Lipoic acid alters the microRNA signature in breast cancer cells.

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. AIM: 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. CONCLUSION: 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.

Alpha lipoic acid administration improved both peripheral sensitivity to insulin and liver clearance of insulin reducing potential risk of diabetes and nonalcoholic fatty liver disease in overweight/obese PCOS patients.

OBJECTIVE: To evaluate the effects of alpha lipoic acid (ALA) on hormonal and metabolic parameters in a group of overweight/obese Polycystic Ovary Syndrome (PCOS) patients. METHODS: This was a retrospective study in which thirty-two overweight/obese patients with PCOS (n = 32) not requiring hormonal treatment were selected from the database of the ambulatory clinic of the Gynecological Endocrinology Center at the University of Modena and Reggio Emilia, Italy. The hormonal profile, routine exams and insulin and C-peptide response to oral glucose tolerance test (OGTT) were evaluated before and after 12 weeks of complementary treatment with ALA (400 mg/day). Hepatic Insulin Extraction (HIE) index was also calculated. RESULTS: ALA administration significantly improved insulin sensitivity and decreased ALT and AST plasma levels in all subjects, though no changes were observed on reproductive hormones. When PCOS patients were subdivided according to the presence or absence of familial diabetes background, the higher effects of ALA were observed in the former group that showed AST and ALT reduction and greater HIE index decrease. CONCLUSION: ALA administration improved insulin sensitivity in overweight/obese PCOS patients, especially in those with familial predisposition to diabetes. ALA administration improved both peripheral sensitivity to insulin and liver clearance of insulin. Such effects potentially decrease the risk of nonalcoholic fat liver disease and diabetes in PCOS patients.

Anti-cancer effects of alpha lipoic acid, cisplatin and paclitaxel combination in the OVCAR-3 ovarian adenocarcinoma cell line.

BACKGROUND: Ovarian cancer is the leading cause of gynecological cancer deaths. One of the major challenges in treating ovarian cancer with chemotherapy is managing the resistance developed by cancer cells to drugs, while also minimizing the side effects caused by these agents In the present study, we aimed to examine the effects of a combination of alpha lipoic acid (ALA), with cisplatin and paclitaxel in ovarian cancer(OVCAR-3). METHODS: The cytotoxic effects of ALA, cisplatin and paclitaxel on OVCAR-3 cells were determined. Four groups were formed: Control, ALA, Cisplatin + Paclitaxel, ALA + Cisplatin + Paclitaxel. The effects of single and combined therapy on cell migration, invasion and colony formation were analyzed. Changes in the expression of genes related to apoptosis, cell adhesion and cell cycle were analyzed with Real-time polymerase chain reaction(RT-PCR). The oxidative stress index and The Annexin V test were performed. RESULTS: The reduction in rapamycin-insensitive companion of mTOR(RICTOR) expression in the ALA + Cisplatin + Paclitaxel group was found statistically significant(p < 0.05). The decrease in MMP-9 and - 11 expressions the ALA + Cisplatin + Paclitaxel group was statistically significant(p < 0.05). The lowest values for mitogen-activated protein kinase(MAPK) proteins were found in the ALA + Cisplatin + Paclitaxel group. No colony formation was observed in the Cisplatin + Paclitaxel and ALA + Cisplatin + Paclitaxel groups. The lowest wound healing at 24 h was seen in the ALA + Cisplatin + Paclitaxel group. CONCLUSIONS: This study is the first one to investigate the combined treatment of ALA, Cisplatin, Paclitaxel on OVCAR-3. While ALA alone was not effective, combined therapy with ALA, has been found to reduce cell invasion, especially wound healing in the first 24 h, along with tumor cell adhesion.

Biological applications of lipoic acid-based polymers: an old material with new promise.

Lipoic acid (LA) is a versatile antioxidant that has been used in the treatment of various oxidation-reduction diseases over the past 70 years. Owing to its large five-membered ring tension, the dynamic disulfide bond of LA is highly active, enabling the formation of poly(lipoic acid) (PLA) via ring-opening polymerization (ROP). Herein, we first summarize disulfide-mediated ROP polymerization strategies, providing basic routes for designing and preparing PLA-based materials. PLA, as a biologically derived, low toxic, and easily modified material, possesses dynamic disulfide bonds and universal non-covalent carboxyl groups. We also shed light on the biomedical applications of PLA-based materials based on their biological and structural features and further divide recent works into six categories: antibacterial, anti-inflammation, anticancer, adhesive, flexible electronics, and 3D-printed tissue scaffolds. Finally, the challenges and future prospects associated with the biomedical applications of PLA are discussed.

Orally fast dissolving α-lipoic acid electrospun nanofibers mitigates lipopolysaccharide induced inflammation in RAW 264.7 macrophages.

α-Lipoic acid (LA), a dietary supplement known for its strong antioxidant and anti-inflammatory potential, faces challenges due to its poor aqueous solubility and thermal instability. To address these issues, herein methyl-beta-cyclodextrin (M-ß-CD) was utilized to create inclusion complex (IC) of LA in 1:1 M stoichiometric ratio of M-ß-CD to LA. The LA-M-ß-CD-IC was further combined with pullulan (PUL), a non-toxic and water-soluble biopolymer, for the development of electrospun nanofibers (NF) by green and sustainable approach. The resulting PUL/LA/M-ß-CD NF formed as a self-standing and flexible material with an average diameter of 569 ± 129 nm and encapsulation efficiency of ∼86.90 %. The developed NF demonstrated an accelerated release, quick dissolution, and disintegration when exposed to artificial saliva replicating the conditions of oral cavity. PUL/LA/M-ß-CD NF attenuated the production of ROS and NO by downregulating pro-inflammatory enzymes (iNOS and COX-2) in lipopolysaccharide (LPS) stimulated RAW 264.7 cells. Moreover, PUL/LA/M-ß-CD NF also significantly downregulated the expression of pro-inflammatory cytokines including TNF-α, IL-6, and IL-1ß along with suppression of NF-ĸB nuclear translocation in comparison to LA (at 250 µM). In nutshell, PUL/LA/M-ß-CD NF demonstrated great potential as a rapid disintegrating delivery system for oral anti-inflammatory treatment due to the enhanced physicochemical characteristics of LA.

Biodegradable Lipid-Modified Poly(Guanidine Thioctic Acid)s: A Fortifier of Lipid Nanoparticles to Promote the Efficacy and Safety of mRNA Cancer Vaccines.

Lipid nanoparticles (LNPs)-based messenger RNA (mRNA) therapeutics have emerged with promising potentials in the fields of infectious diseases, cancer vaccines, and protein replacement therapies; however, their therapeutic efficacy and safety can still be promoted by the optimization of LNPs formulations. Unfortunately, current LNPs suffer from increased production of reactive oxygen species during translation, which leads to a decreased translation efficiency and the onset of inflammation and other side effects. Herein, we synthesize a lipid-modified poly(guanidine thioctic acid) polymer to fabricate novel LNPs for mRNA vaccines. The acquired G-LNPs significantly promote the translation efficiency of loaded mRNA and attenuate inflammation after vaccination through the elimination of reactive oxygen species that are responsible for translational inhibition and inflammatory responses. In vivo studies demonstrate the excellent antitumor efficacy of the G-LNPs@mRNA vaccine, and two-dose vaccination dramatically increases the population and infiltration of cytotoxic T cells due to the intense antitumor immune responses, thus generating superior antitumor outcomes compared with the mRNA vaccine prepared from traditional LNPs. By synergy with immune checkpoint blockade, the tumor inhibition of G-LNPs@mRNA is further boosted, indicating that G-LNPs-based mRNA vaccines will be powerful and versatile platforms to combat cancer.

Pretargeted radiotherapy and synergistic treatment of metastatic, castration-resistant prostate cancer using cross-linked, PSMA-targeted lipoic acid nanoparticles.

Metastatic castration-resistant prostate cancer (CRPC) is a currently incurable disease associated with high mortality. Novel therapeutic approaches for CRPC are urgently needed to improve prognosis. In this study, we developed cross-linked, PSMA-targeted lipoic acid nanoparticles (cPLANPs), which can interact with transmembrane glycoprotein to accumulate inside prostate cancer cells, where they upregulate caspase-3, downregulate anti-apoptotic B-cell lymphoma-2 (BCL-2), and thereby induce apoptosis. The trans-cyclooctene (TCO) decoration on cPLANPs acts as a bioorthogonal handle allowing pretargeted single-photon emission computed tomography and radiotherapy, which revealed significantly enhanced tumor accumulation and minimal off-target toxicity in our experiments. The developed strategy showed a strong synergistic anti-cancer effect in vivo, with a tumor inhibition rate of up to 95.6% after 14 days of treatment. Our results suggest the potential of combining bioorthogonal pretargeted radiotherapy with suitable PSMA-targeted nanoparticles for the treatment of metastatic CRPC.

α-lipoic acid modulates prostate cancer cell growth and bone cell differentiation.

Prostate cancer (PCa) progression leads to bone modulation in approximately 70% of affected men. A nutraceutical, namely, α-lipoic acid (α-LA), is known for its potent anti-cancer properties towards various cancers and has been implicated in treating and promoting bone health. Our study aimed to explore the molecular mechanism behind the role of α-LA as therapeutics in preventing PCa and its associated bone modulation. Notably, α-LA treatment significantly reduced the cell viability, migration, and invasion of PCa cell lines in a dose-dependent manner. In addition, α-LA supplementation dramatically increased reactive oxygen species (ROS) levels and HIF-1α expression, which started the downstream molecular cascade and activated JNK/caspase-3 signaling pathway. Flow cytometry data revealed the arrest of the cell cycle in the S-phase, which has led to apoptosis of PCa cells. Furthermore, the results of ALP (Alkaline phosphatase) and TRAP (tartrate-resistant acid phosphatase) staining signifies that α-LA supplementation diminished the PCa-mediated differentiation of osteoblasts and osteoclasts, respectively, in the MC3T3-E1 and bone marrow macrophages (BMMs) cells. In summary, α-LA supplementation enhanced cellular apoptosis via increased ROS levels, HIF-1α expression, and JNK/caspase-3 signaling pathway in advanced human PCa cell lines. Also, the treatment of α-LA improved bone health by reducing PCa-mediated bone cell modulation.

Effect of caffeine-chitosan nanoparticles and α-lipoic acid on the cardiovascular changes induced in rat model of obesity.

The current research aims to study the therapeutic efficacy of alpha-lipoic acid (α-LA) and caffeine-loaded chitosan nanoparticles (Caf-CNs) against cardiovascular complications induced by obesity. Rats were divided randomly into: control, high fat diet (HFD) induced obesity rat model, obese rats treated with α-LA and/or Caf-CNs. Triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), Interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) as well as activities of lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) significantly increased in the serum of obese rats. In addition, plasma atherogenic index, atherogenic coefficient and Castelli's risk indices I and II showed a significant increase. Additionally, levels of malondialdehyde (MDA) and nitric oxide (NO) and activity of monoamine oxidase (MAO) were significantly elevated in heart tissues of obese rats. However, cardiac Na+/K+-ATPase and acetylcholinesterase (AchE) activities and reduced glutathione (GSH), serotonin (5-HT), norepinephrine (NE) and dopamine (DA) as well as serum high-density lipoprotein cholesterol (HDL-C) were significantly reduced in obese rats. Treatment with α-LA and/or Caf-CNs ameliorated almost all the biochemical and histopathological alterations caused by obesity. In conclusion, the present data revealed that α-LA and/or Caf-CNs may be an effective therapeutic approach against cardiac complications caused by obesity through their antilipemic, anti-atherogenic, antioxidant, and anti-inflammatory activities.

Protective effect of alpha-lipoic acid and epalrestat on oxaliplatin-induced peripheral neuropathy in zebrafish.

INTRODUCTION/AIMS: Oxaliplatin is a platinum-based anti-cancer drug widely used in colorectal cancer patients, but it may cause peripheral neuropathy. As one of the main causes of oxaliplatin-induced peripheral neuropathy (OPN) is oxidative stress, which is also a key factor causing diabetic peripheral neuropathy (DPN), the aim of this study was to evaluate the preventive effects of alpha-lipoic acid (ALA) and epalrestat (EP), which are used for the treatment of DPN, in an OPN zebrafish model. METHODS: Tg(nbt:dsred) transgenic zebrafish, with sensory nerves in the peripheral lateral line, were treated with oxaliplatin, oxaliplatin/EP, and oxaliplatin/ALA for 4 days. A confocal microscope was used to visualize and quantify the number of axon bifurcations in the distal nerve ending. To analyze the formation of synapses on sensory nerve terminals, quantification of membrane-associated guanylate kinase (MAGUK) puncta was performed using immunohistochemistry. RESULTS: The number of axon bifurcations and intensity of MAGUK puncta were significantly reduced in the oxaliplatin-treated group compared with those in the embryo medium-treated group. In both the oxaliplatin/EP and oxaliplatin/ALA-treated groups, the number of axon bifurcations and intensity of MAGUK puncta were greater than those in the oxaliplatin-treated group (p < .0001), and no significant difference was observed between larvae treated with oxaliplatin/ALA 1 µM and oxaliplatin/EP 1 µM (p = .4292). DISCUSSION: ALA and EP have protective effects against OPN in zebrafish. Our findings show that ALA and EP can facilitate more beneficial treatment for OPN.

Chronic Sleep Deprivation Impairs Visual Functions via Oxidative Damage in Mice.

Sleep deprivation (SD) is a global public health burden, and has a detrimental role in the nervous system. Retina is an important part of the central nervous system; however, whether SD affects retinal structures and functions remains largely unknown. Herein, chronic SD mouse model indicated that loss of sleep for 4 months could result in reductions in the visual functions, but without obvious morphologic changes of the retina. Ultrastructural analysis by transmission electron microscope revealed the deterioration of mitochondria, which was accompanied with the decrease of multiple mitochondrial proteins in the retina. Mechanistically, oxidative stress was provoked by chronic SD, which could be ameliorated after rest, and thus restore retinal homeostasis. Moreover, the supplementation of two antioxidants, α-lipoic acid and N-acetyl-l-cysteine, could reduce retinal reactive oxygen species, repair damaged mitochondria, and, as a result, improve the retinal functions. Overall, this work demonstrated the essential roles of sleep in maintaining the integrity and health of the retina. More importantly, it points towards supplementation of antioxidants as an effective intervention strategy for people experiencing sleep shortages.

Stimulatory effect of dietary alpha-lipoic acid on growth performance, antioxidant capacity, liver enzymes, immunity and protection of African catfish, Clarias gariepinus (B.), Edwardsiella tarda infection.

Edwardsiella tarda is one of the most common causes of fish diseases that hinder aquaculture. Oxidative stress in farm animals can induce a number of pathological disorders, production and general animal welfare. The use of exogenous dietary nonenzymatic antioxidants such as alpha-lipoic acid (ALA) can stop a pro-oxidant state and thus appears to have the potential to modulate the immune system and protect fish from bacterial infection. Thus, this study investigates the stimulatory effect of dietary ALA on growth performance, antioxidant capacity, liver enzymes, immunity and protection of African catfish, Clarias gariepinus (B.), against an infection with E. tarda. Five isonitrogenous and isocaloric diets (400 g/kg of crude protein) containing ALA at doses of 0.0 (control), 500, 1000, 1500 or 2000 mg/kg diet were served to 300 juveniles of African catfish (mean weight = 8.2 ± 0.2 g) adequately thrice per day for 12 weeks. Thereafter, 0.1 mL of E. tarda (ATCC 15947; 1.0 × 108 CFU/mL) was intraperitoneally injected into 10 fish from each tank and was monitored for 14 days. The results showed that ALA-fortified diets significantly boosted the fish growth, feed consumption and utilization and feed conversion ratio but no did not affect fish survival rate. The highest final fish weight (g), weight growth (g) and weight gain (%) were all considerably higher in fish fed with ALA-fortified diets (p < 0.05), especially from 1000 to 200 mg/kg ALA than the control group. Also, an enhanced hemato-biochemical, antioxidant and immune indices were noticed in African catfish-fed ALA-enriched diets. In a dose-dependent order, the levels of haematological indices such Ht, Hb, RBCs, WBCs and platelets were markedly increased (p < 0.05). Additionally, fish fed with ALA-based diets showed substantial (p < 0.05) declines in aspartate and alanine aminotransferase values, with the lowest values being found in the 2000 mg/kg diet while control group had highest values. Further, African catfish fed the feed fortified with 2000 mg ALA/kg diet showed the highest levels of lysozyme, respiratory burst, proteases and esterase activities (p < 0.05). Following exposure of fish to E. tarda infection, a significant reduction in the mortality was obtained in African catfish fed with ALA-based diets, especially from 1500 to 2000 mg ALA/kg diet (3.3%); while fish fed with the control diet had highest mortality (86.7%). Therefore, diets supplemented with ALA evoked fish growth performance, antioxidants and nonspecific immunity of African catfish. Also, resistance of African catfish to E. Tarda infection were raised when fed ALA-fortified diets at optimum inclusion rate of 1300 mg ALA/kg diet.

Alpha-Lipoic Acid Reduces Cell Growth, Inhibits Autophagy, and Counteracts Prostate Cancer Cell Migration and Invasion: Evidence from In Vitro Studies.

Alpha-lipoic acid (ALA) is a natural antioxidant dithiol compound, exerting antiproliferative and antimetastatic effects in various cancer cell lines. In our study, we demonstrated that ALA reduces the cell growth of prostate cancer cells LNCaP and DU-145. Western blot results revealed that in both cancer cells, ALA, by upregulating pmTOR expression, reduced the protein content of two autophagy initiation markers, Beclin-1 and MAPLC3. Concomitantly, MTT assays showed that chloroquine (CQ) exposure, a well-known autophagy inhibitor, reduced cells' viability. This was more evident for treatment using the combination ALA + CQ, suggesting that ALA can reduce cells' viability by inhibiting autophagy. In addition, in DU-145 cells we observed that ALA affected the oxidative/redox balance system by deregulating the KEAP1/Nrf2/p62 signaling pathway. ALA decreased ROS production, SOD1 and GSTP1 protein expression, and significantly reduced the cytosolic and nuclear content of the transcription factor Nrf2, concomitantly downregulating p62, suggesting that ALA disrupted p62-Nrf2 feedback loop. Conversely, in LNCaP cells, ALA exposure upregulated both SOD1 and p62 protein expression, but did not affect the KEAP1/Nrf2/p62 signaling pathway. In addition, wound-healing, Western blot, and immunofluorescence assays evidenced that ALA significantly reduced the motility of LNCaP and DU-145 cells and downregulated the protein expression of TGFß1 and vimentin and the deposition of fibronectin. Finally, a soft agar assay revealed that ALA decreased the colony formation of both the prostate cancer cells by affecting the anchorage independent growth. Collectively, our in vitro evidence demonstrated that in prostate cancer cells, ALA reduces cell growth and counteracts both migration and invasion. Further studies are needed in order to achieve a better understanding of the underlined molecular mechanisms.

Alpha-lipoic acid supplementation reverses the declining quality of oocytes exposed to cyclophosphamide.

Cyclophosphamide (CY) is a chemotherapeutic drug that is commonly used to treat malignancies of the ovary, breast, and hematology, as well as autoimmune disorders. As a cofactor of mitochondrial multienzyme complexes, alpha lipoic acid (ALA) is well known for its antioxidant characteristics, which operate directly on the scavenging of reactive oxygen species (ROS) and indirectly on the intracellular recycling of other antioxidants. However, the underlying mechanisms through which CY exerts its toxic effects on meiosis and oocyte quality, as well as a viable approach for protecting oocyte quality and preserving fertility, remain unknown. In present study, immunostaining and fluorescence intensity quantification were applied to assess the effects of CY and ALA supplementation on the key processes during the oocyte meiotic maturation. Our results show that supplementing oocytes with ALA, a well-known antioxidant and free radical scavenger, can reverse CY-induced oocyte meiotic maturation failure. Specifically, we found that CY exposure caused oocyte meiotic failure by disrupting meiotic organelle dynamics and arrangement, as well as a prominently impaired cytoskeleton assembly. In addition, CY caused an abnormal distribution of mitochondrion and cortical granules, two indicators of oocyte cytoplasmic maturation. More importantly, we show that ALA supplementation effectively reverses CY-induced meiotic failure and oocyte quality decline by suppressing oxidative stress-induced DNA damage and apoptosis in oocytes. Collectively, our data reveal that ALA supplementation is a feasible approach to protect oocytes from CY-exposed deterioration, providing a better understanding of the mechanisms involved in chemotherapy-induced meiotic failure.

L-F001, a multifunctional fasudil-lipoic acid dimer, antagonizes hypoxic-ischemic brain damage by inhibiting the TLR4/MyD88 signaling pathway.

INTRODUCTION: Neonatal hypoxic-ischemic brain damage (HIBD) is a serious inflammatory injury. At present, the standard treatment for this disease is hypothermia therapy, and the effect of drug intervention is still limited. L-F001 is a compound of fasudil and lipoic acid. Previous in vitro experiments have confirmed that L-F001 has anti-inflammatory neuroprotective functions. However, its therapeutic effect on neonates with HIBD remains unknown. This study was aimed at exploring the therapeutic effect of L-F001 on HIBD rats. METHODS: The newborn rats were divided into three groups: Sham operation group, HIBD group, and HIBD + L-F001 group. HE staining, Nissil staining, the immunofluorescence of iNOS and COX-2, ELISA (IL-1ß, IL-6, TNF-α, and IL-10), and western blotting analyses were performed to determine the therapeutic effect of L-F001. Finally, we evaluated the growth and development of each group by measuring body weight. RESULTS: The hippocampal structure of HIBD rats was disordered, and the Nissil body was small and shallow. The expressions of iNOS and COX-2 in HIBD rats were increased, whereas the expressions of IL-1ß, IL-6, and TNF-α in plasma were upregulated, and the expression of IL-10 was decreased. L-F001 could improve the tissue structure and reduce the expression of iNOS and COX-2 in HIBD rats. Meanwhile, L-F001 could also reduce the expression of pro-inflammatory cytokines and restore the content of anti-inflammatory cytokines in plasma. We further found that the TLR4 pathway was activated after hypoxic-ischemia in neonatal rats. L-F001 could inhibit the activation of TLR4 pathway. Finally, we found that after L-F001 treatment, the body weight of HIBD rats increased significantly compared with the untreated group. CONCLUSIONS: L-F001 antagonizes the inflammatory response after hypoxic-ischemia by inhibiting the activation of the TLR4 signaling pathway, thus playing a neuroprotective role. L-F001 may be a potential therapeutic agent for neonatal HIBD.

Comparison of the effects of alpha lipoic acid and dexpanthenol in an experimental tracheal reconstruction animal model.

OBJECTIVES: To investigate the positive effects of intraperitoneal administration of alpha-lipolic acid (ALA) and dexpanthenol (DXP) on wound healing after tracheal surgery in rats. METHODS: The study was carried out at Necmettin Erbakan University, Konya, Turkey, from January 2014-2019. A total of 30 healthy and adult Sprague-Dawley type female rats were included in the study. For the experiment, rats were randomly divided into 3 groups: ALA group (n=10), DXP group (n=10), and control group (n=10). After trachea surgery, 100 mg/kg/day ALA was given to group ALA and 100 mg/kg/day intraperitoneal DXP to group DXP for 15 days, and the rats were sacrificed on the 21st day. The excised tracheal sections were evaluated and graded for inflammatory cell infiltration, angiogenesis, fibroblast proliferation, collagen deposition, and epithelial regeneration to evaluate wound healing. RESULTS: Inflammation was found to be less in both the ALA and DXP groups. With the Mann-Whitney test, it was determined that inflammation was less in the ALA group than in the DXP group (C-D [p=0.097] and C-A [p=0.024]). On the other hand, no statistically significant difference was found in epithelial regeneration (p=0.574; >0.05), angiogenesis (p=0.174; >0.05), fibroblast proliferation, and collagen deposition (p=0.102; >0.05). CONCLUSION: Alpha-lipolic acid injected intravenously after tracheal reconstruction in patients can prevent restenosis by reducing inflammation without adversely affecting wound healing.

Alpha-lipoic acid induced apoptosis of PC3 prostate cancer cells through an alteration on mitochondrial membrane depolarization and MMP-9 mRNA expression.

Cancer has become an important cause of mortality and morbidity in the world. Over the past decades, biomedical research revealed insights into the molecular events and signaling pathways involved in carcinogenesis and cancer progression. Matrix metalloproteinases (MMPs) are a diverse family of enzymes that can degrade various components of the extracellular matrix and are considered as potential diagnostic and prognostic biomarkers for many cancer types and cancer stages. Recently, studies on the role of natural-origin active substances in the prevention of cancer development gained importance. Among them, the α-lipoic acid, which is commonly found in plants, displayed potent anti-proliferative effects on cancer cell lines. However, the effect of the compound on the induction of apoptosis and mRNA expression of MMPs in human prostate cancer cells remains unclear. The present study aimed to evaluate the anti-proliferative and apoptotic activity of α-lipoic acid in human PC3 prostate carcinoma cells considering different concentrations and exposure durations. The findings showed that, α-lipoic acid significantly decreased PC3 cell viability with an IC50 value of 1.71 mM at 48 h (p < 0.05). Additionally, the compound significantly increased Annexin-V binding in cells compared to control and induced a significant alteration in mitochondrial membrane potential and caspase levels (p < 0.05). Furhermore, the RT-PCR analyses have revealed that α-lipoic acid reduced MMP-9 mRNA expression in PC3 cells compared to the control (p < 0.05). In conclusion, this study highlights that α-lipoic acid induced apoptosis in human PC3 prostate cancer cells and inhibited the MMP-9 gene at the mRNA level, which is known to play a role in metastasis development.

Administration of α-lipoic acid and silymarin attenuates aggression by modulating endocrine, oxidative stress and inflammatory pathways in mice.

Aggression, a highly prevalent behavior among all the psychological disorders having strong association with psychiatric imbalance, neuroendocrine changes and neurological disturbances (including oxidative stress & neuroinflammation) require both pharmacological and non-pharmacological treatments. Focusing the preclinical neuroendocrine determinants of aggression, this interventional study was designed to elucidate the curative effect of antioxidants on aggression in male mice. Adult albino male mice (n = 140) randomly divided into two main treatment groups for α-lipoic acid (ALA) and silymarin with 5 subgroups (n = 10) for each curative study, namely control, disease (aggression-induced), standard (diazepam, 2.5 mg/kg), low dose (100 mg/kg) and high dose (200 mg/kg) treatment groups of selected antioxidants. Resident-intruder paradigm and levodopa (L-dopa 375 mg/kg, p.o.) induced models were used for aggression. Effect of antioxidant treatment (i.e., 21 days bid) on aggression was assessed by evaluating the changes in aggressive behavior, oxidative stress biomarkers superoxide dismutase, catalase, glutathione, nitrite and malondialdehyde (SOD, CAT, GSH, nitrite & MDA), neurotransmitters (dopamine, nor-adrenaline and serotonin), pro-inflammatory cytokines tumor necrosis factor-α and interleukin- 6 (TNF-α & IL-6) along with serum testosterone examination. This study showed potential ameliorative effect on aggressive behavior with both low (100 mg/kg) and high (200 mg/kg) doses of antioxidants (ALA & silymarin). Resident-intruder or L-dopa induced aggression in male mice was more significantly tuned with ALA treatment than silymarin via down regulating both oxidative stress and inflammatory biomarkers. ALA also exhibited notable effects in managing aggression-induced disturbances on plasma testosterone levels. In conclusion, ALA is more effective than silymarin in attenuating aggression in mice.

Effect of alpha-lipoic acid and caffeine-loaded chitosan nanoparticles on obesity and its complications in liver and kidney in rats.

The present work investigated the effect of α-lipoic acid (ALA) and caffeine-loaded chitosan nanoparticles (CAF-CS NPs) on obesity and its hepatic and renal complications in rats. Rats were divided into control, rat model of obesity induced by high fat diet (HFD), and obese rats treated with ALA and/or CAF-CS NPs. At the end of the experiment, the activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) and the levels of urea, creatinine, interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) were determined in the sera of animals. In addition, malondialdehyde (MDA), nitric oxide (NO), and reduced glutathione (GSH) were measured in hepatic and renal tissues. Renal Na+, K+-ATPase was assessed. The histopathological changes were examined in the hepatic and renal tissues. Obese rats showed a significant increase in AST, ALT, ALP, urea, and creatinine. This was associated with a significant increase in IL-1ß, TNF-α, MDA, and NO. A significant decrease in hepatic and renal GSH and renal Na+, K+-ATPase activity was recorded in obese rats. Obese rats also showed histopathological alterations in hepatic and renal tissues. Treatment with ALA and/or CAF-CS NPs reduced the weight of obese rats and ameliorated almost all the hepatic and renal biochemical and histopathological changes induced in obese rats. In conclusion, the present findings indicate that ALA and/or CAF-CS NPs offered an effective therapy against obesity induced by HFD and its hepatic and renal complications. The therapeutic effect of ALA and CAF-CS NPs could be mediated through their antioxidant and anti-inflammatory properties.

Alpha lipoic acid ameliorates motor deficits by inhibiting ferroptosis in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease. Ferroptosis shares several features with PD pathophysiology, and anti-ferroptosis molecules are neuroprotective in PD animal models. As an antioxidant and iron chelating agent, alpha lipoic acid (ALA) has a neuroprotective effect on PD; however, the influence of ALA on ferroptosis in PD remains unclear. This study aimed to determine the mechanism of ALA in regulating ferroptosis in PD models. Results showed that ALA could ameliorate motor deficits in PD models and regulate iron metabolism by upregulating ferroportin (FPN) and ferritin heavy chain 1 (FTH1) and downregulating iron importer divalent metal transporter 1 (DMT1). Moreover, ALA decreased the accumulation of reactive oxygen species (ROS) and lipid peroxidation, rescued mitochondrial damage, and prevented ferroptosis effectively by inhibiting the downregulation of glutathione peroxidase 4 (GPX4) and cysteine/glutamate transporter (xCT) in PD. Mechanistic study indicated that the activation of SIRT1/NRF2 pathway was involved in the upregulation effect of GPX4 and FTH1. Thus, ALA ameliorates motor deficits in PD models by regulating iron metabolism and mitigating ferroptosis through the SIRT1/NRF2 signaling pathway.