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1.
Int J Mol Med ; 47(4): 1, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33537804

RESUMO

Quercetin (Quer) is a typical antioxidant flavonoid from plants that is involved in bone metabolism, as well as in the progression of inflammatory diseases. Elevated levels of tumor necrosis factor­α (TNF­α), a typical pro­inflammatory cytokine, can affect osteogenesis. In the present study, TNF­α was used to establish an in vitro model of periodontitis. The effects of Quer on, as well as its potential role in the osteogenic response of human periodontal ligament stem cells (hPDLSCs) under TNF­α­induced inflammatory conditions and the underlying mechanisms were then investigated. Within the appropriate concentration range, Quer did not exhibit any cytotoxicity. More importantly, Quer significantly attenuated the TNF­α induced the suppression of osteogenesis­related genes and proteins, alkaline phosphatase (ALP) activity and mineralized matrix in the hPDLSCs. These findings were associated with the fact that Quer inhibited the activation of the NF­κB signaling pathway, as well as the expression of NLRP3 inflammation­associated proteins in the inflammatory microenvironment. Moreover, the silencing of NLRP3 by small interfering RNA (siRNA) was found to protect the hPDLSCs against TNF­α­induced osteogenic damage, which was in accordance with the effects of Quer. On the whole, the present study demonstrates that Quer reduces the impaired osteogenesis of hPDLSCs under TNF­α­induced inflammatory conditions by inhibiting the NF­κB/NLRP3 inflammasome pathway. Thus, Quer may prove to be a potential remedy against periodontal bone defects.


Assuntos
Inflamassomos/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Osteogênese/efeitos dos fármacos , Ligamento Periodontal/patologia , Quercetina/farmacologia , Células-Tronco/patologia , Fator de Necrose Tumoral alfa/toxicidade , Adolescente , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Substâncias Protetoras/farmacologia , Transdução de Sinais/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos , Adulto Jovem
2.
Int J Mol Med ; 47(4): 1, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33537813

RESUMO

The activation of oxidative stress is a primary cause of chondrocyte apoptosis in osteoarthritis (OA). The 78­kDa glucose­regulated protein (GRP78)/mammalian target of rapamycin (mTOR) signaling pathway has been demonstrated to be linked with the endoplasmic reticulum (ER) and autophagy. Hydrogen sulfide (H2S) has been reported to exert antioxidant effects. The present study investigated oxidative stress levels via 2',7'­dichlorofluorescin diacetate and MitoSOX staining, apoptosis rates via flow cytometry and the expression levels of ER stress­related proteins in GYY4137 (donor of H2S)­treated chondrocytes (CHs). CHs were isolated from the bilateral hip joints of male rats to examine mitochondrial permeability transition pore opening­ and mTOR signaling pathway­related proteins. The results demonstrated that tert­Butyl hydroperoxide (TBHP) increased CH apoptosis, and treatment with GYY4137 ameliorated TBHP­mediated the generation of ROS and CH apoptosis. Moreover, TBHP­treated CHs displayed elevated ER stress sensor expression levels and apoptotic rates; however, the TBHP­induced protein expression levels were decreased following GYY4137 treatment. In the present study, treatment with either GYY4137 or transfection with GRP78 siRNA both suppressed the activation of p­P70S6k and p­mTOR. H2S played an important role in regulating ER stress in TBHP­stimulated CHs. GYY4137 promoted autophagy, which was accompanied by the inhibition of ER stress. On the whole, the present study demonstrates that TBHP­induced oxidative stress stimulates ER interactions and CH apoptosis, which are suppressed by exogenous H2S via modulating the GRP78/mTOR signaling pathway.


Assuntos
Condrócitos/metabolismo , Condrócitos/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Proteínas de Choque Térmico/metabolismo , Sulfeto de Hidrogênio/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cloroquina/farmacologia , Condrócitos/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Masculino , Morfolinas/química , Morfolinas/farmacologia , Compostos Organotiofosforados/química , Compostos Organotiofosforados/farmacologia , Peróxidos/farmacologia , Substâncias Protetoras/farmacologia , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
3.
Biomed Environ Sci ; 34(1): 40-49, 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33531106

RESUMO

Objective: Epidemiological studies reveal that exposure to fine particulate matter (aerodynamic diameter ≤ 2.5 µm, PM 2.5) increases the morbidity and mortality of respiratory diseases. Emerging evidence suggests that human circulating extracellular vesicles (EVs) may offer protective effects against injury caused by particulate matter. Currently, however, whether EVs attenuate PM 2.5-induced A549 cell apoptosis is unknown. Methods: EVs were isolated from the serum of healthy subjects, quantified via nanoparticle tracking analysis, and qualified by the marker protein CD63. PM 2.5-exposed (50 µg/mL) A549 cells were pre-treated with 10 µg/mL EVs for 24 h. Cell viability, cell apoptosis, and AKT activation were assessed via Cell Counting Kit-8, flow cytometry, and Western blot, respectively. A rescue experiment was also performed using MK2206, an AKT inhibitor. Results: PM 2.5 exposure caused a 100% increase in cell apoptosis. EVs treatment reduced cell apoptosis by 10%, promoted cell survival, and inhibited the PM 2.5-induced upregulation of Bax/Bcl2 and cleaved caspase 3/caspase 3 in PM 2.5-exposed A549 cells. Moreover, EVs treatment reversed PM 2.5-induced reductions in p-AKT Thr308 and p-AKT Ser473. AKT inhibition attenuated the anti-apoptotic effect of EVs treatment on PM 2.5-exposed A549 cells. Conclusions: EVs treatment promotes cell survival and attenuates PM 2.5-induced cell apoptosis via AKT phosphorylation. Human serum-derived EVs may be an efficacious novel therapeutic strategy in PM 2.5-induced lung injury.


Assuntos
Poluentes Atmosféricos/toxicidade , Vesículas Extracelulares , Material Particulado/toxicidade , Substâncias Protetoras/farmacologia , Soro , Células A549 , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-akt/metabolismo
4.
Medicine (Baltimore) ; 100(5): e24210, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33592865

RESUMO

BACKGROUND: With the development of social economy, people's lives are improving day by day. Chronic diseases represented by diabetes have gradually entered people's field of vision. At present, about 415 million people in the world suffer from diabetes, of which more than 90% are Type 2 diabetic mellitus (T2DM), which causes severe physical and mental pain to patients and their families, and also imposes a huge burden on the health care system. Animal experiments and clinical studies both show that Gegen Qinlian Decoction (GQD) cannot only reduce the blood glucose of T2DM, but also improve the islet function of patients, reduce the insulin resistance index and insulin secretion index, and have no adverse reactions. Therefore, we designed this protocol to evaluate the effect of GQD on clinical Prognosis and islet function for T2DM. METHODS: This review was conducted from January 1, 2000 to October 1, 2020, sourced from the Cochrane Library, Pubmed, Excerpt Medica Database, Science Direct, World Health Organization, International Clinical Trials Registration Platform, Web of Science, Chinese Biomedical Literature, the China National Knowledge Infrastructure Database, Wanfang Database, Chinese Scientific Journal Database. In this study clinical randomized controlled trial is used and we set inclusion criteria and exclusion criteria for screening. The primary outcomes include Fasting plasma glucose,2 h plasma glucose, Hemoglobin A1c, fasting plasma insulin, insulin resistance index and insulin secretion index. Review Manager 5.3 software will be used for data analysis. RESULTS: This study will provide the systematic evidence of the effect of GQD on Clinical Prognosis and islet function for T2DM. CONCLUSION: The findings of this meta-analysis will provide evidence to evaluate the effect of GQD on Clinical Prognosis and islet function for type 2 diabetic mellitus. INPLASY REGISTRATION NUMBER: INPLASY2020110083.


Assuntos
Diabetes Mellitus Tipo 2 , Medicamentos de Ervas Chinesas/farmacologia , Ilhotas Pancreáticas/efeitos dos fármacos , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Hipoglicemiantes/farmacologia , Metanálise como Assunto , Prognóstico , Substâncias Protetoras/farmacologia , Projetos de Pesquisa , Revisões Sistemáticas como Assunto , Resultado do Tratamento
5.
Nurs Clin North Am ; 56(1): 47-57, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33549285

RESUMO

Vitamin D can be obtained from diet, direct sunlight, or supplementation. The most common form is synthesized in the skin after exposure to ultraviolet B radiation. Nevertheless, the thought is that vitamin D is more of a multifunctional hormone or prohormone. This is because vitamin D plays contributes to many processes in the body. Calcitriol has been shown to have enhancing effects on the immune system, the cardiovascular system, the endocrine system, and other metabolic pathways. There is evidence that vitamin D has also a role in depression, pain, and cancer.


Assuntos
Antioxidantes/metabolismo , Calcitriol/metabolismo , Colecalciferol/metabolismo , Suplementos Nutricionais , Deficiência de Vitamina D/prevenção & controle , Antioxidantes/uso terapêutico , Colecalciferol/uso terapêutico , Humanos , Neoplasias/prevenção & controle , Substâncias Protetoras/metabolismo , Receptores de Calcitriol/metabolismo , Luz Solar
6.
Ecotoxicol Environ Saf ; 208: 111725, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33396056

RESUMO

Aflatoxin B1 (AFB1) is a potent hepatotoxic and carcinogenic agent. Curcumin possesses potential anti-inflammatory, anti-oxidative and hepatoprotective effects. However, the role of LncRNAs in the protective mechanisms of curcumin against AFB1-induced liver damage is still elusive. Experimental broilers were randomly divided into 1) control group, 2) AFB1 group (1 mg/kg feed), 3) cur + AFB1 group (1 mg/kg AFB1 plus 300 mg/kg curcumin diet) and 4) curcumin group (300 mg/kg curcumin diet). Liver transcriptome analyses and qPCR were performed to identify shifts in genes expression. In addition, histopathological assessment and oxidant status were determined. Dietary AFB1 caused hepatic morphological injury, significantly increased the production of ROS, decreased liver antioxidant enzymes activities and induced inflammation and apoptosis. However, dietary curcumin partially attenuated the abnormal morphological changes, oxidative stress, and apoptosis in liver tissues. Transcriptional profiling results showed that 34 LncRNAs and 717 mRNAs were differentially expressed with AFB1 and curcumin co-treatment in livers of broilers. Analysis of the LncRNA-mRNA network, GO and KEGG enrichment data suggested that oxidative stress, inflammation and apoptosis pathway were crucial in curcumin's alleviating AFB1-induced liver damage. In conclusion, curcumin prevented AFB1-induced oxidative stress, inflammation and apoptosis through LncRNAs. These results provide new insights for unveiling the protective mechanisms of curcumin against AFB1-induced liver damage.


Assuntos
Aflatoxina B1/toxicidade , Curcumina/farmacologia , Fígado/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/patologia , Galinhas/metabolismo , Dieta , Inflamação/metabolismo , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , RNA Longo não Codificante/metabolismo , RNA Longo não Codificante/farmacologia
7.
Ecotoxicol Environ Saf ; 208: 111743, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33396069

RESUMO

Autophagy dysregulation plays a pivotal role in cadmium (Cd)-induced nephrotoxicity. Quercetin (Qu), a flavonoid antioxidant with autophagy-enhancing effect, has protective effect on Cd-induced toxicity, but whether it can prevent Cd-induced nephrotoxicity via restoration of autophagy remains unknown. Here, primary rat proximal tubular (rPT) cells were exposed to Cd and/or Qu in vitro to clarify this issue. Data first showed that Cd-impaired autophagic flux was markedly alleviated by Qu, including decreased levels of autophagy marker proteins and recovery of autophagosome-lysosome fusion targeted for lysosomes. Meanwhile, Cd-induced lysosomal alkalization due to v-ATPases inhibition was prominently recovered by Qu. Accordingly, Qu enhanced Cd-diminished lysosomal degradation capacity and lysosome-related gene transcription levels. Notably, Qu improved Cd-inhibited TFEB nuclear translocation and its gene transcription level. Furthermore, data showed that the restoration of Cd-impaired autophagy-lysosome pathway and resultant alleviation of cytotoxicity by Qu are TFEB-dependent using TFEB gene silencing and overexpression technologies. In summary, these data provide novel evidences that the protective action of Qu against Cd-induced autophagy inhibition is attributed to its restoration of lysosomal dysfunction, which is dependent on TFEB.


Assuntos
Cádmio/toxicidade , Substâncias Protetoras/farmacologia , Quercetina/farmacologia , Animais , Autofagia/efeitos dos fármacos , Núcleo Celular/metabolismo , Células Epiteliais , Lisossomos/efeitos dos fármacos , Ratos
8.
Ecotoxicol Environ Saf ; 211: 111921, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33486382

RESUMO

Citric acid (CA) can regulate the balance of anions and cations in plants, and improve their resistance to heavy metals. It is not clear if foliar application with CA has any effect on migration of Cd and Mn in rice plant. In this work, a low-Cd-accumulating indica rice line (P7) and a high-Cd-accumulating line (HZ) were used to investigate the influence of CA on the transport of Cd and Mn as well as amino acid metabolism in grains. Content of Cd in grains and other organs increased with the increase of Cd content (0.1-2.4 mg kg-1) in soil, while decreased with the foliar application with CA. With the increase of Cd content in rice grains, the content of most amino acids in HZ, P7, HZ+CA and P7 + CA showed an obvious decline trend. Foliar application with CA efficiently raised the Mn:Cd ratio in grains and nodes of both HZ and P7. Meanwhile, the expression levels of OsNramp2, 3 and 5 in panicles were efficiently enhanced by CA application when plants grew in soil with Cd content of 0.6-2.4 mg kg-1. The increasing effect of CA on the content of 4 amino acids (i.e., Glu, Phe, Thr and Ala) in grains was related to varieties and Cd pollution. These results indicate that foliar application with CA can regulate the transport of Cd and Mn in the opposite directions in tissues and inhibit Cd accumulation in grains by enhancing expression of OsNRAMP 2, 3 or 5 and triggering the defense response of some amino acids in Cd-contaminated environment.


Assuntos
Aminoácidos/metabolismo , Cádmio/metabolismo , Ácido Cítrico/farmacologia , Grão Comestível/fisiologia , Manganês/metabolismo , Substâncias Protetoras/farmacologia , Transporte Biológico , Poluição Ambiental , Metais Pesados/análise , Oryza/metabolismo , Folhas de Planta/metabolismo , Raízes de Plantas/metabolismo , Solo/química , Poluentes do Solo/análise
9.
Ecotoxicol Environ Saf ; 211: 111909, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33450536

RESUMO

Paraquat (PQ) herbicide causes damage to green plant tissues by inducing the production of toxic reactive oxygen species (ROS). SUMOylation is an important post-translational modification that enables plants to defend against multiple stresses. However, it is still unknown whether the SUMOylation is involved in PQ resistance response in crops. Herein, we showed that a maize SUMO conjugating enzyme gene (ZmSCE1b) functioned in PQ resistance. The quantitative real-time PCR (qRT-PCR) analysis revealed that this gene was significantly up-regulated upon PQ exposure. The overexpression of ZmSCE1b increased the levels of SUMO conjugates and improved PQ resistance in transgenic Arabidopsis. The ZmSCE1b-transgenic plants showed lower levels of ROS and lipid peroxidation, as well as higher antioxidant enzyme activities, upon PQ exposure. Furthermore, Western blotting showed that levels of SUMOylation in these transgenic plants were significantly elevated. In addition, the abundance of transcripts of several defense-related genes was apparently up-regulated in the over-expressing lines using qRT-PCR. Collectively, our results manifested the effect of overexpression of ZmSCE1b in improving resistance to PQ, possibly by regulating the levels of SUMO conjugates, antioxidant machinery, and expression of defense genes. Findings of this study can facilitate the understanding of the regulatory mechanisms underlying the involvement of SCE-mediated SUMOylation in PQ resistance response in crop plants. Meanwhile, ZmSCE1b could be utilized for engineering PQ-resistant crops in phytoremediation.


Assuntos
Herbicidas/toxicidade , Paraquat/toxicidade , Proteínas de Plantas/metabolismo , Sumoilação/fisiologia , Zea mays/enzimologia , Antioxidantes/metabolismo , Arabidopsis/metabolismo , Herbicidas/metabolismo , Peroxidação de Lipídeos , Plantas Geneticamente Modificadas/metabolismo , Substâncias Protetoras/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima , Zea mays/metabolismo
10.
Life Sci ; 269: 119013, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33417950

RESUMO

OBJECTIVE: To investigate the protective efficacies and potent mechanisms of combination therapy with semaglutide and rosiglitazone (RSG) on the high-glucose incubated human ARPE-19 cells and diabetic retinopathy (DR) model rats. MAIN METHODS: The CCK-8 methods were used to evaluate the protective effects of semaglutide and RSG alone or combination on the cell viability of high-glucose treated ARPE-19 cells. After the DR rat model was established, the effects of combined treatment on general indexes, retinal morphological changes, retinal Müller cells as well as PI3K/Akt/MTOR related factors of DR model rats were investigated. RESULTS: The CCK-8 assay showed obviously enhanced protective efficacies of combination therapy with semaglutide and RSG on the ARPE-19 with oxidative stress induced by high-glucose with combination index all below 1.5 demonstrating obvious synergistic effects. Combined incubation could also effectively decrease the expression of inflammatory factors, including TNF-α, IL-1ß, IL-6, and the increase of ROS content in ARPE cell culture supernatant induced by high-glucose. Combined use of the antioxidant, PI3K/Akt and mTOR inhibitors, we further demonstrated that combined incubation of semaglutide and RSG could effectively by reduce high glucose-induced inflammatory injury inhibiting ROS/PI3K/Akt/mTOR signaling. Furthermore, chronic combination treatment effectively improved the histopathological characteristics and down-regulated the GFAP expression in Müller cells as well as PI3K/Akt/MTOR signaling pathway-related factors in retina which was better than any monomer treatment group. CONCLUSIONS: Combined semaglutide with RSG exhibited synergistically protective efficacies on retinal cells by decreasing the GFAP expression, inhibiting oxidative stress and PI3K/Akt/MTOR signaling-transduction in DR model rats.


Assuntos
Retinopatia Diabética/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Rosiglitazona/uso terapêutico , Animais , Antioxidantes/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Quimioterapia Combinada , Células Ependimogliais/efeitos dos fármacos , Células Ependimogliais/metabolismo , Células Ependimogliais/patologia , Proteína Glial Fibrilar Ácida/metabolismo , Peptídeos Semelhantes ao Glucagon/farmacologia , Humanos , Inflamação/patologia , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Rosiglitazona/farmacologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
11.
Life Sci ; 269: 119004, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33417960

RESUMO

BACKGROUND: Mesenchymal stem cells (MSCs) are widely applied in various clinical disorders, including acute lung injury (ALI). We aimed to investigate the effects of human umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs)-derived exosomal microRNA-22-3p (miR-22-3p) on lipopolysaccharid (LPS)-induced ALI via regulating frizzled class receptor 6 (FZD6). METHODS: Rat lung cells were selected to construct the LPS-induced ALI cell model. The LPS-treated cells were transfected with restored miR-22-3p and depleted FZD6 for investigating their roles in ALI. Human UCB-MSCs were cultured and exosomes were extracted. Rat lung cells were co-cultured with exosomes that had been transfected with restored miR-22-3p and upregulated FZD6 to detect their roles in inflammatory reaction, oxidative stress, cell proliferation activity and apoptosis. The ALI rat model was established through LPS inhalation and the rats were respectively treated. Then, the pathology, apoptosis and expression of the NF-κB signaling pathway-related factors in rat lung tissues were determined. RESULTS: miR-22-3p expression was reduced and FZD6 expression was enhanced in LPS-treated rat lung cells while exosomes raised miR-22-3p expression and decreased FZD6 expression. In LPS-treated cells, up-regulating miR-22-3p or depleting FZD6 reduced inflammatory reaction and oxidative stress response, raised rat lung cell proliferation activity and inhibited cell apoptosis rate. In the in vivo ALI model, exosomes suppressed pathological changes, apoptosis and NF-κB expression in LPS-treated rats. Upregulated miR-22-3p further attenuated ALI. CONCLUSION: Our study highlights the potential of UCB-MSC-exosomal miR-22-3p in preventing ALI. This study may provide further insights into ALI therapy.


Assuntos
Lesão Pulmonar Aguda/patologia , Exossomos/metabolismo , Sangue Fetal/citologia , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/metabolismo , Substâncias Protetoras/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Adulto , Animais , Apoptose , Sequência de Bases , Linhagem Celular , Proliferação de Células , Modelos Animais de Doenças , Progressão da Doença , Receptores Frizzled/metabolismo , Inativação Gênica , Humanos , Inflamação/patologia , Lipopolissacarídeos , Masculino , Estresse Oxidativo , Ratos Sprague-Dawley
12.
Life Sci ; 269: 119001, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33421527

RESUMO

AIMS: Osteoarthritis (OA) is a common joint disease and the main cause of disability. We sought to determine the effective concentration of emodin on chondrocytes and to identify the dosage of emodin that induces a comparable therapeutic effect with the COX-2 inhibitor drug, celecoxib that is currently used to treat OA. MATERIAL AND METHODS: In vitro experiments induced inflammation of chondrocytes by IL-1ß, and an osteoarthritis model was established in vivo by cutting rat anterior cruciate ligament. Western Blot, Real-time PCR, HE staining, Safranin O-green staining and immunohistochemistry were performed to detect MMP-3, MMP-13, ADAMTS-4, iNOS and COL2A1 on the chondrocytes or the tibial plateau. The cytokine activity and content in serum of six groups of rats were measured by kit. RESULTS: It was found that the surface layer of the cartilage was thicker and smoother after the administration of emodin. Tissue expression of MMP-3, MMP-13, ADAMTS-4 and iNOS were significantly (p < 0.05) decreased in chondrocytes and cartilage treated with different doses of emodin, and the content of COL2A1 was reversed. Emodin also significantly decreased the blood levels of COX-2 and PGE2. The effective emodin in vitro was 5 µmol/L, whereas emodin at 80 mg/kg was equivalent to celecoxib in vivo. CONCLUSION: Emodin reduces the expression of cartilage matrix degradation biomarkers, thereby reducing the degradation of cartilage matrix and protecting the knee joint cartilage. Emodin at 5 µmol/L shows the best concentration to treat chondrocytes, and the protective effect of emodin at 80 mg/kg is comparable to that of celecoxib.


Assuntos
Cartilagem Articular/patologia , Emodina/farmacologia , Matriz Extracelular/metabolismo , Articulação do Joelho/patologia , Substâncias Protetoras/farmacologia , Proteína ADAMTS4/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Condrócitos/patologia , Ciclo-Oxigenase 2/sangue , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Emodina/administração & dosagem , Matriz Extracelular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Metaloproteinases da Matriz/metabolismo , Óxido Nítrico/sangue , Óxido Nítrico Sintase Tipo II/sangue , Óxido Nítrico Sintase Tipo II/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Células Estromais/patologia
13.
Nat Commun ; 12(1): 487, 2021 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-33473105

RESUMO

Stress-induced glucocorticoids disturb mitochondrial bioenergetics and dynamics; however, instead of being removed via mitophagy, the damaged mitochondria accumulate. Therefore, we investigate the role of glucocorticoids in mitophagy inhibition and subsequent synaptic defects in hippocampal neurons, SH-SY5Y cells, and ICR mice. First, we observe that glucocorticoids decrease both synaptic density and vesicle recycling due to suppressed mitophagy. Screening data reveal that glucocorticoids downregulate BNIP3-like (BNIP3L)/NIX, resulting in the reduced mitochondrial respiration function and synaptic density. Notably, we find that glucocorticoids direct the glucocorticoid receptor to bind directly to the PGC1α promoter, downregulating its expression and nuclear translocation. PGC1α downregulation selectively decreases NIX-dependent mitophagy. Consistent with these results, NIX enhancer pre-treatment of a corticosterone-exposed mouse elevates mitophagy and synaptic density in hippocampus, improving the outcome of a spatial memory task. In conclusion, glucocorticoids inhibit mitophagy via downregulating NIX and that NIX activation represents a potential target for restoring synapse function.


Assuntos
Glucocorticoides/efeitos adversos , Proteínas de Membrana/metabolismo , Proteínas Mitocondriais/metabolismo , Mitofagia/fisiologia , Substâncias Protetoras/metabolismo , Sinapses/metabolismo , Animais , Morte Celular , Corticosterona/farmacologia , Hidrocortisona/farmacologia , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos ICR , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Mitofagia/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Proteínas Quinases/metabolismo
14.
RMD Open ; 7(1)2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33455920

RESUMO

BACKGROUND: The recent outbreak of COVID-19 has raised concerns in the rheumatology community about the management of immunosuppressed patients diagnosed with inflammatory rheumatic diseases. It is not clear whether the use of biological agents may suppose a risk or protection against SARS-CoV-2 infection; however, it has been suggested that severe respiratory forms of COVID-19 occur as a result of exacerbated inflammation status and cytokine production. This prompted the use of interleukin 6 (IL-6) (tocilizumab and sarilumab) and IL-1 inhibitors (anakinra) in severe COVID-19 disease and more recently JAK1/2 inhibitor (baricitinib). Therefore, patients with rheumatic diseases provide a great opportunity to learn about the use of biological agents as protective drugs against SARS-CoV-2. OBJECTIVES: To estimate COVID-19 infection rate in patients treated with biological disease-modifying antirheumatic drugs (bDMARDs) for inflammatory rheumatic diseases (RMD), determine the influence of biological agents treatment as risk or protective factors and study the prognosis of patients with rheumatic diseases receiving biological agents compared to the general population in a third-level hospital setting in León, Spain. METHODS: We performed a retrospective observational study including patients seen at our rheumatology department who received bDMARDs for rheumatic diseases between December 1st 2019 and December 1st 2020, and analysed COVID-19 infection rate. All patients who attended our rheumatology outpatient clinic with diagnosis of inflammatory rheumatic disease receiving treatment with biological agents were included. Main variable was the hospital admission related to COVID-19. The covariates were age, sex, comorbidities, biological agent, duration of treatment, mean dose of glucocorticoids and need for intensive care unit . We performed an univariate and multivariate logistic regression models to assess risk factors of COVID-19 infection. RESULTS: There were a total of 4464 patients with COVID-19 requiring hospitalisation. 40 patients out of a total of 820 patients with rheumatic diseases (4.8%) receiving bDMARDs contracted COVID-19 and 4 required hospital care. Crude incidence rate of COVID-19 requiring hospital care among the general population was 3.6%, and it was 0.89% among the group with underlying rheumatic diseases. 90% of patients receiving bDMARDS with COVID-19 did not require hospitalisation. Out of the 4464 patients, 869 patients died, 2 of which received treatment with biological agents. Patients with rheumatic diseases who tested positive for COVID-19 were older (female: median age 60.8 IQR 46-74; male: median age 61.9 IQR 52-70.3) than those who were negative for COVID-19 (female: median age 58.3 IQR 48-69; male: median age 56.2 IQR 47-66), more likely to have hypertension (45% vs 26%, OR 2.25 (CI 1.18-4.27),p 0.02), cardiovascular disease (23 % vs 9.6%, OR 2.73 (1.25-5.95), p 0.02), be smokers (13% vs 4.6%, OR 2.95 (CI 1.09-7.98), p 0.04), receiving treatment with rituximab (20% vs 8%, 2.28 (CI 1.24-6.32), p 0.02) and a higher dose of glucocorticoids (OR 2.5 (1.3-10.33, p 0.02) and were less likely to be receiving treatment with IL-6 inhibitors (2.5% vs 14%, OR 0.16, (CI 0.10-0.97, p 0.03). When exploring the effect of the rest of the therapies between groups (affected patients vs unaffected), we found no significant differences in bDMARD proportions. IL-1 inhibitors, IL-6 inhibitors, JAK inhibitors and belimumab-treated patients showed the lowest incidence of COVID-19 among adult patients with rheumatic diseases. We found no differences in sex or rheumatological disease between patients who tested positive for COVID-19 and patients who tested negative. CONCLUSIONS: Overall, the use of biological disease-modifying antirheumatic drugs (bDMARDs) does not associate with severe manifestations of COVID-19. Patients with rheumatic disease diagnosed with COVID-19 were more likely to be receiving a higher dose of glucocorticoids and treatment with rituximab. IL-6 inhibitors may have a protective effect.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/uso terapêutico , Fatores Biológicos/uso terapêutico , Surtos de Doenças , Glucocorticoides/uso terapêutico , Substâncias Protetoras/uso terapêutico , Doenças Reumáticas/tratamento farmacológico , Rituximab/uso terapêutico , /isolamento & purificação , Idoso , Anticorpos Monoclonais Humanizados/farmacologia , Feminino , Humanos , Interleucina-6/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , /imunologia , Espanha/epidemiologia , Resultado do Tratamento
15.
Chem Biol Interact ; 335: 109332, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33387473

RESUMO

Renal fibrosis is a major cause of renal failure in diabetic nephropathy. Tropisetron is an antagonist of the 5HT3 receptor that exhibits anti-fibrosis effects. The present research aimed to investigate the protected role of tropisetron against renal fibrosis of diabetic nephropathy and its molecular mechanisms. For this purpose, male Wistar rats were allocated into 5 groups of control, tropisetron, diabetes, tropisetron + diabetes, and glibenclamide + diabetes (n = 7). After induction of type 1 diabetes with a single injection of STZ, tropisetron (3 mg/kg) and glibenclamide (1 mg/kg) were given to the rats daily by intraperitoneal injection for 2 weeks. The obtained data revealed that the treatment of diabetic rats with tropisetron led to a significant decrease in the elevated blood glucose, serum cystatin c, and urinary total protein (UTP) level, indicating the improvement of the impaired kidney function. Moreover, the results of Masson's trichrome staining showed that fibrosis attenuated in the kidney of diabetic rats after tropisetron treatment. RT-PCR and Western blotting revealed that TGF-ß1, the apoptotic mediator, and p53 were considerably declined in the kidney of diabetic rats in response to tropisetron treatment. Meanwhile, the expressions of matrix metalloproteinase-9 (MMP-9) and matrix metalloproteinase-2 (MMP-2) were increased. These notable effects were equipotent with glibenclamide, as a standard drug, suggesting that tropisetron can alleviate renal fibrosis in diabetic nephropathy. Our data indicate that tropisetron could improve kidney function and attenuate renal fibrosis through regulation of TGF-ß1, p53, and expression of extracellular matrix metalloproteinases.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Fibrose/tratamento farmacológico , Rim/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Tropizetrona/uso terapêutico , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/patologia , Fibrose/patologia , Fibrose/prevenção & controle , Glucose/metabolismo , Rim/patologia , Masculino , Proteínas/metabolismo , Ratos Wistar , Estreptozocina
16.
Phytomedicine ; 80: 153382, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33113506

RESUMO

BACKGROUND: Although gastroprotective drugs have been used for peptic ulcer disease prevention and treatment, side effects have been observed. Finding a safe and effective treatment strategy is important. PURPOSE: Edible Trichodesma khasianum (T. khasianum) Clarke leaves are considered to protect against peptic ulcers. However, scientific evidence of this effect of T. khasianum Clarke leaves remains limited. STUDY DESIGN/METHODS: In this study, we aimed to evaluate the effect of T. khasianum Clarke leaves on ethanol-induced gastric injury and gut microbiota using RAW 264.7 cells, RGM-1 cells, and BALB/c mice, respectively. RESULT: The rosmarinic acid was identified as the major component of T. khasianum Clarke leaves extracted by 80% ethanol (80EETC). The results showed that 80EETC suppressed inflammatory mediator protein levels in LPS-induced RAW 264.7 cells. Additionally, heat shock protein expression, antiapoptotic ability, and wound healing migration capability were increased by 80EETC pretreatment in RGM-1 cells with the ethanol-induced injury. Remarkably, pretreatment with 80EETC (150 mg/kg b.w.) promoted gastric mucosal healing by decreasing oxidative stress, inflammatory response, proapoptotic protein expression, and gastric mucosa damage in ethanol-induced gastric injury in mice. Crucially, no liver or kidney toxicities were observed by 80EETC oral gavage. Moreover, 80EETC increased gut microbiota diversity and short-chain fatty acid production. CONCLUSION: Our results illustrated the remarkable gastroprotective effect by 80EETC treatment in vitro and in vivo. These findings are the first to demonstrate the powerful protective effect of T. khasianum Clarke leaves against gastric mucosal injury development.


Assuntos
Boraginaceae/química , Cinamatos/farmacologia , Depsídeos/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/metabolismo , Cinamatos/análise , Depsídeos/análise , Etanol/toxicidade , Ácidos Graxos Voláteis/metabolismo , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Microbioma Gastrointestinal/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estresse Oxidativo/efeitos dos fármacos , Úlcera Péptica/prevenção & controle , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Folhas de Planta/química , Substâncias Protetoras/química , Células RAW 264.7
17.
Phytomedicine ; 80: 153402, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33203590

RESUMO

BACKGROUND: Although great achievements have been made in the field of cancer therapy, chemotherapy and radiotherapy remain the mainstay cancer therapeutic modalities. However, they are associated with various side effects, including cardiocytotoxicity, nephrotoxicity, myelosuppression, neurotoxicity, hepatotoxicity, gastrointestinal toxicity, mucositis, and alopecia, which severely affect the quality of life of cancer patients. Plants harbor a great chemical diversity and flexible biological properties that are well-compatible with their use as adjuvant therapy in reducing the side effects of cancer therapy. PURPOSE: This review aimed to comprehensively summarize the molecular mechanisms by which phytochemicals ameliorate the side effects of cancer therapies and their potential clinical applications. METHODS: We obtained information from PubMed, Science Direct, Web of Science, and Google scholar, and introduced the molecular mechanisms by which chemotherapeutic drugs and irradiation induce toxic side effects. Accordingly, we summarized the underlying mechanisms of representative phytochemicals in reducing these side effects. RESULTS: Representative phytochemicals exhibit a great potential in reducing the side effects of chemotherapy and radiotherapy due to their broad range of biological activities, including antioxidation, antimutagenesis, anti-inflammation, myeloprotection, and immunomodulation. However, since a majority of the phytochemicals have only been subjected to preclinical studies, clinical trials are imperative to comprehensively evaluate their therapeutic values. CONCLUSION: This review highlights that phytochemicals have interesting properties in relieving the side effects of chemotherapy and radiotherapy. Future studies are required to explore the clinical benefits of these phytochemicals for exploitation in chemotherapy and radiotherapy.


Assuntos
Antineoplásicos/efeitos adversos , Compostos Fitoquímicos/farmacologia , Substâncias Protetoras/farmacologia , Radioterapia/efeitos adversos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Estresse Oxidativo/efeitos dos fármacos , Lesões por Radiação/prevenção & controle
18.
Ecotoxicol Environ Saf ; 207: 111501, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33254389

RESUMO

Deltamethrin (DLM) is widely used in agriculture and the prevention of human insect-borne diseases. However, the molecular mechanism of DLM induced liver injury remains unclear to date. This study investigated the potential molecular mechanism that DLM induced liver fibrosis in quails. Japanese quails received resveratrol (500 mg/kg) daily with or without DLM (45 mg/kg) exposure for 12 weeks. Histopathology, transmission electron microscopy, biochemical indexes, TUNEL, quantitative real-time PCR, and western blot analysis were performed. DLM exposure induced hepatic steatosis, oxidative stress, inflammation, and apoptosis. Most importantly, the Nrf2/TGF-ß1/Smad3 signaling pathway played an important role on DLM-induced liver fibrosis in quails. Interestingly, the addition of resveratrol, an Nrf2 activator, alleviates oxidative stress and inflammation response by activating Nrf2, thereby inhibits the liver fibrosis induced by DLM in quails. Collectively, these findings demonstrate that chronic exposure to DLM induces oxidative stress via the Nrf2 expression inhibition and apoptosis, and then results in liver fibrosis in quails by the activation of NF-κB/TNF-α and TGF-ß1/Smad3 signaling pathway.


Assuntos
Inseticidas/toxicidade , Cirrose Hepática/induzido quimicamente , Nitrilos/toxicidade , Substâncias Protetoras/farmacologia , Piretrinas/toxicidade , Codorniz/fisiologia , Resveratrol/farmacologia , Animais , Doença Hepática Induzida por Substâncias e Drogas , Humanos , Fator 2 Relacionado a NF-E2 , NF-kappa B/metabolismo , Estresse Oxidativo , Codorniz/metabolismo , Transdução de Sinais , Proteína Smad3 , Fator de Crescimento Transformador beta1/metabolismo
19.
Ecotoxicol Environ Saf ; 207: 111511, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33254391

RESUMO

Decidualization, which endows the endometrium competency to adopt developing embryo and maintain appropriate milieu for following growth, is a pivotal process for human pregnancy. The delicate collaboration between ovarian steroid hormones estrogen and progesterone governs the process of decidualization and subsequent establishment of embryo implantation. Mycotoxin zearalenone (ZEA) is well known as endocrine disruptor due to its potent estrogenic activity. In this study, we investigated effects of ZEA on decidualization of human endometrial stromal cells. Results indicated that ZEA exhibited its inhibitory action through nuclear translocation of ERα. ZEA exposure led to dampened progress of decidualization, which could be attenuated by estrogen receptor antagonist. Notably, resveratrol (RSV) administration restored impaired decidualization process by induction of anti-oxidative gene glutathione peroxidase 3 (GPX3). This study provides novel insights into the mechanism underlying adverse effects of ZEA in human decidual stromal cells and suggests RSV a potential therapeutic candidate to alleviate ZEA-induced cytotoxicity during decidualization.


Assuntos
Disruptores Endócrinos/toxicidade , Estrogênios não Esteroides/toxicidade , Substâncias Protetoras/farmacologia , Resveratrol/farmacologia , Zearalenona/toxicidade , Células Cultivadas , Decídua/efeitos dos fármacos , Implantação do Embrião/efeitos dos fármacos , Endométrio/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Receptor alfa de Estrogênio , Estrogênios/farmacologia , Feminino , Humanos , Gravidez , Progesterona/farmacologia , Células Estromais/efeitos dos fármacos
20.
Ecotoxicol Environ Saf ; 207: 111550, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33254408

RESUMO

Cadmium (Cd) is harmful to plant growth and can be easily transferred from soil to plants. Plant cell wall plays important role in preventing Cd from entering cells. Salicylic acid (SA) mediated defense response increases plant resistance to heavy metals. In this study, all tomato seedlings were pre-treated with 100 µM SA for 3 d, then seedlings were used to analyze the role of SA in regulating plant cell wall resistance to Cd stress. The results showed that exogenous SA significantly reduced Cd accumulation in tomato plants and changed Cd distribution. By analyzing the cell wall composition, it was found cellulose, hemicellulose, pectin, and lignin were induced by SA. Interestingly, the content of Cd in pectin decreased by SA pretreatment, however it was increased in cellulose. Gene expression analysis showed SA up-regulated the expression level of lignin and cellulose synthase genes, but down-regulated the expression of pectin methylesterase related genes. In addition, SA down-regulated the activity of pectin methylesterase. These results indicated that SA pretreatment up-regulated cell wall polysaccharide synthesis and related gene expression to thicken the cell wall and block Cd from passing through. Furthermore, SA decreased pectin methylesterase activity and content to reduce cell wall Cd accumulation and change the Cd partition ratio.


Assuntos
Cádmio/metabolismo , Lycopersicon esculentum/metabolismo , Substâncias Protetoras/farmacologia , Ácido Salicílico/farmacologia , Metabolismo dos Carboidratos , Parede Celular/metabolismo , Metilação , Pectinas/metabolismo , Raízes de Plantas/metabolismo , Polissacarídeos/metabolismo , Plântula/metabolismo
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