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1.
Artigo em Inglês | MEDLINE | ID: mdl-33529089

RESUMO

AIM: Vascular endothelial cell senescence is a leading cause of age-associated diseases and cardiovascular diseases. Interventions and therapies targeting endothelial cell senescence and dysfunction would have important clinical implications. This study was aimed to evaluate the effect of 10 resveratrol analogues, including pterostilbene (Pts) and its derivatives, against endothelial senescence and dysfunction. METHODS AND RESULTS: All the tested compounds at the concentrations from 10-9 M to 10-6 M did not show cytotoxicity in endothelial cells. Among the 10 resveratrol analogues, Pts and Pts nicotinate attenuated the expression of senescence-associated ß-galactosidase, downregulated p21 and p53, and increased the production of NO in both angiotensin II and H2O2-induced endothelial senescence models. In addition, Pts and Pts nicotinate elicited endothelium-dependent relaxations. Pts and Pts nicotinate did not alter Sirtuin 1 (SIRT1) expression but enhanced its activity. Both Pts and Pts nicotinate have high binding activities with SIRT1. Inhibition of SIRT1 by sirtinol reversed the anti-senescent effects of Pts and Pts nicotinate. CONCLUSIONS: This study suggests that the Pts and Pts nicotinate ameliorated vascular endothelial senescence and elicited endothelium-dependent relaxations via activation of SIRT1. These two compounds maybe potential drugs for the treatment of cardiovascular diseases related to endothelial senescence and dysfunction.

2.
Mil Med Res ; 7(1): 61, 2020 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-33287895

RESUMO

In October 2020, Dr. Emmanuelle Charpentier and Dr. Jennifer Doudna won the Nobel Prize in Chemistry for their pioneering work in precise genome editing using the CRISPR technology. Although CRISPR technology has developed rapidly in the last decade, there are still many uncertainties before eventual use in clinical settings. In this mini review, we summarize the current efforts in addressing the limitations of CRISPR technology and future directions.

3.
J Clin Invest ; 2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33206630

RESUMO

Bone is maintained by coupled activities of bone-forming osteoblasts/osteocytes and bone-resorbing osteoclasts. Alterations in this relationship can lead to pathologic bone loss, such as osteoporosis. It is well known that osteogenic cells support osteoclastogenesis via production of RANKL. Interestingly, our recently identified bone marrow mesenchymal cell population-marrow adipogenic lineage precursors (MALPs) that form a multi-dimensional cell network in bone-was computationally demonstrated to be the most interactive with monocyte-macrophage lineage cells through high and specific expression of several osteoclast regulatory factors, including RANKL. Using an adipocyte-specific Adipoq-Cre to label MALPs, we demonstrated that mice with RANKL deficiency in MALPs have a drastic increase in trabecular bone mass in long bones and vertebrae starting from 1 month of age, while their cortical bone appears normal. This phenotype was accompanied by diminished osteoclast number and attenuated bone formation at the trabecular bone surface. Reduced RANKL signaling in calvarial MALPs abolished osteolytic lesions after lipopolysaccharide (LPS) injections. Furthermore, in ovariectomized mice, elevated bone resorption was partially attenuated by RANKL deficiency in MALPs. In summary, our studies identified MALPs as a critical player in controlling bone remodeling during normal bone metabolism and pathological bone loss in a RANKL-dependent fashion.

4.
Phytomedicine ; 79: 153350, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33002827

RESUMO

BACKGROUND: Vascular endothelial activation is pivotal for the pathological development of various infectious and inflammatory diseases. Therapeutic interventions to prevent endothelial activation are of great clinical significance to achieve anti-inflammatory strategy. Previous studies indicate that the total flavonoids from the endemic herbal medicine Nervilia fordii (Hance) Schltr exerts potent anti-inflammatory effect and protective effect against endotoxin lipopolysaccharide (LPS)-induced acute lung injury, and shows clinical benefit in severe acute respiratory syndromes (SARS). However, the exact effective component of Nervilia fordii and its potential mechanism remain unknown. PURPOSE: The aim of this study was to investigate the effect and mechanism of rhamnocitrin (RH), a flavonoid extracted from Nervilia fordii, on LPS-induced endothelial activation. METHODS: The in vitro endothelial cell activation model was induced by LPS in human umbilical vein endothelial cells (HUVECs). Cell viability was measured to determine the cytotoxicity of RH. RT-PCR, Western blot, fluorescent probe and immunofluorescence were conducted to evaluate the effect and mechanism of RH against endothelial activation. RESULTS: RH was extracted and isolated from Nervilia fordii. RH at the concentration from 10-7 M-10-5 M inhibited the expressions of interlukin-6 (IL-6) and -8 (IL-8), monocyte chemotactic protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), vascular cell-adhesion molecule-1 (VCAM-1), and plasminogen activator inhibitor-1 (PAI-1) in response to LPS challenge. Mechanistically, RH repressed calcium store-operated Ca2+ entry (SOCE) induced by LPS, which is due to downregulation of stromal interaction molecule-1 (STIM-1) following upregulating microRNA-185 (miR-185). Ultimately, RH abrogated LPS-induced activation of SOCE-mediated calcineurin/NFATc3 (nuclear factor of activated T cells, cytoplasmic 3) signaling pathway. CONCLUSION: The present study identifies RH as a potent inhibitor of endothelial activation. Since vascular endothelial activation is a pivotal cause of excessive cytokine production, leading to cytokine storm and severe pathology in infectious diseases such as SARS and the ongoing COVID-19 pneumonia disease, RH might suggest promising therapeutic potential in the management of cytokine storm in these diseases.


Assuntos
Endotélio Vascular/efeitos dos fármacos , Proteínas Sensoras de Cálcio Intracelular/metabolismo , Quempferóis/farmacologia , Proteínas de Membrana/metabolismo , Fatores de Transcrição NFATC/metabolismo , Proteínas de Neoplasias/metabolismo , Orchidaceae/química , Molécula 1 de Interação Estromal/metabolismo , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Endotélio Vascular/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Quempferóis/isolamento & purificação , Lipopolissacarídeos/farmacologia , Pandemias , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Molécula 1 de Adesão de Célula Vascular/metabolismo
5.
Acta Physiol (Oxf) ; : e13555, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32886850

RESUMO

AIM: By activating prostacyclin receptors (IP receptors), prostacyclin (PGI2 ) exerts cardiovascular protective effects such as vasodilation and inhibition of vascular smooth muscle cell (VSMC) proliferation. However, IP receptors are dysfunctional under pathological conditions, and PGI2 produces detrimental effects that are opposite to its physiological protective effects via thromboxane-prostanoid (TP) receptors. This attempted to investigate whether or not IP receptor dysfunction facilitates the shift of PGI2 action. METHODS: The effects of PGI2 and its stable analog iloprost on VSMC phenotypic transformation and proliferation were examined in A10 cells silencing IP receptors, in human aortic VSMCs (HAVSMCs) knocked down IP receptor by CRISPR-Cas9, or in HAVSMCs transfected with a dysfunctional mutation of IP receptor IPR212C . RESULTS: PGI2 /iloprost treatment stimulated cell proliferation, upregulated synthetic proteins and downregulated contractile proteins, suggesting that PGI2 /iloprost promotes VSMC phenotypic transformation in IP-deficient cells. The effect of PGI2 /iloprost was prevented by TP antagonist S18886 or TP knockdown, indicating that the VSMC detrimental effect of PGI2 is dependent on TP receptor. RNA sequencing and Western blotting results showed that RhoA/ROCKs, MEK1/2 and JNK signalling cascades were involved. Moreover, IP deficiency increased the distribution of TP receptors at the cell membrane. CONCLUSION: PGI2 induces VSMC phenotypic transformation when IP receptors are impaired. This is attributed to the activation of TP receptor and its downstream signaling cascades, and to the increased membrane distribution of TP receptors. The VSMC detrimental effect of PGI2 medicated by IP dysfunction and TP activation might probably exacerbate vascular remodelling, accelerating cardiovascular diseases.

6.
Biomed Res Int ; 2020: 6297356, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32766310
7.
PLoS One ; 15(3): e0230670, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32231397

RESUMO

The human positive coactivator 4 (PC4) was originally identified as a multi-functional cofactor capable of mediating transcription activation by diverse gene- and tissue-specific activators. Recent studies suggest that PC4 might also function as a novel cancer biomarker and therapeutic target for different types of cancers. siRNA knockdown studies indicated that down-regulation of PC4 expression could inhibit tumorigeneicity of A549 non-small cell lung cancer tumor model in nude mice. Here we show that AG-1031, a small molecule identified by high throughput screening, can inhibit the double-stranded DNA binding activity of PC4, more effectively than its single-stranded DNA binding activity. AG-1031 also specifically inhibited PC4-dependent transcriptional activation in vitro using purified transcription factors. AG-1031 inhibited proliferation of several cultured cell lines derived from non-small cell lung cancers (NSCLC) and growth of tumors that formed from A549 cell xenografts in immuno-compromised mice. Moreover, pre-injection of AG-1031 in these mice not only reduced tumor size, but also prevented tumor formation in 20% of the animals. AG-1031 treated A549 cells and tumors from AG-1031 treated animals showed a significant decrease in the levels of both PC4 and VEGFC, a key mediator of angiogenesis in cancer. On the other hand, all tested mice remained constant weight during animal trials. These results demonstrated that AG-1031 could be a potential therapy for PC4-positive NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proteínas de Ligação a DNA/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Compostos Orgânicos/uso terapêutico , Fatores de Transcrição/antagonistas & inibidores , Células A549 , Animais , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/efeitos dos fármacos , DNA/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Compostos Orgânicos/farmacologia , Ligação Proteica , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcrição Genética/efeitos dos fármacos , Transplante Heterólogo , Fator C de Crescimento do Endotélio Vascular/metabolismo
8.
Biomed Res Int ; 2020: 4791786, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32190665

RESUMO

Heightened activity of osteoclast is considered to be the culprit in breaking the balance during bone remodeling in pathological conditions, such as osteoporosis. As a "foe" of skeletal health, many antiosteoporosis therapies aim to inhibit osteoclastogenesis. However, bone remodeling is a dynamic process that requires the subtle coordination of osteoclasts and osteoblasts. Severe suppression of osteoclast differentiation will impair bone formation because of the coupling effect. Thus, understanding the complex roles of osteoclast in maintaining proper bone remodeling is highly warranted to develop better management of osteoporosis. This review aimed to determine the varied roles of osteoclasts in maintaining skeletal health and to highlight the positive roles of osteoclasts in maintaining normal bone remodeling. Generally, osteoclasts interact with osteocytes to initiate targeted bone remodeling and have crosstalk with mesenchymal stem cells and osteoblasts via secreted factors or cell-cell contact to promote bone formation. We believe that a better outcome of bone remodeling disorders will be achieved when proper strategies are made to coordinate osteoclasts and osteoblasts in managing such disorders.

9.
Elife ; 82019 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-31490121

RESUMO

Regulators of G-protein Signaling are a conserved family of proteins required in various biological processes including cell differentiation. We previously demonstrated that Rgs12 is essential for osteoclast differentiation and its deletion in vivo protected mice against pathological bone loss. To characterize its mechanism in osteoclastogenesis, we selectively deleted Rgs12 in C57BL/6J mice targeting osteoclast precursors using LyzM-driven Cre mice or overexpressed Rgs12 in RAW264.7 cells. Rgs12 deletion in vivo led to an osteopetrotic phenotype evidenced by increased trabecular bone, decreased osteoclast number and activity but no change in osteoblast number and bone formation. Rgs12 overexpression increased osteoclast number and size, and bone resorption activity. Proteomics analysis of Rgs12-depleted osteoclasts identified an upregulation of antioxidant enzymes under the transcriptional regulation of Nrf2, the master regulator of oxidative stress. We confirmed an increase of Nrf2 activity and impaired reactive oxygen species production in Rgs12-deficient cells. Conversely, Rgs12 overexpression suppressed Nrf2 through a mechanism dependent on the 26S proteasome, and promoted RANKL-induced phosphorylation of ERK1/2 and NFκB, which was abrogated by antioxidant treatment. Our study therefore identified a novel role of Rgs12 in regulating Nrf2, thereby controlling cellular redox state and osteoclast differentiation.


Assuntos
Antioxidantes/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Osteogênese , Proteínas RGS/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Animais , Regulação da Expressão Gênica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células RAW 264.7 , Proteínas RGS/deficiência
10.
J Bone Miner Res ; 34(4): 752-764, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30489658

RESUMO

Bone homeostasis intimately relies on the balance between osteoblasts (OBs) and osteoclasts (OCs). Our previous studies have revealed that regulator of G protein signaling protein 12 (Rgs12), the largest protein in the Rgs super family, is essential for osteoclastogenesis from hematopoietic cells and OC precursors. However, how Rgs12 regulates OB differentiation and function is still unknown. To understand that, we generated an OB-targeted Rgs12 conditional knockout (CKO) mice model by crossing Rgs12fl/fl mice with Osterix (Osx)-Cre transgenic mice. We found that Rgs12 was highly expressed in both OB precursor cells (OPCs) and OBs of wild-type (WT) mice, and gradually increased during OB differentiation, whereas Rgs12-CKO mice (OsxCre/+ ; Rgs12fl/fl ) exhibited a dramatic decrease in both trabecular and cortical bone mass, with reduced numbers of OBs and increased apoptotic cell population. Loss of Rgs12 in OPCs in vitro significantly inhibited OB differentiation and the expression of OB marker genes, resulting in suppression of OB maturation and mineralization. Further mechanism study showed that deletion of Rgs12 in OPCs significantly inhibited guanosine triphosphatase (GTPase) activity and cyclic adenosine monophosphate (cAMP) level, and impaired Calcium (Ca2+ ) oscillations via restraints of major Ca2+ entry sources (extracellular Ca2+ influx and intracellular Ca2+ release from endoplasmic reticulum), partially contributed by the blockage of L-type Ca2+ channel mediated Ca2+ influx. Downstream mediator extracellular signal-related protein kinase (ERK) was found inactive in OBs of OsxCre/+ ; Rgs12fl/fl mice and in OPCs after Rgs12 deletion, whereas application of pertussis toxin (PTX) or overexpression of Rgs12 could rescue the defective OB differentiation via restoration of ERK phosphorylation. Our findings reveal that Rgs12 is an important regulator during osteogenesis and highlight Rgs12 as a potential therapeutic target for bone disorders. © 2018 American Society for Bone and Mineral Research.


Assuntos
Sinalização do Cálcio , Diferenciação Celular , Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo , Sistema de Sinalização das MAP Quinases , Osteoblastos/metabolismo , Proteínas RGS/metabolismo , Animais , Canais de Cálcio Tipo L/genética , Canais de Cálcio Tipo L/metabolismo , Feminino , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Masculino , Camundongos , Camundongos Knockout , Osteogênese/genética , Proteínas RGS/genética
11.
Medicine (Baltimore) ; 97(31): e11627, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30075541

RESUMO

BACKGROUND: Irritable bowel syndrome (IBS) is a common functional intestinal disease characterized by chronic or recurrent abdominal pain, abdominal distension, constipation and diarrhea. Many IBS sufferers are usually present with poor quality of life for the abdominal discomfort, diarrhea, constipation, and other complaints. At present, the commonly used drug therapy for IBS in the Western clinic, such as antidiarrheal, laxative, gastrointestinal antispasmodic, often cannot get satisfying curative effect. Thus complementary therapies like electroacupuncture (EA) which may be effective to decrease patients' pain and fewer side-effects will be sought. EA, an innovative form of traditional acupuncture, is drawing more attention to the treatment of IBS due to its roles in symptom improvement. This systematic review protocol aims at describing a meta-analysis to critically evaluate the effectiveness and safety on EA for patients with IBS. METHODS: We search Ovid MEDLINE, Ovid Embase, PubMed, the Cochrane Central Register of Controlled Trials (Cochrane Library), the Allied and Complementary Medicine Databases (AMED), China National Knowledge Infrastructure (CNKI) for random controlled trials EA for IBS from their inception to April 1, 2018. Two reviewers will independently screen studies for data extraction and assess the quality and risk of bias. RevManV5. 3 will be applied to data extraction. Risk of bias for each RCT will be assessed according to criteria by the Cochrane Handbook to evaluate the methodological quality. RESULTS: This study will provide a high-quality synthesis of current evidence of effectiveness and safety on EA for patients with IBS. CONCLUSION: The conclusion of our systematic review will provide evidence to judge whether EA is an effective intervention for patient with IBS. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42018081610.


Assuntos
Eletroacupuntura/métodos , Síndrome do Intestino Irritável/terapia , Adulto , Protocolos Clínicos , Feminino , Humanos , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Revisões Sistemáticas como Assunto , Resultado do Tratamento
12.
Medicine (Baltimore) ; 97(27): e11063, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29979377

RESUMO

BACKGROUND: Insomnia is a highly widespread sleep disorder in the general population. Electroacupuncture (EA) has been widely received attention as a potential treatment for primary insomnia. However, few previous studies are available to report that EA is a beneficial therapeutic approach to primary insomnia. In addition, there is no critical systematic review or meta-analysis published regarding the effectiveness of this treatment. Here, we provide a protocol to systematically evaluate the efficacy and safety of EA for primary insomnia. METHODS: The reference lists of included studies for relevant randomized controlled trials and 8 electronic databases will be systematically searched by 2 review authors in January 2018, including 4 English databases (PubMed, EMBASE, Cochrane Central Register of Controlled Trials and Cumulative Index to Nursing and Allied Health Literature) and 4 Chinese databases (Chinese National Knowledge Infrastructure, Chinese Biomedical Literature Database, VIP Database, and Wanfang Database). The primary outcomes will be assessed according to the Pittsburgh Sleep Quality Index. Data synthesis will be computed with the use of RevManV5.3 software when a data-analysis is allowed. Methodological quality will be evaluated with the risk of bias according to Cochrane Handbook. RESULTS: This study will provide a high-quality synthesis of current evidence of EA for primary insomnia. CONCLUSION: The conclusion of this systematic review will provide evidence to judge whether EA is an effective therapeutic intervention for patient with primary insomnia.


Assuntos
Eletroacupuntura/métodos , Distúrbios do Início e da Manutenção do Sono/terapia , Humanos , Avaliação de Resultados em Cuidados de Saúde , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Transtornos do Sono-Vigília/terapia , Revisões Sistemáticas como Assunto
13.
Medicine (Baltimore) ; 97(27): e11339, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29979410

RESUMO

BACKGROUND: Chronic heart failure (CHF), the final phase of various heart diseases, is a serious public health problem resulting in high hospitalization rates, mortality, and increasing health care costs. Nuanxin capsule (NXC), a Chinese herbal formula, has been widely used in the treatment of CHF. However, the safety and efficacy of NXC used in patients with CHF has been uncertain and there has been no standard clinical trial published to confirm this. Thus, we conduct a study to evaluate the safety and efficacy of NXC for CHF. METHODS: The reference lists of randomized controlled trials and 8 electronic databases will be independently and systematically searched by 2 review authors in May 2018. Four English databases (EMBASE, PubMed, Cumulative Index to Nursing and Allied Health Literature [CINAHL], and Cochrane Central Register of Controlled Trials [CENTRAL]) and 4 Chinese databases (Chinese Biomedical Literature Database [CBM], Chinese National Knowledge Infrastructure [CNKI], Wanfang Database, and VIP Database) will be included. The primary outcomes will be assessed according to the function classification of New York Heart Association (NYHA). Data synthesis will be precisely computed using the RevManV5.3 software when a data-analysis is allowed. Methodological quality will be assessed according to Cochrane Handbook. RESULTS: This study will provide a high-quality synthesis of current evidence of NXC for CHF from different aspects including the mortality, the function classification of NYHA. CONCLUSION: The conclusion of this systematic review will provide evidence to prove whether NXC is an effective therapeutic intervention for patient with CHF.PROSPERO registration number: PROSPERO CRD42018090003.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Doença Crônica , Medicamentos de Ervas Chinesas/efeitos adversos , Teste de Esforço/efeitos dos fármacos , Humanos , Qualidade de Vida , Volume Sistólico/efeitos dos fármacos , Resultado do Tratamento
14.
Aging (Albany NY) ; 10(7): 1722-1744, 2018 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-30048241

RESUMO

AIM: Premature senescence of vascular endothelial cells is a leading cause of various cardiovascular diseases. Therapies targeting endothelial senescence would have important clinical implications. The present study was aimed to evaluate the potential of heme oxygenase-1 (HO-1) as a therapeutic target for endothelial senescence. METHODS AND RESULTS: Upregulation of HO-1 by Hemin or adenovirus infection reversed H2O2-induced senescence in human umbilical vein endothelial cells (HUVECs); whereas depletion of HO-1 by siRNA or HO-1 inhibitor protoporphyrin IX zinc (II) (ZnPP) triggered HUVEC senescence. Mechanistically, overexpression of HO-1 enhanced the interaction between HO-1 and endothelial nitric oxide synthase (eNOS), and promoted the interaction between eNOS and its upstream kinase Akt, thus resulting in an enhancement of eNOS phosphorylation at Ser1177 and a subsequent increase of nitric oxide (NO) production. Moreover, HO-1 induction prevented the decrease of eNOS dimer/monomer ratio stimulated by H2O2 via its antioxidant properties. Contrarily, HO-1 silencing impaired eNOS phosphorylation and accelerated eNOS uncoupling. In vivo, Hemin treatment alleviated senescence of endothelial cells of the aorta from spontaneously hypertensive rats, through upregulating eNOS phosphorylation at Ser1177. CONCLUSIONS: HO-1 ameliorated endothelial senescence through enhancing eNOS activation and defending eNOS uncoupling, suggesting that HO-1 is a potential target for treating endothelial senescence.


Assuntos
Senescência Celular/efeitos dos fármacos , Células Endoteliais/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Hemina/farmacologia , Peróxido de Hidrogênio/toxicidade , Óxido Nítrico Sintase Tipo III/metabolismo , Adenoviridae/fisiologia , Animais , Células Cultivadas , Senescência Celular/fisiologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1 , Humanos , Óxido Nítrico Sintase Tipo III/genética , Estresse Oxidativo , Distribuição Aleatória , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Regulação para Cima
15.
Acta Pharmacol Sin ; 39(12): 1837-1846, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29991711

RESUMO

Vascular endothelial cell senescence is a leading cause of age-associated and vascular diseases. Mammalian target of rapamycin complex 2 (mTORC2) is a conserved serine/threonine (Ser/Thr) protein kinase that plays an important regulatory role in various cellular processes. However, its impact on endothelial senescence remains controversial. In this study we investigated the role and molecular mechanisms of mTORC2 in endothelial senescence. A replicative senescence model and H2O2-induced premature senescence model were established in primary cultured human umbilical vein endothelial cells (HUVECs). In these senescence models, the formation and activation of mTORC2 were significantly increased, evidenced by the increases in binding of Rictor (the essential component of mTORC2) to mTOR, phosphorylation of mTOR at Ser2481 and phosphorylation of Akt (the effector of mTORC2) at Ser473. Knockdown of Rictor or treatment with the Akt inhibitor MK-2206 attenuated senescence-associated ß-galactosidase (ß-gal) staining and expression of p53 and p21 proteins in the senescent endothelial cells, suggesting that mTORC2/Akt facilitates endothelial senescence. The effect of mTORC2/Akt on endothelial senescence was due to suppression of nuclear factor erythroid 2-related factor 2 (Nrf2) at the transcriptional level, since knockdown of Rictor reversed the reduction of Nrf2 mRNA expression in endothelial senescence. Furthermore, mTORC2 suppressed the expression of Nrf2 via the Akt/GSK-3ß/C/EBPα signaling pathway. These results suggest that the mTORC2/Akt/GSK-3ß/C/EBPα/Nrf2 signaling pathway is involved in both replicative and inducible endothelial senescence. The deleterious role of mTORC2 in endothelial cell senescence suggests therapeutic strategies (targeting mTORC2) for aging-associated diseases and vascular diseases.


Assuntos
Senescência Celular/fisiologia , Células Endoteliais/fisiologia , Alvo Mecanístico do Complexo 2 de Rapamicina/fisiologia , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/fisiologia
16.
Mol Med Rep ; 18(1): 541-549, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29749508

RESUMO

The aim of the present study was to investigate the role of microRNA (miR)­27a­3p in osteoarthritis (OA). Reverse transcription­quantitative polymerase chain reaction and western blotting were performed to determine the expression of miR­27a­3p and aggrecanase­2 (ADAMTS5) in cartilage tissues from patients with OA and healthy controls, and also in interleukin (IL)­1ß­treated primary human chondrocytes. Primary human chondrocytes were transfected with miR­27a­3p. A luciferase reporter assay was used to validate the direct contact between miR­27a­3p and its putative binding site in the 3'­untranslated region ADAMTS5 mRNA. Furthermore, the effects of IL­1ß­induced activation of mitogen­activated protein kinase (MAPK) and nuclear factor (NF)­κB on miR­27a­3p were evaluated using specific inhibitors. The results revealed that the level of miR­27a­3p was reduced in OA cartilage tissues compared with those of normal controls. In addition, decreased miR­27a­3p and increased ADAMTS5 expression was observed in a time­ and dose­dependent manner in chondrocytes treated with IL­1ß. Furthermore, overexpression of miR­27a­3p suppressed the expression of ADAMTS5 in human chondrocytes induced by IL­1ß. miR­27a­3p overexpression also decreased the luciferase activity of the wild­type ADAMTS5 reporter plasmid. Mutation of the miR­27a­3p binding site in the 3'­untranslated region of ADAMTS5 mRNA abolished the miR­27a­3p­mediated repression of reporter activity. Furthermore, the use of specific inhibitors demonstrated that IL­1ß may regulate miR­27a­3p expression via NF­κB and MAPK signaling pathways in chondrocytes. The present study concluded that miR­27a­3p was downregulated in human OA and was suppressed by IL­1ß, and functions as a crucial regulator of ADAMTS5 in OA chondrocytes. In addition, IL­1ß­mediated suppression of miR­27a­3p activity may occur via the MAPK and NF­κB pathways. The present study may provide a novel strategy for clinical treatment of OA caused by upregulation of miR­27a­3p.


Assuntos
Cartilagem Articular/metabolismo , Interleucina-1beta/metabolismo , MicroRNAs/genética , Osteoartrite do Joelho/metabolismo , Transdução de Sinais , Proteína ADAMTS5/genética , Adolescente , Adulto , Idoso , Cartilagem Articular/enzimologia , Células Cultivadas , Criança , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Osteoartrite do Joelho/enzimologia , Osteoartrite do Joelho/etiologia
17.
Inflammation ; 41(4): 1498-1507, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29728804

RESUMO

Aseptic implant loosening is a devastating long-term complication of total joint arthroplasty. It is mainly initiated by the interaction of wear debris and macrophages. However, how does the chronic inflammation persist and how to stop it is poorly understood. Sphingosine kinases (SPHKs) are an essential feature of immunosuppressive M2 polarisation in macrophages and a promoter for chronic inflammation. In this study, RAW 264.7 macrophages were exposed to stimulation with titanium particles (0.1 mg/ml), and the subsequent expression of SPHKs and pro-inflammatory cytokines was evaluated. The effect of inhibitors of SPHKs (FTY720, PF543, and ABC294640) on titanium particle-challenged macrophages was analysed. As for results, the amount of sphingosine kinase (SPHK)-1 and SPHK-2 in RAW264.7 macrophages increased in the presence of titanium particles in a time-dependent manner. Two inhibitors of SPHKs (FTY720 and ABC294640) suppressed titanium particle-induced tumour necrosis factor (TNF)-α and interleukin (IL)-6 production in RAW264.7 macrophages. These findings suggest that persistent stimulation with titanium particles may lead to a consistent release of TNF-α and IL-6 via SPHK-2 activity, which may lead to aseptic implant loosening. Appropriate regulation of SPHK-2 may serve as a potential new strategy in the treatment of aseptic implant loosening.


Assuntos
Inflamação/induzido quimicamente , Interleucina-6/metabolismo , Material Particulado/efeitos adversos , Fosfotransferases (Aceptor do Grupo Álcool)/farmacologia , Titânio/efeitos adversos , Fator de Necrose Tumoral alfa/metabolismo , Animais , Camundongos , Falha de Prótese/efeitos dos fármacos , Células RAW 264.7 , Fator de Necrose Tumoral alfa/efeitos dos fármacos
18.
Medicine (Baltimore) ; 97(8): e9957, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29465586

RESUMO

BACKGROUND: Chronic heart AQ4 failure (CHF) is the final stage of various heart diseases. YiQiFuMai injection (YQFMI) has been widely applied in the treatment of CHF. However, to our knowledge, there has been no systematic review or meta-analysis of randomized controlled trails (RCTs) regarding the effectiveness of this treatment. Here, we provide a protocol to evaluate the efficacy and safety of YQFMI for CHF. METHODS: To evaluate the clinical efficacy of YQFMI in treating CHF, 2 researcher members will independently search the RCTs in the following 8 Chinese and English databases, in which the data collection will be from the time when the respective databases were established to January 2018. The databases will include MEDLINE, EMBASE, Cochrane CENTRAL, CINAHL, the Chinese Biomedical Literature Database, the China National Knowledge Infrastructure, VIP Information and Wanfang Data. The therapeutic effects according to the mortality and the New York Heart Association (NYHA) function classification will be accepted as the primary outcomes. We will use RevMan V.5.3 software as well to compute the data synthesis carefully when a meta-analysis is allowed. RESULTS: This study will provide a high-quality synthesis of current evidence of YQFMI for CHF from several aspects including mortality, NYHA function classification. CONCLUSION: The conclusion of our systematic review will provide evidence to judge whether YQFMI is an effective intervention for CHF.PROSPERO registration number: PROSPERO CRD42017079696.


Assuntos
Cardiotônicos/administração & dosagem , Medicamentos de Ervas Chinesas/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Adulto , Doença Crônica , Protocolos Clínicos , Feminino , Humanos , Injeções , Masculino , Revisões Sistemáticas como Assunto , Resultado do Tratamento
19.
Inflammation ; 41(2): 614-625, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29294242

RESUMO

Macrophages play an essential role in inflammation. Protein disulfide isomerase (PDI) is central to the redox system, which is closely linked with the inflammatory function of macrophages. However, the relationship between PDI and inflammation is still unknown. In this study, we tested the effects of PDI on inflammatory responses in RAW 264.7 macrophages stimulated with lipopolysaccharide (LPS). Using CRISPR/Cas9 system, we found that PDI knockout suppressed migration, M1 polarization, and secretion of tumor necrosis factor-α (TNF-α) and interluekin-6 (IL-6). The repression of these inflammatory processes was accompanied by decreased production of reactive oxygen species (ROS). PDI ablation also inactivated the phosphorylation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activated the phosphorylation of NF-κB inhibitor alpha (IκBα). These findings demonstrate that PDI knockout inhibits the inflammatory function of macrophages by decreasing ROS production and inactivating NF-κB pathway.


Assuntos
Inflamação/genética , Macrófagos/imunologia , NF-kappa B/metabolismo , Isomerases de Dissulfetos de Proteínas/genética , Espécies Reativas de Oxigênio/metabolismo , Animais , Técnicas de Inativação de Genes , Camundongos , Oxirredução , Fosforilação , Células RAW 264.7 , Transdução de Sinais
20.
Inorg Chem ; 57(3): 935-950, 2018 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-29356513

RESUMO

The europium ion probes the symmetry disorder in the crystal structure, although the distortion due to charge compensation in the case of aliovalent dopant remains interesting, especially preparation involves low and high temperatures. This work studies the preparation of the ß-Ca2SiO4 (from here on C2S) particle from Pechini (C2SP) and hydrothermal (C2SH) methods, and its luminescence variance upon doping with Eu2+ and Eu3+ ions. The blue shift of the charge-transfer band (CTB) in the excitation spectra indicates a larger Eu3+-O2- distance in Eu3+ doped C2SH. The changes in vibrational frequencies due to stretching and bending vibrations in the FTIR and the Raman spectra and binding energy shift in the XPS analysis confirmed the distorted SiO44- tetrahedra in C2SH. The high hydrothermal temperature and pressure produce distortion, which leads to symmetry lowering although doping of aliovalent ion may slightly change the position of the Ca atoms. The increasing asymmetry ratio value from C2SP to C2SH clearly indicates that the europium ion stabilized in a more distorted geometry. It is also supported by Judd-Ofelt analysis. The concentration quenching and site-occupancy of Eu3+ ions in two nonequivalent sites of C2S were discussed. The charge state and concentration of europium ions in C2SP and C2SH were determined using X-ray photoelectron spectroscopy measurements. The C2S particles were studied by X-ray powder diffraction, FTIR, Raman, BET surface area, TGA/DTA, electron microscopy, XPS, and luminescence spectroscopy. The impact of citrate ion on the morphology and particle size of C2SH has been hypothesized on the basis of the microscopy images. This study provides insights that are needed for further understanding the structure of C2S and thereby improves the applications in optical and biomedical areas and cement hydration.

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