Lipoic Acid Research Articles

Alpha-lipoic acid, as an effective agent against toxic elements: a review

Alpha-lipoic acid, as an effective agent against toxic elements: a review

Effects of Short-Term Treatment with α-Lipoic Acid on Neuropathic Pain and Biomarkers of DNA Damage in Patients with Diabetes Mellitus

Background/Objectives: Diabetes mellitus (DM) is a complex and heterogenous disease classified as a group of metabolic disorders characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both. It leads to various complications, some of which are macrovascular or microvascular complications, like diabetic polyneuropathy (DPN), having a profound impact on patients’ quality of life. Oxidative stress (OS) is one of the significant mechanisms in the development and progression of DPN. Thus, targeting OS pathways by antioxidants, such as α-lipoic acid (ALA), could represent a promising therapeutic strategy for alleviating neuropathic symptoms. The aim of our study was to evaluate whether short-term (from 4 to 9 days) intravenous administration of ALA could cause any measurable improvement in subjects with DM. Methods: Sixteen subjects with DM (six type 1 and ten type 2) and sixteen nondiabetic subjects matched by sex and age were recruited to this study. Only subjects with DM received treatment with ALA (600 mg daily). Pain intensity and biomarkers of DNA damage including plasma concentration of 8-hydroxy-2′-deoxyguanosine (8-OHdG), frequency of micronucleated lymphocytes (MN), and frequency of sister-chromatid exchanges (SCEs), were measured before and after the treatment with ALA. Results: Pain intensity and 8-OHdG levels were significantly lower in DM subjects after the ALA treatment than before the treatment. However, no changes in the frequency of SCEs and MN were observed. Conclusions: Our results show some evidence that even a short-term intravenous treatment with ALA could be beneficial for diabetic subjects, reducing pain intensity and concentration of 8-OHdG in blood plasma.

Nuclear PD-L1 compartmentalization suppresses tumorigenesis and overcomes immunocheckpoint therapy resistance in mice via histone macroH2A1.

Canonically PD-L1 functions as the inhibitory immune checkpoint on cell surface. Recent studies have observed PD-L1 expression in the nucleus of cancer cells. But the biological function of nuclear PD-L1 (nPD-L1) in tumor growth and antitumor immunity is unclear. Here we enforced nPD-L1 expression and established stable cells. nPD-L1 suppressed tumorigenesis and aggressiveness in vitro and in vivo. Compared with PD-L1 deletion, nPD-L1 expression repressed tumor growth and improved survival more markedly in immunocompetent mice. Phosphorylated AMPKα (p-AMPKα) facilitated nuclear PD-L1 compartmentalization and then cooperated with it to directly phosphorylate S146 of histone variant macroH2A1 (mH2A1) to epigenetically activate expression of genes of cellular senescence, JAK/STAT, and Hippo signaling pathways. Lipoic acid (LA) that induced nuclear PD-L1 translocation suppressed tumorigenesis and boosted antitumor immunity. Importantly, LA treatment synergized with PD-1 antibody and overcame immune checkpoint blockade (ICB) resistance, which likely resulted from nPD-L1-increased MHC-I expression and sensitivity of tumor cells to interferon-γ. These findings offer a conceptual advance for PD-L1 function and suggest LA as a promising therapeutic option for overcoming ICB resistance.

Transcriptomic and Metabolomic Insight into the Roles of α-Lipoic Acid in the Antioxidant Mechanisms of Sheep

Transcriptomic and Metabolomic Insight into the Roles of α-Lipoic Acid in the Antioxidant Mechanisms of Sheep

Retraction Note: Hybrid nanoparticulate system of Fluvastatin loaded phospholipid, alpha lipoic acid and melittin for the management of colon cancer.

Retraction Note: Hybrid nanoparticulate system of Fluvastatin loaded phospholipid, alpha lipoic acid and melittin for the management of colon cancer.

Ocular motor mononeuropathies in diabetes mellitus: A brief review.

Ocular motor mononeuropathies affect cranial nerves III, IV and VI and are more frequent in diabetes mellitus, with oculomotor nerve involvement being predominant. The aim of this narrative brief review was to discuss the clinical manifestations, diagnosis and management of ocular motor nerve palsies in subjects with diabetes. Clinical manifestations often include ptosis, diplopia, and periorbital pain. A characteristic of third nerve palsy is pupillary sparing. Differential diagnosis may be challenging due to overlapping symptoms with nerve palsies of other aetiologies. Treatment includes optimised glycaemic control and management of vascular risk factors. Neuroprotective agents, mainly alpha-lipoic acid and botulinum toxin A have been occasionally used, as well. Spontaneous recovery is also seen in many cases.

Rhomboid-like 2 correlated with TME infiltration inhibits cuproptosis-related genes and drives malignant phenotype in clear cell renal cell carcinoma

The crosstalk between cuproptosis and the tumor immune microenvironment (TIME) is vital during clear cell renal cell carcinoma (ccRCC) malignant progression. However, the underlying molecular mechanisms regulate this cross-talk remain elusive. Through tailored machine learning, we analyze clinical ccRCC data from The Cancer Genome Atlas (TCGA) to explore the critical factors that regulate the interaction among cuproptosis, TIME, and tumor progression. We found that rhomboid-like 2 (RHBDL2), critical gene affecting this process, might inhibit cuproptosis-related genes (CRGs) and promotes ccRCC progression through the Wnt/β-catenin pathway. Next, knocking down RHBDL2 expression increased the cuproptosis-related genes ferredoxin 1 (FDX1) and lipoic acid synthase (LIAS) levels but reduced forkhead box P3 (FOXP3) levels and tumor growth in vivo and in vitro models. By employing HLY78, Wnt/β-catenin pathway activator, we rescued the expression of CRGs and the malignant proliferation and metastasis capacity in ccRCC cells with RHBDL2 knockdown. Mechanistically, RHBDL2 inhibits cuproptosis and promotes malignant progression of ccRCC through the Wnt/β-catenin pathway. Abnormal RHBDL2 expression may cause the suppressive TIME formation by regulating Treg-cell infiltration, thus triggering immune escape. In summary, our results indicated that RHBDL2 is an oncogene that induces tumorigenesis and targeting RHBDL2 may be novel therapeutic direction for metastatic ccRCC.

Highly Elastic, Fatigue-Resistant, and Antifreezing MXene Functionalized Organohydrogels as Flexible Pressure Sensors for Human Motion Monitoring.

Conductive organohydrogels-based flexible pressure sensors have gained considerable attention in health monitoring, artificial skin, and human-computer interaction due to their excellent biocompatibility, wearability, and versatility. However, hydrogels' unsatisfactory mechanical and unstable electrical properties hinder their comprehensive application. Herein, an elastic, fatigue-resistant, and antifreezing poly(vinyl alcohol) (PVA)/lipoic acid (LA) organohydrogel with a double-network structure and reversible cross-linking interactions has been designed, and MXene as a conductive filler is functionalized into organohydrogel to further enhance the diverse sensing performance of flexible pressure sensors. The as-fabricated MXene-based PVA/LA organohydrogels (PLBM) exhibit stable fatigue resistance for over 450 cycles under 40% compressive strain, excellent elasticity, antifreezing properties (<-20 °C), and degradability. Furthermore, the pressure sensors based on the PLBM organohydrogels show a fast response time (62 ms), high sensitivity (S = 0.0402 kPa-1), and excellent stability (over 1000 cycles). The exceptional performance enables the sensors to monitor human movements, such as joint flexion and throat swallowing. Moreover, the sensors integrating with the one-dimensional convolutional neural networks and the long-short-term memory networks deep learning algorithms have been developed to recognize letters with a 93.75% accuracy, representing enormous potential in monitoring human motion and human-computer interaction.

Comparative efficacy and safety of Chinese patent medicines as an adjunctive therapy for diabetic peripheral neuropathy: systematic review and network meta-analysis of randomized controlled trials

Context Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes mellitus. Chinese patent medicines (CPMs) are widely used in clinical practice to treat DPN. Objective This study aims to summarize the latest evidence on the harms and benefits of CPMs as adjunctive therapy for DPN. Materials and methods We conducted searches for randomized controlled trials (RCTs) evaluating CPMs in conjunction with mecobalamin (Mec) or alpha-lipoic acid (αLA) across eight databases up to July 2024. The surface under the cumulative ranking area (SUCRA) was utilized to assess the clinical efficacy rate (CER), the peroneal motor nerve conduction velocity (pMNCV), the peroneal sensory nerve conduction velocity (pSNCV), the median motor nerve conduction velocity (mMNCV), and the median sensory nerve conduction velocity (mSNCV). Results The search yielded 128 eligible studies with 31 CPMs with Mec and 39 eligible studies with 17 CPMs with αLA. SUCRA rankings indicated that, when combined with Mec, Mailuoning liquid (lMLN) was the most effective regimen for CER, Honghua injection (iHH) for pMNCV, Maixuekang capsule (cMXK) for pSNCV, Dengzhanxixin injection (iDZXX) for mMNCV, and Tongxinluo capsule (cTXL) for mSNCV. Combined with αLA, Danhong injection (iDH) showed the highest efficacy for CER, pSNCV, and mSNCV, while Xueshuantong injection (iXShT) was the most effective for pMNCV and mMNCV. Conclusion This network meta-analysis confirms the efficacy and safety of 37 CPMs combined with Mec or αLA for treating DPN. However, given the potential risk of bias and the very low certainty of the evidence, these recommendations should be adopted with caution.

Enhanced Asymmetric Circularly Polarized Luminescence in Self-Organized Helical Superstructures Enabled by Macro-Chiral Liquid Crystal Quantum Dots.

Circularly polarized luminescent (CPL) materials have garnered considerable interest for a variety of advanced optical applications including 3D imaging, data encryption, and asymmetric catalysis. However, the development of high-performance CPL has been hindered by the absence of simple synthetic methods for chiral luminescent emitters that exhibit both high quantum yields and dissymmetry factors. In this study, we present an innovative approach for the synthesis of macro-chiral liquid crystal quantum dots (Ch-QDs/LC) and their CPL performance enhancement through doping with 4-cyano-4'-pentylbiphenyl (5CB), thus yielding a CPL-emitting generator (CEG). The Ch-QDs/LCs were synthesized, and their surfaces functionalized with a chiral mesogenic ligand, specifically cholesteryl benzoate, anchored via a lipoic acid linker. Under the regulation of chiral 2S-Zn2+ coordination complexes, the chiral LC encapsulation process promotes coordinated ligand substitution, resulting in an exceptional quantum yield of 56.3%. This is accompanied by high absorption dissymmetry factor (gabs) and luminescence dissymmetry factor (glum) values ranging from 10-3 to 10-2, surpassing most reported dissymmetry factors by at least an order of magnitude. The modular Ch-QDs/LCs demonstrate the ability to transfer chirality to the surrounding medium efficiently and manifest macro-chiral characteristics within a nematic LC matrix. Utilizing Ch-QDs/LC as an effective CPL emitter within achiral 5CB matrices enabled the system to achieve a maximum glum value of 0.35. The resultant CEG device acted as a direct CPL source, initiating enantioselective photopolymerization.

Multifunctional hydrogels loaded with tellurium nanozyme for spinal cord injury repair

Spinal cord injury (SCI) results in severe neurological deficits due to disrupted neural pathways. While the spinal cord possesses limited self-repair capabilities, recent advancements in hydrogel-based therapies have shown promise. Polyphenol-based hydrogels, known for their neuroprotective properties, offer a suitable microenvironment for neural regeneration. In this study, a novel poly(lipoic acid)/poly(dopamine) adhesive hydrogel was developed as a versatile platform for delivering therapeutic agents. This hydrogel was loaded with methylcobalamin, a neurotrophic factor, and tellurium nanoenzymes, potent antioxidants. The nanoenzymes effectively mitigated oxidative stress and inflammation, while methylcobalamin promoted nerve regeneration. The combined therapeutic effects of the nanoenzymatic hydrogel demonstrated significant efficacy in repairing spinal cord injuries, highlighting its potential as a promising strategy for treating this debilitating condition.

Engineered bacterial lipoate protein ligase A (lplA) restores lipoylation in cell models of lipoylation deficiency.

Protein lipoylation, a vital lysine posttranslational modification (PTM), plays a crucial role in the function of key mitochondrial TCA cycle enzymatic complexes. In eukaryotes, lipoyl PTM synthesis occurs exclusively through de novo pathways, relying on lipoyl synthesis/transfer enzymes, dependent upon mitochondrial fatty acid and Fe-S cluster biosynthesis. Dysregulation in any of these pathways leads to diminished cellular lipoylation. Efficient restoration of lipoylation in lipoylation deficiency cell states using either chemical or genetic approaches has been challenging due to pathway complexity and multiple upstream regulators. To address this challenge, we explored the possibility that a bacterial lipoate protein ligase (lplA) enzyme, that can salvage free lipoic acid bypassing the dependency on de novo synthesis, could be engineered to be functional in human cells. Overexpression of the engineered lplA in lipoylation null cells restored lipoylation levels, cellular respiration, and growth in low glucose conditions. Engineered lplA restored lipoylation in all tested lipoylation null cell models, mimicking defects in mitochondrial fatty acid synthesis (MECR KO), Fe-S cluster biosynthesis (BOLA3 KO), and specific lipoylation regulating enzymes (FDX1, LIAS and LIPT1 KOs). Furthermore, we describe a patient with a homozygous c.212C>T variant LIPT1 with a previously uncharacterized syndromic congenital sideroblastic anemia. K562 erythroleukemia cells engineered to harbor this missense LIPT1 allele recapitulate the lipoylation deficient phenotype and exhibit impaired proliferation in low glucose that is completely restored by engineered lplA. This synthetic approach offers a potential therapeutic strategy for treating lipoylation disorders.

Synthesis, Structure, and In Vitro Biological Evaluation of Semi-Synthetic Derivatives of Betulin

Betulin and α-lipoic acid are naturally occurring substances with different biological properties. Combining two phytochemical units into a conjugate is a frequently used method to obtain new compounds with better pharmacokinetic parameters. This research concerned the preparation of lipoate derivatives of betulin using the Steglich method. Experimental lipophilicity values were determined for target compounds 6–10 by reversed-phase thin-layer chromatography. In silico methods were used to calculate the physicochemical parameters and lipophilicity of new derivatives and to determine the probable directions of biological activity. α-Lipoic acid, betulin, and lipoate derivatives 6–10 were tested for antiproliferative activity against MV4-11, A549, MCF-7, PC-3, HCT116, MiaPaca-2, and Hs294T cancer cells. 3-(5-(1,2-Dithiolan-3-yl)pentanoyl))betulin 10 showed moderate anticancer activity against MV4-11, PC-3, and HCT116, with IC50 values in the range of 39.8–76.7 µM. The introduction of a dithiolate substituent at the C3 position in 28-acetylbetulin gave compound 9 the highest activity (IC50 = 37.9 µM), in the ratio of biphenotypic B myelomonocytic leukemia cells (MV4-11). All lipoate derivatives were inactive towards normal cells.

Practical supplements for prevention and management of migraine attacks: a narrative review.

Migraine is one of the most debilitating neurological disorders that causes frequent attacks of headaches and affects approximately 11% of the global population. Deficient or even insufficient levels of vital nutrients would increase the severity and frequency of migraine attacks. Therefore, we aimed to examine the practical supplements for the prevention and management of migraine attacks. This narrative review study was conducted by searching PubMed, ISI web of science, EMBASE, Google Scholar, and Scopus using the keywords of "dietary supplement" and "migraine" plus their MeSH terms. Original articles published in English language from their inception to July 27th, 2024, studies that investigated adult population (aged >18 years), and those assessing the impact of intended nutrient supplementation on clinical symptoms of migraine were included in the study. Oxidative stress and low intake of antioxidants would be risk factors for migraine attacks by inducing inflammation. The secretion of inflammatory cytokines, such as tumor necrosis factor (TNF)-a, would lead to neuroinflammation and migraine episodes by increasing the cellular permeability and interactions. Evidence also indicated a direct association between phases of migraine attacks and calcitonin gene-related peptide (CGRP), mitochondrial disorders, monoaminergic pathway, disruption in brain energy metabolism, and higher serum levels of glutamate and homocysteine. Therefore, supplementation with nutrients involved in mitochondrial function, brain energy metabolism, and even methyl donors would relieve migraine attacks. Evidence indicated that supplementation with riboflavin, omega-3 fatty acids, alpha lipoic acid, magnesium, probiotics, coenzyme Q10, ginger, and caffeine would have favorable effects on migraine patients. However, more prospective studies are required to evaluate the effect of other nutrients on migraine patients.

Analysis of MDA, SOD, TAOC, MNCV, SNCV, and TSS scores in patients with diabetes peripheral neuropathy.

To explore the impact of score in patients with diabetes peripheral neuropathy (DPN) treated with traditional Chinese medicine package (TCMP) plus red light therapy and lipoic acid on malondialdehyde (MDA), erythrocyte superoxide dismutase (SOD), total antioxidant capacity (TAOC), motor nerve conduction velocity (MNCV), sensory nerve conduction velocity (SNCV), and Toronto Clinical Scoring System (TSS). A total of 108 patients with DPN hospitalized in the hospital were chosen and divided into groups with the random number table. In the control group (CG) 54 patients were treated with conventional lipoic acid, and 54 patients in the experimental group (EG) accepted TCMP plus red light on the basis of the CG. The MDA, SOD, TAOC, MNCV, SNCV, and TSS scores before treatment and after treatment were compared between the two groups. Before treatment, there was no statistically significant difference in the levels of oxidation indicators, nerve conduction velocity, and symptom scores between the two groups (P > 0.05). After treatment, the MDA in the EG was lower than that in the CG, with a statistical significance difference (P < 0.05). The SOD and TAOC in the EG were higher than those in the CG, and the difference was statistically significant (P < 0.05). The MNCV and SNCV of median nerve, common peroneal nerve, and tibial nerve in the EG were significantly higher than those in the CG (P < 0.05). The TSS score of the EG was lower than that of the CG, and the difference was statistically significant (P < 0.05). The treatment of patients with DPN with lipoic acid plus TCMP and red light therapy can improve the symptoms and signs of disease, promote the recovery of motor and sensory conduction velocity, and optimize the body oxidation indicators.

Scalable Synthesis of Degradable Copolymers Containing α-Lipoic Acid via Miniemulsion Polymerization.

A robust method is described to synthesize degradable copolymers under aqueous miniemulsion conditions using α-lipoic acid as a cheap and scalable building block. Simple formulations of α-lipoic acid (up to 10 mol %), n-butyl acrylate, a surfactant, and a costabilizer generate stable micelles in water with particle sizes <200 nm. The ready availability of these starting materials facilitated performing polymerization reactions at large scales (4 L), yielding 600 g of poly(n-butyl acrylate-stat-α-lipoic acid) latexes that degrade under reducing conditions (250 kg mol-1 → 20 kg mol-1). Substitution of α-lipoic acid with ethyl lipoate further improves the solubility of dithiolane derivatives in n-butyl acrylate, resulting in copolymers that degrade to even lower molecular weights after polymerization and reduction. In summary, this convenient and scalable strategy provides access to large quantities of degradable copolymers and particles using cheap and commercially available starting materials.

Sustainable and Recyclable Acrylate Resins for Liquid-Crystal Display 3D Printing Based on Lipoic Acid.

The development of renewable vinyl-based photopolymer resins offers a promising solution to reducing the environmental impact associated with 3D printed materials. This study introduces a bifunctional lipoate cross-linker containing a dynamic disulfide bond, which is combined with acrylic monomers (n-butyl acrylate) and conventional photoinitiators to develop photopolymer resins that are compatible with commercial stereolithography 3D printing. The incorporation of disulfide bonds within the polymer network's backbone imparts the 3D printed objects with self-healing capabilities and complete degradability. Remarkably, the degraded resin can be fully recycled and reused for high-resolution reprinting of complex structures while preserving mechanical properties that are comparable to the original material. This proof-of-concept study not only presents a sustainable strategy for advancing acrylate-based 3D printing materials, but also introduces a novel approach for fabricating fully recyclable 3D-printed structures. This method paves the way for reducing the environmental impact while enhancing material reusability, offering significant potential for the development of eco-friendly additive manufacturing.

SIRT3, a New Hope in Liver Diseases from Pathogenic Mechanisms to Therapeutic Strategies.

The liver, the largest internal organ in the human body, regulates multiple reactions and processes, including detoxification, regeneration, and immune defense. Liver diseases have emerged as a significant global public health issue. Numerous studies have indicated that the mitochondrial deacetylase SIRT3 has played various roles in the pathogenesis and pathological progression of liver diseases. Objectives: This review aims to explore the advances in the study of SIRT3 and liver disease and review possible mechanisms. Natural and chemical activators of SIRT3 are also discussed. The role of SIRT3 in the pathogenic mechanisms and therapeutic strategies of liver disease is summarized by reviewing Pubmed. SIRT3 alleviates liver diseases by regulating fatty acid metabolism, mitochondrial function, and immune-inflammatory response. Meanwhile, Withaferin A, lipoic acid, major royal jelly proteins, and berberine can activate SIRT3 or upregulate its expression, thereby alleviating liver damage. SIRT3 can effectively slow down the progression of liver disease and protect the liver from further damage. The use of SIRT3 as a pharmacological target for the treatment of liver disease is a potential therapeutic approach.

Early Metabolomic Profiling as a Predictor of Renal Function Six Months After Kidney Transplantation

Background: Kidney transplantation is the therapy of choice for patients with advanced chronic kidney disease; however, predicting graft outcomes remains a significant challenge. Early identification of reliable biomarkers could enhance post-transplant management and improve long-term outcomes. This study aimed to identify metabolomic biomarkers within the first week after kidney transplantation that predict renal function at six months. Methods: We conducted a prospective study involving 50 adult patients who received deceased donor kidney transplants. Plasma samples collected one week after transplant were analyzed using liquid chromatography–mass spectrometry in a semi-targeted metabolomic approach. A Partial Least Squares-Discriminant Analysis (PLS-DA) model identified metabolites associated with serum creatinine &gt; 1.5 mg/dL at six months. Metabolites were selected based on a Variable Importance in Projection (VIP) score &gt; 1.5, which was used to optimize model performance. Results: The PLS-DA model demonstrated strong predictive performance with an area under the curve (AUC) of 0.958. The metabolites negatively associated with serum creatinine &gt; 1.5 mg/dL were 3-methylindole, guaiacol, histidine, 3-indolepropionic acid, and α-lipoic acid. Conversely, the metabolites positively associated with worse kidney graft outcomes included homocarnosine, 5-methylcytosine, xanthosine, choline, phenylalanine, kynurenic acid, and L-kynurenine. Conclusions: Early metabolomic profiling after transplantation shows promise in predicting renal function. Identifying metabolites with antioxidant and anti-inflammatory properties, as well as those that are harmful and could be targeted therapeutically, underscores their potential clinical significance. The link between several metabolites and the tryptophan pathway suggests that further specific evaluation of this pathway is warranted. These biomarkers can enhance patient management and graft survival.

Antibody Modification via Lipoic Acid Ligase A-Mediated Site-Specific Labeling.

Enzymatic modification, particularly utilizing lipoic acid ligase (LplA), has emerged as a transformative approach in biopharmaceuticals, enabling precise and site-specific protein modifications. This review delves into the innovative applications of LplA in antibody modifications, including the creation of antibody-drug conjugates (ADCs) and the advancement of tag-free conjugation techniques. LplA's ability to facilitate the incorporation of bioorthogonal groups and its adaptability to various substrates underscores its versatility. Key developments include the successful generation of dual-labeled antibodies and the application of LplA in modifying antibody fragments. Additionally, the review explores the potential for LplA to enhance the therapeutic efficacy of ADCs through improved drug-to-antibody ratios and site-specific payload attachment. The implications of these advancements are significant, suggesting that LplA-mediated modifications could lead to more effective and targeted antibody-based therapies. This review aims to provide a comprehensive overview of LplA's role in expanding the possibilities of enzymatic conjugation, setting the stage for future research and clinical applications.