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1.
Eur J Med Chem ; 245(Pt 2): 114919, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36399877

RESUMO

Abnormal activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome is closely associated with a variety of inflammatory diseases. Herein, we describe the discovery and optimization of a series of NLRP3 inflammasome inhibitors based on the oridonin skeleton. These inhibitors exhibited moderate to potent inhibitory activity against interleukin 1ß (IL-1ß) release. Compound E6 showed the strongest inhibitory activity and better safety range against IL-1ß (IC50 = 0.45 ± 0.02 µM, selectivity index = 36.49). Compared with oridonin, the activity and selectivity index of compound E6 increased 11.5 and 7.2 times, respectively. Compound E6 also exhibited broad-spectrum activity and specificity. Compound E6 mainly reduced the release of IL-1ß by targeting the NLRP3 protein, thereby inhibiting the NLRP3-caspase 1-gasdermin D (GSDMD), as well as inhibiting the caspase 4-GSDMD signaling pathway. Further studies revealed an important therapeutic effect of E6 on dextran sulfate sodium-induced colitis. Compound E6 may be promising for the treatment of NLRP3-related diseases including inflammatory bowel disease.


Assuntos
Colite , Inflamassomos , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Sulfato de Dextrana , Colite/induzido quimicamente , Colite/tratamento farmacológico
2.
Eur J Med Chem ; 245(Pt 2): 114918, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36401884

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized with high mortality, unknown etiology, and lack of effective treatment. Many evidences validate that inhibiting the activation of STAT3 is an attractive therapeutic strategy for IPF. Herein, based on our previous findings that nifuroxazide (NIF) could effectively attenuate pulmonary fibrosis by inhibiting STAT3 activation, a series of diarylacylhydrazones derivatives have been designed and synthesized. Among them, compounds 44 and 52 could inhibit TGF-ß1-induced abnormal activation of NIH-3T3 and A549 cells, as well as migration and EMT of A549 cells. In a bleomycin-induced mouse pulmonary fibrosis model, the oral administration of 44 and 52 (bioavailability F = 31.75% and 42.08%) improved mouse lung function and slowed the progression of IPF. Moreover, 52 could reverse the pulmonary fibrosis in treatment model. Collectively, this work shows 44 and 52 could be a potential lead compound for the treatment of IPF, and it is worthy of further study.


Assuntos
Fibrose Pulmonar Idiopática , Animais , Camundongos , Humanos , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/tratamento farmacológico , Células A549 , Bleomicina/farmacologia , Disponibilidade Biológica , Administração Oral , Modelos Animais de Doenças
3.
Int J Cancer ; 152(2): 259-266, 2023 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-35913764

RESUMO

Anti-GD2 monoclonal antibodies (mAb) improve the prognosis of high-risk neuroblastoma (HR-NB). Worldwide experience almost exclusively involves toddlers and older patients treated after multimodality or second-line therapies, that is, many months postdiagnosis. In contrast, at our center, infants received anti-GD2 mAbs because this immunotherapy started during or immediately after induction chemotherapy. We now report on the feasibility, safety, and long-term survival in this vulnerable age group. Thirty-three HR-NB patients were <19 months old when started on 3F8 (murine mAb; n = 21) or naxitamab (humanized-3F8; n = 12), with 30″ to 90″ intravenous infusions. Patients received analgesics and antihistamines. Common toxicities (pain, urticaria, cough) were manageable, allowing outpatient treatment. Capillary leak, posterior reversible encephalopathy syndrome, and mAb-related long-term toxicities did not occur. Two 3F8 cycles were aborted due to bradycardia (a preexisting condition) and asthmatic symptoms, respectively. One patient received ½ dose of Day 1 naxitamab because of hypotension; full doses were subsequently administered. Post-mAb treatments included chemotherapy, radiotherapy, and anti-NB vaccine. Among 3F8 patients, 17/21 are in complete remission off all treatment at 5.6+ to 24.1+ (median 13.4+) years from diagnosis. Among naxitamab patients, 10/12 remain relapse-free post-mAb at 1.7+ to 4.3+ (median 3.1+) years from diagnosis. Toxicity was similar with short outpatient infusions and matched that observed with these and other anti-GD2 mAbs in older patients. These findings were reassuring given that naxitamab is dosed >2.5× higher (~270 mg/m2 /cycle) than 3F8, dinutuximab, and dinutuximab beta (70-100 mg/m2 /cycle). HR-NB in infants proved to be highly curable.


Assuntos
Antineoplásicos , Neuroblastoma , Síndrome da Leucoencefalopatia Posterior , Humanos , Lactente , Camundongos , Animais , Idoso , Síndrome da Leucoencefalopatia Posterior/induzido quimicamente , Síndrome da Leucoencefalopatia Posterior/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Anticorpos Monoclonais/efeitos adversos , Neuroblastoma/tratamento farmacológico , Imunoterapia , Fatores Imunológicos/uso terapêutico , Antineoplásicos/uso terapêutico
4.
Methods Mol Biol ; 2598: 375-379, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36355306

RESUMO

The collagenase-induced experimental osteoarthritis model is in general applied in mice but can also be used in other small species. The model is mainly based on the induction of joint laxity but has also a major inflammatory component. In this chapter, the induction is described by two injections of collagenase at the start of the model. Investigators who will use this model have to have ample experience in intra-articular injection in mice.


Assuntos
Cartilagem Articular , Osteoartrite , Camundongos , Animais , Modelos Animais de Doenças , Osteoartrite/induzido quimicamente , Osteoartrite/tratamento farmacológico , Colagenases/efeitos adversos , Injeções Intra-Articulares
5.
Environ Res ; 216(Pt 3): 114685, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36341787

RESUMO

Obesity is a major threat to health, but the etiology of obesity is incompletely understood. Phthalates, synthetic chemicals ubiquitous in the environment, are suspected to have obesogenic effects, but the relationship of phthalates and obesity in humans remains uncertain. We examined whether phthalate exposure was associated with body fat gain in midlife women. We analyzed data from 1369 women in the Study of Women's Health Across the Nation Multi-Pollutant Study. Eleven phthalate metabolites measured in spot urine samples at baseline (1999/2000) were standardized with covariate-adjusted creatinine. Body weight (BW), fat mass (FM) from dual-energy X-ray absorptiometry (DXA), and body fat percentage (BF%) from DXA were measured near-annually until 2016/2017. For each metabolite, linear mixed effects models with time and log2(metabolite) interactions were examined, adjusting for demographic, lifestyle, and menopause-related factors. Analyses were conducted overall and stratified by baseline obesity status. As sensitivity analyses, all analyses were repeated using a second set of metabolites measured in 2002/2003. Higher levels of all metabolites except mono-carboxy-isononyl phthalate were associated with faster increases in BF%. Per doubling of metabolite concentrations, differences in five-year BF% change ranged from 0.03 percentage point (ppt) (95% confidence interval (CI): -0.03, 0.09) for mono-isobutyl phthalate to 0.09 ppt (95% CI: 0.02, 0.16) for mono(3-carboxypropyl) phthalate. Results were similar for FM change, but associations with BW change were mostly null. In stratified analyses by baseline obesity status, positive associations were strongest in women who were normal/underweight at baseline. When metabolites from 2002/2003 were used as exposures, most associations were attenuated and not statistically significant, but they remained positive for normal/underweight women. In conclusion, phthalate metabolites were associated with more rapid body fat gain in midlife women, but our results need confirmation given attenuation of estimates in the sensitivity analyses.


Assuntos
Poluentes Ambientais , Ácidos Ftálicos , Feminino , Humanos , Poluentes Ambientais/urina , Magreza , Exposição Ambiental/análise , Ácidos Ftálicos/urina , Obesidade/induzido quimicamente , Obesidade/epidemiologia , Tecido Adiposo/metabolismo , Saúde da Mulher
6.
Environ Res ; 216(Pt 3): 114686, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36341798

RESUMO

Exposure to polychlorinated biphenyls (PCBs) has been associated with liver injury in human cohorts and with nonalcoholic steatohepatitis (NASH) in mice fed a high fat diet (HFD). N (6)-methyladenosine (m6A) modification of mRNA regulates transcript fate, but the contribution of m6A modification on the regulation of transcripts in PCB-induced steatosis and fibrosis is unknown. This study tested the hypothesis that PCB and HFD exposure alters the levels of m6A modification in transcripts that play a role in NASH in vivo. Male C57Bl6/J mice were fed a HFD (12 wks) and administered a single oral dose of Aroclor1260, PCB126, or Aroclor1260 + PCB126. Genome-wide identification of m6A peaks was accomplished by m6A mRNA immunoprecipitation sequencing (m6A-RIP) and the mRNA transcriptome identified by RNA-seq. Exposure of HFD-fed mice to Aroclor1260 decreased the number of m6A peaks and m6A-containing genes relative to PCB vehicle control whereas PCB126 or the combination of Aroclor1260 + PCB126 increased m6A modification frequency. ∼41% of genes had one m6A peak and ∼49% had 2-4 m6A peaks. 117 m6A peaks were common in the four experimental groups. The Aroclor1260 + PCB126 exposure group showed the highest number (52) of m6A-peaks. qRT-PCR confirmed enrichment of m6A-containing fragments of the Apob transcript with PCB exposure. A1cf transcript abundance, m6A peak count, and protein abundance was increased with Aroclor1260 + PCB126 co-exposure. Irrespective of the PCB type, all PCB groups exhibited enriched pathways related to lipid/lipoprotein metabolism and inflammation through the m6A modification. Integrated analysis of m6A-RIP-seq and mRNA-seq identified 242 differentially expressed genes (DEGs) with increased or reduced number of m6A peaks. These data show that PCB exposure in HFD-fed mice alters the m6A landscape offering an additional layer of regulation of gene expression affecting a subset of gene responses in NASH.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Bifenilos Policlorados , Masculino , Camundongos , Humanos , Animais , Bifenilos Policlorados/toxicidade , Bifenilos Policlorados/metabolismo , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/genética , Metilação , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
7.
Phytomedicine ; 108: 154529, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36343550

RESUMO

BACKGROUND: Previous studies have shown that the anti-cholestatic effect of oleanolic acid (OA) is associated with FXR and NRF2. However, how the two signaling pathways cooperate to regulate the anti-cholestatic effect of OA remains unclear. PURPOSE: This study aimed to further demonstrate the effect of OA on alpha-naphthyl isothiocyanate (ANIT)-induced cholestatic liver injury and the interaction mechanism between NRF2 and FXR signaling pathways in maintaining bile acid homeostasis. METHODS: Gene knockout animals and cell models, metabolomics analysis, and co-immunoprecipitation were used to investigate the mechanism of OA against cholestatic liver injury. RESULTS: The effect of OA against ANIT-induced liver injury in rats was dramatically reduced after Nrf2 gene knockdown. With the silencing of Fxr, the hepatoprotective effect of OA was weakened, but it still effectively alleviated cholestatic liver injury in rats. In L02 cells, OA can up-regulate the levels of NRF2, FXR, BSEP and UGT1A1, and reduce the expression of CYP7A1. Silencing of NRF2 or FXR significantly attenuated the protective effect of OA on ANIT-induced L02 cell injury and its regulation on downstream target genes, and the influence of NRF2 gene silencing on OA appeared to be greater. The NRF2 activator sulforaphane, and the FXR activator GW4064 both remarkably promoted NRF2 binding to P300 and FXR to RXRα, but reduced ß-catenin binding to P300 and ß-catenin binding to FXR. CONCLUSION: The effect of OA on cholestatic liver injury is closely related to the simultaneous activation of NRF2 and FXR dual signaling pathways, in which NRF2 signaling pathway plays a more important role. The dual signaling pathways of NRF2 and FXR cooperatively regulate bile acid metabolic homeostasis through the interaction mechanism with ß-catenin/P300.


Assuntos
Colestase , Ácido Oleanólico , Ratos , Animais , Ácido Oleanólico/farmacologia , Ácido Oleanólico/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , beta Catenina/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Colestase/tratamento farmacológico , Colestase/induzido quimicamente , Fígado , Ácidos e Sais Biliares/metabolismo , Transdução de Sinais , Fator de Transcrição de Proteínas de Ligação GA/metabolismo
8.
Sci Total Environ ; 858(Pt 1): 159509, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36257414

RESUMO

With a remarkable increase in industrialization among fast-developing countries, air pollution is rising at an alarming rate and has become a public health concern. The study aims to examine the effect of air pollution on patient's hospital visits for respiratory diseases, particularly Acute Respiratory Infections (ARI). Outpatient hospital visits, air pollution and meteorological parameters were collected from March 2018 to October 2021. Eight machine learning algorithms (Random Forest model, K-Nearest Neighbors regression model, Linear regression model, LASSO regression model, Decision Tree Regressor, Support Vector Regression, X.G. Boost and Deep Neural Network with 5-layers) were applied for the analysis of daily air pollutants and outpatient visits for ARI. The evaluation was done by using 5-cross-fold confirmations. The data was randomly divided into test and training data sets at a scale of 1:2, respectively. Results show that among the studied eight machine learning models, the Random Forest model has given the best performance with R2 = 0.606, 0.608 without lag and 1-day lag respectively on ARI patients and R2 = 0.872, 0.871 without lag and 1-day lag respectively on total patients. All eight models did not perform well with the lag effect on the ARI patient dataset but performed better on the total patient dataset. Thus, the study did not find any significant association between ARI patients and ambient air pollution due to the intermittent availability of data during the COVID-19 period. This study gives insight into developing machine learning programs for risk prediction that can be used to predict analytics for several other diseases apart from ARI, such as heart disease and other respiratory diseases.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , COVID-19 , Transtornos Respiratórios , Infecções Respiratórias , Humanos , Pacientes Ambulatoriais , Poluição do Ar/análise , Poluentes Atmosféricos/análise , Transtornos Respiratórios/induzido quimicamente , Aprendizado de Máquina , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/induzido quimicamente , China , Material Particulado/análise
9.
Gene ; 851: 146976, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36261081

RESUMO

Epigenetics is the science of altering gene expression without changing nucleotide sequences and may be induced by various environmental factors, including pesticides. The aim of this study was to investigate certain epigenetic changes including the methylation of CDKN2B, CDKN2A, and MGMT gene promoters and histone modifications of H3K9ac, H4K16ac, H4K20me3, and H3K4me3, as well as their association with the levels of organochlorine pesticides (OCPs) in children with acute lymphoblastic leukemia (ALL). The evaluation of OCP levels, promoter methylation, gene expression, and expression of histone modifications was performed by gas chromatography (GC), methylation-specific polymerase chain reaction (MS-PCR), reverse transcription PCR (RT-PCR), and western blotting, respectively. The results indicated that 76.2 % of CDKN2B promoters and 85.1 % of MGMT promoters were hypermethylated in children with ALL compared to healthy children. In addition, the relative expression of CDKN2B, MGMT, H4K16ac, and H3K4me3 showed a significant decrease in children with ALL compared to healthy children. Levels of OCPs in children with ALL were significantly higher than in healthy children. Furthermore, the results revealed that the rise in the OCP levels was associated with an increase in methylation at the promoter level of CDKN2B and MGMT as well as a decrease in the relative expression of H4K16ac and H3K4me3. Therefore, it can be concluded that exposure to OCPs is associated with the induction of epigenetic changes at the level of DNA and histones, which may lead to leukemia.


Assuntos
Inibidor de Quinase Dependente de Ciclina p15 , Metilases de Modificação do DNA , Hidrocarbonetos Clorados , Leucemia , Praguicidas , Criança , Humanos , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Código das Histonas , Hidrocarbonetos Clorados/toxicidade , Leucemia/induzido quimicamente , Leucemia/genética , Praguicidas/toxicidade , Regiões Promotoras Genéticas , Proteínas Supressoras de Tumor/genética , Inibidor de Quinase Dependente de Ciclina p15/genética
10.
Environ Res ; 216(Pt 2): 114524, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36228692

RESUMO

Road transport contributes over 70% of air pollution in urban areas and is the second largest contributor to the total carbon dioxide emissions in Malaysia at 21% in 2016. Transport-related air pollutants (TRAPs) such as NOx, SO2, CO and particulate matter (PM) pose significant threats to the urban population's health. Malaysia has targeted to deploy 885,000 EV cars on the road by 2030 in the Low Carbon Mobility Blueprint (LCMB). This study aims to quantify the health co-benefits of electric vehicle adoption from their impacts on air quality in Malaysia. Two EV uptake projections, i.e. LCMB and Revised EV Adoption (REVA) projections, and five electricity generation mix scenarios were modelled up to 2040. We used comparative health risk assessment to estimate the potential changes in mortality and burden of diseases (BoD) from the emissions in each scenario. Intake fractions and exposure-risk functions were used to calculate the burden from respiratory diseases (PM2.5, NOx, SO2, CO), cardiovascular diseases and lung cancer (PM2.5). Results showed that along with a net reduction of carbon emissions across all scenarios, there could be reduced respiratory mortality from NOx by 10,200 mortality (176,200 DALYs) and SO2 by 2600 mortality (45,400 DALYs) per year in 2040. However, there could also be additional 719 mortality (9900 DALYs) per year from PM2.5 and 329 mortality (5600 DALYs) from CO per year. The scale of reduction in mortality and BoD from NOx and SO2 are significantly larger than the scale of increase from PM2.5 and CO, indicating potential net positive health impacts from the EV adoption in the scenarios. The health cost savings from the reduced BoD of respiratory mortality could reach up to RM 7.5 billion per year in 2040. In conclusion, EV is a way forward in promoting a healthy and sustainable future transport in Malaysia.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Doenças Respiratórias , Humanos , Poluentes Atmosféricos/toxicidade , Poluentes Atmosféricos/análise , Emissões de Veículos/toxicidade , Emissões de Veículos/análise , Malásia , Poluição do Ar/análise , Material Particulado/toxicidade , Material Particulado/análise , Eletricidade , Doenças Respiratórias/induzido quimicamente , Doenças Respiratórias/epidemiologia
11.
Environ Res ; 216(Pt 2): 114571, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36243047

RESUMO

Few epidemiological studies have focused on prenatal phthalates (PAEs) and polybrominated diphenyl ethers (PBDEs) exposure to neonatal health in China. This study aimed to assess the associations between prenatal PAEs and PBDEs exposure and neonatal health in Guangxi, a Zhuang autonomous region of China. Concentrations of 4 PAEs metabolites (mPAEs) and 5 PBDEs congeners were measured in the serum of 267 healthy pregnant women. Birth outcomes and clinical data of neonates were collected after delivery. Mono-(2-Ethylhexyl) phthalate (MEHP) (81.52%) and BDE47 (35.21%) were the mPAEs and PBDEs congeners with the highest detection rate in serum. Prenatal exposures to mono-n-butyl phthalate (MBP), MEHP, and ΣmPAEs were negatively associated with birth weight (BW), birth length (BL), and gestational age (GA). Higher exposures to MBP, MEHP, and ΣmPAEs were associated with an increased odds ratio (OR) for low birth weight (LBW), but exposure to BDE28 exhibited the opposite effect. Moreover, higher exposures to MBP, MEHP, ΣmPAEs, BDE99, and ΣPBDEswere associated with an increased OR for premature birth (PTB) (P < 0.05). In contrast to MBP exposure, BDE28 exposure was associated with a higher OR for neonatal jaundice (NNJ) (P < 0.05). The interaction analysis showed a positive interaction between monoethyl phthalate (MEP) and BDE28 on the risk of NNJ and positive interaction between ΣmPAEs and BDE47 on the risk of NNJ. In addition, there are ethnicity-specific associations of prenatal PBDEs exposure with neonatal health in individuals of Zhuang and Han nationalities, and boy neonates were more sensitive to prenatal PBDEs exposure than girl neonates. The results revealed that prenatal exposure to mPAEs and PBDEs might have adverse effects on neonatal development, and the effects might be ethnicity- and sex-specific.


Assuntos
Ácidos Ftálicos , Efeitos Tardios da Exposição Pré-Natal , Recém-Nascido , Masculino , Humanos , Feminino , Gravidez , Éteres Difenil Halogenados/toxicidade , Estudos de Coortes , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Saúde do Lactente , Coorte de Nascimento , China/epidemiologia , Ácidos Ftálicos/toxicidade
12.
J Environ Sci (China) ; 124: 451-461, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36182153

RESUMO

Inflammation is a major adverse outcome induced by inhaled particulate matter with a diameter of ≤ 2.5 µm (PM2.5), and a critical trigger of most PM2.5 exposure-associated diseases. However, the key molecular events regulating the PM2.5-induced airway inflammation are yet to be elucidated. Considering the critical role of circular RNAs (circRNAs) in regulating inflammation, we predicted 11 circRNAs that may be involved in the PM2.5-induced airway inflammation using three previously reported miRNAs through the starBase website. A novel circRNA circ_0008553 was identified to be responsible for the PM2.5-activated inflammatory response in human bronchial epithelial cells (16HBE) via inducing oxidative stress. Using a combinatorial model PM2.5 library, we found that the synergistic effect of the insoluble core and loaded Zn2+ ions at environmentally relevant concentrations was the major contributor to the upregulation of circ_0008553 and subsequent induction of oxidative stress and inflammation in response to PM2.5 exposures. Our findings provided new insight into the intervention of PM2.5-induced adverse outcomes.


Assuntos
MicroRNAs , RNA Circular , Células Epiteliais/metabolismo , Humanos , Inflamação/induzido quimicamente , MicroRNAs/metabolismo , Estresse Oxidativo , Material Particulado/toxicidade , Zinco/toxicidade
13.
J Environ Sci (China) ; 124: 472-480, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36182155

RESUMO

Antibiotics have been identified as obesogens contributing to the prevalence of obesity. Moreover, their environmental toxicity shows sex dependence, which might also explain the sex-dependent obesity observed. Yet, the direct evidence for such a connection and the underlying mechanisms remain to be explored. In this study, the effects of tetracycline, which is a representative antibiotic found in both environmental and food samples, on Drosophila melanogaster were studied with consideration of both sex and circadian rhythms (represented by the eclosion rhythm). Results showed that in morning-eclosed adults, tetracycline significantly stimulated the body weight of females (AM females) at 0.1, 1.0, 10.0 and 100.0 µg/L, while tetracycline only stimulated the body weight of males (AM males) at 1.0 µg/L. In the afternoon-eclosed adults, tetracycline significantly stimulated the body weight of females (PM females) at 0.1, 1.0 and 100.0 µg/L, while it showed more significant stimulation in males (PM males) at all concentrations. Notably, the stimulation levels were the greatest in PM males among all the adults. The results showed the clear sex dependence of the obesogenic effects, which was diminished by dysrhythmia. Further biochemical assays and clustering analysis suggested that the sex- and rhythm-dependent obesogenic effects resulted from the bias toward lipogenesis against lipolysis. Moreover, they were closely related to the preference for the energy storage forms of lactate and glucose and also to the presence of excessive insulin, with the involvement of glucolipid metabolism. Such relationships indicated potential bridges between the obesogenic effects of pollutants and other diseases, e.g., cancer and diabetes.


Assuntos
Poluentes Ambientais , Compostos Heterocíclicos , Insulinas , Animais , Antibacterianos/farmacologia , Peso Corporal , Ritmo Circadiano , Drosophila melanogaster , Feminino , Glucose , Insulinas/farmacologia , Lactatos/farmacologia , Masculino , Obesidade/induzido quimicamente , Tetraciclina/toxicidade
14.
J Environ Sci (China) ; 124: 481-490, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36182156

RESUMO

Triclosan (TCS) is a ubiquitous antimicrobial used in daily consumer products. Previous reports have shown that TCS could induce hepatotoxicity, endocrine disruption, disturbance on immune function and impaired thyroid function. Kidney is critical in the elimination of toxins, while the effects of TCS on kidney have not yet been well-characterized. The aim of the present study was to investigate the effects of TCS exposure on kidney function and the possible underlying mechanisms in mice. Male C57BL/6 mice were orally exposed to TCS with the doses of 10 and 100 mg/(kg•day) for 13 weeks. TCS was dissolved in dimethyl sulfoxide (DMSO) and diluted by corn oil for exposure. Corn oil containing DMSO was used as vehicle control. Serum and kidney tissues were collected for study. Biomarkers associated with kidney function, oxidative stress, inflammation and fibrosis were assessed. Our results showed that TCS could cause renal injury as was revealed by increased levels of renal function markers including serum creatinine, urea nitrogen and uric acid, as well as increased oxidative stress, pro-inflammatory cytokines and fibrotic markers in a dose dependent manner, which were more significantly in 100 mg/(kg•day) group. Mass spectrometry-based analysis of metabolites related with lipid metabolism demonstrated the occurrence of lipid accumulation and defective fatty acid oxidation in 100 mg/(kg•day) TCS-exposed mouse kidney. These processes might lead to lipotoxicity and energy depletion, thus resulting in kidney fibrosis and functional decline. Taken together, the present study demonstrated that TCS could induce lipid accumulation and fatty acid metabolism disturbance in mouse kidney, which might contribute to renal function impairment. The present study further widens our insights into the adverse effects of TCS.


Assuntos
Anti-Infecciosos , Transtornos do Metabolismo dos Lipídeos , Triclosan , Animais , Óleo de Milho/metabolismo , Óleo de Milho/farmacologia , Creatinina/metabolismo , Creatinina/farmacologia , Citocinas/metabolismo , Citocinas/farmacologia , Dimetil Sulfóxido/metabolismo , Dimetil Sulfóxido/farmacologia , Ácidos Graxos/metabolismo , Fibrose , Rim/metabolismo , Metabolismo dos Lipídeos , Transtornos do Metabolismo dos Lipídeos/induzido quimicamente , Transtornos do Metabolismo dos Lipídeos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nitrogênio/metabolismo , Triclosan/toxicidade , Ureia , Ácido Úrico/metabolismo , Ácido Úrico/farmacologia
15.
J Hazard Mater ; 441: 129792, 2023 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-36084470

RESUMO

Cooking Oil Fumes (COFs) contain carcinogenic organic substances such as polycyclic aromatic hydrocarbons (PAHs) and heterocyclic amines (HCAs), of which 2-Amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) is known as mainly meat-borne carcinogens. In this work, to identify the mechanisms to induce the inflammation response in human lung cells (A549) exposed to COFs, we investigated the physicochemical and biological characteristics of COFs generated with PhIP precursors (L-phenylalanine, creatinine, and glucose) at high cooking temperatures (300 °C and 600 °C). Interestingly, we found that PhIP was not formed both at 300 °C and 600 °C, while a large number of carbon nanoparticles were generated from soybean oil containing the PhIP precursors at 600 °C. From the biological analysis, COFs generated with the PhIP precursors at 600 °C induced the most significant pro-inflammatory cytokine (IL-6). This result indicates that the particulate matter in COFs generated with the PhIP precursors above the smoke temperature is the primary factor directly affecting the lung inflammatory response rather than PhIP. This study demonstrates for the first time a novel principle of the inflammatory response that the PhIP precursors can aggravate lung injury by affecting the physical properties of COFs depending on cooking temperature. Therefore, our finding is a significant result of overcoming the bias in previous studies focusing only on the chemical toxicity of PhIP in the inflammatory response of COFs.


Assuntos
Material Particulado , Hidrocarbonetos Policíclicos Aromáticos , Aminas/análise , Carbono/análise , Carcinógenos/análise , Culinária , Creatinina/análise , Glucose , Humanos , Inflamação/induzido quimicamente , Interleucina-6 , Pulmão , Carne/análise , Material Particulado/análise , Material Particulado/toxicidade , Fenilalanina , Hidrocarbonetos Policíclicos Aromáticos/análise , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Fumaça/análise , Óleo de Soja/análise , Temperatura
16.
J Hazard Mater ; 441: 129903, 2023 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-36087528

RESUMO

Microplastics (MP) and nanoplastics (NP) exist in the disposable plastic take-away containers. This study aims to determine the gut and oral microbiota alterations in the individuals frequently and occasionally consuming take-away food in disposable plastic containers (TFDPC), and explore the effect of micro/nanoplastics (MNP) reduction on gut microbiota in mice. TFDPC consumption are associated with greater presences of gastrointestinal dysfunction and cough. Both occasional and frequent consumers have altered gut and oral microbiota, and their gut diversity and evenness are greater than those of non-TFDPC consuming cohort. Multiple gut and oral bacteria are associated with TFDPC consumers, among which intestinal Collinsella and oral Thiobacillus are most associated with the frequent consumers, while intestinal Faecalibacterium is most associated with the occasional consumers. Although some gut bacteria associated with the mice treated with 500 µg NP and 500 µg MP are decreased in the mice treated with 200 µg NP, the gut microbiota of the three MNP groups are all different from the control group. This study demonstrates that TFDPC induces gut and oral microbiota alterations in the consumers, and partial reduction of the size and amount of MNP cannot rectify the MNP-induced gut microbial dysbiosis.


Assuntos
Microbioma Gastrointestinal , Microbiota , Animais , Disbiose/induzido quimicamente , Camundongos , Microplásticos , Plásticos/toxicidade
17.
J Ethnopharmacol ; 300: 115741, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36162543

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Pulsatilla decoction (PD), is an herbal formula commonly used for the treatment of ulcerative colitis (UC) in clinical practice, but the mechanism of PD alters the colitis remains elusive. AIM OF THE STUDY: To evaluate the intervention effect of PD on Dextran Sodium Sulfate (DSS)-induced UC based on gut microbiota and intestinal short-chain fatty acid (SCFAs) metabolism, and to investigate the mechanism of action of PD in treating UC. MATERIALS AND METHODS: A 3% (wt/vol) DSS-induced ulcerative colitis model in C57BL/6 male mice was used to evaluate the effect of oral PD in treating UC. The changes in gut microbiota in mice were analyzed by 16SrDNA gene sequencing, and the content of SCFAs in the intestinal contents of mice was determined by gas chromatography-mass spectrometry (GC-MS). Enzyme-linked immunosorbent assay (ELISA) was applied to analyze the expression of inflammatory cytokines in serum and colonic tissues, and western blotting (WB) was applied to analyze the expression of tight junction proteins in colonic tissues. RESULTS: PD can alleviate the symptoms of UC mice, Pulsatilla Decoction high dose treatment group (PDHT) shows the best effect. Compared with the DSS group, the PDHT had significantly lower body mass, disease activity index (DAI) score, colonic macroscopic damage index (CMDI) score, and pathological damage score, at the phylum level, the relative abundance of Bacteroidetes increased while that of Firmicutes and Proteobacteria decreased, at the Genus level, the abundance of Bacteroides and Lachnospiraceae.NK4A136.group increased while that of Clostridium. sensu.stricto。, Escherichia. shigella and Turicibacter decreased. Compared with the DSS group, acetate, propionate, and total SCFAs in the PDHT with significantly higher levels. The concentrations of interleukin-1ß (L-1ß), tumor necrosis factor-alpha (TNF-α), and interleukin-17 (IL-17) decreased whereby the concentration of interleukin-10 (IL-10) increased in the PDHT group. The expression levels of Occludin, zonula occludens-1 (ZO-1), Claudin1, Claudin5, G protein-coupled receptor43 (GPR43) protein, and the relative expression of ZO-1 and Occludin mRNA were significantly increased PDHT group. CONCLUSIONS: PD has a good therapeutic effect on UC mice. The pharmacological mechanism is probably maintaining the homeostasis and diversity of gut microbiota, increasing the content of SCFAs, and repairing the colonic mucosal barrier.


Assuntos
Colite Ulcerativa , Colite , Pulsatilla , Animais , Bactérias/metabolismo , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Colo , Citocinas/metabolismo , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Ácidos Graxos Voláteis/metabolismo , Interleucina-10/metabolismo , Interleucina-17/metabolismo , Interleucina-1beta/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ocludina/metabolismo , Propionatos , RNA Mensageiro/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
18.
J Ethnopharmacol ; 300: 115756, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36170958

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Rhus genus is commonly known as sumac and widely used in the folk medicine. Rhus virens is a plant commonly used to treat diabetes or pain in the northern territory of Mexico. Even though R. virens is used in the folk medicine there is still a lack of evidence about the pharmacological effect of this species. AIM OF THE STUDY: The aim of this study was to determine the antinociceptive, anti-inflammatory and antioxidant effect of R. virens through a bio-guided chemical separation. MATERIALS AND METHODS: The aqueous, methanolic, and hexane extract of R. virens were obtained and tested in the formalin test, TPA-induced ear edema, and DPPH, ABTS, and FRAP assay. Also, possible interaction of pain pathways was studied using naloxone, bicuculline, L-NAME, ODQ, and glibenclamide in the formalin test in mice. RESULTS: Rhus virens methanolic extract (30 mg/kg, p.o.) produced higher antinociceptive activity in both the early and late phases of the formalin test (35.0 and 52.9%, respectively). Also, pre-administration with naloxone, bicuculline, L-NAME, ODQ and glibenclamide prevented the antinociceptive effect of R. virens in the early phase of the formalin test. Meanwhile, only naloxone and bicuculline prevented the antinociceptive effect on the late phase of the formalin test. Chemical separation of methanolic extract allowed to isolate 1,2,3,4,6-penta-O-galloyl-glucopyranose (PGG), it was tested in the formalin test, producing an antinociceptive effect on the late phase of the formalin test. On the other hand, topical application of the derivatives of R. virens methanolic extract produced an anti-inflammatory effect in the TPA-induced ear edema, being PGG an anti-inflammatory molecule. Lastly, radical scavenging activity was higher in the extracts of higher polarity, comparable to the standard used Camellia sinensis. CONCLUSIONS: In conclusion, R. virens produce an antinociceptive, anti-inflammatory and free-radical scavenging activity. The antinociceptive effect could be related to the opioidergic, GABAergic, and NO-GMPc-K + ATP channels pathways. These effects could be partially produced by the presence of PGG.


Assuntos
Rhus , Trifosfato de Adenosina , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Bicuculina , Edema/induzido quimicamente , Edema/tratamento farmacológico , Glibureto , Hexanos , Camundongos , NG-Nitroarginina Metil Éster , Naloxona/farmacologia , Dor/induzido quimicamente , Dor/tratamento farmacológico , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Folhas de Planta/química
19.
J Ethnopharmacol ; 300: 115725, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36115602

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Cimicifuga foetida L. is a well-established traditional Chinese medicine with heat-clearing and detoxifying effects and has good therapeutic effect on oral mucosal ulcer and pharyngitis. The rhizome of this herb is rich in triterpenoid glycosides, including 23-O-acetylshengmanol-3-o-α-L-arabinoside (DA). AIM OF THE STUDY: Whether and how DA attenuates acute lung injury (ALI) are unclear. Accordingly, we focused on its anti-inflammatory effects and underlying molecular mechanisms in lipopolysaccharide (LPS)-stimulated ALI mice and RAW264.7 cells. MATERIALS AND METHODS: The model of ALI mice was established by exposed intratracheal instillation of LPS. Lung pathological changes were evaluated by hematoxylin and eosin staining. Pulmonary function was assessed by whole-body plethysmography. Total protein content in bronchoalveolar lavage fluid (BALF) was detected by bicinchoninic acid method. Wet/dry lung ratio was used to evaluate the degree of pulmonary edema in mice. The levels of pro-inflammatory mediators were measured using enzyme-linked immunosorbent assay. The relative expression of pro-inflammatory gene mRNA was examined by RT-qPCR. The expression of inflammatory-related proteins was detected by Western blot. RAW264.7 cells were used to test the anti-inflammatory effects of DA in vitro. Cytotoxicity was assessed using a MTT assay. Nitric oxide production was measured by Griess assay. The production and expression of inflammatory mediators and the protein levels of inflammatory signaling molecules in the NF-κB and MAPK pathways were measured. Furthermore, immunofluorescence staining was used to analyze the expression of p-IκBα, p-ERK, and p-p38 in lung macrophages and the nuclear translocation of NF-κB p65 and AP-1 in cells. RESULTS: DA evidently alleviated histopathological changes and ameliorated pulmonary edema. Moreover, DA could reduce excessive inflammatory reaction in lung tissue as manifested by the reduction of proinflammatory mediators (IL-1ß, IL-6, TNF-α, MCP-1, iNOS, and COX-2) in BALF, serum, and lung tissues. Further, DA inhibited the activation of the NLRP3/caspase-1 pathway in the lung. DA reduced the production and expression of the proinflammatory mediators above in RAW264.7 cells. Mechanistically, DA remarkably blocked the nuclear translocation of NF-κB p65, suppressed IκBα phosphorylation, and markedly reduced the nuclear translocation of AP-1 and the phosphorylation of ERK and p38. CONCLUSIONS: The findings demonstrated that DA exerts anti-inflammatory effects in LPS-stimulated ALI mice and macrophages by downregulating the NLRP3/caspase-1 signaling pathway in lung tissue and the IκB/NF-κB and MAPKs/AP-1 pathways in macrophages, suggesting that DA may be promising in ALI treatment.


Assuntos
Lesão Pulmonar Aguda , Edema Pulmonar , Triterpenos , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Animais , Anti-Inflamatórios , Caspases/metabolismo , Ciclo-Oxigenase 2/metabolismo , Amarelo de Eosina-(YS) , Glicosídeos/farmacologia , Hematoxilina/farmacologia , Hematoxilina/uso terapêutico , Proteínas I-kappa B/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-6 , Lipopolissacarídeos/toxicidade , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR , Óxido Nítrico/metabolismo , RNA Mensageiro , Transdução de Sinais , Fator de Transcrição AP-1/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
20.
J Ethnopharmacol ; 300: 115757, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36167233

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Callicarpa arborea Roxb. is widely used as traditional medicine especially by the tribal people of Bangladesh in the management of wide range of ailments. In addition to Bangladesh, the leaves of this plant is utilized as a remedy to various painful and inflammatory conditions including rheumatism, toothache and stomachache in other countries of Indian subcontinent. AIM OF THE STUDY: Depending on the ethnomedicinal uses, we undertook this study to investigate the in-vivo analgesic and anti-inflammatory activities of the methanolic extract of C. arborea Roxb. leaves in Swiss albino mice as well as its chemical composition. MATERIALS AND METHODS: We evaluated the analgesic activity of Callicarpa arborea Roxb. leaves by the acetic acid induced writhing test, the hot plate test, and the formalin test. We undertook the egg albumin induced paw edema test to determine the anti-inflammatory activity of the plant. Furthermore, we conducted the phytochemical profiling by gas chromatography-mass spectrometry (GC-MS). RESULTS: In acute toxicity test, no mortality was observed at the highest dose of 2000 mg/kg b.w. Significant (p < 0.005) inhibition of acetic acid induced writhing was observed at both doses of the extract. A dose dependent increase in the response time was seen in the hot-plate test. In the formalin test, the extract significantly inhibited pain response in both early and late phase. We observed marked anti-inflammatory activity manifested by a significant (p < 0.005) reduction in egg albumin induced paw edema. We identified a total of twenty one compounds in the extract of by GC-MS analysis. CONCLUSION: Taken all into consideration we conclude that the leaves of C. arborea Roxb. possesses potent analgesic and anti-inflammatory activity, thus justifying its's ethnomedicinal use against painful and inflammatory pathological conditions.


Assuntos
Callicarpa , Ácido Acético/uso terapêutico , Albuminas/análise , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Edema/induzido quimicamente , Edema/tratamento farmacológico , Humanos , Metanol/uso terapêutico , Camundongos , Dor/induzido quimicamente , Dor/tratamento farmacológico , Dor/patologia , Extratos Vegetais/uso terapêutico , Extratos Vegetais/toxicidade , Folhas de Planta/química
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