RESUMEN
Manganese (Mn) overexposure has been associated with the development of neurological damage reminiscent of Parkinson's disease, while the underlying mechanisms have yet to be fully characterized. This study aimed to investigate the mechanisms leading to injury in dopaminergic neurons induced by Mn and identify novel treatment approaches. In the in vivo and in vitro models, ICR mice and dopaminergic neuron-like PC12 cells were exposed to Mn, respectively. We treated them with anti-ferroptotic agents ferrostatin-1 (Fer-1), deferoxamine (DFO), HIF-1α activator dimethyloxalylglycine (DMOG) and inhibitor LW6. We also used p53-siRNA to verify the mechanism underlying Mn-induced neurotoxicity. Fe and Mn concentrations increased in ICR mice brains overexposed to Mn. Additionally, Mn-exposed mice exhibited movement impairment and encephalic pathological changes, with decreased HIF-1α, SLC7A11, and GPX4 proteins and increased p53 protein levels. Fer-1 exhibited protective effects against Mn-induced both behavioral and biochemical changes. Consistently, in vitro, Mn exposure caused ferroptosis-related changes and decreased HIF-1α levels, all ameliorated by Fer-1. Upregulation of HIF-1α by DMOG alleviated the Mn-associated ferroptosis, while LW6 exacerbated Mn-induced neurotoxicity through downregulating HIF-1α. p53 knock-down also rescued Mn-induced ferroptosis without altering HIF-1α protein expression. Mn overexposure resulted in ferroptosis in dopaminergic neurons, mediated through the HIF-1α/p53/SLC7A11 pathway.
Asunto(s)
Sistema de Transporte de Aminoácidos y+ , Encéfalo , Ferroptosis , Subunidad alfa del Factor 1 Inducible por Hipoxia , Manganeso , Ratones Endogámicos ICR , Proteína p53 Supresora de Tumor , Animales , Ferroptosis/efectos de los fármacos , Células PC12 , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Ratones , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Manganeso/toxicidad , Encéfalo/efectos de los fármacos , Sistema de Transporte de Aminoácidos y+/metabolismo , Sistema de Transporte de Aminoácidos y+/genética , Ratas , Masculino , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Ciclohexilaminas/farmacología , Fenilendiaminas/toxicidad , Fenilendiaminas/farmacología , Deferoxamina/farmacología , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Aminoácidos DicarboxílicosRESUMEN
OBJECTIVE: To examine the development and challenges of public health nursing education in China during the period of the Republic of China (1912-1949). METHODS: This study utilized a historical research design that combined a social framework and a policy framework to explore the early history of public health nursing education in China. Historical data were collected from periodicals, newspapers, archives, books and other sources. RESULTS: Public health was integrated into the nursing school curriculum for the first time during the period of the Republic of China, and health facilities and nursing schools conducted early explorations of public health nurse training. However, public health nursing education faced difficulties in terms of the curriculum, personnel training, and the localization of education. CONCLUSIONS: The achievements and difficulties associated with public health nursing education in China during the period of the Republic of China provide a historical reference for the integration of public health into current basic nursing education and the compatibility between the training of public health nurses and practical needs. Comparative studies of early public health nursing education across countries are expected to offer a better understanding of current public health nursing education.
Asunto(s)
Educación en Enfermería , Enfermería en Salud Pública , Humanos , Curriculum , Educación en Salud , Facultades de Enfermería , ChinaRESUMEN
This study was to investigate the prevalence and severity of children's dental fluorosis (DF) in Shandong and identified the potential risk factors for DF. A total of 87 villages in Shandong were investigated to calculate the prevalence of DF and Community Fluorosis Index (CFI) in 2018-2019. Six hundred and seventy children were enrolled to identify the potential risk factors using univariate and multivariate logistic regressions. Goodman-Kruskal Gamma was used to explore the factors related to the severity of DF. In 87 villages, 1249 of 8700 (14.36%) children still have DF. The prevalence of DF in most villages was below 40% in 2018-2019. Water fluorine concentration when selected for the study and urinary fluorine concentration were related to the risk of DF (P < 0.001). Some eating habits, like lower frequency of eating fresh vegetables, eggs, and beans, were associated with the risk of DF (P < 0.001). The high water fluorine concentration, and lower frequency of eating fresh vegetables, eggs, and beans were also related to the severity of DF (P < 0.001). DF in children in Shandong province is still a common endemic disease. This study tries to provide a useful guide for the prevention and control of DF.
Asunto(s)
Fluorosis Dental , Niño , Humanos , Fluorosis Dental/epidemiología , Fluorosis Dental/etiología , Fluoruros/toxicidad , Prevalencia , Flúor , Agua , China/epidemiología , Factores de RiesgoRESUMEN
Dibromoacetonitrile (DBAN) is a high-risk haloacetonitrile (HAN) generated as a byproduct of chloramine disinfection in drinking water. DBAN-induced neurotoxicity in mouse hippocampal neuronal cells (HT22) and mammals was observed to be related to reactive oxygen species (ROS). ROS, endoplasmic reticulum stress (ERS) and autophagy play crucial roles in regulating a variety of cellular processes. However, whether ERS and autophagy are associated with HAN-responsive apoptosis remains unclear. This study indicated that DBAN (10 µM, 24 h) activated the ERS protein kinase like endoplasmic reticulum kinase (PERK) signaling pathway. The ERS inhibitor 4-phenylbutyric acid (4-PBA) reversed DBAN-inhibited cell viability and alleviated DBAN-induced apoptosis in HT22 cell, indicating that activation of the ERS PERK pathway mediates DBAN induced cytotoxicity. Moreover, DBAN activated autophagy. The autophagy inhibitor 3-methyladenine(3-MA) reversed DBAN-inhibited cell viability and alleviated DBAN-induced apoptosis in HT22 cell, suggesting that autophagy activation mediates DBAN-induced cell toxicity. Notably, the results showed that 4-PBA inhibited DBAN-activated autophagy, demonstrating that ERS-PERK promotes DBAN-induced cellular autophagy. Pretreatment with antioxidant N-acetylcysteine (NAC) inhibited the increase in ROS production and the activation of ERS, and protected cells from toxicity. Furthermore, 4-PBA pretreatment reduced the increase in ROS production, indicating that the ROS and PERK promote each other and form a positive feedback loop. ROS also promoted DBAN-induced autophagy. In summary, our findings indicate that DBAN induced autophagy by mediating the PERK signalling pathway and ROS interaction, leading to HT22 cell damage. Accordingly, targeting these pathogenic mechanisms may provide a potential target and theoretical basis for preventing and improving HAN-induced neurotoxicity.
Asunto(s)
Proteínas Quinasas , Transducción de Señal , Ratones , Animales , Especies Reactivas de Oxígeno/metabolismo , Proteínas Quinasas/metabolismo , Retículo Endoplásmico/metabolismo , Autofagia , Estrés del Retículo Endoplásmico , Apoptosis , Mamíferos/metabolismoRESUMEN
The objective of the present review was to summarize the molecular mechanisms associated with the effects of the vitamins A, C, E and K, and group B vitamins on bone and their potential roles in the development of osteoporosis. Epidemiological findings have demonstrated an association between vitamin deficiency and a higher risk of developing osteoporosis; vitamins are positively related to bone health upon their intake at the physiological range. Excessive vitamin intake can also adversely affect bone formation, as clearly demonstrated for vitamin A. Vitamins E (tocopherols and tocotrienols), K2 (menaquinones 4 and 7) and C have also been shown to promote osteoblast development through bone morphogenetic protein (BMP)/Smad and Wnt/ßcatenin signaling, as well as the TGFß/Smad pathway (αtocopherol). Vitamin A metabolite (alltrans retinoic acid) exerts both inhibitory and stimulatory effects on BMP and Wnt/ßcateninmediated osteogenesis at the nanomolar and micromolar range, respectively. Certain vitamins significantly reduce receptor activator of nuclear factor kappaB ligand (RANKL) production and RANKL/RANK signaling, while increasing the level of osteoprotegerin (OPG), thus reducing the RANKL/OPG ratio and exerting antiosteoclastogenic effects. Ascorbic acid can both promote and inhibit RANKL signaling, being essential for osteoclastogenesis. Vitamin K2 has also been shown to prevent vascular calcification by activating matrix Gla protein through its carboxylation. Therefore, the maintenance of a physiological intake of vitamins should be considered as a nutritional strategy for the prevention of osteoporosis.
Asunto(s)
Osteoporosis , Vitaminas , Humanos , Vitaminas/farmacología , Colecalciferol/farmacología , beta Catenina/metabolismo , Vitamina A , Densidad Ósea , Osteoporosis/metabolismo , Vitamina K , Proteínas Morfogenéticas Óseas , Vía de Señalización WntRESUMEN
The objective of the present study was to evaluate serum and hair trace element and mineral levels in women with osteoporosis, as well as to estimate the impact of menopausal status on the profile of trace element and mineral status in women with osteoporosis. 207 women with diagnosed osteoporosis 22-85 years-of-age, and 197 healthy women of the respective age participated in the present study. Analysis of the levels of mineral and trace element in hair and serum samples was performed by inductively-coupled plasma mass-spectrometry (ICP-MS). Women with osteoporosis were characterized by significantly lower hair Ca, Mg, Co, I, Li, and Mn levels, as well as serum Ca, Mg, Co, Fe, V, and Zn concentrations compared to women in the control group. After additional grouping according to menopausal status, the lowest hair Ca and Mg content was observed in postmenopausal osteoporotic women, whereas serum Ca and Mg concentrations were the lowest in premenopausal osteoporotic women. Hair Co, Mn, and Zn levels in postmenopausal osteoporotic women were lower than in healthy postmenopausal women. The lowest circulating Zn levels were observed in osteoporotic postmenopausal women. Taken together, decreased hair and serum levels in osteoporotic women are indicative of increased risk of Ca, Mg, Co, and Zn deficiency in women with osteoporosis. In turn, alterations in hair trace element and mineral levels in osteoporosis are more profound in postmenopausal women. Hypothetically, improvement in trace element and mineral metabolism especially in postmenopausal women may be considered as a potential strategy for mitigating osteoporosis.
RESUMEN
Titanium dioxide nanoparticles (TiO2NPs) are widely produced and used nanoparticles. Yet, TiO2NP exposure may possess toxic effects to different cells and tissues, including the brain. Recent studies significantly expanded the understanding of the molecular mechanisms underlying TiO2NP neurotoxicity implicating a number of both direct and indirect mechanisms. In view of the significant recent progress in research on TiO2NP neurotoxicity, the objective of the present study is to provide a narrative review on the molecular mechanisms involved in its neurotoxicity, with a special focus on the studies published in the last decade. The existing data demosntrate that although TiO2NP may cross blood-brain barrier and accumulate in brain, its neurotoxic effects may be mediated by systemic toxicity. In addition to neuronal damage and impaired neurogenesis, TiO2NP exposure also results in reduced neurite outgrowth and impaired neurotransmitter metabolism, especially dopamine and glutamate. TiO2NP exposure was also shown to promote α-synuclein and ß-amyloid aggregation, thus increasing its toxicity. Recent findings also suggest that epigenetic effects and alterations in gut microbiota biodiversity contribute to TiO2NP neurotoxicity. Correspondingly, in vivo studies demosntrated that TiO2NPs induce a wide spectrum of adverse neurobehavioral effects, while epidemiological data are lacking. In addition, TiO2NPs were shown to promote neurotoxic effects of other toxic compounds. Here we show the contribution of a wide spectrum of molecular mechanisms to TiO2NP-induced neurotoxicity; yet, the role of TiO2NP exposure in adverse neurological outcomes in humans has yet to be fully appreciated.
Asunto(s)
Nanopartículas del Metal , Nanopartículas , Humanos , Nanopartículas/toxicidad , Antioxidantes/farmacología , Titanio/toxicidad , Nanopartículas del Metal/toxicidadRESUMEN
Objective: Low awareness of hypertension and diabetes is a public health concern in Ghana. Assessing the general population's behaviour via knowledge, attitude, and practice (KAP) will be invaluable in these diseases, where prevention and control need a lifelong commitment to a healthy lifestyle. Hence, our goal was to assess the behaviour of Akatsi South residents towards the diseases to assist health providers in implementing tailored intervention programs. Methods: This was a population-based cross-sectional study with 150 adults (18-70 years) from November to December 2021. A semi-structured questionnaire with face-to-face interviews was used to obtain data. All variables in the model had descriptive statistics. The Chi-square (χ2) test was used to examine correlations between variables, and a value of p < 0.05 was considered statistically significant. The factors associated with checking blood sugar levels and blood pressure were determined using binary logistic regression. Results: The respondents' mean age and BMI were 32.40 years (± 12.07) and 24.98 kg/m2 (± 2.36), respectively. Only 46.67% of the respondents frequently monitor their blood pressure and 17.33% their blood glucose (at least once a year). Less than half of those surveyed had a good knowledge of hypertension (42.7%) and diabetes (32.0%), whereas nearly 3/4 had poor attitudes regarding both conditions. A binary logistic regression analysis revealed that having a good attitude toward hypertension (exp B = 2.479, p = 0.036) and diabetes (exp B = 4.547, p = 0.009) were the participants' strongest predictor of blood pressure and sugar level checks. However, being overweight (exp B = 0.046, p = 0.002,) or obese (exp B = 0.144, p = 0.034) negatively influenced the frequency with which our respondents checked their blood glucose levels. Conclusion: In the study, we found that the population generally has poor knowledge, which affects their behaviour (attitudes and practices) towards the diseases. To enable healthcare practitioners to reduce disease-associated mortality and morbidity in the future, frequent public health education and promotion about the conditions is critical to closing the knowledge gap.
Asunto(s)
Diabetes Mellitus , Hipertensión , Adulto , Humanos , Conocimientos, Actitudes y Práctica en Salud , Ghana , Estudios Transversales , Glucemia , Diabetes Mellitus/epidemiología , Hipertensión/epidemiología , Encuestas y CuestionariosRESUMEN
Hypoxia-inducible factor 1 (HIF-1) is an oxygen-sensing transcriptional regulator orchestrating a complex of adaptive cellular responses to hypoxia. Several studies have demonstrated that toxic metal exposure may also modulate HIF-1α signal transduction pathway, although the existing data are scarce. Therefore, the present review aims to summarize the existing data on the effects of toxic metals on HIF-1 signaling and the potential underlying mechanisms with a special focus on prooxidant effect of the metals. The particular effect of metals was shown to be dependent on cell type, varying from down- to up-regulation of HIF-1 pathway. Inhibition of HIF-1 signaling may contribute to impaired hypoxic tolerance and adaptation, thus promoting hypoxic damage in the cells. In contrast, its metal-induced activation may result in increased tolerance to hypoxia through increased angiogenesis, thus promoting tumor growth and contributing to carcinogenic effect of heavy metals. Up-regulation of HIF-1 signaling is mainly observed upon Cr, As, and Ni exposure, whereas Cd and Hg may both stimulate and inhibit HIF-1 pathway. The mechanisms underlying the influence of toxic metal exposure on HIF-1 signaling involve modulation of prolyl hydroxylases (PHD2) activity, as well as interference with other tightly related pathways including Nrf2, PI3K/Akt, NF-κB, and MAPK signaling. These effects are at least partially mediated by metal-induced ROS generation. Hypothetically, maintenance of adequate HIF-1 signaling upon toxic metal exposure through direct (PHD2 modulation) or indirect (antioxidant) mechanisms may provide an additional strategy for prevention of adverse effects of metal toxicity.
Asunto(s)
Metales Pesados , Fosfatidilinositol 3-Quinasas , Humanos , Transducción de Señal , Hipoxia , Metales Pesados/toxicidad , Factor 1 Inducible por Hipoxia/farmacología , Subunidad alfa del Factor 1 Inducible por Hipoxia , Prolina Dioxigenasas del Factor Inducible por Hipoxia/farmacologíaRESUMEN
Evidence for an association between the amount of particulate matter (PM) in the atmosphere and vitamin D status of pregnant women is limited. We aimed to examine the independent association between PM and maternal levels of serum 25-hydroxyvitamin D (25OHD) during the second trimester and to explore possible modifications to the association by meteorological factors. 27,768 pregnant women presenting for prenatal examination who were tested for serum 25OHD concentration during the second trimester between January 1, 2016, and December 31, 2020, were included in this retrospective analysis. Exposure to PM was evaluated based on daily average PM with an aerodynamic diameter of ≤ 2.5 µm (PM2.5) and PM with an aerodynamic diameter of ≤ 10 µm (PM10). Corresponding meteorological data for daily average atmospheric temperature, atmospheric pressure, relative humidity, sunshine duration, and wind speed were collected. The maximum cumulative effects of PM2.5 occurred at lag 45 days, and the maximum cumulative effects of PM10 occurred at lag 60 days. In crude models, 45-day moving daily average PM2.5 concentrations were negatively associated with 25OHD levels (ß, - 0.20; 95% CI - 0.21 to - 0.19), as were 60-day moving daily average PM10 concentrations (ß, - 0.14; 95% CI - 0.15 to - 0.14). After adjusting for temporal and meteorological factors, the effect values were drastically reduced (adjusted ß of PM2.5, - 0.032; 95% CI - 0.046 to - 0.018; adjusted ß of PM10, - 0.039; 95% CI - 0.049 to - 0.028). Our study showed there was a small, independent, negative association between PM in the atmosphere and maternal serum 25OHD levels during the second trimester of pregnancy after adjusting for temporal and/or meteorological factors, which indicates that PM may have a limited influence on maternal serum 25OHD levels. Besides taking vitamin D supplements, pregnant women should keep participating in outdoor activities while taking PM protection measures to improve their vitamin D levels when PM levels are high in winter and spring.
Asunto(s)
Contaminantes Atmosféricos , Contaminación del Aire , Colestanos , Contaminantes Atmosféricos/efectos adversos , Contaminantes Atmosféricos/análisis , Contaminación del Aire/análisis , China , Femenino , Humanos , Conceptos Meteorológicos , Material Particulado/análisis , Embarazo , Estudios Retrospectivos , Estaciones del Año , Vitamina D/análisis , Vitaminas/análisisRESUMEN
Iron (Fe) is an essential trace element required for several physiological processes. It plays important roles in mitochondrial function, synthesis, and metabolism of the neurotransmitter, as well as oxygen transport. However, excess Fe can cause toxicity. Particularly, Fe overload may result in neurotoxicity, contributing to the development and progression of neurodegenerative diseases, although the molecular mechanisms underlying Fe-induced neurodegeneration have yet to be entirely understood. Alternative (non-rodent) experimental models have been pointed as important approaches to elucidate molecular and physiological events mediating Fe-induced pathology. Among such alternative strategies, an advantageous experimental worm-model system, Caenorhabditis elegans (C. elegans), has been used to investigate Fe-induced neurotoxicity and neurodegenerative disorders. Its genome has been fully sequenced, corroborating that it shares significant homology with mammalians, and has approximately 40% of human disease-related genes. As part of this review, we discuss studies using the C. elegans model to study molecular mechanisms such as oxidative stress, mitochondrial dysfunction, disturbed homeostasis, and its potential contribution to the study of metal-induced neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD).
RESUMEN
Identifying novel agents for cancer treatment is critical because of obstacles with anticancer drug resistance and lack of drug effectiveness. Intracellular calcium ion (Ca2+), a common second messenger, regulates various cellular pathophysiological processes including cell proliferation, differentiation and apoptosis. Recent studies have shown that the remodeling of Ca2+ signals is associated with cancer occurrence, progression and metastasis. Ca2+ channels, transporter and pumps regulate calcium movement, and alteration of Ca2+ signal component expression/activity is associated with numerous cancer cell activities. Therefore, targeting Ca2+ signals is an attractive research focus in cancer treatment. Phytochemicals, secondary metabolites in plants, exhibit multifaceted effective anticancer activities in various cancers. Although the mechanisms of the anticancer effects of phytochemicals remain unclarified, studies have indicated that many phytochemicals inhibit cancer progression through modulating calcium signals. In this review, we summarize the phytochemicals with demonstrated anticancer effects through their influence on calcium signaling, which may provide new ideas and directions in cancer research.
Asunto(s)
Calcio , Neoplasias , Proliferación Celular , Quimioprevención , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Neoplasias/prevención & control , Fitoquímicos/farmacología , Fitoquímicos/uso terapéuticoRESUMEN
Cytochrome P450 2E1 (CYP2E1) plays an essential role in the susceptibility to acute acrylonitrile (AN)-induced toxicity. Here, we investigated the toxicity and mechanism of AN in fasting mice and potential underlying mechanisms. Convulsions, loss of righting reflex, and death 4 h after AN treatment were observed and recorded for each group of mice. Relative to ad lib-fed mice, 48 h fasting significantly increased the acute toxicity of AN, as noted by a more rapid onset of convulsions and death. In addition, fasting significantly enhanced CYP2E1-mediated oxidative metabolism of AN, resulting in increased formation of CN- (one of the end-metabolites of AN). Moreover, fasting decreased hepatic GSH content, abrogating the detoxification of GSH. However, trans-1,2-dichloroethylene (DCE), a CYP2E1 inhibitor, altered the level of hepatic CYP2E1 activity in response to fasting, reduced the acute toxic symptoms of AN and the content of CN- in AN-treated mice. These data establish that fasting predisposes to AN toxicity, attributable to induced CYP2E1 and reduced hepatic GSH.
RESUMEN
Ferroptosis is a recently discovered form of regulated cell death, implicated in multiple pathologies. Given that the toxicity elicited by some metals is linked to alterations in iron metabolism and induction of oxidative stress and lipid peroxidation, ferroptosis might be involved in such toxicity. Although direct evidence is insufficient, certain pioneering studies have demonstrated a crosstalk between metal toxicity and ferroptosis. Specifically, the mechanisms underlying metal-induced ferroptosis include induction of ferritinophagy, increased DMT-1 and TfR cellular iron uptake, mitochondrial dysfunction and mitochondrial reactive oxygen species (mitoROS) generation, inhibition of Xc-system and glutathione peroxidase 4 (GPX4) activity, altogether resulting in oxidative stress and lipid peroxidation. In addition, there is direct evidence of the role of ferroptosis in the toxicity of arsenic, cadmium, zinc, manganese, copper, and aluminum exposure. In contrast, findings on the impact of cobalt and nickel on ferroptosis are scant and nearly lacking altogether for mercury and especially lead. Other gaps in the field include limited studies on the role of metal speciation in ferroptosis and the critical cellular targets. Although further detailed studies are required, it seems reasonable to propose even at this early stage that ferroptosis may play a significant role in metal toxicity, and its modulation may be considered as a potential therapeutic tool for the amelioration of metal toxicity.
Asunto(s)
Ferroptosis , Antioxidantes/farmacología , Hierro/metabolismo , Peroxidación de Lípido , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Dibromoacetonitrile (DBAN) and dichloroacetonitrile (DCAN) are haloacetonitriles (HANs) produced as by-products of chloramine disinfection of drinking water and can cause neurotoxicity. The molecular pathways leading to HAN-induced neuronal cell death remain unclear. The nuclear factor erythroid 2-related factor 2 (Nrf2) is an important regulator of oxidation reactions. We explored the role of the sequestosome 1 (p62)-Kelch-like ECH-associated protein 1 (Keap1)-Nrf2 pathway in DBAN- and DCAN-induced mouse hippocampal neuronal (HT22) cell injury. DBAN and DCAN reduced cell viability, increased lactate dehydrogenase release rate, and promoted apoptosis. Over the same treatment time, DBAN at lower concentrations caused cell injury, suggesting that DBAN is more cytotoxic than DCAN. DBAN and DCAN triggered oxidative stress by reducing intracellular glutathione and increasing reactive oxygen species concentrations. DBAN and DCAN activated the Nrf2 pathway. Furthermore, Nrf2 inhibitors (all-trans retinoic acid) attenuated DBAN- and DCAN-induced toxicity, whereas Nrf2 activators (tert-Butylhydroquinone) achieved the opposite effect. This indicates that activation of the Nrf2 pathway mediates DBAN- and DCAN-induced cell injury. Notably, the expression of p62, a noncanonical pathway that mediates Nrf2 activation, increased, whereas the expression of Keap1, another regulator of Nrf2, decreased. We noted that high p62 expression activated the Nrf2 pathway, and p62 was regulated through Nrf2, forming a positive feedback loop. N-acetyl-L-cysteine, a mercaptan substance, protected against DBAN- and DCAN-induced toxicity and inhibited the Nrf2 pathway. In summary, Nrf2 pathway inhibition and mercaptan supplementation prevent DBAN- and DCAN-induced HT22 cell injury, accordingly, targeting them is a potential approach to preventing HAN-induced neurotoxicity.
Asunto(s)
Agua Potable , Acetonitrilos , Acetilcisteína/farmacología , Animales , Desinfección , Hipocampo , Proteína 1 Asociada A ECH Tipo Kelch , Ratones , Factor 2 Relacionado con NF-E2 , Estrés Oxidativo , Compuestos de SulfhidriloRESUMEN
Background: Hydrogen sulfide (H2S), as the third gasotransmitter participates in both cellular physiological and pathological processes, including chemical-induced injuries. We recently reported acute acrylonitrile (AN) treatment inhibited endogenous H2S biosynthesis pathway in rat and astrocyte models. However, there is still no evidence to address the correlation between endogenous H2S and sub-chronic AN exposure. Objectives: This study aims to explore the modulatory effects of prolonged AN exposure on endogenous H2S levels and its biosynthetic enzymes in rat blood, brain and liver. Methods: A total of 50 male Sprague-Dawley rats were randomly divided into 5 groups, including the control group and AN-treated groups at dosages of 6.25, 12.5, 25 or 50 mg/kg. Rats received one exposure/day, 5 days/week, for 4 consecutive weeks. The rat bodyweight and brain/liver organ coefficient were detected, along with liver cytochrome P450 2E1(CYP2E1) expression. In addition, the H2S contents in rat serum and plasma, and in cerebral cortex and liver tissues were measured by methylene blue method. The expression of H2S-generating enzymes, including cystathionine ß-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MPST) was also measured with Western blot both in rat cerebral cortex and liver. Results: Subchronic exposure to AN significantly inhibited bodyweight-gain and increased the liver CYP2E1 expression compared with the control. In addition, AN significantly increased H2S levels in rat plasma and serum, but not in liver. The endogenous H2S level in rat cerebral cortex was also significantly increased upon AN treatment, when expression of the major H2S-generating enzymes, CBS and 3-MPST were significantly enhanced. However, hepatic protein levels of CBS and CSE were significantly increased, whereas hepatic levels of 3-MPST were significantly decreased. Conclusion: This study showed that sub-chronic AN exposure increased endogenous H2S contents in rat blood and brain tissues, but not liver, which may be resulted from the distinct expression profile of H2S-producing enzymes in response to AN. The blood H2S contents may be applied as a potential novel biomarker for surveillance of chronically AN-exposed populations. Highlights: Subchronic intraperitoneal exposure to acrylonitrile increased H2S content in rat blood and cerebral cortex, but not in liver.Distinct tissue expression profiles of H2S-producing enzymes contribute to the acrylonitrile-induced differential effects on the H2S level.Blood H2S level may be a biomarker for subchronic exposure to acrylonitrile.
RESUMEN
Curcumin as a hydrophobic polyphenol has great potential for tumor therapy, yet its rapid degradation and hydrophobicity severely impair its therapeutic effect in the clinic. Herein, we report a novel strategy for the formation of curcumin doped zeolitic imidazolate framework nanoparticles (Cur-ZIF NPs) by zinc ion driven simultaneous coordination of curcumin and 2-methylimidazole. The resultant Cur-ZIF NPs with a uniform nanosize exhibit favorable stability and dispersibility in water, as well as high drug-loading capacities. The pH and redox sensitivity of ZIF NPs enable the controlled release of curcumin in vivo. Moreover, Cur-ZIF NPs serve as nanocarriers that can load the toll-like-receptor-7 agonist (imiquimod, IQ) and be coated by homotypic cancer cell membranes to enhance tumor-targeted delivery. This study provides an attractive nanoplatform to effectively utilize curcumin and integrate multiple therapeutic modalities into a single system for tumor treatment.
Asunto(s)
Curcumina , Nanopartículas , Neoplasias , Zeolitas , Curcumina/química , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Humanos , Inmunoterapia , Nanopartículas/química , Neoplasias/tratamiento farmacológico , Zeolitas/químicaRESUMEN
OBJECTIVE: Ferroptosis is an iron-dependent nonapoptotic form of cell death, characterized by iron accumulation and lipid peroxidation. However, the role of ferroptosis in methylmercury (MeHg)-induced cytotoxicity has yet to be fully characterized. The purpose of this study was to investigate the role of ferroptosis in MeHg-induced cytotoxicity in both brain and liver cells. METHODS: The effects of MeHg on cell viability, cytotoxicity, intracellular iron content, reduced glutathione (GSH) content, ferroptosis-related proteins, cytosolic and lipid reactive oxygen species (ROS) generation were determined in rat primary astrocytes (AST) and Buffalo Rat Liver (BRL) cells in the absence or presence of the ferroptosis inhibitors deferoxamine (DFO) or ferrostatin-1 (Fer-1). RESULTS: MeHg treatment decreased cell viability and increased cytotoxicity in AST and BRL cells. MeHg induced ferroptosis in AST and BRL cells was reflected by increased cytosolic ROS, lipid ROS and intracellular iron content, all of which were inhibited by the ferroptosis inhibitors DFO and/or Fer-1. MeHg inhibited the expression of ferritin heavy chain 1 (FTH1). Furthermore, MeHg treatment decreased the expression of glutathione peroxidase 4 (GPx4) without altering solute carrier family 7 member 11 (SLC7A11). DFO and Fer-1 significantly increased the expression of GPx4, yet had no effect on SLC7A11 upon MeHg treatment. CONCLUSIONS: Our novel results are consistent with ferroptosis as a key event mediating MeHg-induced toxicity, inhibiting GPx4 in AST and BRL cells. Ferroptosis may offer a new target for attenuating MeHg-induced toxic injury.
Asunto(s)
Ferroptosis , Compuestos de Metilmercurio , Animales , Astrocitos/metabolismo , Hierro/metabolismo , Lípidos , Hígado/metabolismo , Compuestos de Metilmercurio/toxicidad , Ratas , Especies Reactivas de Oxígeno/metabolismoRESUMEN
To investigate the effect and potential mechanism of 3,3'-diindolylmethane (DIM) on ferroptosis against gastric cancer, cells proliferation, lipid reactive oxygen species (ROS) and GSH level were measured in the BGC-823 gastric cancer cells after DIM treatment. Western blotting was used to detect the expression of SLC7A11, GPX4, IP3R and BAP1. Results showed that DIM could induce ferroptosis in the BGC-823 gastric cancer cells via upregulating lipid-ROS level and decreasing GSH generation. Besides, DIM also significantly reduced the protein level of SLC7A11 and GPX4, which was an important regulator of ferroptosis. In addition, DIM promoted the protein level of BAP1 and IP3R in a concentration-dependent manner in the BGC-823 gastric cancer cells. The knockdown of BAP1 could reduce IP3R level and DIM-induced ferroptosis of gastric cancer cells. Taken together, these results indicated that DIM could induce ferroptosis to exert anti-cancer effects via BAP1-IP3R axis, suggesting its effective therapeutic potential in gastric cancer.
Asunto(s)
Ferroptosis , Neoplasias Gástricas , Línea Celular Tumoral , Humanos , Indoles , Lípidos , Especies Reactivas de Oxígeno/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/metabolismo , Proteínas Supresoras de Tumor , Ubiquitina Tiolesterasa/metabolismo , Ubiquitina Tiolesterasa/uso terapéuticoRESUMEN
The present study aimed to examine the multi-faceted self-supporting ability profiles of rural empty-nesters in northwestern China on the basis of the self-care ability, economic self-support ability, health self-maintenance ability, physical health self-maintenance ability, and psychological health self-maintenance ability using latent profile analysis. It identified the association of self-supporting ability profiles with demographic variables and sense of coherence. The analysis included 1066 participants (mean age = 70.2; SD = 4.3). The results of latent profile analysis identified three distinctive patterns of self-supporting abilitylow physical health self-maintenance ability (C1, 20.5%), low psychological health self-maintenance ability (C2, 31.4%), and high social self-adaption ability (C3, 48.0%). The specific demographic variable age (p < 0.05), monthly income (p < 0.05), education level (p < 0.05), how often their children visit (p < 0.05), how often their children contact them (p < 0.05), whether they drink (p < 0.05), the frequency of physical exercise (p < 0.05), relationship with children (p < 0.05), relationship with neighbours (p < 0.05), medical insurance (p < 0.05), and the number of chronic diseases (p < 0.05) were significantly different among the identified three profiles. A statistically significant positive association existed between self-supporting ability profiles and sense of coherence (SOC) (p < 0.001). The results of multinomial logistic regression showed that a greater sense of coherence (SOC), age ≥ 80, monthly income (RMB) (RMB is the abbreviation for Renminbi) < 1000, a good relationship with neighbours, and one type of chronic disease were significantly associated with C1 when compared with C3 (p < 0.05). Furthermore, a greater SOC, their children visiting and contacting them many times per week or once per week were more significantly related to C2 than to C3 (p < 0.05). This study revealed three groups of self-supporting ability and its related predictors in empty-nesters. The predictors related to particular classes of self-supporting ability can provide information for targeted interventions to improve the self-supporting ability of empty-nesters living in rural areas.