Histological damage to glomeruli, tubule epithelial cells and basement membrane was observed in group 4. Administration of AT and AL reduced renal injury in the diabetic rats. Group 5 exhibited a greater curative effect on diabetic rats than group 6. AT and AL may be useful for preventing diabetic renal damage.
Cardiac injury is a dangerous disease and become a greater issue in the forthcoming decades. The ultimate goal is to prevent the progression of heart failure and apoptotic processes. Cardiac tissue may regenerate itself but to certain extent depending on the number of resident stem cells that is limited. Thus, research had been focused on bone marrow derived stem cells (BM-MSCs) as a promising therapy in different types of tissues, including the heart. This study is designed not only to assess the therapeutic effect of BM-MSCs but also to improve their therapeutic effect in combination with antioxidant α-lipoic acid (ALA) and antihypertensive therapeutic drug form (AP) against isoproterenol-induced cardiac injury and compared with that of BM-MSCs alone. Cardiac injury was induced in 70 male rats by Isoproterenol (ISO was injected s.c. for four consecutive days). Experimental animals were divided into six ISO-treated groups beside a control non treated one. The six ISO-treated groups were divided into: ISO group, ISO+BM-MSCs group, ISO+ALA group, ISO+AP group, ISO+ALA+AP group and ISO+ALA+AP+BM-MSCs group, the last five groups were treated with the examined materials after one week of ISO injection. Isoproterenol significantly increased serum CK-MB, LDH activities, Troponin1 and TNF-α. Oxidative stress is evidenced by the increased MDA, NO and Caspase-3 activity associated with significant reduction of GSH content and SOD activity in cardiac tissue. Furthermore, mRNA expression of NFκB and iNOS were significantly up regulated and eNOS mRNA expression was down regulated. Administration of BM-MSCs, ALA and AP alone significantly mitigated the induced cardiac injury. Concomitant administration of ALA and AP after BM-MSCs induced a more pronounced improving effect on cardiac functions. In conclusion, the concomitant administration of ALA and AP after BM-MSCs infusion increases the cellular antioxidant levels of cardiac tissue that improves the repairing function of BM-MSCs. © 2018 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM)
Freie Radikale sind Atome oder Moleküle mit einem oder mehreren unpaaren Elektronen und dadurch ausgeprägter Reaktionsfähigkeit. Vom Sauerstoffmolekül abgeleitete freie Radikale werden auch als Oxidanzien bezeichnet. Beide Begriffe werden oft synonym gebraucht, da medizinisch relevante freie Radikale meist reaktive Sauerstoffspezies oder daraus entstehende Verbindungen sind. Durch ihre extreme Reaktivität können Oxidanzien die Struktur und damit die Funktion nahezu aller Zielmoleküle verändern. Zellen können irreversibel geschädigt werden, indem Oxidanzien strukturelle Bestandteile angreifen, mit vitalen Stoffwechselprozessen interferieren oder die DNA verändern. Die extrazelluläre Inak-tivierung wichtiger Moleküle kann indirekt Schäden hervorrufen (Schraufstätter u. Cochrane 1991; Warren et al. 1991).
This chapter illustrates the essentiality of nutrition in AIDS, focusing specifically on the role of micronutrients in restoring the immune system leading to delay, deceleration, or reversal of disease progression. Human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS) have become global health crises. Despite the existence of antiretroviral (ARV) drugs, there is no cure, which indicates the need for alternative/complementary therapy. There is an intricate relationship between nutrition, HIV, and AIDS. Very early on in the AIDS epidemic, it was recognized that persons with HIV infection and AIDS have nutritional deficiencies that predispose them to disease progression. Experimental evidence generated prior to the advent of AIDS had established a clear link between nutrition, immunity, and infection. It is well known that nutritional deficiency lowers immunity and predisposes to infection. Nutritional supplementation modulates the immune system and provides resistance to infection and, hence, may provide the needed solution to this epidemic. In the case of HIV, infection has been linked to virus-induced enteropathy involving damage to the intestinal mucosa and contributing to nutrient deficiency. In turn, nutrient loss can exacerbate diarrhea, weight loss, and wasting, which are the physical symptoms associated with AIDS. Malnutrition, viral infection, and nutrient loss constitute a triumvirate, creating a vicious circle leading to immune deficiency and increased susceptibility to opportunistic infection.
Diabetes is a metabolic syndrome associated with the onset of numerous complications. Among these complications, diabetic cardiomyopathy represents one of the most common causes of death in diabetic patients. In recent years, experimental evidence has indicated a major role of reactive oxygen species (ROS) and lipid peroxidation products in the ethio-pathogenesis of diabetes and its complications. Disagreement, however, exists about the sites and mechanisms involved in ROS formation, the role of hyperglycemia in exacerbating their formation, and the effectiveness of antioxidant levels in counteracting the formation of ROS and peroxidation products. Studies from our laboratory have provided compelling evidence that type-I diabetes is associated with the endogenous production of 4-hydroxynonenal (HNE). Generated via lipid peroxidation, this highly reactive aldehyde rapidly reacts and forms stable adducts with specific proteins within the cardiac mitochondria of diabetic rats. One of the modified proteins has been successfully identified as the FAD containing subunit of succinate dehydrogenase, and the defect has been correlated to a comparable decline in succinate-supported oxygen consumption in the intact mitochondria and in complex II activity in the purified complex. The process leading to HNE production appears to be independent of glycemia level, but is strictly associated to the decline in circulating insulin level. Streptozotocin-injected animals presenting levels of circulating insulin higher than 65 pmol/L show low levels of HNE-induced modification of mitochondrial proteins and near normal oxygen consumption in intact mitochondria despite presenting hyperglycemia levels comparable to those of frankly diabetic animals (i.e. >400 mg glucose/dl). In contrast, frankly diabetic animals present endogenous circulating insulin levels below 25 pmol/L, high levels of HNE-induced modifications, and defects in mitochondrial respiration. Supplementation of the latter group of animals with exogenous insulin for a minimum of 2 weeks results in a marked decrease in HNE-mediated adducts and the restoration of succinate dehydrogenase activity to levels comparable to those observed in non-diabetic animals. The identification of two distinct pools of hyperglycemic animals that present or lack HNE-induced modifications and related mitochondrial dysfunction has provided a new rationale to explain some of the functional inconsistencies observed in mitochondria purified from various tissues of diabetic animals. Utilizing a proteomics approach, we have identified about 12 mitochondrial proteins that form stable adducts with HNE. Determining to what extent these proteins are functionally impaired by the formation of adducts with HNE will undoubtedly help to shed light on the role of mitochondrial impairment in the onset of diabetic cardiomyopathy.
The tripeptide thiol glutathione (GSH) has facile electron-donating capacity, linked to its sulfhydryl (-SH) group. Glutathione is an important water-phase antioxidant and essential cofactor for antioxidant enzymes; it provides protection also for the mitochondria against endogenous oxygen radicals. Its high electron-donating capacity combined with its high intracellular concentration endows GSH with great reducing power, which is used to regulate a complex thiol-exchange system (-SH ⇋ -S-S-). This functions at all levels of cell activity, from the relatively simple (circulating cysteine/SH thiols, ascorbate, other small molecules) to the most complex (cellular-SH proteins). Glutathione is homeostatically controlled, both inside the cell and outside. Enzyme systems synthesize it, utilize it, and regenerate it as per the gamma-glutamyl cycle. Glutathione is most concentrated in the liver (10 mM), where the ©P450 Phase II" enzymes require it to convert fat-soluble substances into water-soluble GSH conjugates, in order to facilitate their excretion. While providing GSH for their specific needs, the liver parenchymal cells export GSH to the outside, where it serves as systemic source of -SH/reducing power. GSH depletion leads to cell death, and has been documented in many degenerative conditions. Mitochondrial GSH depletion may be the ultimate factor determining vulnerability to oxidant attack. Oral ascorbate helps conserve GSH; cysteine is not a safe oral supplement, and of all the oral GSH precursors probably the least flawed and most cost-effective is MAC (N-acetylcysteine).
Export Date: 18 October 2014
alpha -Lipoic acid (LA) and its corresponding derivative, a-lipoamide (LM), have been described as antioxidants, but the mechanisms of their putative antioxidant effects remain largely uncharacterised. The vicinal thiols present in the reduced forms of these compounds suggest that they might possess metal chelating properties. We have shown previously that cell death caused by oxidants may be initiated by lysosomal rupture and that this latter event may involve intralysosomal iron which catalyzes Fenton-type chemistry and resultant peroxidative damage to lysosomal membranes. Here, using cultured J774 cells as a model, we show that both LA and LM stabilize lysosomes against oxidative stress, probably by chelating intralysosomal iron and, consequently, preventing intralysosomal Fenton reactions. In preventing oxidant-mediated apoptosis, LM is significantly more effective than LA, as would be expected from their differing capacities to enter cells and concentrate within the acidic lysosomal compartment. As previously reported, the powerful iron-chelator, desferrioxamine (Des) (which also locates within the lysosomal compartment), also provides protection against oxidant-mediated cell death. Interestingly, although Des enhances the partial protection afforded by LA, it confers no additional protection when added with LM. Therefore, the antioxidant actions of LA and LM may arise from intralysosomal iron chelation, with LM being more effective in this regard.
Cadmium as an environmental pollutant has aroused great concern due to its toxic effects on various body tissues. Supplementation of thiol compounds has been suggested to protect against the toxic effects of reduced oxygen species by contributing to the thiol pool of the cell. The present study was designed to determine whether dietary supplementation of DL α-lipoic acid (15 and 30 mg/kg), a “meta-vitamin,” to cadmium-intoxicated rats (3 mg/kg) affords protection against the oxidative stress caused by the metal. The liver and kidney of the metal-administered rats showed elevated levels of hydroxyl radicals and malondialdehyde (basal and induced), a decreased level of antioxidants-reduced glutathione, total thiols, protein thiols, nonprotein thiols, ascorbate, α-tocopherol and retinol and antioxidizing enzymes-superoxide dismutase, catalase, τ-glutamyl transpeptidase, glutathione peroxidase, glucose-6-phosphate dehydrogenase, glutathione reductase, and glutathione-S-transferase. Lipoate supplementation changed the tissue redox state directly by scavenging the free radicals and indirectly by bolstering the antioxidants and antioxidizing enzyme defenses. In vitro studies revealed that, among the mono and dithiols (glutathione, cysteine, dithiothreitol, and lipoic acid), lipoic acid was the most potent scavenger of free radicals produced during cadmium-induced hepatotoxicity. The drug contributes its thiol groups to detoxify the divalent metal and subsequently ameliorates the cell membrane integrity.
Oxidative stress impacts many age-related degenerative processes, such as in postmenopausal bone loss and in antioxidant defenses that are significantly decreased in elderly osteoporotic women. The authors evaluated the effect of oral supplementation with antioxidant agents containing alpha lipoic acid (ALA) on bone mineral density (BMD) of osteopenic postmenopausal women.
Fifty postmenopausal women with osteopenia (-2.5 < T-score < -1) were prospectively enrolled and randomly assigned to orally receive ALA and other antioxidant agents (vitamin C, vitamin E, and selenium) plus calcium and vitamin D3 (n = 25), or only calcium and vitamin D3 (n = 25). The BMD was estimated at baseline and after 12 months of treatment by heel quantitative ultrasonometry (QUS).
Forty-four patients completed the one-year study: 23 in the ALA group, 21 in the control group. The treatment of ALA group led to a better estimated BMD compared to the control group (0.401 +/- 0.026 vs 0.388 +/- 0.025 g/cm2), although this difference barely achieved a statistical significance (p = 0.048).
These findings, although in a small population, could suggest that oral supplementation with antioxidant agents containing ALA may mitigate bone loss in osteopenic postmenopausal women.
Background: There has been an increase in the number of adults seeking liver transplantation for hepatitis C in the last few years and the count is going up rapidly. There is no reliable and effective therapy for chronic hepatitis C since interferon and antivirals work no more than 30% of the time, and liver transplant surgery is uncertain and tentative over the long run. This is because, ultimately, residual hepatitis C viremia infects the new liver. Furthermore, liver transplantation can be painful, disabling and extremely costly.
Modulation of cellular thiols is an effective therapeutic strategy, particularly in the treatment of AIDS. Lipoic acid, a metabolic antioxidant, functions as a redox modulator and has proven clinically beneficial effects. It is also used as a dietary supplement. We utilized the specific capabilities of N-ethylmaleimide to block total cellular thiols, phenylarsine oxide to block vicinal dithiols, and buthionine sulfoximine to deplete cellular GSH to flow cytometrically investigate how these thiol pools are influenced by exogenous lipoate treatment. Low concentrations of lipoate and its analogue lipoamide increased Jurkat cell GSH in a dose-dependent manner between 10 (25 μM for lipoamide) to 100 μM. This was also observed in mitogenically stimulated peripheral blood lymphocytes (PBL). Studies with Jurkat cells and its Wurzburg subclone showed that lipoate dependent increase in cellular GSH was similar in CD4+ and − cells. Chronic (16 week) exposure of cells to lipoate resulted in further increase of total cellular thiols, vicinal dithiols, and GSH. High concentration (2 and 5 mM) of lipoate exhibited cell shrinkage, thiol depletion, and DNA fragmentation effects. Based on similar effects of octanoic acid, the cytotoxic effects of lipoate at high concentration could be attributed to its fatty acid structure. In certain diseases such as AIDS and cancer, elevated plasma glutamate lowers cellular GSH by inhibiting cystine uptake. Low concentrations of lipoate and lipoamide were able to bypass the adverse effect of elevated extracellular glutamate. A heterogeneity in the thiol status of PBL was observed. Lipoate, lipoamide, or N-acetylcysteine corrected the deficient thiol status of cell subpopulations. Hence, the favorable effects of low concentrations of lipoate treatment appears clinically relevant. © 1997 Elsevier Science Inc.
This study was designed to examine the cardioprotective effects of alpha-lipoic acid and amlodipine against isoproterenol-induced myocardial infarction in rats. Electrocardiograph parameters were monitored, diagnostic cardiac marker enzymes and myocardial antioxidative parameters were measured. Histopathological examination of heart tissues was also performed. Subcutaneous injection of isoproterenol (85 mg/kg at 24 h intervals for 2 days) to male Wistar rats induced marked alterations in ECG-patterns, as well as significant increases in serum level of creatine phosphokinase–MB (CPK-MB), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Moreover, the level of myocardial thiobarbituric acid-reactive substances was significantly increased, while reduced glutathione content and the activities of antiperoxidative enzymes [catalase and superoxide dismutase] in heart tissue were significantly decreased. Daily pre-treatment with either alpha-lipoic acid (100 mg/kg p.o.) or amlodipine (5.0 mg/kg p.o.) for respective periods of 15 or 7 days altered almost all of the above mentioned myocardial changes induced by isoproterenol. Meanwhile, the combination of alpha-lipoic acid and amlodipine significantly reduced isoproterenol-induced elevations in diagnostic marker enzyme levels and almost restored normal ECG-patterns in experimental animals. In addition, this combination exerted a synergistic antioxidant effect by blocking the induction of lipid peroxidation. The same combination also prevented isoproterenol-induced alterations in the level of reduced glutathione and the activities of antiperoxidative enzymes. Histopathological observations were found to support these biochemical results. These findings indicate that alpha-lipoic acid and amlodipine exerted a synergistic cardioprotective effect on acute myocardial infarction induced by isoproterenol in rats.
alpha-Lipoic acid, which plays an essential role in mitochondrial dehydrogenase reactions, has recently gained considerable attention as an antioxidant. Lipoate, or its reduced form, dihydrolipoate, reacts with reactive oxygen species such as superoxide radicals, hydroxyl radicals, hypochlorous acid, peroxyl radicals, and singlet oxygen. It also protects membranes by interacting with vitamin C and glutathione, which may in turn recycle vitamin E. In addition to its antioxidant activities, dihydrolipoate may exert prooxidant actions through reduction of iron. alpha-Lipoic acid administration has been shown to be beneficial in a number of oxidative stress models such as ischemia-reperfusion injury, diabetes (both alpha-lipoic acid and dihydrolipoic acid exhibit hydrophobic binding to proteins such as albumin, which can prevent glycation reactions), cataract formation, HIV activation, neurodegeneration, and radiation injury. Furthermore, lipoate can function as a redox regulator of proteins such as myoglobin, prolactin, thioredoxin and NF-kappa B transcription factor. We review the properties of lipoate in terms of (1) reactions with reactive oxygen species; (2) interactions with other antioxidants; (3) beneficial effects in oxidative stress models or clinical conditions.
The effect of 4-hydroxynonenal (4-HNE), a circulating lipid peroxidation product, on the vascular tone of human mesenteric arteries is studied. 4-HNE promotes relaxation of human mesenteric arterial rings in a concentration-dependent manner. Removal of the endothelium or treatment with N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME; 10(-4) M) partially prevented 4-HNE-induced relaxation, thus suggesting the intervention of nitric oxide from endothelial origin in the vascular effects of 4-HNE.
Lipoic acid (thiotic acid) is being used as a dietary supplement, and as a therapeutic agent, and is reported to have beneficial effects in disorders associated with oxidative stress, but its mechanism of action remains unclear. We present evidence that lipoic acid induces a substantial increase in cellular reduced glutathione in cultured human Jurkat T cells human erythrocytes, C6 glial cells, NB41A3 neuroblastoma cells, and peripheral blood lymphocytes. The effect depends on metabolic reduction of lipoic acid to dihydrolipoic acid. Dihydrolipoic acid is released into the culture medium where it reduces cystine. Cysteine thus formed is readily taken up by the neutral amino acid transport system and utilized for glutathione synthesis. By this mechanism lipoic acid enables cystine to bypass the xc- transport system, which is weakly expressed in lymphocytes and inhibited by glutamate. Thereby lipoic acid enables the key enzyme of glutathione synthesis, gamma-glutamylcysteine synthetase, which is regulated by uptake-limited cysteine supply, to work at optimum conditions. Flow cytometric analysis of freshly prepared human peripheral blood lymphocytes, using monobromobimane labeling of cellular thiols, reveals that lipoic acid acts mainly to normalize a subpopulation of cells severely compromised in thiol status rather than to increase thiol content beyond physiological levels. Hence lipoic acid may have clinical relevance in restoration of severely glutathione deficient cells.
Lipid peroxidation (LPO) is a free radical-related process that in biologic systems may occur under enzymatic control, e.g., for the generation of lipid-derived inflammatory mediators, or nonenzymatically. This latter form is associated mostly with cellular damage as a result of oxidative stress, which also involves cellular antioxidants in this process. This article focuses on the relevance of two LPO products, malondialdehyde (MDA) and 4-hydroxynonenal (HNE), to the pathophysiology of human disease. The former has been studied in human serum samples of hepatitis C virus-infected adults and human immunodeficiency virus-infected children. In these two cases it is shown that the specific assay of serum MDA is useful for the clinical management of these patients. The presence of MDA in subretinal fluid of patients with retinal detachment suggests the involvement of oxidative stress in this process. Moreover, we were able to report the dependence of this involvement on the degree of myopia in these patients. The assay of MDA contents in the peripheral nerves of rats fed a chronic alcohol-containing diet or diabetic mice also confirms the pathophysiologic role of oxidative stress in these experimental models. In these two cases, associated with an increase in tissue LPO products content, we detected a decrease of glutathione peroxidase (GSHPx) activity in peripheral nerve, among other modifications. We have demonstrated that in vitro HNE is able to inhibit GSHPx activity in an apparent competitive manner, and that glutathione may partially protect and/or prevent this inactivation. The accumulation of LPO products in the brain of patients with Alzheimer's disease has also been described, and it is on the basis of this observation that we have tried to elucidate the role of oxidative stress and cellular antioxidants in beta-amyloid-induced apoptotic cell death of rat embryo neurons. Finally, we discuss the possible role of the observed vascular effects of HNE on human arteries.
The role of antioxidants in preventing apoptosis and viral activation in HIV is well documented. N-acetylcysteine, glutathione, and alpha-lipoic acid have been shown to interrupt the process of viral activation and CD4 cell death. L-glutamine has been shown to improve glutathione levels and significantly increase lean body mass in HIV infection. The literature on the use of L-carnitine and acetyl-L-carnitine in treating mitochondrial toxicity, both in muscle and nerve pathologies is relevant in nutritional treatment of HIV, given the mitochondrial toxicity of nucleoside analog reverse transcriptase inhibitor therapy. The current use of highly active antiviral therapies, their toxicity, and significant failure rates have created the need for a more conservative reassessment of HIV treatment. The adjunctive use of nutrient therapy in the treatment of HIV is reviewed here.
Even in the era of highly active antiretroviral therapy, AIDS dementia remains an important and devastating complication of human immunodeficiency virus (HIV-1) infection. Based on the 1997 AIDS case rate of 56 per 100 000 population in the USA, a reasonable estimated incidence of AIDS dementia is 3-8 per 100000, similar to that of multiple sclerosis. The pharmacology of AIDS dementia has been dominated by antiretroviral therapies, the best studied of which is azidothymidine. New and specific therapies are needed to treat and prevent brain injury in the setting of HIV infection. Rational therapy has been limited by the absence of large, adequate and well-controlled clinical trials using neuroprotective agents or those with disease-modifying potential, as well as by an incomplete understanding of the pathophysiology of AIDS dementia. In this review, a summary of evidence-based hypotheses of HIV-associated brain injury is followed by information on current nonantiretroviral therapeutic trials and their scientific rationale.
Thiols represent preferential targets of peroxynitrite in biological systems. In this work, we investigated the mechanisms and kinetics of the reaction of peroxynitrite with the dithiol dihydrolipoic acid (DHLA) and its oxidized form, lipoic acid (LA). Peroxynitrite reacted with DHLA being oxidation yields higher at alkaline pH. The stoichiometry for the reaction was two thiols oxidized per peroxynitrite. LA formation accounted for approximately 50% DHLA consumption at pH 7.4, probably reflecting secondary reactions between LA and peroxynitrite. Indeed, peroxynitrous acid reacted with LA with an apparent second-order rate constant (k(2app)) of 1400 M(-1) s(-1) at pH 7.4 and 37 degrees C. Nitrite and LA-thiosufinate were formed as reaction products. Surprisingly, the k(2app) for peroxynitrite-dependent DHLA oxidation was only 250 M(-1) s(-1) per thiol, at pH 7.4 and 37 degrees C. Testing various low-molecular-weight thiols, we found that an increase in the thiol pK (pK(SH)) value correlated with a decrease of k(2app) for the reaction with peroxynitrite at pH 7.4. The pK(SH) for DHLA is 10.7, in agreement with its modest reactivity with peroxynitrite.
Increased oxidative stress and impaired antioxidant defense mechanisms are important factors in the pathogenesis and progression of diabetes mellitus and other oxidant-related diseases. This study was designed to determine whether alpha-lipoic acid, which has been shown to have substantial antioxidant properties, when administered (10 mg/kg ip) once daily for 14 days to normal and diabetic female Sprague-Dawley rats would prevent diabetes-induced changes in biomarkers of oxidative stress in liver, kidney and heart. Serum glucose concentrations, aspartate aminotransferase activity, and glycated hemoglobin levels, which were increased in diabetes, were not significantly altered by alpha-lipoic acid treatment. Normal rats treated with a high dose of alpha-lipoic acid (50 mg/kg) survived but diabetic rats on similar treatment died during the course of the experiment. The activity of glutathione peroxidase was increased in livers of normal rats treated with alpha-lipoic acid, but decreased in diabetic rats after alpha-lipoic acid treatment. Hepatic catalase activity was decreased in both normal and diabetic rats after alpha-lipoic acid treatment. Concentrations of reduced glutathione and glutathione disulfide in liver were increased after alpha-lipoic acid treatment of normal rats, but were not altered in diabetics. In kidney, glutathione peroxidase activity was elevated in diabetic rats, and in both normal and diabetic animals after alpha-lipoic acid treatment. Superoxide dismutase activity in heart was decreased in diabetic rats but normalized after treatment with alpha-lipoic acid; other cardiac enzyme activities were not influenced by either diabetes or antioxidant treatment. These results suggest that after 14 days of treatment with an appropriate pharmacological dose, alpha-lipoic acid may reduce oxidative stress in STZ-induced diabetic rats, perhaps by modulating the thiol status of the cells.
The Nuclear Factor Kappa B (NF-kappaB) is a lymphoid-specific transcription factor, which is sequestered in the cytoplasm by the protein IkappaB. NF-kappaB plays a major role in the regulation of HIV-1 gene expression. Upon activation, NF-kappaB is released from IkappaB, moves to the nucleus, and binds to its sites on the HIV long terminal repeat to start transcription of integrated HIV genome. The present review focuses on the NF-kappaB as a potential target for the development of chemotherapy against HIV-1. Beginning from the viral-binding to reverse transcription, integration, and gene expression, to the virion maturation, the life cycle of HIV presents drug-targets at all the stages. As a result, many drugs have been developed and have entered clinical trials. Some of the most important of these are reverse transcriptase and protease inhibitors, which have been used mostly in clinical studies in the form of combined therapy. But, this combined therapy has presented the problem of resistance, due to mutations in the virus. However, targeting NF-kappaB for the suppression of virus does not present the problem of resistance, as NF-kappaB is a normal part of the human T-4 cell, and is not subject to mutations, as is the virus. An overview of the NF-kappaB system and its role in HIV-1 is presented, followed by a critical review of its current and potential synthetic inhibitors. The drugs studied against NF-kappaB fall mainly into three categories: (1) Antioxidants, against oxidative stress conditions, which aid in NF-kappaB activation, (2) IkappaB phosphorylation and degradation inhibitors (the phosphorylation and degradation of IkappaB is necessary to make NF-kappaB free and move to the nucleus), and (3) NF-kappaB DNA binding inhibitors. The antioxidants include N-Acetyl-L-cysteine (NAC), alpha-Lipoic acid, glutathione monoester, pyrrolidine dithiocarbamate, and tepoxalin, of which NAC is the best studied. The IkappaB phosphorylation and degradation inhibitors, which have been studied in the context of HIV-1 include the salicylates (sodium salicylate, and acetylsalicylic acid (aspirin)). Finally, the NF-kappaB DNA binding inhibitors, which have received attention only recently, are reviewed. These include the most potential, aurine tricarboxylic acid (ATA), a chelating agent, which has been found to inhibit NF-kappaB DNA binding at a low concentration of 30 micro M. The probable mechanism of action of these drugs is discussed alongwith relevant suggestions and conclusions.
Impaired antioxidant defense mechanisms and oxidative stress are implicated in the pathogenesis of arsenic toxicity. Our study was designed to determine whether alpha-lipoic acid, which has been shown to have substantial antioxidant properties, when administered (70 mg/kg body weight) once daily for 60 days along with arsenic (100 ppm sodium arsenite mixed in drinking water) would prevent arsenic-induced changes in antioxidant defense system, superoxide dismutase (SOD-total SOD, Mn SOD, Cu/Zn SOD), catalase (CAT) and glutathione peroxidase (GSH-PX) in rat brain regions such as cortex, hypothalamus, striatum, cerebellum and hippocampus. The present study also examined the effect of alpha-lipoic acid over arsenic-induced oxidant production and lipid peroxidation level (LPO) in discrete brain regions of rats. The cortex, striatum and hippocampus showed greater decreases in GSH-Px enzyme activity than cerebellum and hypothalamus with arsenic exposure. Striatum had the greatest percentage of decreased activities of total SOD and Mn SOD, whereas cortex had the greatest percentage decrease in the activity of Cu/Zn SOD in arsenic-alone treated rats. Hypothalamus and cerebellum exhibited the lowest catalase activity among all tested regions in arsenic-only treated rats. Rate of dichlorofluorescin oxidation, an indication of reactive oxygen species and other intracellular oxidants production was increased with arsenic exposure in all brain regions studied. Cortex, hippocampus and striatum exhibited greater increase of LPO levels than cerebellum and hypothalamus. SOD, CAT, GSH-Px activities were upregulated in arsenic plus lipoic acid treated versus arsenic-only treated rats. Also, simultaneous lipoic acid treatment along with arsenic proved to be sufficient in reducing oxidant production and LPO level in all rat brain regions. Our results demonstrate that arsenic-induced deficits in antioxidant enzyme activities and increase in oxidant production and lipid peroxidation level in brain regions can be overcome through simultaneous treatment with lipoic acid.
To determine whether supplementation with alpha-lipoic acid (ALA), a glutathione-replenishing disulfide, modulates whole blood total glutathione (GSH + GSSG) levels and improves lymphocyte function in human immunodeficiency virus (HIV)-infected subjects with history of unresponsiveness to highly active antiretroviral treatment (HAART).
Randomized, double-blinded, placebo-controlled trial conducted at two study sites: an eye clinic at a county hospital in San Jose and a research clinic in San Francisco, California.
A total of 33 HIV-infected men and women with viral load >10,000 copies/cm(3), despite HAART, aged 44-47 years, approximately 36% nonwhite, were enrolled.
Patients were randomly assigned to receive either ALA (300 mg three times a day) or matching placebo for 6 months.
The change over 6 months in blood total glutathione status, lymphocyte proliferation response to T-cell mitogens, CD4 cell count, and viral load in patients receiving ALA compared to placebo.
The mean blood total glutathione level in ALA-supplemented subjects was significantly elevated after 6 months (1.34+/-0.79 vs. 0.81+/-0.18 mmol/L) compared to insignificant change (0.76+/-0.34 vs. 0.76+/-0.22 mmol/L) in the placebo group (ALA vs. placebo: p=0.04). The lymphocyte proliferation response was significantly enhanced or stabilized after 6 months of ALA supplementation compared to progressive decline in the placebo group (ALA vs. placebo: p<0.001 with phytohemagglutinin; p=0.02 with anti-CD3 monoclonal antibody). A positive correlation was seen between blood total glutathione level and lymphocyte response to anti-CD3 stimulation (R(2)=0.889). There was no significant change in either HIV RNA level or CD4 count over 6 months in the ALA-supplemented compared to the control group.
Supplementation with alpha-lipoic acid may positively impact patients with HIV and acquired immune deficiency syndrome by restoring blood total glutathione level and improving functional reactivity of lymphocytes to T-cell mitogens.
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