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1.
BMC Genomics ; 20(1): 911, 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31783728

RESUMO

BACKGROUND: GRAS gene is an important transcription factor gene family that plays a crucial role in plant growth, development, adaptation to adverse environmental condition. Sweet potato is an important food, vegetable, industrial raw material, and biofuel crop in the world, which plays an essential role in food security in China. However, the function of sweet potato GRAS genes remains unknown. RESULTS: In this study, we identified and characterised 70 GRAS members from Ipomoea trifida, which is the progenitor of sweet potato. The chromosome distribution, phylogenetic tree, exon-intron structure and expression profiles were analysed. The distribution map showed that GRAS genes were randomly located in 15 chromosomes. In combination with phylogenetic analysis and previous reports in Arabidopsis and rice, the GRAS proteins from I. trifida were divided into 11 subfamilies. Gene structure showed that most of the GRAS genes in I. trifida lacked introns. The tissue-specific expression patterns and the patterns under abiotic stresses of ItfGRAS genes were investigated via RNA-seq and further tested by RT-qPCR. Results indicated the potential functions of ItfGRAS during plant development and stress responses. CONCLUSIONS: Our findings will further facilitate the functional study of GRAS gene and molecular breeding of sweet potato.

2.
BMC Genet ; 20(1): 90, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31795942

RESUMO

BACKGROUND: WRKY DNA-binding protein (WRKY) is a large gene family involved in plant responses and adaptation to salt, drought, cold and heat stresses. Sweet potato from the genus Ipomoea is a staple food crop, but the WRKY genes in Ipomoea species remain unknown to date. Hence, we carried out a genome-wide analysis of WRKYs in Ipomoea trifida (H.B.K.) G. Don., the wild ancestor of sweet potato. RESULTS: A total of 83 WRKY genes encoding 96 proteins were identified in I. trifida, and their gene distribution, duplication, structure, phylogeny and expression patterns were studied. ItfWRKYs were distributed on 15 chromosomes of I. trifida. Gene duplication analysis showed that segmental duplication played an important role in the WRKY gene family expansion in I. trifida. Gene structure analysis showed that the intron-exon model of the ItfWRKY gene was highly conserved. Meanwhile, the ItfWRKYs were divided into five groups (I, IIa + IIb, IIc, IId + IIe and III) on the basis of the phylogenetic analysis on I. trifida and Arabidopsis thaliana WRKY proteins. In addition, gene expression profiles confirmed by quantitative polymerase chain reaction showed that ItfWRKYs were highly up-regulated or down-regulated under salt, drought, cold and heat stress conditions, implying that these genes play important roles in response and adaptation to abiotic stresses. CONCLUSIONS: In summary, genome-wide identification, gene structure, phylogeny and expression analysis of WRKY gene in I. trifida provide basic information for further functional studies of ItfWRKYs and for the molecular breeding of sweet potato.

3.
Org Lett ; 21(22): 9276-9279, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31686514

RESUMO

An efficient in situ Pd-NHC catalytic system for regioselective arylation of B(3,6)-H bonds of o-carborane has been developed for the first time. A series of symmetric and unsymmetric 3,6-diaryl-o-carboranes anchored with active groups have been synthesized with moderate to good yields under mild conditions. This work offers an efficient protocol for selective activation of B(3,6)-H bonds and has important value in design coupling reactions for selective functionalization of o-carboranes.

4.
World Neurosurg ; 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31712116

RESUMO

OBJECTIVE: To demonstrate the use of 3D-printed intracranial lesion models for complex neurosurgery to increase the success rate of clinical surgeries via practice in simulated surgeries. METHODS: We collected CT, MRI, and CTA images from patients with intracranial tumor or aneurysm, conducted multi-modal image reconstruction, and then constructed a 3D-printed model with the skull base, cerebral arteries, and brain tumor or aneurysm. 49 simulated surgeries were carried out on the model under microscope and actual surgery was carried out after validation and accumulation of experience. RESULTS: The 3D-printed brain tumor models were used to design the surgical route, to simulate piecemeal resection of tumors through keyhole approach, and to verify extent of tumor resection. A drill was used for bone flap removal and milling of bony structures such as the anterior clinoid process, tuberculum sellae, petrous apex, and internal acoustic meatus. The tumors were removed by laser knife and CUSA. The 3D-printed aneurysm models were used to assess the feasibility of different keyhole approaches and to select the aneurysm clip. Actual surgery was carried out based on the results of the simulated surgery. Postoperative MR image review showed that 84%(21/25)of patients had total tumor resection, and 16%(4/25)subtotal resection. DSA confirmed complete clipping of all aneurysms (24 cases/39 aneurysms). CONCLUSIONS: 3D-printed craniocerebral models provide effective simulated-surgery conditions for keyhole surgeries of complex brain tumors or aneurysms and aid in preoperative surgical design, accumulation of surgical experience, and validation of surgical outcomes.

5.
Eur J Pharmacol ; : 172787, 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31712061

RESUMO

Zinc finger E-box binding homeobox 1 (ZEB1) (previously known as TCF8), a transcriptional repressor, is a member of the zinc-finger family of proteins. Numerous studies have demonstrated that abnormal expression of ZEB1 in many types of liver disease including hepatocellular carcinoma (HCC). Liver fibrosis is the basis and central link in the progression of liver disease. Thereby, the function of ZEB1 in liver fibrosis has been investigated. The aim of the present study was to investigate the role of ZEB1 in liver fibrosis and to elucidate the mechanism. In this study, we explored the effect of ZEB1 in hepatic stellate cells (HSCs) activation and the regulatory mechanism of the Wnt/ß-catenin signaling pathway. Additionally, ZEB1 positively regulated the expression levels of α-SMA and Col.I in vivo and in vitro, which were correlated with the activated HSCs. Furthermore, overexpression of ZEB1 could inhibit HSCs apoptosis and promote IL-6 and TNF-α secretion in LX-2 cells. Conversely, ZEB1 silencing led to the promotion of cell proliferation and the reduction of IL-6 and TNF-α secretion in LX-2 cells. Mechanically, canonical Wnt/ß-catenin signaling pathway could be regulated by ZEB1. Collectively, the data suggested that ZEB1 might play a significant role in the activation of LX-2 cells, and Wnt/ß-catenin signaling pathway might participate in this progression.

6.
J Cell Physiol ; 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31674013

RESUMO

MicroRNA-142-3p (miR-142-3p) was previously investigated in various cancers, whereas, it's role in breast cancer (BC) remains far from understood. In this study, we found that miR-142-3p was markedly decreased both in cell lines and BC tumor tissues. Elevated miR-142-3p expression suppressed growth and metastasis of BC cell lines via gain-of-function assay in vitro and in vivo. Mechanistically, miR-142-3p could regulate the ras-related C3 botulinum toxin substrate 1 (RAC1) expression in protein level, which simultaneously suppressed the epithelial-to-mesenchymal transition related protein levels and the activity of PAK1 phosphorylation, respectively. In addition, rescue experiments revealed RAC1 overexpression could reverse tumor-suppressive role of miR-142-3p. Our results showed miR-142-3p could function as a tumor suppressor via targeting RAC1/PAK1 pathway in BC, suggesting a potent therapeutic target for BC treatment.

7.
Pharmacol Res ; 150: 104501, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31689520

RESUMO

Alcoholic liver disease (ALD) is a major cause of chronic liver disease worldwide that afflicts human health. With the in-depth study of the disease, its pathogenesis has gradually become clear. Although great breakthroughs have been made in the research of ALD, the research and development of drugs related to ALD has lagged behind seriously. However, natural products have always inspired the development of drugs. Meanwhile, there is evidence that some natural products can also play a certain role in the treatment of ALD. Thus, we reviewed the natural products, extracts and formulations with potential anti-ALD activities by consulting the relevant data in the databases of PubMed, Web of Science and CNKI databases, in order to elucidate the regulated mechanism of these natural products. Sum up, the insights provided in present review will be needed for further exploration of botanical drugs in the development of ALD therapy.

8.
Cancer ; 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31730714

RESUMO

BACKGROUND: Racial disparities in cancer outcomes are increasingly recognized, but comprehensive analyses, including molecular studies, are limited. The objective of the current study was to perform a pan-cancer clinical and epigenetic molecular analysis of outcomes in African American (AA) and European American (EA) patients. METHODS: Cross-platform analyses using cancer databases (the Surveillance, Epidemiology, and End Results program database and the National Cancer Data Base) and a molecular database (The Cancer Genome Ancestry Atlas) were performed to evaluate clinical and epigenetic molecular differences between AA and EA patients based on genetic ancestry. RESULTS: In the primary pan-cancer survival analysis using the Surveillance, Epidemiology, and End Results database (2,045,839 patients; 87.5% EA and 12.5% AA), AA patients had higher mortality rates for 28 of 42 cancer types analyzed (hazard ratio, >1.0). AAs continued to have higher mortality in 13 cancer types after adjustment for socioeconomic variables using the National Cancer Database (5,150,023 patients; 11.6% AA and 88.4% EA). Then, molecular features of 5,283 tumors were analyzed in patients who had genetic ancestry data available (87.2% EA and 12.8% AA). Genes were identified with altered DNA methylation along with increased microRNA expression levels unique to AA patients that are associated with cancer drug resistance. Increased miRNAs (miR-15a, miR-17, miR-130-3p, miR-181a) were noted in common among AAs with breast, kidney, thyroid, or prostate carcinomas. CONCLUSIONS: The current results identified epigenetic features in AA patients who have cancer that may contribute to higher mortality rates compared with EA patients who have cancer. Therefore, a focus on molecular signatures unique to AAs may identify actionable molecular abnormalities.

9.
Int J Biol Sci ; 15(12): 2719-2732, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31754342

RESUMO

The Tibet minipig is a rare highland pig breed worldwide and has many applications in biomedical and agricultural research. However, Tibet minipigs are not like domesticated pigs in that their ovulation number is low, which is unfavourable for the collection of zygotes. Partly for this reason, few studies have reported the successful generation of genetically modified Tibet minipigs by zygote injection. To address this issue, we described an efficient way to generate gene-edited Tibet minipigs, the major elements of which include the utilization of synchronized oestrus instead of superovulation to obtain zygotes, optimization of the preparation strategy, and co-injection of clustered regularly interspaced short palindromic repeat sequences associated protein 9 (Cas9) mRNA and single-guide RNAs (sgRNAs) into the cytoplasm of zygotes. We successfully obtained allelic TYR gene knockout (TYR -/-) Tibet minipigs with a typical albino phenotype (i.e., red-coloured eyes with light pink-tinted irises and no pigmentation in the skin and hair) as well as TYR -/- IL2RG -/- and TYR -/- RAG1 -/- Tibet minipigs with typical phenotypes of albinism and immunodeficiency, which was characterized by thymic atrophy and abnormal immunocyte proportions. The overall gene editing efficiency was 75% for the TYR single gene knockout, while for TYR-IL2RG and TYR-RAG1 dual gene editing, the values were 25% and 75%, respectively. No detectable off-target mutations were observed. By intercrossing F0 generation minipigs, targeted genetic mutations can also be transmitted to gene-edited minipigs' offspring through germ line transmission. This study is a valuable exploration for the efficient generation of gene-edited Tibet minipigs with medical research value in the future.

10.
Medicine (Baltimore) ; 98(45): e17844, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31702641

RESUMO

BACKGROUND: Several treatments are beneficial for patients with cancer-related pain (CRP), and there are numbers of systematic reviews evaluating the effectiveness and safety of these treatments. However, the overall quality of the evidence has not been quantitatively assessed. The aim of this study is to overcome the inconclusive evidence about the interventions of CRP. METHODS: We will perform an umbrella systematic review to identify eligible randomised controlled trials (RCTs). A comprehensive literature search will be conducted in MEDLINE, EMBASE, and the Cochrane library for systematic reviews, meta-analyses and RCTs. We will describe the general information of the RCTs for participants, interventions, outcome measurements, comparisons, and results. Network meta-analysis will be developed to determine the comparative effectiveness of the treatments. RESULTS: The result of this network meta-analysis will provide direct and indirect evidence of treatments for CRP. CONCLUSION: The conclusion of our study will help clinicians and CRP patients to choose suitable treatment options. ETHICS AND DISSEMINATION: Formal ethical approval is not required, as the data are not individualized. The findings of this systematic review will be disseminated in a peer-reviewed publication and/or presented at relevant conferences. PROSPERO REGISTRATION NUMBER: CRD42019131721.


Assuntos
Dor do Câncer/terapia , Manejo da Dor/métodos , Humanos , Meta-Análise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa
11.
Mediators Inflamm ; 2019: 7898095, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31736656

RESUMO

Accumulated evidences show that neuroinflammation play a pivotal role in the pathogenesis of depression. Neuropeptide Y (NPY) and its receptors have been demonstrated to have anti-inflammative as well as antidepressant effects. In the present study, the ability of NPY to modulate depressive-like behaviors induced by lipopolysaccharides (LPS) in rats and the receptors and signaling mechanisms involved were investigated. Continuous injection LPS (i.p) for 4 days led to development of depressive-like behaviors in rats, accompanied with M1-type microglia activation and increased levels of IL-1ß as well as decreased levels of NPY and Y2R expression in the mPFC selectively. Local injection of NPY into the medial prefrontal cortex (mPFC) ameliorated the depression-like behaviors and suppressed the NLRP3 inflammasome signaling pathway. Y2R agonist PYY (3-36) mimicked and Y2R antagonist BIIE0246 abolished the NPY effects in the mPFC. All these results suggest that NPY and Y2R in the mPFC are involved in the pathophysiology of depression and NPY plays an antidepressant role in the mPFC mainly via Y2R, which suppresses the NLRP3 signaling pathway, in LPS-induced depression model rats.

12.
Eur J Pediatr ; 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31754776

RESUMO

X-linked lymphoproliferative syndrome (XLP) is a rare primary immunodeficiency disease that can be divided into two types: SAP deficiency (XLP1) and XIAP deficiency (XLP2), caused by mutations in the SH2D1A and XIAP genes, respectively. Few cases of XLP (particularly XIAP deficiency) have been reported in mainland China; hence, little is known about the characteristics of Chinese patients with XLP. We identified 13 and 7 patients with SAP and XIAP deficiency, respectively, in our center. Of our 20 patients, 19/20 (95%) presented with disease symptoms at a very early age: six in infancy and 13 in childhood. One XIAP- and three SAP-deficient patients died, while 3/7(42.9%) and 4/13(30.8%), respectively, developed hemophagocytic lymphohistiocytosis (HLH). Epstein-Barr virus (EBV) infection was significantly more common in SAP-deficient 10/13 (76.9%) than XIAP-deficient 2/7 (28.6%) patients, as was hypogammaglobulinemia (10/13 (76.9%) vs. 1/7 (14.3%)). None of the seven XIAP-deficient patients had colitis or lymphoma. Nine SAP-deficient patients and five XIAP-deficient patients showed markedly deficient SAP and XIAP expression, respectively, in lymphocytes. Significantly reduced levels of switched memory B cells were observed in six SAP-deficient patients with persistent hypogammaglobulinemia. One of 13 (7.7%) SAP-deficient patients and 1 of 7 (12.3%) XIAP-deficient patients have received HSCT treatment and are now alive and well; the other alive patients were waiting for HSCT. We also summarized clinical, genetic, and immunological characteristics of all 55 patients (including our 20 patients) reported in the literature in mainland China today.Conclusion: The overall characteristics of SAP deficiency in mainland China were consistent with those in previous reports, whereas manifestations of XIAP deficiency varied significantly. None of inflammatory bowel disease (IBD) has been reported among XIAP-deficient patients in our center; however, whether Chinese XIAP-deficient patients will develop colitis in the future warrants further investigation. HSCT is the only curative therapy for XLP and this therapy should be urgently considered.What is Known:• SAP and XIAP deficiencies share common clinical feature, HLH, whereas they also have their own specific manifestations.• IBD affects 25-30% of XIAP-deficient patients, which has been reported in other countries especially in European country and Japan.What is New:• This is the largest patient cohort study of XLP in China.• We firstly summarized the clinical features and outcomes of Chinese XIAP-deficient patients and found only 1 in 22 patients developed IBD and diet background may contribute to it; Asian SAP-deficient patients carrying SH2D1A R55X mutation were more prone to HLH.

13.
Biosci Rep ; 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31763668

RESUMO

Spinal cord injury (SCI) often occurs in young and middle-aged population. This study aimed to clarify the function of Gal-3 in neuroinflammation of SCI. Sprague Dawley (SD) rat models with SCI were established in vivo. PC12 cell model in vitro was induced by lipopolysaccharide (LPS). Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and gene chip were used to analyze the expression levels of genes in the signaling pathway. Histological assessment, ELISA and Western blotting were conducted to evaluate the effects of Gal-3 upon the SCI model. In the in vivo SD rat model, Gal-3 expression level was up-regulated. The inhibition of Gal-3 attenuated the neuroinflammation in SCI model. The inhibition of Gal-3 could also mitigate the neuroinflammation and reactive oxygen species (ROS) in in vitro model. ROS reduced the effect of Gal-3 on oxidative stress in in vitro model. Down-regulating the content of TXNIP decreased the effect of Gal-3 on neuroinflammation in in vitro model. Suppressing the level of NLRP3 could weaken the effect of Gal-3 on neuroinflammation in in vitro model. Our data highlight the Gal-3 plays a vital role in regulating the severity of neuroinflammation of SCI by enhancing the activation of ROS/TXNIP/NLRP3 signaling pathway. In addition, inflammasome/ IL-1ß production probably acts as the therapeutic target in SCI.

14.
Oxid Med Cell Longev ; 2019: 9030563, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781356

RESUMO

ROS functions as a second messenger and modulates multiple signaling pathways under the physiological conditions. However, excessive intracellular ROS causes damage to the molecular components of the cell, which promotes the pathogenesis of various human diseases. Cardiovascular diseases are serious threats to human health with extremely high rates of morbidity and mortality. Dysregulation of cell death promotes the pathogenesis of cardiovascular diseases and is the clinical target during the disease treatment. Numerous studies show that ROS production is closely linked to the cell death process and promotes the occurrence and development of the cardiovascular diseases. In this review, we summarize the regulation of intracellular ROS, the roles of ROS played in the development of cardiovascular diseases, and the programmed cell death induced by intracellular ROS. We also focus on anti-ROS system and the potential application of anti-ROS strategy in the treatment of cardiovascular diseases.

15.
BMC Neurol ; 19(1): 289, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31729962

RESUMO

BACKGROUND: Ischemia-reperfusion (I/R)-induced vascular dysfunction is the main factor to acute ischemic stroke. Sirt3 is one of the sirtuin family members, which plays an important role in the development of neurological diseases. METHODS: In this study, we constructed I/R injury model on HBMEC cells and induced the overexpression of Sirt3 in model cells. Meanwhile, the p38 activator U-46619 was used to examine the connection between Sirt3 and p38. We also examined the level of endothelial associated proteins, including occluding, ZO-1 and claudin-4 by using qRT-PCR and western blot. RESULTS: Our findings indicated that overexpression of Sirt3 decreased the permeability of model cells and promoted in the growth of endothelial cells. However, the activation of p38 could antagonize the function of Sirt3 in HBMEC cells. Moreover, Our results indicated a positive correlation between Sirt3 and inter-endothelial junction proteins. Importantly, PPAR-γ agonist and inhibitor were utilized to investigate the role of PPAR-γ in Sirt3 mediated cell function. Sirt3 was targeted by PPAR-γ in model cells. CONCLUSIONS: Taken together, this research not only demonstrated PPAR-γ might benefit to the growth of endothelial cell though activating Sirt3 but also indicated its potential value in the treatment for ischemic stroke.

16.
Environ Pollut ; : 113593, 2019 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-31771930

RESUMO

Di (2-ethyl-hexyl)phthalate (DEHP) is an environmental endocrine disruptor and commonly used as plasticizer. Maternal DEHP exposure during pregnancy reduces placental size and destroys placental structure. However, the underlying mechanisms were unclear. In this study, we supposed that DEHP disturbs endocrine function of placenta to inhibit the proliferation of placental cell. Using radioimmunoassay and ELISA, we found that DEHP and its active metabolite mono (2-ethyl-hexyl) phthalate (MEHP) promoted progesterone secretion in pregnant mouse and in JEG-3 cells, respectively. Therefore, placental endocrine function was altered by DEHP. The mRNA and protein level of progesterone synthetase 3ß-HSD1 was elevated by DEHP, which is conducive to the synthesis of progesterone. The level of progesterone receptor was down-regulated by DEHP and MEHP in mouse placenta and in JEG-3 cells, respectively. PR deficiency further promoted the level of 3ß-HSD1, which leads to a higher progesterone level. In turn, higher concentration of progesterone further inhibited the expression of PGR (PR gene). Therefore, higher progesterone down-regulated the level of its receptor PR. Meanwhile, decreased PR induced more progesterone secretion. There is a feedback loop between progesterone and PR. PR deficiency down-regulated the protein level of Cyclin D1 which plays an important role in cell proliferation. Accordingly, DEHP and its active metabolite MEHP can restrain proliferation of placental cell and disturb the progesterone secretion via decreasing the level of PR.

17.
J Sex Med ; 16(12): 2011-2017, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31668731

RESUMO

INTRODUCTION: Acellular dermal matrix (ADM) is a common filler used widely in clinical practice to increase penile girth for cosmetic reasons, but there are few studies on its complications. AIM: The aim of this study was to investigate and analyze the complications of penile girth enhancement (PGE) with ADM. METHODS: The medical records of 78 patients who underwent PGE with ADM between June 2016 and January 2019 were retrospectively reviewed. MAIN OUTCOME MEASURE: Related complications and their subsequent management were summarized and analyzed. RESULTS: 78 patients (mean age 31.14 years [21-66 years]) received PGE with ADM. At the 3-month follow-up, the penile circumference was increased by 1.1 (0.5-2.1) cm on average. There were 47 patients with erectile discomfort, 12 with delayed healing, 10 with unobvious augmentation effect, 8 with wound hematoma, 7 with prepuce edema, 4 with wound infection, and 3 patients with skin necrosis of the dorsal side. 7 patients eventually underwent ADM removal. CLINICAL IMPLICATIONS: These adverse complications indicate that ADM should be used with caution for PGE. STRENGTH & LIMITATIONS: This study adds important data, as there are few published reports on the complications of PGE with ADM. However, this study did not compare postoperative complications with ADM to those seen with other filler material. CONCLUSION: Even with standardized surgical methods and rigorous postoperative care, complications of PGE using ADM are severe, which indicates that it is not an ideal or safe method for PGE. Xu T, Zhang G, Bai W, et al. Complications and Management of Penile Girth Enhancement with Acellular Dermal Matrix. J Sex Med 2019;16:2011-2017.

18.
Neurosci Lett ; : 134643, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31760085

RESUMO

Neural plasticity, especially central sensitization, is essential for developing and maintaining neuropathic pain. Unfortunately, the analgesic potency of morphine is greatly reduced in animal models and patients with neuropathic pain. We hypothesized that pre-activation of spinal N-methyl-d-aspartate receptors (NMDARs) by agonist or neuropathic pain facilitated the development of morphine-induced analgesic tolerance. We therefore investigated the effects of spinal NMDAR activation, induced by neuropathic pain, on the development of morphine-induced analgesic tolerance in male Sprague-Dawley rats. Four days of chronic constriction injury (CCI) induced upregulation of spinal NR1. Once established, spinal central sensitization accelerated the development of morphine-induced analgesic tolerance. Continuous ropivacaine infusion prevented CCI-induced increases in spinal Substance P (SP), NR1, and TRPV1. Blockade of peripheral nociceptive inputs prevented chronic morphine-induced increases in spinal SP, NR1, and TRPV1 and a rightward shift of the morphine dose-response curve in the CCI model. These findings suggest that pre-activation of spinal NMDARs contributes to central sensitization and potentiates the development of morphine-induced analgesic tolerance. Interruption of the peripheral nociceptive inputs during the induction phase could prevent spinal central sensitization and retain morphine efficacy, thereby delaying the development of morphine-induced tolerance in patients with neuropathic conditions.

19.
Cell Death Dis ; 10(11): 825, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31672961

RESUMO

C-X-C motif chemokine receptor 7 (CXCR7), which mediates the immune response in the brain, was recently reported to regulate neurological functions. However, the role of CXCR7 in epilepsy remains unclear. Here, we found that CXCR7 was upregulated in the hippocampal dentate gyrus (DG) of mice subjected to kainic acid (KA)-induced epilepsy and in the brain tissues of patients with temporal lobe epilepsy. Silencing CXCR7 in the hippocampal DG region exerted an antiepileptic effect on the KA-induced mouse model of epilepsy, whereas CXCR7 overexpression produced a seizure-aggravating effect. Mechanistically, CXCR7 selectively regulated N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic neurotransmission in hippocampal dentate granule cells by modulating the cell membrane expression of the NMDAR subunit2A, which requires the activation of extracellular signal-regulated kinase 1/2 (ERK1/2). Thus, CXCR7 may regulate epileptic seizures and represents a novel target for antiepileptic treatments.

20.
J Clin Immunol ; 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31686315

RESUMO

PURPOSE: Signal transducer and activator of transcription 1 (STAT1) is a transcription factor that mediates cellular responses to interferons (IFNs) and other cytokines and growth factors in diverse cell types. STAT1 gain-of-function (GOF) mutations result in an unexpectedly wide range of clinical features. It remains unclear why STAT1 GOF mutations result in such a broad spectrum of phenotypes. METHODS: We analyzed the clinical, molecular, and phenotypic characteristics of nine Chinese patients with STAT1 GOF mutations. RESULTS: This study enrolled nine patients with STAT1 GOF mutations including five novel mutations. We discuss the molecular and phenotypic characterization such as unique Penicillium marneffei lymphadenitis. Patients with STAT1 GOF mutations had defects in both innate and adaptive immunity, including impaired T cell receptor (TCR) diversity; reduced numbers of naïve and effector memory CD4+ T cells, memory B cells, and NK cells; and defects in the production of IL-17A and IFN-γ. In addition, experiments with primary immune cells revealed that enhanced STAT1 phosphorylation resulted from not only lower rates of STAT1 dephosphorylation but also increased total STAT1 expression. CONCLUSIONS: Our report provides the first comprehensive overview of the molecular genetics, clinical heterogeneity, and underlying immunological abnormalities of patients with STAT1 GOF mutations in China. In further study, to find the relationship between different STAT1 GOF mutations and clinical phenotype as well as the mechanism of increased total STAT1 expression will be needed.

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