Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 153
Filtrar
1.
Autophagy ; : 1-20, 2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33843441

RESUMO

Zinc oxide nanoparticles (ZnONPs) hold great promise for biomedical applications. Previous studies have revealed that ZnONPs exposure can induce toxicity in endothelial cells, but the underlying mechanisms have not been fully elucidated. In this study, we report that ZnONPs can induce ferroptosis of both HUVECs and EA.hy926 cells, as evidenced by the elevation of intracellular iron levels, lipid peroxidation and cell death in a dose- and time-dependent manner. In addition, both the lipid reactive oxygen species (ROS) scavenger ferrostatin-1 and the iron chelator deferiprone attenuated ZnONPs-induced cell death. Intriguingly, we found that ZnONPs-induced ferroptosis is macroautophagy/autophagy-dependent, because the inhibition of autophagy with a pharmacological inhibitor or by ATG5 gene knockout profoundly mitigated ZnONPs-induced ferroptosis. We further demonstrated that NCOA4 (nuclear receptor coactivator 4)-mediated ferritinophagy (autophagic degradation of the major intracellular iron storage protein ferritin) was required for the ferroptosis induced by ZnONPs, by showing that NCOA4 knockdown can reduce the intracellular iron level and lipid peroxidation, and subsequently alleviate ZnONPs-induced cell death. Furthermore, we showed that ROS originating from mitochondria (mtROS) probably activated the AMPK-ULK1 axis to trigger ferritinophagy. Most importantly, pulmonary ZnONPs exposure caused vascular inflammation and ferritinophagy in mice, and ferrostatin-1 supplementation significantly reversed the vascular injury induced by pulmonary ZnONPs exposure. Overall, our study indicates that ferroptosis is a novel mechanism for ZnONPs-induced endothelial cytotoxicity, and that NCOA4-mediated ferritinophagy is required for ZnONPs-induced ferroptotic cell death.

2.
Biochem Pharmacol ; 188: 114542, 2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33819469

RESUMO

Cisplatin (cis-dichloro-diammine platinum, CDDP) is a well-known chemotherapeutic drug against a broad spectrum of human malignancies. However, the clinical utility of this effective chemotherapy agent is dose limited by its toxic side effects such as nephrotoxicity and ototoxicity. Necroptosis is a form of programmed necrotic cell death that is mediated by serine/threonine kinases, RIPK1 and RIPK3, together with MLKL. In this study, we identified that the multitargeted kinase inhibitor KW-2449 inhibited cisplatin-induced necroptosis, while potentiated cisplatin-induced apoptosis in cancer cells. Mechanistic studies indicated that KW-2449 directly inhibited RIPK1 kinase activity to block necroptosis. Oral administration of KW-2449 attenuated renal cell necrosis and reduced pro-inflammatory responses in mouse models of cisplatin-induced nephrotoxicity. Taken together, our study shows that KW-2449 is a novel necroptosis inhibitor by targeting RIPK1 kinase activity and has great clinic potential for the treatment of cisplatin-induced nephrotoxicity.

3.
Neurotox Res ; 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33826131

RESUMO

Copper oxide nanoparticles (CuONPs) are widely used in pharmaceutical, food, and textile industries. They have been shown to cause lung, liver, and kidney damage. However, whether an intratracheal instillation of CuONPs would affect the brain and its underlying mechanisms remain poorly studied. In this study, healthy C57BL/6J male mice were equally subdivided into control group, low-dose (30 µg/animal), medium-dose (50 µg/animal), and high-dose (100 µg/animal) CuONPs-treated groups. Mice were subjected to acute exposure of CuONPs via intratracheal instillation. Brain histopathology, inflammatory factors, oxidative stress markers, and mitochondrial function-related protein expression were determined. Our results demonstrated that CuONPs caused a dose-dependent brain damage in mice. Histopathological changes in the brain, elevation of inflammatory factors (Tnf, Il-6), and significant alterations in oxidative stress markers were also observed after treatment with CuONPs. Intriguingly, we did not observe infiltration of macrophage cell. Moreover, Tim23, TFAM, and MFN2 protein expression levels showed the decreasing trend after treatment with CuONPs. Taken together, these results indicate that pulmonary exposure to CuONPs induces pathological damage, inflammation, oxidative stress, and mitochondrial dysfunction in the cerebral cortex, suggesting that neurotoxicity caused by pulmonary exposure of CuONPs needs more attention from the public and relevant departments.

4.
Psychol Health Med ; : 1-13, 2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33779436

RESUMO

The aims of the study were to assess the contribution of resilience, coping style, and COVID-19 stress on the quality of life (QOL) in frontline health care workers (HCWs). The study was a cross-sectional surveyperformed among 309 HCWs in a tertiaryhospital during the outbreak of COVID-19 in China. Data were collected through an anonymous, self-rated questionnaire, including demographic data, a 10-item COVID-19 stress questionnaire, Generic QOL Inventory-74, Connor-Davidson Resilience Scale, and the Simplified Coping Style Questionnaire. Hierarchical regression was used to analyse the relationship between the study variables and the QOL. Among the 309 participants, resilience and active coping were positively correlated with the QOL (P<0.001), whereas, working in confirmed case wards, COVID-19 stress, and passive coping were negatively correlated with the QOL (P<0.001). Resilience and the active coping were negatively correlated with COVID-19 stress (P<0.001). Resilience, coping style,and COVID-19 stressaccounted for 32%, 13%, and 8% of the variance in predicting the Global QOL, respectively. In conclusion, working in confirmed COVID-19 case wards and COVID-19 stress impaired the QOL in HCWs. Psychological intervention to improve the resilience and coping style, and reduce COVID-19 stress are important in improving the QOL and mental health of HCWs.

5.
J Psychopharmacol ; : 269881120985183, 2021 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-33749357

RESUMO

BACKGROUND: Long-term morphine use is associated with serious side effects, such as morphine-induced hyperalgesia and analgesic tolerance. Previous investigations have documented the association between dopamine (DA) neurons in the ventral tegmental area (VTA) and pain. However, whether VTA DA neurons are implicated in morphine-induced hyperalgesia and analgesic tolerance remains elusive. METHODS: Initially, we observed behavioural effects of lidocaine administration into VTA or ablation of VTA DA neurons on morphine-induced hyperalgesia and anti-nociceptive tolerance. Subsequently, c-Fos expression in nucleus accumbens (NAc) shell-projecting and medial prefrontal cortex (mPFC)-projecting VTA DA neurons after chronic morphine treatment was respectively investigated. Afterwards, the effects of chemogenetic manipulation of NAc shell-projecting or mPFC-projecting DA neurons on morphine-induced hyperalgesia and anti-nociceptive tolerance were observed. Additionally, effects of chemogenetic manipulation of VTA GABA neurons on c-Fos expression in VTA DA neurons were investigated. RESULTS: Lidocaine injection into VTA relieved established hyperalgesia and anti-nociceptive tolerance whereas ablation of VTA DA neurons prevented the development of morphine-induced hyperalgesia and anti-nociceptive tolerance. Chronic morphine treatment increased c-Fos expression in NAc shell-projecting DA neurons, rather than in mPFC-projecting DA neurons. Chemogenetic manipulation of NAc shell-projecting DA neurons had influence on morphine-induced hyperalgesia and tolerance. However, chemogenetic manipulation of mPFC-projecting DA neurons had no significant effects on morphine-induced hyperalgesia and anti-nociceptive tolerance. Chemogenetic manipulation of VTA GABA neurons affected the c-Fos expression in VTA DA neurons. CONCLUSIONS: These findings revealed the involvement of NAc shell-projecting VTA DA neurons in morphine-induced hyperalgesia and anti-nociceptive tolerance, and may shed new light on the clinical management of morphine-induced hyperalgesia and analgesic tolerance. PERSPECTIVE: This study demonstrated that NAc shell-projecting DA neurons rather than mPFC-projecting DA neurons in the VTA were implicated in morphine-induced hyperalgesia and anti-nociceptive tolerance. Our findings may pave the way for the discovery of novel therapies for morphine-induced hyperalgesia and analgesic tolerance.

6.
Food Chem Toxicol ; 151: 112114, 2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33722599

RESUMO

Ferroptosis is a novel form of cell death that involves in the pathophysiological process of diverse brain diseases. However, how arsenite induces ferroptosis in the neuronal cells remains unsolved. In this study, by using in vitro and in vivo models, we demonstrated that arsenite was able to trigger ferroptosis in the neuronal cells. Exposure of arsenite for 6 months at 0.5, 5 and 50 mg/L arsenite via drinking water significantly reduced the number of neurons and caused the pathological changes in the mitochondria of hippocampus. Treatment of arsenite elevated the contents of lipid peroxidation products, disrupted the iron homeostasis, altered the expressions of ferroptosis-related proteins in the hippocampus and PC-12 cells. The results also showed that arsenite significantly decreased the expressions of ferritin and NCOA4, but sharply enhanced the level of autophagy marker LC3B, suggesting the activation of ferritinophagy by arsenite. Co-treatment of arsenite with ferroptosis inhibitor ferrostatin-1, or autophagy inhibitors 3-MA and BafA1, all remarkably attenuated the cytotoxic effects of arsenite. These findings not only present a novel mechanism that arsenite triggers ferroptosis in the neuronal cells via activation of ferritinophagy, but also indicate that regulating ferritinophagy to control iron level may provide a clue for prevention against arsenite neurotoxicity.

7.
Biomed Res Int ; 2021: 8830606, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33628818

RESUMO

There is a lack of data on drug-related problems (DRPs) among elderly patients from surgical departments. The current study is aimed at identifying and categorizing types of DRPs and assessing the severities of the DRPs. Medication orders for hospitalized patients aged ≥65 years from six surgery departments were reviewed to determine DRPs over 6 months in a tertiary teaching hospital of Chongqing, China. DRPs were classified based on the Pharmaceutical Care Network Europe classification V8.02. The severity ratings of the DRPs were assessed using the National Coordinating Council for Medication Error Reporting and Prevention classification. A total of 53,231 medication orders from 1,707 elderly patients were reviewed, and 1,061 DRPs were identified. Treatment safety (44.9%) was the most common DRP type. Drug selection (43.1%) and dose selection (43.1%) were the major causes of DRPs. A total of 75.1% of the DRPs were classified into severity categories B to D (causing no or potential harm), and 24.9% were classified as categories E to H (causing actual harm). DRPs are common in hospitalized elderly surgical patients. Pharmacists should provide medication order reviews in this vulnerable patient population.

8.
BMC Geriatr ; 21(1): 26, 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33413141

RESUMO

BACKGROUND: We aimed to examine the association between social capital and loneliness in Anhui Province, China. METHODS: Data were collected from a cross-sectional study using a multi-stage stratified cluster sampling strategy. Data on demographic characteristics, socioeconomic factors, social capital, and loneliness in 1810 older adults (aged 60 years and older) were used for analysis. Binary logistic regression models and a classification and regression tree model were performed to assess the association of social capital and loneliness. RESULTS: Our results indicated that social capital in terms of lower level of social participation (AOR = 1.38; 95% CI: 1.10-1.74), social connection (AOR = 1.51; 95% CI: 1.18-1.93), and reciprocity (AOR = 1.47; 95% CI: 1.13-1.90) were associated with higher odds of developing loneliness. We noted the interactive effect of different social capital dimensions on loneliness, suggesting that the risk for suffering loneliness was greatest in older people limited in functional ability, with less trust, less social connection, and less social participation. CONCLUSIONS: Our findings show that social capital is associated with loneliness in older adults. This implies that social capital, especially in terms of trust, social connection, and social participation may be significant for alleviating loneliness in later life.

9.
Pharmacol Res ; 164: 105391, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33352230

RESUMO

Baroreflex plays a crucial role in regulation of arterial blood pressure (BP). Recently, Piezo1 and Piezo2, the mechanically-activated (MA) ion channels, have been identified as baroreceptors. However, the underlying molecular mechanism for regulating these baroreceptors in hypertension remains unknown. In this study, we used spontaneously hypertensive rats (SHR) and NG-Nitro-l-Arginine (L-NNA)- and Angiotensin II (Ang II)-induced hypertensive model rats to determine the role and mechanism of Piezo1 and Piezo2 in hypertension. We found that Piezo2 was dominantly expressed in baroreceptor nodose ganglia (NG) neurons and aortic nerve endings in Wistar-Kyoto (WKY) rats. The expression of Piezo2 not Piezo1 was significantly downregulated in these regions in SHR and hypertensive model rats. Electrophysiological results showed that the rapidly adapting mechanically-activated (RA-MA) currents and the responsive neuron numbers were significantly reduced in baroreceptor NG neurons in SHR. In WKY rats, the arterial BP was elevated by knocking down the expression of Piezo2 or inhibiting MA channel activity by GsMTx4 in NG. Knockdown of Piezo2 in NG also attenuated the baroreflex and increased serum norepinephrine (NE) concentration in WKY rats. Co-immunoprecipitation experiment suggested that Piezo2 interacted with Neural precursor cell-expressed developmentally downregulated gene 4 type 2 (Nedd4-2, also known as Nedd4L); Electrophysiological results showed that Nedd4-2 inhibited Piezo2 MA currents in co-expressed HEK293T cells. Additionally, Nedd4-2 was upregulated in NG baroreceptor neurons in SHR. Collectively, our results demonstrate that Piezo2 not Piezo1 may act as baroreceptor to regulate arterial BP in rats. Nedd4-2 induced downregulation of Piezo2 in baroreceptor NG neurons leads to hypertension in rats. Our findings provide a novel insight into the molecular mechanism for the regulation of baroreceptor Piezo2 and its critical role in the pathogenesis of hypertension.

10.
Pediatr Transplant ; : e13825, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33131184

RESUMO

BACKGROUND: HSCT is the only proven curative therapy for JMML. Matching donor and recipient HLA alleles is considered optimal to reduce the risk of GVHD after HSCT but is not always possible. Only a limited number of studies have compared the influence of HLA disparities on HSCT outcomes for patients with JMML. METHODS: We conducted a retrospective study among 47 children with JMML who received related or unrelated unmanipulated HSCT (March 2010-October 2018). Among our participants, 27 (57.4%) donor-recipient pairs had 0-1 HLA disparities (Group 1: HLA-matched or ≤1 allele/antigen mismatch donor) and 20 (42.6%) had ≥2 HLA disparities (Group 2: 2-3 mismatched/haploidentical donors). RESULTS: The median follow-up period was 26.0 months (range: 1-105 months), and the 5-year probabilities of DFS and RI for the whole cohort were 54.6 ± 7.7% and 34.8 ± 15.0%, respectively. Compared to Group 1, Group 2 patients had a significantly lower RI (5.3 ± 10.5% vs 55.5 ± 20.9%, P Ë‚ .001), though similar rates of grade II-IV acute GVHD (60.0 ± 22.4% vs 33.3 ± 18.2%, P = .08), grade III-IV acute GVHD (25.0 ± 19.5% vs 7.4 ± 10.1%, P = .08), chronic GVHD (30.0 ± 20.9% vs 34.9 ± 18.8%, P = .85), NRM (20.0 ± 18.0% vs 3.9 ± 7.7%, P = .07), and DFS (74.4 ± 9.9% vs 41.3 ± 10.0%, P = .08). CONCLUSIONS: Disease relapse remains the major cause of treatment failure in JMML patients, especially in patients receiving HLA-matched and limited HLA-mismatched HSCT. Our findings suggest that donor-recipient HLA disparities may improve the outcome of HSCT in children with JMML.

11.
Int J Soc Psychiatry ; : 20764020968119, 2020 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-33100114

RESUMO

BACKGROUND: The pandemic of coronavirus disease (Covid-19) seriously impacts the health and well-being of all of us. AIMS: We aim to assess the psychological impact of Covid-19 on frontline health care workers (HCWs), including anxiety, depression and stress of threat of the disease. METHOD: The study was a cross-sectional survey among the frontline HCWs in a hospital at Jinan, China. Data were collected through an anonymous, self-rated questionnaire, including basic demographic data, a 10-item Covid-19 stress questionnaire, the Self-Rating Anxiety Scale (SAS) and the Self-Rating Depression Scale (SDS). The risk and rate of anxiety, depression and stress of Covid-19 were estimated. RESULTS: Among the 309 participants, there were 88 (28.5%) with anxiety and 172 (56.0%) with depression. Multivariate logistic regression analyses showed that age ⩽ 30 years, age > 30 to 45 years, working in confirmed case isolation wards, and worrying about disinfection measures being not sufficient were independently associated with anxiety with an odds ratio (95% confidence interval, CI) of 4.4 (1.6-12.2), 3.1 (1.1-8.8), 2.3 (1.4-4.0) and 2.5 (1.5-4.3), respectively; age ⩽ 30 years, age > 30 to 45 years, nurse and worrying about disinfection measure being not sufficient were independently associated with depression with an odds ratio (95% CI) of 3.8 (1.8-7.8), 2.7 (1.3-5.7), 2.5 (1.1-5.6) and 2.1 (1.3-3.5), respectively. CONCLUSIONS: A high prevalence of anxiety and depression was found among frontline HCWs during the COVID-19 outbreak. More psychological care should be given to young staffs and nurses. Measures to prevent professional exposure is important for HCWs' physical and mental health.

12.
PLoS One ; 15(10): e0240616, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33035272

RESUMO

Alisma orientale (Sam.) Juzep (A. orientale) is a traditional herb that is often used to treat disease including edema and hyperlipidemia. However, the molecular mechanism by which Alisma orientale (Sam.) Juzep exerts its hypolipidemic effects remains unclear. In this study, a diabetic rat model was established by feeding a high-fat and high-sugar diet combined with a low-dose streptozotocin injection (HFS). Then the rats were treated with an A. orientale water extract (AOW), an A. orientale ethanolic extract (AOE) or metform (MET). The gut microflora and liver transcriptome were analyzed by high-throughput next-generation sequencing. Ultra-performance liquid chromatography-triple quadrupole-mass spectrometry was employed to analyze the major compounds in the AOE. The results showed that the serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) levels in rats of the AOE group (2.10 g/kg/day, 14 days) were significantly lower than those in the HFS group (p<0.01). Moreover, AOE treatment altered the gut microecology, particularly modulating the relative abundance of gut microflora involved in lipid metabolism compared with the HFS group. Furthermore, compared with the HFS group, the mRNA expression levels of Fam13a, Mapk7, Mpp7, Chac1, Insig1, Mcpt10, Noct, Greb1l, Fabp12 and Hba-a3 were upregulated after the administration of AOE. In contrast, the mRNA expression levels of Lox, Mybl1, Arrdc3, Cyp4a2, Krt20, Vxn, Ggt1, Nr1d1 and S100a9 were downregulated. Moreover, AOE treatment for two weeks markedly promoted the relative abundance of Lachnospiraceae (p = 0.0013). The triterpenoids contents in AOE were alisol A, alisol A 24-acetate, alisol B, alisol B 23-acetate, alisol C 23-acetate, alisol F, alisol F 24-acetate, and alisol G. Our findings above illustrated that the hypolipidemic effect of the triterpenoids of A. orientale is mediated mainly through alteration of the gut microecology and the regulation of genes involved in cholesterol metabolism, especially Insig1.

13.
Rev Cardiovasc Med ; 21(3): 443-451, 2020 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-33070548

RESUMO

Atrial fibrillation (AF) is the most common arrhythmia among the elderly, and more frequently occur in those with chronic kidney disease (CKD). Left atrial appendage occlusion (LAAO) is used as a mechanical alternative approach for prevention of AF-related thromboembolisms. This meta-analysis was conducted to provide suggestions for the clinical application of LAAO in AF patients with CKD. The incidence of perioperative adverse events and other clinical effects after operation was by a single rate meta-analysis. Results showed that incidence of adverse events in the perioperative period after LAAO was generally low, with only pericardial effusion / tamponade (1.90%) and mortality rate (1.10%). During the follow-up period, the incidence of stroke/transient ischemic attack (TIA) and bleeding were 2.17% and 4.53%, respectively. A low incidence rate of adverse events was found in the perioperative period following LAAO. These results indicate that LAAO more effectively prevents the occurrence of stroke/TIA and minimizes bleeding events than oral anticoagulants.

14.
Nanoscale ; 12(41): 21429-21439, 2020 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-33079119

RESUMO

The gut microbiome can be readily influenced by external factors, such as nanomaterials. However, the role of the microbiota-gut-brain axis in nanomaterials-induced neurotoxicity remains largely unknown. In this study, young mice aged 4 weeks were treated with either a vehicle solution or 26 mg kg-1 zinc oxide nanoparticles (ZnONPs) by intragastric administration for 30 days. The neurobehavioral alterations were assessed by the Morris water maze and open field test. Gut microbiota and the metabolites in both blood and hippocampus were detected using 16S rRNA sequencing and liquid chromatography-mass spectrometry metabolomics, respectively. The results demonstrated that oral exposure to ZnONPs resulted in neurobehavioral impairments in young mice, mainly manifested by spatial learning and memory deficits, and the inhibition of locomotor activity. Intriguingly, ZnONPs caused a marked disturbance of the gut microbial composition, but did not alter the α-diversity of the microbiota. The correlation analysis further revealed that neurobehavioral impairments induced by ZnONPs were closely associated with a perturbation in the gut microbiota composition that were specific to changes of neurobehavior-related genes (such as Bdnf and Dlg4), and correlated with serum and hippocampal metabolites. We also identified a unique metabolite [DG(15:0/0:0/22:4n6)] that linked relationships among the gut microbiota, metabolites and neurobehavior-related genes. Taken together, our results illustrated that oral exposure to ZnONPs not only altered the gut microbiome community, but also substantially disturbed the metabolic profiles leading to neurobehavioral impairments via the microbiota-gut-brain axis. These findings will provide a novel view for understanding the neurotoxicity of ZnONPs, and are helpful for identifying potential prevention and treatment strategies.

15.
BMC Public Health ; 20(1): 1560, 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33066764

RESUMO

BACKGROUND: To examine the relationship between social capital and depression among community-dwelling older adults in Anhui Province, China. METHODS: A cross-sectional study was conducted among older people selected from three cities of Anhui Province, China using a multi-stage stratified cluster random sampling method. Data were collected through questionnaire interviews and information on demographic characteristics, social capital, and depression was collected. The generalized linear model and classification and regression tree model were employed to assess the association between social capital and depression. RESULTS: Totally, 1810 older people aged ≥60 years were included in the final analysis. Overall, all of the social capital dimensions were positively associated with depression: social participation (coefficient: 0.35, 95% CI: 0.22-0.48), social support (coefficient:0.18, 95% CI:0.07-0.28), social connection (coefficient: 0.76, 95% CI:0.53-1.00), trust (coefficient:0.62, 95% CI:0.33-0.92), cohesion (coefficient:0.31, 95% CI:0.17-0.44) and reciprocity (coefficient:0.30, 95% CI:0.11-0.48), which suggested that older people with higher social capital had a smaller chance to develop depression. A complex joint effect of certain social capital dimensions on depression was also observed. The association with depression and the combinative effect of social capital varied among older adults across the cities. CONCLUSIONS: Our study suggests that improving social capital could aid in the prevention of depression among older adults.


Assuntos
Depressão/epidemiologia , Capital Social , Idoso , China/epidemiologia , Estudos Transversais , Feminino , Humanos , Vida Independente , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários
16.
Int J Nanomedicine ; 15: 5299-5315, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32884256

RESUMO

Purpose: Zinc oxide nanoparticles (ZnONPs) are one of the most important nanomaterials that are widely used in the food, cosmetic and medical industries. Humans are often exposed to ZnONPs via inhalation, and they may reach the brain where neurotoxic effects could occur via systemic distribution. However, the mechanisms underlying how ZnONPs produce neurotoxic effects in the brain remain unclear. In this study, we aimed to investigate the novel mechanism involved in ZnONPs-induced neurotoxicity. Methods and Results: We demonstrated for the first time that pulmonary exposure to ZnONPs by intratracheal instillation could trigger ferroptosis, a new form of cell death, in the neuronal cells of mouse cerebral cortex. A similar phenomenon was also observed in cultured neuron-like PC-12 cell line. By using a specific inhibitor of ferroptosis ferrostatin-1 (Fer-1), our results showed that inhibition of ferroptosis by Fer-1 could significantly alleviate the ZnONPs-induced neuronal cell death both in vivo and in vitro. Mechanistic investigation revealed that ZnONPs selectively activated the JNK pathway and thus resulted in the ferroptotic phenotypes, JNK inhibitor SP600125 could reverse lipid peroxidation upregulation and ferroptotic cell death induced by ZnONPs in PC-12 cells. Conclusion: Taken together, this study not only demonstrates that pulmonary exposure of ZnONPs can induce JNK-involved ferroptotic cell death in mouse cortex and PC-12 cells, but also provides a clue that inhibition of ferroptosis by specific agents or drugs may serve as a feasible approach for reducing the untreatable neurotoxicity induced by ZnONPs.


Assuntos
Ferroptose/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Neurônios/efeitos dos fármacos , Síndromes Neurotóxicas/patologia , Óxido de Zinco/toxicidade , Administração por Inalação , Animais , Antracenos/farmacologia , Morte Celular/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Cicloexilaminas/farmacologia , Ferroptose/fisiologia , Peroxidação de Lipídeos/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Nanopartículas Metálicas/administração & dosagem , Camundongos Endogâmicos C57BL , Neurônios/patologia , Síndromes Neurotóxicas/etiologia , Células PC12 , Fenilenodiaminas/farmacologia , Ratos , Óxido de Zinco/administração & dosagem
17.
Neurotoxicology ; 81: 40-50, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32783905

RESUMO

Increasing occupational and accidental exposure to carbon black nanoparticles (CBNPs) raise concerns over their possible effects on the nervous system. However, the influences of CBNPs on the neurodevelopment remain unclear. Thus, in this study, pregnant mice were exposed to different doses of CBNPs by intranasal instillation on gestation days 9-18. Our results demonstrated that maternal exposure to CBNPs caused significant changes on maternal behaviors. Pregnancy exposure to CBNPs also delayed the onset of incisor eruption, testes descent and vaginal opening in offspring, and caused the reduced body weight until adulthood. In the neurobehavioral tests, CBNPs-exposed offspring exhibited the elevated latency of negative geotaxis and surface right reflex, reduced grasping time and increased cliff avoidance. Histopathological changes were present in F1 generation but not in F2 generation. Intriguingly, our data revealed that the levels of total m6A modification were significantly decreased by CBNPs. Similar trends were observed on the mRNA expressions of m6A methyltransferases and demethylases. In summary, these findings provide the novel evidence that pregnancy exposure to CBNPs affects the maternal behaviors and partially induces the neurobehavioral, muscular and histopathological changes in offspring. Of note, these adverse effects may be associated with reduced levels of total m6A modification in brain.

18.
Cancer Manag Res ; 12: 6563-6573, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801894

RESUMO

Background: Non-small cell lung carcinoma (NSCLC) is often fatal; advanced NSCLC has a 5-year survival rate less than 20%. Platinum-based chemotherapy, in particular, cis-diamminedichloroplatinum (II) (cisplatin or DDP), is employed for the treatment of NSCLC; however, the drug resistance occurs frequently. Autophagy is defined as the process of intracellular degradation of cytoplasmic materials in the lysosome; however, the correlation between autophagy and drug resistance remains controversial. Herein, we investigated the correlation between autophagy and cisplatin resistance and also explored the underlying mechanisms. Methods and Results: We demonstrated that DDP-resistant NSCLC A549 (A549/DDP) cells had higher autophagy activity in comparison with its parental A549 cells; DDP treatment induced a time- and dose-dependent decrease of autophagy. Intriguingly, inhibition of autophagy with pharmacological drugs or knockdown of ATG5 or Beclin-1 aggravated cell death induced by DDP treatment, indicating that autophagy played protective roles during DDP treatment. Further mechanistic investigation revealed that DDP treatment could decrease the mRNA expression level of key autophagy-related genes, such as ATG5, Beclin-1, and ATG7, suggesting DDP repressed autophagy at the transcriptional level. The MiTF/TFE family (including TFEB, TFE3, TFEC, and MiTF) were involved in nutrient sensing and organelle biogenesis, and specifically, the lysosomal biogenesis. We found that only MiTF was dramatically decreased upon DDP treatment, and also a profound decrease of lysosomal markers, LAMP-1 or LAMP-2, suggesting that MiTF was involved in the modulation of lysosomal biogenesis and, consequently, the autophagy. Moreover, the knockdown of MiTF resulted in more severe cell death in A549/DDP cells, indicting the substantial correlation between MiTF and cisplatin chemoresistance. Conclusion: Our study provides novel insights into the association between MiTF and DDP chemoresistance in NSCLC cells, and suggests targeting MiTF and/or autophagy might be a potential strategy for the reversal of DDP chemoresistance for NSCLC treatment.

19.
Pharmacol Res ; 161: 105128, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32805354

RESUMO

Cannabidiol (CBD) is a major phytocannabinoid in Cannabis sativa. CBD is being increasingly reported as a clinical treatment for neurological diseases. Febrile seizure is one of the most common diseases in children with limited therapeutic options. We investigated possible therapeutic effects of CBD on febrile seizures and the underlying mechanism. Use of a hyperthermia-induced seizures model revealed that CBD significantly prolonged seizure latency and reduced the severity of thermally-induced seizures. Hippocampal neuronal excitability was significantly decreased by CBD. Further, CBD significantly reduced the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) mediated evoked excitatory postsynaptic currents (eEPSCs) and the amplitude and frequency of miniature EPSCs (mEPSCs). Furthermore, CBD significantly accelerated deactivation in GluA1 and GluA2 subunits. Interestingly, CBD slowed receptor recovery from desensitization of GluA1, but not GluA2. These effects on kinetics were even more prominent when AMPAR was co-expressed with γ-8, the high expression isoform 8 of transmembrane AMPAR regulated protein (TARPγ8) in the hippocampus. The inhibitory effects of CBD on AMPAR depended on its interaction with the distal N-terminal domain of GluA1/GluA2. CBD inhibited AMPAR activity and reduced hippocampal neuronal excitability, thereby improving the symptoms of febrile seizure in mice. The putative binding site of CBD in the N-terminal domain of GluA1/GluA2 may be a drug target for allosteric gating modulation of AMPAR.

20.
J Hazard Mater ; 398: 122748, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-32768853

RESUMO

Gut microbiota is intimately involved in numerous aspects of human health. Arsenite expouse can perturb gut microbiota and is linked to increased susceptibility of individual to arsenite-related diseases. However, how microbiome factors influence arsenite-induced neurotoxicity remains largely unknown. In this study, after treating of healthy adult female mice with arsenite via drinking water for 6 months, our results clearly revealed that chronic arsenite exposure not only perturbed the composition of gut microbiota but also caused neurobehavioral dysfunctions, which manifested by learning and memory deficits and anxiety-like behavior. Given that the overactive autophagy directly leads to gut pathological changes, we further assessed whether inhibiton of autophagy by genetic mean could reverse arsenite-induced neurobehavioral dysfunctions. Our results illustrated for the first time that heterozygous disruption of beclin 1, which played a central role in autophagy, alleviated the perturbation of gut microbiome phenotypes induced by arsenite, and ultimately leading to the improvement of neurobehavioral deficits through gut-brain communication. These findings provide a new clue that regulation of autophagy is a potential approach for probing the functional impacts of arsenite on the gut microbiome, and it also may be severed as a way for protection strategies against arsenite neurotoxicity.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...