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1.
Ecotoxicol Environ Saf ; 280: 116569, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38878331

RESUMO

Manganese (Mn) exposure is a common environmental risk factor for Parkinson's disease (PD), with pathogenic mechanisms associated with dopaminergic neuron damage and neuroinflammation. Mesenchymal stem cells (MSCs)-derived small extracellular vesicles (sEVs) have emerged as a novel therapeutic approach for neural damage repair. The functional sEVs released from MSCs when they are induced into dopaminergic progenitors may have a better repair effect on neural injury. Therefore, we collected sEVs obtained from primary human nasal mucosal mesenchymal stem cells (hnmMSC-sEVs) or cells in the process of dopaminergic progenitor cell differentiation (da-hnmMSC-sEVs), which were cultured in a 3D dynamic system, and observed their repair effects and mechanisms of Mn-induced neural damage by intranasal administration of sEVs. In Mn-exposed mice, sEVs could reach the site of brain injury after intranasal administration, da-hnmMSC enhanced the repair effects of sEVs in neural damage and behavioral competence, as evidenced by restoration of motor dysfunction, enhanced neurogenesis, decreased microglia activation, up-regulation of anti-inflammatory factors, and down-regulation of pro-inflammatory factors. The transcriptomics of hnmMSC-sEVs and da-hnmMSC-sEVs revealed that miRNAs, especially miR-494-3p in sEVs were involved in neuroprotective and anti-inflammatory effects. Overexpression of miR-494-3p in sEVs inhibited Mn-induced inflammation and neural injury, and its repair mechanism might be related to the down-regulation of CMPK2 and NLRP3 in vitro experiments. Thus, intranasal delivery of da-hnmMSC-sEVs is an effective strategy for the treatment of neural injury repair.


Assuntos
Diferenciação Celular , Neurônios Dopaminérgicos , Vesículas Extracelulares , Células-Tronco Mesenquimais , MicroRNAs , Mucosa Nasal , Animais , MicroRNAs/genética , Camundongos , Humanos , Diferenciação Celular/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Manganês/toxicidade , Masculino , Administração Intranasal , Células Cultivadas , Camundongos Endogâmicos C57BL
2.
J Environ Sci (China) ; 141: 102-128, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38408813

RESUMO

Electrochemical filtration can not only enrich low concentrations of pollutants but also produce reactive oxygen species to interact with toxic pollutants with the assistance of a power supply, making it an effective strategy for drinking water purification. In addition, the application of electrochemical filtration facilitates the reduction of pretreatment procedures and the use of chemicals, which has outstanding potential for maximizing process simplicity and reducing operating costs, enabling the production of safe drinking water in smaller installations. In recent years, the research on electrochemical filtration has gradually increased, but there has been a lack of attention on its application in the removal of low concentrations of pollutants from low conductivity water. In this review, membrane substrates and electrocatalysts used to improve the performance of electrochemical membranes are briefly summarized. Meanwhile, the application prospects of emerging single-atom catalysts in electrochemical filtration are also presented. Thereafter, several electrochemical advanced oxidation processes coupled with membrane filtration are described, and the related working mechanisms and their advantages and shortcomings used in drinking water purification are illustrated. Finally, the roles of electrochemical filtration in drinking water purification are presented, and the main problems and future perspectives of electrochemical filtration in the removal of low concentration pollutants are discussed.


Assuntos
Água Potável , Poluentes Químicos da Água , Purificação da Água , Membranas Artificiais , Poluentes Químicos da Água/análise , Purificação da Água/métodos , Filtração/métodos
3.
Small ; 19(42): e2301638, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37345962

RESUMO

Developing composite materials with optimized mechanics, degradation, and bioactivity for bone regeneration has long been a crucial mission. Herein, a multifunctional Mg/Poly-l-lactic acid (Mg/PLLA) composite membrane based on the "materials plain" concept through the accumulative rolling (AR) method is proposed. Results show that at a rolling ratio of 75%, the comprehensive mechanical properties of the membrane in the rolling direction are self-reinforced significantly (elongation at break ≈53.2%, tensile strength ≈104.0 MPa, Young's modulus ≈2.13 GPa). This enhancement is attributed to the directional arrangement and increased crystallization of PLLA molecular chains, as demonstrated by SAXS and DSC results. Furthermore, the AR composite membrane presents a lamellar heterostructure, which not only avoids the accumulation of Mg microparticles (MgMPs) but also regulates the degradation rate. Through the contribution of bioactive MgMPs and their photothermal effect synergistically, the membrane effectively eliminates bacterial infection and accelerates vascularized bone regeneration both in vitro and in vivo. Notably, the membrane exhibits outstanding rat skull bone regeneration performance in only 4 weeks, surpassing most literature reports. In short, this work develops a composite membrane with a "one stone, four birds" effect, opening an efficient avenue toward high-performance orthopedic materials.


Assuntos
Regeneração Óssea , Poliésteres , Ratos , Animais , Espalhamento a Baixo Ângulo , Difração de Raios X , Poliésteres/química , Bactérias
4.
Soft Matter ; 19(18): 3325-3336, 2023 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-37096323

RESUMO

Particle morphology is one of the most significant factors influencing the packing structures of granular materials. With certain targeted properties or optimization criteria, inverse packing problems have drawn extensive attention in terms of their adaptability to many material design tasks. An important question hard to answer is which particle shape, especially within given shape families, forms the densest (loosest) random packing? In this paper, we address this issue for the disk assembly model in two dimensions with an infinite variety of shapes, which are simulated in the random sequential adsorption process to suppress crystallization. Via a unique shape representation method, particle shapes are transformed into genotype sequences in the continuous shape space where we utilize the genetic algorithm as an efficient shape optimizer. Specifically, we consider three representative species of disk assembly, i.e., congruent tangent disks, incongruent tangent disks, and congruent overlapping disks, and carry out shape optimization on their packing densities in the saturated random state. We numerically search optimal shapes in the three species with a variable number of constituent disks which yield the maximal and minimal packing densities. We obtain an isosceles circulo-triangle and an unclosed ring for the maximal and minimal packing density in saturated random packings, respectively. The perfect sno-cone and isosceles circulo-triangle are also specifically investigated which give remarkably high packing densities of around 0.6, much denser than those of ellipses. This study is beneficial for guiding the design of particle shapes as well as the inverse design of granular materials.

5.
Ecotoxicol Environ Saf ; 253: 114616, 2023 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-36796209

RESUMO

Manganese (Mn) accumulates in the central nervous system and can cause neurotoxicity, but the mechanisms of Mn-induced neurotoxicity remain unclear. We performed single-cell RNA sequencing (scRNA-seq) of zebrafish brain after Mn exposure and identified 10 cell types by marker genes: cholinergic neurons, dopaminergic (DA) neurons, glutaminergic neurons, GABAergic neurons, neuronal precursors, other neurons, microglia, oligodendrocyte, radial glia, and undefined cells. Each cell type has its distinct transcriptome profile. Pseudotime analysis revealed that DA neurons had a critical role in Mn-induced neurological damage. Combined with metabolomic data, chronic Mn exposure significantly impaired amino acid and lipid metabolic processes in the brain. Furthermore, we found that Mn exposure disrupted the ferroptosis signaling pathway in the DA neurons in zebrafish. Overall, our study employed joint analysis of multi-omics and revealed ferroptosis signaling pathway is a novel potential mechanism of Mn neurotoxicity.


Assuntos
Ferroptose , Manganês , Animais , Manganês/toxicidade , Peixe-Zebra/genética , Ferroptose/genética , Multiômica , Encéfalo , Neurônios Dopaminérgicos
6.
Sensors (Basel) ; 23(3)2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36772221

RESUMO

In this paper, we propose a new method to quantitatively evaluate the quality of the carrier phase observation signals of the BeiDou Navigation Satellite System (BDS) during weak and moderate geomagnetic storms. We take a moderate geomagnetic storm that occurred on 12 May 2021 during the 25th solar cycle as an example. The results show that the newly defined PAS (Percentage of Affected Satellites) index shows significant anomaly changes during the moderate geomagnetic storm. Its variation trend has good correlations with the geomagnetic storm Kp index and Dst index. The anomaly stations are mainly distributed in the equatorial region and auroral region in the northern and southern hemispheres. The proposed PAS index has a good indication for both BDS2 and BDS3 satellites. We further validated this index by calculating the Precise Point Position (PPP) positioning error. We found that the anomaly period of PAS has strong consistency with the abnormal period of PPP positioning accuracy. This study could provide methodological support for the evaluation of the signal quality and analysis of positioning accuracy for the BeiDou satellite navigation system under different space weather conditions.

7.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 54(6): 1184-1190, 2023 Nov 20.
Artigo em Zh | MEDLINE | ID: mdl-38162074

RESUMO

Objective: To comprehensively investigate and analyze the distribution characteristics of high altitude deterioration (HADT) among people working in 7 cities of Tibet Autonomous Region, to examine the relevant influencing factors, and to provide baseline survey data for further research on HADT. Methods: A self-designed questionnaire was used to conduct a self-administered survey among employees in seven prefectures or cities (Lhasa City, Qamdo City, Shigatse City, Nyingchi City, Shannan City, Naqu City, and Ngari Prefecture) in Tibet. The respondents were selected through random cluster sampling. The survey covered 21 symptoms involving 4 systems of the human body, including the respiratory, nervous, circulatory, and digestive systems. The distributive characteristics of HADT (as manifested by maladaptation to high altitude) were described and Spearman's correlation was used to examine the influencing factors of maladaptation to high altitude. Results: A total of 3 901 respondents were included in the sample analyzed in the study, including 2 107 (54%) native Tibetans and 1 794 (46%) immigrant Han people. There were 1 994 males (51%) and 1 907 females (49%). Their age ranged from 20 to 57 years, averaging (34.45±8.11) years. The subjects lived at a high altitude for a duration of 0.5 to 54 years, averaging (19.51±13.84) years. The overall rates of maladaptation for the 21 symptoms among native Tibetans and immigrant Han people were 60.10% (26 578/44 247) and 73.20% (27 565/37 674), respectively. The maladaptation rates of the native Tibetan population for the respiratory, nervous, circulatory, and digestive systems of the human body were all lower than those of the immigrant Han population (P<0.001). There were no significant differences in the maladaptation rates of employees from different regions of Tibet (66.21% for Ngari Prefecture, 65.02% for Qamdo City, 66.67% for Lhasa City, 62.29% for Shigatse City, 65.03% for Shannan City, 64.42% for Nyingchi City, and 61.65% for Naqu City). The type of high-altitude residents (i.e., being native Tibetan or immigrant Han) was the main influencing factor for high-altitude maladaptation of the respiratory, nervous, circulatory, and digestive systems (P<0.001). According to the findings of the correlation analysis, age, type of high-altitude residents, and the duration of residence at a high altitude were associated with high-altitude maladaptation of the respiratory system, while type of high-altitude residents was the only factor associated with maladaptation of the nervous system, circulatory system, and digestive systems. Age and duration of living at at high altitude had significant effect on self-perceived dyspnea, a type of maladaptation of the respiratory system (P<0.001). Duration of high-altitude residence had significant effect on cyanotic lips or redness in the cheeks, a type of maladaptation of the circulatory system, and self-perceived loss of appetite, a type of maladaptation of the digestive system (P<0.05). Conclusion: More attention should be given to the HADT among employees of public institutions and enterprises who are living in Tibet Autonomous Region and immigrant Han people, in particular, should pay special attention to the protection of their respiratory, nervous, circulatory, and digestive systems.


Assuntos
Altitude , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Tibet/epidemiologia
8.
J Integr Neurosci ; 21(5): 127, 2022 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-36137967

RESUMO

BACKGROUND: Overexposure to manganese (Mn) can lead to neurodegenerative damage, resulting in manganism with similar syndromes to Parkinson's disease (PD). However, little is known about changes in transcriptomics induced by the toxicological level of Mn. In this study, we conducted RNA-seq to explore the candidate genes and signaling pathways included by Mn in human SH-SY5Y neuroblastoma cells. METHODS: The differentially expressed genes (DEGs) between the Mn-treated group and the control group were screened, and weighted gene co-expression network analysis (WGCNA) was employed to identify hub genes. Then, pathway enrichment analyses for those candidate genes were performed in Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). We further validated the concentration- and time-response effects of Mn exposure (0-500 µM, 3-12 h) on mitochondrial unfolded protein response (UPRMT) by real-time quantitative reverse transcription PCR (qRT-PCR). RESULTS: The results showed 179 up-regulated differentially expressed genes (DEGs) and 681 down-regulated DEGs after Mn exposure. Based on the intersection of DEGs genes and hub genes, 73 DEGs were related to neurotoxicity. The comprehensive pathway analysis showed Mn had widespread effects on the mitogen-activated protein kinase (MAPK) signaling pathway, unfolded protein response, longevity regulating pathway, inflammatory bowel disease, and mitophagy signaling pathway. After Mn exposure, the expressions of activating transcription factor 3 (ATF3) and C-C motif chemokine ligand 2 (CCL2) increased, while the expressions of C/EBP homologous protein (CHOP), caseinolytic protease P (CLPP), and Lon protease 1 (LONP1) decreased in a concentration- and time-dependent manner. CONCLUSIONS: Overall, our study suggests that UPRMT is a new sight in understanding the mechanism of Mn-induced neurotoxicity.


Assuntos
Neuroblastoma , Protease La , Proteases Dependentes de ATP , Fator 3 Ativador da Transcrição , Quimiocinas , Humanos , Ligantes , Manganês/toxicidade , Proteínas Mitocondriais , Proteínas Quinases Ativadas por Mitógeno , Transcriptoma , Resposta a Proteínas não Dobradas
9.
Cost Eff Resour Alloc ; 19(1): 26, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33933057

RESUMO

BACKGROUND: The detection of thyroid cancer has rapidly increased over last few decades without an increase in disease specific mortality. Several studies claim that the diagnose of thyroid nodules through routine ultrasound imaging is often the trigger for cascade effects leading to unnecessary follow-up over many years or to invasive treatment. The objective of this study was to explore physicians' and patients' insights and preferences regarding the current interventions on thyroid nodules. METHODS: An online survey was developed using a comprehensive multi-criteria decision analysis (MCDA) framework, the EVIdence based Decision-Making (EVIDEM). The EVIDEM core model used in this study encompassed 13 quantitative criteria and four qualitative criteria. Participants were asked to provide weights referring to what matters most important in general for each criterion, performance scores for appraising the interventions on thyroid nodules and their consideration of impact of contextual criteria. Normalized weights and standardized scores were combined to calculate a value contribution across all participants, additionally differences across physicians and patients' group were explored. RESULTS: 48 patients and 31 physicians were included in the analysis. The value estimate of the interventions on thyroid nodules reached 0.549 for patients' group and 0.5 was reported by the physicians' group, compared to 0.543 for all participants. The highest value contributor was 'Comparative effectiveness' (0.073 ± 0.020). For the physicians' group, 'Comparative safety' (0.050 ± 0.023) was given with higher value. And for the patients' group, 'Type of preventive benefits' (0.059 ± 0.022) contributed more positively to the value estimation. 51% participants considered 'Population priorities and access' having a negative impact on the interventions of nodules.66% participants thought that the 'system capacity' had a negative impact. CONCLUSION: Our study shows participants' preferences on each criterion, i.e., physician indicated keeping the interventions safe and effective more important, patients indicated quality of life after receiving interventions more important. Through comparison among participants, differences have been highlighted, which can make better communication between physicians and patients. This study provides a supportive decision-making for healthcare providers when they explored the interventions on thyroid nodules.

10.
Ecotoxicol Environ Saf ; 221: 112439, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34166938

RESUMO

Drinking water fluoridation was a mid-twentieth century innovation based on the medical hypothesis that consuming low doses of fluoride at the teeth forming years provided protection against dental decays. Numerous studies showed that high level exposure to fluoride could cause dental and skeleton fluorosis. However, there was limited study focusing on the fluorosis effect of low levels of exposure to fluoride. Therefore, our study aimed to examine whether the low level of fluoride exposure (measured in blood plasma and household tap water) was associated with the risk of dental fluorosis based on data of the National Health and Nutrition Examination Survey (NHANES) 2015-2016. We analyzed data in 2098 children and adolescents who had Dean's Index scores, and water and plasma fluoride measures. The Dean's Index score was measured by calibrated dental examiners using the modified Dean's fluorosis classification system. Fluoride was measured in plasma and household tap water. In this study, we found that the rate of fluoride concentration in water above the recommended level of 0.7 mg/L was 25%, but the prevalence of dental fluorosis was 70%. Binary logistic regression adjusted for covariates showed that higher water fluoride concentrations (0.31-0.50, 0.51-0.70, > 0.70 compared 0.00-0.30) were associated with higher odds of dental fluorosis (OR = 1.48, 95% CI: 1.13-1.96, p = 0.005; OR = 1.92, 95% CI: 1.44-2.58, p < 0.001, and OR = 2.30, 95% CI: 1.75-3.07, p < 0.001, respectively). The pattern of regression between plasma fluoride and dental fluorosis was similar. Inclusion, our study showed that even low level of water or plasma fluoride exposure was associated with increased the risk of dental fluorosis. The safety of public health approach of drinking water fluoridation for global dental caries reduction are urgently needed further research.


Assuntos
Fluoretos/toxicidade , Fluorose Dentária/etiologia , Adolescente , Criança , Pré-Escolar , Exposição Ambiental/efeitos adversos , Fluoretação/efeitos adversos , Humanos , Inquéritos Nutricionais , Prevalência , Dente/efeitos dos fármacos , Água/química
11.
Environ Toxicol ; 34(4): 539-547, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30672645

RESUMO

The mechanism of manganism caused by manganese (Mn), an important environmental risk factor for Parkinson's disease, is still unclear. Recent evidence suggested that autophagy participated in neurodegenerative diseases, in which microRNA played a crucial role. However, roles of microRNA in the aberrant autophagy that occurs in neurodegenerative diseases remains controversial. In nervous system, miRNA-138-5p is highly expressed and plays a key role in regulating memory and axon regeneration. Importantly, we also found that miR-138-5p expression decreased significantly after SH-SY5Y cells exposed to manganese chloride (MnCl2 ) in previous study. To explore the role of miR-138-5p in Mn-induced autophagy, autophagy associated indicators were detected. And we found that MnCl2 could induce autophagic dysregulation and inhibit expression of miR-138-5p. While the levels of LC3-II/LC3-I, Beclin1, and p62, the number of autophagosome formation significantly decreased after miR-138-5p over-expression, which demonstrated that miR-138-5p could clearly retard Mn-induced autophagy. In additional, we found there were classical and evolutionarily conserved miR-138-5p binding sites in 3'-UTR region of SIRT1, which was inhibited when overexpression of miR-138-5p. Therefore, it was speculated that elevated expression of SIRT1 may be resulted from inhibition of miR-138-5p after cells exposed to MnCl2 . Finally, we found that SIRT1 inhibitor EX-527 suppressed Mn-induced autophagy as well as miR-138-5p, while the suppression was reversed by SIRT1-specific activator SRT1720. These results indicated that overexpression of miR-138-5p suppressed Mn-induced autophagy by targeting SIRT1.


Assuntos
Autofagia/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Manganês/toxicidade , MicroRNAs/genética , Sirtuína 1/metabolismo , Regiões 3' não Traduzidas/genética , Autofagia/genética , Carbazóis/farmacologia , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Humanos , Sirtuína 1/antagonistas & inibidores
12.
Environ Toxicol ; 33(2): 142-148, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29134718

RESUMO

Tertiary butyl alcohol (TBA) is a principal metabolite of methyl tertiary-butyl ether (MTBE), a common pollutant worldwide in the ground or underground water, which is found to produce nervous system damage. Nevertheless, few data regarding the effects of TBA has been reported. Studies indicated that oxidative stress plays a pivotal role in MTBE neurotoxic mechanism. Sirtuin 1 (SIRT1) has been reported to exert a neuroprotective effect on various neurologic diseases via resistance to oxidative stress by deacetylating its substrates. In this study, we examined levels of oxidative stress after exposure to TBA for 6 h in HT22 cells and HT22 cells with SIRT1 silencing (transfected with SIRT1 siRNA) or high expression (preconditioned with agonists SRT1720). We found that TBA activated oxidative stress by increasing generation of intracellular reactive oxygen species (ROS), malondialdehyde (MDA) and Oxidized glutathione (GSSG), and decreasing contents of superoxide dismutase (SOD) and glutathione reductase (GSH). In additional, levels of TBA-induced oxidative stress were aggravated when SIRT1 silenced but alleviated when SIRT1 enhanced. Our study indicated that SIRT1 mitigated oxidative stress induced by TBA.


Assuntos
Antioxidantes/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Sirtuína 1/metabolismo , terc-Butil Álcool/farmacologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Glutationa/metabolismo , Glutationa Redutase/metabolismo , Malondialdeído/metabolismo , Camundongos , Microscopia de Fluorescência , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/genética , Superóxido Dismutase/metabolismo
13.
J Interv Cardiol ; 28(3): 257-63, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25989965

RESUMO

OBJECTIVES: We investigated whether the combination coating of a novel "prohealing coating" hyaluronan-chitosan (HC) and anti-CD34 antibody applied on an SES (HCASES) can reduce neointimal formation while promoting endothelialization compared to either agent alone. BACKGROUND: Drug-eluting stents have considerably reduced the incidence of in-stent restenosis compared with bare metal stents. However, the beneficial effect of drug elution is overshadowed by delayed re-endothelialization as well as later "catch-up" proliferation related to the drug. METHODS: Three different stents: Sirolimus-eluting stents (SES), Genous anti-CD34 antibody stents (GS), and the combination of HC-anti-CD34 antibody with sirolimus-eluting stents (HCASES) were deployed in 54 normal porcine coronary arteries and harvested for scanning electron microscopy (SEM) and histological analysis at 60, 90, and 120 days. RESULTS: At 60 and 90 days, SEM analysis showed stent surface endothelial coverage was nearly completed in the HCASES (87 ± 3%, 95 ± 3%) compared with that in the SES (68 ± 6%, 77 ± 8%, P = 0.03). Histological examination at 90 days showed that the HCASES group had less percentage of stenosis than the GS group (P < 0.05). At 120 days, SEM showed a significantly higher extent of endothelial coverage above struts in the HCASES (96 ± 2%) and the GS (95 ± 3%) as compared with the SES group (66 ± 3%; P = 0.02). The HCASES group showed less stenosis than that in the GS group (P < 0.05), but it was not significantly different from the SES group (P = 0.063). CONCLUSIONS: Histological and SEM analyses demonstrate that the HCASES can reduce neointimal formation and inflammation while promoting endothelialization in the long term.


Assuntos
Anticorpos/administração & dosagem , Antígenos CD34/imunologia , Stents Farmacológicos , Células Endoteliais/citologia , Sirolimo/administração & dosagem , Animais , Microscopia Eletrônica de Varredura , Neointima/prevenção & controle , Suínos
14.
Anticancer Drugs ; 25(6): 614-23, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24525588

RESUMO

A novel series of cyclane-aminol 10-hydroxycamptothecin (HCPT) analogs was designed and synthesized through the Mannich reaction using HCPT as the lead compound, such as 10-hydroxyl-9-L-prolinol (+) methylcamptothecin (PRPT), 10-hydroxyl-9-(4'-hydroxy) piperidinylmethylcamptothecin (PPPT), and 10-hydroxy-9-(4'-hydroxyethyl)-piperazinylmethycamptothecin (QPPT). Three kinds of new cyclane-aminols were introduced into the structure of HCPT, which modified strong cytotoxic HCPT into cyclane-aminol HCPT analogs with moderate cytotoxicity and improved selectivity toward DNA topoisomerase I inhibition in tumor cells. Special metabolic pathways for cyclane-aminol HCPT analogs in rats were discovered, which differed from other HCPT analogs. Cyclane-aminol HCPT analogs can capture O2 and cause an increase in intracellular hydrogen peroxide levels with selective induction of apoptosis in tumor cells rather than in normal peripheral blood mononuclear cells. Among them, PPPT has a much better druggability than topotecan (TPT) and has the potential to be developed into an antitumor agent.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Inibidores da Topoisomerase I/farmacologia , Animais , Antineoplásicos/síntese química , Camptotecina/síntese química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ratos , Espécies Reativas de Oxigênio/metabolismo , Inibidores da Topoisomerase I/síntese química
15.
Environ Pollut ; 341: 122908, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-37952916

RESUMO

Manganese (Mn) is considered as an important environmental risk factor for Parkinson's disease. Excessive exposure to Mn can damage various neural cells and affect the neurogenesis, resulting in neurological dysfunction. However, the specific mechanisms of Mn exposure affecting neurogenesis have not been well understood, including compositional changes and heterogeneity of various neural cells. Zebrafish have been successfully used as a neurotoxicity model due to its homology with mammals in several key regions of the brain, as well as its advantages such as small size. We performed single-cell RNA sequencing of zebrafish brains from normal and Mn-exposed groups. Our results suggested that low levels of Mn exposure activated neurogenesis in the zebrafish brain, including promoting the proliferation of neural progenitor cells and differentiation to newborn neurons and oligodendrocytes, while high levels of Mn exposure inhibited neurogenesis and neural function. Mn could affect neurogenesis through specific molecular pathways. In addition, Mn regulated intercellular communication and affected cellular communication in neural cells through specific signaling pathways. Taken together, our study elucidates the cellular composition of the zebrafish brain and adds to the understanding of the mechanisms involved in Mn-induced neurogenesis damage.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Manganês , Animais , Manganês/toxicidade , Manganês/metabolismo , Peixe-Zebra , Neurogênese , Encéfalo/metabolismo , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/metabolismo , Perfilação da Expressão Gênica , Mamíferos
16.
Adv Mater ; 36(15): e2310982, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38216153

RESUMO

The immunomodulatory effects of many therapeutic agents are significantly challenged by their insufficient delivery efficiency and short retention time in tumors. Regarding the distinctively upregulated fibronectin (FN1) and tenascin C (TNC) in tumor stroma, herein a protease-activated FN1 and/or TNC binding peptide (FTF) is designed and an extracellular matrix (ECM)-trapped bioinspired lipoprotein (BL) (FTF-BL-CP) is proposed that can be preferentially captured by the TNC and/or FN1 for tumor retention, and then be responsively dissociated from the matrix to potentiate the antitumor immunity. The FTF-BL-CP treatment produces a 6.96-, 9.24-, 6.72-, 7.32-, and 6.73-fold increase of CD3+CD8+ T cells and their interferon-γ-, granzyme B-, perforin-, and Ki67-expressing subtypes versus the negative control, thereby profoundly eliciting the antitumor immunity. In orthotopic and lung metastatic breast cancer models, FTF-BL-CP produces notable therapeutic benefits of retarding tumor growth, extending survivals, and inhibiting lung metastasis. Therefore, this ECM-trapping strategy provides an encouraging possibility of prolonging tumor retention to potentiate the antitumor immunity for anticancer immunotherapy.


Assuntos
Linfócitos T CD8-Positivos , Neoplasias Pulmonares , Humanos , Matriz Extracelular/metabolismo , Tenascina/metabolismo , Neoplasias Pulmonares/terapia , Lipoproteínas/metabolismo
17.
Free Radic Biol Med ; 221: 155-168, 2024 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-38777204

RESUMO

Transient receptor potential vanilloid (TRPV) ion channels play a crucial role in various cellular functions by regulating intracellular Ca2+ levels and have been extensively studied in the context of several metabolic diseases. However, the regulatory effects of TRPV3 in obesity and lipolysis are not well understood. In this study, utilizing a TRPV3 gain-of-function mouse model (TRPV3G568V/G568V), we assessed the metabolic phenotype of both TRPV3G568V/G568V mice and their control littermates, which were randomly assigned to either a 12-week high-fat diet or a control diet. We investigated the potential mechanisms underlying the role of TRPV3 in restraining obesity and promoting lipolysis both in vivo and in vitro. Our findings indicate that a high-fat diet led to significant obesity, characterized by increased epididymal and inguinal white adipose tissue weight and higher fat mass. However, the gain-of-function mutation in TRPV3 appeared to counteract these adverse effects by enhancing lipolysis in visceral fat through the upregulation of the major lipolytic enzyme, adipocyte triglyceride lipase (ATGL). In vitro experiments using carvacrol, a TRPV3 agonist, demonstrated the promotion of lipolysis and antioxidation in 3T3-L1 adipocytes after TRPV3 activation. Notably, carvacrol failed to stimulate Ca2+ influx, lipolysis, and antioxidation in 3T3-L1 adipocytes treated with BAPTA-AM, a cell-permeable calcium chelator. Our results revealed that TRPV3 activation induced the action of transcriptional factor nuclear factor erythroid 2-related factor 2 (NRF2), resulting in increased expression of ferroptosis suppressor protein 1 (FSP1) and superoxide dismutase2 (SOD2). Moreover, the inhibition of NRF2 impeded carvacrol-induced lipolysis and antioxidation in 3T3-L1 adipocytes, with downregulation of ATGL, FSP1, and SOD2. In summary, our study suggests that TRPV3 promotes visceral fat lipolysis and inhibits diet-induced obesity through the activation of the NRF2/FSP1 signaling axis. We propose that TRPV3 may be a potential therapeutic target in the treatment of obesity.


Assuntos
Dieta Hiperlipídica , Lipólise , Fator 2 Relacionado a NF-E2 , Obesidade , Transdução de Sinais , Canais de Cátion TRPV , Animais , Masculino , Camundongos , Células 3T3-L1 , Aciltransferases , Adipócitos/metabolismo , Adipócitos/patologia , Dieta Hiperlipídica/efeitos adversos , Mutação com Ganho de Função , Lipase/metabolismo , Lipase/genética , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Obesidade/metabolismo , Obesidade/genética , Obesidade/patologia , Obesidade/etiologia , Canais de Cátion TRPV/metabolismo , Canais de Cátion TRPV/genética
18.
China CDC Wkly ; 6(19): 424-430, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38854751

RESUMO

What is already known about this topic?: The quadrivalent influenza vaccine (QIV) provides protection against a broader range of influenza strains by including strains of influenza A/H1N1, A/H3N2, B/Yamagata, and B/Victoria. What is added by this report?: This study aimed to assess the immunogenicity and safety of administering a single dose compared to two doses of QIV in children, taking into consideration their previous influenza vaccination history. What are the implications for public health practice?: This study provides evidence supporting the use of a single dose of the QIV in children aged 3-8 years who have previously received two or more doses of influenza vaccine. However, children who have not been previously vaccinated with influenza vaccine should still adhere to the recommended schedule of receiving two doses.

19.
Chemosphere ; 325: 138410, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36925019

RESUMO

Microbial fuel cells (MFCs) are a promising and sustainable technology which can generate electricity and treat antibiotic wastewater simultaneously. However, the antibiotic resistance genes (ARGs) induced by antibiotics in MFCs increase risks to ecosystems and human health. In this study, the activities of enzymes and regulation genes related to ARGs in MFCs spiked with sulfamethoxazole (SMX) were evaluated to explore the induction mechanism of ARGs. Under lower doses of SMX (10 mg/L and 20 mg/L SMX in this study), microorganisms tend to up regulate catalase and RpoS regulon to induce sul1, sul3 and intI1. The microorganisms exposed to higher doses of SMX (30 mg/L and 40 mg/L SMX in this study) tend to up regulate superoxide dismutase and SOS response to generate sul2 and sulA. Moreover, the exposure concentrations of SMX had no significant effect on the electricity production of MFCs. This work suggested that the ARGs in MFCs might be inhibited by affecting enzymatic activities and regulatory genes according to the antibiotic concentration without affecting the electricity production.


Assuntos
Fontes de Energia Bioelétrica , Sulfametoxazol , Humanos , Sulfametoxazol/toxicidade , Ecossistema , Antibacterianos/toxicidade , Genes Bacterianos , Resistência Microbiana a Medicamentos/genética
20.
iScience ; 26(7): 107136, 2023 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-37408687

RESUMO

Excessive exposure to manganese (Mn) can cause neurological abnormalities, but the mechanism of Mn neurotoxicity remains unclear. Previous studies have shown that abnormal mitochondrial metabolism is a crucial mechanism underlying Mn neurotoxicity. Therefore, improving neurometabolic in neuronal mitochondria may be a potential therapy for Mn neurotoxicity. Here, single-cell sequencing revealed that Mn affected mitochondrial neurometabolic pathways and unfolded protein response in zebrafish dopaminergic neurons. Metabolomic analysis indicated that Mn inhibited the glutathione metabolic pathway in human neuroblastoma (SH-SY5Y) cells. Mechanistically, Mn exposure inhibited glutathione (GSH) and mitochondrial unfolded protein response (UPRmt). Furthermore, supplementation with glutamine (Gln) can effectively increase the concentration of GSH and triggered UPRmt which can alleviate mitochondrial dysfunction and counteract the neurotoxicity of Mn. Our findings highlight that UPRmt is involved in Mn-induced neurotoxicity and glutathione metabolic pathway affects UPRmt to reverse Mn neurotoxicity. In addition, Gln supplementation may have potential therapeutic benefits for Mn-related neurological disorders.

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