Heatmaps of the leading-edge genes of the HSC cluster genes showed that ALA up-regulated HSC maintenance-related gene NR4A2 35 and lymphocyte development-related genes NFAT5 36 and NFATC2 NFAT1 37 Fig.

While the NUPHOXA9 pathway is more related to myeloid leukemia development, heatmaps of leading-edge genes of NUPUHOXA9 target genes showed that ALA did not up-regulate the leukemia development-related genes MESI1 , PBX3 , 38 and MLL KMT2A , 39 but upregulated HOXA9 , which plays an important role in the hematopoietic commitment of hESCs 40 and in HSC self-renewal 41 Fig.

These results indicated that ALA might promote hematopoiesis. ALA upregulates hematopoiesis- and oxygen response-related genes and inhibits apoptosis of human umbilical vein endothelial cells induced by high glucose. The results indicated that ALA did not improve the percentage of viable hemogenic endothelium cells Supplementary Fig.

S3A and B. The results indicated that the positive regulating endothelial-to-hematopoietic transition genes RUNX1 , GFI1 , GFI1B , HIFIA , MEIS2 , and CBFB were up-regulated Fig.

The endothelial-to-hematopoietic transition negative regulating genes SOX17 , NOTCH1 , TGFB1 , TGFB2 , TGFB3 , TGFBR1 , and TGFBR2 were down-regulated Fig. These results indicate that ALA might promote the endothelial-to-hematopoietic transition by changing the expression of endothelial-to-hematopoietic transition related genes.

Together, these results indicate that ALA promotes endothelial-to-hematopoietic transition by up-regulating endothelial-to-hematopoietic transition positive regulating genes and down-regulating endothelial-to-hematopoietic transition negative regulating genes.

ALA promotes endothelial-to-hematopoietic transition progress. Heatmaps show the expression of endothelial-to-hematopoietic transition positive regulated genes A and endothelial-to-hematopoietic transition negative regulated genes B.

Sorted hemogenic endothelium cells were seeded onto AGM-S3 stroma cells and cultured for 4 days. Numbers in quadrants indicate percentages. E Heatmaps represent the expression of ROS sensor-responsive genes. G Mean fluorescence intensity MFI was calculated. Each symbol C and G represents an individual replicate; small horizontal lines indicate the mean ± sd.

Columns represent the indicated replicates of each population A, B , and E. The data in the bar graphs in C , and G are presented as the mean ± sd. In addition, ALA activated the oxidative stress response pathway Supplementary Fig.

S3F , upregulated crucial regulators of ROS and redox sensor molecules that associated with HSC normal function, 11 namely HIF1A , FOXO1 , FOXO3 , MTOR , ATM , PTEN , TSC1 , SIRT1 , and AKT2 Fig. The results showed that ALA significantly reduced the percentage of early apoptotic cells 4.

In addition, we used RT-PCR to check the expression levels of genes related to ROS and apoptosis. First, we performed RT-PCR to detect ROS-related genes HIF1A and FOXO3 , which were up-regulated in hemogenic endothelium cells Fig.

As ROS downstream effect genes, P53 , P16 , and P21 trigger cell differentiation and senescence in HSCs. B Mean fluorescence intensity MFI of ROS DCFH-DA was calculated.

D The percentages of live cells, early apoptosis E-apoptosis , late apoptosis L-apoptosis , and cell death were calculated. Data in the bar graphs in B and D—F are presented as the mean ± sd. The results showed that ALA significantly up-regulated the protein expression of both HIF1A Fig.

In short, the decreasing of ROS up-regulated HIF1A and P53 to inhibit cell cycle and cell apoptosis. The results indicated that there were scarcely human blood cells were detected in the peripheral blood of NSG mice data do not show.

The results indicated that ALA significantly inhibited the cell cycle progress Supplementary Fig. S4A and B and reduced ROS level Supplementary Fig.

Sequentially, we used CFU assay and in vivo transplantation system to assay the effect of ALA exerting on HSCs Fig. We isolated the nucleated cells from cord blood and then cultured for 7 days using SFEMII culture medium with ALA treatment or not.

CFU assay was performed to reveal the differentiation potential of Ctrl or ALA-treated cultures. At the same time, the components of hematopoietic stem or progenitor cells were analyzed by flow cytometry. We conducted flow cytometry to analysis the chimerism of human blood cells in the recipient mice peripheral blood at 3 months post transplantation.

The results indicated that ALA-treated cultures contributed significantly higher percentages of chimerism in mice peripheral blood compared to Ctrl cultures 1.

However, based on the effects that ALA affects the cell proliferation and ROS level of hematopoietic stem and progenitor cells Supplementary Fig. All these results suggested that ALA can maintains HSCs function partially through inhibiting cell cycle and decreasing ROS level in ex vivo culture.

ALA maintained functional HSC in ex vivo culture. A Strategy of analysis the effect of ALA exerted on HSC. B CFU assay of Ctrl or ALA-treated cultures with 7 days ex vivo culture.

Total nucleated cells of cord blood were used as input cells for ex vivo culture. Five hundred total cells derived from Ctrl or ALA-treated cultures were used for CFU assay, and absolute colony numbers were counted on day E Representative flow cytometry plots of human blood cells chimerism at 3 months post-transplantation.

Fresh cord blood nucleated cells, Ctrl cultures, and ALA-treated cultures were transplanted into 1. F Statistic analysis the percentages of donor derived cells at 3 months post-transplantation. Each point indicates an individual recipient.

The data in the bar graphs in B, D , and F are presented as the mean ± sd. In this study, we used an in vitro coculture system to provide a new insight into the effects of ALA on hPSCs hematopoiesis.

At early coculture stages, a high proportion of hemogenic endothelium cells with a low level of ROS was observed in ALA-treated cocultures, suggesting that ALA may promote development of hemogenic endothelium cells by modulating the ROS level.

Transcriptome analysis of hemogenic endothelium cells indicated that ALA up-regulates genes promoting hematopoietic commitment, such as RUNX1 , GFI1 , GFI1B , MEIS2 , and HOXA9 , 43 , 45 , 47 and down-regulates signals in TGFβ pathways that negatively regulate endothelial-to-hematopoietic transition.

Among ALA up-regulated transcription factors, HIF1A , RUNX1 , GFI1 , GFI1B , and HOXA9 are crucial factors involved in modulating hemogenic endothelial cells development.

As reported previously, HIF1A acts as an upstream regulator of RUNX1 and NOTCH signaling, 46 and GFI1 and GFI1B act as downstream targets of RUNX1. ALA also significantly up-regulated the protein expression of both HIF1A Fig. In short, ALA decreased of ROS to up-regulated HIF1A and up-regulated P53 to inhibit cell cycle and cell apoptosis.

Throughout the current study, we showed the role of ALA of affecting hematopoietic development or function by regulating ROS. The effect of ALA exerted on hematopoietic differentiation of human embryonic stem cells in three stages.

This observation is reminiscent of a previous report showing that modulation of ROS signaling affects development of primitive hematopoietic progenitors from hPSCs.

Particularly, ALA treatment allows observation of the mechanism by which ROS signals control early events during developmental hematopoiesis from hPSCs, which can never be mimicked using adult-type HSCs. Thus, ALA treatment might have the potential use in promoting in vitro expansion and maintenance of adult HSCs for clinical transplantation.

Subsequently, both ex vivo and in vivo experiments were performed to assay the effect of ALA exerted on human cord blood HSCs. These results confirmed that ALA efficiently maintained functional HSCs in ex vivo culture. In summary, ALA could be added to hematopoietic differentiation systems to study development of HSCs from hPSCs.

and J. performed the core experiments and data analysis. performed some of the experiments. and F. designed the project, discussed the data, and wrote the manuscript. approved the manuscript. contributed equally to this study. This research was supported by the China Postdoctoral Fund Program Grand M and the CAMS Initiatives for Innovative Medicine I2M, I2M, I2M Wielockx B , Grinenko T , Mirtschink P , et al.

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Nat Commun. Vargel O , Zhang Y , Kosim K , et al. It is also promptly removed, with a mean plasma elimination half-life of 0. Exogenous racemic mixture of α-lipoic acid is orally administered for therapeutic treatment of diabetic polyneuropathy and demonstrated that completely absorbed by gastrointestinal tract and limited absolute bioavailability by hepatic extraction.

The racemic misture of α-lipoic acid mg administered daily in 9 healthy volunteers and observed the metabolites S -methylated β-oxidation products 4,6-bismethylthio-hexanoic acid and 2,4-bismethylthio-butanoic acid confirmed by HPLC-electrochemical assay Teichert et al.

Several studies have provided facts that acts as a biological antioxidant and plays a leading function in cellular growth due to its ability to scavenge reactive oxygen species and renew endogenous antioxidants Attia et al.

Numerous women suffer from breast cancer every year and though this disease is lethal, there is a need for new therapeutic approaches which surpasses the shortcomings of the present treatments Kumar et al. α-Lipoic acid inhibits cell proliferation via the epidermal growth factor receptor EGFR and the protein kinase B PKB , also known as the Akt signaling, and induces apoptosis in human breast cancer cells Na et al.

α-Lipoic acid drives pyruvate dehydrogenase by downregulating aerobic glycolysis and activation of apoptosis in breast cancer cells, lactate production, induces apoptosis, and diminishes cell viability, implying that the inadequate uptake might be due to reduced cell death caused by α-lipoic acid Feuerecker et al.

Most basic symptoms of colon cancer are rectal bleeding and anemia. These symptoms sum up and lead to changes in bowel habits and weight loss, with a complication of uncontrolled cell growth in the colon, leading to colorectal cancer which is the third most diagnosed cancer in the world Malgras et al.

Dihydrolipoic acid scavenges the cytosolic oxygen in HT human colon cancer cells; furthermore, it escalates in a dose-dependent manner the caspaselike activity associated with DNA fragmentation. It was concluded that α-lipoic acid induces apoptosis by a pro-oxidant mechanism triggered by an escalated uptake of mitochondrial substrates in oxidizable form Wenzel et al.

This involves monocarboxylates uptake amplification in mitochondria through glycolysis after their oxidation into the citric acid cycle, and then the increased depletion equivalents delivery into the respiratory chain drastically increases the production of mitochondrial oxygen.

This high oxygen burden overcomes the high antioxidative capacity of anti-apoptotic proteins and allows apoptosis to be executed in tumor cells Kang et al. Lifestyle modification in daily activity and diet pattern is the foundation of an effective strategy to improve metabolic disorders and reduce obesity.

α-Lipoic acid shows a wide array of metabolic benefits, including glucose lowering, anti-obesity, lipid lowering, and an insulin sensitizing effect Carrier and Rideout α-Lipoic acid and coenzyme Q10 prevent apoptosis and degeneration of dorsal root ganglion DRG neurons mediated by regulation of uncoupling protein 2 UCP2 and caspase-3 expression, inducing ATP and improving diabetic neuropathy induced changes in DRG neurons Galeshkalami et al.

It is used in the treatment of diabetic polyneuropathy and insulin resistance Bustamante et al. According to a clinical study, α-lipoic acid supplementation reduces body weight and body mass index Namazi et al.

The combination of curcumin and α-lipoic acid reduces weight gain and adiposity. α-Lipoic acid helps in regenerating glutathione, along with vitamins C and E, and promotes glutathione synthesis.

Hirata disease, or insulin autoimmune syndrome IAS , is characterized by elevated insulin levels and anti-insulin autoantibodies. This disease is a rare form of autoimmune hypoglycemia caused by sulfhydryl-containing medicines, which trigger the creation of insulin autoantibodies.

α-Lipoic acid has lately emerged as a cause of IAS. Furthermore, greater care is needed for suggesting this damage as a consequence of α-lipoic acid supplementation Moffa et al. Free radical induced damaged makes an important contribution to secondary neuronal brain injury in stroke therapy Dwivedi There is currently no treatment available to prevent this effect.

The antioxidant property of α-lipoic acid is associated with its neurorestorative and neuroprotective effects. α-Lipoic acid induces the M2 phenotype in microglia, modulates the expression of pro-inflammatory cytokines IL-6, IL-1, IL, and tumor necrosis factor TNF , and inhibits the transcription factor NF-κB, a key mediator of inflammatory responses Wang et al.

Sleep is involved in regulating heat, maintaining energy, and recovering tissues. The protective effect of α-lipoic acid on social interaction memory was observed in sleep-deprived rats Rezaie et al. This neurotoxin triggers the death signaling pathway by activating apoptosis signal regulating kinase 1 ASK1 and translocating the death domain associated protein DAXX in the substantia nigra pars compacta SNpc of mice; α-lipoic acid terminates this cascade and affords neuroprotection Karunakaran et al.

In scopolamine-induced memory loss, α-lipoic acid inhibits brain weight loss, downregulates oxidative tissue damage resulting in neuronal cell loss, repairs memory and motor function, reduces reactive astrocyte proliferation, and decreases chromatolysis in the cerebello-hippocampal cortex Bastianetto and Quirion Oxidative alteration of low-density lipoprotein enhances atherogenicity Wollin and Jones It has been discovered that macrophages, smooth muscle cells, and ROS scavenger receptors on monocytes unrestrainedly take oxidized LDL, resulting in lipid accumulation and the formation of atherosclerotic plaques.

Enhanced oxidative stresses as well as inflammatory action give rise to hydroxyl radicals, peroxides, and superoxides inside the endothelium, which accelerate the progression of cardiovascular disease.

The inflammatory conditions continue to harm the vasculature one after another Wollin and Jones Dihydrolipoic acid is reported for its blood lipid modulating characteristics, protection against LDL oxidation, and modulation of hypertension, indicating that α-lipoic acid might be a possible protective agent against cardiovascular diseases Wollin and Jones The incidence of cardiovascular diseases decreases as the dietary intake of α-lipoic acid increases.

Chronic kidney disease is a gradual loss of kidney function that leads to the accumulation of waste products in the blood. Diabetes and high blood pressure are two of the major risk factors for chronic kidney disease Granata et al.

In this condition, cellular metabolic changes occur that may lead to the major production of free radicals that play a crucial role in the development of renal damage and the onset of treatment resistance. Hypoxia, ROS, and oxidative stress may cause severe kidney injury and ischemic reperfusion injury Zhang and McCullough Patients suffering from end-stage renal disease and kept on hemodialysis have very high chances of cardiovascular mortality Levey et al.

Intravenous iron infusion has become an essential segment of anemia management in end-stage renal disease patients. Iron injection intake leads to oxidative stress in the patients Lim et al. After administration of intravenous iron, oxidative stress markers formed, including lipid hydroperoxide, F2 isoprostane, and malondialdehyde, a reactive aldehyde that gives rise to toxic stress in cells Del et al.

Research shows that after the administration of intravenous iron to chronic kidney disease and hemodialysis patients, malondialdehyde increases speedily Lim et al.

The generation of lipid hydroperoxide results in oxidative damage in lipoproteins, cell membranes, and other lipid-containing structures Girotti and Kriska The antioxidant activities of α-lipoic acid were better than N -acetylcysteine at curing oxidative stress, including diabetic neuropathy and glomerular injury.

α-Lipoic acid administration leads to a reduction in oxidative stress markers low-density lipoprotein oxidizability and plasma protein carbonyls ; thus, it is appreciable that administration of this agent may reduce oxidative stress induced by intravenous IV iron Marangon et al.

However, in diabetic nephropathy, TGFβ1 is related to MAPK and induces the production of fibronectin in mesangial cells. α-Lipoic acid ameliorates the proteinuria by decreasing expressions of the TGFβ1 and fibronectin protein Lee et al.

The patients with autosomal dominant polycystic kidney disease treated with α-lipoic acid showed a significant improvement in metabolic, inflammatory, and endothelial functions Lai et al. As a short-chain fatty acid, α-lipoic acid is synthesized inside the human body to work as an antioxidant, safeguarding body cells from injury, and helping restore the scales of other antioxidants, like vitamins C and E Moura et al.

Several studies have shown that combining α-lipoic acid with fructose can reduce fructose-induced inflammation, hepatic oxidative stress, and insulin resistance. It is also found that α-lipoic acid can act as a chemopreventive agent because it inhibits the inflammation linked to carcinogenesis Moon α-Lipoic acid can reduce inflammatory markers in patients with heart disease, as oxidative stress is assumed to be the main cause of many cardiovascular diseases, together with hypertension, and heart failure.

Oxidative stress increases during the aging process, resulting in either enhanced ROS generation or diminished antioxidant safeguards. Aging is also related to oxidative stress, which in turn leads to hastened cellular senescence and organ dysfunction.

Antioxidants may assist in reducing the incidence of some pathologies of heart diseases and have anti-aging properties Wollin and Jones Several studies also show that infusion of irbesartan and α-lipoic acid to patients with the metabolic syndrome diminishes pro-inflammatory markers and enhances endothelial function, elements that are indicated in the pathogenesis of aterosclerosis Sola et al.

Along with that, it is found that α-lipoic acid can protect the liver from inflammatory disorders as well. Additionally, α-lipoic acid may help reduce the blood levels of several inflammatory markers, including IL-6 and ICAM-1 Liu et al.

Infertility is defined as the inability to conceive after engaging in regular sexual activity without using contraception for at least a year. Numerous medications have been utilized to improve sperm quality due to therapeutic limitations Dong et al.

Male infertility is partially caused by anatomical anomalies such as ductal blockages, varicocele, and ejaculatory problems. Depending on the kind and concentration of the ROS as well as the location and length of exposure to the ROS, sperm function may be positively or negatively impacted by ROS Thuwanut et al.

According to studies, male germ cells can create ROS at different stages of their development. Due to the depletion of intracellular ATP and the reduced phosphorylation of axonemal proteins, it has been discovered that somewhat elevated quantities of ROS have no effect on sperm survival but instead render them immobile Takei et al.

Excessive hydrogen peroxide concentrations, a major ROS producer, also cause lipid peroxidation and cell death. By reducing ROS generation, antioxidant medications maintain sperm viability and motility and can help safeguard sperm DNA integrity.

Consuming dietary antioxidants may also improve semen conditions. It has been determined that male infertility is associated with a lower intake of specific antioxidant nutrients, such as vitamins A, C, and E, folate, zinc, carnitine, and selenium Buhling and Laakmann α-Lipoic acid is also a powerful antioxidant that helps in the regulation of ROS production.

α-Lipoic acid or its reduced form dihydrolipoic acid quenches several oxygen-free radical species in both aqueous and lipid phases Sacks et al. The available report suggests that α-lipoic acid could improve the sperm motility rate and reduce sperm DNA damage, thereby improving sperm quality Ibrahim et al.

Also, α-lipoic acid shows the positive effect in oocyte maturation, embryo development, and reproductive outcome Dong et al. Regular administration of α-lipoic acid reduces the pelvic pain in endometriosis and regularizes the menstrual blood flow. α-Lipoic acid represents a promising new molecule for infertility and additional clinical studies are recommended in the future.

Cigarette smoking is a detrimental effect on the genital system of rat models due to oxidative stress. Smoking has a negative effect on the genital system via hypoxia-inducible factors HIF-1α and HIF-2α , TNF-α, caspase 3, and the calcitonin gene-related peptide CGRP in the uterus, and α-lipoic acid protected against the negative effects on the female reproductive system Asci et al.

α-Lipoic acid also promoted decreasing effects of nicotine-induced skin, lung, and liver damage Ateyya et al. Microorganisms are responsible for various types of skin- and gut-related disorders.

The gradual enhancements in the rapidity of resistance to antibiotics turn to rise in oral pathologies. α-Lipoic acid was found to inhibit the growth of various oral microorganisms to a large extent, such as Pseudomonas species, Escherichia coli , Staphylococcus aureus , and Candida albicans. α-Lipoic acid can arrest the growth of Candida albicans thereby exhibiting antifungal activity which is directly proportional to its concentration Zhao et al.

α-Lipoic acid also arrests the growth of Cronobacter sakazakii strains with the minimum inhibitory concentration MIC in the range from 2.

It was corroborated that α-lipoic acid shows antimicrobial potential for affecting the membrane integrity, causing dysfunction of the cell membrane and alterations in cellular morphology. Recent studies also state that ALA is also effective against Rickettsia rickettsii , which is a constrained intracellular bacterium that generates Rocky Mountain spotted fever.

α-Lipoic acid has significant ability to penetrate nucleus and affect intracellular actin-based mobility Eremeeva and Silverman ; Sahni et al.

α-Lipoic acid has the potential for protection against mycotoxin and treatment of mycotoxicosis Rogers Another report suggested that α-lipoic acid has protective efficacies against aflatoxin B1-induced oxidative damage in the liver Li et al.

The beneficial effect of α-lipoic acid combined with other antioxidants, such as epigallocatechin gallate, affects the life span and age-dependent behavior of the nematode Caenorhabditis elegans Phulara et al.

In a nutshell, α-lipoic acid is an important molecule as antimicrobial, antifungal, antinematodal, and antiviral properties affecting multiple targets. This combination affects the menstrual rate of women with PCOS positively, irrespective of their metabolic phenotype and with a higher dose of myo-inositol more evident and insulin-independent effect is seen de Cicco et al.

D-Chiro-inositol and α-lipoic acid, in a combination treatment, may have a strong impact on metabolic profile in women with PCOS Cianci et al. In PCOS, α-lipoic acid also decreases oxidative damage and insulin resistance.

Endometriosis can be prevented and treated by a combination of N -acetyl cysteine, α-lipoic acid, and bromelain. α-Lipoic acid supplementation in patients with a suspected miscarriage to improve subchorionic hematoma resorption is a promising field of investigation.

In addition, α-lipoic acid could be used to prevent diabetic embryopathy and premature fetal membrane rupture caused by inflammation. Finally, α-lipoic acid can be used safely to treat neuropathic pain and as a dietary supplement during pregnancy di Tucci et al.

The severe acute respiratory syndrome coronavirus-2 SARS-CoV-2 epidemic COVID has emerged as a rapidly spreading communicable disease that currently affects all nations throughout the world. Although the virus has been found in the stool and urine of infected people, the likelihood of alternative channels of transference cannot be ruled out.

The sickness is primarily spread through large respiratory droplets Princess Diabetes patients are more likely to get an infection. According to research, patients with the coronavirus that causes the severe acute respiratory syndrome SARS and pandemic influenza A were seen as having diabetes as a substantial risk factor for mortality with H1N1 influenza Yang et al.

Of people who died from COVID in Wuhan, China, According to a theory Sayıner and Serakıncı, , α-lipoic acid controls the immune system by controlling T-cell activation, making it a useful treatment candidate for the cytokine storm that causes SARS-CoV-2 infection.

According to studies, treating diabetic patients with α-lipoic acid will help them fight COVID Cure and Cure α-Lipoic acid is a short-chain fatty acids SCFAs derived from the fermentation of vegetables and meat and modulates the gut microbiota without reducing the microbial diversity Tripathi et al.

A recent study showed that α-lipoic acid and the SCFAs produced by Ruminococcaceae rejuvenated aged intestinal stem cells by preventing the age-associated endosome reduction Du et al. α-Lipoic acid takes part in crucial biological operations, together with the fixation and modulation of mitochondrial multi-enzyme complexes, oxidation of amino acids and carbohydrates, removal of ROS, and harmonization of energetic metabolism Shay et al.

At a younger age, the human body can synthesize α-lipoic acid itself in the required amount, but its quantity remarkably decreases with age, which is supposed to be connected to age-related organic dysfunction Hagen et al. Drosophila midgut is an appropriate prototype structure for the learning of mechanisms underlying the age-associated decline in stem cell function.

A decrease in differentiation efficiency and a malignant increase in proliferation rate takes place in the intestinal stem cells inside the midguts of Drosophila when it ages. Thus, the mRNA and protein expression of Las in Drosophila intestinal stem cells go through a significant depletion in response to aging, which in turn causes a curtailment of α-lipoic acid in midguts of aged flies.

α-Lipoic acid has so many molecular targets for disease management and biological action Fig. It doubles the levels of PPAR-mRNA and protein while decreasing the activation of the c-Jun N -terminal kinase JNK signaling pathway Rousseau et al.

α-Lipoic acid reduces endoplasmic reticulum stress and enhances glucose absorption by targeting the DNAJB3 DnaJ heat shock protein family and mRNA molecule Diane et al.

According to reports, it lowers the NALP-3 inflammasome in the endometrium of women who experience idiopathic recurrent pregnancy loss Di et al. By inhibiting breast cancer cell proliferation, cell cycle progression, and the epithelial-to-mesenchymal transition, α-lipoic acid has significant antiproliferative effects.

By blocking the transforming growth factor beta TGFβ signaling pathway, α-lipoic acid prevents breast cancer cells from migrating and encroaching Tripathy et al.

Glucose fluctuations in diabetic encephalopathy encourage neuronal death. α-Lipoic acid has renoprotective effects on rat kidneys damage brought on by iron overload through inhibiting NADPH oxidase 4 and p38 MAPK signaling Cavdar et al. α-Lipoic acid diminishes the serum immunoglobulin E IgE levels of the atopic dermatitis mice model and enhances splenic B cell counts in endotoxemia mice which showed that IgE plays a modulating role in the expansion, death, and function of B-cells.

Recent studies show that α-lipoic acid enhances cAMP synthesis by activation of EP2 and EP4 prostaglandin receptors in peripheral blood T-cells. The enhanced level of cAMP inside cells reduces the expression of IL-2 and IL-2Rα CD25 that in turn influence expansion, death, and function of T-cells.

Natural killer NK cells have two main functions: cytotoxicity and interferon gamma IFN-γ secretion. IFN-γ is a powerful macrophage activator for both lysis and phagocytosis. Although α-lipoic acid has long been discovered as an antioxidant, it has also been demonstrated to improve glucose and ascorbate treatment, activate phase II detoxification via the transcription factor Nrf2, increase eNOS activity, and lower expression of MMP-9 and VCAM-1 through repression of NF-κB.

α-Lipoic acid and its reduced form, dihydrolipoic acid, could be used for their chemical properties as a redox pair to modify protein conformations by forming mixed disulfides.

Beneficial effects are accomplished with low micromolar levels of α-lipoic acid, suggesting that its therapeutic potential extents beyond the precise definition of an antioxidant agent. α-Lipoic acid is a well-known antioxidant consumed to remedy a variety of disorders, though it is assumed a very secure supplement and intoxication is extremely infrequent, acute excessive-dose ingestions can cause mortality Emir et al.

The safety of α-lipoic acid can be evaluated using sub-chronic and acute toxicity studies. Studies have estimated an adult dose of α-lipoic acid up to mg with no severe side effects; however, excessive dose of α-lipoic acid is not suggested as it does not add any other therapeutic or nutritional advantage Cremer et al.

Furthermore, studies associated with α-lipoic acid conducted on primates displayed that more lethal dose would lead to hepatic necrosis, indicating that excess doses of intravenous α-lipoic acid can be able to produce resistance Vigil et al. α-Lipoic acid has also been shown to reverse the adverse health effects of mycotoxins Rogers Skin and gastrointestinal disorders are the most frequently reported adverse effects for α-lipoic acid-containing dietary supplements Gatti et al.

Allergic reactions like rashes, hives, and itching are the side effects of the oral intake of α-lipoic acid. However, effects like vertigo, diarrhea, and vomiting are dose dependent. It is suggested that the use of α-lipoic acid should be discouraged immediately if any allergic reaction occurs Ziegler et al.

α-Lipoic acid is used either as an excipient or as a main therapeutic ingredient in various types of nanoformulations size of about 1— nm ; due to this small size, it has a very large surface area and hence high area of contact which enhances the therapeutic effect of drug particle incorporated Jong and Borm It can be formulated in the form of nanostructure lipid carriers, solid lipid nanoparticles, and nano-emulsion.

Silver nanoparticles AgNPs are extensively considered for their broad-spectrum antimicrobial outcome and can be employed instantly in biomaterials; however, the cellular protection of specific AgNP formulations should be profiled earlier for clinical utilization.

AgNPs can be able to outcome the evocation of oxidative harm and inflammatory lesions in human gingival fibroblast cells Jin et al. AgNPs capped with α-lipoic acid decrease toxicity as compared to other capping agents Verma et al.

Studies show that α-lipoic acid-capped AgNPs possess antimicrobial effects at low concentrations 2. Docetaxel, acytotoxic taxane diterpenoid sold under the brand name taxotere, is an antimicrotubule agent effective as chemotherapy medication to treat several types of cancer, including metastatic breast cancer Lyseng-Williamson and Fenton Co-delivery of docetaxel and α-lipoic acid using solid lipid nanoparticles SLNs as a carrier demonstrated remarkably higher uptake efficiency along with better cytotoxic and apoptotic capability and assured a better treatment of breast cancer Kothari et al.

The anti-inflammatory, antioxidant, and anti-apoptotic actions of α-lipoic acid, as well as the effectiveness of the encapsulation approach, can boost the efficiency and stability of α-lipoic acid, and reduce the neurotoxicity caused by AlCl3.

Furthermore, α-lipoic acid-SLNs outperform α-lipoic acid-chitosan nanoparticles Metwaly et al. HOMO—LUMO plots of the two enantiomers of α-lipoic acid a S -enantiomer; b R -enantiomer.

The biological roles of α-lipoic acid are highly varied, as this review has shown. In fact, as a bioactive agent, we are aware of only a few substances that act as diverse as α-lipoic acid. Determining the specific cause-and-effect relationship between α-lipoic acid and its cellular targets will therefore be crucial.

Whether α-lipoic acid directly controls the hormonal signals that trigger subsequent pharmacological effects on target organs is a subject that needs more investigation.

In this way, α-lipoic acid strengthens learning and short-term memory in aged rodents and encourages an anorectic effect in rodents that is AMPK-dependent Shay et al.

Given that α-lipoic acid is almost entirely absorbed from the human gastrointestinal tract, metabolized, and excreted, negligible free α-lipoic acid is retained in tissues. As recently established in mice, rats, and dogs, different β-oxidation and mono- and bis- S -methylation products of the sulfydryl groups appear to be implicated in urine metabolic patterns Fig.

Additionally, biliary elimination should be the focus of future research on the human metabolism of α-lipoic acid Teichert et al. Many studies have reported on the pleiotropic and medicinal activities of α-lipoic acid since its discovery in , followed by isolation and synthesis in the s Gomes and Negrato A molecular and electronic structure study of α-lipoic acid suggests that its antioxidant potential is responsible for its anti-disease activities.

However, preclinical and clinical studies form the foundation of much of the discussion presented here. As a result, α-lipoic acid has powerful anti-disease properties, such as those against cancer, metabolic syndrome, and inflammatory diseases.

Several potential molecular targets have been investigated in relation to a variety of diseases. The capacity of this substance to neutralize ROS, lessen oxidative stress, and trigger apoptosis is the fundamental mechanism underlying its effectiveness against various diseases and chronic disorders.

In all the clinical trials that were conducted with α-lipoic acid, it was either used alone or in conjunction with other medications. The safe dose for action was reported to be between and mg per day for the term stated for each illness condition.

In the context of COVID, it is also hypothesized as a repurposed drug to investigate the inhibitory action on new molecular targets. However, it is important to design computational studies and in vitro and in vivo investigations to offer comprehensive proof. Based on the information presented here, α-lipoic acid is useful in the treatment of reproductive diseases, which has been briefly explored in the context of polycystic ovary syndrome.

Despite all these reports and multiple clinical trials, it has not yet been approved for use in humans. Although its bioavailability is increased in the form of nanoformulations, α-lipoic acid changes the metabolism and bioavailability of co-administered medicines when taken in combination.

Despite there being few active clinical trials, this chemical is the subject of an increasing number of publications. As new information about the health benefits of α-lipoic acid will be gathered, its use in the clinic is more likely to be widely accepted.

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Clinics — Atherosclerosis —