RESUMEN
Fully restoring the lost population of cardiomyocytes and heart function remains the greatest challenge in cardiac repair post myocardial infarction. In this study, a pioneered highly ROS-eliminating hydrogel was designed to enhance miR-19a/b induced cardiomyocyte proliferation by lowering the oxidative stress and continuously releasing miR-19a/b in infarcted myocardium in situ. In vivo lineage tracing revealed that â¼20.47 % of adult cardiomyocytes at the injected sites underwent cell division in MI mice. In MI pig the infarcted size was significantly reduced from 40 % to 18 %, and thereby marked improvement of cardiac function and increased muscle mass. Most importantly, our treatment solved the challenge of animal death--all the treated pigs managed to live until their hearts were harvested at day 50. Therefore, our strategy provides clinical conversion advantages and safety for healing damaged hearts and restoring heart function post MI, which will be a powerful tool to battle cardiovascular diseases in patients.
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Proliferación Celular , MicroARNs , Infarto del Miocardio , Miocitos Cardíacos , Estrés Oxidativo , Animales , MicroARNs/metabolismo , MicroARNs/genética , Miocitos Cardíacos/metabolismo , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Estrés Oxidativo/efectos de los fármacos , Ratones , Porcinos , Hidrogeles/química , Ratones Endogámicos C57BL , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Insulin resistance and pancreatic ß-cell dysfunction are the main pathogenesis of type 2 diabetes mellitus (T2DM). However, insulin therapy and diabetes medications do not effectively solve the two problems simultaneously. In this study, a biomimetic oral hydrogen nanogenerator that leverages the benefits of edible plant-derived exosomes and hydrogen therapy was constructed to overcome this dilemma by modulating gut microbiota and ameliorating oxidative stress and inflammatory responses. Hollow mesoporous silica (HMS) nanoparticles encapsulating ammonia borane (A) were used to overcome the inefficiency of H2 delivery in traditional hydrogen therapy, and exosomes originating from ginger (GE) were employed to enhance biocompatibility and regulate intestinal flora. Our study showed that HMS/A@GE not only considerably ameliorated insulin resistance and liver steatosis, but inhibited the dedifferentiation of islet ß-cell and enhanced pancreatic ß-cell proportion in T2DM model mice. In addition to its antioxidant and anti-inflammatory effects, HMS/A@GE augmented the abundance of Lactobacilli spp. and tryptophan metabolites, such as indole and indole acetic acid, which further activated the AhR/IL-22 pathway to improve intestinal-barrier function and metabolic impairments. This study offers a potentially viable strategy for addressing the current limitations of diabetes treatment by integrating gut-microbiota remodelling with antioxidant therapies.
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Antioxidantes , Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Resistencia a la Insulina , Células Secretoras de Insulina , Nanopartículas , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Animales , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Antioxidantes/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Nanopartículas/química , Ratones , Masculino , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Ratones Endogámicos C57BL , Zingiber officinale/química , Dióxido de Silicio/química , Exosomas/metabolismo , Biomimética/métodos , Estrés Oxidativo/efectos de los fármacosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Tackling phlegm and improving blood circulation is vital in the treatment of ischemic stroke (IS), culminating in the development of Zhongfeng Decoction (ZFD), a method grounded in this approach and serving as an effective therapy for IS. Nonetheless, the defensive mechanism of the ZFD in preventing cerebral ischemia-reperfusion damage remains ambiguous. AIM OF THE STUDY: Determine the active ingredients in ZFD that have neuroprotective effects, and identify its mechanism of action against IS. MATERIALS AND METHODS: A cerebral ischemia model in rats was developed, utilizing TTC, Nissl staining, and an oxidative stress kit to evaluate the neuroprotective impact of ZFD on this rat model. Following this, an amalgamation of LC-MS and network pharmacology techniques was employed to pinpoint potential active components, primary targets, and crucial action mechanisms of ZFD in treating IS. Finally, key targets and signaling pathways were detected using qRT-PCR, ELISA, Western blotting, electron microscopy, and other methods. RESULTS: Through LC-MS and network analysis, 15 active ingredients and 6 hub targets were identified from ZFD. Analysis of pathway enrichment revealed that ZFD predominantly engages in the AGE-RAGE signaling route. Kaempferol, quercetin, luteolin, baicalein, and nobiletin in ZFD are the main active ingredients for treating IS. In vivo validation showed that ZFD can improve nerve damage in cerebral ischemic rats, reduce the mRNA expression of IL6, SERPINE1, CCL2, and TGFB1 related to inflammation. Furthermore, we also confirmed that ZFD can inhibit the protein expression of AGEs, RAGE, p-IKBα/IKBα, p-NF-κB p65/NF-κB p65, reduce autophagy levels, and thus decrease neuronal apoptosis. CONCLUSIONS: The mechanism of action of ZFD in treating IS primarily includes inflammation suppression, oxidative stress response alleviation, post-stroke cell autophagy and apoptosis regulation, and potential mediation of the AGE-RAGE signaling pathway. This study elucidates how ZFD functions in treating IS, establishing a theoretical basis for its clinical application.
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Autofagia , Medicamentos Herbarios Chinos , Fármacos Neuroprotectores , Ratas Sprague-Dawley , Daño por Reperfusión , Transducción de Señal , Animales , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Medicamentos Herbarios Chinos/farmacología , Transducción de Señal/efectos de los fármacos , Masculino , Autofagia/efectos de los fármacos , Ratas , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Isquemia Encefálica/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Modelos Animales de Enfermedad , Productos Finales de Glicación Avanzada/metabolismoRESUMEN
Currently, mitochondrial dysfunction caused by oxidative stress is a growing concern in degenerative diseases, notably intervertebral disc degeneration (IVDD). Dysregulation of the balance of mitochondrial quality control (MQC) has been considered the key contributor, while it's still challenging to effectively harmonize different MQC components in a simple and biologically safe way. Hydrogen gas (H2) is a promising mitochondrial therapeutic molecule due to its bio-reductivity and diffusibility across cellular membranes, yet its relationship with MQC regulation remains unknown. Herein, we propose a mitochondrial 'Birth-Death' coordinator achieved by an intelligent hydrogen nanogenerator (Fe@HP-OD), which can sustainably release H2 in response to the unique microenvironment in degenerated IVDs. Both in vitro and in vivo results prove alleviation of cellular oxidative stress and restoration of nucleus pulposus cells function, thereby facilitating successful IVD regeneration. Significantly, this study for the first time proposes the mitochondrial 'Birth-Death' coordination mechanism: 1) attenuation of overactivated mitochondrial 'Death' process (UPRmt and unselective mitophagy); and 2) activation of Adenosine 5'-monophosphate-activated protein kinase (AMPK) signaling pathway for mitochondrial 'Birth-Death' balance (mitochondrial biogenesis and controlled mitophagy). These pioneering findings can fill in the gaps in molecular mechanisms for H2 regulation on MQC homeostasis, and pave the way for future strategies towards restoring equilibrium of MQC system against degenerative diseases.
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Hidrógeno , Degeneración del Disco Intervertebral , Mitocondrias , Estrés Oxidativo , Hidrógeno/química , Animales , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Regeneración/efectos de los fármacos , Disco Intervertebral/efectos de los fármacos , Humanos , Mitofagia/efectos de los fármacos , Ratas Sprague-Dawley , Masculino , Núcleo Pulposo/metabolismo , RatasRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Gelsemium dynamized dilutions (GDD) are known as a remedy for a wide range of behavioral and psychological symptoms of depression and anxiety at ultra-low doses, yet the underlying mechanisms of the mode of action of G. sempervirens itself are not well understood. AIM OF THE STUDY: The present study was designed to examine the neuroprotective effects of Gelsemium preparations in counteracting stress-related mitochondrial dysfunctions in neuronal cells. MATERIALS AND METHODS: We started by studying how serum deprivation affects the mitochondrial functions of human neuroblastoma (SH-SY5Y) cells. Next, we looked into the potential of various Gelsemium dilutions to improve cell survival and ATP levels. After identifying the most effective dilutions, 3C and 5C, we tested their ability to protect SH-SY5Y cells from stress-induced mitochondrial deficits. We measured total and mitochondrial superoxide anion radicals using fluorescent dyes dihydroethidium (DHE) and the red mitochondrial superoxide indicator (MitoSOX). Additionally, we assessed total nitric oxide levels with 4,5-diaminofluorescein diacetate (DAF-2DA), examined the redox state using pRA305 cells stably transfected with a plasmid encoding a redox-sensitive green fluorescent protein, and analyzed mitochondrial network morphology using an automated high-content analysis device, Cytation3. Furthermore, we investigated bioenergetics by measuring ATP production with a bioluminescence assay (ViaLighTM HT) and evaluated mitochondrial respiration (OCR) and glycolysis (ECAR) using the Seahorse Bioscience XF24 Analyzer. Finally, we determined cell survival using an MTT reduction assay. RESULTS: Our research indicates that Gelsemium dilutions (3C and 5C) exhibited neuroprotective effects by: - Normalizing total and mitochondrial superoxide anion radicals and total nitric oxide levels. - Regulating the mitochondrial redox environment and mitochondrial networks morphology. - Increasing ATP generation as well as OCR and ECAR levels, thereby reducing the viability loss induced by serum withdrawal stress. CONCLUSIONS: These findings highlight that dynamized Gelsemium preparations may have neuroprotective effects against stress-induced cellular changes in the brain by regulating mitochondrial functions, essential for the survival, plasticity, and function of neurons in depression.
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Supervivencia Celular , Mitocondrias , Neuronas , Fármacos Neuroprotectores , Humanos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Adenosina Trifosfato/metabolismo , Estrés Oxidativo/efectos de los fármacos , Óxido Nítrico/metabolismo , Extractos Vegetales/farmacología , Relación Dosis-Respuesta a Droga , Superóxidos/metabolismoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Melastoma dodecandrum Lour. (MD), a traditional Chinese medicine used by the She ethnic group, has been used to treat cerebral ischemia-reperfusion (CIR) injury due to its efficacy in promoting blood circulation and removing blood stasiss; however, the therapeutic effects and mechanisms of MD in treating CIR injury remain unclear. AIM: To investigate the protective effects of MD on CIR injury, in addition to its impact on oxidative stress, endoplasmic reticulum (ER) stress, and cell apoptosis. MATERIALS AND METHODS: The research was conducted using both cell experiments and animal experiments. The CCK-8 method, immunofluorescence staining, and flow cytometry were used to analyze the effects of MD-containing serum on oxygen-glucose deprivation/reperfusion (OGD/R)-induced PC12 cell viability, reactive oxygen species (ROS) clearance, anti-inflammatory, neuroprotection and inhibition of apoptosis. Furthermore, 2,3,5-Triphenyl tetrazolium chloride staining, hematoxylin and eosin staining, Nissl staining, and immunohistochemistry were used to detect infarct size, pathological changes, Nissl corpuscula and neuronal protein expression in middle cerebral artery occlusion (MCAO) rats. Polymerase chain reaction and Western Blotting were conducted in cell and animal experiments to detect the expression levels of ER stress-related genes and proteins. RESULTS: The MD extract enhanced the viability of PC12 cells under OGD/R modeling, reduced ROS and IL-6 levels, increased MBP levels, and inhibited cell apoptosis. Furthermore, MD improved the infarct area in MCAO rats, increased the number of Nissl bodies, and regulated neuronal protein levels including Microtubule-Associated Protein 2 (MAP-2), Myelin Basic Protein (MBP), Glial Fibrillary Acidic Protein (GFAP), and Neurofilament 200 (NF200). Additionally, MD could regulate the expression levels of oxidative stress proteins malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), and catalase (CAT). Both cell and animal experiments demonstrated that MD could inhibit ER stress-related proteins (GRP78, ATF4, ATF6, CHOP) and reduce cell apoptosis. CONCLUSION: This study confirmed that the therapeutic mechanism of the MD extract on CIR injury was via the inhibition of oxidative stress and the ER stress pathway, in addition to the inhibition of apoptosis.
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Apoptosis , Estrés del Retículo Endoplásmico , Fármacos Neuroprotectores , Estrés Oxidativo , Ratas Sprague-Dawley , Daño por Reperfusión , Animales , Estrés del Retículo Endoplásmico/efectos de los fármacos , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Daño por Reperfusión/prevención & control , Estrés Oxidativo/efectos de los fármacos , Ratas , Células PC12 , Masculino , Fármacos Neuroprotectores/farmacología , Apoptosis/efectos de los fármacos , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Especies Reactivas de Oxígeno/metabolismo , Supervivencia Celular/efectos de los fármacos , Isquemia Encefálica/tratamiento farmacológico , Extractos Vegetales/farmacología , Extractos Vegetales/química , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéuticoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Calyptrochilum emarginatum (Afzel. Ex Sw.) Schltr. (Orchidaceae) is a traditional medicinal plant known for its antimicrobial properties and efficacy in managing convulsive fever and menstrual disorders and addressing conditions such as malaria, tuberculosis, and cough. AIM OF THE STUDY: The study aims to examine the memory-enhancing and neuroprotective properties of ethanol extract of Calyptrochilum emarginatum leaves (EECEL) in scopolamine-induced amnesia mice model. MATERIALS AND METHODS: Forty-two male mice were divided into six groups (n = 7). Group 1 served as control, administered distilled water (10 mL/kg, p. o), group 2 received scopolamine only (3 mg/kg, i. p.), groups 3 to 6 received pretreatments of EECEL (50, 100, and 200 mg/kg, p. o.) and donepezil (1 mg/kg, p. o.) 30 min before scopolamine (3 mg/kg), for seven days. Following treatments, behavioral (learning and memory) assessments were carried out, while biochemical (acetylcholinesterase activity, oxidative stress markers, inflammatory cytokines markers) and histological evaluations were done after euthanasia. RESULTS: Scopolamine significantly impaired spatial, long term and recognition memory. Nevertheless, administration of EECEL (50, 100, and 200 mg/kg orally) enhanced memory function in mice, as observed in the Y maze [F (5, 30) = 20.23, p < 0.0001], Morris water maze [F (10, 90) = 3.105, p = 0.0019; [F (5, 30) = 21.13, p < 0.0001]], and novel object recognition tasks [F (5, 30) = 37.22, p < 0.0001)]. Scopolamine-treated mice exhibited significant dysfunction in the cholinergic system, as evidenced by elevated AChE activity [0.099 ± 0.005 vs. 0.063 ± 0.004 mol/min/g] with an elevation in oxidative stress. On the other hand, administration of EECEL counteracted these consequences by reducing AChE activity, mitigating oxidative damage, reducing pro-inflammatory cytokines, and preventing degeneration of neurons. CONCLUSION: The results demonstrated that EECEL effectively mitigates scopolamine-induced memory impairment via an oxido-inflammatory mechanism and modulation of the central cholinergic system.
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Amnesia , Etanol , Fármacos Neuroprotectores , Orchidaceae , Extractos Vegetales , Hojas de la Planta , Escopolamina , Animales , Masculino , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Ratones , Amnesia/tratamiento farmacológico , Amnesia/inducido químicamente , Etanol/química , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/aislamiento & purificación , Orchidaceae/química , Estrés Oxidativo/efectos de los fármacos , Acetilcolinesterasa/metabolismo , Aprendizaje por Laberinto/efectos de los fármacos , Modelos Animales de Enfermedad , Memoria/efectos de los fármacos , Solventes/química , Donepezilo/farmacología , Donepezilo/uso terapéuticoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Pogostemonis Herba has long been used in traditional Chinese medicine to treat inflammatory disorders. Patchouli essential oil (PEO) is the primary component of Pogostemonis Herba, and it has been suggested to offer curative potential when applied to treat ulcerative colitis (UC). However, the pharmacological mechanisms of PEO for treating UC remain to be clarified. AIM OF THE STUDY: To elucidate the pharmacological mechanisms of PEO for treating UC. METHODS AND RESULTS: In the present study, transcriptomic and network pharmacology approaches were combined to clarify the mechanisms of PEO for treating UC. Our results reveal that rectal PEO administration in UC model mice significantly alleviated symptoms of UC. In addition, PEO effectively suppressed colonic inflammation and oxidative stress. Mechanistically, PEO can ameliorate UC mice by modulating gut microbiota, inhibiting inflammatory targets (OPTC, PTN, IFIT3, EGFR, and TLR4), and inhibiting the PI3K-AKT pathway. Next, the 11 potential bioactive components that play a role in PEO's anti-UC mechanism were identified, and the therapeutic efficacy of the pogostone (a bioactive component) in UC mice was partially validated. CONCLUSION: This study highlights the mechanisms through which PEO can treat UC, providing a rigorous scientific foundation for future efforts to develop and apply PEO for treating UC.
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Colitis Ulcerosa , Aceites Volátiles , Animales , Colitis Ulcerosa/tratamiento farmacológico , Aceites Volátiles/farmacología , Ratones , Masculino , Microbioma Gastrointestinal/efectos de los fármacos , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Antiinflamatorios/farmacología , Pogostemon/química , Estrés Oxidativo/efectos de los fármacos , Farmacología en Red , Colon/efectos de los fármacos , Colon/metabolismo , Colon/patologíaRESUMEN
The underlying toxicity mechanisms of microplastics on oysters have rarely been explored. To fill this gap, the present study investigated the metabolic profile and protein expression responses of oysters to microplastic stress through metabolomics and biochemical analyses. Oysters were exposed to microplastics for 21 days, and the results indicated that the microplastics induced oxidative stress, with a significant decrease in SOD activity in the 0.1 mg/L exposure group. Metabolomics revealed that exposure to microplastics disturbed many metabolic pathways, such as amino acid metabolism, lipid metabolism, biosynthesis of amino acids, aminoacyl-tRNA biosynthesis, and that different concentrations of microplastics induced diverse metabolomic profiles in oysters. Overall, the current study provides new reference data and insights for assessing food safety and consumer health risks caused by microplastic contamination.
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Crassostrea , Microplásticos , Estrés Oxidativo , Poliestirenos , Contaminantes Químicos del Agua , Animales , Crassostrea/metabolismo , Crassostrea/efectos de los fármacos , Crassostrea/química , Microplásticos/metabolismo , Contaminantes Químicos del Agua/metabolismo , Estrés Oxidativo/efectos de los fármacos , Poliestirenos/química , Poliestirenos/metabolismo , Metaboloma/efectos de los fármacos , Mariscos/análisis , Metabolómica , Contaminación de Alimentos/análisisRESUMEN
The use of direct injection ion mobility mass spectrometry (DI-IM-MS) to detect and identify betacyanin pigments in A. hortensis 'rubra' extracts was explored for the first time, with results compared to conventional LC-MS/MS analysis. The anti-inflammatory activities of leaf and seed extracts, alongside purified amaranthin and celosianin pigments, were investigated using a model of lipopolysaccharide (LPS)-activated murine macrophages. Extracts and purified pigments significantly inhibited the production of prostaglandin E2 and NO by up to 90% and 70%, respectively, and reduced the expression of Il6, Il1b, Nos2, and Cox2. Leaf and seed extracts also decreased secretion of Il6 and Il1b cytokines and reduced protein levels of Nos2 and Cox2. Furthermore, extracts and purified pigments demonstrated potent dose-dependent radical scavenging activity in a cellular antioxidant activity assay (CAA) without any cytotoxic effects. Our research highlights the promising biological potential of edible, climate-resilient A. hortensis 'rubra' as a valuable source of bioactive compounds.
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Lipopolisacáridos , Macrófagos , Estrés Oxidativo , Extractos Vegetales , Ratones , Animales , Extractos Vegetales/farmacología , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Células RAW 264.7 , Estrés Oxidativo/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Lipopolisacáridos/farmacología , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/inmunología , Ciclooxigenasa 2/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Espectrometría de Masas en TándemRESUMEN
The human milk fat globule membrane (hMFGM) and Lactobacillus modulate the infant's gut and benefit health. Hence, the current study assesses the probiotic potential of Lactiplantibacillus plantarum (MRK3), Limosilactobacillus ferementum (MK1) isolated from infant feces, and its interaction with hMFGM during conditions mimicking infant digestive tract. Both strains showed high tolerance to gastrointestinal conditions, cell surface hydrophobicity, and strong anti-pathogen activity against Staphylococcus aureus. During digestion, hMFGM significantly exhibited xanthine oxidase activity, membrane roughness, and surface topography. In the presence of hMFGM, survival of MRK3 was higher than MK1, and electron microscopic observation revealed successful entrapment of MRK3 in the membrane matrix throughout digestion. Interestingly, probiotic-membrane matrix interaction showed significant synergy to alleviate oxidative stress and damage induced by cell-free supernatant of Escherichia coli in Caco-2 cells. Our results show that a probiotic-encapsulated membrane matrix potentially opens the functional infant formula development pathway.
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Glucolípidos , Glicoproteínas , Gotas Lipídicas , Leche Humana , Estrés Oxidativo , Probióticos , Humanos , Probióticos/farmacología , Probióticos/química , Gotas Lipídicas/química , Gotas Lipídicas/metabolismo , Glicoproteínas/química , Glicoproteínas/farmacología , Glicoproteínas/metabolismo , Células CACO-2 , Glucolípidos/química , Glucolípidos/farmacología , Glucolípidos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Leche Humana/química , Lactante , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/crecimiento & desarrollo , Fórmulas Infantiles/química , Escherichia coli/efectos de los fármacos , Escherichia coli/metabolismo , Tracto Gastrointestinal/microbiología , Tracto Gastrointestinal/metabolismoRESUMEN
ETHNOPHARMACOLOGICAL PREVALENCE: Hyperglycemia in diabetes increases the generation of advanced glycation end products (AGEs) through non-enzymatic reactions. The interaction between AGEs and their receptors (RAGE) leads to oxidative and inflammatory stress, which plays a pivotal role in developing diabetic nephropathy. Syzygium cumini (SC) L. (DC.) homeopathic preparations viz. 200C, 30C, and mother tincture [MT] are used to treat diabetes. This study aimed to elucidate the regulatory effects of SC preparations (200C, 30C, and MT) on the nuclear factor erythroid 2-related factor 2 (Nrf2) - nuclear factor-κB (NF-κB) pathways and mitochondrial dysfunction in mitigating diabetic nephropathy (DN). MATERIALS AND METHODS: Streptozotocin-induced diabetic rats were treated with SC preparations (200C, 30C, MT; 1:20 dilution in distilled water; 600 µL/kg body weight) and metformin (45 mg/kg body weight) twice daily for 40 days. DN was evaluated through biochemical parameters and histological examination. Renal tissue lysates were analyzed for glycation markers. Protein and gene levels of Nrf2, NF-κB, and mitochondrial dysfunctional signaling were determined via western blotting and RT-qPCR. An immunohistochemical analysis of the kidneys was performed. In vitro, human serum albumin (HSA - 10 mg/ml) was glycated with methylglyoxal (MGO - 55 mM) in the presence of SC preparations (200C, 30C, MT) for eight days. Glycated samples (400 µg/mL) were incubated with renal cells (HEK-293) for 24 h. Further reactive oxygen species production, Nrf2 nuclear translocation, and protein or gene expression of Nrf2 and apoptosis markers were analyzed by western blotting, RT-qPCR, and flow cytometry. Molecular docking of gallic and ellagic acid with the HSA-MGO complex was performed. RESULT: In vivo experiments using streptozotocin-induced diabetic rats treated with SC preparations exhibited improved biochemical parameters, preserved kidney function, and reduced glycation adduct formation in a dose-dependent manner. Furthermore, SC preparations downregulated inflammatory mediators such as RAGE, NF-κB, vascular endothelial growth factor (VEGF), and Tumor necrosis factor α (TNF-α) while upregulating the Nrf2-dependent antioxidant and detoxification pathways. They downregulated B-cell lymphoma 2 (Bcl-2) associated X-protein (BAX), C/EBP homologous protein (CHOP), Dynamin-related protein 1 (DRP1), and upregulated BCL 2 gene expression. Notably, SC preparations facilitated nuclear translocation of Nrf2, leading to the upregulation of antioxidant enzymes and the downregulation of oxidative stress markers. Molecular docking studies revealed favorable interactions between gallic (-5.26 kcal/mol) and ellagic acid (-4.71 kcal/mol) with the HSA-MGO complex. CONCLUSION: SC preparations mitigate renal cell apoptosis and mitochondrial dysfunction through Nrf2-dependent mechanisms.
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Diabetes Mellitus Experimental , Nefropatías Diabéticas , Factor 2 Relacionado con NF-E2 , Syzygium , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/metabolismo , Syzygium/química , Humanos , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Masculino , Ratas , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , FN-kappa B/metabolismo , Extractos Vegetales/farmacología , Transducción de Señal/efectos de los fármacos , Células HEK293 , Estrés Oxidativo/efectos de los fármacos , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Productos Finales de Glicación Avanzada/metabolismo , Estreptozocina , Ratas Wistar , Antioxidantes/farmacología , Ratas Sprague-DawleyRESUMEN
Bisphenol A (BPA) is an industrial pollutant that can cause immune impairment. Selenium acts as an antioxidant, as selenium deficiency often accompanies oxidative stress, resulting in organ damage. This study is the first to demonstrate that BPA and/or selenium deficiency induce pyroptosis and ferroptosis-mediated thymic injury in chicken and chicken lymphoma cell (MDCC-MSB-1) via oxidative stress-induced endoplasmic reticulum (ER) stress. We established a broiler chicken model of BPA and/or selenium deficiency exposure and collected thymus samples as research subjects after 42 days. The results demonstrated that BPA or selenium deficiency led to a decrease in antioxidant enzyme activities (T-AOC, CAT, and GSH-Px), accumulation of peroxides (H2O2 and MDA), significant upregulation of ER stress-related markers (GRP78, IER 1, PERK, EIF-2α, ATF4, and CHOP), a significant increase in iron ion levels, significant upregulation of pyroptosis-related gene (NLRP3, ASC, Caspase1, GSDMD, IL-18 and IL-1ß), significantly increase ferroptosis-related genes (TFRC, COX2) and downregulate GPX4, HO-1, FTH, NADPH. In vitro experiments conducted in MDCC-MSB-1 cells confirmed the results, demonstrating that the addition of antioxidant (NAC), ER stress inhibitor (TUDCA) and pyroptosis inhibitor (Vx765) alleviated oxidative stress, endoplasmic reticulum stress, pyroptosis, and ferroptosis. Overall, this study concludes that the combined effects of oxidative stress and ER stress mediate pyroptosis and ferroptosis in chicken thymus induced by BPA exposure and selenium deficiency.
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Compuestos de Bencidrilo , Pollos , Estrés del Retículo Endoplásmico , Ferroptosis , Fenoles , Piroptosis , Especies Reactivas de Oxígeno , Selenio , Animales , Compuestos de Bencidrilo/toxicidad , Ferroptosis/efectos de los fármacos , Piroptosis/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Selenio/deficiencia , Fenoles/toxicidad , Especies Reactivas de Oxígeno/metabolismo , Timo/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacosRESUMEN
4-Nitrophenol (4-NP), as a toxic and refractory pollutant, has generated significant concern due to its adverse effects. However, the potential toxic effects and mechanism remained unclear. In this study, the reproduction, development, locomotion and reactive oxygen species (ROS) production of Caenorhabditis elegans were investigated to evaluate the 4-NP toxicity. We used metabolomics to assess the potential damage mechanisms. The role of metabolites in mediating the relationship between 4-NP and phenotypes was examined by correlation and mediation analysis. 4-NP (8 ng/L and 8 µg/L) caused significant reduction of brood size, ovulation rate, total germ cells numbers, head thrashes and body bends, and an increase in ROS. However, the oosperm numbers in uterus, body length and body width were decreased in 8 µg/L. Moreover, 36 differential metabolites were enriched in the significant metabolic pathways, including lysine biosynthesis, ß-alanine metabolism, tryptophan metabolism, pentose phosphate pathway, pentose and glucuronate interconversions, amino sugar and nucleotide sugar metabolism, starch and sucrose metabolism, galactose metabolism, propanoate metabolism, glycerolipid metabolism, and estrogen signaling pathway. The mechanism of 4-NP toxicity was that oxidative stress caused by the perturbation of amino acid, which had effects on energy metabolism through disturbing carbohydrate and lipid metabolism, and finally affected the estrogen signaling pathway to exert toxic effects. Moreover, correlation and mediation analysis showed glycerol-3P, glucosamine-6P, glucosamine-1P, UDP-galactose, L-aspartic acid, and uracil were potential markers for the reproduction and glucose-1,6P2 for developmental toxicity. The results provided insight into the pathways involved in the toxic effects caused by 4-NP and developed potential biomarkers to evaluate 4-NP toxicity.
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Caenorhabditis elegans , Estrógenos , Nitrofenoles , Reproducción , Transducción de Señal , Animales , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/fisiología , Reproducción/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Nitrofenoles/toxicidad , Estrógenos/toxicidad , Especies Reactivas de Oxígeno/metabolismo , Estrés Oxidativo/efectos de los fármacosRESUMEN
Arsenic-related oxidative stress and resultant diseases have attracted global concern, while longitudinal studies are scarce. To assess the relationship between arsenic exposure and systemic oxidative damage, we performed two repeated measures among 5236 observations (4067 participants) in the Wuhan-Zhuhai cohort at the baseline and follow-up after 3 years. Urinary total arsenic, biomarkers of DNA oxidative damage (8-hydroxy-2'-deoxyguanosine (8-OHdG)), lipid peroxidation (8-isoprostaglandin F2alpha (8-isoPGF2α)), and protein oxidative damage (protein carbonyls (PCO)) were detected for all observations. Here we used linear mixed models to estimate the cross-sectional and longitudinal associations between arsenic exposure and oxidative damage. Exposure-response curves were constructed by utilizing the generalized additive mixed models with thin plate regressions. After adjusting for potential confounders, arsenic level was significantly and positively related to the levels of global oxidative damage and their annual increased rates in dose-response manners. In cross-sectional analyses, each 1% increase in arsenic level was associated with a 0.406% (95% confidence interval (CI): 0.379% to 0.433%), 0.360% (0.301% to 0.420%), and 0.079% (0.055% to 0.103%) increase in 8-isoPGF2α, 8-OHdG, and PCO, respectively. More importantly, arsenic was further found to be associated with increased annual change rates of 8-isoPGF2α (ß: 0.147; 95% CI: 0.130 to 0.164), 8-OHdG (0.155; 0.118 to 0.192), and PCO (0.050; 0.035 to 0.064) in the longitudinal analyses. Our study suggested that arsenic exposure was not only positively related with global oxidative damage to lipid, DNA, and protein in cross-sectional analyses, but also associated with annual increased rates of these biomarkers in dose-dependent manners.
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Arsénico , Exposición a Riesgos Ambientales , Estrés Oxidativo , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , 8-Hidroxi-2'-Desoxicoguanosina , Arsénico/toxicidad , Biomarcadores/orina , China , Estudios Transversales , Daño del ADN , Pueblos del Este de Asia , Exposición a Riesgos Ambientales/efectos adversos , Contaminantes Ambientales/toxicidad , Peroxidación de Lípido/efectos de los fármacos , Estudios Longitudinales , Estrés Oxidativo/efectos de los fármacosRESUMEN
Oxidative stress is a major pathogenic factor in many intestinal diseases, such as inflammatory bowel disease (IBD) and colorectal cancer (CRC). The Nrf2 signaling pathway and mitophagy can reduce reactive oxygen species (ROS) and alleviate oxidative stress, but their relationship is unclear. Hydroxytyrosol (HT), a polyphenolic compound abundant in olive oil, has strong antioxidant activity and may help treat these diseases. We used pigs as a model to investigate HT's effect on intestinal oxidative damage and its mechanisms. Diquat (DQ) induced oxidative stress and impaired intestinal barrier function, which HT mitigated. Mechanistic studies in IPEC-J2 cells showed that HT protected against oxidative damage by activating the PI3K/Akt-Nrf2 signaling pathway and promoting mitophagy. Our study highlighted the synergistic relationship between Nrf2 and mitophagy in mediating HT's antioxidant effects. Inhibition studies confirmed that disrupting either pathway compromised HT's protective effects. Maintaining redox balance through Nrf2 and mitophagy is important for eliminating excess ROS. Nrf2 increases antioxidant enzymes to clear existing ROS, while mitophagy removes damaged mitochondria and reduces ROS generation. This study demonstrates that these pathways collaboratively modulate the antioxidant effects of HT, with neither being dispensable. Targeting Nrf2 and mitophagy could be a promising strategy for treating oxidative stress-related intestinal diseases, with HT as a potential treatment.
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Mitofagia , Factor 2 Relacionado con NF-E2 , Estrés Oxidativo , Alcohol Feniletílico , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Especies Reactivas de Oxígeno , Transducción de Señal , Alcohol Feniletílico/análogos & derivados , Alcohol Feniletílico/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Animales , Estrés Oxidativo/efectos de los fármacos , Mitofagia/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Porcinos , Antioxidantes/farmacología , Intestinos/efectos de los fármacos , Línea CelularRESUMEN
BACKGROUND: Kidney diseases are a major global health problem affecting millions of people. Despite this, there is as yet no effective drug therapy improving outcome in patients with renal disease. The aim of this study was to examine the nephroprotective effect of α-lipoic acid (ALA) in vitro and to examine the effect of ALA administered in vivo on the production of reactive sulfur species (RSS), including hydrogen sulfide (H2S) and compounds containing sulfane sulfur. METHODS: The effect of ALA was studied in vitro by determining the viability of human embryonic kidney cells (HEK293) in normoxic and hypoxic conditions as well as in vivo in two groups of chronic kidney disease (CKD) patients: non-dialyzed (ND) and undergoing continuous ambulatory peritoneal dialysis (PD) after 30 days of ALA supplementation. RESULTS: The results revealed that the viability of HEK293 cells was significantly decreased by hypoxic conditions, while ALA administered during hypoxia increased the viability to the level observed in normoxic conditions. Studies performed in plasma of CKD patients after ALA supplementation suggested that ALA did not affect the parameters of oxidative stress, while significantly increased the level of reactive sulfane sulfur in both ND and PD patients suffering from CKD. The results suggest that ALA can exert nephroprotective effects which are related to sulfane sulfur production.
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Insuficiencia Renal Crónica , Ácido Tióctico , Humanos , Ácido Tióctico/farmacología , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/tratamiento farmacológico , Células HEK293 , Masculino , Femenino , Supervivencia Celular/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Persona de Mediana Edad , Antioxidantes/farmacología , Sulfuro de Hidrógeno/farmacologíaRESUMEN
In the present study, we investigated whether curcumin administration would interfere with the main renal features of l-NAME-induced hypertension model. For this purpose, we conducted both in vitro and in vivo experiments to evaluate renal indicators of inflammation, oxidative stress, and metalloproteinases (MMPs) expression/activity. Hypertension was induced by l-NAME (70 mg/kg/day), and Wistar rats from both control and hypertensive groups were treated with curcumin (50 or 100 mg/kg/day; gavage) or vehicle for 14 days. Blood and kidneys were collected to determine serum creatinine levels, histological alterations, oxidative stress, MMPs expression and activity, and ED1 expression. l-NAME increased blood pressure, but both doses of curcumin treatment reduced these values. l-NAME treatment increased creatinine levels, glomeruli area, Bowman's space, kidney MMP-2 activity, as well as MMP-9 and ED1 expression, and reduced the number of glomeruli. Curcumin treatment prevented the increase in creatinine levels, MMP-2 activity, and reduced MMP-2, MMP-9, ED1, and superoxide levels, as well as increased superoxide dismutase activity and partially prevented glomeruli alterations. Moreover, curcumin directly inhibited MMP-2 activity in vitro. Thus, our main findings demonstrate that curcumin reduced l-NAME-induced hypertension and renal glomerular alterations, inhibited MMP-2 and MMP-9 expression/activity, and reduced oxidative stress and inflammatory processes, which may indirectly impact hypertension-induced renal outcomes.
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Curcumina , Hipertensión , Metaloproteinasa 2 de la Matriz , Metaloproteinasa 9 de la Matriz , NG-Nitroarginina Metil Éster , Ratas Wistar , Animales , Curcumina/farmacología , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , NG-Nitroarginina Metil Éster/farmacología , Hipertensión/inducido químicamente , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , Ratas , Masculino , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Estrés Oxidativo/efectos de los fármacos , Enfermedades Renales/inducido químicamente , Enfermedades Renales/prevención & control , Enfermedades Renales/patología , Enfermedades Renales/metabolismo , Enfermedades Renales/tratamiento farmacológicoRESUMEN
The natural process of skin aging is influenced by a variety of factors, including oxidative stress, inflammation, collagen degradation, and UV radiation exposure. The potential of polyphenols in controlling skin aging has been the subject of much investigation throughout the years. Due to their complex molecular pathways, polyphenols, a broad class of bioactive substances present in large quantities in plants, have emerged as attractive candidates for skin anti-aging therapies. This review aims to provide a comprehensive overview of the molecular mechanisms through which polyphenols exert their anti-aging effects on the skin. Various chemical mechanisms contribute to reducing skin aging signs and maintaining a vibrant appearance. These mechanisms include UV protection, moisturization, hydration, stimulation of collagen synthesis, antioxidant activity, and anti-inflammatory actions. These mechanisms work together to reduce signs of aging and keep the skin looking youthful. Polyphenols, with their antioxidant properties, are particularly noteworthy. They can neutralize free radicals, lessening oxidative stress that might otherwise cause collagen breakdown and DNA damage. The anti-inflammatory effects of polyphenols are explored, focusing on their ability to suppress pro-inflammatory cytokines and enzymes, thereby alleviating inflammation and its detrimental effects on the skin. Understanding these mechanisms can guide future research and development, leading to the development of innovative polyphenol-based strategies for maintaining healthy skin.
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Antiinflamatorios , Antioxidantes , Estrés Oxidativo , Polifenoles , Envejecimiento de la Piel , Piel , Envejecimiento de la Piel/efectos de los fármacos , Polifenoles/farmacología , Polifenoles/uso terapéutico , Humanos , Piel/efectos de los fármacos , Piel/metabolismo , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Rayos Ultravioleta/efectos adversos , Mediadores de Inflamación/metabolismoRESUMEN
Calcium oxalate (CaOx) urolithiasis is a prevalent urinary disorder with significant clinical impact. This study investigates the therapeutic potential of Morin Hydrate (MH), a natural bioflavonoid, in preventing CaOx stone formation. Molecular docking studies revealed that MH binds strongly to glycolate oxidase (GO), suggesting its inhibitory effect on oxalate synthesis. In vitro assays demonstrated that MH effectively inhibits CaOx crystal nucleation, aggregation, and growth, altering crystal morphology to less stable forms. Diuretic activity studies in Wistar rats showed that MH substantially increased urine volume and ion excretion, indicating its moderate diuretic effect. In vivo experiments further supported these findings, with MH treatment improving urinary and serum markers, reducing oxidative stress, and protecting renal tissue, as evidenced by histopathological analysis. Notably, MH administration significantly decreased GO and lactate dehydrogenase activities in urolithiatic rats, indicating a reduction in oxalate production. These results suggest that MH is a promising candidate for the prevention and treatment of CaOx urolithiasis, with the potential for clinical application in reducing the risk and recurrence of kidney stones.