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1.
Acta Pharmacol Sin ; 45(1): 112-124, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37731037

RESUMO

Proinflammatory M1 macrophages are critical for the progression of atherosclerosis. The Par3-like protein (Par3L) is a homolog of the Par3 family involved in cell polarity establishment. Par3L has been shown to maintain the stemness of mammary stem cells and promote the survival of colorectal cancer cells. In this study, we investigated the roles of the polar protein Par3L in M1 macrophage polarization and atherosclerosis. To induce atherosclerosis, Apoe-/- mice were fed with an atherosclerotic Western diet for 8 or 16 weeks. We showed that Par3L expression was significantly increased in human and mouse atherosclerotic plaques. In primary mouse macrophages, oxidized low-density lipoprotein (oxLDL, 50 µg/mL) time-dependently increased Par3L expression. In Apoe-/- mice, adenovirus-mediated Par3L overexpression aggravated atherosclerotic plaque formation accompanied by increased M1 macrophages in atherosclerotic plaques and bone marrow. In mouse bone marrow-derived macrophages (BMDMs) or peritoneal macrophages (PMs), we revealed that Par3L overexpression promoted LPS and IFNγ-induced M1 macrophage polarization by activating p65 and extracellular signal-regulated kinase (ERK) rather than p38 and JNK signaling. Our results uncover a previously unidentified role for the polarity protein Par3L in aggravating atherosclerosis and favoring M1 macrophage polarization, suggesting that Par3L may serve as a potential therapeutic target for atherosclerosis.


Assuntos
Aterosclerose , Placa Aterosclerótica , Camundongos , Humanos , Animais , Placa Aterosclerótica/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Aterosclerose/metabolismo , Macrófagos/metabolismo , Apolipoproteínas E/metabolismo , Ativação de Macrófagos , Camundongos Endogâmicos C57BL
2.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 46(1): 62-67, 2024 Feb.
Artigo em Zh | MEDLINE | ID: mdl-38433633

RESUMO

Objective To investigate clinicians' practice and opinions on sedation therapy in end-stage patients at Peking Union Medical College Hospital. Methods From August,2022 to April,2023,an online questionnaire survey was conducted among clinicians involved in end-stage patient management. Results A total of 205 questionnaires were distributed,with an effective response rate of 56.1%.Among the clinicians,55.7% of them had experience of applying sedation therapy in end-stage patients;85.2% of clinicians believed that sedation could relieve the suffering of terminal patients from physical refractory symptoms;75.7% of clinicians considered that sedation therapy could be used to relieve agony from psycho-existential distress.Most clinicians had concerns about sedation therapy due to the lack of legal support(86.1%)and the lack of understanding of patients or families(59.1%).The majority (90.4%) of clinicians were willing to receive training on palliative sedation. Conclusions A majority of clinicians agree that sedation therapy could relieve the physical distress and psycho-existential distress in end-stage patients.However,most clinicians have concerns about the application of sedation therapy due to the lack of legal support.It is necessary to enhance the training on palliative sedation.


Assuntos
Anestesia , Assistência Terminal , Humanos , Hospitais , Universidades
3.
Acta Pharmacol Sin ; 44(1): 71-80, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35778487

RESUMO

Atherosclerosis is a chronic inflammatory disease of arterial wall, and circulating monocyte adhesion to endothelial cells is a crucial step in the pathogenesis of atherosclerosis. Epithelial-stromal interaction 1 (EPSTI1) is a novel gene, which is dramatically induced by epithelial-stromal interaction in human breast cancer. EPSTI1 expression is not only restricted to the breast but also in other normal tissues. In this study we investigated the role of EPSTI1 in monocyte-endothelial cell adhesion and its expression pattern in atherosclerotic plaques. We showed that EPSTI1 was dramatically upregulated in human and mouse atherosclerotic plaques when compared with normal arteries. In addition, the expression of EPSTI1 in endothelial cells of human and mouse atherosclerotic plaques is significantly higher than that of the normal arteries. Furthermore, we demonstrated that EPSTI1 promoted human monocytic THP-1 cell adhesion to human umbilical vein endothelial cells (HUVECs) via upregulating VCAM-1 and ICAM-1 expression in HUVECs. Treatment with LPS (100, 500, 1000 ng/mL) induced EPSTI1 expression in HUVECs at both mRNA and protein levels in a dose- and time-dependent manner. Knockdown of EPSTI1 significantly inhibited LPS-induced monocyte-endothelial cell adhesion via downregulation of VCAM-1 and ICAM-1. Moreover, we revealed that LPS induced EPSTI1 expression through p65 nuclear translocation. Thus, we conclude that EPSTI1 promotes THP-1 cell adhesion to endothelial cells by upregulating VCAM-1 and ICAM-1 expression, implying its potential role in the development of atherosclerosis.


Assuntos
Aterosclerose , Placa Aterosclerótica , Animais , Humanos , Camundongos , Aterosclerose/metabolismo , Adesão Celular , Células Cultivadas , Células Endoteliais da Veia Umbilical Humana/metabolismo , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Lipopolissacarídeos , Monócitos/metabolismo , Proteínas de Neoplasias/metabolismo , Placa Aterosclerótica/metabolismo , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismo
4.
Acta Pharmacol Sin ; 44(2): 321-331, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35655094

RESUMO

Metabolic cardiomyopathy (MC) is characterized by intracellular lipid accumulation and utilizing fatty acids as a foremost energy source, thereby leading to excess oxidative stress and mitochondrial dysfunction. There is no effective therapy available yet. In this study we investigated whether defective mitophagy contributed to MC and whether urolithin A (UA), a naturally occurring microflora-derived metabolite, could protect against MC in experimental obese mice. Mice were fed high fat diet for 20 weeks to establish a diet-induced obese model. We showed that mitochondrial autophagy or mitophagy was significantly downregulated in the heart of experimental obese mice. UA (50 mg·kg-1·d-1, for 4 weeks) markedly activated mitophagy and ameliorated MC in obese mice by gavage. In PA-challenged H9C2 cardiomyocytes, UA (5 µM) significantly increased autophagosomes and decreased autolysosomes. Furthermore, UA administration rescued PINK1/Parkin-dependent mitophagy and relieved mitochondrial defects in the heart of obese mice, which led to improving cardiac diastolic function and ameliorating cardiac remodelling. In PA-challenged primarily isolated cardiomyocytes, both application of mitophagy inhibitor Mdivi-1 (15 µM) and silencing of mitophagy gene Parkin blunted the myocardial protective effect of UA. In summary, our data suggest that restoration of mitophagy with UA ameliorates symptoms of MC, which highlights a therapeutic potential of UA in the treatment of MC.


Assuntos
Cardiomiopatias , Mitofagia , Camundongos , Animais , Camundongos Obesos , Proteínas Quinases/metabolismo , Cardiomiopatias/metabolismo , Miócitos Cardíacos/metabolismo , Obesidade/complicações , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
5.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 45(1): 77-79, 2023 Feb.
Artigo em Zh | MEDLINE | ID: mdl-36861159

RESUMO

We provided the palliative care of a multiple disciplinary team care mode to a patient diagnosed with advanced head and neck cancer and her caregivers.People-centered integrated health services were provided according to the specific needs and preferences of individuals.The team-based palliative care relieved the suffering and improved the quality of life of the patient and that of her family who were facing challenges associated with life-threatening illness.


Assuntos
Neoplasias de Cabeça e Pescoço , Cuidados Paliativos , Humanos , Feminino , Qualidade de Vida , Neoplasias de Cabeça e Pescoço/terapia
6.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 45(1): 64-70, 2023 Feb.
Artigo em Zh | MEDLINE | ID: mdl-36861157

RESUMO

End-stage patients experience unbearable pain because of refractory symptoms.Palliative sedation is a form of palliative care which relieves patients' agony by lowering their consciousness.Standard palliative sedation can help patients die with dignity.It is distinct from euthanasia and does not alter the survival of patients.Sufficient palliative care is the premise of palliative sedation.Repeated and detailed clinical evaluation,as well as multidisciplinary involvement,is necessary for the standardized implementation of palliative sedation.Here,we proposed the standard process and specifications of palliative sedation in Peking Union Medical College Hospital.Furthermore,we reported a case of palliative sedation for an advanced cancer patient with refractory delirium and living pain to demonstrate its application in clinical practice.


Assuntos
Anestesia , Humanos , Dor , Hospitais , Cuidados Paliativos , Universidades
7.
Acta Pharmacol Sin ; 43(6): 1408-1418, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34552216

RESUMO

Despite improvements in cardiovascular disease (CVD) outcomes by cholesterol-lowering statin therapy, the high rate of CVD is still a great concern worldwide. Dehydrocorydaline (DHC) is an alkaloidal compound isolated from the traditional Chinese herb Corydalis yanhusuo. Emerging evidence shows that DHC has anti-inflammatory and antithrombotic benefits, but whether DHC exerts any antiatherosclerotic effects remains unclear. Our study revealed that intraperitoneal (i.p.) injection of DHC in apolipoprotein E-deficient (ApoE-/-) mice not only inhibited atherosclerosis development but also improved aortic compliance and increased plaque stability. In addition, DHC attenuated systemic and vascular inflammation in ApoE-/- mice. As macrophage inflammation plays an essential role in the pathogenesis of atherosclerosis, we next examined the direct effects of DHC on bone marrow-derived macrophages (BMDMs) in vitro. Our RNA-seq data revealed that DHC dramatically decreased the levels of proinflammatory gene clusters. We verified that DHC significantly downregulated proinflammatory interleukin (IL)-1ß and IL-18 mRNA levels in a time- and concentration-dependent manner. Furthermore, DHC decreased lipopolysaccharide (LPS)-induced inflammation in BMDMs, as evidenced by the reduced protein levels of CD80, iNOS, NLRP3, IL-1ß, and IL-18. Importantly, DHC attenuated LPS-induced activation of p65 and the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. Thus, we conclude that DHC ameliorates atherosclerosis in ApoE-/- mice by inhibiting inflammation, likely by targeting macrophage p65- and ERK1/2-mediated pathways.


Assuntos
Aterosclerose , Interleucina-18 , Alcaloides , Animais , Apolipoproteínas E , Aterosclerose/metabolismo , Inflamação/metabolismo , Interleucina-18/metabolismo , Lipopolissacarídeos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
8.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 44(5): 750-756, 2022 Oct.
Artigo em Zh | MEDLINE | ID: mdl-36325769

RESUMO

Objective To explore the obstacles in palliative care consultation services and put forward the suggestions for improving the services in grade A tertiary hospitals. Methods A semi-structured interview was conducted with 17 medical workers who had requested palliative care consultation services in Peking Union Medical College Hospital. Results The palliative care consultation services were hindered by five obstacle factors including insufficient knowledge of patients and their families about palliative care,unsound understanding of medical workers about palliative care,poor implementation of consultation opinions,limited labor of palliative care team,and poor economic benefits from palliative care.In view of such obstacles,the following suggestions were put forward,which included increasing the acceptance of palliative care by patients and their families,enriching the knowledge of medical staff on palliative care,establishing a new cooperation model between consultation team and medical staff,strengthening the institutional guarantee for the development of palliative care,and establishing and perfecting the laws and policies related to palliative care. Conclusion Although there are many difficulties in the in-hospital palliative care consultation services in grade A tertiary hospitals,the demand and expectation of medical staff for palliative care are still increasing.


Assuntos
Cuidados Paliativos , Encaminhamento e Consulta , Humanos , Centros de Atenção Terciária , Hospitalização
9.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 44(5): 763-767, 2022 Oct.
Artigo em Zh | MEDLINE | ID: mdl-36325771

RESUMO

Objective To summarize the palliative care consultations proposed by the Emergency Department of Peking Union Medical College Hospital. Methods A retrospective study was conducted on 22 palliative care consultations in the Emergency Department of Peking Union Medical College Hospital from January 2017 to June 2020. Results A total of 18 patients (6 males and 12 females) received palliative care consultations in the Emergency Department,with the average age of (65±8) years (36-88 years).Specifically,10 and 6 patients received once and twice consultations,respectively,and 2 patients did not complete the consultation.Of the patients receiving palliative care consultations,15 had malignant tumors and 3 had non-neoplastic diseases.The reasons for palliative care consultations included communication (61.1%,11/18) and pain relief (61.1%,11/18).In terms of the place of death,8 patients died in the hospital and 6 patients in other medical institutions. Conclusion There is a clear demand for palliative care consultation in the Emergency Department of Peking Union Medical College Hospital,and the consultation can bring help to both emergency doctors and patients.


Assuntos
Cuidados Paliativos , Encaminhamento e Consulta , Masculino , Feminino , Humanos , Pessoa de Meia-Idade , Idoso , Cuidados Paliativos/métodos , Estudos Retrospectivos , Hospitais , Serviço Hospitalar de Emergência
10.
Acta Pharmacol Sin ; 42(12): 2033-2045, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33664417

RESUMO

Caffeine induces multiple vascular effects. In this study we investigated the angiogenic effect of physiological concentrations of caffeine with focus on endothelial cell behaviors (migration and proliferation) during angiogenesis and its mitochondrial and bioenergetic mechanisms. We showed that caffeine (10-50 µM) significantly enhanced angiogenesis in vitro, evidenced by concentration-dependent increases in tube formation, and migration of human umbilical vein endothelial cells (HUVECs) without affecting cell proliferation. Caffeine (50 µM) enhanced endothelial migration via activation of cAMP/PKA/AMPK signaling pathway, which was mimicked by cAMP analog 8-Br-cAMP, and blocked by PKA inhibitor H89, adenylate cyclase inhibitor SQ22536 or AMPK inhibitor compound C. Furthermore, caffeine (50 µM) induced significant mitochondrial shortening through the increased phosphorylation of mitochondrial fission protein dynamin-related protein 1 (Drp1) in HUVECs, which increased its activity to regulate mitochondrial fission. Pharmacological blockade of Drp1 by Mdivi-1 (10 µM) or disturbance of mitochondrial fission by Drp1 silencing markedly suppressed caffeine-induced lamellipodia formation and endothelial cell migration. Moreover, we showed that caffeine-induced mitochondrial fission led to accumulation of more mitochondria in lamellipodia regions and augmentation of mitochondrial energetics, both of which were necessary for cell migration. In a mouse model of hindlimb ischemia, administration of caffeine (0.05% in 200 mL drinking water daily, for 14 days) significantly promoted angiogenesis and perfusion as well as activation of endothelial AMPK signaling in the ischemic hindlimb. Taken together, caffeine induces mitochondrial fission through cAMP/PKA/AMPK signaling pathway. Mitochondrial fission is an integral process in caffeine-induced endothelial cell migration by altering mitochondrial distribution and energetics.


Assuntos
Cafeína/uso terapêutico , Endotélio/efeitos dos fármacos , Isquemia/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Animais , Movimento Celular/efeitos dos fármacos , Membro Posterior/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos Endogâmicos C57BL , Pseudópodes/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
11.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 43(1): 9-14, 2021 Feb 28.
Artigo em Zh | MEDLINE | ID: mdl-33663655

RESUMO

Objective To explore the effects of palliative care consultation on medical professionals who have requested it in Peking Union Medical College Hospital. Methods Semi-structured interviews were conducted with 17 medical professionals who had requested palliative care consultation.Results Palliative care consultation had the following positive effects:building a bridge for doctor-patient communication,providing psychological support to reduce the sense of occupational exhaustion for medical professionals,providing technical support for medical professionals to help patients relieve symptoms,helping medical professionals in the multidisciplinary learning of palliative care,adding humanistic care and neglected ethical concerns.Conclusion Palliative care consultation improves the quality of care for dying patients,and the capacity of consultation needs to be enhanced urgently.


Assuntos
Cuidados Paliativos , Encaminhamento e Consulta , Hospitais , Humanos , Pesquisa Qualitativa
12.
Circ J ; 83(3): 515-523, 2019 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-30662023

RESUMO

BACKGROUND: Recent studies have suggested that pregnancy-associated plasma protein-A (PAPP-A) is involved in the pathogenesis of atherosclerosis. This study aim is to investigate the role and mechanisms of PAPP-A in reverse cholesterol transport (RCT) and inflammation during the development of atherosclerosis. Methods and Results: PAPP-A was silenced in apolipoprotein E (apoE-/-) mice with administration of PAPP-A shRNA. Oil Red O staining of the whole aorta root revealed that PAPP-A knockdown reduced lipid accumulation in aortas. Oil Red O, hematoxylin and eosin (HE) and Masson staining of aortic sinus further showed that PAPP-A knockdown alleviated the formation of atherosclerotic lesions. It was found that PAPP-A knockdown reduced the insulin-like growth factor 1 (IGF-1) levels and repressed the PI3K/Akt pathway in both aorta and peritoneal macrophages. The expression levels of LXRα, ABCA1, ABCG1, and SR-B1 were increased in the aorta and peritoneal macrophages from apoE-/-mice administered with PAPP-A shRNA. Furthermore, PAPP-A knockdown promoted RCT from macrophages to plasma, the liver, and feces in apoE-/-mice. In addition, PAPP-A knockdown elevated the expression and secretion of monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), tumor necrosis factor-α, and interleukin-1ß through the nuclear factor kappa-B (NF-κB) pathway. CONCLUSIONS: The present study results suggest that PAPP-A promotes the development of atherosclerosis in apoE-/-mice through reducing RCT capacity and activating an inflammatory response.


Assuntos
Aterosclerose/etiologia , Colesterol/metabolismo , Inflamação/etiologia , Proteína Plasmática A Associada à Gravidez/fisiologia , Animais , Aorta/metabolismo , Aorta/patologia , Aterosclerose/patologia , Transporte Biológico , Feminino , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Knockout para ApoE , NF-kappa B/metabolismo , Gravidez , Proteína Plasmática A Associada à Gravidez/farmacologia
13.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1863(8): 806-822, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29678642

RESUMO

BACKGROUND AND AIMS: Recent studies have suggested that heat shock protein 70 (HSP70) may play critical roles in cardiovascular disease. However, the effects of HSP70 on the development of atherosclerosis in apoE-/- mice remain largely unknown. This study was to investigate the role and potential mechanism of HSP70 in atherosclerosis. METHODS: HSP70 was overexpressed in apoE-/- mice and THP-1-derived macrophages with lentiviral vectors. Oil Red O, hematoxylin-eosin, and Masson staining were performed to evaluate atherosclerotic plaque in apoE-/- mice fed the Western type diet. Moreover, immunostaining was employed to detect the expression of relative proteins in aortic sinus. Reporter gene and chromatin immunoprecipitation were performed to analyze the effect of Elk-1 on the promoter activity of ABCA1 and ABCG1; [3H] labeled cholesterol was used to assess the capacity of cholesterol efflux and reverse cholesterol transport (RCT). RESULTS: Our results showed that HSP70 increased lipid accumulation in arteries and promoted the formation of atherosclerotic lesion. The capacity of cholesterol efflux was reduced in peritoneal macrophages isolated from HSP70-overexpressed apoE-/- mice. The levels of ABCA1 and ABCG1 expression were also reduced in the peritoneal macrophages and the aorta from apoE-/- mice in response to HSP70. The c-Jun N-terminal kinase (JNK) and ETS transcription factor (Elk-1) played a critical role in HSP70-induced downregulation ABCA1 and ABCG1. Further, HSP70 reduced RCT from macrophages to plasma, liver, and feces in apoE-/- mice. CONCLUSIONS: HSP70 promotes the progression of atherosclerosis in apoE-/- mice by suppressing the expression of ABCA1 and ABCG1 through the JNK/Elk-1 pathway.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Aterosclerose/patologia , Proteínas de Choque Térmico HSP70/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Aterosclerose/etiologia , Linhagem Celular , Colesterol/metabolismo , Dieta Ocidental/efeitos adversos , Modelos Animais de Doenças , Progressão da Doença , Regulação para Baixo , Humanos , Sistema de Sinalização das MAP Quinases , Macrófagos , Masculino , Camundongos , Camundongos Knockout para ApoE , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Regiões Promotoras Genéticas , Seio Aórtico/metabolismo , Seio Aórtico/patologia , Proteínas Elk-1 do Domínio ets/metabolismo
14.
Circ J ; 82(11): 2861-2871, 2018 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-30232292

RESUMO

BACKGROUND: Lipoprotein lipase (LPL) plays an important role in triglyceride metabolism. It is translocated across endothelial cells to reach the luminal surface of capillaries by glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1), where it hydrolyzes triglycerides in lipoproteins. MicroRNA 377 (miR-377) is highly associated with lipid levels. However, how miR-377 regulates triglyceride metabolism and whether it is involved in the development of atherosclerosis remain largely unexplored. Methods and Results: The clinical examination displayed that miR-377 expression was markedly lower in plasma from patients with hypertriglyceridemia compared with non-hypertriglyceridemic subjects. Bioinformatics analyses and a luciferase reporter assay showed that DNA methyltransferase 1 (DNMT1) was a target gene of miR-377. Moreover, miR-377 increased LPL binding to GPIHBP1 by directly targeting DNMT1 in human umbilical vein endothelial cells (HUVECs) and apolipoprotein E (ApoE)-knockout (KO) mice aorta endothelial cells (MAECs). In vivo, hematoxylin-eosin (H&E), Oil Red O and Masson's trichrome staining showed that ApoE-KO mice treated with miR-377 developed less atherosclerotic plaques, accompanied by reduced plasma triglyceride levels. CONCLUSIONS: It is concluded that miR-377 upregulates GPIHBP1 expression, increases the LPL binding to GPIHBP1, and reduces plasma triglyceride levels, likely through targeting DNMT1, inhibiting atherosclerosis in ApoE-KO mice.


Assuntos
Aorta/metabolismo , Aterosclerose/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , MicroRNAs/metabolismo , Placa Aterosclerótica/metabolismo , Triglicerídeos/metabolismo , Animais , Aorta/patologia , Aterosclerose/genética , Aterosclerose/patologia , DNA (Citosina-5-)-Metiltransferase 1/genética , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Lipase Lipoproteica/genética , Lipase Lipoproteica/metabolismo , Camundongos , Camundongos Knockout para ApoE , MicroRNAs/genética , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologia , Receptores de Lipoproteínas/biossíntese , Receptores de Lipoproteínas/genética
15.
Am J Physiol Renal Physiol ; 312(4): F689-F701, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28100503

RESUMO

White adipose tissue plays an important role in the development of metabolic disturbance, which is a common feature in patients with chronic kidney disease (CKD). The effect of CKD on white adipose tissue remains poorly appreciated. Here, we evaluated the inflammatory potential of visceral white adipose tissue in a rat model of CKD. The results showed that production of proinflammatory cytokines and infiltration of macrophage in the tissue were increased significantly in CKD rats compared with sham rats. Moreover, the primary adipocytes and stromal vascular fraction under the condition of CKD could trigger the inflammatory response in each other. Free fatty acid induced robust inflammatory response in ex vivo peritoneal-derived macrophages from CKD rats, which was associated with reduced activity of silent information regulator T1 (SIRT1). Improvement of SIRT1 activity by an activator could alleviate free fatty acid-induced inflammatory response in the macrophages and inflammation in the white adipose tissue. Moreover, oxidative stress occurred in the tissue and linked with the reduced activity of SIRT1 in macrophages and enhanced release of free fatty acid in the tissue. We thus identified CKD as a risk factor for chronic inflammation in white adipose tissue. These observations might open up new therapeutic strategies for metabolic disturbance in CKD via the modulation of adipose tissue-related pathways.


Assuntos
Adipócitos/metabolismo , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Gordura Intra-Abdominal/metabolismo , Macrófagos/metabolismo , Paniculite/etiologia , Insuficiência Renal Crônica/complicações , Animais , Comunicação Celular , Células Cultivadas , Técnicas de Cocultura , Citocinas/genética , Modelos Animais de Doenças , Metabolismo Energético , Ácidos Graxos não Esterificados/metabolismo , Gordura Intra-Abdominal/fisiopatologia , Masculino , Estresse Oxidativo , Paniculite/genética , Paniculite/metabolismo , Paniculite/fisiopatologia , Ratos Sprague-Dawley , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Transdução de Sinais , Sirtuína 1/metabolismo , Fatores de Tempo
16.
Biochem Biophys Res Commun ; 493(1): 611-617, 2017 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-28867181

RESUMO

Insulin is involved in the development of diabetic heart disease and is important in the activities of mitochondrial complex I. However, the effect of insulin on cardiac mitochondrial nicotinamide adenine dinucleotide dehydrogenase (ubiquinone) 1 subunit of retinoic-interferon-induced mortality 19 (GRIM-19) has not been characterized. The aim of this study was to investigate the effect of insulin on the mitochondrial GRIM-19 in the hearts of rats with streptozotocin (STZ)-induced type 1 diabetes. Protein changes of GRIM-19 were evaluated by western blotting and reverse transcription-quantitative polymerase chain reaction. Furthermore, the effects of insulin on mitochondrial complex I were detected in HeLa cells and H9C2 cardiac myocytes. During the development of diabetic heart disease, the cardiac function did not change within the 8 weeks, but the mitochondrial morphology was altered. The hearts from the rats with STZ-induced diabetes exhibited reduced expression of GRIM-19. Prior to the overt cardiac dilatation, mitochondrial alterations were already present. Following subcutaneous insulin injection, it was demonstrated that GRIM-19 protein was altered, as well as the mitochondrial morphology. The phosphoinositide 3-kinase inhibitor LY294002 had an effect on insulin signaling in H9C2 cardiacmyocytes, and decreased the level of GRIM-19 by half compared with that in the insulin group. The results indicate that insulin is essential for the control of cardiac mitochondrial morphology and the GRIM-19 expression partly via PI3K/AKT signaling pathways.


Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Complexo I de Transporte de Elétrons/metabolismo , Insulina/administração & dosagem , Mitocôndrias Cardíacas/patologia , Chaperonas Moleculares/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Células HeLa , Humanos , Masculino , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Estreptozocina , Regulação para Cima/efeitos dos fármacos
17.
Bioorg Med Chem Lett ; 26(13): 3103-3108, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27185329

RESUMO

Two groups of novel hydroxypyridinone derivatives 6(a-e) and 12(a-c), were designed as potential tyrosinase inhibitors, and synthesized using kojic acid as a starting material. The tyrosinase inhibitory activity of these two groups was demonstrated to be potent, especially compounds 6e and 12a, whose IC50 values for monophenolase activity were 1.95µM and 2.79µM, respectively. Both of these values are lower than that of kojic acid (IC50=12.50µM). Compounds 6e and 12a were investigated for the inhibitory effect on diphenolase activity. The results showed that the inhibitory mechanism of these two compounds was reversible and that the inhibitory type was a competitive-uncompetitive mixed-type. The values of IC50 of 6e and 12a on the diphenolase activity of tyrosinase were determined to be 8.97µM and 26.20µM, respectively. The inhibitory constants (KI and KIS) of 6e were determined as 17.17µM and 22.09µM, respectively; and the KI and KIS values of 12a were 34.41µM and 79.02µM, respectively. Compound 6e showed a greater ability to reduce copper and a stronger copper chelating ability than kojic acid.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Piridinas/farmacologia , Agaricales/enzimologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Modelos Moleculares , Estrutura Molecular , Monofenol Mono-Oxigenase/metabolismo , Piridinas/síntese química , Piridinas/química , Relação Estrutura-Atividade
18.
Acta Pharmacol Sin ; 37(2): 196-203, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26687933

RESUMO

AIM: Recent evidence suggests that the essential amino acid leucine may be involved in systemic cholesterol metabolism. In this study, we investigated the effects of leucine supplementation on the development of atherosclerosis in apoE null mice. METHODS: ApoE null mice were fed with chow supplemented with leucine (1.5% w/v) in drinking water for 8 week. Aortic atherosclerotic lesions were examined using Oil Red O staining. Plasma lipoprotein-cholesterol levels were measured with fast protein liquid chromatography. Hepatic gene expression was detected using real-time PCR and Western blot analyses. RESULTS: Leucine supplementation resulted in 57.6% reduction of aortic atherosclerotic lesion area in apoE null mice, accompanied by 41.2% decrease of serum LDL-C levels and 40.2% increase of serum HDL-C levels. The body weight, food intake and blood glucose level were not affected by leucine supplementation. Furthermore, leucine supplementation increased the expression of Abcg5 and Abcg8 (that were involved in hepatic cholesterol efflux) by 1.28- and 0.86-fold, respectively, and significantly increased their protein levels. Leucine supplementation also increased the expression of Srebf1, Scd1 and Pgc1b (that were involved in hepatic triglyceride metabolism) by 3.73-, 1.35- and 1.71-fold, respectively. Consequently, leucine supplementation resulted in 51.77% reduction of liver cholesterol content and 2.2-fold increase of liver triglyceride content. Additionally, leucine supplementation did not affect the serum levels of IL-6, IFN-γ, TNF-α, IL-10 and IL-12, but markedly decreased the serum level of MCP-1. CONCLUSION: Leucine supplementation effectively attenuates atherosclerosis in apoE null mice by improving the plasma lipid profile and reducing systemic inflammation.


Assuntos
Aorta/efeitos dos fármacos , Aorta/patologia , Apolipoproteínas E/genética , Aterosclerose/tratamento farmacológico , Aterosclerose/patologia , Leucina/uso terapêutico , Animais , Aorta/metabolismo , Aterosclerose/sangue , Aterosclerose/genética , Suplementos Nutricionais/análise , Água Potável/administração & dosagem , Água Potável/análise , Feminino , Deleção de Genes , Inflamação/sangue , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Leucina/administração & dosagem , Leucina/análise , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
19.
Zhonghua Nan Ke Xue ; 22(10): 872-876, 2016 Oct.
Artigo em Zh | MEDLINE | ID: mdl-29278466

RESUMO

OBJECTIVE: To investigate sexual satisfaction (SS) and the factors associated with decreased SS among individuals with hearing disability. METHODS: We conducted an investigation on SS among 439 individuals (268 males and 171 females, aged ≥18 yr) with hearing disability using a general information questionnaire, Center for Epidemiologic Studies Depression Scale, Social Support Rating Scale, and a self-report on SS. We identified the factors of decreased SS by multivariate ordinal logistic regression analysis. RESULTS: Totally 76 (17.3%) of the hearing-disability individuals investigated were dissatisfied with their sexual life. SS reduction was significantly correlated with the status of being single (OR=1.72), grade-1 or -2 disability (OR=1.78), physical diseases (OR=2.46), depression (OR=6.61), or inadequate subjective social support (OR=3.28). CONCLUSIONS: SS of hearing-disability persons is relatively low, which can be improved by treating physical diseases, promoting mental health, and providing psycho-social support.


Assuntos
Pessoas com Deficiência , Perda Auditiva/fisiopatologia , Satisfação Pessoal , Qualidade de Vida , Comportamento Sexual , Feminino , Humanos , Masculino , Inquéritos e Questionários
20.
Zhongguo Zhong Yao Za Zhi ; 39(3): 520-5, 2014 Feb.
Artigo em Zh | MEDLINE | ID: mdl-24946560

RESUMO

This study aim to reveal the total pharmacokinetics of rhein and chrysophanol after oral administration of Quyu Qingre granules (QUQRG) in normal and acute blood stasis rabbits, to identify the pharmacokinetics differences between two groups of rabbits and to evaluate the applicability of the total statistical moment analysis. Based on the concentrations of rhein and chrysophanol in plasma determined by an established HPLC method, and the calculation of main total pharmacokinetic parameters, this study found that total pharmacokinetic parameters VRT, value of blood stasis group is lager than that of normal group and the difference is significant Compared with normal group, total pharmacokinetic parameters AUC,, MRT,, t1/2t, and Vt value of blood stasis group is lager, while the k, and CL, value is smaller. The findings indicated that the absorbed and released time of rhein and chrysophanol was accelerated and the total absorptive amount of these two compounds was increased in rabbits with acute blood stasis, compared with the normal rabbits. Total quantity statistical moment analysis can combine the pharmacokinetics of rhein and chrysophanol and express the pharmacokinetic behavior of these two compounds in QUQRG. The parameters in this paper can provide reference frames for the follow-up development of QUQRG.


Assuntos
Antraquinonas/farmacocinética , Circulação Sanguínea/efeitos dos fármacos , Medicamentos de Ervas Chinesas/administração & dosagem , Medicina Tradicional Chinesa/métodos , Estatística como Assunto , Administração Oral , Animais , Antraquinonas/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Coelhos
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