RESUMO
OBJECTIVE: Ferroptosis of neurons is a significant cause of brain injury following intracerebral hemorrhage (ICH). As an iron-containing compound in hemoglobin, heme contributes to nerve injury post-ICH. Melatonin has been shown to mitigate the effects of ICH, yet its specific functions remain largely elusive. In this study, we aimed to explore the roles and mechanisms of melatonin in heme-induced ferroptosis subsequent to ICH. MATERIALS AND METHODS: C57BL/6 mice were intracranially injected with heme and then treated with melatonin. Behavior tests [modified neurological severity score (mNSS), forelimb placing, and corner turn tests], H&E staining, Nissl staining, and Prussian blue staining were used to evaluate mouse brain tissue injury. In vitro, HT-22 cells were stimulated with heme and cell viability was determined by crystal violet staining. The iron contents were determined in heme-treated brains and cells, and the levels of 4-hydroxynonenal (4-HNE) and malonaldehyde (MDA) were assessed by ELISA. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to investigate the mRNA levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Immunoblotting was used to analyze the protein expression of glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), Nrf2, and HO-1. Finally, small interfering RNA (siRNA) was used to knock down Nrf2 in HT-22 cells. RESULTS: Melatonin treatment alleviated heme-induced injuries to neural function, as indicated by improved behavior in the mice. Moreover, melatonin decreased cell death and iron concentrations, increased MDA and 4-HNE levels, and reversed the decreases in GPX4, SLC7A11, Nrf2, and HO-1 induced by heme in vitro and in vivo. These results indicated that melatonin could improve the ferroptosis induced by heme. In addition, we found that Nrf2 knockdown attenuated the therapeutic effect of melatonin on neuronal ferroptosis induced by heme. CONCLUSIONS: In general, melatonin alleviates heme-induced ferroptosis by activating the Nrf2/HO-1 pathway, which implies that melatonin is a promising treatment for ferroptosis in ICH.
Assuntos
Ferroptose , Heme Oxigenase-1 , Heme , Melatonina , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2 , Neurônios , Animais , Ferroptose/efeitos dos fármacos , Melatonina/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Heme Oxigenase-1/metabolismo , Heme/metabolismo , Masculino , Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/patologia , Transdução de Sinais/efeitos dos fármacos , Modelos Animais de Doenças , Proteínas de MembranaRESUMO
BACKGROUND AND RATIONALE: Ultraviolet-B (UVB) light induces dermal inflammation, although it is mostly absorbed in the epidermis. Recent reports suggest extracellular vesicles (EVs) act as a mediator of photodamage signaling. Melatonin is reported to be a protective factor against UV-induced damage. We hypothesized that EVs derived from UVB-irradiated keratinocytes might trigger proinflammatory responses in dermal cells and tested whether melatonin can ameliorate UVB-induced inflammation. METHODS: We used UVB-irradiated HaCaT cells, primary keratinocytes and STING knock-out mice to model production of EVs under photodamaging conditions and performed immunoblotting and ELISA to measure their effect on dermal macrophages. RESULTS: UVB-irradiated keratinocytes produce an increased number of EVs that contain higher concentrations of DNA and protein compared with controls. KC-derived EVs (KEVs) induced a STING- and inflammasome-mediated proinflammatory response in macrophages in vitro, and a pronounced inflammatory infiltrate in mouse dermis in vivo. Melatonin ameliorated KEVs inflammatory effect both in vitro and in vivo. CONCLUSIONS: This data suggests EVs are mediators in a crosstalk that takes place between keratinocytes and their neighboring cells as a result of photodamage. Further studies exploring EVs induced by damaging doses of UVB, and their impact on other cells will provide insight into photodamage and may help develop targeted therapeutic approaches.
Assuntos
Derme , Epiderme , Vesículas Extracelulares , Queratinócitos , Raios Ultravioleta , Vesículas Extracelulares/metabolismo , Queratinócitos/metabolismo , Queratinócitos/efeitos da radiação , Animais , Humanos , Epiderme/efeitos da radiação , Epiderme/metabolismo , Epiderme/patologia , Camundongos , Derme/patologia , Derme/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Melatonina/farmacologia , Melatonina/metabolismo , Macrófagos/metabolismo , Macrófagos/efeitos da radiação , Camundongos Knockout , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Células HaCaTRESUMO
Drought stress (DS) adversely affects a plant's development and growth by negatively altering the plant's physio-biochemical functions. Previous investigations have illustrated that seed priming with growth regulators is an accessible, affordable, and effective practice to elevate a plant's tolerance to drought stress. Melatonin (MT) is derived from the precursor tryptophan and can improve germination, biomass, and photosynthesis under stress conditions. The current study examined the effect of melatonin seed priming on two wheat cultivars (Fakhar-e-Bhakkar and Akber-19) cultivated under severe drought conditions (35% FC). There were 6 levels of melatonin (i.e., M0 = control, M1 = 1 mg L- 1, M2 = 2 mg L- 1, M3 = 3 mg L- 1, M4 = 4 mg L- 1 and M5 = mg L- 1) which were used for seed priming. Our results confirmed that seed priming with M2 = 2 mgL- 1 concentration of MT alleviates the negative effects of DS by boosting the germination rate by 54.84% in Akber-19 and 33.33% in Fakhar-e-Bhakkar. Similarly, leaf-relative water contents were enhanced by 22.38% and 13.28% in Akber-19 and Fakhar-e-Bhakkar, respectively. Melatonin pre-treatment with 2 mgL- 1 significantly enhanced fresh and dry biomass of shoot and root, leaf area, photosynthetic pigments, osmoprotectants accumulation [total soluble proteins (TSP), total free amino acids (TFAA), proline, soluble sugars, glycine betaine (GB)] and lowered the amount of malondialdehyde (MDA) and hydrogen peroxide (H2O2) production by elevating antioxidants [Ascorbic acid, catalase (CAT), Phenolics, peroxidase (POD) and superoxide dismutase (SOD)] activity under drought stress (DS). Meanwhile, under control conditions (NoDS), the melatonin treatment M1 = 1 mgL- 1 effectively enhanced all the growth-related physio-biochemical attributes in both wheat cultivars. In the future, more investigations are suggested on different crops under variable agroclimatic conditions to declare 2 mgL- 1 melatonin as an efficacious amendment to alleviate drought stress.
Assuntos
Secas , Germinação , Melatonina , Sementes , Triticum , Melatonina/farmacologia , Melatonina/metabolismo , Triticum/crescimento & desenvolvimento , Triticum/efeitos dos fármacos , Triticum/fisiologia , Triticum/metabolismo , Sementes/efeitos dos fármacos , Sementes/crescimento & desenvolvimento , Sementes/fisiologia , Germinação/efeitos dos fármacos , Antioxidantes/metabolismo , Reguladores de Crescimento de Plantas/metabolismo , Fotossíntese/efeitos dos fármacos , Resistência à SecaRESUMO
Recent evidence indicates that the damaged regions in osteoarthritis are accompanied by the accumulation of iron ions. Ferroptosis, as an iron-dependent form of cell death, holds significant implications in osteoarthritis. Melatonin, a natural product with strong scavenging abilities against reactive oxygen species and lipid peroxidation, plays a crucial role in the treatment of osteoarthritis. This study aims to demonstrate the existence of ferroptosis in osteoarthritis and explore the specific mechanism of melatonin in suppressing ferroptosis and alleviating osteoarthritis. Our findings reveal that melatonin reverses inflammation-induced oxidative stress and lipid peroxidation while promoting the expression of extracellular matrix components in chondrocytes, safeguarding the cells. Our research has revealed that NADPH oxidase 4 (NOX4) serves as a crucial molecule in the ferroptosis process of osteoarthritis. Specifically, NOX4 is located on mitochondria in chondrocytes, which can induce disorders in mitochondrial energy metabolism and dysfunction, thereby intensifying oxidative stress and lipid peroxidation. LC-MS analysis further uncovered that GRP78 is a downstream binding protein of NOX4. NOX4 induces ferroptosis by weakening GRP78's protective effect on GPX4 and reducing its expression. Melatonin can inhibit the upregulation of NOX4 on mitochondria and mitigate mitochondrial dysfunction, effectively suppressing ferroptosis and alleviating osteoarthritis. This suggests that melatonin therapy represents a promising new approach for the treatment of osteoarthritis.
Assuntos
Ferroptose , Melatonina , Mitocôndrias , NADPH Oxidase 4 , Osteoartrite , Melatonina/farmacologia , Ferroptose/efeitos dos fármacos , Osteoartrite/metabolismo , Osteoartrite/tratamento farmacológico , Osteoartrite/patologia , NADPH Oxidase 4/metabolismo , Animais , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Condrócitos/metabolismo , Condrócitos/efeitos dos fármacos , Condrócitos/patologia , Estresse Oxidativo/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Humanos , CamundongosRESUMO
Intestinal barrier dysfunction with high serum endotoxin is common in patients with liver fibrosis, but the mechanisms underlying liver fibrosis remain unclear. Melatonin is a well-recognized antioxidant and an anti-inflammatory agent that benefits multiple organs. However, the beneficial effects of melatonin on gut leakiness-associated liver fibrosis have not been systemically studied. Here, we investigated the protective mechanisms of melatonin against thioacetamide (TAA)-induced gut barrier dysfunction and hepatic fibrosis by focusing on posttranslational protein modifications through the gut-liver axis. Our results showed that gut leakiness markers, including decreased gut tight/adherens junction proteins (TJ/AJs) with increased intestinal deformation, apoptosis, and serum endotoxin, were observed early at 1 week after TAA exposure. Liver injury, apoptosis, and fibrosis were prominent at 2 and 4 weeks. Mechanistically, we found that gut TJ/AJs were hyper-acetylated, followed by ubiquitin-dependent proteolysis, leading to their degradation and gut leakiness. Gut dysbiosis, hepatic protein hyper-acetylation, and SIRT1 downregulation were also observed. Consistently, intestinal Sirt1 deficiency greatly enhanced protein hyper-acetylation, gut leakiness, endotoxemia, and liver fibrosis. Pretreatment with melatonin prevented or improved all these changes in both the gut and liver. Furthermore, melatonin blunted protein acetylation and injury in TAA-exposed T84 human intestinal and AML12 mouse liver cells. Overall, this study demonstrated novel mechanisms by which melatonin prevents gut leakiness and liver fibrosis through the gut-liver axis by attenuating the acetylation of intestinal and hepatic proteins. Thus, melatonin consumption can become a potentially safe supplement for liver fibrosis patients by preventing protein hyper-acetylation and gut leakiness.
Assuntos
Cirrose Hepática , Melatonina , Sirtuína 1 , Tioacetamida , Tioacetamida/toxicidade , Sirtuína 1/metabolismo , Melatonina/farmacologia , Animais , Cirrose Hepática/metabolismo , Cirrose Hepática/induzido quimicamente , Camundongos , Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Acetilação/efeitos dos fármacos , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologiaRESUMO
Salinity stress represents a major threat to crop production by inhibiting seed germination, growth of seedlings, and final yield and, therefore, to the social and economic prosperity of developing countries. Recently, plant growth-promoting substances have been widely used as a chemical strategy for improving plant resilience towards abiotic stresses. This study aimed to determine whether melatonin (MT) and glycine betaine (GB) alone or in combination could alleviate the salinity-induced impacts on seed germination and growth of maize seedlings. Increasing NaCl concentration from 100 to 200 mM declined seed germination rate (4.6-37.7%), germination potential (24.5-46.7%), radical length (7.7-40.0%), plumule length (2.2-35.6%), seedling fresh (1.7-41.3%) and dry weight (23.0-56.1%) compared to control (CN) plants. However, MT and GB treatments lessened the adverse effects of 100 and 150 mM NaCl and enhanced germination comparable to control plants. In addition, results from the pot experiments show that 200 mM NaCl stress disrupted the osmotic balance and persuaded oxidative stress, presented by higher electrolyte leakage, hydrogen peroxide, superoxide radicals, and malondialdehyde compared to control plants. However, compared to the NaCl treatment, NaCl+MT+GB treatment decreased the accumulation of malondialdehyde (24.2-42.1%), hydrogen peroxide (36.2-44.0%), and superoxide radicals (20.1-50.9%) by up-regulating the activity of superoxide dismutase (28.4-51.2%), catalase (82.2-111.5%), ascorbate peroxidase (40.3-59.2%), and peroxidase (62.2-117.9%), and by enhancing osmolytes accumulation, thereby reducing NaCl-induced oxidative damages. Based on these findings, the application of MT+GB is an efficient chemical strategy for improving seed germination and growth of seedlings by improving the physiological and biochemical attributes of maize under 200 mM NaCl stress.
Assuntos
Betaína , Germinação , Melatonina , Estresse Salino , Plântula , Sementes , Zea mays , Melatonina/farmacologia , Zea mays/efeitos dos fármacos , Zea mays/crescimento & desenvolvimento , Zea mays/fisiologia , Zea mays/metabolismo , Betaína/farmacologia , Betaína/metabolismo , Germinação/efeitos dos fármacos , Plântula/efeitos dos fármacos , Plântula/crescimento & desenvolvimento , Plântula/fisiologia , Estresse Salino/efeitos dos fármacos , Sementes/efeitos dos fármacos , Sementes/crescimento & desenvolvimento , Sementes/fisiologia , Cloreto de Sódio/farmacologia , Malondialdeído/metabolismo , Salinidade , Antioxidantes/metabolismo , Peróxido de Hidrogênio/metabolismo , Sinergismo Farmacológico , Estresse Oxidativo/efeitos dos fármacosRESUMO
The yield of Tartary buckwheat is significantly affected by continuous cropping. Melatonin plays a crucial role in plant defense mechanisms against abiotic stresses. However, the relationship between melatonin and continuous cropping tolerance remains unclear. This study aimed to analyze the physiological mechanism of melatonin in enhancing the continuous cropping tolerance (abiotic stress) of Tartary buckwheat. A field experiment was conducted on Tartary buckwheat cultivar Jinqiao 2 under continuous cropping with five melatonin application rates, 0 (Control), 10, 50, 100, and 200 µmol L-1, applied during the early budding stage. The chlorophyll content, antioxidant enzyme activity, osmolyte and auxin (IAA) contents, root activity, rhizosphere soil nutrient content, and agronomic traits of Tartary buckwheat initially increased and then decreased with an increase in the concentration of exogenous melatonin application, with the best effects observed at 100 µmol L-1. Compared with the Control treatment, the 100 µmol L-1 treatment decreased the contents of malondialdehyde, superoxide anion free radical, and abscisic acid (ABA) by an average of 28.79%, 27.08%, and 31.64%, respectively. Exogenous melatonin treatment significantly increased the yield of Tartary buckwheat under continuous cropping. Plants treated with 10, 50, 100, and 200 µM respectively had 1.88, 2.01, 2.20, and 1.78 times higher yield than those of the Control treatment. In summary, melatonin treatment, particularly 100 µmol L-1, enhanced the continuous cropping tolerance of Tartary buckwheat by increasing antioxidant capacity and osmotica content, coordinating endogenous ABA and IAA content levels, and delaying senescence, ultimately increasing yield.
Assuntos
Antioxidantes , Fagopyrum , Melatonina , Fagopyrum/efeitos dos fármacos , Fagopyrum/metabolismo , Fagopyrum/crescimento & desenvolvimento , Fagopyrum/fisiologia , Melatonina/farmacologia , Melatonina/metabolismo , Antioxidantes/metabolismo , Ácido Abscísico/metabolismo , Ácido Abscísico/farmacologia , Clorofila/metabolismo , Ácidos Indolacéticos/metabolismo , Malondialdeído/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/metabolismo , Raízes de Plantas/crescimento & desenvolvimentoRESUMO
Melatonin (MLT), a main product of pineal gland, recently has attracted the attention of scientists due to its benefits in various diseases and also regulation of cellular homeostasis. Its receptor scares widely distributed indicating that it influences numerous organs. Programmed cell death (PCD), of which there several types, is a regulated by highly conserved mechanisms and important for development and function of different organs. Enhancement or inhibition of PCDs could be a useful technique for treatment of different diseases and MLT, due to its direct effects on these pathways, is a good candidate for this strategy. Many studies investigated the role of MLT on PCDs in different diseases and in this review, we summarized some of the most significant studies in this field to provide a better insight into the mechanisms of modulation of PCD by MLT modulation.
Assuntos
Apoptose , Melatonina , Melatonina/metabolismo , Melatonina/farmacologia , Humanos , Apoptose/efeitos dos fármacos , AnimaisRESUMO
Background: Seed hypocotyl germination signifies the initiation of the life cycle for plants and represents a critical stage that heavily influences subsequent plant growth and development. While previous studies have established the melatonin (MEL; N-acetyl-5-methoxytrytamine) effect to stimulate seed germination of some plants, its specific role in peony germination and underlying physiological mechanism have yet to be determined. This study aims to evaluate the MEL effect for the hypocotyl germination of peony seeds, further ascertain its physiological regulation factors. Methods: In this work, seeds of Paeonia ostia 'Fengdan' were soaked into MEL solution at concentrations of 50, 100, 200, and 400 µM for 48 h and then germinated in darkness in incubators. Seeds immersed in distilled water without MEL for the same time were served as the control group. Results: At concentrations of 100 and 200 µM, MEL treatments improved the rooting rate of peony seeds, while 400 µM inhibited the process. During seed germination, the 100 and 200 µM MEL treatments significantly reduced the starch concentration, and α-amylase was the primary amylase involved in the action of melatonin. Additionally, compared to the control group, 100 µM MEL treatment significantly increased the GA3 concentration and radicle thickness of seeds, but decreased ABA concentration. The promotion effect of 200 µM MEL pretreatment on GA1 and GA7 was the most pronounced, while GA4 concentration was most significantly impacted by 50 µM and 100 µM MEL. Conclusion: Correlation analysis established that 100 µM MEL pretreatment most effectively improved the rooting rate characterized by increasing α-amylase activity to facilitate starch decomposition, boosting GA3 levels, inhibiting ABA production to increase the relative ratio of GA3 to ABA. Moreover, MEL increased radicle thickness of peony seeds correlating with promoting starch decomposition and enhancing the synthesis of GA1 and GA7.
Assuntos
Germinação , Hipocótilo , Melatonina , Paeonia , Reguladores de Crescimento de Plantas , Sementes , Amido , Melatonina/farmacologia , Germinação/efeitos dos fármacos , Paeonia/efeitos dos fármacos , Paeonia/metabolismo , Hipocótilo/efeitos dos fármacos , Hipocótilo/crescimento & desenvolvimento , Reguladores de Crescimento de Plantas/farmacologia , Reguladores de Crescimento de Plantas/metabolismo , Sementes/efeitos dos fármacos , Sementes/crescimento & desenvolvimento , Sementes/metabolismo , Amido/metabolismo , Giberelinas/farmacologia , Giberelinas/metabolismo , alfa-Amilases/metabolismoRESUMO
Melatonin has been reported to regulate circadian rhythms and have anti-inflammatory characteristics in various inflammatory autoimmune diseases, but its effects in diseases-associated muscle atrophy remain controversial. This study is aimed to determine the evidence of melatonin in rheumatoid arthritis (RA)-related pathological muscle atrophy. We used initially bioinformatics results to show that melatonin regulated significantly the correlation between pro-inflammation and myogenesis in RA synovial fibroblasts (RASF) and myoblasts. The conditioned medium (CM) from melatonin-treated RASF was incubated in myoblasts with growth medium and differentiated medium to investigate the markers of pro-inflammation, atrophy, and myogenesis. We found that melatonin regulated RASF CM-induced pathological muscle pro-inflammation and atrophy in myoblasts and differentiated myocytes through NF-κB signaling pathways. We also showed for the first time that miR-30c-1-3p is negatively regulated by three inflammatory cytokines in human RASF, which is associated with murine-differentiated myocytes. Importantly, oral administration with melatonin in a collagen-induced arthritis (CIA) mouse model also significantly improved arthritic swelling, hind limb grip strength as well as pathological muscle atrophy. In conclusion, our study is the first to demonstrate not only the underlying mechanism whereby melatonin decreases pro-inflammation in RA-induced pathological muscle atrophy but also increases myogenesis in myoblasts and differentiated myocytes.
Assuntos
Artrite Reumatoide , Fibroblastos , Melatonina , Músculo Esquelético , Melatonina/farmacologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Artrite Reumatoide/tratamento farmacológico , Humanos , Fibroblastos/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Animais , Camundongos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Músculo Esquelético/efeitos dos fármacos , Inflamação/metabolismo , Inflamação/patologia , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , Membrana Sinovial/efeitos dos fármacos , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Artrite Experimental/tratamento farmacológico , Masculino , Mioblastos/metabolismo , Mioblastos/efeitos dos fármacos , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Atrofia Muscular/tratamento farmacológico , Camundongos Endogâmicos DBARESUMO
Diabetic retinopathy (DR) is characterized as a microvascular disease. Nonproliferative diabetic retinopathy (NPDR) presents with alterations in retinal blood flow and vascular permeability, thickening of the basement membrane, loss of pericytes, and formation of acellular capillaries. Endothelial-mesenchymal transition (EndMT) of retinal microvessels may play a critical role in advancing NPDR. Melatonin, a hormone primarily secreted by the pineal gland, is a promising therapeutic for DR. This study explored the EndMT in retinal microvessels of NPDR and its related mechanisms. The effect of melatonin on the retina of diabetic rats was evaluated by electroretinogram (ERG) and histopathologic slide staining. Furthermore, the effect of melatonin on human retinal microvascular endothelial cells (HRMECs) was detected by EdU incorporation assay, scratch assay, transwell assay, and tube formation test. Techniques such as RNA-sequencing, overexpression or knockdown of target genes, extraction of cytoplasmic and nuclear protein, co-immunoprecipitation (co-IP), and multiplex immunofluorescence facilitated the exploration of the mechanisms involved. Our findings reveal, for the first time, that melatonin attenuates diabetic retinopathy by regulating EndMT of retinal vascular endothelial cells via inhibiting the HDAC7/FOXO1/ZEB1 axis. Collectively, these results suggest that melatonin holds potential as a therapeutic strategy to reduce retinal vascular damage and protect vision in NPDR.
Assuntos
Diabetes Mellitus Experimental , Retinopatia Diabética , Células Endoteliais , Histona Desacetilases , Melatonina , Homeobox 1 de Ligação a E-box em Dedo de Zinco , Melatonina/farmacologia , Retinopatia Diabética/metabolismo , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/patologia , Animais , Ratos , Células Endoteliais/metabolismo , Células Endoteliais/efeitos dos fármacos , Histona Desacetilases/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Humanos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Masculino , Proteína Forkhead Box O1/metabolismo , Vasos Retinianos/efeitos dos fármacos , Vasos Retinianos/metabolismo , Vasos Retinianos/patologia , Ratos Sprague-Dawley , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Retina/metabolismo , Retina/efeitos dos fármacos , Retina/patologia , Transição Endotélio-MesênquimaRESUMO
As a novel pollutant, microplastic pollution has become a global environmental concern. Melatonin (MT) has a protective effect on the damage caused by pollutants. However, there is still a lack of research on the transgenerational toxicity of microplastics and the alleviation of microplastics toxicity by MT. In this study, the adult zebrafish was exposed to (0, 0.1 and 1 mg/L) polystyrene nanoplastics (PSNP) with or without (1 µM) MT for 14 days, and embryos (F1) were used for experiments. Our study found that long-term exposure of parents to 1 mg/L PSNP reduced fertilization rate and survival rate of offspring, increased the deformity rate and induced embryos to hatch in advance. The growth inhibition of offspring was related to the gene transcription of the growth hormone/insulin-like growth factor axis. Moreover, PSNP caused oxidative stress in offspring, damaged immune system, reduced antioxidant capacity and induced apoptosis. MT supplementation could effectively alleviate the developmental toxicity and oxidative damage of offspring, but the negative effects brought by PSNP could not be completely eliminated. Our research provided a new reference for the protective effect of MT on transgenerational toxicity induced by PSNP.
Assuntos
Melatonina , Microplásticos , Poluentes Químicos da Água , Peixe-Zebra , Animais , Melatonina/farmacologia , Poluentes Químicos da Água/toxicidade , Microplásticos/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Antioxidantes , Embrião não Mamífero/efeitos dos fármacos , Nanopartículas/toxicidadeRESUMO
Lemon fruit (Citrus limon (L.) Burm.) is highly appreciated by consumers due to its antioxidant properties and health benefits. However, its shelf life can be limited by various factors, reducing the economy, and thereafter, new strategies to maintain the quality of lemons are necessary. Melatonin is a derivative of tryptamine, which is ubiquitously found in plants and has a wide range of functions regulating numerous physiological processes in plants. During two consecutive harvests, we evaluated the effect of preharvest treatments with melatonin on crop yield and on quality and functional properties of fruit of lemon cv. Verna at harvest and weekly after storage up to 28 days at 2 and 10 °C plus 2 days at 20 °C. Melatonin was applied as foliar spray treatments at dosages of 0.1, 0.3, and 0.5 mM and at three different stages of fruit development. The results showed that melatonin treatment had a positive impact on crop yield as well as in fruit quality parameters, such as firmness, content of bioactive compounds, and antioxidant activity, especially for a 0.5 mM dose. Taking all these effects into account, the application of melatonin along the growth cycle of fruit development could be considered a non-contaminant and eco-friendly tool for improving crop yield and quality of 'Verna' lemons at harvest and during postharvest storage.
Assuntos
Antioxidantes , Citrus , Armazenamento de Alimentos , Frutas , Melatonina , Melatonina/farmacologia , Citrus/crescimento & desenvolvimento , Citrus/efeitos dos fármacos , Antioxidantes/farmacologia , Frutas/efeitos dos fármacos , Frutas/crescimento & desenvolvimento , Frutas/química , Armazenamento de Alimentos/métodosRESUMO
Cartilage damage caused by injuries or degenerative diseases remains a major challenge in the field of regenerative medicine. In this study, we developed a composite hydrogel system for the delivery of melatonin and menstrual blood stem cells (MenSCs) to treat a rat model of cartilage defect. The composite delivery system was produced by incorporation of melatonin into the gelatin fibers and dispersing these fibers into calcium alginate hydrogels. Various characterization methods including cell viability assay, microstructure studies, degradation rate measurement, drug release, anti-inflammatory assay, and radical scavenging assay were used to characterize the hydrogel system. MenSCs were encapsulated within the nanocomposite hydrogel and implanted into a rat model of full-thickness cartilage defect. A 1.3 mm diameter drilled in the femoral trochlea and used for the in vivo study. Results showed that the healing potential of nanocomposite hydrogels containing melatonin and MenSCs was significantly higher than polymer-only hydrogels. Our study introduces a novel composite hydrogel system, combining melatonin and MenSCs, demonstrating enhanced cartilage repair efficacy, offering a promising avenue for regenerative medicine.
Assuntos
Gelatina , Hidrogéis , Melatonina , Nanocompostos , Nanofibras , Melatonina/farmacologia , Melatonina/química , Melatonina/administração & dosagem , Animais , Gelatina/química , Hidrogéis/química , Nanocompostos/química , Ratos , Nanofibras/química , Feminino , Humanos , Cartilagem/efeitos dos fármacos , Ratos Sprague-Dawley , Menstruação/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Alginatos/química , Cicatrização/efeitos dos fármacos , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacosRESUMO
Oogenesis involves two phases: initial volumetric growth driven by nutrient accumulation and subsequent nuclear maturation. While melatonin (MLT) has been employed as a supplement to enhance the quality of fully grown oocytes during nuclear maturation phase, its impact on oocyte growth remains poorly studied. Here, we provide in vivo evidence demonstrating that follicle-stimulating hormone increases MLT content in ovary. Administration of MLT improves oocyte growth and quality in mice and goats by enhancing nutrient reserves and mitochondrial function. Conversely, MLT-deficient mice have smaller oocytes and dysfunctional mitochondria. Exploring the clinical implications of MLT in promoting oocyte growth, we observe that a brief 2-day MLT treatment enhances oocyte quality and reproductive performance in older mice. These findings highlight the role of MLT in regulating oocyte growth and provide a specific treatment window for optimizing oocyte quality and reproductive performance in female animals.
Assuntos
Cabras , Melatonina , Mitocôndrias , Oócitos , Animais , Melatonina/farmacologia , Melatonina/metabolismo , Oócitos/metabolismo , Oócitos/efeitos dos fármacos , Oócitos/crescimento & desenvolvimento , Camundongos , Feminino , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Oogênese/efeitos dos fármacos , Oogênese/fisiologia , Hormônio Foliculoestimulante/metabolismo , Nutrientes/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Maize (Zea mays L.) is sensitive to salt stress, especially during seed germination and seedling morphogenesis, which limits maize growth and productivity formation. As a novel recognized plant hormone, melatonin (MT) participates in multiple growth and developmental processes and mediates biotic/abiotic stress responses, yet the effects of salt stress on maize seedlings remain unclear. Herein, we investigated the effects of 150 µM exogenous MT on multiple phenotypes and physiologic metabolisms in three-leaf seedlings across eight maize inbred lines under 180 mM NaCl salt stress, including growth parameters, stomatal morphology, photosynthetic metabolisms, antioxidant enzyme activities, and reactive oxygen species (ROS). Meanwhile, the six gene expression levels controlling antioxidant enzyme activities and photosynthetic pigment biosynthesis in two materials with contrasting salt resistance were examined for all treatments to explore the possible molecular mechanism of exogenous MT alleviating salt injury in maize. The results showed that 150 µM exogenous MT application protected membrane integrity and reduced ROS accumulation by activating the antioxidant system in leaves of maize seedlings under salt stress, their relative conductivity and H2O2 level average reduced by 20.91% and 17.22%, while the activities of superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), and ascorbate peroxidase (APX) averaged increased by 13.90%, 17.02%, 22.00%, and 14.24% relative to salt stress alone. The improvement of stomatal size and the deposition of photosynthetic pigments were more favorable to enhancing photosynthesis in leaves when these seedlings treated with MT application under salt stress, their stomatal size, chlorophyll content, and net photosynthetic rate averaged increased by 11.60%, 19.64%, and 27.62%. Additionally, Gene expression analysis showed that MT stimulation significantly increased the expression of antioxidant enzyme genes (Zm00001d009990, Zm00001d047479, Zm00001d014848, and Zm00001d007234) and photosynthetic pigment biosynthesis genes (Zm00001d011819 and Zm00001d017766) under salt stress. At the same time, 150 µM MT significantly promoted seedling growth and biomass accumulation. In conclusion, our study may unravel crucial evidence of the role of MT in maize seedlings against salt stress, which can provide a novel strategy for improving maize salt stress resistance.
Assuntos
Antioxidantes , Melatonina , Fotossíntese , Estômatos de Plantas , Espécies Reativas de Oxigênio , Estresse Salino , Plântula , Zea mays , Zea mays/efeitos dos fármacos , Zea mays/metabolismo , Zea mays/crescimento & desenvolvimento , Melatonina/farmacologia , Melatonina/metabolismo , Fotossíntese/efeitos dos fármacos , Antioxidantes/metabolismo , Estômatos de Plantas/efeitos dos fármacos , Estômatos de Plantas/metabolismo , Plântula/metabolismo , Plântula/efeitos dos fármacos , Plântula/crescimento & desenvolvimento , Espécies Reativas de Oxigênio/metabolismo , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Cloreto de Sódio/farmacologia , Folhas de Planta/metabolismo , Folhas de Planta/efeitos dos fármacosRESUMO
Melatonin, as an endocrine neurotransmitter, can promote the development of the ovary. Meanwhile, it also has protective effect on the ovary as an antioxidant. Thyroid hormone (TH) is essential for normal human reproductive function. Many studies have shown that 3,5,3'-triiodothyronine (T3) regulates the development of ovarian granulosa cells. However, little is known about the specific mechanisms by which melatonin combines with T3 to regulate granulosa cell development. The aim of present study was to investigate the effects and the possible mechanisms of melatonin and T3 on ovarian granulosa cell development. In the present study, cell development and apoptosis were detected by CCK8, EdU and TUNEL, respectively. The levels of related proteins were analyzed by Western blotting. The results showed that oxidative stress (OS) and reactive oxygen species (ROS) were induced by H2O2 in granulosa cells, and cell apoptosis was also increased accompanied with the decreased cellular proliferation and viability. Melatonin protects granulosa cells from H2O2-induced apoptosis and OS by downregulating ROS levels, especially in the presence of T3. Co-treatment of cell with melatonin and T3 also promotes the expression of GRP78 and AMH, while inhibiting CHOP, Caspase-3, and P16. It was demonstrated that melatonin alone or in combination with T3 had positive effect on the development of granulosa cells. In addition, the AMPK/SIRT1 signaling pathway is involved in the process of melatonin/T3 promoting granulosa cell development.
Assuntos
Apoptose , Células da Granulosa , Melatonina , Estresse Oxidativo , Tri-Iodotironina , Melatonina/farmacologia , Células da Granulosa/efeitos dos fármacos , Células da Granulosa/metabolismo , Feminino , Animais , Tri-Iodotironina/farmacologia , Ratos , Apoptose/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Chaperona BiP do Retículo Endoplasmático/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proliferação de Células/efeitos dos fármacos , Peróxido de Hidrogênio , Ratos Sprague-Dawley , Sobrevivência Celular/efeitos dos fármacos , Antioxidantes/farmacologia , Células CultivadasRESUMO
Despite extensive progress in the knowledge and understanding of cardiovascular diseases and significant advances in pharmacological treatments and procedural interventions, cardiovascular diseases (CVD) remain the leading cause of death globally. Mitochondrial dynamics refers to the repetitive cycle of fission and fusion of the mitochondrial network. Fission and fusion balance regulate mitochondrial shape and influence physiology, quality and homeostasis. Mitophagy is a process that eliminates aberrant mitochondria. Melatonin (Mel) is a pineal-synthesized hormone with a range of pharmacological properties. Numerous nonclinical trials have demonstrated that Mel provides cardioprotection against ischemia/reperfusion, cardiomyopathies, atherosclerosis and cardiotoxicity. Recently, interest has grown in how mitochondrial dynamics contribute to melatonin cardioprotective effects. This review assesses the literature on the protective effects of Mel against CVD via the regulation of mitochondrial dynamics and mitophagy in both in-vivo and in-vitro studies. The signalling pathways underlying its cardioprotective effects were reviewed. Mel modulated mitochondrial dynamics and mitophagy proteins by upregulation of mitofusin, inhibition of DRP1 and regulation of mitophagy-related proteins. The evidence supports a significant role of Mel in mitochondrial dynamics and mitophagy quality control in CVD.
Assuntos
Doenças Cardiovasculares , Melatonina , Dinâmica Mitocondrial , Mitofagia , Melatonina/farmacologia , Mitofagia/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Humanos , Animais , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/prevenção & controle , Cardiotônicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacosRESUMO
Tumor-associated macrophages (TAMs), present within the tumor microenvironment (TME), strictly modulate tumor angiogenesis and lymphangiogenesis. Nevertheless, the associated signaling networks and candidate drug targets for these events remains to be elucidated. Given its antioxidative activities, we speculated that melatonin may reduce pyroptosis, and thereby modulate both angiogenesis and lymphangiogenesis. We revealed that a co-culture of A549 cells and THP-1 macrophages strongly enhanced expressions of the NLRP3 inflammasome axis members, and augmented angiogenesis and lymphangiogenesis. Next, we overexpressed NLRP3 in the A549 cells, and demonstrated that excess NLRP3 expression substantially upregulated VEGF and CXCL cytokine expressions, and enhanced lymphatic endothelial cells (LECs) tube formation. In contrast, NLRP3 inhibition produced the opposite effect. In addition, relative to controls, melatonin administration strongly inhibited the NLRP3 inflammasome axis, as well as angiogenesis and lymphangiogenesis in the co-culture system. Subsequent animal experiments using a Lewis Lung Carcinoma (LLC) subcutaneous tumor model in mice corroborate these findings. Melatonin treatment and NLRP3 knockdown significantly inhibit tumor growth and downregulate NLRP3 and IL-1ß expression in tumor tissues. Furthermore, melatonin downregulates the expression of angiogenic and lymphangiogenic markers in tumor tissues. Taken together, the evidence suggested that a THP-1 macrophage and A549 cell co-culture stimulates angiogenesis and lymphangiogenesis via the NLRP3 axis. Melatonin protected against the TAMs- and NLRP3 axis-associated promotion of the aforementioned events in vitro and in vivo. Hence, melatonin is a promising candidate for managing for tumor-related angiogenesis and lymphangiogenesis in lung adenocarcinoma.
Assuntos
Adenocarcinoma de Pulmão , Inflamassomos , Neoplasias Pulmonares , Linfangiogênese , Melatonina , Proteína 3 que Contém Domínio de Pirina da Família NLR , Neovascularização Patológica , Macrófagos Associados a Tumor , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Melatonina/farmacologia , Linfangiogênese/efeitos dos fármacos , Humanos , Animais , Neovascularização Patológica/metabolismo , Neovascularização Patológica/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Camundongos , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/efeitos dos fármacos , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Células A549 , Técnicas de Cocultura , Microambiente Tumoral/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Células THP-1 , Camundongos Endogâmicos C57BL , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/patologia , AngiogêneseRESUMO
BACKGROUND: Melatonin has been shown to be neuroprotective in different animal models of neonatal hypoxic-ischemic brain injury. However, its exact molecular mechanism of action remains unknown. Our aim was to prove melatonin's short- and long-term neuroprotection and investigate its role on the AMPK (AMP-activated protein kinase)/mTOR (mammalian target of rapamycin) pathway following neonatal hypoxic-ischemic brain injury. METHODS AND RESULTS: Seven-day-old Wistar rat pups were exposed to hypoxia-ischemia, followed by melatonin or vehicle treatment. Detailed analysis of the AMPK/mTOR/autophagy pathway, short- and long-term neuroprotection, myelination, and oligodendrogenesis was performed at different time points. At 7 days after hypoxia-ischemia, melatonin-treated animals showed a significant decrease in tissue loss, increased oligodendrogenesis, and myelination. Long-term neurobehavioral results showed significant motor improvement following melatonin treatment. Molecular pathway analysis showed a decrease in the AMPK expression, with a significant increase at mTOR's downstream substrates, and a significant decrease at the autophagy marker levels in the melatonin group compared with the vehicle group. CONCLUSIONS: Melatonin treatment reduced brain area loss and promoted oligodendrogenesis with a clear improvement of motor function. We found that melatonin associated neuroprotection is regulated via the AMPK/mTOR/autophagy pathway. Considering the beneficial effects of melatonin and the results of our study, melatonin seems to be an optimal candidate for the treatment of newborns with hypoxic-ischemic brain injury in high- as well as in low- and middle-income countries.