RESUMO
Introduction: Photoaging-induced skin damage leads to appearance issues and dermatoma. Selenium nanoparticles (SeNPs) possess high antioxidant properties but are prone to inactivation. In this study, human serum albumin/SeNPs (HSA-SeNPs) were synthesized for enhanced stability. Methods: HSA-SeNPs were prepared by self-assembling denatured human serum albumin and inorganic selenite. The cytotoxicity of HSA-SeNPs was assessed using the MTT method. Cell survival and proliferation rates were tested to observe the protective effect of HSA-SeNPs on human skin keratinocytes against photoaging. Simultaneously, ICR mice were used for animal experiments. H&E and Masson trichromatic staining were employed to observe morphological changes in skin structure and collagen fiber disorders after UVB irradiation. Quantitative RT-PCR was utilized to measure changes in mRNA expression levels of factors related to collagen metabolism, inflammation, oxidative stress regulation, and senescence markers. Results: The HSA-SeNPs group exhibited significantly higher survival and proliferation rates of UVB-irradiated keratinocytes than the control group. Following UVB irradiation, the back skin of ICR mice displayed severe sunburn with disrupted collagen fibers. However, HSA-SeNPs demonstrated superior efficacy in alleviating these symptoms compared to SeNPs alone. In a UVB-irradiated mice model, mRNA expression of collagen type I and III was dysregulated while MMP1, inflammatory factors, and p21 mRNA expression were upregulated; concurrently Nrf2 and Gpx1 mRNA expression were downregulated. In contrast, HSA-SeNPs maintained the mRNA expression of those factors to be stable In addition, the level of SOD decreased, and MDA elevated significantly in the skin after UVB irradiation, but no significant differences in SOD and MDA levels between the HSA-SeNPs group with UVB irradiation and the UVB-free untreated group. Discussion: HSA-SeNPs have more anti-photoaging effects on the skin than SeNPs, including the protective effects on skin cell proliferation, cell survival, and structure under photoaging conditions. HSA-SeNPs can be used to protect skin from photoaging and repair skin injury caused by UVB exposure.
Assuntos
Proliferação de Células , Sobrevivência Celular , Queratinócitos , Camundongos Endogâmicos ICR , Nanopartículas , Selênio , Envelhecimento da Pele , Pele , Raios Ultravioleta , Animais , Humanos , Envelhecimento da Pele/efeitos dos fármacos , Envelhecimento da Pele/efeitos da radiação , Selênio/química , Selênio/farmacologia , Selênio/administração & dosagem , Raios Ultravioleta/efeitos adversos , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Nanopartículas/química , Queratinócitos/efeitos dos fármacos , Queratinócitos/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Camundongos , Albumina Sérica Humana/química , Estresse Oxidativo/efeitos dos fármacos , Antioxidantes/farmacologia , Antioxidantes/químicaRESUMO
Microplastics (MPs), a brand-new class of worldwide environmental pollutant, have received a lot of attention. MPs are consumed by both humans and animals through water, food chain and other ways, which may cause potential health risks. However, the effects of MPs on embryonic development, especially placental function, and its related mechanisms still need to be further studied. We investigated the impact on fetal development and placental physiological function of pregnant mice by consecutive gavages of MPs at 0, 25, 50, 100 mg/kg body weight during gestational days (GDs 0-14). The results showed that continuous exposure to high concentrations of MP significantly reduced daily weight gain and impaired reproductive performance of pregnant mice. In addition, MPs could significantly induce oxidative stress and placental dysfunction in pregnant mice. On the other hand, MPs exposure significantly decreased placental barrier function and induced placental inflammation. Specifically, MPs treatment significantly reduced the expression of tight junction proteins in placentas, accompanied by inflammatory cell infiltration and increased mRNA levels of pro-inflammatory cytokines and chemokines in placentas. Finally, we found that MPs induced placental apoptosis and endoplasmic reticulum (ER) stress through the GRP78/IRE1α/JNK axis, leading to placental dysfunction and decreased reproductive performance in pregnant mice. We revealed for the first time that the effects of MPs on placental dysfunction in pregnant animals. Blocking the targets of MPs mediated ER stress will provide potential therapeutic ideas for the toxic effects of MPs on maternal pregnancy.
Assuntos
Apoptose , Chaperona BiP do Retículo Endoplasmático , Estresse do Retículo Endoplasmático , Microplásticos , Placenta , Animais , Feminino , Gravidez , Chaperona BiP do Retículo Endoplasmático/metabolismo , Apoptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Placenta/efeitos dos fármacos , Placenta/metabolismo , Microplásticos/toxicidade , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas de Choque Térmico/metabolismo , Proteínas de Choque Térmico/genética , Retardo do Crescimento Fetal/induzido quimicamente , Camundongos Endogâmicos ICRRESUMO
The interest in transporter-mediated drug interactions has been increasing in the field of drug development. In this study, we measured the plasma and urinary concentrations of coproporphyrin (CP) I and CP III as endogenous substrates for organic anion-transporting polypeptide (OATP) using chimeric mice with human hepatocytes (PXB mice) and examined the influence of an OATP inhibitor, rifampicin (RIF). CP I and CP III were actively taken up intracellularly, and RIF inhibited the uptake in a concentration-dependent manner for both CP I and CP III in human hepatocytes (PXB-cells). Single doses of RIF at 10 and 30 mg/kg were orally or intravenously administered to PXB mice and wild-type ICR mice. Plasma concentrations (AUC0-8h) of CP I increased in both mice. However, a marked increase in CP III was only observed in ICR mice, after intravenous administration of RIF at 30 mg/kg. The IC50 values of RIF for intracellular CP I/III uptake and the unbound plasma concentrations of RIF suggested that the increase in plasma CP I is associated with the exposure of RIF to OATPs. The 24-h cumulative urinary excretions of CP I and CP III increased in both mice, but more markedly in PXB mice. Thus, RIF increased the plasma and urinary concentrations of CP I and CP III in the mice, as reported in humans, and CP I may be a more sensitive biomarker of OATP-mediated drug interactions in PXB mice.
Assuntos
Coproporfirinas , Hepatócitos , Camundongos Endogâmicos ICR , Rifampina , Rifampina/farmacologia , Rifampina/administração & dosagem , Animais , Humanos , Hepatócitos/metabolismo , Hepatócitos/efeitos dos fármacos , Camundongos , Masculino , Coproporfirinas/urina , Coproporfirinas/sangue , Transportadores de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Interações Medicamentosas , Quimera , Administração IntravenosaRESUMO
BACKGROUND: A broad suite of bisphenol S (BPS) derivatives as alternatives for BPS have been identified in various human biological samples, including 4-hydroxyphenyl 4-isopropoxyphenylsulfone (BPSIP) detected in human umbilical cord plasma and breast milk. However, very little is known about the health outcomes of prenatal BPS derivative exposure to offspring. OBJECTIVES: Our study aimed to investigate the response of hepatic cholesterol metabolism by sex in offspring of dams exposed to BPSIP. METHODS: Pregnant ICR mice were exposed to 5µg/kg body weight (BW)/day of BPSIP, BPS, or E2 through drinking water from gestational day one until the pups were weaned. The concentration of BPSIP, BPS, or E2 in the plasma and liver of pups was determined by liquid chromatography-tandem mass spectrometry. Metabolic phenotypes were recorded, and histopathology was examined for liver impairment. Transcriptome analysis was employed to characterize the distribution and expression patterns of differentially expressed genes across sexes. The metabolic regulation was validated by quantitative real-time PCR, immunohistochemistry, and immunoblotting. The role of estrogen receptors (ERs) in mediating sex-dependent effects was investigated using animal models and liver organoids. RESULTS: Pups of dams exposed to BPSIP showed a higher serum cholesterol level, and liver cholesterol levels were higher in females and lower in males than in the controls. BPSIP concentration in the male liver was 1.22±0.25 ng/g and 0.69±0.27 ng/g in the female liver. Histopathology analysis showed steatosis and lipid deposition in both male and female offspring. Transcriptome and gene expression analyses identified sex-specific differences in cholesterol biosynthesis, absorption, disposal, and efflux between pups of dams exposed to BPSIP and those in controls. In vivo, chromatin immunoprecipitation analysis revealed that the binding of ERα protein to key genes such as Hmgcr, Pcsk9, and Abcg5 was attenuated in BPSIP-exposed females compared to controls, while it was enhanced in males. In vitro, the liver organoid experiments demonstrated that restoration of differential expression induced by BPSIP in key genes, such as Hmgcr, Ldlr, and Cyp7a1, to levels comparable to the controls was only achieved when treated with a combination of ERα agonist and ERß agonist. DISCUSSION: Findings from this study suggest that perinatal exposure to BPSIP disrupted cholesterol metabolism in a sex-specific manner in a mouse model, in which ERα played a crucial role both in vivo and in vitro. Therefore, it is crucial to systematically evaluate BPS derivatives to protect maternal health during pregnancy and prevent the transmission of metabolic disorders across generations. https://doi.org/10.1289/EHP14643.
Assuntos
Colesterol , Fígado , Camundongos Endogâmicos ICR , Fenóis , Animais , Feminino , Masculino , Camundongos , Colesterol/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Gravidez , Fenóis/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Sulfonas/toxicidade , Exposição MaternaRESUMO
Polyphenols have been well-established to exert sedative-hypnotic effects in psychopharmacology. Lime (Citrus aurantifolia) peel is rich in biologically active polyphenols; however, the effects of lime peel extract on sleep have not yet been demonstrated. A comparison was conducted in mice, between the sleep-promoting effects of a standardized lime peel supplement (SLPS) and a well-known hypnotic drug, zolpidem, and its hypnotic mechanism was investigated using in vivo and in vitro assays. The effects of SLPS on sleep were assessed using a pentobarbital-induced sleep test and sleep architecture analysis based on recording electroencephalograms and electromyograms. Additionally, a GABAA receptor binding assay, electrophysiological measurements, and in vivo animal models were used to elucidate the hypnotic mechanism. SLPS (200 and 400â¯mg/kg) was found to significantly decrease sleep latency and increase the amount of non-rapid eye movement sleep without altering delta activity. The hypnotic effects of SLPS were attributed to its flavonoid-rich ethyl acetate fraction. SLPS had a binding affinity to the GABA-binding site of the GABAA receptor and directly activated the GABAA receptors. The hypnotic effects and GABAA receptor activity of SLPS were completely blocked by bicuculline, a competitive antagonist of the GABAA receptor, in both in vitro and in vivo assays. To the best of our knowledge, this study is the first to demonstrate the hypnotic effects of SLPS, which acts via the GABA-binding site of the GABAA receptor. Our results suggest that lime peel, a by-product abundantly generated during juice processing, can potentially be used as a novel sedative-hypnotic.
Assuntos
Hipnóticos e Sedativos , Extratos Vegetais , Receptores de GABA-A , Sono , Animais , Receptores de GABA-A/metabolismo , Receptores de GABA-A/efeitos dos fármacos , Masculino , Extratos Vegetais/farmacologia , Camundongos , Hipnóticos e Sedativos/farmacologia , Sono/efeitos dos fármacos , Citrus/química , Suplementos Nutricionais , Zolpidem/farmacologia , Eletroencefalografia , Citrus aurantiifolia/química , Camundongos Endogâmicos ICR , Agonistas de Receptores de GABA-A/farmacologiaRESUMO
Streptococcus agalactiae (S. agalactiae) is an opportunistic pathogen, and to date, studies have mainly focused on S. agalactiae strains isolated from humans, dairy cows, and fish. We reported one S. agalactiae strain, named CFFB, which was isolated from a healthy Sichuan golden snub-nosed monkey. Classical bacteriological approaches, as well as, next-generation sequencing, comparative genomics, and mice challenge test were used to characterize this strain. CFFB was identified as serotype III, ST19 combination which is a common type found in human strains. Phylogenetic analysis showed that the genome of CFFB was closely related to human clinical isolates, rather far away from animal strains. In total, CFFB contained fewer virulence-associated genes and antibiotic resistance genes than human isolates that were close to CFFB in evolutionary relationships. In the mice challenge test, CFFB had a relative weak virulence that just caused death in 33 % of ICR mice at a dose of 108 CFU by intraperitoneal injection, and CFFB was reisolated from the cardiac blood of the dead mice. Meanwhile, two intact prophages (prophage 1 and 2) were identified in the CFFB genome and shared high similarities with phage Javan52 and Javan29 which from human S. agalactiae isolate Gottschalk 1002A and RBH03, respectively. Moreover, the type II-A CRISPR-Cas system was detected in the CFFB genome, and the spacers from CFFB were the same to the streptococci isolates from human. These results suggest that CFFB isolated from healthy Sichuan golden snub-nosed monkeys may have its origin in human S. agalactiae. Our results suggested some genomic similarities between the S. agalactiae colonized in Sichuan golden snub-nosed monkey and those in infected humans.
Assuntos
Genoma Bacteriano , Filogenia , Infecções Estreptocócicas , Streptococcus agalactiae , Animais , Streptococcus agalactiae/genética , Streptococcus agalactiae/isolamento & purificação , Streptococcus agalactiae/patogenicidade , Infecções Estreptocócicas/microbiologia , Infecções Estreptocócicas/veterinária , China , Virulência/genética , Camundongos , Colobinae/microbiologia , Humanos , Prófagos/genética , Camundongos Endogâmicos ICR , Fatores de Virulência/genética , Sorogrupo , Sequenciamento de Nucleotídeos em Larga Escala , Doenças dos Macacos/microbiologiaRESUMO
The neurotoxicity of bisphenol A (BPA) exposure has been confirmed in vitro and in vivo, and inflammatory response is considered the main pathway. Green tea is a healthy life habit as it is rich in various anti-inflammatory components. To confirm that green tea diet is an effective measure to antagonize BPA-induced neurotoxicity, mice were treated with 0.5 and 5000 µg/kg/day of BPA from postnatal days (PNDs) 10-50 and supplemented with green tea on PND 21. From PND 51, behavioral tests were conducted on mice to assess their emotional, cognitive, and spatial learning memory capabilities. The open field test and elevated plus maze test indicated anxiety-like behaviors induced by BPA. Interestingly, green tea diet significantly alleviated BPA-induced anxiety-like behaviors. Meanwhile, the green tea diet effectively reversed BPA-induced microglia activation and morphological changes in the hippocampus of mice. Molecularly, green tea inhibited hippocampal neuroinflammation of mice by reducing BPA-induced expressions of NLRP3, ASC, cleaved-caspase-1, GSDMD-N, IL-6, and IL-1ß, as well as significantly reducing the expression of Bak1, Bax, caspase-9, and Cytc c genes (p < 0.05). Molecular docking suggests that various anti-inflammatory components of green tea can competitively bind to the estrogen receptors with BPA. In general, a green tea diet alleviates BPA-induced emotional disorders by inhibiting microglial polarization and hippocampal pyroptosis, indicating its effective antagonistic ability against the neurotoxicity induced by environmental BPA exposure.
Assuntos
Compostos Benzidrílicos , Hipocampo , Simulação de Acoplamento Molecular , Fenóis , Chá , Animais , Compostos Benzidrílicos/toxicidade , Camundongos , Fenóis/química , Chá/química , Masculino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Camellia sinensis/química , Camundongos Endogâmicos ICR , FemininoRESUMO
Background: 18KHT01 is a novel synergistic composition of Quercus acutissima, Camellia sinensis, Geranium thunbergii, and a small portion of Citrus limon. Our previous report demonstrated that the 18KHT01 exhibits potent antiobesity effects, with synergistic antioxidant, antiadipogenic, and antiobesity activities in diet-induced obese mice. This study explores the toxicity profile and quality control parameters of the 18KHT01 formulation. Methods: Broad-spectrum acute and subacute oral toxicity studies were performed using male and female ICR mice. In order to simultaneous analysis of the 18KHT01 formulation, an ultraperformance liquid chromatography coupled with a diode array detector (UPLC-DAD) method was developed and validated using six marker compounds. Results: Acute oral toxicity evaluation of 18KHT01, administered at single high doses of 2, 2.5, 3, and 5 g/kg, identified 2 g/kg as the no-observed adverse effect level (NOAEL). The LD50 (50% lethal dose) and LD100 (100% lethal dose) of 18KHT01 for male ICR mice were 3.99 and 7.77 g/kg, and those for the female mice were 2.94 and 4.70 g/kg, respectively. In addition, a 30-day repeated dose oral subacute toxicity evaluation indicated that 18KHT01 is safe below 500 mg/kg/day for long-term administration in ICR mice of either sex. UPLC-DAD method validation revealed that each calibration curve for the marker compounds showed good linearity, as well as the validation parameters such as precision, specificity, and accuracy met the acceptance criteria. Conclusion: The present study evidenced the toxicological profile of 18KHT01 polyherbal formulation in mice as well as developed a simple, rapid, and accurate chromatographic method for quality control.
Assuntos
Camundongos Endogâmicos ICR , Animais , Masculino , Feminino , Camundongos , Cromatografia Líquida de Alta Pressão/métodos , Controle de Qualidade , Extratos Vegetais/toxicidade , Extratos Vegetais/química , Extratos Vegetais/farmacologiaRESUMO
As organophosphorus flame retardants (OPFRs) are constantly detected in human samples, the neurotoxicity of OPFRs is of concern. In this study, pregnant ICR mice were exposed to 2-ethylhexyl diphenyl phosphate (EHDPP) in drinking water from gestation to lactation to investigate its effects on autism spectrum disorder-like (ASD-like) behaviors in offspring. Serum EHDPP concentrations in dams in the 0.4, 2, and 10 mg/kg groups were 0.282 ± 0.051, 0.713 ± 0.115, and 0.974 ± 0.048 ng/mL, respectively, within the concentration range in humans. At the highest dose, EHDPP exposure induced ASD-like behaviors in both female and male offspring. Significant reductions in mature dendritic spines and structural damage to the postsynaptic density zone were noted in all but the lowest exposure groups, indicating postsynaptic membrane impairment. Mechanistically, EHDPP significantly downregulated disc large MAGUK scaffold protein 4 expression by inhibiting protein kinase B and type 1 insulin-like growth factor receptor phosphorylation. In the heterologous synapse formation assay in vivo, EHDPP significantly reduced the levels of postsynaptic density protein 95 expression in neurons at 1 µM. Overall, the study utilized in vitro and in vivo experiments to confirm that EHDPP damaged postsynaptic membrane formation and might increase the incidence of ASD in offspring.
Assuntos
Transtorno do Espectro Autista , Camundongos Endogâmicos ICR , Animais , Transtorno do Espectro Autista/induzido quimicamente , Camundongos , Feminino , Gravidez , Masculino , Retardadores de Chama/toxicidade , Comportamento Animal/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-NatalRESUMO
Extended exposure to UVB (280-315 nm) radiation results in oxidative damage and inflammation of the skin. Previous research has demonstrated that pilose antler extracts have strong anti-inflammatory properties and possess antioxidant effects. This study aimed to elucidate the mechanism of pilose antler protein in repairing photodamage caused by UVB radiation in HaCaT cells and ICR mice. Pilose antler protein (PAP) was found to increase the expression of type I collagen and hyaluronic acid in HaCaT cells under UVB irradiation while also inhibiting reactive oxygen species (ROS) production and oxidative stress in vitro. In vivo, the topical application of pilose antler protein effectively attenuated UVB-induced skin damage in ICR mice by reducing interleukin-1ß (IL-ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) and inhibiting skin inflammation while alleviating UVB-induced oxidative stress. It was shown that pilose antler protein repaired UVB-induced photodamage through the MAPK and TGF-ß/Smad pathways.
Assuntos
Chifres de Veado , Células HaCaT , Camundongos Endogâmicos ICR , Estresse Oxidativo , Espécies Reativas de Oxigênio , Pele , Raios Ultravioleta , Raios Ultravioleta/efeitos adversos , Animais , Humanos , Chifres de Veado/química , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Pele/patologia , Pele/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Colágeno Tipo I/metabolismo , Cervos , Ácido Hialurônico/farmacologia , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
Salvia elegans Vahl is a plant commonly used in Mexico as a remedy for nervous disorders, inflammatory diseases, and "ringing in the ears"; the latter can be associated with arteriosclerotic conditions and arterial hypertension. Therefore, based on medicinal use, this work aimed to evaluate the hydroalcoholic extract (SeHA, 100 mg/kg) of this plant and two fractions, ethyl acetate (SeFAc, 50 mg/kg), and obtained from SeFAc fractionation denominated SeF3 (10 mg/kg), on several alterations derived from metabolic syndrome (MetS) derived from the ingestion of a high-calorie diet (high-fat diet), in ICR (Institute of Cancer Research) mice, leading to chronic inflammation that results in neurological damage such as depression. Therefore, several MetS-related parameters, such as forced swim tests, hypertension, serum corticosterone levels, glucose, triglycerides, cholesterol, adiposity index, and insulin resistance, will be evaluated. Additionally, tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and IL-10 levels were measured in kidneys, fat tissue, brains, and spleens. It was proven that all those S. elegans-derived treatments reversed the damage, showing antidepressant, antihypertensive, antihyperglycemic, and antidyslipidemic effects and decreased adiposity, insulin resistance, and serum corticosterone. They induced a modulatory response by modifying the levels of TNF-α, IL-1ß, IL-6, and IL-10 in different organs. High-performance liquid chromatography (HPLC) analysis of the acetate of ethyl fraction from S. elegans (SeFAc) fraction revealed the presence of rosmarinic and caffeic acids as well as flavonoids, while the fraction from SeFAc called SeF3 Was identified by gas mass as methyl glucose, glycerol, and known sterols, among others. Thus, it was concluded that S. elegans protects against the harmful effects of MetS.
Assuntos
Depressão , Dieta Hiperlipídica , Síndrome Metabólica , Extratos Vegetais , Salvia , Animais , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/metabolismo , Síndrome Metabólica/etiologia , Dieta Hiperlipídica/efeitos adversos , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Camundongos , Salvia/química , Depressão/tratamento farmacológico , Depressão/etiologia , Depressão/metabolismo , Masculino , Modelos Animais de Doenças , Camundongos Endogâmicos ICRRESUMO
Long-term exposure to ultraviolet (UV) radiation induces skin photoaging, which manifests as oxidative stress, inflammation, and collagen degradation. Multiple approaches (topical or systemic retinoids, antioxidants, alpha-hydroxy acids, laser, surgery) are used in the treatment of photoaged skin, and the use of topical retinoids is currently a primary clinical treatment. Previous studies revealed that retinoic acid promotes keratinocyte proliferation and reduces melanin deposition and matrix metalloproteinase (MMP) secretion; it also causes potential allergic and inflammatory damage to the skin. This study aimed to investigate the therapeutic effects and mechanisms of trifarotene, a functional retinoic acid analog, on UV-irradiated photoaging ICR and BALB/c nude mice and UVB photodamaged human epidermal keratinocyte (HaCaT) cells by examining indicators such as collagen, oxidoreductase, and inflammatory factor presence through histochemical staining, Western blot, and ELISA. Results suggested that trifarotene significantly reduced UV-induced photoaging in mouse skin tissue, potentially by reducing oxidative stress damage and inflammatory factor release, and inhibiting melanin deposition and collagen degradation by downregulating MMP expression. Concentrations of malondialdehyde, tyrosinase, interleukin-6, interleukin- 12, and tumor necrosis factor-alpha in photoaged skin decreased, while SOD content in photodamaged HaCaT cells significantly increased. Trifarotene (3.3 µmol L-1) inhibited phosphorylated JNK and c-Jun expression both independently and collaboratively with the JNK activator anisomycin, demonstrating that trifarotene mitigates UV-induced collagen degradation and apoptosis through inhibition of the JNK/c-Jun/MMPs signaling pathway.
Assuntos
Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Envelhecimento da Pele , Raios Ultravioleta , Envelhecimento da Pele/efeitos dos fármacos , Animais , Humanos , Raios Ultravioleta/efeitos adversos , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Metaloproteinases da Matriz/metabolismo , Queratinócitos/efeitos dos fármacos , Camundongos Nus , Pele/efeitos dos fármacos , Pele/patologia , Pele/metabolismo , Pele/efeitos da radiação , Células HaCaT , Masculino , Melaninas/metabolismo , Colágeno/metabolismo , FemininoRESUMO
SCOPE: Chalcones are widely present in most plants and have various health beneficial functions. This study investigates the suppressive effect of 13 natural and synthetic chalcones on transformation of aryl hydrocarbon receptor (AhR) induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 3-methylcholanthrene (3-MC) in a cell-free system, Hepa-1c1c7 cells, and liver of ICR mice. METHODS AND RESULTS: In the cell-free system, cardamonin dose-dependently inhibits AhR transformation. Chalcones with substitution on 2' and/or 6' position is important for the suppressive effect, while the substitution on 4' position is negatively for the effect. Moreover, cardamonin and 2'-hydroxychalcone competitively inhibit the binding of [3H]-3-MC to the AhR. In Hepa-1c1c7 cells, cardamonin inhibits AhR transformation and expression of cytochrome P4501A1 (CYP1A1) in a dose-dependent manner through suppressing TCDD-induced phosphorylation of both AhR and AhR nuclear translocator, heterodimerization of them, and nuclear translocation of AhR. In the liver of mice, oral administered cardamonin also inhibits 3-MC-induced AhR translocation and expression of CYP1A1. CONCLUSION: Among used chalcones, a natural chalcone cardamonin competitively binds to AhR and suppresses its transformation. Thus, cardamonin is an effective food factor for suppression of the dioxin-caused biochemical alterations and toxicities.
Assuntos
Chalconas , Citocromo P-450 CYP1A1 , Fígado , Camundongos Endogâmicos ICR , Dibenzodioxinas Policloradas , Receptores de Hidrocarboneto Arílico , Animais , Chalconas/farmacologia , Receptores de Hidrocarboneto Arílico/metabolismo , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1A1/genética , Fígado/metabolismo , Fígado/efeitos dos fármacos , Camundongos , Metilcolantreno , Masculino , Translocador Nuclear Receptor Aril Hidrocarboneto/metabolismo , Translocador Nuclear Receptor Aril Hidrocarboneto/genética , Fosforilação/efeitos dos fármacos , Ligação CompetitivaRESUMO
AIM: The binding of integrin αvß3 with endometrial fibronectin (FN) promotes the migration of preimplantation embryos in mice. We have previously shown that cyclosporine A (CsA) improves the adhesion and invasion of mouse preimplantation embryos. In this study, we evaluated the roles of calcium ions and downstream signaling factors in the binding of integrin αvß3 to FN. METHODS: Female Institute of Cancer Research (ICR) mice were superovulated and mated, and two-cell embryos were harvested from the oviducts and cultured to the blastocyst stage The adhesion and stretching growth of hatched embryos in laminin-coated dishes were evaluated, and integrinß3 expression was determined using qPCR. Blastocytes were cultured with 0 or 1 µM cyclosporine A (CsA) and the attachment of embryonic integrin αvß3 to FN120 was observed using a fluorescent bead. To further determine the mechanism, the cells were also incubated with calcium ions and protein kinase C and calmodulin antagonists. The binding of integrin αvß3 to FN120 was examined via confocal laser scanning microscopy. RESULTS: The adhesion and stretching growth of peri-implantation embryos were greater and integrinß3 expression was higher in the 1 µM CsA group than in the 0 µM CsA group (p < 0.05). When incubated with calcium ions and protein kinase C and calmodulin antagonists, the ability of peri-implantation embryos to bind to FN decreased; CsA treatment promoted this binding. CONCLUSION: This study revealed that CsA up - regulates integrinß3 expression in peri - implantation embryos and promotes binding to FN via calcium ions, and protein kinase C, and calmodulin. These findings provide evidence supporting the beneficial effect of CsA on the peri - implantation embryo adhesion.
Assuntos
Ciclosporina , Fibronectinas , Animais , Camundongos , Fibronectinas/metabolismo , Ciclosporina/farmacologia , Feminino , Camundongos Endogâmicos ICR , Blastocisto/efeitos dos fármacos , Blastocisto/metabolismo , Integrina alfaVbeta3/metabolismoRESUMO
The giant jellyfish Nemopilema nomurai sting can cause local and systemic reactions; however, comparative analysis of the tentacle extract (TE) and nematocyst venom extract (NV), and its toxicity, mechanism, and potential intervention are still limited. This study compared venom from TE and NV for their composition, toxicity, and efficacy in vitro and in vivo used RAW264.7 cells and ICR mice. A total of 239 and 225 toxin proteins were identified in TE and NV by proteomics, respectively. Pathological analysis revealed that TE and NV caused heart and liver damage through apoptosis, necrosis, and inflammation, while TE exhibited higher toxicity ex vivo and in vivo. Biochemical markers indicated TE and NV elevated creatine kinase, lactatedehydrogenase, and aspartate aminotransferase, with the TE group showing a more significant increase. Transcriptomics and Western blotting indicated both venoms increased cytokines expression and MAPK signaling pathways. Additionally, 1 mg/kg PACOCF3 (the phospholipase A2 inhibitor) improved survival from 16.7% to 75% in mice. Our results indicate that different extraction methods impact venom activities, tentacle autolysis preserves toxin proteins and their toxicity, and PACOCF3 is a potential antidote, which establishes a good extraction method of jellyfish venom, expands our understanding of jellyfish toxicity, mechanism, and provides a promising intervention.
Assuntos
Venenos de Cnidários , Camundongos Endogâmicos ICR , Nematocisto , Animais , Camundongos , Venenos de Cnidários/toxicidade , Venenos de Cnidários/farmacologia , Nematocisto/química , Células RAW 264.7 , Cifozoários , Proteômica , Masculino , Apoptose/efeitos dos fármacos , Inibidores de Fosfolipase A2/farmacologiaRESUMO
The radioprotective properties of copper chlorophyllin (100 and 150 µg/g), the standard antioxidant trolox (100 and 200 µg/g), and the standard radioprotector indralin (100 and 150 µg/g) were compared in male ICR mice (CD-1) subjected to whole-body irradiation (X-ray radiation) in doses of 6, 6.5, and 6.75 Gy. Animal survival was analyzed using the Kaplan-Meier method, and the significance of differences was evaluated using the log-rank test method. Dose change factors determined using the Phinney probit analysis were 1.1, 1.0, and 1.8 for chlorophyllin, trolox, and indralin at a dose of 100 µg/g body weight, respectively. The insignificant radioprotective properties of chlorophyllin and their absence in trolox when administered prophylactically do not rule out their possible radioprotective properties like a radiomodulator that protects the body after irradiation.
Assuntos
Antioxidantes , Clorofilídeos , Cromanos , Camundongos Endogâmicos ICR , Protetores contra Radiação , Irradiação Corporal Total , Animais , Protetores contra Radiação/farmacologia , Cromanos/farmacologia , Masculino , Camundongos , Clorofilídeos/farmacologia , Antioxidantes/farmacologia , Raios X , FenóisRESUMO
BACKGROUND: Acute lung injury (ALI) following pneumonia involves uncontrolled inflammation and tissue injury, leading to high mortality. We previously confirmed the significantly increased cargo content and extracellular vesicle (EV) production in thrombin-preconditioned human mesenchymal stromal cells (thMSCs) compared to those in naïve and other preconditioning methods. This study aimed to investigate the therapeutic efficacy of EVs derived from thMSCs in protecting against inflammation and tissue injury in an Escherichia coli (E. coli)-induced ALI mouse model. METHODS: In vitro, RAW 264.7 cells were stimulated with 0.1 µg/mL liposaccharides (LPS) for 1 h, then were treated with either PBS (LPS Ctrl) or 5 × 107 particles of thMSC-EVs (LPS + thMSC-EVs) for 24 h. Cells and media were harvested for flow cytometry and ELISA. In vivo, ICR mice were anesthetized, intubated, administered 2 × 107 CFU/100 µl of E. coli. 50 min after, mice were then either administered 50 µL saline (ECS) or 1 × 109 particles/50 µL of thMSC-EVs (EME). Three days later, the therapeutic efficacy of thMSC-EVs was assessed using extracted lung tissue, bronchoalveolar lavage fluid (BALF), and in vivo computed tomography scans. One-way analysis of variance with post-hoc TUKEY test was used to compare the experimental groups statistically. RESULTS: In vitro, IL-1ß, CCL-2, and MMP-9 levels were significantly lower in the LPS + thMSC-EVs group than in the LPS Ctrl group. The percentages of M1 macrophages in the normal control, LPS Ctrl, and LPS + thMSC-EV groups were 12.5, 98.4, and 65.9%, respectively. In vivo, the EME group exhibited significantly lower histological scores for alveolar congestion, hemorrhage, wall thickening, and leukocyte infiltration than the ECS group. The wet-dry ratio for the lungs was significantly lower in the EME group than in the ECS group. The BALF levels of CCL2, TNF-a, and IL-6 were significantly lower in the EME group than in the ECS group. In vivo CT analysis revealed a significantly lower percentage of damaged lungs in the EME group than in the ECS group. CONCLUSION: Intratracheal thMSC-EVs administration significantly reduced E. coli-induced inflammation and lung tissue damage. Overall, these results suggest therapeutically enhanced thMSC-EVs as a novel promising therapeutic option for ARDS/ALI.
Assuntos
Lesão Pulmonar Aguda , Vesículas Extracelulares , Células-Tronco Mesenquimais , Camundongos Endogâmicos ICR , Trombina , Animais , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/transplante , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/microbiologia , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/terapia , Camundongos , Células-Tronco Mesenquimais/metabolismo , Células RAW 264.7 , Trombina/metabolismo , Escherichia coli , Masculino , Infecções por Escherichia coli/metabolismo , Infecções por Escherichia coli/microbiologia , Infecções por Escherichia coli/patologia , Infecções por Escherichia coli/terapia , Resultado do Tratamento , Modelos Animais de Doenças , HumanosRESUMO
Reactive oxygen species production might be prevented by xanthine oxidoreductase (XOR) inhibitors, which can cause glomerulosclerosis. We aimed to investigate whether topiroxostat, an XOR inhibitor, prevents diabetic kidney disease development in mice. Six-week-old control Institute of Cancer Research (ICR) mice and type 2 diabetic Nagoya Shibata Yasuda (NSY) mice were divided into the ICR group (ICR mice which received a lard-containing high-fat diet [HFD] based on the AIN-93G diet), NSY control group (NSY mice which received the same aforementioned diet), and NSY + topiroxostat group (NSY mice which received the same aforementioned diet with addition of 0.0012% topiroxostat). After 20 weeks, plasma biomarkers, XOR activity and oxidative stress levels, which were assessed using malondialdehyde (MDA), were measured through enzyme-linked immunosorbent assay or enzymatic methods. Renal pathology was evaluated using periodic acid-Schiff staining. Redox gene and protein expression were determined using RT-qPCR and western blotting, respectively. Plasma XOR activity was lower in NSY mice treated with topiroxostat than those without. Plasma cystatin C and creatinine levels did not differ between the ICR and NSY control groups or between the NSY control and NSY + topiroxostat groups. The NSY + topiroxostat group showed a smaller mesangial area than the NSY control group. The mRNA expression of Sod3, Prdx1, Gpx2, and Gpx3 was higher in the NSY + topiroxostat group than in the NSY control group. Renal MDA levels were lower in the NSY + topiroxostat group than in the NSY control group. Topiroxostat can reduce glomerulosclerosis, and the reduction is associated with renal oxidative markers.
Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Animais , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/metabolismo , Camundongos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Masculino , Estresse Oxidativo/efeitos dos fármacos , Xantina Desidrogenase/metabolismo , Xantina Desidrogenase/antagonistas & inibidores , Xantina Desidrogenase/genética , Camundongos Endogâmicos ICR , Piridinas/farmacologia , Piridinas/uso terapêutico , Rim/efeitos dos fármacos , Rim/patologia , Rim/metabolismo , Biomarcadores/sangue , NitrilasRESUMO
As an oleanolic acid derivative, CDDO-Me lacks selectivity for tumors. Based on the high reactive oxygen species (ROS) level in cancer cells, compound 4 was selected from 17 new CDDO arylboronate ester derivatives. A preliminary study revealed that 4 displayed the highest selectivity for cancer cells. Furthermore, 4 could be transformed to 4H by ROS to increase its covalent binding ability and antiproliferation effect (IC50 of 2.11 vs 0.37 µM) in BGC-823 cells. Interestingly, 4 increased ROS levels to induce apoptosis in BGC-823 cells. Moreover, the LD50 of 4 (91.2 mg/kg) was much greater than that of CDDO-Me (61.7 mg/kg) in ICR mice. A pharmacokinetic study indicated that 4 could be transformed to 4H in vivo. In addition, 4 exhibited a greater tumor inhibition rate (86.2%) than CDDO-Me (51.7%). Overall, the design of 4 provided an effective modification strategy for CDDO to increase the selectivity for cancer cells.
Assuntos
Antineoplásicos , Apoptose , Proliferação de Células , Camundongos Endogâmicos ICR , Ácido Oleanólico , Animais , Humanos , Masculino , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Ácidos Borônicos/química , Ácidos Borônicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Ésteres/química , Ésteres/farmacologia , Ésteres/síntese química , Estrutura Molecular , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/química , Ácido Oleanólico/farmacologia , Ácido Oleanólico/farmacocinética , Ácido Oleanólico/síntese química , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Formamidas/química , Formamidas/farmacologia , Etilaminas/química , Etilaminas/farmacologiaRESUMO
Two-dimension graphene oxide (GO) nanosheets with high and low serum protein binding profiles (high/low hard-bound protein corona/HChigh/low) are used in this study as model materials and screening tools to investigate the underlying roles of the protein corona on nanomaterial toxicities in vivo. We proposed that the in vivo biocompatibility/nanotoxicity of GO is protein corona-dependent and host immunity-dependent. The hypothesis was tested by injecting HChigh/low GO nanosheets in immunocompetent ICR/CD1 and immunodeficient NOD-scid II2rγnull mice and performed histopathological and hematological evaluation studies on days 1 and 14 post-injection. HClow GO induced more severe acute lung injury compared to HChigh GO in both immunocompetent and immunodeficient mice, with the effect being particularly pronounced in immunocompetent animals. Additionally, HClow GO caused more significant liver injury in both types of mice, with immunodeficient mice being more susceptible to its hepatotoxic effects. Moreover, administration of HClow GO resulted in increased hematological toxicity and elevated levels of serum pro-inflammatory cytokines in immunocompromised and immunocompetent mice, respectively. Correlation studies were conducted to explore the impact of distinct protein corona compositions on resulting toxicities in both immunocompetent and immunodeficient mice. This facilitated the identification of consistent patterns, aligning with those observed in vitro, thus indicating a robust in vitro-in vivo correlation. This research will advance our comprehension of how hard corona proteins interact with immune cells, leading to toxicity, and will facilitate the development of improved immune-modulating nanomaterials for therapeutic purposes.