Chronic stress has been linked to a large number of pathologies, including cancer, premature aging, and neurodegenerative diseases. The accumulation of molecular waste resulting from oxidative and heavy metal-induced stress has been ascribed as a major factor contributing to these diseases. With this in mind, we started by screening 13 small molecules to determine their antistress potential in heavy metal stress-exposed C6 glioblastoma and found that alpha-lipoic acid (ALA) (a natural antioxidant abundantly present in yeast, spinach, broccoli, and meat) was the most effective candidate. We then conducted molecular analyses to validate its mechanism of action. Dose-dependent toxicity assays of cells treated with two ALA enantiomers, R-ALA and S-ALA, showed that they are nontoxic and can be tolerated at relatively high doses. Cells exposed to heavy metal, heat, and oxidative stress showed better recovery when cultured in R-ALA-/S-ALA-supplemented medium, supported by reduction of reactive oxygen species (ROS), aggregated proteins, and mitochondrial and deoxyribonucleic acid (DNA) damage. Molecular analyses revealed protection against stress-induced apoptosis and induction of autophagy in R-ALA- and S-ALA-treated C6/U2OS cells. Consistent with these findings, normal human fibroblasts showed lifespan extension. Taken together, this study demonstrates that lipoic acid has antiaging and antistress potential and warrants further attention in laboratory and clinical studies.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a prevalent condition characterized by hepatic fat accumulation, often progressing to severe liver injury, for which approved treatments are currently lacking. This study explores the potential therapeutic impact of alpha-lipoic acid (ALA), a natural compound crucial in lipid metabolism, on NAFLD using an in vitro model.
METHODS: HepG2 cells were treated with a palmitic acid:oleic acid (PA:OA) mixture, representing a cellular model of steatosis. Subsequent treatment with ALA at concentrations of 1 µM and 5 µM aimed to evaluate its effects on lipid content and metabolism. Real-time polymerase chain reaction (PCR), BODIPY staining, cytofluorimetric analysis, and lipidomics were used to assess gene expression, lipid droplet accumulation, and fatty acid profiles.
RESULTS: Our results showed that ALA significantly reduced lipid droplets in PA:OA-treated HepG2 cells, with a concentration-dependent effect. Analysis of fatty acid profiles demonstrated a decrease in palmitic acid levels with ALA treatment, while oleic acid reduction was observed only at the higher concentration. Moreover, ALA modulated the expression of genes involved in cholesterol biosynthesis and low-density lipoprotein (LDL) metabolism, indicating a potential role in lipid homeostasis. Further insights into molecular mechanisms revealed that ALA modulated peroxisome proliferator activated receptors (PPARs), specifically PPAR-alpha and PPAR-gamma, involved in fatty acid metabolism and insulin sensitivity. Finally, ALA counteracted the overexpression of thermogenic genes induced by exogenous fatty acids, suggesting a regulatory role in energy dissipation pathways.
CONCLUSIONS: In conclusion, this study highlights ALA as a therapeutic agent in mitigating lipid accumulation and dysregulation in NAFLD.

Mitochondrial fatty acids synthesis (mtFAS) is a conserved metabolic pathway essential for mitochondrial respiration. The best characterized mtFAS product is the medium-chain fatty acid octanoate (C8) used as a substrate in the synthesis of lipoic acid (LA), a cofactor required by several mitochondrial enzyme complexes. In humans, mutations in the mtFAS component enoyl reductase MECR cause childhood-onset neurodegenerative disorder MEPAN. A complete deletion of Mecr in mice is embryonically lethal, while selective deletion of Mecr in cerebellar Purkinje cells causes neurodegeneration in these cells. A fundamental question in the research of mtFAS deficiency is if the defect is amenable to treatment by supplementation with known mtFAS products. Here we used the Purkinje-cell specific mtFAS deficiency neurodegeneration model mice to study if feeding the mice with a medium-chain triacylglycerol-rich formula supplemented with LA could slow down or prevent the neurodegeneration in Purkinje cell-specific Mecr KO mice. Feeding started at the age of 4 weeks and continued until the age of 9 months. The neurological status on the mice was assessed at the age of 3, 6 and 9 months with behavioral tests and the state of the Purkinje cell deterioration in the cerebellum was studied histologically. We showed that feeding the mice with medium chain triacylglycerols and LA affected fatty acid profiles in the cerebellum and plasma but did not prevent the development of neurodegeneration in these mice. Our results indicate that dietary supplementation with medium chain fatty acids and LA alone is not an efficient way to treat mtFAS disorders.

Lipoic acid (LA) is an essential cofactor in prokaryotic and eukaryotic organisms, required for the function of several multienzyme complexes such as oxoacid dehydrogenases. Prokaryotes either synthesize LA or salvage it from the environment. The salvage pathway in Staphylococcus aureus includes two lipoate-protein ligases, LplA1 and LplA2, as well as the amidotransferase LipL. In this study, we intended to hijack the salvage pathway by LA analogues that are transferred via LplA2 and LipL to the E2 subunits of various dehydrogenases, thereby resulting in nonfunctional enzymes that eventually impair viability of the bacterium. Initially, a virtual screening campaign was carried out to identify potential LA analogues that bind to LplA2. Three selected compounds affected S. aureus USA300 growth in minimal medium at concentrations ranging from 2.5 to 10 μg/mL. Further analysis of the most potent compound (Lpl-004) revealed its transfer to E2 subunits of dehydrogenase complexes and a negative impact on its functionality. Growth impairment caused by Lpl-004 treatment was restored by adding products of the lipoate-dependent enzyme complexes. In addition, Caenorhabditis elegans infected with LpL-004-treated USA300 demonstrated a significantly expanded lifespan compared to worms infected with untreated bacteria. Our results provide evidence that LA analogues exploiting the LA salvage pathway represent an innovative strategy for the development of novel antimicrobial substances.

UNASSIGNED: Neural epidermal growth factor like 1 membranous nephropathy (NELL1 MN) is associated with various secondary etiologies. However, previous studies on the frequency of these associations and their impact on outcomes are limited. We report a large multiinstitutional series of patients with NELL1 MN with a focus on secondary associations, pathology findings, and their impact on outcome.
UNASSIGNED: We retrospectively reviewed clinicopathologic features of NELL1 MN from 3 institutions and analyzed clinical and histologic associations with outcome.
UNASSIGNED: Of 70 patients, 53% were male with a median age of 66 years; median proteinuria was 5.9 g/d. NELL1 MN was associated with lipoic acid (36%), heavy nonsteroidal antiinflammatory drug (NSAID) use (27%), autoimmune disease (23%), malignancy (10% recent, 23% any), mercury exposure (1%), and 11% had no known secondary association. At median follow-up of 11 months, 72% achieved complete or partial remission. Remission rate was 91% in patients with lipoic acid-associated NELL1 MN and ≥6 months of follow-up. On multivariable analyses, patients with primary NELL1 MN (adjusted odds ratio [OR]: 19.7, P = 0.01) and increasing degree of tubular atrophy and interstitial fibrosis (IFTA) (adjusted OR 1.1, P = 0.01) were less likely to achieve any remission, whereas complete remission (CR) was associated with lipoic acid use (adjusted OR: 10.9, P = 0.04, 95% confidence interval [CI]: 1.2-100) and lesser degrees of IFTA (adjusted OR: 0.79, P = 0.16, 95% CI: 0.66-0.96).
UNASSIGNED: Our findings strengthen the association between lipoic acid and NELL1 MN. Furthermore, our findings suggest that discontinuation of lipoic acid without immunosuppression should be considered as the first-line treatment.

UNASSIGNED: Exogenous use of potential organic compounds through different modes is a promising strategy for the induction of water stress tolerance in crop plants for better yield.
UNASSIGNED: The present study aimed to explore the potential role of alpha-lipoic acid (ALA) in inducing water stress tolerance in mungbean lines when applied exogenously through various modes.
UNASSIGNED: The experiment was conducted in a field with a split-plot arrangement, having three replicates for each treatment. Two irrigation regimes, including normal and reduced irrigation, were applied. The plants allocated to reduced irrigation were watered only at the reproductive stage. Three levels of ALA (0, 0.1, 0.15 mM) were applied through different modes (seed priming, foliar or priming+foliar).
UNASSIGNED: ALA treatment through different modes manifested higher growth under reduced irrigation (water stress) and normal irrigation. Compared to the other two modes, the application of ALA as seed priming was found more effective in ameliorating the adverse impacts of water stress on growth and yield associated with their better content of leaf photosynthetic pigments, maintenance of plant water relations, levels of non-enzymatic antioxidants, improved activities of enzymatic antioxidants, and decreased lipid peroxidation and H2O2 levels. The maximum increase in shoot fresh weight (29% and 28%), shoot dry weight (27% and 24%), 100-grain weight (24% and 23%) and total grain yield (20% and 21%) in water-stressed mungbean plants of line 16003 and 16004, respectively, was recorded due to ALA seed priming than other modes of applications.
UNASSIGNED: Conclusively, 0.1 and 0.15 mM levels of ALA as seed priming were found to reduce the adverse impact of water stress on mungbean yield that was associated with improved physio-biochemical mechanisms.
UNASSIGNED: The findings of the study will be helpful for the agriculturalists working in arid and semi-arid regions to obtain a better yield of mungbean that will be helpful to fulfill the food demand in those areas to some extent.

BACKGROUND: Breast cancer, the deadliest disease affecting women globally, exhibits heterogeneity with distinct molecular subtypes. Despite advances in cancer therapy, the persistence of high mortality rates due to chemotherapy resistance remains a major challenge. Lipoic acid (LA), a natural antioxidant, has proven potent anticancer properties. Yet, the impact of LA on microRNA (miRNA) expression profile in breast cancer remains unexplored.
OBJECTIVE: The aim of this study was to unravel the effect of LA on miRNA expression profiles in different breast cancer cell lines.
METHODS: The MiRCURY LNA miRNA miRNome qPCR Panel was used to compare the miRNA signature in MDA-MB-231 and MCF-7 cells treated or not with LA.
RESULTS: We identified six upregulated and six downregulated miRNAs in LA-treated MDA-MB-231 cells and 14 upregulated and four downregulated miRNAs in LA-treated MCF-7 cells compared to control cells. KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis revealed that the deregulated miRNAs could alter different signaling cascades including FoxO, P53 and Hippo pathways.
CONCLUSIONS: The outcome of this study provides further insights into the molecular mechanisms underlying the therapeutic benefit of LA. This in turn could assist the amelioration of LA-based anticancer therapies.

SUMMARYLipoic acid-modified proteins are essential for central metabolism and pathogenesis. In recent years, the Escherichia coli and Bacillus subtilis lipoyl assembly pathways have been modified and extended to archaea and diverse eukaryotes including humans. These extensions include a new pathway to insert the key sulfur atoms of lipoate, several new pathways of lipoate salvage, and a novel use of lipoic acid in sulfur-oxidizing bacteria. Other advances are the modification of E. coli LplA for studies of protein localization and protein-protein interactions in cell biology and in enzymatic removal of lipoate from lipoyl proteins. Finally, scenarios have been put forth for the evolution of lipoate assembly in archaea.

Neural epidermal growth factor-like 1 (NELL1) membranous nephropathy (MN) is notable for its segmental deposit distribution, IgG1 dominant deposits, and comparatively high rate of spontaneous remission. It has been associated with a variety of exposures and secondary conditions, specifically use of thiol-containing medications - including lipoic acid, bucillamine, and tiopronin - as well as traditional indigenous medications (TIM) particularly those with high mercury content, and non-steroid anti-inflammatory drugs (NSAIDs). Malignancies, graft vs. host disease (GVHD), infection, and autoimmune conditions have also been associated with NELL1 MN. Herein, we provide a detailed summary of the clinicopathologic features of NELL1 and associations with underlying conditions, with a focus on treatment and outcomes. Rare cases of dual NELL1 and phospholipase A2 receptor (PLA2R) positive MN are reviewed. Genome-wide association study of NELL1, role of NELL1 in other physiologic and pathologic processes, and connection between NELL1 MN and malignancy with relevance of NELL1 tumor staining are examined. Finally, relationships and potential disease mechanisms of thiol- and mercury- associated NELL1 MN are discussed.

Local drug delivery has been exploited recently to treat hearing loss, as this method can both bypass the blood-labyrinth barrier and provide sustained drug release. Combined drug microcrystals (MCs) offer additional advantages for sensorineural hearing loss treatment via intratympanic (IT) injection due to their shape effect and combination strategy. In this study, to endow viscous effects of hydrogels, nonspherical dexamethasone (DEX) and lipoic acid (LA) MCs were incorporated into silk fibroin (SF) hydrogels, which were subsequently administered to the tympanic cavity to investigate their pharmaceutical properties. First, we prepared DEX and LA MCs by a traditional precipitation technique followed by SF hydrogel incorporation (SF+DEX+LA). After characterization of the physicochemical features, including morphology, rheology, and dissolution, both a suspension of combined DEX and LA MCs (DEX+LA) and SF+DEX+LA were administered to guinea pigs by IT injection, after which the pharmacokinetics, biodegradation and biocompatibility were evaluated. To our surprise, compared to the DEX+LA group, the pharmacokinetics of the SF+DEX+LA hydrogel group did not improve significantly, which may be ascribed to their nonspherical shape and deposition effects of the drugs MCs. The cochlear tissue in each group displayed good morphology, with no obvious inflammatory reactions. This combined MC suspension has the clear advantages of no vehicle, easy scale-up preparation, and good biocompatibility and outcomes, which paves the way for practical treatment of hearing loss via local drug delivery.