Free Melatonin Research Articles

Exploring MIL-68(Al) nanocarrier for melatonin delivery: probing pro-oxidant effects in cancer cells and achieving sustained drug release

This study explored the synthesis of MIL-68(Al), characterized its properties, and investigated its ability to encapsulate and release melatonin (MEL) in response to changes in pH, intending to develop a more effective drug delivery system. Analyses were directed to characterize the designed nanocarriers before and after drug loading. The drug loading efficiency (DLE) and drug loading content (DLC) of MIL-68(Al) were 78.8% and 44.0%, respectively. The extended drug release period of MEL@MIL-68(Al) was observed to exhibit a faster release under acidic conditions compared to neutral conditions. The cell treatment with free MEL, MIL-68(Al), and MEL@MIL-68(Al) was completed, and a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed at lung cancer A549 cells and normal fibroblastic MRC-5 cells for the cytotoxicity study. MEL@MIL-68(Al) was more cytotoxic than MIL-68(Al) in A549 cells. Analyzing reactive oxygen species (ROS) levels via fluorescent microscopic analysis showed ROS overproduction in cells treated with MEL@MIL-68(Al) in comparison to other interventions. Additionally, MEL@MIL-68(Al) modulated the protein expression levels of Nrf-2, Keap-1, and HO-1 in cells. Therefore, MEL@MIL-68(Al) exerts its potent anticancer effects via ROS overproduction and downregulation of the Nrf2/Keap-1 pathway. Therefore, this system can be a promising nanoplatform for the successful delivery of MEL and potentiating its anticancer effects.

Green synthesis, characterization of melatonin-like drug bioconjugated CoS quantum dots and its antiproliferative effect on different cancer cells.

Quantum dots are usually particles smaller than 100nm and have a low toxic effect. This study aimed to bioconjugate the anticancer effective melatonin agonist to quantum dots and demonstrate its effects in two cancer lines. This is the first study that aims to examine the anticancer activity of ramelteon bioconjugation to quantum dots, providing a new perspective on the use of Melatonin and its derivatives in cancer. For this purpose, first of all, cobalt sulfide (CoS) quantum dots were synthesized, bioconjugated and characterized with Punica granatum extract by green synthesis method. The effects of synthesized nanomaterials on neuroblastoma and prostate cancer cells were investigated. It was noted that nanomaterials reduced cell viability by 50% in neuroblastoma and prostate cancer lines at a dose of 50µg/mL. Ramelteon bioconjugated nanomaterials reduced cancer cell viability by 1.4 times more than free melatonin. CoS quantum dots were determined to double the oxidative stress in the neuroblastoma cell line compared to the control, while no change was observed in prostate cancer. In the gene expression findings, it was observed that CoS nanoparticles caused an increase in the expression levels of apoptosis-related genes in the neuroblastoma cell line and induced key protein expression levels of pathways such as ROR-alpha in the prostate cancer cell line. As a result, it was observed that the viability of the neuroblastoma cell line decreased with apoptosis induced by oxidative stress, while this effect was observed in the DU-145 cell line via the ROR-alpha pathway.

Therapeutic effect of melatonin-loaded chitosan/lecithin nanoparticles on hyperglycemia and pancreatic beta cells regeneration in streptozotocin-induced diabetic rats

Nanotechnology is used to overcome fundamental flaws in today's marketed pharmaceuticals that obstruct therapy, like restricted solubility and quick release of drugs into the bloodstream. In both human and animal researches, melatonin was demonstrated to regulate glucose levels. Despite the fact that melatonin is quickly transported through the mucosa, its sensitivity to be oxidized creates a difficulty in achieving the required dose. Additionally, due to its variable absorption and poor oral bioavailability necessitates the development of alternative delivery methods. The study aimed to synthesize melatonin loaded chitosan/lecithin (Mel-C/L) nanoparticles to be assessed in the treatment of streptozotocin (STZ)-induced diabetes in rats. The antioxidant, anti-inflammatory, and cytotoxicity properties of nanoparticles were estimated to determine the safety of manufactured nanoparticles for in vivo studies. In addition, Mel-C/L nanoparticles were administered to rats for eight weeks after inducing hyperglycemia. The therapeutic effect of Mel-C/L nanoparticles was assessed in all experimental groups by detecting insulin and blood glucose levels; observing improvements in liver and kidney functions as well as histological and immunohistochemical evaluation of rats’ pancreatic sections. The results proved that Mel-C/L nanoparticles showed remarkable anti-inflammatory, anti-coagulant, and anti-oxidant effects, in addition to its efficiency in reducing blood glucose levels of STZ-induced diabetic rats and great ability to promote the regeneration of pancreatic beta (β)-cells. Furthermore, Mel-C/L nanoparticles elevated the insulin level; and decreased the elevated levels of urea, creatinine and cholesterol. In conclusion, nanoparticles application decreased the administrated melatonin dose that in turn can diminish the side effects of free melatonin administration.

Topical Administration of Melatonin-Loaded Extracellular Vesicle-Mimetic Nanovesicles Improves 2,4-Dinitrofluorobenzene-Induced Atopic Dermatitis.

Atopic dermatitis (AD) is caused by multiple factors that trigger chronic skin inflammation, including a defective skin barrier, immune cell activation, and microbial exposure. Although melatonin has an excellent biosafety profile and a potential to treat AD, there is limited clinical evidence from controlled trials that support the use of melatonin as an AD treatment. The delivery of melatonin via the transdermal delivery system is also a challenge in designing melatonin-based AD treatments. In this study, we generated melatonin-loaded extracellular vesicle-mimetic nanoparticles (MelaNVs) to improve the transdermal delivery of melatonin and to evaluate their therapeutic potential in AD. The MelaNVs were spherical nanoparticles with an average size of 100 nm, which is the optimal size for the transdermal delivery of drugs. MelaNVs showed anti-inflammatory effects by suppressing the release of TNF-α and β-hexosaminidase in LPS-treated RAW264.7 cells and compound 48/80-treated RBL-2H3 cells, respectively. MelaNVs showed a superior suppressive effect compared to an equivalent concentration of free melatonin. Treating a 2,4-dinitrofluorobenzene (DNCB)-induced AD-like mouse model with MelaNVs improved AD by suppressing local inflammation, mast cell infiltration, and fibrosis. In addition, MelaNVs effectively suppressed serum IgE levels and regulated serum IFN-γ and IL-4 levels. Taken together, these results suggest that MelaNVs are novel and efficient transdermal delivery systems of melatonin and that MelaNVs can be used as a treatment to improve AD.

Melatonin-Loaded Nanocarriers: New Horizons for Therapeutic Applications.

The use of nanosized particles has emerged to facilitate selective applications in medicine. Drug-delivery systems represent novel opportunities to provide stricter, focused, and fine-tuned therapy, enhancing the therapeutic efficacy of chemical agents at the molecular level while reducing their toxic effects. Melatonin (N-acetyl-5-methoxytriptamine) is a small indoleamine secreted essentially by the pineal gland during darkness, but also produced by most cells in a non-circadian manner from which it is not released into the blood. Although the therapeutic promise of melatonin is indisputable, aspects regarding optimal dosage, biotransformation and metabolism, route and time of administration, and targeted therapy remain to be examined for proper treatment results. Recently, prolonged release of melatonin has shown greater efficacy and safety when combined with a nanostructured formulation. This review summarizes the role of melatonin incorporated into different nanocarriers (e.g., lipid-based vesicles, polymeric vesicles, non-ionic surfactant-based vesicles, charge carriers in graphene, electro spun nanofibers, silica-based carriers, metallic and non-metallic nanocomposites) as drug delivery system platforms or multilevel determinations in various in vivo and in vitro experimental conditions. Melatonin incorporated into nanosized materials exhibits superior effectiveness in multiple diseases and pathological processes than does free melatonin; thus, such information has functional significance for clinical intervention.

Characterization of pH-sensitive chitosan/hydroxypropyl methylcellulose composite nanoparticles for delivery of melatonin in cancer therapy

This work describes the development of novel pH-sensitive nanoparticles (NPs) for the delivery of melatonin (MLT) in breast cancer therapy. The MLT was encapsulated in composite NPs consisting of chitosan (CTS) and hydroxypropyl methylcellulose (HPMC) crosslinked in the presence of tripolyphosphate (TPP). The structure of the composite NPs was characterized using fourier transform infrared (FT-IR), wide angle X-ray diffraction (XRD), scanning electron microscope (SEM) and transmission electron microscopy (TEM). The release behavior of MLT from the composite NPs were investigated in acidic and neutral medium in vitro. Cytotoxicity of MLT encapsulated in the NPs toward MDA-MB-231 breast cancer cells was measured using thiazolyl blue tetrazolium bromide assay (MTT) and compared with that of the free MLT. Results demonstrate that MLT encapsulated in CTS/HPMC NPs had higher toxicity toward the MDA-MB-231 cancer cells compared to the free MLT, thus making the NPs potentially useful in breast cancer therapy.

The Sensitization of Melatonin in Osteosarcoma Cells by Suppression of Anti-Apoptotic Proteins

Background:Investigation of anti-cancer agents with desirable selective toxicity is critical for cancer therapy. The use of natural adjuvants can be a promising option in reducing the toxicity of the anti-cancer agent. The aim of this study was to investigate the potential application of melatonin (MLT) as a natural adjuvant molecule along with doxorubicin (DOX) to induce cytotoxicity in osteosarcoma (OS) cells.Methods:Human OS cell lines included Saos-2, MG-63, and Human Bone Marrow Mesenchymal Stem Cells (hBM-MSCs) were treated with free DOX, free MLT, DOX-loaded NPs (DOX-NPs), MLT-loaded NPs (MLT-NPs), combination of DOX and MLT (DOX-MLT) and combination of DOX and MLT-loaded NPs (DOX-MLT-NPs) in separated cell culture. Cell proliferation of experiments were evaluated by MTT assay after 24 h. Total protein levels were determined by enzyme immunoassay ELISA.Results:Herein, we found the combination of MLT with DOX, especially formulated in nano-form, is resulted in a significant reduction in the protein levels of both X-linked Inhibitor of Apoptosis (XIAP) and Survivin (p<0.0001). Indeed, there was a significant decrease in the expression of XIAP and Survivin when MLT is combined with DOX compared to the individual treatments.Conclusion:Our findings indicated the synergism of the antitumor effect could be due to the down-regulation of XIAP and Survivin in the levels of protein.

The phytomelatonin receptor (PMRT1) Arabidopsis Cand2 is not a bona fide G protein–coupled melatonin receptor

It was recently suggested that the protein Cand2 acts as a G protein–coupled receptor (GPCR) for melatonin in Arabidopsis by mediating stomatal closure via H2O2 production and Ca2+ influx. Here, we examined whether Cand2 is indeed a melatonin receptor. Contrary to previous reports, confocal microscopy analyses indicated that Cand2 protein is localized in the cytoplasm rather than the plasma membrane. The role of Cand2 was further investigated in genetic analyses using two Arabidopsis cand2 knockout mutant lines, SALK_071302 (cand2-1) and SALK_068848 (cand2-2). We found that melatonin-mediated mitogen-activated protein kinase (MAPK) activation was not abolished in the cand2 mutant lines, nor did melatonin-mediated defense gene induction (e.g., GST1) change relative to that in the wild type Col-0. Following ER stress, the two cand2 mutant lines were identical to Col-0 in terms of defense gene induction, ion leakage, and ROS levels. Two G protein mutants, gpa1 (Gα mutant) and agb1 (Gβ mutant), also exhibited no disturbance in melatonin-mediated defense gene induction or melatonin-mediated MAPK activation. Collectively, our data indicate that Cand2 is neither a phytomelatonin receptor localized in the plasma membrane nor is it involved in the melatonin-mediated defense signaling pathway via G protein components. However, it remains unclear how melatonin-mediated MAPK activation was slightly decreased in the mutant cand2-2 without affecting downstream defense gene induction. Also, it cannot rule out the possibility that Cand2 may be a melatonin binding protein and that its binding may result in a decrease of free melatonin level in plants.

PolyRad \u2013 Protection Against Free Radical Damage

The effects of elevated levels of radiation contribute to the instability of pharmaceutical formulations in space compared to those on earth. Existing technologies are ineffective at maintaining the therapeutic efficacies of drugs in space. Thus, there is an urgent need to develop novel space-hardy formulations for preserving the stability and efficacy of drug formulations. This work aims to develop a novel approach for the protection of space pharmaceutical drug molecules from the radiation-induced damage to help extend or at least preserve their structural integrity and potency. To achieve this, free radical scavenging antioxidant, Trolox was conjugated on the surface of poly-lactic-co-glycolic acid (PLGA) nanoparticles for the protection of a candidate drug, melatonin that is used as a sleep aid medication in International Space Station (ISS). Melatonin-PLGA-PLL-Trolox nanoparticle as named as PolyRad was synthesized employing single oil in water (o/w) emulsion solvent evaporation method. PolyRad is spherical in shape and has an average diameter of ~600 nm with a low polydispersity index of 0.2. PolyRad and free melatonin (control) were irradiated by UV light after being exposed to a strong oxidant, hydrogen peroxide (H2O2). Bare melatonin lost ~80% of the active structure of the drug following irradiation with UV light or treatment with H2O2. In contrast, PolyRad protected >80% of the active structure of melatonin. The ability of PolyRad to protect melatonin structure was also carried out using 0, 1, 5 and 10 Gy gamma radiation. Gamma irradiation showed >98% active structures of melatonin encapsulated in PolyRads. Drug release and effectiveness of melatonin using PolyRad were evaluated on human umbilical vein endothelial cells (HUVEC) in vitro. Non-irradiated PolyRad demonstrated maximum drug release of ~70% after 72 h, while UV-irradiated and H2O2-treated PolyRad showed a maximum drug release of ~85%. Cytotoxicity of melatonin was carried out using both live/dead and MTT assays. Melatonin, non-radiated PolyRad and irradiated PolyRad inhibited the viability of HUVEC in a dose-dependent manner. Cell viability of melatonin, PolyRad alone without melatonin (PolyRad carrier control), non-radiated PolyRad, and irradiated PolyRad were ~98, 87, 75 and 70%, respectively at a concentration sim 0.01 {mg}/{ml} (10mu g/{ml}). Taken together, PolyRad nanoparticle provides an attractive formulation platform for preventing damage to pharmaceutical drugs in potential space mission applications.

Melatonin-loaded lipid-core nanocapsules protect against lipid peroxidation caused by paraquat through increased SOD expression in Caenorhabditis elegans

BackgroundMelatonin has been described in the literature as a potent antioxidant. However, melatonin presents variable, low bioavailability and a short half-life. The use of polymeric nanoparticulated systems has been proposed for controlled release. Thus, the purpose of this study was to investigate the action of melatonin-loaded lipid-core nanocapsules (Mel-LNC) in the antioxidant system of Caenorhabditis elegans, and the possible protective effect of this formulation against lipid peroxidation caused by paraquat (PQ).MethodsThe suspensions were prepared by interfacial deposition of the polymer and were physiochemically characterized. C. elegans N2 wild type and transgenic worm CF1553, muls84 [sod-3p::gfp; rol6(su1006)] were obtained from the Caenorhabditis Genetics Center (CGC). The worms were divided into 5 groups: Control, PQ 0.5 mM, PQ 0.5 mM + Mel-LNC 10 μg/mL, PQ + unloaded lipid-core nanocapsules (LNC), and PQ + free melatonin (Mel) 10 μg/mL. The lipid peroxidation was assessed through thiobarbituric acid (TBARS) levels and the fluorescence levels of the transgenic worms expressing GFP were measured.ResultsThe LNC and Mel-LNC presented a bluish-white liquid, with pH values of 5.56 and 5.69, respectively. The zeta potential was − 6.4 ± 0.6 and − 5.2 ± 0.2, respectively. The mean particle diameter was 205 ± 4 nm and 203 ± 3 nm, respectively. The total melatonin content was 0.967 mg/ml. The TBARS levels were significantly higher in the PQ group when compared to the control group (p < 0.001). Mel-LNC reduced TBARS levels to similar levels found in the control group. Moreover, only Mel-LNC significantly enhanced the SOD-3 expression (p < 0.05). Mel-LNC was capable of protecting C. elegans from lipid peroxidation caused by PQ and this was not observed when free melatonin was used. Moreover, Mel-LNC increased the fluorescence intensity of the transgenic strain that encodes the antioxidant enzyme SOD-3, demonstrating a possible mechanism of protection from PQ-induced damage.ConclusionThese findings demonstrated that melatonin, when associated with nanocapsules, had improved antioxidant properties and the protective activity against PQ-induced lipid peroxidation could be associated with the activation of antioxidant enzymes by Mel-LNC in C. elegans.

Stimuli-Responsive Nanocapsules for the Spatiotemporal Release of Melatonin: Protection against Gastric Inflammation.

Melatonin is a secretory product of the pineal gland that regulates circadian rhythm. It is also well-known for its anti-inflammatory and antioxidant properties against the damaging influences of reactive oxygen species. To improve its therapeutic efficacy, a new formulation with melatonin loaded in a stimuli-responsive polymeric nanocapsule has been prepared following an inverse mini-emulsion technique. The colloidal stability of the melatonin-loaded nanocapsules (MNCs) is studied using dynamic light scattering, while the morphology of these MNCs is characterized using various electron microscopies. These MNCs have an inner diameter of 80-120 nm with a cell wall thickness of 29 ± 11 nm. The emission band maximum for melatonin appears at 350 nm following excitation at 305 nm (quantum yield, Φ350 = 0.13). The self-quenching nature of the entrapped melatonin molecules inside the nanocapsules attributes to a lower Φ350 value for the MNCs. The controlled release of melatonin from MNCs in an in vitro condition is achieved by inducing a rupture of the polymeric backbone through maintaining a certain media pH (∼2.0-4.0) as an external stimulus, and this accounts for a significant enhancement in its characteristic luminescence. The H,K-ATPase, an integral membrane protein, maintains this specific pH range in the interior of the gastrointestinal tract. This methodology is adopted for developing an efficient drug delivery process in the gastric environment. A significant improvement in the AGS cell survival under oxidative stress conditions is observed during preincubation with MNCs compared to free melatonin. In a murine model of the stress-induced gastric ulcer, MNCs outperformed free melatonin in terms of drug efficacy. The value for the gastric ulcer index is reduced from ∼30 to ∼15 by free melatonin and from ∼30 to ∼8 by MNCs treatments, respectively. Such formulation could be a step forward for developing more efficient melatonin-based gastroprotective supplements.

Binding of Pb-Melatonin and Pb-(Melatonin-metabolites) complexes with DMT1 and ZIP8: implications for lead detoxification.

We have applied the docking methodology to characterize the binding modes of the divalent metal transporter 1 (DMT1) and the zinc transporter 8 (ZIP8) protein channels with: melatonin, some melatonin metabolites, and a few lead complexes of melatonin and its metabolites, in three different coordination modes (mono-coordinated, bi-coordinated and tri-coordinated). Our results show that bi-coordinated and tri-coordinated lead complexes prefer to bind inside the central region of ZIP8. Moreover, the interaction strength is larger compared with that of the free melatonin and melatonin metabolites. On the other hand, the binding modes with DMT1 of such complexes display lower binding energies, compared with the free melatonin and melatonin metabolites. Our results suggest that ZIP8 plays a major role in the translocation of Pb, bi or tri coordinated, when melatonin metabolites are present. Finally, we have characterized the binding modes responsible for the ZIP8 large affinities, found in bi-coordinated and tri-coordinated lead complexes. Our results show that such interactions are greater, because of an increase of the number of hydrogen bonds, the number and intensity of electrostatic interactions, and the interaction overlay degree in each binding mode. Our results give insight into the importance of the ZIP8 channel on lead transport and a possible elimination mechanism in lead detoxification processes. Graphical abstract .

Enhanced cellular uptake and osteogenic differentiation efficiency of melatonin by inclusion complexation with 2-hydroxypropyl β-cyclodextrin

Melatonin (MLT), a hormone secreted from the pineal gland, is recognized as a potential candidate for stimulation of bone regeneration. However, because of its hydrophobicity, the administration of MLT to stimulate bone regeneration is difficult. In this study, an inclusion complex of MLT with 2-hydroxypropyl β-cyclodextrin (HP-β-CD) was prepared to improve the water solubility, and the osteogenic differentiation ability of the inclusion complex was investigated in MC3T3-E1 cells. The formation of HP-β-CD/MLT inclusion complex was confirmed by 1H and 13C nuclear magnetic resonance spectroscopy and wide-angle X-ray diffraction. The water solubility of MLT increased linearly upon addition of HP-β-CD because of the formation of the inclusion complex. Additionally, treatment of the cells with HP-β-CD/MLT inclusion complex showed higher uptake amount of MLT than that treated with free MLT. In addition, treatment of MC3T3-E1 cells with HP-β-CD/MLT inclusion complex increased alkaline phosphatase activity and mineralized matrix deposition, compared to that in free MLT-treated and untreated cells. Furthermore, cells treated with HP-β-CD/MLT inclusion complex exhibited higher expression levels of osteogenic differentiation genes than those in the untreated and free MLT-treated cells. Accordingly, these results suggested that inclusion complexation of MLT with HP-β-CD would be a potential formulation for bone regeneration because of its improved solubility and enhanced osteogenic differentiation efficiency.

Poly(Lactide-Co-Glycolide)-Monomethoxy-Poly-(Polyethylene Glycol) Nanoparticles Loaded with Melatonin Protect Adipose-Derived Stem Cells Transplanted in Infarcted Heart Tissue.

Stem cell transplantation is a promising therapeutic strategy for myocardial infarction. However, transplanted cells face low survival rates due to oxidative stress and the inflammatory microenvironment in ischemic heart tissue. Melatonin has been used as a powerful endogenous antioxidant to protect cells from oxidative injury. However, melatonin cannot play a long-lasting effect against the hostile microenvironment. Nano drug delivery carriers have the ability to protect the loaded drug from degradation in physiological environments in a controlled manner, which results in longer effects and decreased side effects. Therefore, we constructed poly(lactide-co-glycolide)-monomethoxy-poly-(polyethylene glycol) (PLGA-mPEG) nanoparticles to encapsulate melatonin. We tested whether the protective effect of melatonin encapsulated by PLGA-mPEG nanoparticles (melatonin nanoparticles [Mel-NPs]) on adipose-derived mesenchymal stem cells (ADSCs) was enhanced compared to that of free melatonin both in vitro and in vivo. In the in vitro study, we found that Mel-NPs reduced formation of the p53- cyclophilin D complex, prevented mitochondrial permeability transition pores from opening, and rescued ADSCs from hypoxia/reoxygenation injury. Moreover, Mel-NPs can achieve higher ADSC survival rates than free melatonin in rat myocardial infarction areas, and the therapeutic effects of ADSCs pretreated with Mel-NPs were more apparent. Hence, the combination of Mel-NPs and stem cell transplantation may be a promising strategy for myocardial infarction therapy. Stem Cells 2018;36:540-550.

Protective roles of nanomelatonin in cerebral ischemia-reperfusion of aged brain: Matrixmetalloproteinases as regulators

Cerebral ischemia-reperfusion (CIR) injury occurs as a result of oxygen occlusion in the carotid artery through embolus or thrombus formation or cerebrovascular hemorrhage. The oxygen thrust during reperfusion causes the generation of reactive oxidative species (ROS) which exert a potential threat to neuronal survival. ROS may possibly be arrested by antioxidants. After CIR, extracellular matrix remodeling takes place, which is governed by matrix metalloproteinases (MMPs). Augmentation of lipid per oxidation, perturbation of antioxidant enzyme activities and the loss of pyramidal neuronal cells in rat brain were attributed to CIR injury. Melatonin can readily cross the blood-brain barrier (BBB) to exert protective effects as an antioxidant but it is quickly cleared by the circulating blood. Also melatonin is easily degraded by light and hence is found to be ineffective during daytime. Results of the present study showed that unlike free melatonin (FM), the application of nanocapsulated melatonin (NM) exhibited significantly higher potential even at much lower concentrations to rescue neuronal cells and mitochondria during CIR insult and also restored the activities of antioxidative enzymes and MMPs to their normal levels. Hence, nanoencapsulated melatonin may be considered as a suitable drug delivery system for brain to exert protection against CIR injury.

Age- and sex-related differences in the lipid profile and stress response in human aging

We analyzed the dynamics of the main lipid profile parameters, the plasma concentration of brainderived neurotrophic factor (BDNF), and the 24-hour urinary concentration of free cortisol, melatonin sulfate, metanephrine, and normetanephrine in 1136 subjects of different ages and sexes. Pronounced age- and sex-related differences were discovered both in the blood concentration of atherogenic lipid fractions and in the types of hyperlipidemia. We also found significant differences in the age dynamics of the parameters of stress response in men and women and in the correlation between these parameters and the levels of low-density lipoprotein (LDL) and its atherogenic index. These data suggest that the mechanisms of atherosclerosis development and pathological aging caused by this disorder differ between the sexes and age groups. The results of this study can be used to solve the problem of early detection and prediction of different age-related pathological conditions.

Antioxidant potential of different melatonin-loaded nanomedicines in an experimental model of sepsis

Oxidative stress has been shown to play a major role in the complex pathophysiological processes leading to organ failure during sepsis. The aim of the present research was to evaluate the effect of different melatonin nanoparticle (NP) carriers in an experimental animal model of sepsis. Poly-D,L-lactide-co-glycolide (PLGA [NP-A]) and polyethylene glycol-co-(poly-D,L-lactide-co-glycolide) (PLGA-PEG [NP-B]) were used to obtain melatonin-loaded nanocarriers (10 mg/kg). Oxidative stress was measured in tissue homogenates by measuring heme oxygenase-1 (HO-1) expression, total thiol groups and lipid hydroperoxides (LOOH). In vitro NPs showed a long lag time followed by a controlled release of melatonin. All the different melatonin formulations restored total thiol group levels to those of controls in all the examined organs, with no significant changes among them. Both melatonin NP formulations significantly decreased LOOH levels when compared with sepsis vehicle animals. The stealth formulation NP-B was able to produce a more significant reduction in LOOH levels in the heart, lung and liver when compared with NP-A. No significant changes were observed between the two NP formulations in the kidney. Interestingly, HO-1 expression was differently affected following treatment with various melatonin formulations. The NP-B formulation was more effective in inducing HO-1 protein compared with free melatonin and NP-A, with the exception of the kidney. Taken together, our results show that melatonin possesses a significant antioxidant activity during sepsis and that it is possible to improve this ability by delivering the compound with specific drug delivery systems.

Influence of astragaloside on gastric mucosal oxygen free radicals and melatonin receptors of rats with stress ulcer

Influence of astragaloside on gastric mucosal oxygen free radicals and melatonin receptors of rats with stress ulcer

Effects of Melatonin on Plasma S-Nitrosoglutathione and Glutathione in Streptozotocin-Treated Rats

The aim of this study was to determine the effects of streptozotocin-induced diabetes on plasma reduced glutathione (GSH) and S-nitrosoglutathione (GSNO) levels. Further, the study investigated whether an antioxidant, pineal hormone melatonin, could protect against STZ-induced effects. STZ significantly decreased plasma GSH but increased the levels of plasma GSNO. Daily supplementation with melatonin restored plasma thiol to control values. Data suggest that STZ-induced hyperglycemia and compounds that act as scavengers of free radicals and peroxynitrite like melatonin may exert protection against STZ-induced toxicity.

Novel B melatonin-loaded chitosan microcapsules: in vitro characterization and antiapoptosis efficacy for aflatoxin B1-induced apoptosis in rat liver

The aim of this study was to prepare buoyant (B) melatonin (MT)-loaded chitosan microcapsules having favourable sustained release characteristics (in simulated gastric fluid (SGF), pH 1.2) in comparison with non-buoyant (NB) chitosan particles. The new buoyant microcapsules were prepared by the ionotropic gelation method using sodium lauryl sulfate (NaLS) for coagulation. The microcapsule characteristics were affected by the initial drug and NaLS concentrations, as well as the presence of sodium dioctyl sulfosuccinate (DOS) or pectin with NaLS in the external phase. In general, spherical microcapsules with 36.90–56.23% encapsulation efficiencies, hollow core and satisfactory release properties were produced. The best sustained release profiles ( t 50%: 5 h) with near zero-order kinetics were observed with the higher theoretical payload microcapsules prepared with both NaLS and DOS in a 1:2 ratio. In vivo studies were also carried out to exploit the protective effect of the MT-loaded NaLS–DOS microcapsules against aflatoxin B1 (AFB1)-induced toxicity (liver apoptosis) in male rats. The results implied that apoptotic rate was significantly reduced when MT or its microcapsules formulation was co-administered with AFB1. The levels of the oxidative stress indices (malondialdehyde (MDA), a lipid peroxidation product and nitric oxide (NO)) in liver tissues were significantly reduced, while the levels of the hepatic antioxidants (glutathione (GSH) and zinc (Zn), as well as the enzyme activities of glutathione reductase (GR), glutathione peroxidase (GSPx) and glutathione- S-transferase (GST)) which act as antiapoptosis were significantly increased as compared to AFB1 group (without MT). MT microcapsules appeared more effective in reduction of apoptotic rate than free MT as indicated by the decline of caspase-3 activities (an apoptotic marker) and confirmed by histopathology.