Alpha lipoic acid diminishes migration and invasion in hepatocellular carcinoma cells through an AMPK-p53 axis.

Hepatocellular carcinoma (HCC) associated with viral or metabolic liver diseases is a growing cancer without effective therapy. AMPK is downregulated in HCC and its activation diminishes tumor growth. Alpha lipoic acid (ALA), an indirect AMPK activator that inhibits hepatic steatosis, shows antitumor effects in different cancers. We aimed to study its putative action in liver-cancer derived cell lines through AMPK signaling. We performed cytometric studies for apoptosis and cell cycle, and 2D and 3D migration analysis in HepG2/C3A and Hep3B cells. ALA led to significant inhibition of cell migration/invasion only in HepG2/C3A cells. We showed that these effects depended on AMPK, and ALA also increased the levels and nuclear compartmentalization of the AMPK target p53. The anti-invasive effect of ALA was abrogated in stable-silenced (shTP53) versus isogenic-TP53 HepG2/C3A cells. Furthermore, ALA inhibited epithelial-mesenchymal transition (EMT) in control HepG2/C3A but not in shTP53 nor in Hep3B cells. Besides, we spotted that in patients from the HCC-TCGA dataset some EMT genes showed different expression patterns or survival depending on TP53. ALA emerges as a potent activator of AMPK-p53 axis in HCC cells, and it decreases migration/invasion by reducing EMT which could mitigate the disease in wild-type TP53 patients.

Effects of alfa lipoic acid and coenzyme Q10 treatment on AFB1-induced oxidative, inflammatory, and DNA damages in rats.

Food contamination with Aflatoxin B1 (AFB1) is a worldwide concern that adversely affects animal and human health. The study aimed to evaluate the protective effect of alpha lipoic acid (ALA) and/or co-enzyme Q10 (CQ10) against the harmful effects of AFB1 on the liver and kidneys. Fifty-six mature male Wistar Albino rats (180-200 g) were divided into seven groups, each with eight rats: (1) saline was given as a control, (2) ALA (100 mg/kg bw/day) was given by stomach gavage for fifteen days, and (3) CQ10 (10 mg/kg bw/day) was given by stomach gavage for fifteen days. Group (4) orally given AFB1 (2.5 mg/kg bw) on days 12th and 14th, (5) received AFB1 and ALA, (6) received AFB1 and CQ10, and (7) received AFB1, ALA, and CQ10, as previously described in the ALA, CQ10, and AFB1 groups. After the exposure to AFB1, a significant increase in liver markers (AST, ALT, ALP, and LDH) and renal function tests (BUN and creatinine) was observed compared with the control. ALA and/or CQ10 significantly reduced enzymes of liver and renal functions, as compared with AFB1. AFB1 exposure threw off the balance between oxidants and antioxidants. Still, ALA and/or CQ10 made oxidative stress (MDA, NO, and 8-OHdG) much lower and antioxidant activities (GSH, GSH-Px, SOD, and CAT) much higher. When we used the two together, the activities matched the control levels. Interestingly, this study shows that ALA and CQ10 significantly lowered IL-1ß, IL-6, and TNF-α levels compared to the control values when used together after AFB1 exposure caused robust inflammation. Some CQ10 treatment parameters significantly outperformed those of ALA. ALA and CQ10 together worked better than either one alone to protect against AFB1-induced toxicity in the hepatic and renal parenchyma in terms of reducing inflammation, preventing DNA damage, and fighting free radicals.

Synthesis and evaluation of lipoic acid - donepezil hybrids for Alzheimer's disease using a straightforward strategy.

Alzheimer's disease is associated with a progressive loss of neurons and synaptic connections in the cholinergic system. Oxidative stress contributes to neuronal damages and to the development of amyloid plaques and neurofibrillary tangles. Therefore, antioxidants have been widely studied to mitigate the progression of Alzheimer's disease, and among these, lipoic acid has demonstrated a neuroprotective effect. Here, we present the synthesis, the molecular modelling, and the evaluation of lipoic acid-donepezil hybrids based on O-desmethyldonepezil. As compounds 5 and 6 display a high inhibition of acetylcholinesterase (IC50 = 7.6 nM and 9.1 nM, respectively), selective against butyrylcholinesterase, and a notable neuroprotective effect, slightly better than that of lipoic acid, the present study suggests that O-desmethyldonepezil could serve as a platform for the straightforward design of donepezil hybrids.

α-Lipoic acid increases the viability of nephrocytes and elevates sulfane sulfur level in plasma of patients with chronic kidney disease.

BACKGROUND: Kidney diseases are a major global health problem affecting millions of people. Despite this, there is as yet no effective drug therapy improving outcome in patients with renal disease. The aim of this study was to examine the nephroprotective effect of α-lipoic acid (ALA) in vitro and to examine the effect of ALA administered in vivo on the production of reactive sulfur species (RSS), including hydrogen sulfide (H2S) and compounds containing sulfane sulfur. METHODS: The effect of ALA was studied in vitro by determining the viability of human embryonic kidney cells (HEK293) in normoxic and hypoxic conditions as well as in vivo in two groups of chronic kidney disease (CKD) patients: non-dialyzed (ND) and undergoing continuous ambulatory peritoneal dialysis (PD) after 30 days of ALA supplementation. RESULTS: The results revealed that the viability of HEK293 cells was significantly decreased by hypoxic conditions, while ALA administered during hypoxia increased the viability to the level observed in normoxic conditions. Studies performed in plasma of CKD patients after ALA supplementation suggested that ALA did not affect the parameters of oxidative stress, while significantly increased the level of reactive sulfane sulfur in both ND and PD patients suffering from CKD. The results suggest that ALA can exert nephroprotective effects which are related to sulfane sulfur production.

Ischemic Microenvironment-Targeted Bioinspired Lipoprotein Sequentially Penetrates Cerebral Ischemic Lesions to Rescue Ischemic Stroke.

Reperfusion injury represents a significant impediment to recovery after recanalization in an ischemic stroke and can be alleviated by neuroprotectants. However, inadequate drug delivery to ischemic lesions impairs the therapeutic effects of neuroprotectants. To address this issue, an ischemic microenvironment-targeted bioinspired lipoprotein system encapsulating lipoic acid (LA@PHDL) is herein designed to sequentially penetrate ischemic lesions and be readily taken up by neurons and microglia. In transient middle cerebral artery occlusion (tMCAO) mouse models, LA@PHDL accumulates rapidly and preferentially in the ischemic brain, with a 2.29-fold higher than the nontargeted nanoplatform in the early stage. Furthermore, LA@PHDL effectively restores neurological function, reduces infarct volume to 17.70%, prevents brain cell necrosis and apoptosis, and attenuates inflammation in tMCAO mouse models. This design presents new opportunities for delivering neuroprotectants to cerebral ischemic lesions to improve the outcome of an ischemic stroke.

Mitochondria as a primary determinant of angiogenic modality in pulmonary arterial hypertension.

Impaired pulmonary angiogenesis plays a pivotal role in the progression of pulmonary arterial hypertension (PAH) and patient mortality, yet the molecular mechanisms driving this process remain enigmatic. Our study uncovered a striking connection between mitochondrial dysfunction (MD), caused by a humanized mutation in the NFU1 gene, and severely disrupted pulmonary angiogenesis in adult lungs. Restoring the bioavailability of the NFU1 downstream target, lipoic acid (LA), alleviated MD and angiogenic deficiency and rescued the progressive PAH phenotype in the NFU1G206C model. Notably, significant NFU1 expression and signaling insufficiencies were also identified in idiopathic PAH (iPAH) patients' lungs, emphasizing this study's relevance beyond NFU1 mutation cases. The remarkable improvement in mitochondrial function of PAH patient-derived pulmonary artery endothelial cells (PAECs) following LA supplementation introduces LA as a potential therapeutic approach. In conclusion, this study unveils a novel role for MD in dysregulated pulmonary angiogenesis and PAH manifestation, emphasizing the need to correct MD in PAH patients with unrecognized NFU1/LA deficiency.

In situ gel-forming oil solubilizing α-lipoic acid as a physical shielding alleviated chemotherapy-induced oral mucositis via inhibiting oxidative stress.

Oral mucositis (OM) is a common and serious complication of cancer chemoradiotherapy. OM managements mainly focused on topical healthcare or analgesia, which offers limited wound healing. Herein, in situ gel-forming oil (LGF) have been developed as a physical shielding for OM treatment. LGF oil, composed of soybean phosphatidyl choline (40 %, w/w), glycerol dioleate (54 %, w/w), and alcohols (6 %, w/w), is a viscous oil-like liquid. The contact angle of LGF oil on porcine buccal mucosa were 30°, significantly smaller than that of water (60°), indicating its good wetting and spreading properties. Besides, the adhesion force and adhesion energy of LGF oil toward porcine buccal mucosa was as high as 3.9 ± 0.2 N and 60 ± 2 J/m2, respectively, indicating its good adhesive property. Moreover, the hydrophobic α-lipoic acid (LA) as a native antioxidative agent was highly solubilized in LGF oil, its solubility in which was above 100 mg/mL. Upon contacting with saliva, LA-loaded LGF oil (LA-LGF) could rapidly transform from oil into gel that adheres on oral mucosa. Moreover, LA was slowly released from the formed LA-LGF gel, which benefited alleviating oxidative stress caused by chemoradiotherapy. In vivo animal experiments showed that LA-LGF could effectively promote the repairing of oral mucosa wound of 5-fluorouracil induced OM rats. Besides, the mucosa edema was greatly improved and new granulation around wound was produced after LA-LGF treatment. Meanwhile, the production of proinflammatory cytokines such as IL-1ß, TNF-α, 1L-6 was substantially inhibited by LA-LGF. Collectively, LGF oil as carrier of hydrophobic drug might be a promising strategy for oral mucositis.

Alpha-Lipoic Acid Ameliorates Impaired Steroidogenesis in Human Granulosa Cells Induced by Advanced Glycation End-Products.

Background: Ovarian granulosa cells (GCs) are essential for follicular development. Ovarian advanced glycation end-products (AGEs) accumulation is related to GCs dysfunction. Alpha-lipoic acid (ALA) illustrates therapeutic capabilities for infertility-related disorders. Therefore, this study assessed the effects of ALA on AGEs-induced GCs hormonal dysfunction. Methods: The study was conducted from October 2021 to September 2022 at the Department of Medical Genetics, Shiraz University of Medical Sciences. Isolated GCs (n=50) were divided into control, human glycated albumin (HGA), HGA+ALA, and ALA treatments. Steroidogenic enzymes and AGE receptor (RAGE) genes were assessed by qRT-PCR. Steroid hormones and RAGE protein were evaluated using ELISA and Western blotting. Data were analyzed using GraphPad Prism software (ver. 9), and P<0.05 was considered significant. Results: Our findings showed that HGA treatment significantly (P=0.0001) increased RAGE (by 140.66%), STAR (by 117.65%), 3ß-HSD (by 165.68%), and 17ß-HSD (by 122.15%) expression, while it decreased CYP19A1 (by 68.37%) expression. RAGE protein level (by 267.10%) was also increased in HGA-treated GCs. A significant decrease in estradiol (by 59.66%) and a slight and sharp elevation in progesterone (by 30.40%) and total testosterone (by 158.24%) levels was also observed. ALA treatment ameliorated the HGA-induced changes in steroidogenic enzyme mRNA levels (P=0.001) and steroid hormone secretion (P=0.010). Conclusion: This work shows that ALA therapy likely corrects hormonal dysfunctions caused by AGEs in luteinized GCs. This effect is probably achieved by decreased RAGE expression. Clinical research is needed to understand how AGEs and ALA interact in the ovary, which might lead to a more targeted ovarian dysfunction therapy.

The neuroprotective effects of alpha lipoic acid in rotenone-induced Parkinson's disease in mice via activating PI3K/AKT pathway and antagonizing related inflammatory cascades.

Parkinson's disease (PD) is an idiopathic disease caused by the loss or degeneration of the dopaminergic (dopamine-producing) neurons in the brain and characterized by various inflammatory and apoptotic responses in the neuronal cells. Phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) axis is responsible for neuronal survival by providing a number of anti-inflammatory and anti-apoptotic milieu that prevent the progression of PD. Alpha-lipoic acid (ALA) is a natural cofactor that has antioxidant capacity and contributes to various metabolic processes. ALA can penetrate the blood-brain barrier and contribute to numerous neuroprotective effects. It can activate PI3K/AKT pathway with consequent reduction of different inflammatory and oxidative biomarkers. Our work aims to unfold the neuroprotective effects of ALA via targeting PI3k/AKT pathway. Forty male mice were divided into four groups: control, ALA (100 mg/kg/day; i.p.), rotenone (ROT) (1.5 mg/kg/2 days, i.p.) and rotenone + ALA for 21 days. ALA showed obvious neuroprotective effects via significant activation of PI3K/AKT pathway with subsequent decreasing level of Caspase-3. ALA resulted in prominent anti-inflammatory actions by decreasing interlukin-1ß (IL-1ß), tumor necrosis factor (TNF)-α and nuclear factor kabba (NFk)-B. ALA remarkably induced antioxidant activities via increasing reduced glutathione (GSH) and superoxide dismutase (SOD) levels as well as decreasing malondialdehyde (MDA) level. The substantial behavioral improvement reflected in these results was noticed in the ALA-treated mice as a reflection of the neuroprotective activities of ALA. In conclusion, ALA showed promising neuroprotective effects in rotenone-induced PD via activating the PI3K/AKT pathway and consequent inhibition of apoptotic and inflammatory biomarkers.

Protective effects of alpha-lipoic acid and alagebrium chloride against testicular dysfunction induced by varicocele and advanced glycation end (AGE) - Rich diet in a rat mode.

Heat stress from varicocele can heighten oxidative stress in the testes, impacting sperm function and male fertility. Antioxidant therapy is explored as a remedy for varicocele, while dietary factors like processed foods, sugar, and saturated fats correlate with male infertility. Advanced glycation end products (AGEs), generated through glycation processes, can provoke oxidative stress, inflammation, and adverse health consequences. Alpha-lipoic acid (ALA), a versatile antioxidant, may alleviate oxidative stress and counteract the impact of AGEs, potentially by enhancing glucose reabsorption. Alagebrium chloride (ALT711), an anti-AGE compound, exhibits promise in cardiovascular disease by disrupting AGE cross-links. This study investigates the effects of ALA and ALT-711 on testicular function in varicocele and AGEs animal models. Both AGE and varicocele were found to alter the natural trends, leading to abnormal patterns in sperm parameters, testicular functional tests, as well as the expression of CML, RAGE, and TNF-α proteins. However, the administration of ALA or ALT711 helped mitigate these effects. While ALA demonstrated a slightly greater overall benefit compared to ALT, the difference was not statistically significant.

Taurine, alpha lipoic acid and vitamin B6 ameliorate the reduced developmental competence of immature mouse oocytes exposed to methylglyoxal.

Advanced glycation end products (AGEs) are the final products of the Maillard reaction, formed through the interaction of carbohydrates and proteins. Reactive dicarbonyl compounds such as methylglyoxal (MGO) serve as precursors for AGEs formation. Elevated levels of MGO/AGEs are observed in conditions like obesity, polycystic ovarian syndrome (PCOS), and diabetes, negatively impacting oocyte development. Previous studies have shown that hydrogen sulfide, a gasotransmitter with anti-AGEs effects, is produced in a process influenced by vitamin B6. R-α-lipoic acid (ALA) inhibits protein glycation and AGEs formation while stimulating glutathione (GSH) production. Taurine mitigates oxidative stress and acts as an anti-glycation compound, preventing in vitro glycation and AGEs accumulation. This study aimed to explore the ameliorative effects of a micronutrient support (Taurine, ALA and B6: TAB) on mouse oocytes challenged with MGO. Our results indicate that MGO reduces oocyte developmental competence, while TAB supplementation improves maturation, fertilization, and blastocyst formation rates. TAB also restores cell lineage allocation, redox balance and mitigates mitochondrial dysfunction in MGO-challenged oocytes. Furthermore, cumulus cells express key enzymes in the transsulfuration pathway, and TAB enhances their mRNA expression. However, TAB does not rescue MGO-induced damage in denuded oocytes, emphasizing the supportive role of cumulus cells. Overall, these findings suggest that TAB interventions may have significant implications for addressing reproductive dysfunctions associated with elevated MGO/AGEs levels. This study highlights the potential of TAB supplementation in preserving the developmental competence of COCs exposed to MGO stress, providing insights into mitigating the impact of dicarbonyl stress on oocyte quality and reproductive outcomes.

The Antioxidant and HDAC-Inhibitor α-Lipoic Acid Is Synergistic with Exemestane in Estrogen Receptor-Positive Breast Cancer Cells.

Anti-estrogenic therapy is established in the management of estrogen receptor (ER)-positive breast cancer. However, to overcome resistance and improve therapeutic outcome, novel strategies are needed such as targeting widely recognized aberrant epigenetics. The study aims to investigate the combination of the aromatase inhibitor exemestane and the histone deacetylase (HDAC) inhibitor and antioxidant α-lipoic acid in ER-positive breast cancer cells. First, the enantiomers and the racemic mixture of α-lipoic acid, and rac-dihydro-lipoic acid were investigated for HDAC inhibition. We found HDAC inhibitory activity in the 1-3-digit micromolar range with a preference for HDAC6. Rac-dihydro-lipoic acid is slightly more potent than rac-α-lipoic acid. The antiproliferative IC50 value of α-lipoic acid is in the 3-digit micromolar range. Notably, the combination of exemestane and α-lipoic acid resulted in synergistic behavior under various incubation times (24 h to 10 d) and readouts (MTT, live-cell fluorescence microscopy, caspase activation) analyzed by the Chou-Talalay method. α-lipoic acid increases mitochondrial fusion and the expression of apoptosis-related proteins p21, APAF-1, BIM, FOXO1, and decreases expression of anti-apoptotic proteins survivin, BCL-2, and c-myc. In conclusion, combining exemestane with α-lipoic acid is a promising novel treatment option for ER-positive breast cancer.

Targeted nanoparticles triggered by plaque microenvironment for atherosclerosis treatment through cascade effects of reactive oxygen species scavenging and anti-inflammation.

Inflammatory factors and reactive oxygen species (ROS) are risk factors for atherosclerosis. Many existing therapies use ROS-sensitive delivery systems to alleviate atherosclerosis, which achieved certain efficacy, but cannot eliminate excessive ROS. Moreover, the potential biological safety concerns of carrier materials through chemical synthesis cannot be ignored. Herein, an amphiphilic low molecular weight heparin- lipoic acid conjugate (LMWH-LA) was used as a ROS-sensitive carrier material, which consisted of injectable drug molecules used clinically, avoiding unknown side effects. LMWH-LA and curcumin (Cur) self-assembled to form LLC nanoparticles (LLC NPs) with LMWH as shell and LA/Cur as core, in which LMWH could target P-selectin on plaque endothelial cells and competitively block the migration of monocytes to endothelial cells to inhibit the origin of ROS and inflammatory factors, and LA could be oxidized to trigger hydrophilic-hydrophobic transformation and accelerate the release of Cur. Cur released within plaques further exerted anti-inflammatory and antioxidant effects, thereby suppressing ROS and inflammatory factors. We used ultrasound imaging, pathology and serum analysis to evaluate the therapeutic effect of nanoparticles on atherosclerotic plaques in apoe-/- mice, and the results showed that LLC showed significant anti-atherosclerotic effects. Our finding provided a promising therapeutic nanomedicine for the treatment of atherosclerosis.

Potential effects of Resatorvid and alpha lipoic acid on gentamicin-induced nephrotoxicity in rats.

Gentamicin is an aminoglycoside antibiotic with a rapid bactericidal effect on the treatment of many infections. However, its use at high concentrations for more than 7 days causes nephrotoxic side effects. This study investigated the potential of Resatorvid and alpha lipoic acid (ALA) in mitigating gentamicin-induced nephrotoxicity in rats, considering biochemical, histopathological, and molecular parameters. This study randomly distributed 34 Wistar albino rats into four groups: healthy control (n = 6), Gentamicin (80 mg/kg, n = 7), Gentamicin + Sham (%10 hydroalcoholic solution, n = 7), Gentamicin + Resatorvid (5 mg/kg, n = 7), and Gentamicin + ALA (100 mg/kg, n = 7). Resatorvid treatment led to a statistically significant decrease in urinary IL-18, KIM-1, and NGAL levels, whereas ALA treatment significantly reduced KIM-1 levels compared to the gentamicin-only group. Both Resatorvid and ALA showed partial reductions in urine creatinine levels. Moreover, treatments with Resatorvid and ALA resulted in statistically significant decreases in NRF-2, CAS-3, and NR4A2 expressions. However, only Resatorvid demonstrated a statistically significant decrease in NF-B expression. These findings highlight the potential of Resatorvid in ameliorating gentamicin-induced nephrotoxicity, thereby expanding the therapeutic utility of gentamicin and enhancing its efficacy against infections.

Outcomes of dietary alpha-lipoic acid on testicular vascularization, steroid hormones, and seminal quality in aged Baladi bucks.

BACKGROUND: Senescence is accompanied by a progressive decrease in male reproductive performance, mainly due to oxidative stress and endothelial dysfunction. Alpha lipoic acid (ALA) is a potent antioxidant, that diffuses freely in aqueous and lipid phases, possessing anti-inflammatory and anti-apoptotic properties. This study aimed to examine the effects of supplemental dietary ALA on testicular hemodynamics (TH), circulating hormones, and semen quality in aged goats. Twelve Baladi bucks were divided into two groups (n = 6 each); the first fed a basic ration and served as a control group (CON), while the second received the basic ration supplemented with 600 mg ALA/ kg daily for consecutive eight weeks (ALA). RESULTS: There were improvements in testicular blood flow in the ALA group evidenced by a lower resistance index (RI) and pulsatility index (PI) concurrent with higher pampiniform-colored areas/pixel (W3-W6). There were increases in testicular volume and decreases in echogenicity (W3-W5; ALA vs. CON). Compared to the CON, ALA-bucks had higher serum concentrations of testosterone, estradiol, and nitric oxide (W3-W5). There were enhancements in semen traits (progressive motility, viability, morphology, and concentration, alanine aminotransferase enzyme) and oxidative biomarkers (catalase, total antioxidant capacity, and malondialdehyde). CONCLUSIONS: ALA dietary supplementation (600 mg/kg diet) improved aged bucks' reproductive performance by enhancing the testicular volume, testicular hemodynamics, sex steroids, and semen quality.

Protective effects of the R-(+)-thioctic acid treatment: possible anti-inflammatory activity on heart of hypertensive rats.

BACKGROUND: In cardiovascular disease, high blood pressure is associated with oxidative stress, promoting endothelial dysfunction, vascular remodeling, and inflammation. Clinical trials are discordant that the most effective treatment in the management of hypertension seems to be the administration of anti-hypertensive drugs with antioxidant properties. The study aims to evaluate the effects of the eutomer of thioctic acid on oxidative stress and inflammation in the heart of spontaneously hypertensive rats compared to normotensive Wistar Kyoto rats. METHODS: To study the oxidative status, the malondialdehyde and 4-hydroxynonenal concentration, protein oxidation were measured in the heart. Morphological analysis were performed. Immunohistochemistry and Western blot were done for alpha-smooth muscle actin and transforming growth factor beta to assess fibrosis; cytokines and nuclear factor kappaB to assess inflammatory processes. RESULTS: Spontaneously hypertensive rats were characterized by hypertension with increased malondialdehyde levels in the heart. OxyBlot in the heart of spontaneously hypertensive rats showed an increase in proteins' oxidative status. Cardiomyocyte hypertrophy and fibrosis in the ventricles were associated with an increased expression of alpha-smooth muscle actin and pro-inflammatory cytokines, reduced by the eutomer of thioctic acid supplementation. CONCLUSIONS: Based on this evidence, eutomer of thioctic acid could represent an appropriate antioxidant molecule to reduce oxidative stress and prevent inflammatory processes on the cardiomyocytes and cardiac vascular endothelium.

Exogenous alpha-lipoic acid treatments reduce the oxidative damage caused by drought stress in two grapevine rootstocks.

Drought represents the predominant and most critical abiotic stress challenge within the domain of viticulture, necessitating the identification and application of efficacious strategies to ameliorate its deleterious effects. In the contemporary realm of abiotic stress management, the deployment of α-lipoic acid (α-Lipo), known for its antioxidant capabilities, as an exogenous treatment has been investigated for mitigating various abiotic stresses in numerous plant species, yet a detailed exploration of its efficacy in alleviating drought stress in grapevines remains to be conclusively determined. This study aimed to elucidate the adaptive mechanisms against drought stress by examining the effects of different α-Lipo concentrations (0, 1, 25 and 50 µM) applied on the foliar under well-irrigated and drought conditions on American grapevine rootstocks '1103 P' (drought tolerant) and '3309 C' (drought sensitive). Our findings revealed that the efficacy of α-Lipo varied significantly depending on rootstock type and irrigation status. 1103 P rootstock treated with 1 µM α-Lipo under well-irrigated conditions showed greater positive effects on growth traits, photosynthetic and osmotic parameters. In contrast, in rootstock 3309 C under the same conditions, the highest effects were obtained at 25 and 50 µM α-Lipo concentrations. Under drought stress conditions, 50 µM α-Lipo treatment improved physiological parameters (chlorophyll content, proportional water coverage and stomatal conductance), proline content and antioxidant enzyme activities (SOD, CAT and APX), while reducing electrolyte leakage and MDA levels in both rootstocks, showing a strong potential to increase oxidative stress tolerance and sustain plant growth. Heatmap visualization analysis confirmed the data obtained from Principal Component Analysis (PCA) and revealed that 1103 P treated with 50 µM α-Lipo under drought stress conditions exhibited superior physiological performance compared to 3309 C under the same conditions. This indicates the importance of potential rootstock differences in stress adaptation or α-Lipo uptake efficiency. These findings suggest that α-Lipo holds promise as an eco-friendly, natural bio-stimulant for use in arid environments, contributing to the advancement of sustainable agricultural practices in the foreseeable future.

α-Lipoic acid treatment regulates enzymatic browning and nutritional quality of fresh-cut pear fruit by affecting phenolic and carbohydrate metabolism.

Fresh-cut pear fruit is greatly impacted by enzymatic browning, and maintaining quality remains a challenge. This study examined the impact of exogenous α-lipoic acid (α-LA) treatment on enzymatic browning and nutritional quality of fresh-cut pears. Results revealed that 0.5 g/L α-LA treatment effectively maintained color and firmness, and inhibited the increase in microbial number. The α-LA treatment also reduced MDA and H2O2 contents, decreased PPO activity, and enhanced SOD, CAT, and PAL activities. The α-LA treatment notably upregulated phenolic metabolism-related gene expression, including PbPAL, Pb4CL, PbC4H, PbCHI and PbCHS, and then increasing total phenols and flavonoids contents. Furthermore, it also influenced carbohydrate metabolism-related gene expression, including PbSS, PbSPS, PbAI and PbNI, maintaining a high level of sucrose content. These findings indicated that α-LA treatment showed promise in reducing browning and enhancing fresh-cut pears quality, offering a potential postharvest method to prolong the lifespan and maintain nutritional quality.

Alpha-lipoic acid alleviates cognitive deficits in transgenic APP23/PS45 mice through a mitophagy-mediated increase in ADAM10 α-secretase cleavage of APP.

BACKGROUND: Alpha-lipoic acid (ALA) has a neuroprotective effect on neurodegenerative diseases. In the clinic, ALA can improve cognitive impairments in patients with Alzheimer's disease (AD) and other dementias. Animal studies have confirmed the anti-amyloidosis effect of ALA, but its underlying mechanism remains unclear. In particular, the role of ALA in amyloid-ß precursor protein (APP) metabolism has not been fully elucidated. OBJECTIVE: To investigate whether ALA can reduce the amyloidogenic effect of APP in a transgenic mouse model of AD, and to study the mechanism underlying this effect. METHODS: ALA was infused into 2-month-old APP23/PS45 transgenic mice for 4 consecutive months and their cognitive function and AD-like pathology were then evaluated. An ALA drug concentration gradient was applied to 20E2 cells in vitro to evaluate its effect on the expression of APP proteolytic enzymes and metabolites. The mechanism by which ALA affects APP processing was studied using GI254023X, an inhibitor of A Disintegrin and Metalloproteinase 10 (ADAM10), as well as the mitochondrial toxic drug carbonyl cyanide m-chlorophenylhydrazone (CCCP). RESULTS: Administration of ALA ameliorated amyloid plaque neuropathology in the brain tissue of APP23/PS45 mice and reduced learning and memory impairment. ALA also increased the expression of ADAM10 in 20E2 cells and the non-amyloidogenic processing of APP to produce the 83 amino acid C-terminal fragment (C83). In addition to activating autophagy, ALA also significantly promoted mitophagy. BNIP3L-knockdown reduced the mat/pro ratio of ADAM10. By using CCCP, ALA was found to regulate BNIP3L-mediated mitophagy, thereby promoting the α-cleavage of APP. CONCLUSIONS: The enhanced α-secretase cleavage of APP by ADAM10 is the primary mechanism through which ALA ameliorates the cognitive deficits in APP23/PS45 transgenic mice. BNIP3L-mediated mitophagy contributes to the anti-amyloid properties of ALA by facilitating the maturation of ADAM10. This study provides novel experimental evidence for the treatment of AD with ALA.

Hepatoprotective potential of alpha-lipoic acid against gliclazide-induced liver injury in high-glucose-exposed human liver cells and experimental type 2 diabetic rats.

Growing clinical evidence shows that sulfonylurea therapy for patients with type 2 diabetic mellitus (T2DM) contributes to progressive worsening of their liver. The present study presents hepatotoxicity induced by gliclazide, a second-generation sulfonylurea, and alpha-lipoic acid (ALA) as a novel and promising drug for T2DM treatment. Normal human liver cells (HL-7702) were incubated with high-glucose DMEM in the presence or absence of gliclazide and ALA for 72 h, and cell viability and death were measured by flow cytometry. Next, Sprague-Dawley rats were subjected to 12 h of fasting, and fasting blood glucose was measured. The rats were randomized into four groups: HC (healthy control; n = 7), T2DM (diabetic rats without treatment; n = 9), GLC (diabetic rats with 15 mg/kg gliclazide treatment; n = 7) and GLC+ALA (diabetic rats with gliclazide and 60 mg/kg ALA treatment; n = 7). T2DM was induced by a bolus administration of 110 mg/kg nicotinamide and 55 mg/kg streptozotocin intraperitoneally. The experimental protocol lasted for 6 weeks after which the animals were sacrificed and pancreas, liver and blood samples were collected for biochemical, histological and molecular analyses. Compared to healthy control (HC) group, exposure of HL-7702 cells to high glucose induced significant cell death by 19 % (p < 0.001), which was exacerbated with gliclazide treatment by 29 % (p < 0.0001) but markedly reduced by 6 % to near HC value following ALA treatment. In vivo, GLC-treated rats had severe liver damage characterized by increased hepatocellular vacuolation, and significant expression of ED-1, iNOS and caspase-3 as well as markedly high levels of liver enzymes (aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase compared to T2DM rats. Interestingly, ALA administration prevented these pathological changes and protected the diabetic liver to levels comparable to HC rats. ALA showed hepatoprotective effect against gliclazide-induced hepatotoxicity by suppressing inflammation and apoptosis while activating antioxidant pathway in the diabetic liver. Abbreviations: ALA, Alpha-lipoic acid; ALT, Alanine aminotransferase; ALP, Alkaline phosphatase; AMPK, Adenosine monophosphate-activated protein kinase; AST, Aspartate aminotransferase; ATP, Adenosine triphosphate; DMEM, Dulbecco's Modified Eagle Medium; EDTA, ethylenediaminetetraacetic acid; FBG, Fasting blood glucose; FBS, Fetal bovine serum; GLC, Gliclazide; GLUT4, Glucose transporter type 4; GSH, Glutathione; H&E, Hematoxylin/Eosin; HbA1c, Glycosylated haemoglobin A1c; HC, Healthy control; HG, Hyperglycemic group; HOMA-ß, Homeostasis model assessment of ß-cell function; IL-1ß, Interleukin-1ß; IL-6, Interleukin-6; iNOS, Inducible nitric oxide synthase; KATP, ATP-dependent potassium channels; MDA, Malondialdehyde; MPTP, Mitochondrial permeability transition pore; NO, Nitric oxide; P/S, Penicillin/streptomycin; PAS, Periodic acid-Schiff; RIA, Radioimmunoassay; ROS, Reactive oxygen species; SOD, Superoxide dismutase; T2DM, Type 2 diabetes mellitus; TBARS, Thiobarbituric acid reactive substances; TNF-α, Tumor necrosis factor-alpha.