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1.
Am J Hum Genet ; 110(10): 1661-1672, 2023 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-37741276

RESUMO

In the effort to treat Mendelian disorders, correcting the underlying molecular imbalance may be more effective than symptomatic treatment. Identifying treatments that might accomplish this goal requires extensive and up-to-date knowledge of molecular pathways-including drug-gene and gene-gene relationships. To address this challenge, we present "parsing modifiers via article annotations" (PARMESAN), a computational tool that searches PubMed and PubMed Central for information to assemble these relationships into a central knowledge base. PARMESAN then predicts putatively novel drug-gene relationships, assigning an evidence-based score to each prediction. We compare PARMESAN's drug-gene predictions to all of the drug-gene relationships displayed by the Drug-Gene Interaction Database (DGIdb) and show that higher-scoring relationship predictions are more likely to match the directionality (up- versus down-regulation) indicated by this database. PARMESAN had more than 200,000 drug predictions scoring above 8 (as one example cutoff), for more than 3,700 genes. Among these predicted relationships, 210 were registered in DGIdb and 201 (96%) had matching directionality. This publicly available tool provides an automated way to prioritize drug screens to target the most-promising drugs to test, thereby saving time and resources in the development of therapeutics for genetic disorders.


Assuntos
PubMed , Humanos , Bases de Dados Factuais
2.
EMBO J ; 40(7): e106106, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33709453

RESUMO

A critical question in neurodegeneration is why the accumulation of disease-driving proteins causes selective neuronal loss despite their brain-wide expression. In Spinocerebellar ataxia type 1 (SCA1), accumulation of polyglutamine-expanded Ataxin-1 (ATXN1) causes selective degeneration of cerebellar and brainstem neurons. Previous studies revealed that inhibiting Msk1 reduces phosphorylation of ATXN1 at S776 as well as its levels leading to improved cerebellar function. However, there are no regulators that modulate ATXN1 in the brainstem-the brain region whose pathology is most closely linked to premature death. To identify new regulators of ATXN1, we performed genetic screens and identified a transcription factor-kinase axis (ZBTB7B-RSK3) that regulates ATXN1 levels. Unlike MSK1, RSK3 is highly expressed in the human and mouse brainstems where it regulates Atxn1 by phosphorylating S776. Reducing Rsk3 rescues brainstem-associated pathologies and deficits, and lowering Rsk3 and Msk1 together improves cerebellar and brainstem function in an SCA1 mouse model. Our results demonstrate that selective vulnerability of brain regions in SCA1 is governed by region-specific regulators of ATXN1, and targeting multiple regulators could rescue multiple degenerating brain areas.


Assuntos
Tronco Encefálico/metabolismo , Cerebelo/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Ataxias Espinocerebelares/metabolismo , Fatores de Transcrição/metabolismo , Animais , Ataxina-1/genética , Ataxina-1/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Proteínas de Ligação a DNA/genética , Drosophila melanogaster , Células HEK293 , Humanos , Camundongos , Fosforilação , Estabilidade Proteica , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Ataxias Espinocerebelares/genética , Fatores de Transcrição/genética
3.
J Infect Dis ; 2024 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-38679784

RESUMO

Rotavirus is linked to severe childhood gastroenteritis and neurological complications, but its impact on neurodevelopment remains uncertain. We examined data from 1,420,941 Korean children born between 2009 and 2011, using the Korean National Health Insurance System. At age 6, we assessed neurodevelopmental outcomes using the validated Korean Developmental Test, covering six major domains. Utilizing propensity score-based Inverse Probability Weighting to ensure covariates including considering covariates including sex, birth weight, changes in body weight from birth to 4-6 months of age, head circumference at 4-6 months of age, residence at birth, economic status, infant feeding types, and birth year. The main analysis that encompassed 5,451 children with rotavirus hospitalization and 310,874 unexposed individuals reveled heightened odds of suspected delays in fine motor skills and cognition among exposed children. Our results suggest an association between rotavirus-related hospitalization in infancy and suspected delays in fine motor function and cognition in 6-year-olds.

4.
Small ; 20(40): e2401987, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38805737

RESUMO

Alternative strategies to design sustainable-element-based electrocatalysts enhancing oxygen evolution reaction (OER) kinetics are demanded to develop affordable yet high-performance water-electrolyzers for green hydrogen production. Here, it is demonstrated that the spontaneous-spin-polarized 2D π-d conjugated framework comprising abundant elements of nickel and iron with a ratio of Ni:Fe = 1:4 with benzenehexathiol linker (BHT) can improve OER kinetics by its unique electronic property. Among the bimetallic NiFex:y-BHTs with various ratios with Ni:Fe = x:y, the NiFe1:4-BHT exhibits the highest OER activity. The NiFe1:4-BHT shows a specific current density of 140 A g-1 at the overpotential of 350 mV. This performance is one of the best activities among state-of-the-art non-precious OER electrocatalysts and even comparable to that of the platinum-group-metals of RuO2 and IrO2. The density functional theory calculations uncover that introducing Ni into the homometallic Fe-BHT (e.g., Ni:Fe = 0:1) can emerge a spontaneous-spin-polarized state. Thus, this material can achieve improved OER kinetics with spin-polarization which previously required external magnetic fields. This work shows that a rational design of 2D π-d conjugated frameworks can be a powerful strategy to synthesize promising electrocatalysts with abundant elements for a wide spectrum of next-generation energy devices.

5.
Soft Matter ; 20(4): 796-803, 2024 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-38168689

RESUMO

Here we introduce sub-millimeter self-oscillating gels that undergo the Belousov-Zhabotinsky (BZ) reaction and can anisotropically oscillate like cardiomyocytes. The anisotropically self-oscillating gels in this study were realized by spatially patterning an acrylic acid-based interpenetrating network (AA-IPN). We found that the patterned AA-IPN regions, locally introduced at both ends of the gels through UV photolithography, can constrain the horizontal gel shape deformation during the BZ reaction. In other words, the two AA-IPN regions could act as a physical barrier to prevent isotropic deformation. Furthermore, we controlled the anisotropic deformation behavior during the BZ reaction by varying the concentration of acrylic acid used in the patterning process of the AA-IPN. As a result, a specific directional deformation behavior (66% horizontal/vertical amplitude ratio) was fulfilled, similar to that of cardiomyocytes. Our study can provide a promising insight to fabricating robust gel systems for cardiomyocyte modeling or designing novel autonomous microscale soft actuators.

6.
Macromol Rapid Commun ; 45(13): e2400038, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38684191

RESUMO

Self-oscillating gel systems exhibiting an expanded operating temperature and accompanying functional adaptability are showcased. The developed system contains nonthermoresponsive main-monomers, such as N,N-dimethylacrylamide (DMAAm) or 2-acrylamido-2-methylpropane sulfonic acid (AMPS) or acrylamide (AAm) or 3-(methacryloylamino)propyl trimethylammonium chloride (MAPTAC). The gels volumetrically self-oscillate within the range of the conventional (20.0 °C) and extended (27.0 and 36.5 °C) temperatures. Moreover, the gels successfully adapt to the environmental changes; they beat faster and smaller as the temperature increases. The period and amplitude are also controlled by tuning the amount of main-monomers and N-(3-aminopropyl) acrylamide. Furthermore, the record amplitude in the bulk gel system consisting of polymer strand and cross-linker at 36.5 °C is achieved (≈10.8%). The study shows new self-oscillation systems composed of unprecedented combinations of materials, giving the community a robust material-based insight for developing more life-like autonomous biomimetic soft robots with various operating temperatures and beyond.


Assuntos
Géis , Temperatura , Géis/química , Acrilamidas/química , Polímeros/química , Materiais Biomiméticos/química , Biomimética/métodos
7.
Int J Mol Sci ; 25(11)2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38892278

RESUMO

Alzheimer's disease (AD) presents a significant challenge due to its multifaceted nature, characterized by cognitive decline, memory loss, and neuroinflammation. Though AD is an extensively researched topic, effective pharmacological interventions remain elusive, prompting explorations into non-pharmacological approaches. Microcurrent (MC) therapy, which utilizes imperceptible currents, has emerged as a potent clinical protocol. While previous studies have focused on its therapeutic effects, this study investigates the impact of MC on neuronal damage and neuroinflammation in an AD mouse model, specifically addressing potential side effects. Utilizing 5xFAD transgenic mice, we examined the effects of MC therapy on neuronal integrity and inflammation. Our findings suggest that MC therapy attenuates memory impairment and reduces neurodegeneration, as evidenced by improved performance in memory tests and the preservation of the neuronal structure. Additionally, MC therapy significantly decreases amyloid-beta (Aß) plaque deposition and inhibits apoptosis, indicating its potential to mitigate AD pathology. This study determined that glial activation is effectively reduced by using MC therapy to suppress the TLR4-MyD88-NFκB pathway, which consequently causes the levels of inflammatory factors TNF-α, IL-1ß, and IL-6 to decrease, thus implicating TLR4 in neurodegenerative disease-related neuroinflammation. Furthermore, while our study did not observe significant adverse effects, a further clinical trial into potential side effects and neuroinflammatory responses associated with MC therapy is warranted.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Modelos Animais de Doenças , Camundongos Transgênicos , Neurônios , Animais , Doença de Alzheimer/terapia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Camundongos , Disfunção Cognitiva/terapia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Fator 88 de Diferenciação Mieloide/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Receptor 4 Toll-Like/metabolismo , Peptídeos beta-Amiloides/metabolismo , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/etiologia , Doenças Neuroinflamatórias/patologia , Placa Amiloide/patologia , Placa Amiloide/metabolismo , NF-kappa B/metabolismo , Apoptose
8.
Allergol Int ; 73(2): 243-254, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38238236

RESUMO

BACKGROUND: Atopic dermatitis and autoimmune diseases are highly heritable conditions that may co-occur from an early age. METHODS: The primary study is a national administrative cohort study involving 499,428 children born in 2002, tracked until 2017. Atopic dermatitis was defined as five or more principal diagnoses of atopic dermatitis and two or more topical steroid prescriptions. We estimated the risks for the occurrence of 41 autoimmune diseases, controlling for risk factors. In addition, we sourced a gene library from the National Library of Medicine to conduct a comprehensive gene ontology. We used Gene Weaver to identify gene set similarity and clustering, and used GeneMania to generate a network for shared genes. RESULTS: Exposed and unexposed groups included 39,832 and 159,328 children, respectively. During a mean follow-up of 12 years, the exposed group had an increased risk of autoimmune disease (hazard ratio, 1.27 [95 % confidence interval, 1.23-1.32]) compared to the unexposed group. The hazard ratios of autoimmune illnesses consistently increased with two- and five years lag times and alternative atopic dermatitis definitions. Shared genes between atopic dermatitis and autoimmune diseases were associated with comorbidities such as asthma, bronchiolitis, and specific infections. Genetic interactions of these shared genes revealed clustering in Th1, Th2, Th17, and non-classifiable pathways. CONCLUSIONS: Atopic dermatitis was significantly associated with an increased risk of subsequent autoimmune disease. we identified the genetically associated disease in atopic dermatitis patients comorbid with autoimmune disease and demonstrated a genetic network between atopic dermatitis and autoimmune diseases.


Assuntos
Doenças Autoimunes , Dermatite Atópica , Criança , Humanos , Adulto Jovem , Adulto , Dermatite Atópica/epidemiologia , Dermatite Atópica/genética , Dermatite Atópica/diagnóstico , Estudos de Coortes , Seguimentos , Ontologia Genética , Redes Reguladoras de Genes , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/genética
9.
J Pediatr ; 256: 85-91.e3, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36516893

RESUMO

OBJECTIVE: To investigate the association of feeding to sleep during infancy and subsequent childhood health burdens. STUDY DESIGN: Information was collected from the parents of children who participated in the national health screening survey when the child was 9-12 months old. The exposure group included participants who were fed to sleep. The primary outcome was all-cause hospital admission (inpatient care, intensive care unit [ICU] admission, or general anesthesia) after age 24 months. Secondary outcomes were subsequent childhood diseases (ie, adenoidectomy and/or tonsillectomy, nasal polyps, allergic rhinitis, acute otitis media, asthma, pneumonia, and aspiration pneumonia), and growth status, as measured by weight-to-age and height-to-age z-scores. RESULTS: The study cohort consisted of 224 075 children who participated in the health screening program, 29 392 of whom (13.1%; 51% males) were fed to sleep. Exposure was associated with an increased risk of all-cause hospitalization after age 24 months (hazard ratio [HR], 1.05; 95% CI, 1.03-1.07), but not with admission to an ICU or receipt of general anesthesia. This also was related to adenoidectomy and/or tonsillectomy (HR, 1.08; 95% CI, 1.01-1.15), dental caries (HR, 1.32; 95% CI, 1.23-1.40), asthma (HR, 1.14; 95% CI, 1.14-1.24), pneumonia (HR, 1.10; 95% CI, 1.07-1.13), overweight (HR, 1.06; 95% CI, 1.03-1.09), and obesity (HR, 1.11; 95% CI, 1.06-1.16). CONCLUSIONS: Several adverse health outcomes are related to feeding to sleep during early childhood.


Assuntos
Asma , Cárie Dentária , Criança , Masculino , Humanos , Pré-Escolar , Lactente , Feminino , Adenoidectomia/efeitos adversos , Asma/etiologia , Asma/complicações , Sono , Efeitos Psicossociais da Doença
10.
Pediatr Allergy Immunol ; 34(7): e13996, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37492912

RESUMO

BACKGROUND: Although atopic dermatitis (AD) in children affects diverse stages of life, no studies have reported on the association between school readiness and AD. METHODS: This study used Korean National Health Insurance data and the Health Screening Program for Infants and Children. Among all children born between 2008 and 2012 in Korea, those who were assessed for school readiness through questionnaires in a health screening program performed at 54 and 60 months old were enrolled. AD was defined based on the International Classification of Diseases codes, with two or more prescriptions of topical corticosteroids during the first 54-60 months of life. The primary outcome was the association between school readiness and AD. The questionnaire relating to school readiness comprised six items - cognitive skills, social development, activeness, concentration, emotional development, and language skills. Logistic regression analysis was used to identify the associations between school readiness and AD. RESULTS: This study included 239,673 children without AD and 38,229 children with AD. The average age at which school readiness was assessed was 4.8 years. AD was associated with vulnerability in activeness (adjusted odds ratio: 1.127; 95% confidence interval: 1.071-1.186) and concentrations (1.170; 1.093-1.254). The impact of AD on concentrations showed consistent results regardless of sex, exposure to systemic corticosteroids and antihistamines, and age at the diagnosis of AD. CONCLUSIONS: Children with AD have vulnerability in school readiness in the aspects of activeness and concentration.


Assuntos
Dermatite Atópica , Lactente , Humanos , Pré-Escolar , Dermatite Atópica/diagnóstico , Dermatite Atópica/epidemiologia , Inquéritos e Questionários , Corticosteroides/uso terapêutico , Instituições Acadêmicas
11.
Soft Matter ; 19(9): 1772-1781, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36779908

RESUMO

In this study, we established a fabrication method and analyzed the volumetric self-oscillatory behaviors of submillimeter-sized spherical self-oscillating gels. We validated that the manufactured submillimeter-sized spherical self-oscillating gels exhibited isotropic volumetric oscillations during the Belousov-Zhabotinsky (BZ) reaction. In addition, we experimentally elucidated that the volumetric self-oscillatory behaviors (i.e., period and amplitude) and the oscillatory profiles depended on the following parameters: (1) the molar composition of N-(3-aminopropyl)methacrylamide hydrochloride (NAPMAm) in the gels and (2) the concentration of Ru(bpy)3-NHS solution containing an active ester group on conjugation. These clarified relationships imply that controlling the amount of Ru(bpy)3 in the gel network could influence the gel volumetric oscillation during the BZ reaction. These results of submillimeter-sized and spherical self-oscillating gels bridge knowledge gaps in the current field because the gels with corresponding sizes and shapes have not been systematically explored yet. Therefore, our study could be a cornerstone for diverse applications of (self-powered) gels in various scales and shapes, including soft actuators exhibiting life-like functions.

12.
Int J Mol Sci ; 24(11)2023 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-37298502

RESUMO

Iron accumulation in the brain accelerates Alzheimer's disease progression. To cure iron toxicity, we assessed the therapeutic effects of noncontact transcranial electric field stimulation to the brain on toxic iron deposits in either the Aß fibril structure or the Aß plaque in a mouse model of Alzheimer's disease (AD) as a pilot study. A capacitive electrode-based alternating electric field (AEF) was applied to a suspension of magnetite (Fe3O4) to measure field-sensitized reactive oxygen species (ROS) generation. The increase in ROS generation compared to the untreated control was both exposure-time and AEF-frequency dependent. The frequency-specific exposure of AEF to 0.7-1.4 V/cm on a magnetite-bound Aß-fibril or a transgenic Alzheimer's disease (AD) mouse model revealed the degradation of the Aß fibril or the removal of the Aß-plaque burden and ferrous magnetite compared to the untreated control. The results of the behavioral tests show an improvement in impaired cognitive function following AEF treatment on the AD mouse model. Tissue clearing and 3D-imaging analysis revealed no induced damage to the neuronal structures of normal brain tissue following AEF treatment. In conclusion, our results suggest that the effective degradation of magnetite-bound amyloid fibrils or plaques in the AD brain by the electro-Fenton effect from electric field-sensitized magnetite offers a potential electroceutical treatment option for AD.


Assuntos
Doença de Alzheimer , Camundongos , Animais , Doença de Alzheimer/metabolismo , Camundongos Transgênicos , Ferro/metabolismo , Peptídeos beta-Amiloides/metabolismo , Espécies Reativas de Oxigênio , Estudos de Viabilidade , Óxido Ferroso-Férrico , Projetos Piloto , Oxirredução , Modelos Animais de Doenças , Placa Amiloide/terapia , Placa Amiloide/metabolismo
13.
Waste Manag Res ; 41(1): 195-204, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35913072

RESUMO

Incineration is the most effective method for reducing the increasing waste volume. However, as the pollutants generated during incineration may cause secondary pollution, blocking them in advance is necessary. During incineration, prevention facilities are operated to reduce the amount of pollutants. Conventional selective non-catalytic reduction (SNCR) reduces nitrogen oxides (NOx) by injecting ammonia and urea as reducing agents. In this study, the NOx reduction effect on food wastewater (FW) was examined. In addition, the removal efficiency was compared at different concentrations of urea mixed with FW. When different concentrations of urea were injected in SNCR facilities A, B and C, NOx removal efficiencies of up to 75% were observed; with FW injection only, removal efficiency was 56%; and when both urea and FW were injected, removal efficiency was up to 79%. Although FW showed a lower NOx removal efficiency than urea, injecting both increased the efficiency. In addition, when air pollutant emissions and the incinerator temperature were analysed, we found that they could be managed without exceeding the allowed limits. However, for the injection and incineration of reducing agents, the characteristics of the incineration facility and reducing agents must be considered.


Assuntos
Poluentes Atmosféricos , Poluentes Ambientais , Incineração , Águas Residuárias , Substâncias Redutoras , Ureia
14.
J Nanobiotechnology ; 20(1): 367, 2022 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-35953847

RESUMO

BACKGROUND: Astrocyte is a key regulator of neuronal activity and excitatory/inhibitory balance via gliotransmission. Recently, gliotransmission has been identified as a novel target for neurological diseases. However, using the properties of nanomaterials to modulate gliotransmission has not been uncovered. RESULTS: We prepared non-invasive CNT platforms for cells with different nanotopography and properties such as hydrophilicity and conductivity. Using CNT platforms, we investigated the effect of CNT on astrocyte functions participating in synaptic transmission by releasing gliotransmitters. Astrocytes on CNT platforms showed improved cell adhesion and proliferation with upregulated integrin and GFAP expression. In addition, intracellular GABA and glutamate in astrocytes were augmented on CNT platforms. We also demonstrated that gliotransmitters in brain slices were increased by ex vivo incubation with CNT. Additionally, intracellular resting Ca2+ level, which is important for gliotransmission, was also increased via TRPV1 on CNT platforms. CONCLUSION: CNT can improve astrocyte function including adhesion, proliferation and gliotransmission by increasing resting Ca2+ level. Therefore, our study suggests that CNT would be utilized as a new therapeutic platform for central nervous system diseases by modulating gliotransmission.


Assuntos
Nanotubos de Carbono , Astrócitos , Encéfalo , Neurônios/metabolismo , Transmissão Sináptica/fisiologia
15.
Sensors (Basel) ; 21(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34450737

RESUMO

This paper proposes an efficient channel information feedback scheme to reduce the feedback overhead of multi-user multiple-input multiple-output (MU-MIMO) hybrid beamforming systems. As massive machine type communication (mMTC) was considered in the deployments of 5G, a transmitter of the hybrid beamforming system should communicate with multiple devices at the same time. To communicate with multiple devices in the same time and frequency slot, high-dimensional channel information should be used to control interferences between the receivers. Therefore, the feedback overhead for the channels of the devices is impractically high. To reduce the overhead, this paper uses common sparsity of channel and nonlinear quantization. To find a common sparse part of a wide frequency band, the proposed system uses minimum mean squared error orthogonal matching pursuit (MMSE-OMP). After the search of the common sparse basis, sparse vectors of subcarriers are searched by using the basis. The sparse vectors are quantized by a nonlinear codebook that is generated by conditional random vector quantization (RVQ). For the conditional RVQ, the Linde-Buzo-Gray (LBG) algorithm is used in conditional vector space. Typically, elements of sparse vectors are sorted according to magnitude by the OMP algorithm. The proposed quantization scheme considers the property for the conditional RVQ. For feedback, indices of the common sparse basis and the quantized sparse vectors are delivered and the channel is recovered at a transmitter for precoding of MU-MIMO. The simulation results show that the proposed scheme achieves lower MMSE for the recovered channel than that of the linear quantization scheme. Furthermore, the transmitter can adopt analog and digital precoding matrix freely by the recovered channel and achieve higher sum rate than that of conventional codebook-based MU-MIMO precoding schemes.

16.
Bioorg Med Chem Lett ; 30(2): 126809, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31839539

RESUMO

As the most abundant heat shock protein (HSP), Hsp90 is actively involved in tumor cell growth and various responses to anti-carcinogenic stress. Hsp90 has thus emerged as a potential drug target. A structure-based drug design approach was applied to develop novel resorcinolyltriazole derivatives as Hsp90 inhibitors. Structure-activity relationships (SARs) and molecular docking were investigated to provide a rationale for binding affinity and paralog selectivity. Click chemistry between iodoethynylresorcinol and an azido derivative was used to synthesize a new family of 2-((4-resorcinolyl)-5-aryl-1,2,3-triazol-1-yl) acetates that exhibited Hsp90 binding affinities of 40-100 nM (IC50). Among the synthesized molecules, the triazole alkyl acetates displayed the highest Hsp90 binding affinities. Their potency against Hsp90 was over 100-fold stronger than against TRAP1 and 1-3-fold stronger than against Grp94. In particular, compounds 18, 19, and 30 had Hsp90 inhibitory activities of ~45 nM (IC50) and they displayed over 350-fold selectivity for Hsp90 over TRAP1.


Assuntos
Acetatos/uso terapêutico , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Acetatos/farmacologia , Proteínas de Choque Térmico HSP90/efeitos dos fármacos , Humanos , Relação Estrutura-Atividade
17.
Environ Sci Technol ; 54(3): 1503-1512, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-31898898

RESUMO

Large quantities of microplastics are thought to be emitted to freshwater environments via wastewater treatment plants (WWTPs). To evaluate the occurrence of microplastics in Korean WWTPs, a nationwide study was conducted for the first time in 50 representative WWTPs with large treatment capacities. Grab sampling and laboratory filtration were used for influents, whereas in situ filtration using a custom-made sampling device was used for effluents. The filtrates were pretreated using wet peroxidation and density separation prior to the identification of microplastics with a dissection microscope and Fourier-transform infrared spectroscopy. Pooled analyses of the microplastics revealed that they were predominantly fragment-shaped, and thermoplastics and synthetic fibers were the dominant microplastic materials in WWTPs. The concentration ranged from 10 to 470 L-1 in influents and 0.004 to 0.51 L-1 in effluents. The removal efficiency of microplastics during wastewater treatment was calculated to be 98.7-99.99% in 31 WWTPs. Additionally, WWTPs using advanced phosphorus removal processes exhibited higher removal efficiency than those not implementing such processes. Power-law distribution was successful in describing microplastic particle sizes down to 100 µm, although it was not applicable for smaller particles. This comprehensive monitoring study provides information on the current level and characteristics of microplastics in WWTPs in Korea.


Assuntos
Águas Residuárias , Poluentes Químicos da Água , Monitoramento Ambiental , Microplásticos , Plásticos , República da Coreia , Inquéritos e Questionários , Eliminação de Resíduos Líquidos
18.
Cell Biol Int ; 42(4): 393-402, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28833755

RESUMO

Tacrolimus is an immunosuppressive drug that inhibits the release of inflammatory cytokines involved in rheumatoid arthritis development by blocking T cell activation. "Endoplasmic reticulum stress," an imbalance between protein folding load and capacity leading to the accumulation of unfolded proteins in the endoplasmic reticulum lumen, has been implicated in rheumatoid arthritis and other inflammatory and metabolic diseases. We aimed to investigate the effect of tacrolimus on endoplasmic reticulum stress-mediated osteoclastogenesis and inflammation and elucidate the underlying mechanisms. In vitro studies were performed using mouse bone marrow cells that were cultured with or without interleukin-1ß, thapsigargin, or tacrolimus to induce osteoclast differentiation. A mouse model of arthritis was established by immunizing mice with bovine type II collagen. Tacrolimus was orally administered to mice from day 20 to 45 following the initial immunization, and histopathological changes and expression of specific biomarkers of endoplasmic reticulum stress-mediated inflammatory signaling pathways were examined. In vitro, tacrolimus inhibited receptor activator of nuclear factor-κB ligand-mediated osteoclast formation augmented by interleukin-1ß, thapsigargin, or both. Furthermore, tacrolimus inhibited glucose-regulated protein (GRP78), protein kinase R-like endoplasmic reticulum kinase, inositol-requiring enzyme 1 (IRE 1), and activating transcription factor 6 (ATF6) augmented by interleukin-1ß, thapsigargin, or both. Tacrolimus significantly ameliorated osteolysis and endoplasmic reticulum stress intensity in mice. Simultaneously, it reduced inflammatory cell infiltration, osteoclastogenesis, and inflammatory responses by inhibiting GRP78, IRE 1, and ATF6. These findings suggest that tacrolimus exhibits an anti-inflammation effect in rheumatoid arthritis and might inhibit joint damage progression by inhibiting endoplasmic reticulum stress.


Assuntos
Artrite/metabolismo , Osteogênese/efeitos dos fármacos , Tacrolimo/farmacologia , Animais , Artrite/induzido quimicamente , Artrite/fisiopatologia , Artrite Experimental , Colágeno , Modelos Animais de Doenças , Chaperona BiP do Retículo Endoplasmático , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Inflamação/tratamento farmacológico , Interleucina-1beta/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos DBA , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteogênese/fisiologia , Transdução de Sinais/efeitos dos fármacos , Tacrolimo/metabolismo , Tapsigargina/farmacologia
19.
Rapid Commun Mass Spectrom ; 30(13): 1567-75, 2016 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-27321844

RESUMO

RATIONALE: Stable isotope (δ(13) C, δ(15) N, δ(34) S values) analysis has become increasingly important for tracing contaminant sources in environments. Pretreatment of environmental samples allows accurate analysis of stable isotope ratios. The pretreatment of a sample and its subsequent preservation could either contaminate or create experimental artifacts affecting the validity of the resulting C/N ratios and the elemental isotopic contents of a sample. METHODS: The effects of acid pretreatment (0.1, 0.5, 1, 2, 5, 13 M HCl) and exposure period (2, 6, 12, 24, and 48 h) on the stable isotopic ratios of marine sediment (MS), river sediment (RS) and terrestrial soil (TS) samples were evaluated. The effects of storage temperatures (-80, -20 and 2°C), storage duration (1 week, 1 to 12 months) and washing steps (1, 2, 3, 5, 7 or 12 times) on the stable isotopic ratios were also considered. The %C, %N and %S, as well as the δ(13) C, δ(15) N, and δ(34) S values, of each sample were measured using continuous flow Elemental Analyzer/Isotope Ratio Mass Spectrometry (EA/IRMS). RESULTS: The HCl treatment was applicable for δ(13) C analysis. However, the acid concentration and duration of exposure that brought about total removal of carbonate for the three sample types varied; e.g. the TS sample required stronger acid and a shorter exposure time. Storage time also had an effect: the δ(13) C values were lower and the δ(15) N and δ(34) S values higher after storage for 300 days. CONCLUSIONS: HCl pretreatment effectively eliminates carbonates and thereby helps δ(13) C analysis of the organic fraction. HCl pretreatment is not recommended for δ(15) N and δ(34) S analysis. Freeze-drying of samples is recommended rather than oven drying. A temperature-dependent change in the isotopic ratios of long-term stored samples was observed during this study; therefore, relatively short-term storage (-80°C) of freeze-dried samples is preferable. Copyright © 2016 John Wiley & Sons, Ltd.

20.
Analyst ; 140(2): 616-22, 2015 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-25426595

RESUMO

Recently, there has been increased interest in electrospun-titanium dioxide nanofibers (TiO2 NFs) as antibacterial agents owing to their advantages, such as simple and cost-effective fabrication processes, and high surface areas. However, the photocatalytic effects of TiO2 NFs are relatively low because of their low-ordered crystalline structure, and the antibacterial effect is only effective under UV illumination owing to their large band-gap energy. In this paper, we have demonstrated a significantly enhanced antibacterial activity of hierarchical anatase TiO2 NFs against Staphylococcus aureus in the presence of UV light. Furthermore, the uniform deposition of a large quantity of Ag nanoparticles on the surface of the TiO2 NFs ensured a significant enhancement of the antibacterial performance, even under dark conditions. These results were obtained by exploiting the enhanced photocatalytic effect achieved through control of the crystallinity, as well as the enhanced surface area of the nanomaterials.


Assuntos
Antibacterianos/farmacologia , Nanopartículas Metálicas/química , Nanofibras/química , Staphylococcus aureus/efeitos dos fármacos , Titânio/farmacologia , Testes de Sensibilidade Microbiana , Prata/química , Staphylococcus aureus/efeitos da radiação , Raios Ultravioleta
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