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1.
Cell Rep ; 37(5): 109905, 2021 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-34731623

RESUMO

Despite the undisputable role of the small GTPase Rac1 in the regulation of actin cytoskeleton reorganization, the Rac guanine-nucleotide exchange factors (Rac-GEFs) involved in Rac1-mediated motility and invasion in human lung adenocarcinoma cells remain largely unknown. Here, we identify FARP1, ARHGEF39, and TIAM2 as essential Rac-GEFs responsible for Rac1-mediated lung cancer cell migration upon EGFR and c-Met activation. Noteworthily, these Rac-GEFs operate in a non-redundant manner by controlling distinctive aspects of ruffle dynamics formation. Mechanistic analysis reveals a leading role of the AXL-Gab1-PI3K axis in conferring pro-motility traits downstream of EGFR. Along with the positive association between the overexpression of Rac-GEFs and poor lung adenocarcinoma patient survival, we show that FARP1 and ARHGEF39 are upregulated in EpCam+ cells sorted from primary human lung adenocarcinomas. Overall, our study reveals fundamental insights into the complex intricacies underlying Rac-GEF-mediated cancer cell motility signaling, hence underscoring promising targets for metastatic lung cancer therapy.

2.
Cell Death Discov ; 7(1): 340, 2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34750352

RESUMO

Heart failure is the terminal stage of many cardiac diseases, in which ß1-adrenoceptor (ß1-AR) autoantibody (ß1-AA) has a causative role. By continuously activating ß1-AR, ß1-AA can induce cytotoxicity, leading to cardiomyocyte apoptosis and heart dysfunction. However, the mechanism underlying the persistent activation of ß1-AR by ß1-AA is not fully understood. Receptor endocytosis has a critical role in terminating signals over time. ß2-adrenoceptor (ß2-AR) is involved in the regulation of ß1-AR signaling. This research aimed to clarify the mechanism of the ß1-AA-induced sustained activation of ß1-AR and explore the role of the ß2-AR/Gi-signaling pathway in this process. The beating frequency of neonatal rat cardiomyocytes, cyclic adenosine monophosphate content, and intracellular Ca2+ levels were examined to detect the activation of ß1-AA. Total internal reflection fluorescence microscopy was used to detect the endocytosis of ß1-AR. ICI118551 was used to assess ß2-AR/Gi function in ß1-AR sustained activation induced by ß1-AA in vitro and in vivo. Monoclonal ß1-AA derived from a mouse hybridoma could continuously activate ß1-AR. ß1-AA-restricted ß1-AR endocytosis, which was reversed by overexpressing the endocytosis scaffold protein ß-arrestin1/2, resulting in the cessation of ß1-AR signaling. ß2-AR could promote ß1-AR endocytosis, as demonstrated by overexpressing/interfering with ß2-AR in HL-1 cells, whereas ß1-AA inhibited the binding of ß2-AR to ß1-AR, as determined by surface plasmon resonance. ICI118551 biasedly activated the ß2-AR/Gi/G protein-coupled receptor kinase 2 (GRK2) pathway, leading to the arrest of limited endocytosis and continuous activation of ß1-AR by ß1-AA in vitro. In vivo, ICI118551 treatment attenuated myocardial fiber rupture and left ventricular dysfunction in ß1-AA-positive mice. This study showed that ß1-AA continuously activated ß1-AR by inhibiting receptor endocytosis. Biased activation of the ß2-AR/Gi/GRK2 signaling pathway could promote ß1-AR endocytosis restricted by ß1-AA, terminate signal transduction, and alleviate heart damage.

3.
Acta Biochim Biophys Sin (Shanghai) ; 53(10): 1354-1366, 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34532739

RESUMO

An increase in cardiomyocyte apoptosis is the main contributor to the observed high morbidity of cardiac disease during aging. Mitochondria play important roles in cardiac apoptosis, and dynamin-related protein 1 (Drp1) is the critical factor that participates in mitochondrial fission and induces mitophagy to maintain mitochondria quality. However, whether Drp1 is involved in the increase of apoptosis in aging heart remains unclear. The purpose of this study was to determine whether Drp1 participates in inducing the apoptosis through regulating mitophagy in aging myocardium. To explore the effect of mitophagy and apoptosis in aging heart, we detected the expression of COX IV and the co-localization of COX IV and LC3 II, which reflect mitophagy, and measured adenosine triphosphate and reactive oxygen species contents, which reflect mitochondrial injury. Cell apoptosis was detected by measuring the activity of caspase-3 and the expression of cleaved caspase-3 and further confirmed by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay. The results showed an increase in apoptosis and a decrease in mitophagy in aging cardiomyocytes, and apoptosis was ameliorated after the induction of mitophagy by carbonyl cyanide m-chlorophenyl hydrazone (a mitophagy activator) in D-galactose (D-gal)-induced senescence H9c2 cells. To clarify the role of Drp1 in apoptosis, we knocked down Drp1 by transfecting si-Drp1, or overexpressed Drp1 in senescent cells, and then detected mitophagy, mitochondrial injury, and apoptosis. The data showed that downregulated Drp1 induces mitochondrial damage and apoptosis. In addition, to explore the regulatory relationship between Drp1 and phosphatase and tensin homologue (PTEN)-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy, we detected the expressions of PINK1 and Parkin after the overexpression of Drp1 in the D-gal group cells and found that Drp1-mediated mitophagy inhibited the PINK1/Parkin pathway in senescent cells. Our results demonstrated that insufficient Drp1 induces cardiomyocyte apoptosis by inhibiting mitophagy, and Drp1 affects the PINK1/Parkin pathway of mitophagy in the aging heart.

4.
Biochem Biophys Res Commun ; 570: 8-14, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34271438

RESUMO

Large conductance calcium-activated potassium channel (BK channel) is widely expressed in skeletal muscle, myocardium, smooth muscle and other muscle tissues. Mutation, abnormal expression and altered activity of BK channel are linked to muscle-related diseases such as dyskinesia, epilepsy and erectile dysfunction. In order to compare the effects of BK channel on different muscle tissues, we constructed BK channel gene knockout rats||||||| (BK-/- rats). HE staining, open field and grip strength tests, ultrasound, blood pressure measurement and vascular tension test were utilized to explore the effects of BK channel deletion on the structure and function changes in skeletal muscle, myocardium, and vascular smooth muscle (VSM). It was found that compared with wild-type rats, the BK-/- rats showed decreased skeletal muscle fiber area, grip, movement distance and speed at 2 and 12 months of ages. At heart, the muscle fiber area, cardiac systolic/diastolic function and heart rate decreased in BK-/- rats. The wall of the left ventricle became thin. However, the vascular wall of BK-/- rats thickened, the pulse wave velocity was increased, and the VSM contraction was enhanced. Unexpectedly, both systolic and diastolic blood pressure were reduced in BK-/- rats, while pulse pressure difference was increased. These results suggest that BK channel may have different effects on different types of muscle tissue, and it should be noted that different parts of muscle tissue may have different effects when BK channel-related drugs are used.


Assuntos
Deleção de Genes , Canais de Potássio Ativados por Cálcio de Condutância Alta/genética , Contração Muscular/fisiologia , Músculo Esquelético/fisiologia , Músculo Liso/fisiologia , Miocárdio/metabolismo , Animais , Vasos Sanguíneos/fisiologia , Diástole/fisiologia , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Condicionamento Físico Animal , Ratos , Sístole/fisiologia
5.
J Ethnopharmacol ; 280: 114457, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34329712

RESUMO

ETHNOPHARMACOLOGY RELEVANCE: Pain often causes a series of abnormal changes in physiology and psychology, which can lead to disease and even death. Drug therapy is the most basic and commonly used method for pain relief and management. Interestingly, at present, hundreds of traditional Chinese medicines have been reported to be used for pain relief, most of which are monomer preparations, which have been developed into new painkillers. Corydalis yanhusuo is a representative of one of these medicines and is available for pain relief. AIM OF THE STUDY: This study aims to determine the analgesic effect and the potential targets of the monomers derived from Corydalis yanhusuo, and to explore any possible associated cardiac risk factors. MATERIALS AND METHODS: In this study, four monomers derived from Corydalis yanhusuo (tetrahydropalmatine, corydaline, protopine, dehydrocorydaline) were tested in vivo, using the formalin-induced pain model to determine their analgesic properties. Their potential targets were also determined using whole cell patch clamp recordings and myocardial enzyme assays. RESULTS: The results showed that all monomers showed analgesic activity and inhibited the peak currents, promoted the activation and inactivation phases of Nav1.7, which indicating that Nav1.7 might be involved in the analgesic mechanism of Corydalis yanhusuo. Protopine increased the level of creatine kinase-MB (CK-MB) and inhibited the peak currents, promoted the activation and inactivation phases of Nav1.5, indicating that Nav1.5 might be involved in the cardiac risk associated with protopine treatment. CONCLUSION: These data showed that tetrahydropalmatine produced the best analgesic effect and the lowest cardiac risk. Thus, voltage gated sodium channels (VGSCs) might be the main targets associated with Corydalis yanhusuo. This study, therefore, provides valuable information for future studies and use of traditional Chines medicines for the alleviation of pain.

6.
J Cardiovasc Pharmacol ; 78(1): e105-e111, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33958549

RESUMO

ABSTRACT: Warfarin is a commonly prescribed anticoagulant for valvular heart disease that plays an important role in clinical management to prevent thrombotic events. In this study, we aim to perform a comprehensive study to investigate the genetic biomarkers of stable warfarin dose in the Han Chinese population. We performed an integrative study on 211 Han Chinese patients with valvular heart disease. A total of 40 single nucleotide polymorphisms (SNPs) in 10 important genes (CYP2C9, VKORC1, ABCB1, CYP4F2, APOE, PROC, GGCX, EPHX1, CALU, and SETD1A) which are involved in the warfarin metabolic pathway and equilibrium of coagulation and anticoagulation were selected. We applied MassARRAY technology to genotype the 40 SNPs identified in these Han Chinese patients. Our results showed that 13 SNPs on 6 genes (CYP2C9, VKORC1, ABCB1, PROC, EPHX1, and SETD1A) were associated with the individual stable warfarin dose. Two VKORC1 SNPs (rs9934438 and rs2359612) were the strongest genetic factors determining warfarin dose requirements (P = 8 × 10-6 and 9 × 10-6, respectively). Rs4889599 in SETD1A was first reported to be associated with warfarin dose at a significant level of 0.001 in our study (Padjust = 0.040 after Bonferroni correction). We discovered that genetic variants in CYP2C9, VKORC1, ABCB1, PROC, EPHX1, and SETD1A may affect the stable warfarin dose requirement in Han Chinese patients with valvular disease. The discovery of these potential genetic markers will facilitate the development of advanced personalized anticoagulation therapy in Han Chinese patients.

7.
Front Neurol ; 12: 597992, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33658974

RESUMO

Objective: Carotid atherosclerosis is a known marker of increased cardiovascular risk. We aimed to assess the current epidemiology of carotid atherosclerosis, carotid plaque and related risk factors in rural northeast China. Methods: The population-based, cross-sectional study was conducted in 5,838 adults aged ≥40 years residing in rural northeast China in 2017-2018. A multi-stage cluster sampling method was used to select the representative sample. Carotid atherosclerosis was defined as carotid intima-media thickness (CIMT) ≥1.0 mm or presence of plaque. Results: The mean CIMT was 0.72 ± 0.13 mm and increased with age in this population. Among 2,457 individuals with carotid atherosclerosis, 2,333 were diagnosed with carotid plaque, and 210 individuals were moderate or severe carotid stenosis. Crude prevalence of carotid atherosclerosis and plaque were 42.1 and 40.0%, significantly higher in men than in women (p < 0.001). The age-standardized prevalence of carotid atherosclerosis and carotid plaque were 33.1 and 31.5%, respectively. Advancing age, men, hypertension, diabetes, current smoking, ever-smoking and lack of exercise were risk factors for carotid atherosclerosis. Hypertension (69.1%), dyslipidemia (26.0%) and diabetes (16.1%) were highly prevalent in participants with carotid atherosclerosis. However, the control rates of those comorbidities were frustratingly low (4.7, 8.2, and 14.2%, respectively). Conclusions: The high prevalence of carotid atherosclerosis, carotid plaque, carotid stenosis and uncontrolled risk factors indicated the high burden of cardiovascular disease in rural northeast China, particularly in men. Strategies of prevention and management of atherosclerosis and related risk factors were urgently needed in rural northeast China.

8.
Chem Biol Interact ; 338: 109425, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33617802

RESUMO

Non-steroidal Anti-inflammatory Drugs (NSAIDs) are widely used because of their excellent anti-inflammatory and analgesic effects. However, NSAIDs could cause certain cardiac side effects, such as myocardial infarction, heart failure, atrial fibrillation, arrhythmia and sudden cardiac death. Therefore, meloxicam, nimesulide, piroxicam, and diclofenac were selected and the whole cell patch clamp technique was used to investigate the electrophysiological regulatory effects of them on the sodium channel hNav1.5 and potassium channel hKv11.1, which were closely associated to the biotoxicity of cardiac, and to explore the potential cardiac risk mechanism. The results showed that the four NSAIDs could inhibit the peak currents of hNav1.5 and hKv11.1. Furthermore, the four NSAIDs could affect both the activation and inactivation processes of hNav1.5 with I-V curves left-shifted to hyperpolarized direction in activation phase. These data indicate that the inhibition effects of Nav1.5 and Kv11.1 by meloxicam, nimesulide, piroxicam, and diclofenac might contribute to their potential cardiac risk. These findings provide a basis for the discovery of other potential cardiac risk targets for NSAIDs.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Canal de Potássio ERG1/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Animais , Anti-Inflamatórios não Esteroides/química , Células CHO , Cricetulus , Células HEK293 , Humanos , Ativação do Canal Iônico/efeitos dos fármacos , Cinética
9.
J Ethnopharmacol ; 269: 113736, 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33359917

RESUMO

ETHNOPHARMACOLOGY RELEVANCE: Pain is an unpleasant sensory and emotional experience, often accompanied by the occurrence of a variety of diseases. More than 800 kinds of traditional Chinese medicines (TCM) has now been reported for pain relief and several monomers have been developed into novel analgesic drugs. Bupleurum chinense and Angelica biserrata were representatives of the TCM that are currently available for the treatment of pain. AIM OF THE STUDY: The study aims to detect the potential analgesic activity of each monomer of Bupleurum chinense and Angelica biserrata and to explore whether Nav1.7 is one of the targets for its analgesic activity. MATERIALS AND METHODS: In this study, five monomers from Bupleurum chinense (Saikosaponin A, Saikosaponin B1, Saikosaponin B2, Saikosaponin C, Saikosaponin D) and five monomers from the Angelica biserrata (Osthole, Xanthotoxin, Imperatorin, Isoimperatorin, Psoralen) were examined by whole-cell patch-clamp on Nav1.7, which was closely associated with pain. Classical mouse pain models were also used to further verify the analgesic activity in vivo. RESULTS: The results showed that monomers of Saikosaponins and Angelica biserrata all inhibited the peak currents of Nav1.7, indicating that Nav1.7 might be involved in the analgesic mechanism of Saikosaponins and Angelica biserrata. Among them, Saikosaponin A and Imperatorin showed the strongest inhibitory effect on Nav1.7. Furthermore, both Saikosaponin A and Imperatorin showed inhibitory effects on thermal pain and formalin-induced pain in phase II in vivo. CONCLUSION: The results provide valuable information for future studies on the potential of TCM in alleviating pain.


Assuntos
Analgésicos/farmacologia , Angelica/química , Bupleurum/química , Medicamentos de Ervas Chinesas/farmacologia , Canal de Sódio Disparado por Voltagem NAV1.7/efeitos dos fármacos , Dor/tratamento farmacológico , Analgésicos/química , Analgésicos/uso terapêutico , Animais , Células CHO , Cricetulus , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/uso terapêutico , Feminino , Formaldeído/toxicidade , Furocumarinas/farmacologia , Furocumarinas/uso terapêutico , Temperatura Alta/efeitos adversos , Masculino , Medicina Tradicional Chinesa , Camundongos , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/farmacologia , Ácido Oleanólico/uso terapêutico , Dor/etiologia , Raízes de Plantas/química , Saponinas/farmacologia , Saponinas/uso terapêutico , Sódio/fisiologia
10.
Acta Biochim Biophys Sin (Shanghai) ; 52(12): 1373-1381, 2020 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-33231607

RESUMO

Exposure to adverse factors in utero may lead to adaptive changes in cardiac structure and metabolism, which increases the risk of chronic cardiovascular disease later in life. Studies showed that the angiotensin II type 1 receptor autoantibodies (AT1-AAs) are able to cross the placenta into the circulation of pregnant rodents' embryo, which adversely affects embryogenesis. However, the effects of AT1-AA exposure on the fetal heart in utero are still unknown. In this study, we investigated whether intrauterine AT1-AA exposure has adverse effects on fetal heart structure, function and metabolism. AT1-AA-positive pregnant mouse models were successfully established by passive immunity, evidenced by increased AT1-AA content. Morphological and ultrasonic results showed that the fetal mice on embryonic day 18 (E18) of AT1-AA group have loose and disordered myocardial structure, and decreased left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), compared with control groups. The myocardium of AT1-AA group fetal mice on E18 exhibited increased expression of the key molecules in the glycolytic pathway, pyruvate and lactic acid content and ATP production, suggesting that the glycolysis rate was enhanced. Furthermore, the enhanced effect of glycolysis caused by AT1-AA is mainly through the PPARß/δ pathway. These data confirmed that fetus exposure to AT1-AA in utero developed left ventricular dysfunction, myocardial structural arrangement disorders, and enhanced glycolysis on E18. Our results support AT1-AA being a potentially harmful factor for cardiovascular disease in fetal mice.


Assuntos
Autoanticorpos/toxicidade , Cardiomiopatias/etiologia , Feto/imunologia , Feto/fisiopatologia , Glicólise/imunologia , Receptor Tipo 1 de Angiotensina/imunologia , Animais , Autoanticorpos/sangue , Autoanticorpos/imunologia , Cardiomiopatias/patologia , Modelos Animais de Doenças , Feminino , Camundongos Endogâmicos BALB C , PPAR gama/metabolismo , PPAR beta/metabolismo , Placenta/fisiologia , Gravidez , Segundo Trimestre da Gravidez , Volume Sistólico/imunologia , Função Ventricular Esquerda/imunologia
11.
Adv Biol Regul ; 78: 100755, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33017725

RESUMO

Classical and novel protein kinase C (PKC) isozymes (c/nPKCs), members of the PKC family that become activated by the lipid second messenger diacylglycerol (DAG) and phorbol esters, exert a myriad of cellular effects that impact proliferative and motile cellular responses. While c/nPKCs have been indisputably associated with tumor promotion, their roles exceed by far their sole involvement as promoter kinases. Indeed, this original dogma has been subsequently redefined by the introduction of several new concepts: the identification of tumor suppressing roles for c/nPKCs, and their participation in early and late stages of carcinogenesis. This review dives deep into the intricate roles of c/nPKCs in cancer initiation as well as in the different stages of the metastatic cascade, with great emphasis in their involvement in cancer cell motility via regulation of small Rho GTPases, the production of extracellular matrix (ECM)-degrading proteases, and the epithelial-to-mesenchymal transition (EMT) program required for the acquisition of highly invasive traits. Here, we highlight functional interplays between either PKCα or PKCε and mesenchymal features that may ultimately contribute to anticancer drug resistance in cellular and animal models. We also introduce the novel hypothesis that c/nPKCs may be implicated in the control of immune evasion through the regulation of immune checkpoint protein expression. In summary, dissecting the colossal complexity of c/nPKC signaling in the wide spectrum of cancer progression may bring new opportunities for the development of meaningful tools aiding for cancer prognosis and therapy.


Assuntos
Metástase Neoplásica , Neoplasias/patologia , Isoformas de Proteínas/metabolismo , Proteína Quinase C/metabolismo , Animais , Carcinogênese , Diglicerídeos/metabolismo , Transição Epitelial-Mesenquimal , Humanos , Mutação , Neoplasias/enzimologia , Conformação Proteica , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Proteína Quinase C/química , Proteína Quinase C/genética
12.
Mol Cell Endocrinol ; 518: 111022, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32871226

RESUMO

Blood glucose is of great importance to development and metabolic homeostasis in fetuses. Stimulation of harmful factors during gestation induces pathoglycemia. Angiotensin II type 1 receptor autoantibody (AT1-AA), a newly discovered gestational harmful factor, has been shown to induce intrauterine growth restriction in fetuses and glucose disorders in adults. However, whether and how AT1-AA influences the blood glucose level of fetuses during gestation is not yet clear. The purpose of the current study was to observe the fetal blood glucose level of AT1-AA-positive pregnant rats during late pregnancy and to determine the roles that hepatic glucose transporters play in this process. We established AT1-AA-positive pregnant rats by injecting AT1-AA into the caudal veins of rats in the 2nd trimester of gestation. Although the fetal blood glucose level in the 3rd trimester of gestation decreased, hepatic glucose uptake increased detected. Through separating membrane and cytosolic proteins, we demonstrated that both the expression and membrane transport ratio of glucose transporter 1 (GLUT1), which is responsible for glucose transport in fetal hepatocytes, were upregulated, accompanied by increased expression of N-glycosyltransferase STT3A, which contributes to the N-glycosylation of GLUT1. In vitro, we identified that AT1-AA increased glucose uptake, the expression and membrane transport ratio of GLUT1 and the expression of STT3A in HepG2 cell lines via separating membrane and cytosolic proteins and immunofluorescence, resulting in the decreased glucose content in the medium. The GLUT1 inhibitor WZB117 reversed the decreases in glucose content in the medium, the increases in glucose uptake, the increases in the expression and membrane transport ratio of GLUT1 caused by AT1-AA. The N-glycosyltransferase inhibitor NGI as well as si-STT3A reversed the AT1-AA-induced upregulation of the STT3A-GLUT1-glucose uptake effect. This study demonstrates that AT1-AA lowers the blood glucose level of fetuses via the STT3A-GLUT1-glucose uptake axis in liver.


Assuntos
Autoanticorpos/fisiologia , Glucose/metabolismo , Hipoglicemia/etiologia , Fígado/metabolismo , Receptor Tipo 1 de Angiotensina/imunologia , Animais , Autoanticorpos/efeitos adversos , Embrião de Mamíferos , Feminino , Feto/imunologia , Feto/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Células Hep G2 , Hexosiltransferases/metabolismo , Humanos , Hipoglicemia/imunologia , Hipoglicemia/metabolismo , Fígado/imunologia , Masculino , Proteínas de Membrana/metabolismo , Gravidez , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
13.
Am J Physiol Cell Physiol ; 319(5): C877-C884, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32845720

RESUMO

Tunneling nanotubes (TNTs) emerged as important specialized actin-rich membrane protrusions for cell-to-cell communication. These structures allow the intercellular exchange of material, such as ions, soluble proteins, receptors, vesicles and organelles, therefore exerting critical roles in normal cell function. Indeed, TNTs participate in a number of physiological processes, including embryogenesis, immune response, and osteoclastogenesis. TNTs have been also shown to contribute to the transmission of retroviruses (e.g., human immunodeficiency virus-1, HIV-1) and coronaviruses. As with other membrane protrusions, the involvement of Rho GTPases in the formation of these elongated structures is undisputable, although the mechanisms involved are not yet fully elucidated. The tight control of Rho GTPase function by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) strongly suggests that localized control of these Rho regulators may contribute to TNT assembly and disassembly. Deciphering the intricacies of the complex signaling mechanisms leading to actin reorganization and TNT development would reveal important information about their involvement in normal cellular physiology as well as unveil potential targets for disease management.


Assuntos
Betacoronavirus , Comunicação Celular , Infecções por Coronavirus/transmissão , Nanotubos , Pneumonia Viral/transmissão , Proteínas rho de Ligação ao GTP/metabolismo , Betacoronavirus/fisiologia , COVID-19 , Infecções por HIV/transmissão , Humanos , Pandemias , SARS-CoV-2 , Proteínas rho de Ligação ao GTP/genética
14.
J Int Med Res ; 48(6): 300060520906747, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32500784

RESUMO

Primitive neuroectodermal tumours (PNETs) are rare malignant small round cell tumours. Notably, despite widespread reports of PNET in multiple parts of the body, it is extremely rare in the pelvis. Here, a rare case of giant PNET of the pelvis, that was treated with surgical intervention comprising hemipelvectomy and amputation, is reported. A 42-year-old female patient presented with an enlarged mass on the left hip and severe pain in the left lower extremity for the previous 6 months. Preoperative imaging examinations indicated an irregular soft tissue-like signal shadow sized 19 × 15 × 12 cm at the left ilium and sacrum. After surgical intervention involving left hemipelvectomy and amputation, the tumour was diagnosed by pathology as PNET. During the courses of postoperative radiotherapy and chemotherapy, local recurrence and distant metastasis occurred, and the patient died 9 months following surgical treatment. To the best of the authors' knowledge, the current case is the largest pelvic PNET resection reported to date. Pelvic PNET is extremely malignant and has a high mortality rate regardless of surgical treatment, however, surgical resection of the lesion may relieve the symptoms, extend life, and improve quality of life to a certain extent.


Assuntos
Tumores Neuroectodérmicos Primitivos/diagnóstico , Tumores Neuroectodérmicos Primitivos/cirurgia , Adulto , Biópsia/métodos , Feminino , Humanos , Recidiva Local de Neoplasia/cirurgia , Neoplasias Pélvicas/diagnóstico , Neoplasias Pélvicas/cirurgia , Pelve/fisiologia , Qualidade de Vida
15.
Cell Death Dis ; 11(6): 432, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-32514012

RESUMO

Vascular remodeling can be caused by angiotensin II type 1 receptor (AT1R) autoantibody (AT1-AA), although the related mechanism remains unknown. Angiotensin II type 2 receptor (AT2R) plays multiple roles in vascular remodeling through cross-talk with AT1R in the cytoplasm. Here, we aimed to explore the role and mechanism of AT2R in AT1-AA-induced vascular smooth muscle cell (VSMC) migration, which is a key event in vascular remodeling. In vitro and in vivo, we found that AT2R can promote VSMC migration in AT1-AA-induced vascular remodeling. Moreover, AT2R expression was upregulated via Klf-5/IRF-1-mediated transcriptional and circErbB4/miR-29a-5p-mediated posttranscriptional mechanisms in response to AT1-AA. Our data provide a molecular basis for AT1-AA-induced AT2R expression by transcription factors, namely, a circular RNA and a microRNA, and showed that AT2R participated in AT1-AA-induced VSMC migration during the development of vascular remodeling. AT2R may be a potential target for the treatment of AT1-AA-induced vascular diseases.


Assuntos
Autoanticorpos/farmacologia , MicroRNAs/metabolismo , Músculo Liso Vascular/metabolismo , Receptor Tipo 1 de Angiotensina/imunologia , Receptor Tipo 2 de Angiotensina/biossíntese , Animais , Movimento Celular/fisiologia , Células HEK293 , Humanos , Fator Regulador 1 de Interferon/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Músculo Liso Vascular/citologia , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Receptor ErbB-4/metabolismo , Transfecção
16.
J Int Med Res ; 48(5): 300060520925992, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32459154

RESUMO

OBJECTIVE: As a minimally invasive intervertebral fusion technique popularized in recent years, extreme lateral interbody fusion (XLIF) has various advantages. In this study, we describe the application and efficacy of XLIF for the treatment of thoracic tuberculosis (TB), as this may be an emerging treatment option for thoracic TB in the future. METHODS: We present the case of a 75-year-old man who had suffered from chest and back pain for 1 month. Imaging studies showed destruction of the T12 and L1 vertebral bodies and the T12-L1 intervertebral disc, accompanied by formation of a paravertebral abscess. After 2 weeks of standard anti-TB treatment, the patient underwent debridement of the lesions, XLIF, and percutaneous pedicle screw fixation. RESULTS: The patient's chest and back pain were significantly alleviated after the operation. The patient recovered well, and as of the most recent follow-up had no obvious limitation in thoracolumbar spine function. CONCLUSIONS: XLIF combined with percutaneous pedicle screw fixation for the treatment of thoracic TB can allow for TB lesion debridement, discectomy, and interbody fusion under direct visualization, and can effectively improve patient prognosis.


Assuntos
Dor nas Costas/etiologia , Degeneração do Disco Intervertebral/cirurgia , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Fusão Vertebral/métodos , Tuberculose da Coluna Vertebral/cirurgia , Idoso , Dor nas Costas/sangue , Dor nas Costas/cirurgia , Sedimentação Sanguínea , Proteína C-Reativa/análise , Estudos de Viabilidade , Humanos , Fixadores Internos , Disco Intervertebral/diagnóstico por imagem , Disco Intervertebral/cirurgia , Degeneração do Disco Intervertebral/sangue , Degeneração do Disco Intervertebral/diagnóstico , Degeneração do Disco Intervertebral/etiologia , Masculino , Procedimentos Cirúrgicos Minimamente Invasivos/instrumentação , Parafusos Pediculares , Fusão Vertebral/instrumentação , Vértebras Torácicas/diagnóstico por imagem , Vértebras Torácicas/cirurgia , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Tuberculose da Coluna Vertebral/sangue , Tuberculose da Coluna Vertebral/complicações , Tuberculose da Coluna Vertebral/diagnóstico
17.
Cardiol Res Pract ; 2020: 1845969, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32190383

RESUMO

Objective: Hypercholesterolemia- (HC-) induced endothelial dysfunction is the first step of atherogenesis, and the peroxisome proliferator-activated receptor γ (PPARγ (PPARγ (PPARγ) has been reported to attenuate atherosclerosis formation; however, the underlying mechanisms are not fully understood. The present study was designed to determine whether myeloperoxidase (MPO) mediates HC-induced endothelial dysfunction and the role of the PPARγ agonist pioglitazone (PIO) in attenuating endothelial dysfunction. Methods: Male Wistar rats were fed with normal or high cholesterol diets for 8 weeks. HC rats were randomized to receive dapsone (DDS, the MPO inhibitor) during the last 6 days or PIO for the remaining 4 weeks. Vascular endothelial function was determined by comparing vasorelaxation to ACh, an endothelium-dependent vasodilator, and SNP, an endothelium-independent vasodilator in vascular rings in vitro. The vascular MPO activity, NO x content, and cGMP level were measured by the MPO activity assay kit, NO assay kit, and cGMP RIA kit. Results: Compared with rats fed with normal diet, endothelium-dependent vasodilation, NO x content, and cGMP level were decreased, and MPO activity was increased in thoracic aortas of rats fed with HC diet. There was a negative correlation between vascular endothelial function, NO x content or cGMP level, and MPO activity. PIO obviously reduced the MPO activity, increased NO x content and cGMP level, and improved endothelium-dependent vasodilation function in HC rats, which was essentially the same as that seen with DDS. And, there was a negative correlation between vascular endothelial function, NO x content or cGMP level, and MPO activity in the HC group and the PIO intervention group. Conclusion: MPO might provoke vascular endothelial dysfunction in hypercholesterolemic rats by reducing the NO biological activity and impairing the NO/cGMP/cGK signaling pathway. PIO might inhibit vascular MPO activity and increase NO bioavailability with the net result of reversing endothelial dysfunction.

18.
J Clin Pharm Ther ; 45(2): 354-364, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31778586

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Myelosuppression, an adverse drug reaction (ADR), often causes medical treatment termination in cancer patients. It has been known that genetic components, such as single-nucleotide polymorphisms (SNPs), influence the risk of myelosuppression at the individual-patient level. However, due to ethnic variation in frequency of genetic polymorphisms, results reported in Caucasian patients may not be generalizable to the Chinese Han population. Until now, few researches on myelosuppression included Chinese Han patients. In this study, we conducted a systematic study of potential biomarkers for docetaxel-induced myelosuppression in Han Chinese patients. METHODS: We examined 61 SNPs in 36 genes that code for drug transporters, metabolism enzymes, nuclear receptors and DNA repair pathway in 110 Chinese Han patients receiving docetaxel-based chemotherapy. Genotyping was conducted using the Sequenom MassARRAY system. Significant SNPs were identified by logistic regression, and gene-gene interactions were investigated by generalized multifactor dimensionality reduction (GMDR) analysis. RESULTS AND DISCUSSION: Our results revealed that 11 SNPs in nine genes (SLC15A1, SLCO1A2, CYP2D6, FMO3, UGT1A1, NAT2, SULT2A1, PXR and HNF4α) were associated with docetaxel-induced myelosuppression. GMDR analyses suggested that a 3-locus model: SLC15A1 rs2297322-PXR rs3732359-FMO3 rs2266782 was an appropriate predictive model of docetaxel-induced myelosuppression (P = .017, Testing Bal.Acc = 0.653, CV Consistency = 10/10). WHAT IS NEW AND CONCLUSION: Our findings suggest multiple novel predictive biomarkers of docetaxel-induced myelosuppression: SLC15A1 rs2297322, PXR rs3732359 and FMO3 rs2266782. These discoveries should help in advancing future personalized therapy of docetaxel-based chemotherapy specific to Chinese Han patients.


Assuntos
Antineoplásicos/efeitos adversos , Grupo com Ancestrais do Continente Asiático/genética , Docetaxel/efeitos adversos , Predisposição Genética para Doença , Idoso , Antineoplásicos/administração & dosagem , Biomarcadores/metabolismo , Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Docetaxel/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Polimorfismo de Nucleotídeo Único
19.
J Orthop Surg Res ; 14(1): 353, 2019 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-31706346

RESUMO

BACKGROUND: This present study is aimed to retrospectively assess the efficacy of three-dimensional (3D) printing assisted osteotomy guide plate in accurate osteotomy of adolescent cubitus varus deformity. MATERIAL AND METHODS: Twenty-five patients (15 males and 10 females) with the cubitus varus deformity from June 2014 to December 2017 were included in this study and were enrolled into the conventional group (n = 11) and 3D printing group (n = 14) according to the different surgical approaches. The operation time, intraoperative blood loss, osteotomy degrees, osteotomy end union time, and postoperative complications between the two groups were observed and recorded. RESULTS: Compared with the conventional group, the 3D printing group has the advantages of shorter operation time, less intraoperative blood loss, higher rate of excellent correction, and higher rate of the parents' excellent satisfaction with appearance after deformity correction (P < 0.001, P < 0.001, P = 0.019, P = 0.023). Nevertheless, no significant difference was presented in postoperative carrying angle of the deformed side and total complication rate between the two groups (P = 0.626, P = 0.371). CONCLUSIONS: The operation assisted by 3D printing osteotomy guide plate to correct the adolescent cubitus varus deformity is feasible and effective, which might be an optional approach to promote the accurate osteotomy and optimize the efficacy.


Assuntos
Placas Ósseas , Articulação do Cotovelo/diagnóstico por imagem , Fraturas do Úmero/diagnóstico por imagem , Fraturas do Úmero/cirurgia , Osteotomia/métodos , Impressão Tridimensional , Adolescente , Placas Ósseas/tendências , Articulação do Cotovelo/anormalidades , Feminino , Seguimentos , Humanos , Masculino , Osteotomia/tendências , Impressão Tridimensional/tendências , Estudos Retrospectivos , Resultado do Tratamento
20.
Medicine (Baltimore) ; 98(38): e17227, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31567983

RESUMO

RATIONALE: Autologous peripheral nerve injury caused by crush syndrome due to alcohol intoxication is relatively rare, and to our knowledge, the compression of 3 upper limb nerves at the same time has not been reported previously. If a compressive peripheral nerve injury is not treated in a timely manner, it is difficult to recover neurological function, and the prognosis is poor. PATIENT CONCERNS: Here, we present a case of a 50-year-old man with ipsilateral radial nerve, median nerve, and ulnar nerve injuries caused by autogenous compression after drunkenness. DIAGNOSIS: Electromyography and nerve conduction studies suggested peripheral nerve injury in the left upper limb. The diagnosis was injury to the radial nerve, median nerve, and ulnar nerve in the left upper arm. INTERVENTIONS: Exploratory neurolysis surgery of the radial nerve, median nerve, and ulnar nerve was performed in the left upper arm. Postoperative oral neurotrophic drugs were administered, and functional exercise was performed. OUTCOMES: After timely diagnosis and treatment, the strength of the left upper arm muscle recovered, and the prognosis of neurological function was satisfactory during 3 years of follow-up sessions. LESSONS: In the treatment of such patients, a comprehensive understanding of their medical history and a strict physical examination should be performed. Combined with neuroelectrophysiological and imaging examination, the diagnosis can be confirmed. After timely diagnosis and treatment, the prognosis is mostly excellent.


Assuntos
Intoxicação Alcoólica/complicações , Síndrome de Esmagamento/etiologia , Nervo Mediano/lesões , Nervo Radial/lesões , Nervo Ulnar/lesões , Intoxicação Alcoólica/patologia , Síndrome de Esmagamento/patologia , Síndrome de Esmagamento/terapia , Humanos , Masculino , Nervo Mediano/patologia , Pessoa de Meia-Idade , Nervo Radial/patologia , Nervo Ulnar/patologia
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