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1.
Parkinsonism Relat Disord ; 73: 1-2, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32151945

RESUMO

We screened the RFC1 intronic AAGGG repeat expansions in late-onset ataxia cases, MSA patients and controls. The data suggested that no biallelic repeat expansion carrier was found in our cohort and the heterozygous intronic AAGGG repeat expansions may not lead to an increased risk of late-onset ataxia or MSA.

3.
Cytokine ; 128: 155019, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32018068

RESUMO

BACKGROUND: Previous studies showed that GTS-21, a selective alpha 7 nAchR agonist, can trigger anti-inflammatory effects and improve the survival of septic animals. However, whether GTS-21 affects autophagy responses remains unclear. Here, we tested the hypothesis that GTS-21 ameliorates sepsis-induced hepatic injury by modulating autophagy in mice. METHOD: C57BL/6 male mice were randomly separated and categorized into four groups: the sham group, and CLP group subjected to caecal ligation and puncture (CLP, a model of polymicrobial sepsis). The CLP + GTS-21 group was administered GTS-21 immediately after CLP challenge. α-Bungarotoxin (an alpha 7 nAchR antagonist) was injected before CLP was performed, and then, after CLP challenge, GTS-21 was administered to α-BGT + CLP + GTS-21 group. The hepatic tissue and blood samples were harvested 6 h after the operation. RESULTS: CLP challenge increased TNF-α and IL-6 production, and hepatic enzyme alanine aminotransferase and aspartate transaminase levels. CLP also elevated the expression of hepatic LC3-II, sequestosome-1/p62, Atg7 and Atg5. The administration of GTS-21 inhibited pro-inflammatory cytokine production and hepatic enzymatic marker expression, promoted the expression of LC3-II, Atg7, Atg5, and decreased the expression of p62, which could be reversed by α-BGT treatment. CONCLUSION: Our findings suggested that α7nAchR is involved in diminishing hepatic damage by inhibiting inflammatory responses and improving autophagy in mice with polymicrobial sepsis.

4.
J Surg Res ; 248: 98-108, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31877436

RESUMO

BACKGROUND: This study aimed to investigate the role of Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway in protection by peritoneal resuscitation (PR) using pyruvate-peritoneal dialysis solution (PY-PDS) against intestinal injury from hemorrhagic shock (HS) in rats. MATERIALS AND METHODS: Sixty-four rats were assigned to eight groups: group SHAM; group intravenous resuscitation (VR); groups NS, LA, and PY in which the rats were subjected to HS and PR with normal saline (NS), lactate-peritoneal dialysis solution (LA-PDS), and PY-PDS, respectively, combined with VR; and groups DMSO, RPM, and AG490 in which the rats were subjected to HS and VR with pretreatment of dimethyl sulfoxide (DMSO), rapamycin (RPM), and tyrphostin B42 (AG490). RESULTS: At 2 h after HS and resuscitation, the levels of diamine oxidase, 15-F2t-isoprostane, thromboxane B2, and endothelin-1, in the blood and the intestinal mucosal apoptotic index and caspase-3 were lower in groups PY, RPM, and AG490 than in groups VR, NS, LA, and DMSO. Group PY showed lower levels of malondialdehyde and myeloperoxidase and a higher level of superoxide dismutase than groups VR, NS, and LA. Phosphorylated JAK2 and phosphorylated STAT3 levels were lower in groups PY, RPM, AG490, and LA than in groups VR, NS, and DMSO. CONCLUSIONS: The protection mechanism of PR with PY-PDS combined with VR was related to the inhibition of the JAK/STAT signaling pathway during HS and resuscitation. The process might include suppression of oxidative stress, reduction of neutrophil infiltration, regulation of microcirculation, and inhibition of apoptosis.

5.
Front Neurol ; 10: 1094, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31749756

RESUMO

Background: Spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease (MJD) is the most common type of autosomal dominant ataxia. Like other neurodegenerative diseases, is characterized by the dysfunction of the protein quality control (PQC) system. The carboxyl terminus of the Hsp70-interacting protein (CHIP), an important component of PQC, participates in the clearance of misfolded proteins to maintain cellular homeostasis. While no cure for SCA3 exists, the disease progresses slowly. Thus, the identification of biomarkers that indicate the severity and prognosis of this disease would be valuable. Methods: In this exploratory case-control study, we quantitatively evaluated the concentrations of CHIP in the sera of 80 patients with SCA3 and 80 age and sex-matched controls, using the enzyme-linked immunosorbent assay (ELISA). CHIP levels in the cerebrospinal fluid (CSF) donated by six patients and six healthy volunteers, who were matched for sex and age were also measured. All the baseline data were collected, and the patients underwent clinical evaluation. The correlations between CHIP levels and several clinical measurements were analyzed. Results: The serum CHIP level in the SCA3 group was (80.93 ± 28.68) ng/mL, which was significantly higher than those in the control group [(40.37 ± 18.55) ng/mL]. Similar results were observed for the CSF [(164.59 ± 42.99) ng/mL and (37.47 ± 7.85) ng/mL, respectively]. CSF CHIP levels were significantly higher than the serum CHIP levels in the SCA3 group but not in the control group. The Dunn-Bonferroni post-hoc for Kruskal-Wallis test revealed no significant difference between the serum and CSF of the patients and the control group. Multivariate linear regression showed that serum CHIP levels correlated positively with disease severity, as measured by the Scale for the Assessment and Rating of Ataxia (SARA) and the International Cooperative Ataxia Rating Scale (ICARS). Moreover, we found that serum CHIP levels were moderately correlated with age in healthy controls. Conclusion: The present study determined that CHIP levels increased significantly in the serum and CSF of patients with SCA3 and that serum CHIP levels were corelated with disease severity. Thus, CHIP is a promising biomarker for SCA3.

6.
Life Sci ; 239: 116946, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31610202

RESUMO

AIMS: Infantile hemangioma (IH) is the most common vascular neoplasm in infant and young children. Long non-coding RNAs (lncRNAs) are known to be associated with IH. This study aims to investigate the role and underlying mechanism of lncRNA-MALAT1 in IH. MAIN METHODS: qRT-PCR was used to quantify the expressions of MALAT1, miR-424, and MEKK3 in IH tissues. The cell proliferation, apoptosis, migration, invasion, and tube formation ability were assessed by MTT assay, colony formation assay, flow cytometric analysis, transwell assay and tube formation assay, respectively. The interaction among MALAT1, miR-424 and MEKK3 was evaluated by luciferase reporter assay. Immunohistochemistry (IHC) and Western blotting were utilized to evaluate the expression levels of MEKK3, Ki-67 and NF-κB pathway-related proteins both in vitro and in vivo. KEY FINDINGS: In IH tissues, MALAT1 and MEKK3 were overexpressed while miR-424 was down-regulated. Silencing MALAT1 or overexpression of miR-424 significantly inhibited the IH cell proliferation, migration and tube formation, but promoted the cell apoptosis. Knockdown of MALAT1 suppressed the expression of MEKK3 and inactivated the IKK/NF-κB pathway by sponging miR-424. Overexpression of MEKK3 in HemEcs reversed the impact of knockdown of MALAT1 and overexpression of miR-424 on the cell proliferation, apoptosis, migration, invasion and tube formation rate. The tumor xenografts experiments demonstrated that silencing MALAT1 significantly inhibited the tumor growth in vivo and Ki-67 in the tumor tissues was also significantly suppressed. SIGNIFICANCE: MALAT1 promoted the IH progression through inhibiting miR-424 to activate MEKK3-mediated IKK/NF-κB pathway, suggesting that MALAT1, miR-424 and MEKK3 could be used as potential targets to improve IH treatment efficiency.


Assuntos
Hemangioma/metabolismo , MAP Quinase Quinase Quinase 3/metabolismo , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Apoptose/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Hemangioma/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , NF-kappa B/metabolismo , Invasividade Neoplásica , RNA Longo não Codificante/genética , RNA Interferente Pequeno/genética , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Neuromuscul Disord ; 29(7): 549-553, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31255525

RESUMO

Limb-girdle myasthenia with tubular aggregates, a subtype of congenital myasthenic syndrome, is an extremely rare autosomal recessive genetic disease characterized by prominent limb-girdle weakness and good response to acetylcholinesterase inhibitor therapy. Herein, we reported two novel mutations of GFPT1 gene in a Chinese pedigree. Two siblings presented with fatigue, weakness of limb-girdle and decrement of the muscle action potential with repetitive nerve stimulation. Thus, myasthenia gravis was initially suspected, but anti-AChR antibodies were negative. Two novel missense mutations (p.Lys154Asn and p.Asn363Ser) in GFPT1 were identified through genetic testing conducted on 167 well-established genes associated with muscular diseases by targeted high throughput sequencing. Both mutations have not been recorded in the dsSNP database, Exome Aggregation Consortium database and 1000 Genomes Project database. The mutation sites were co-segregated with the phenotype and conserved between the different species. The mutations were not found in the 200 unrelated normal controls. Muscle biopsies revealed tubular aggregates, in accordance with previous reports with GFPT1 mutations. Subsequently, dramatic improvement in strength occurred following anti-cholinesterase therapy. Our study will be helpful for the diagnosis and treatment for Limb-girdle myasthenia with tubular aggregates.

9.
Taiwan J Obstet Gynecol ; 58(4): 501-504, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31307741

RESUMO

OBJECTIVE: This study aims to evaluate the value of the ultrasound-related scoring system on pregnant patients receiving assisted reproductive technology (IVF/ICSI) and early pregnancy outcome. MATERIALS AND METHODS: This prospective study included 208 pregnant women receiving assisted reproductive technology (IVF/ICSI). The following ultrasound parameters were measured: gestational sac size, the proportion of the embryo and gestational sac (embryo/gestational sac), yolk sac size, and fetal cardiac activity. The above data were assigned according to the ongoing pregnancy rate (up to 14 weeks), and the score increased parallel to the pregnancy rate. All patients were grouped according to their scores. RESULTS: Patients with a score of 4-5 had a low ongoing pregnancy rate of 14.29%, while patients with a score of 6-7 had an ongoing pregnancy rate of 55.56%. Surprisingly, patients with a score of 8-9 had an ongoing pregnancy rate of 97.22%. In addition, it was found that the ongoing pregnancy rate was 100% (36/36) in patients with a score of 9. Conversely, there was no ongoing pregnancy in patients with a score of 4. CONCLUSION: First, this scoring system is strongly associated with an ongoing pregnancy of over 14 weeks. Second, some reassurance can be given to patients with favorable ultrasound parameters, regardless of maternal age or previous pregnancy loss. Third, it would be meaningless to continue the pregnancy in patients with a score of 4, according to the scoring system. Fourth, patients without cardiac activity and embryos at days 33-35 after embryo transfer should discontinue the pregnancy, while patients with embryos should proceed with the pregnancy.


Assuntos
Desenvolvimento Embrionário/fisiologia , Coração Fetal/embriologia , Saco Gestacional/embriologia , Primeiro Trimestre da Gravidez , Injeções de Esperma Intracitoplásmicas/métodos , Ultrassonografia Pré-Natal , Adulto , Transferência Embrionária/métodos , Feminino , Desenvolvimento Fetal/fisiologia , Coração Fetal/diagnóstico por imagem , Seguimentos , Saco Gestacional/diagnóstico por imagem , Humanos , Valor Preditivo dos Testes , Gravidez , Estudos Prospectivos
10.
J Matern Fetal Neonatal Med ; : 1-6, 2019 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-30688128

RESUMO

OBJECTIVE: To evaluate submicroscopic chromosomal abnormalities in fetuses with increased nuchal translucency (NT) and normal karyotype. METHODS: A total of 319 fetuses with increased NT (≥3.0 mm) were tested using conventional karyotyping. When cytogenetic analysis showed normal chromosomes, the parents then received a consultation for chromosomal microarray (CMA) analysis, and a subsequent morphology scan was performed between 20 and 24 weeks gestation. Submicroscopic chromosomal abnormalities were assessed and compared between the fetuses with and without structural defects. Likewise, the prevalence of pathologic copy number variants (CNVs) among cases with increased NT was compared with the 926 low-risk cases consisted of patients whose sole indication for testing was advanced maternal age. RESULTS: Chromosomal abnormality was identified in 32.29 (103/319) of fetuses, and 137 samples were tested using CMA. Additional pathogenic copy number variants (CNVs) were also detected in 5.12% (7/137) of the fetuses. There was no significant difference in the abnormal detection rate between fetuses showing an abnormal morphology scan and those with a normal morphology scan (11.11% [2/18] versus 4.20% [5/119], respectively; p > .05). The prevalence of pathological CMA results in cases with increased NT was significantly higher when compared with the low-risk patients (5.12% [7/137] versus 1.19% [11/926], respectively; p = .0009). CONCLUSIONS: Nuchal translucency (NT) ≥3.0 mm are associated with the highest risk for a CMA abnormality. Submicroscopic chromosomal abnormalities should be accessed when the fetus was found to be with increased NT and normal karyotype. It is, therefore, important to inform parents in a professional prenatal counseling setting regarding the potential advantages of CMA.

11.
Acta Pharmacol Sin ; 40(3): 365-373, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29967454

RESUMO

Cannabinoid CB1 receptors (CB1Rs) have been shown to be a promising target in medication development for the treatment of addiction. However, clinical trials with SR141716A (rimonabant, a selective CB1R antagonist/inverse agonist) for the treatment of obesity and smoking cessation failed due to unwanted side effects, such as depression, anxiety, and suicidal tendencies. Recent preclinical studies suggest that the neutral CB1R antagonist AM4113 may retain the therapeutic anti-addictive effects of SR141716A in nicotine self-administration models and possibly has fewer unwanted side effects. However, little is known about whether AM4113 is also effective for other drugs of abuse, such as opioids and psychostimulants, and whether it produces depressive side effects similar to SR141716A in experimental animals. In this study, we demonstrated that systemic administration of AM4113 (3 and 10 mg/kg) dose-dependently inhibited the self-administration of intravenous heroin but not cocaine or methamphetamine, whereas SR141716A (3 and 10 mg/kg) dose-dependently inhibited the self-administration of heroin and methamphetamine but not cocaine. In the electrical brain-stimulation reward (BSR) paradigm, SR141716A (3 and 10 mg/kg) dose-dependently increased the BSR stimulation threshold (i.e., decreased the stimulation reward), but AM4113 had no effect on BSR at the same doses, suggesting that SR141716A may produce aversive effects while AM4113 may not. Together, these findings show that neutral CB1R antagonists such as AM4113 deserve further research as a new class of CB1R-based medications for the treatment of opioid addiction without SR141716A-like aversive effects.


Assuntos
Antagonistas de Receptores de Canabinoides/farmacologia , Depressão/prevenção & controle , Comportamento de Procura de Droga/efeitos dos fármacos , Dependência de Heroína/prevenção & controle , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Animais , Comportamento Animal/efeitos dos fármacos , Cocaína/efeitos adversos , Condicionamento Operante/efeitos dos fármacos , Heroína/efeitos adversos , Dependência de Heroína/psicologia , Masculino , Metanfetamina/efeitos adversos , Ratos Long-Evans , Recompensa , Rimonabanto/efeitos adversos , Rimonabanto/farmacologia , Autoadministração
12.
J Cell Physiol ; 234(5): 6688-6695, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30478830

RESUMO

Neuropathic pain (NP) may cause serious brain diseases, but the genes associated with the metabolic pathway and transcript factors of NP remain unclear. This study is aimed to identify the therapy target genes for NP and to investigate the metabolic pathways and transcript factors associated with NP. The differentially expressed genes of three brain tissues (nucleus accumbens, periaqueductal gray, and prefrontal cortex) dealt with NP stimulation were analyzed. Besides, The Database for Annotation, Visualization, and Integrated Discovery and Tfacts datasets were used in the analysis of the genes related to the metabolic pathway and transcript factors of the brain. Eight genes were found to coexpress in all three tissues. A functional enrichment analysis showed that the upregulated genes were mostly enriched in pathways as inflammatory response, calcium-mediated signaling, cytokine-cytokine receptor interaction, and extracellular matrix (ECM)-receptor interaction, whereas the downregulated genes were mostly enriched in pathways as phospholipid metabolic processes, positive regulation of protein kinase B signaling, and metabolism of xenobiotics by cytochrome P450. Finally, 135 and 98 transcript factors genes were upregulated and downregulated, among which SP1, MYC, CTNNB1, CREB1, JUN were identified as the most critical genes because the number of up- and downregulated gene ranked at the top. In conclusion, the pathways of immune response and cytokine-cytokine receptor interaction were determined as the main metabolic pathways of NP affecting the brain, and SP1, MYC, CTNNB1, CREB1, JUN genes were recognized as the most enriched genes in this process, which may provide evidence for the diagnosis and treatment research of neuropathic pain.

13.
Materials (Basel) ; 11(12)2018 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-30513589

RESUMO

In order to obtain the adsorption mechanism and failure characteristics of CO2 adsorption by potassium-based adsorbents with different supports, five types of supports (circulating fluidized bed boiler fly ash, pulverized coal boiler fly ash, activated carbon, molecular sieve, and alumina) and three kinds of adsorbents under the modified conditions of K2CO3 theoretical loading (10%, 30%, and 50%) were studied. The effect of the reaction temperature (50 °C, 60 °C, 70 °C, 80 °C, and 90 °C) and CO2 concentration (5%, 7.5%, 10%, 12.5%, and 15%) on the adsorption of CO2 by the adsorbent after loading and the effect of flue gas composition on the failure characteristics of adsorbents were obtained. At the same time, the microscopic characteristics of the adsorbents before and after loading and the reaction were studied by using a specific surface area and porosity analyzer as well as a scanning electron microscope and X-ray diffractometer. Combining its reaction and adsorption kinetics process, the mechanism of influence was explored. The results show that the optimal theoretical loading of the five adsorbents is 30% and the reaction temperature of 70 °C and the concentration of 12.5% CO2 are the best reaction conditions. The actual loading and CO2 adsorption performance of the K2CO3/AC adsorbent are the best while the K2CO3/Al2O3 adsorbent is the worst. During the carbonation reaction of the adsorbent, the cumulative pore volume plays a more important role in the adsorption process than the specific surface area. As the reaction temperature increases, the internal diffusion resistance increases remarkably. K2CO3/AC has the lowest activation energy and the carbonation reaction is the easiest to carry out. SO2 and HCl react with K2CO3 to produce new substances, which leads to the gradual failure of the adsorbents and K2CO3/AC has the best cycle failure performance.

14.
Curr Med Sci ; 38(4): 666-671, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30128876

RESUMO

The aim of the present study was to investigate the effect of lipoxin A4 (LXA4) pretreatment on cognitive function of aged rats after global cerebral ischemia reperfusion, and to explore its possible mechanism. Thirty-six aged male Sprague-Dawley rats were randomly divided into three groups (n=2 each): sham-operation group (S group), global cerebral ischemia reperfusion group (I/R group) and LXA4-pretreatment group (L group). The rat model of global cerebral ischemia reperfüsion was established by occlusion of the bilateral common carotid artery with hypotension. The cognitive function of rats was determined by a step-down type passive avoidance test and Morris Water Maze test on the third day after reperfUsion. Rats were sacrificed after Water Maze test and the pathological changes of hippocampal CAI region were observed and the related inflammatory mediators were determined. As compared with S group, the escape latency in I/R group was prolonged from the first day to the fifth day, while that in L group was prolonged from the first day to the third day. The retention time in I/R group and L group in the first quadrant was shortened. The reaction time, frequency of reaction mistake and frequency of escape mistake in I/R group increased, and the latent period shortened. The frequency of escape mistake in L group increased, and the damage in the hippocampal CAI region of I/R group and L group was obvious. The levels of S-100ß, TNP-α, IL-lß, IL-10 and NF-κB in I/R group and L group increased. As compared with I/R group, the escape latency in L group was shortened from the first day to the fifth day, and the retention time in the first quadrant prolonged. The reaction time, frequency of reaction mistake and frequency of escape mistake in L group decreased, and the latent period prolonged. The damage in the hippocampal CAI region of L group was alleviated as well. The levels of S-100ß, TNP-α, IL-lß and NF-κB in L group decreased, and those of IL-10 increased. It can be concluded that LXA4 pretreatment can improve the cognitive function in aged rats after global cerebral ischemia reperfusion probably by inhibiting the inflammatory reaction.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Cognição , Lipoxinas/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Região CA1 Hipocampal/irrigação sanguínea , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/patologia , Citocinas/genética , Citocinas/metabolismo , Lipoxinas/administração & dosagem , Masculino , Aprendizagem em Labirinto , NF-kappa B/genética , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Subunidade beta da Proteína Ligante de Cálcio S100/genética , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo
15.
Neuropharmacology ; 141: 11-20, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30138692

RESUMO

Despite extensive research, the neurobiological risk factors that convey vulnerability to opioid abuse are still unknown. Recent studies suggest that the dopamine D3 receptor (D3R) is involved in opioid self-administration, but it remains unclear whether altered D3R availability is a risk factor for the development of opioid abuse and addiction. Here we used dopamine D3 receptor-knockout (D3-KO) mice to investigate the role of this receptor in the different phases of opioid addiction. D3-KO mice learned to self-administer heroin faster and took more heroin than wild-type mice during acquisition and maintenance of self-administration. D3R-KO mice also displayed higher motivation to work to obtain heroin reward during self-administration under progressive-ratio reinforcement, as well as elevated heroin-seeking during extinction and reinstatement testing. In addition, deletion of the D3R induced higher baseline levels of extracellular dopamine (DA) in the nucleus accumbens (NAc), higher basal levels of locomotion, and reduced NAc DA and locomotor responses to lower doses of heroin. These findings suggest that the D3R is critically involved in regulatory processes that normally limit opioid intake via DA-related mechanisms. Deletion of D3R augments opioid-taking and opioid-seeking behaviors. Therefore, low D3R availability in the brain may represent a risk factor for the development of opioid abuse and addiction.


Assuntos
Heroína/farmacologia , Receptores de Dopamina D3/genética , Receptores de Dopamina D3/metabolismo , Animais , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Extinção Psicológica , Locomoção/genética , Camundongos , Camundongos Knockout , Motivação/genética , Núcleo Accumbens/metabolismo , Esquema de Reforço , Autoadministração
16.
Neurobiol Aging ; 68: 159.e1-159.e2, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29801756

RESUMO

Recently, mutations of DNAJC12 gene were reported to be associated with early-onset parkinsonism, progressive neurodevelopmental delay, and dystonia in several unrelated pedigrees. This study aimed to evaluate DNAJC12 coding mutations in sporadic Chinese Han patients with Parkinson's disease (PD) and test whether an age-of-onset effect exists. Seven hundred two Chinese Han sporadic PD patients, including 181 early-onset PD and 521 late-onset PD, and 728 healthy controls were recruited. No documented disease-causing mutation of DNAJC12 was identified, but we found 7 single-nucleotide polymorphisms. Allele frequencies did not differ between all the PD patients and controls or between any 2 subgroups for all these single-nucleotide polymorphisms. Our study suggests that DNAJC12 mutation is not a risk factor of PD in Chinese Han population, and no age-of-onset effect was verified.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença/genética , Mutação , Doença de Parkinson/genética , Proteínas Repressoras/genética , Adulto , Idade de Início , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
17.
Inflammation ; 41(5): 1610-1620, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29766401

RESUMO

Penehyclidine hydrochloride (PHC), a type of hyoscyamus drug, has both antimuscarinic and antinicotinic activities and retains potent central and peripheral anticholinergic activities. Compared with other hyoscyamine, the notable advantage of PHC is that it has few M2 receptor-associated cardiovascular side effects. Recent studies and clinical trials have suggested that treatment with penehyclidine hydrochloride may also possess good effects in the treatment of lung injury. The mechanism responsible for this effect has yet to be determined; however, one possibility is that they might do so by a direct effect on pulmonary vascular endothelium. Since inflammatory reactions of the endothelium are signs of endothelial injury in the pathogenesis of lung injury, we determined the effects of penehyclidine hydrochloride on endothelial inflammatory injury in cultured human pulmonary microvascular endothelial cells (HPMVEC). Furthermore, human pulmonary microvascular endothelial cells were transfected with a shRNA-containing plasmid that specifically targets beta-arrestin-1 mRNA, to test whether the effect of penehyclidine hydrochloride on lipopolysaccharide (LPS)-induced endothelial cell injury is dependent on its upregulation of beta-arrestin-1 or not. Penehyclidine hydrochloride reduced the inflammatory responses to LPS stimulation, as evidenced by reduced lactate dehydrogenase (LDH), tumor necrosis factor-alpha (TNF-α), and interleukelin-6 (IL-6) levels, as well as vascular cell adhesion molecule 1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1) expressions. This was found to result from increased beta-arrestin-1 expression and decreased nuclear transcription factor-κB (NF-κB) activation. Expression of a shRNA-containing plasmid that specifically targets beta-arrestin-1 mRNA nullified these effects of penehyclidine hydrochloride. The results indicate that penehyclidine hydrochloride exerts a protective effect on pulmonary microvascular endothelial inflammatory injury induced by LPS. We also demonstrate that this is due to its ability to increase beta-arrestin-1, which in turn inhibits NF-κB activation.


Assuntos
Células Endoteliais/patologia , Inflamação/tratamento farmacológico , Lesão Pulmonar/tratamento farmacológico , Quinuclidinas/farmacologia , beta-Arrestina 1/metabolismo , Células Cultivadas , Humanos , Inflamação/induzido quimicamente , Lipopolissacarídeos , Lesão Pulmonar/induzido quimicamente , Microvasos/patologia , NF-kappa B/antagonistas & inibidores , Quinuclidinas/uso terapêutico , Regulação para Cima/efeitos dos fármacos
18.
Oxid Med Cell Longev ; 2018: 6403861, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29682161

RESUMO

Oxidative stress and inflammation have been identified to play a vital role in the pathogenesis of lung injury induced by septic shock. Heme oxygenase-1 (HO-1), an effective antioxidant and anti-inflammatory and antiapoptotic substance, has been used for the treatment of heart, lung, and liver diseases. Thus, we postulated that administration of exogenous HO-1 protein transduced by cell-penetrating peptide PEP-1 has a protective role against septic shock-induced lung injury. Septic shock produced by cecal ligation and puncture caused severe lung damage, manifested in the increase in the lung wet/dry ratio, oxidative stress, inflammation, and apoptosis. However, these changes were reversed by treatment with the PEP-1-HO-1 fusion protein, whereas lung injury in septic shock rats was alleviated. Furthermore, the septic shock upregulated the expression of Toll-like receptor 4 (TLR4) and transcription factor NF-κB, accompanied by the increase of lung injury. Administration of PEP-1-HO-1 fusion protein reversed septic shock-induced lung injury by downregulating the expression of TLR4 and NF-κB. Our study indicates that treatment with HO-1 protein transduced by PEP-1 confers protection against septic shock-induced lung injury by its antioxidant, anti-inflammatory, and antiapoptotic effects.


Assuntos
Heme Oxigenase-1/uso terapêutico , Lesão Pulmonar/tratamento farmacológico , Proteínas Recombinantes de Fusão/uso terapêutico , Choque Séptico/tratamento farmacológico , Animais , Western Blotting , Lesão Pulmonar/etiologia , Masculino , Malondialdeído/metabolismo , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Choque Séptico/complicações , Superóxido Dismutase/metabolismo , Receptor 4 Toll-Like/metabolismo
19.
J Cell Physiol ; 233(8): 6098-6106, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29323698

RESUMO

LncRNAs are reported to participate in neuropathic pain development. LncRNA X-inactive specific transcript (XIST) is involved in the progression of various cancers. However, the role of XIST in neuropathic pain remains unclear. In our present study, we established a chronic constriction injury (CCI) rat model and XIST was found to be greatly upregulated both in the spinal cord tissues and in the isolated microglias of CCI rats. Inhibition of XIST inhibited neuropathic pain behaviors including mechanical and thermal hyperalgesia. Moreover, decrease of XIST repressed neuroinflammation through inhibiting COX-2, tumor necrosis factor (TNF)-α and IL-6 and in CCI rats. Previously, miR-150 has been reported to restrain neuropathic pain by targeting TLR5. Currently, miR-150 was predicted to be a microRNA target of XIST, which indicated a negative correlation between miR-150 and XIST. miR-150 was remarkably decreased in CCI rats and overexpression of miR-150 can significantly suppress neuroinflammation-related cytokines. Furthermore, ZEB1 was exhibited to be a direct target of miR-150 and we found it was overexpressed in CCI rats. Silencing ZEB1 was able to inhibit neuropathic pain in vivo and downreguation of XIST decreased ZEB1, which can be reversed by miR-150 inhibitors. Taken these together, we indicated that XIST can induce neuropathic pain development in CCI rats via upregulating ZEB1 by acting as a sponge of miR-150. It was revealed that XIST/miR-150/ZEB1 axis can be provided as a therapeutic target in neuropathic pain.


Assuntos
MicroRNAs/genética , Neuralgia/genética , RNA Longo não Codificante/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Animais , Linhagem Celular , Citocinas/genética , Progressão da Doença , Feminino , Células HEK293 , Humanos , Hiperalgesia/genética , Interleucina-6/genética , Microglia/patologia , Neuralgia/patologia , Ratos , Ratos Sprague-Dawley , Medula Espinal/patologia , Fator de Necrose Tumoral alfa/genética
20.
Int J Mol Med ; 41(3): 1635-1642, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29328403

RESUMO

The aim of the present study was to determine whether arcuate nucleus (ARC) lesions affect the ghrelin level in the plasma and the stomach in monosodium glutamate (MSG)­treated mice. The aim of the present study was to investigate whether the ARC was destroyed in mice treated neonatally with MSG, and whether the ARC lesions affect the ghrelin level in the plasma and lipid mobilization in MSG­treated mice. The results revealed that MSG led to a marked reduction in ARC cresyl violet staining, tyrosine hydroxylase-immunoreactive (IR) neurons and neuropeptide Y­IR fibers, compared with saline controls. MSG­treated mice exhibited significantly increased body mass compared with saline controls, and MSG treatment did not prevent food deprivation­induced decrease in white adipose tissue mass compared with controls. Plasma ghrelin levels were significantly increased in MSG­treated mice that were fasted for 48 h, compared with the levels prior to fasting and re­feeding, and the preprandial peak of plasma ghrelin persisted in MSG­treated mice. In summary, the ARC was not found to be essential for food deprivation­induced lipid mobilization and preprandial peak in MSG­treated mice. However, this finding does not mean that ARC neurons do not contribute to food sensing and lipid mobilization under normal conditions, as compensatory mechanisms may have emerged after the ablation of ARC neurons.


Assuntos
Núcleo Arqueado do Hipotálamo/metabolismo , Grelina/sangue , Glutamato de Sódio/administração & dosagem , Tecido Adiposo Branco/anatomia & histologia , Tecido Adiposo Branco/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Área Postrema/efeitos dos fármacos , Área Postrema/metabolismo , Peso Corporal/efeitos dos fármacos , Contagem de Células , Comportamento Alimentar/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Grelina/genética , Grelina/metabolismo , Camundongos , Tamanho do Órgão/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Glutamato de Sódio/farmacologia , Estômago/efeitos dos fármacos
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