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1.
Redox Biol ; 67: 102868, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37690165

RESUMO

Kidney fibrosis is associated with tubular injury, oxidative stress and activation of interstitial fibroblasts. However, whether these events are somehow connected is poorly understood. In this study, we show that glutathione peroxidase-3 (GPX3) depletion in renal tubular epithelium after kidney injury plays a central role in orchestrating an oxidatively stressed extracellular microenvironment, which drives interstitial fibroblast activation and proliferation. Through transcriptional profiling by RNA-sequencing, we found that the expression of GPX3 was down-regulated in various models of chronic kidney disease (CKD), which was correlated with induction of nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase-4 (NOX4). By using decellularized extracellular matrix (ECM) scaffold, we demonstrated that GPX3-depleted extracellular microenvironment spontaneously induced NOX4 expression and reactive oxygen species (ROS) production in renal fibroblasts and triggered their activation and proliferation. Activation of NOX4 by advanced oxidation protein products (AOPPs) mimicked the loss of GPX3, increased the production of ROS, stimulated fibroblast activation and proliferation, and activated protein kinase C-α (PKCα)/mitogen-activated protein kinase (MAPK)/signal transducer and activator of transcription 3 (STAT3) signaling. Silencing NOX4 or inhibition of MAPK with small molecule inhibitors hampered fibroblast activation and proliferation. In mouse model of CKD, knockdown of NOX4 repressed renal fibroblast activation and proliferation and alleviated kidney fibrosis. These results indicate that loss of GPX3 orchestrates an oxidatively stressed extracellular microenvironment, which promotes fibroblast activation and proliferation through a cascade of signal transduction. Our studies underscore the crucial role of extracellular microenvironment in driving fibroblast activation and kidney fibrosis.


Assuntos
Rim , Insuficiência Renal Crônica , Camundongos , Animais , Espécies Reativas de Oxigênio/metabolismo , Rim/metabolismo , Insuficiência Renal Crônica/metabolismo , Fibroblastos/metabolismo , NADPH Oxidase 4/genética , NADPH Oxidase 4/metabolismo , Fibrose
2.
Kidney Int ; 103(6): 1063-1076, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36805449

RESUMO

The extracellular matrix (ECM) is a complex three-dimensional network of proteins surrounding cells, forming a niche that controls cell adhesion, proliferation, migration and differentiation. The ECM network provides an architectural scaffold for surrounding cells and undergoes dynamic changes in composition and contents during the evolution of chronic kidney disease (CKD). Here, we unveiled the proteomic landscape of the ECM by delineating proteome-wide and ECM-specific alterations in normal and fibrotic kidneys. Decellularized kidney tissue scaffolds were made and subjected to proteomic profiling by liquid chromatography with tandem mass spectrometry. A total of 172 differentially expressed proteins were identified in these scaffolds from mice with CKD. Through bioinformatics analysis and experimental validation, we identified a core set of nine signature proteins, which could play a role in establishing an oxidatively stressed, profibrotic, proinflammatory and antiangiogenetic microenvironment. Among these nine proteins, glutathione peroxidase 3 (GPX3) was the only protein with downregulated expression during CKD. Knockdown of GPX3 in vivo augmented ECM expression and aggravated kidney fibrotic lesions after obstructive injury. Transcriptomic profiling revealed that GPX3 depletion resulted in an altered expression of the genes enriched in hypoxia pathway. Knockdown of GPX3 induced NADPH oxidase 2 expression, promoted kidney generation of reactive oxygen species and activated p38 mitogen-activated protein kinase. Conversely, overexpression of exogenous GPX3 alleviated kidney fibrosis, inhibited NADPH oxidase 2 and p38 mitogen-activated protein kinase. These findings suggest that oxidative stress is a pivotal element of the fibrogenic microenvironment. Thus, our studies represent a comprehensive proteomic characterization of the ECM in the fibrotic kidney and provide novel insights into molecular composition of the fibrogenic microenvironment.


Assuntos
Proteômica , Insuficiência Renal Crônica , Camundongos , Animais , NADPH Oxidase 2/metabolismo , Matriz Extracelular/metabolismo , Fibrose , Rim/patologia , Insuficiência Renal Crônica/patologia , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo
3.
Artigo em Inglês | MEDLINE | ID: mdl-36031057

RESUMO

In the evolutionary model of dosage compensation, per-allele expression level of the X chromosome has been proposed to have twofold up-regulation to compensate its dose reduction in males (XY) compared to females (XX). However, the expression regulation of X-linked genes is still controversial, and comprehensive evaluations are still lacking. By integrating multi-omics datasets in mammals, we investigated the expression ratios including X to autosomes (X:AA ratio) and X to orthologs (X:XX ratio) at the transcriptome, translatome, and proteome levels. We revealed a dynamic spatial-temporal X:AA ratio during development in humans and mice. Meanwhile, by tracing the evolution of orthologous gene expression in chickens, platypuses, and opossums, we found a stable expression ratio of X-linked genes in humans to their autosomal orthologs in other species (X:XX ≈ 1) across tissues and developmental stages, demonstrating stable dosage compensation in mammals. We also found that different epigenetic regulations contributed to the high tissue specificity and stage specificity of X-linked gene expression, thus affecting X:AA ratios. It could be concluded that the dynamics of X:AA ratios were attributed to the different gene contents and expression preferences of the X chromosome, rather than the stable dosage compensation.

4.
Artigo em Inglês | MEDLINE | ID: mdl-30103464

RESUMO

Background: This paper investigates the problems regarding caffeinated drinks intake, late chronotype, and increased body mass index (BMI) among medical students at a Chinese university. Methods: This cross-sectional study was conducted in 2018 with 616 medical students from Chongqing Medical University in Chongqing, China, whose information were collected by a self-reported questionnaire that included four sections: Demographic characteristics; Caffeinated drinks intake and physical state; Morningness-Eveningness Questionnaire; Depression Anxiety Stress Scale 21. Multiple mediation analyses were conducted to test the impact of late chronotype on increased BMI through caffeinated drinks consumption through two models. Results: The significantly mediated effect of caffeinated drinks consumption was revealed (estimate: -0.01, SE = 0.01, 95% CI [-0.02, -0.01]), and which played a positive role in linking late chronotype (B = -0.01, SE = 0.01, p < 0.001) and increased BMI (B = 1.37, SE = 0.21, p < 0.01), but their significant association did not be found in reversed model. In addition, physical activity and inactivity times demonstrated significant indirect effects in the two models. Conclusions: Interventions should focus on reducing caffeinated drinks intake and sedentary behavior time, enhancing physical activity among medical students.


Assuntos
Bebidas/estatística & dados numéricos , Índice de Massa Corporal , Cafeína/administração & dosagem , Transtornos do Sono do Ritmo Circadiano/epidemiologia , Estudantes de Medicina/estatística & dados numéricos , China/epidemiologia , Estudos Transversais , Exercício Físico/fisiologia , Feminino , Humanos , Masculino , Transtornos do Sono do Ritmo Circadiano/induzido quimicamente , Inquéritos e Questionários , Universidades , Adulto Jovem
5.
PLoS One ; 13(6): e0199232, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29920547

RESUMO

BACKGROUND: The optimal antithrombotic therapy for atrial fibrillation (AF) patients undergoing coronary stenting is unknown. The present meta-analysis sought to investigate the efficacy and safety of triple therapy (TT; warfarin, clopidogrel and aspirin) vs dual antiplatelet therapy (DAPT; clopidogrel plus aspirin) in those patients. METHODS: PubMed and Cochrane Library were searched for studies enrolling AF patients undergoing coronary stenting on TT and DAPT up to September 2016, and fourteen studies were included. Efficacy outcomes included ischemic stroke, stent thrombosis, major adverse cardiovascular event (MACE), all-cause mortality and myocardial infarction (MI); safety outcome was major bleeding. We conducted meta-analysis and used odds ratio (OR) with 95% confidence intervals (CI) to compare TT and DAPT. Meta-regression, sensitivity and subgroup analysis were taken to investigate the source of heterogeneity in the outcome of major bleeding. RESULTS: 14 eligible observational studies with 11,697 subjects were identified. Compared with DAPT, TT had decreased the risk of ischemic stroke [OR = 0.74, 95% CI (0.59, 0.93), P = 0.009] and stent thrombosis [OR = 0.40, 95% CI (0.18, 0.93), P = 0.033]. While, there was an increased risk of major bleeding [OR = 1.55, 95% CI (1.16, 2.09), P = 0.004] associated with TT. The risk of MACE, all-cause mortality and MI had no significant statistical difference between TT and DAPT. Furthermore, the results of univariate and multivariate meta-regression analysis implicated that there were no obvious correlations between certain baseline characteristics (age, gender, race, hypertension, study design) and risk of major bleeding. Also of major bleeding, the findings of sensitivity analysis were generally robust, and a prespecified subgroup analysis of race demonstrated that the source of heterogeneity might attribute to Asian studies mostly. CONCLUSIONS: TT reduced the risk of ischemic stroke and stent thrombosis with an acceptable major bleeding risk compared with DAPT, and TT was considered as a valid alternative in AF patients undergoing coronary stenting. Further prospective randomized trials are needed to ensure the reliability of these data and find the optimal therapeutic strategy in this setting of patients.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Fibrinolíticos/efeitos adversos , Inibidores da Agregação Plaquetária/efeitos adversos , Aspirina/efeitos adversos , Aspirina/uso terapêutico , Fibrilação Atrial/complicações , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/cirurgia , Clopidogrel/efeitos adversos , Clopidogrel/uso terapêutico , Combinação de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Fibrinolíticos/uso terapêutico , Hemorragia/complicações , Hemorragia/tratamento farmacológico , Hemorragia/patologia , Humanos , Hipertensão/epidemiologia , Hipertensão/patologia , Masculino , Infarto do Miocárdio/complicações , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/patologia , Inibidores da Agregação Plaquetária/uso terapêutico , Fatores de Risco , Stents , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/patologia , Trombose/complicações , Trombose/epidemiologia , Trombose/patologia , Varfarina/efeitos adversos , Varfarina/uso terapêutico
6.
Oncol Res ; 20(2-3): 61-9, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23193912

RESUMO

Fentanyl is used as an analgesic to treat pain in a variety of patients with cancer. Moreover, fentanyl may affect tumor growth in many cell lines. To gain better insight into the interaction between fentanyl and tumor, we investigated the effects of fentanyl on the growth of gastric carcinoma cells and the expression of some apoptosis-related genes including NF-kappaB and PTEN. A human gastric cancer cell line MGC-803 was used. The viability and proliferation of gastric cancer MGC-803 cells were detected by MTT assay and colony formation assay. The cell cycle progression and apoptosis were assessed by flow cytometry and the ultrastructure of cells was examined with transmission electron microscope. The migration of cells was investigated by wound healing assay. The expression of NF-kappaB and PTEN was evaluated by semiquantitative RT-PCR and Western blot. Our data showed that fentanyl could inhibit cell growth and proliferation and made cell cycle arrest at G2/M phase. Compared with control cells, MGC-803 cells that were incubated with fentanyl also had a higher apoptotic rate. Fentanyl could lead to morphological changes of gastric cancer cells and reduce the motility of MGC-803 cells. Moreover, fentanyl could downregulate NF-kappaB and upregulate PTEN, which might be the mechanism of fentanyl inhibiting gastric cancer progression in vitro.


Assuntos
Apoptose/efeitos dos fármacos , Fentanila/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , NF-kappa B/metabolismo , Entorpecentes/farmacologia , PTEN Fosfo-Hidrolase/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Western Blotting , Divisão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citometria de Fluxo , Fase G2/efeitos dos fármacos , Humanos , NF-kappa B/genética , PTEN Fosfo-Hidrolase/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Gástricas/patologia , Células Tumorais Cultivadas , Cicatrização/efeitos dos fármacos
7.
Zhonghua Er Ke Za Zhi ; 50(5): 361-5, 2012 May.
Artigo em Chinês | MEDLINE | ID: mdl-22883038

RESUMO

OBJECTIVE: Intravenous anesthetics, such as propofol, are widely used in general anesthesia. Neurodegeneration and neurocognitive impairment after exposure to propofol in neonatal rats have raised concerns regarding the safety of pediatric anesthesia. We examined the effects of neonatal propofol exposure on brain cell viability, as well as expression of hippocampal survivin and Caspase-3 mRNA and protein. METHODS: One hundred male Sprague-Dawley rats aged 7 d that were weighed 10-15 g were randomly divided into 4 groups (n = 25 each group). Group A: the rats were injected with no drugs. Group B: the rats were intraperitoneally injected with 50 mg/kg propofol. Group C: the rats were first intraperitoneally injected with 50 mg/kg propofol and another 50 mg/kg propofol was used when the dynamic response of rats appeared again. Group D: the rats were first intraperitoneally injected with 50 mg/kg propofol and another 50 mg/kg propofol was used three times once the dynamic response of rats appeared. To study the effects of propofol exposure on respiratory and metabolic function, arterial blood was aspirated from the left ventricle of neonatal rats 2 h after discontinuation of propofol. pH, PaO(2), PaCO(2), HCO(3)(-), BE and SaO(2) were detected by blood gas analyzer. Moreover, to examine the effects of propofol exposure on short-term cellular viability, the ultrastructure of neurons was observed by transmission electron microscope and Fluoro-Jade B (FJB) staining was performed to examine neuronal degeneration in hippocampal CA1 region of neonatal rats. Survivin and Caspase-3 mRNA and protein expression in hippocampus were detected by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) and Western blotting 2 h after discontinuation of propofol. RESULTS: The time of anesthesia maintaince in newborn rats was the longest in Group D and the time of anesthesia maintaince in Group C was longer than that in Group B. Two hours after discontinuation of propofol, pH, PaO(2), PaCO(2), HCO(3)(-), BE and SaO(2) of arterial blood in rats were not significantly different among groups A, B, C and D (P > 0.05). The structure of hippocampal neurons was normal in Group A and Group B while 100 mg/kg propofol resulted in nuclear blebbing and 200 mg/kg propofol led to nuclear fragmentation, chromatin condensation and apoptotic bodies. Cellular degeneration, as measured by Fluoro-Jade B staining, significantly increased in hippocampal CA1 region in the anesthesia groups compared with littermates in the no anesthesia group. FJB-positive stained degenerative neurons in groups B, C and D were (2.5 ± 1.3), (7.1 ± 2.3) and (9.4 ± 2.6), which were different from that in Group A (0.6 ± 0.3) (P < 0.05). Moreover, the number of FJB-positive neurons was the highest in Group D, that in Group C was more than that in Group B. At the same time point, apoptosis was measured by expression of Caspase-3 and Survivin mRNA and protein in hippocampus of rats. Caspase-3 mRNA in groups A, B and C was (0.78 ± 0.12), (0.84 ± 0.17) and (0.89 ± 0.19), while Caspase-3 protein in groups A, B and C was (0.22 ± 0.05), (0.26 ± 0.07) and (0.21 ± 0.06). Survivin mRNA in groups A, B and C was (0.56 ± 0.12), (0.58 ± 0.15) and (0.53 ± 0.16), while Survivin protein in these 3 groups was (0.24 ± 0.07), (0.21 ± 0.05) and (0.23 ± 0.06). Compared with that in Group A, Caspase-3 and Survivin mRNA and protein were not significantly different among Group B and Group C (P > 0.05). However, Caspase-3 mRNA and protein in Group D were (1.21 ± 0.14) and (0.42 ± 0.12), which were higher than that in the other 3 groups (P < 0.05). Survivin mRNA and protein in Group D were lower than that in the other 3 groups (P < 0.05). CONCLUSIONS: A high dose of propofol exposure may destroy the structure of neurons, induce neurodegeneration, increase Caspase-3 activity and inhibit survivin expression in hippocampus of newborn rats in vivo.


Assuntos
Anestésicos Intravenosos/administração & dosagem , Caspase 3/metabolismo , Hipocampo/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Propofol/administração & dosagem , Anestésicos Intravenosos/farmacologia , Animais , Animais Recém-Nascidos , Gasometria , Caspase 3/genética , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Injeções Intraperitoneais , Masculino , Proteínas Associadas aos Microtúbulos/genética , Neurônios/metabolismo , Neurônios/patologia , Propofol/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Survivina
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