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Assembly of Lipoic Acid on Its Cognate Enzymes: an Extraordinary and Essential Biosynthetic Pathway.Microbiology and Molecular Biology... Jun 2016Although the structure of lipoic acid and its role in bacterial metabolism were clear over 50 years ago, it is only in the past decade that the pathways of biosynthesis... (Review)
Review
Although the structure of lipoic acid and its role in bacterial metabolism were clear over 50 years ago, it is only in the past decade that the pathways of biosynthesis of this universally conserved cofactor have become understood. Unlike most cofactors, lipoic acid must be covalently bound to its cognate enzyme proteins (the 2-oxoacid dehydrogenases and the glycine cleavage system) in order to function in central metabolism. Indeed, the cofactor is assembled on its cognate proteins rather than being assembled and subsequently attached as in the typical pathway, like that of biotin attachment. The first lipoate biosynthetic pathway determined was that of Escherichia coli, which utilizes two enzymes to form the active lipoylated protein from a fatty acid biosynthetic intermediate. Recently, a more complex pathway requiring four proteins was discovered in Bacillus subtilis, which is probably an evolutionary relic. This pathway requires the H protein of the glycine cleavage system of single-carbon metabolism to form active (lipoyl) 2-oxoacid dehydrogenases. The bacterial pathways inform the lipoate pathways of eukaryotic organisms. Plants use the E. coli pathway, whereas mammals and fungi probably use the B. subtilis pathway. The lipoate metabolism enzymes (except those of sulfur insertion) are members of PFAM family PF03099 (the cofactor transferase family). Although these enzymes share some sequence similarity, they catalyze three markedly distinct enzyme reactions, making the usual assignment of function based on alignments prone to frequent mistaken annotations. This state of affairs has possibly clouded the interpretation of one of the disorders of human lipoate metabolism.
Topics: Amino Acid Oxidoreductases; Amino Acid Sequence; Animals; Biosynthetic Pathways; Carrier Proteins; Humans; Multienzyme Complexes; Protein Processing, Post-Translational; Thioctic Acid; Transferases
PubMed: 27074917
DOI: 10.1128/MMBR.00073-15 -
International Journal of Molecular... Jan 2021The incidence of neurodegenerative diseases has increased greatly worldwide due to the rise in life expectancy. In spite of notable development in the understanding of... (Review)
Review
The incidence of neurodegenerative diseases has increased greatly worldwide due to the rise in life expectancy. In spite of notable development in the understanding of these disorders, there has been limited success in the development of neuroprotective agents that can slow the progression of the disease and prevent neuronal death. Some natural products and molecules are very promising neuroprotective agents because of their structural diversity and wide variety of biological activities. In addition to their neuroprotective effect, they are known for their antioxidant, anti-inflammatory and antiapoptotic effects and often serve as a starting point for drug discovery. In this review, the following natural molecules are discussed: firstly, kynurenic acid, the main neuroprotective agent formed via the kynurenine pathway of tryptophan metabolism, as it is known mainly for its role in glutamate excitotoxicity, secondly, the dietary supplement pantethine, that is many sided, well tolerated and safe, and the third molecule, α-lipoic acid is a universal antioxidant. As a conclusion, because of their beneficial properties, these molecules are potential candidates for neuroprotective therapies suitable in managing neurodegenerative diseases.
Topics: Animals; Antioxidants; Humans; Kynurenic Acid; Metabolic Networks and Pathways; Neurodegenerative Diseases; Neuroprotection; Neuroprotective Agents; Oxidative Stress; Pantetheine; Thioctic Acid
PubMed: 33401674
DOI: 10.3390/ijms22010403 -
Poly(lipoic acid)-Based Nanoparticles as Self-Organized, Biocompatible, and Corona-Free Nanovectors.Biomacromolecules Feb 2021Herein we present an innovative approach to produce biocompatible, degradable, and stealth polymeric nanoparticles based on poly(lipoic acid), stabilized by a PEG-ended...
Herein we present an innovative approach to produce biocompatible, degradable, and stealth polymeric nanoparticles based on poly(lipoic acid), stabilized by a PEG-ended surfactant. Taking advantage of the well-known thiol-induced polymerization of lipoic acid, a universal and nontoxic nanovector consisted of a solid cross-linked polymeric matrix of lipoic acid monomers was prepared and loaded with active species with a one-step protocol. The biological studies demonstrated a high stability in biological media, the virtual absence of "protein" corona in biological fluids, the absence of acute toxicity in vitro and in vivo, complete clearance from the organism, and a relevant preference for short-term accumulation in the heart. All these features make these nanoparticles candidates as a promising tool for nanomedicine.
Topics: Nanomedicine; Nanoparticles; Polyethylene Glycols; Polymers; Protein Corona; Thioctic Acid
PubMed: 33347750
DOI: 10.1021/acs.biomac.0c01321 -
Advanced Science (Weinheim,... Nov 2022Inspired by the bottom-up assembly in nature, an artificial self-assembly pattern is introduced into 3D-fused deposition modeling (FDM) printing to achieve additive...
Inspired by the bottom-up assembly in nature, an artificial self-assembly pattern is introduced into 3D-fused deposition modeling (FDM) printing to achieve additive manufacturing on the macroscopic scale. Thermally activated polymerization of thioctic acid (TA) enabled the bulk construction of poly(TA), and yielded unique time-dependent self-assembly. Freshly prepared poly(TA) can spontaneously and continuously transfer into higher-molecular-weight species and low-molecular-weight TA monomers. Poly(TA) and the newly formed TA further assembled into self-reinforcing materials via microscopic-phase separation. Bottom-up self-assembly patterns on different scales are fully realized by 3D FDM printing of poly(TA): thermally induced polymerization of TA (microscopic-scale assembly) to poly(TA) and 3D printing (macroscopic-scale assembly) of poly(TA) are simultaneously achieved in the 3D-printing process; after 3D printing, the poly(TA) modes show mechanically enhanced features over time, arising from the microscopic self-assembly of poly(TA) and TA. This study clearly demonstrates that micro- and macroscopic bottom-up self-assembly can be applied in 3D additive manufacturing.
Topics: Thioctic Acid; Printing, Three-Dimensional
PubMed: 36220340
DOI: 10.1002/advs.202203630 -
CNS Neuroscience & Therapeutics Mar 2022Lipoic acid (LA) is an endogenous antioxidant that exists widely in nature. Supplementation with LA is a promising approach to improve the outcomes of patients with... (Review)
Review
Lipoic acid (LA) is an endogenous antioxidant that exists widely in nature. Supplementation with LA is a promising approach to improve the outcomes of patients with multiple sclerosis (MS). This systematic review aimed to provide a comprehensive overview of both in vitro and in vivo studies describing the pharmacokinetics, efficacy, safety, and mechanism of LA in MS-related experiments and clinical trials. A total of 516 records were identified by searching five databases, including PubMed, Web of Science, Embase, Scopus, and Cochrane Library. Overall, we included 20 studies reporting LA effects in cell and mouse models of MS and 12 studies reporting LA effects in patients with MS. Briefly, cell experiments revealed that LA protected neurons by inhibiting the expression of inflammatory mediators and activities of immune cells. Experimental autoimmune encephalomyelitis mouse experiments demonstrated that LA consistently reduced the number of infiltrating immune cells in the central nervous system and decreased the clinical disability scores. Patients with MS showed relatively stable Expanded Disability Status Scale scores and better walking performance with few adverse events after the oral administration of LA. Notably, heterogeneity of this evidence existed among modeling methods, LA usage, MS stage, and trial duration. In conclusion, this review provides evidence for the anti-inflammatory and antioxidative effects of LA in both in vitro and in vivo experiments; therefore, patients with MS may benefit from LA administration. Whether LA can be a routine supplementary therapy warrants further study.
Topics: Animals; Antioxidants; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Humans; Mice; Multiple Sclerosis; Thioctic Acid
PubMed: 34964271
DOI: 10.1111/cns.13793 -
International Journal of Molecular... Sep 2023Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of lipids within hepatocytes, which compromises liver functionality following...
Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of lipids within hepatocytes, which compromises liver functionality following mitochondrial dysfunction and increased production of reactive oxygen species (ROS). Lipoic acid is one of the prosthetic groups of the pyruvate dehydrogenase complex also known for its ability to confer protection from oxidative damage because of its antioxidant properties. In this study, we aimed to investigate the effects of lipoic acid on lipotoxicity and mitochondrial dynamics in an in vitro model of liver steatosis. HepG2 cells were treated with palmitic acid and oleic acid (1:2) to induce steatosis, without and with 1 and 5 µM lipoic acid. Following treatments, cell proliferation and lipid droplets accumulation were evaluated. Mitochondrial functions were assessed through the evaluation of membrane potential, MitoTracker Red staining, expression of genes of the mitochondrial quality control, and analysis of energy metabolism by HPLC and Seahorse. We showed that lipoic acid treatment restored membrane potential to values comparable to control cells, as well as protected cells from mitochondrial fragmentation following PA:OA treatment. Furthermore, our data showed that lipoic acid was able to determine an increase in the expression of mitochondrial fusion genes and a decrease in mitochondrial fission genes, as well as to restore the bioenergetics of cells after treatment with palmitic acid and oleic acid. In conclusion, our data suggest that lipoic acid reduces lipotoxicity and improves mitochondrial functions in an in vitro model of steatosis, thus providing a potentially valuable pharmacological tool for NAFLD treatment.
Topics: Humans; Thioctic Acid; Non-alcoholic Fatty Liver Disease; Palmitic Acid; Oleic Acid; Mitochondria; Hepatocytes; Oxidative Stress; Energy Metabolism; Liver
PubMed: 37833939
DOI: 10.3390/ijms241914491 -
Oxidative Medicine and Cellular... 2021Ischemia-reperfusion (I/R) injury often occurred in some pathologies and surgeries. I/R injury not only harmed to physiological functions of corresponding organ and... (Review)
Review
Ischemia-reperfusion (I/R) injury often occurred in some pathologies and surgeries. I/R injury not only harmed to physiological functions of corresponding organ and tissue but also induced multiple tissue or organ dysfunctions (even these in distant locations). Although the reperfusion of blood attenuated I/R injury to a certain degree, the risk of secondary damages was difficult to be controlled and it even caused failures of these tissues and organs. Lipoic acid (LA), as an endogenous active substance and a functional agent in food, owns better safety and effects in our body (e.g., enhancing antioxidant activity, improving cognition and dementia, controlling weight, and preventing multiple sclerosis, diabetes complication, and cancer). The literature searching was conducted in PubMed, Embase, Cochrane Library, Web of Science, and SCOPUS from inception to 20 May 2021. It had showed that endogenous LA was exhausted in the process of I/R, which further aggravated I/R injury. Thus, supplements with LA timely (especially pretreatments) may be the prospective way to prevent I/R injury. Recently, studies had demonstrated that LA supplements significantly attenuated I/R injuries of many organs, though clinic investigations were short at present. Hence, it was urgent to summarize these progresses about the effects of LA on different I/R organs as well as the potential mechanisms, which would enlighten further investigations and prepare for clinic applications in the future.
Topics: Animals; Antioxidants; Cognition; Humans; Ischemia; Reperfusion Injury; Spinal Cord Injuries; Thioctic Acid
PubMed: 34650663
DOI: 10.1155/2021/5093216 -
Nutrients Apr 2023The kidney is a crucial organ that eliminates metabolic waste and reabsorbs nutritious elements. It also participates in the regulation of blood pressure, maintenance of... (Review)
Review
The kidney is a crucial organ that eliminates metabolic waste and reabsorbs nutritious elements. It also participates in the regulation of blood pressure, maintenance of electrolyte balance and blood pH homeostasis, as well as erythropoiesis and vitamin D maturation. Due to such a heavy workload, the kidney is an energy-demanding organ and is constantly exposed to endogenous and exogenous insults, leading to the development of either acute kidney injury (AKI) or chronic kidney disease (CKD). Nevertheless, there are no therapeutic managements to treat AKI or CKD effectively. Therefore, novel therapeutic approaches for fighting kidney injury are urgently needed. This review article discusses the role of α-lipoic acid (ALA) in preventing and treating kidney diseases. We focus on various animal models of kidney injury by which the underlying renoprotective mechanisms of ALA have been unraveled. The animal models covered include diabetic nephropathy, sepsis-induced kidney injury, renal ischemic injury, unilateral ureteral obstruction, and kidney injuries induced by folic acid and metals such as cisplatin, cadmium, and iron. We highlight the common mechanisms of ALA's renal protective actions that include decreasing oxidative damage, increasing antioxidant capacities, counteracting inflammation, mitigating renal fibrosis, and attenuating nephron cell death. It is by these mechanisms that ALA achieves its biological function of alleviating kidney injury and improving kidney function. Nevertheless, we also point out that more comprehensive, preclinical, and clinical studies will be needed to make ALA a better therapeutic agent for targeting kidney disorders.
Topics: Animals; Thioctic Acid; Kidney; Renal Insufficiency, Chronic; Antioxidants; Acute Kidney Injury; Disease Models, Animal
PubMed: 37049574
DOI: 10.3390/nu15071732 -
European Review For Medical and... Aug 2023Changes in hormone levels, improper lipid metabolism, and oxidative stress all significantly contribute to the pathogenic process of polycystic ovarian syndrome (PCOS)....
OBJECTIVE
Changes in hormone levels, improper lipid metabolism, and oxidative stress all significantly contribute to the pathogenic process of polycystic ovarian syndrome (PCOS). According to earlier research, pioglitazone and alpha-lipoic acid are crucial in the emergence of PCOS. The beneficial effects of pioglitazone and alpha-lipoic acid on PCOS were examined in the current study.
PATIENTS AND METHODS
The 120 patients with PCOS received three months of treatment in pioglitazone groups (n=40 case, 30 mg/time, 1 time/day), α-lipoic acid (n=40 case, 0.6 g/time, 1 time/day), and combination therapy (n=40 case, pioglitazone 30 mg/time, 1 time/day and α-lipoic acid, 0.6 g/time, 1 time/day). Before and after therapy, the following factors were evaluated: the hormonal profile, fasting serum insulin, body weight, body mass index (BMI), menstruation status, oxidative stress, and indications of lipid metabolism.
RESULTS
The combination of pioglitazone and α-lipoic acid has a significantly improving effect on BMI, body weight, oxidative stress levels, lipid metabolism, and menstrual status. A significant increase in body weight, BMI, and follicle-stimulating hormone (FSH) levels were found in mice after being treated with α-lipoic acid alone. However, the use pioglitazone alone improves body weight, BMI, the calculation of insulin resistance index (HOMA-IR), Area under the curve (AUC)-insulin, fasting glucose/insulin (G/I) ratio, total testosterone, and malondialdehyde (MDA) levels in post-treatment than pre-treatment.
CONCLUSIONS
These findings suggest that pioglitazone alone has a better effect than alpha-lipoic acid in improving oxidative stress levels, BMI, and menstrual cyclicity. Additionally, treatment with pioglitazone and alpha-lipoic acid did demonstrate a greater effect than monotherapy with each medication alone.
Topics: Female; Humans; Animals; Mice; Thioctic Acid; Polycystic Ovary Syndrome; Pioglitazone; Body Weight; Insulin
PubMed: 37606122
DOI: 10.26355/eurrev_202308_33285 -
Oxidative Medicine and Cellular... 2019Alzheimer's disease (AD) is a neurodegenerative disorder characterised by impairments in the cognitive domains associated with orientation, recording, and memory. This... (Review)
Review
Alzheimer's disease (AD) is a neurodegenerative disorder characterised by impairments in the cognitive domains associated with orientation, recording, and memory. This pathology results from an abnormal deposition of the -amyloid (A) peptide and the intracellular accumulation of neurofibrillary tangles. Mitochondrial dysfunctions play an important role in the pathogenesis of AD, due to disturbances in the bioenergetic properties of cells. To date, the usual therapeutic drugs are limited because of the diversity of cellular routes in AD and the toxic potential of these agents. In this context, alpha-lipoic acid (-LA) is a well-known fatty acid used as a supplement in several health conditions and diseases, such as periphery neuropathies and neurodegenerative disorders. It is produced in several cell types, eukaryotes, and prokaryotes, showing antioxidant and anti-inflammatory properties. -LA acts as an enzymatic cofactor able to regulate metabolism, energy production, and mitochondrial biogenesis. In addition, the antioxidant capacity of -LA is associated with two thiol groups that can be oxidised or reduced, prevent excess free radical formation, and act on improvement of mitochondrial performance. Moreover, -LA has mechanisms of epigenetic regulation in genes related to the expression of various inflammatory mediators, such PGE2, COX-2, iNOS, TNF-, IL-1, and IL-6. Regarding the pharmacokinetic profile, -LA has rapid uptake and low bioavailability and the metabolism is primarily hepatic. However, -LA has low risk in prolonged use, although its therapeutic potential, interactions with other substances, and adverse reactions have not been well established in clinical trials with populations at higher risk for diseases of aging. Thus, this review aimed to describe the pharmacokinetic profile, bioavailability, therapeutic efficacy, safety, and effects of combined use with centrally acting drugs, as well as report in vitro and in vivo studies that demonstrate the mitochondrial mechanisms of -LA involved in AD protection.
Topics: Aging; Alzheimer Disease; Amyloid beta-Peptides; Animals; Cytokines; Humans; Inflammation Mediators; Mitochondria; Neurofibrillary Tangles; Neurons; Neuroprotective Agents; Thioctic Acid
PubMed: 31885820
DOI: 10.1155/2019/8409329