RESUMO
The precise molecular mechanism behind fetal growth restriction (FGR) is still unclear, although there is a strong connection between placental dysfunction, inadequate trophoblast invasion, and its etiology and pathogenesis. As a new type of non-coding RNA, circRNA has been shown to play a crucial role in the development of FGR. This investigation identified the downregulation of hsa_circ_0034533 (circTHBS1) in FGR placentas through high-sequencing analysis and confirmed this finding in 25 clinical placenta samples using qRT-PCR. Subsequent in vitro functional assays demonstrated that silencing circTHBS1 inhibited trophoblast proliferation, migration, invasion, and epithelial mesenchymal transition (EMT) progression and promoted apoptosis. Furthermore, when circTHBS1 was overexpressed, cell function experiments showed the opposite result. Analysis using fluorescence in situ hybridization revealed that circTHBS1 was primarily found in the cytoplasmic region. Through bioinformatics analysis, we anticipated the involvement of miR-136-3p and IGF2R in downstream processes, which was subsequently validated through qRT-PCR and dual-luciferase assays. Moreover, the inhibition of miR-136-3p or the overexpression of IGF2R partially reinstated proliferation, migration, and invasion abilities following the silencing of circTHBS1. In summary, the circTHBS1/miR-136-3p/IGF2R axis plays a crucial role in the progression and development of FGR, offering potential avenues for the exploration of biological indicators and treatment targets.
Assuntos
MicroRNAs , Feminino , Humanos , Gravidez , Apoptose/genética , Movimento Celular/genética , Proliferação de Células/genética , Retardo do Crescimento Fetal/metabolismo , Hibridização in Situ Fluorescente , MicroRNAs/genética , MicroRNAs/metabolismo , Placenta/metabolismo , Trofoblastos/metabolismoRESUMO
Heparin has been documented to reduce myocardial injury caused by ischemia/reperfusion (I/R), but its clinical application is limited due to its strong intrinsic anticoagulant property. Some desulfated derivatives of heparin display low anticoagulant activity and may have potential value as therapeutic agents for myocardial I/R injury. In this study, we observed that 6-O-desulfated heparin, a desulfated derivative of heparin, shortened the activated partial thromboplastin time and exhibited lower anticoagulant activity compared with heparin or 2-O-desulfated heparin (another desulfated derivative of heparin). Then, we explored whether 6-O-desulfated heparin could protect against myocardial I/R injury, and elucidated its possible mechanisms. Administration of 6-O-desulfated heparin significantly reduced creatine kinase activity, myocardial infarct size and cell apoptosis in mice subjected to 30 min of myocardial ischemia following 2 h of reperfusion, accompanied by a reverse in miR-199a-5p elevation, klotho downregulation and reactive oxygen species (ROS) accumulation. In cultured H9c2 cells, the mechanism of 6-O-desulfated heparin against myocardial I/R injury was further explored. Consistent with the results in vivo, 6-O-desulfated heparin significantly ameliorated hypoxia/reoxygenation-induced injury, upregulated klotho and decreased miR-199a-5p levels and ROS accumulation, and these effects were reversed by miR-199a-5p mimics. In conclusion, these results suggested that 6-O-desulfated heparin with lower anticoagulant activity attenuated myocardial I/R injury through miR-199a-5p/klotho and ROS signaling. Our study may also indicate that 6-O-desulfated heparin, as an excellent heparin derivative, is a potential therapeutic agent for myocardial I/R injury.
Assuntos
Heparina , Proteínas Klotho , MicroRNAs , Traumatismo por Reperfusão Miocárdica , Animais , Camundongos , Apoptose , Modelos Animais de Doenças , Heparina/farmacologia , Heparina/uso terapêutico , Proteínas Klotho/metabolismo , MicroRNAs/genética , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Transdução de SinaisRESUMO
Zinc and selenium may protect against colorectal cancer (CRC) progression through their anti-oxidative effects. This study examined the independent and combined effect of dietary zinc and selenium intake, and polymorphisms of the oxidative stress-related genes (superoxide dismutase 1, superoxide dismutase 2, glutathione peroxidase, and catalase) on CRC risk in a Chinese case-control study. A total of 493 cases and 498 sex and age-matched controls were randomly selected from an ongoing case-control study. Dietary information was assessed through face-to-face interviews using a validated food frequency questionnaire. Multiplex PCR-ligase detection reaction was used for genotyping the target SNPs. Multivariable logistic regression was used to estimate the odds ratios (ORs) and 95% confidence interval (CI). Intake of selenium was found to be inversely associated with CRC risk, while zinc was not associated with CRC risk. The ORs (95% CI) for the highest vs. the lowest quartile were 0.42 (95% CI 0.28, 0.64, Ptrend < 0.001) for selenium and 0.96 (95% CI 0.63, 1.47, Ptrend = 0.505) for zinc. Combined effect was observed between zinc and SOD1 rs4998557 on CRC risk (Pinteraction < 0.05). This study identified a novel diet-gene interaction in the oxidative stress pathway on CRC risk in Chinese population.
Assuntos
Neoplasias Colorretais , Selênio , Estudos de Casos e Controles , China/epidemiologia , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/prevenção & controle , Dieta , Humanos , Modelos Logísticos , Estresse Oxidativo , Polimorfismo de Nucleotídeo Único , Fatores de Risco , ZincoRESUMO
BACKGROUND: Vitamin D has anticarcinogenic properties and acts through vitamin D receptor (VDR) to carry out its functions. AIMS: This study explored the independent and combined effects of dietary vitamin D and calcium, and VDR genetic polymorphisms on colorectal cancer risk in a Chinese population. METHODS: This ongoing case-control study recruited 488 cases with histologically confirmed colorectal cancer and 496 sex- and age-matched controls. Vitamin D and calcium intakes were assessed by a validated food frequency questionnaire, and VDR genotype was conducted for Fok I (rs2228570), Bsm I (rs1544410), Apa I (rs7975232), and Taq I (rs731236). Unconditional logistic regression was used to calculate odds ratio and 95% confidence interval after adjusting for various confounders. RESULTS: No significant association was found between Fok I, Bsm I, Apa I, Taq I, and colorectal cancer risk. Higher intakes of dietary vitamin D and calcium were associated with 47% and 50% reduction in colorectal cancer risk. Significant interaction was observed between dietary vitamin D intake and Apa I polymorphisms in relation to colorectal cancer risk (Pinteraction = 0.006). Subjects with higher dietary vitamin D intake and mutant Apa I A allele had a substantially decreased risk of colorectal cancer compared to Apa I aa carriers with lower vitamin D intake. CONCLUSIONS: Our study supports that Apa I may interact with dietary vitamin D intake on colorectal cancer risk. However, no interactions were found between dietary vitamin D or calcium intakes and Fok I, Bsm I, and Taq I in relation to colorectal cancer risk.
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Cálcio da Dieta/administração & dosagem , Neoplasias Colorretais/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Calcitriol/genética , Vitamina D/administração & dosagem , Adulto , Idoso , Estudos de Casos e Controles , China/epidemiologia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Feminino , Predisposição Genética para Doença/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
OBJECTIVE: The current study evaluated the associations between different forms and sources of Fe and breast cancer risk in Southern Chinese women. DESIGN: Case-control study. We collected data on the consumption of Fe from different forms and food sources by using a validated FFQ. Multivariable logistic regression and restricted cubic spline (RCS) analysis was used to reveal potential associations between Fe intake and breast cancer risk. SETTING: A case-control study of women at three major hospitals in Guangzhou, China. PARTICIPANTS: From June 2007 to March 2019, 1591 breast cancer cases and 1622 age-matched controls were recruited. RESULTS: In quartile analyses, Fe from plants and Fe from white meat intake were inversely associated with breast cancer risk, with OR of 0·65 (95 % CI 0·47, 0·89, Ptrend = 0·006) and 0·76 (95 % CI 0·61, 0·96, Ptrend = 0·014), respectively, comparing the highest with the lowest quartile. No associations were observed between total dietary Fe, heme or non-heme Fe, Fe from meat or red meat and breast cancer risk. RCS analysis demonstrated J-shaped associations between total dietary Fe, non-heme Fe and breast cancer, and reverse L-shaped associations between heme Fe, Fe from meat and Fe from red meat and breast cancer. CONCLUSION: Fe from plants and white meat were inversely associated with breast cancer risk. Significant non-linear J-shaped associations were found between total dietary Fe, non-heme Fe and breast cancer risk, and reverse L-shaped associations were found between heme Fe, Fe from meat or red meat and breast cancer risk.
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Neoplasias da Mama , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , Estudos de Casos e Controles , Feminino , Humanos , Ferro , Ferro da Dieta , Modelos Logísticos , Carne , Fatores de RiscoRESUMO
BACKGROUND & AIMS: N-nicotinamide methyltransferase (NNMT) is emerging as an important enzyme in the regulation of metabolism. NNMT is highly expressed in the liver. However, the exact regulatory mechanism(s) underlying NNMT expression remains unclear and its potential involvement in alcohol-related liver disease (ALD) is completely unknown. METHODS: Both traditional Lieber-De Carli and the NIAAA mouse models of ALD were employed. A small-scale chemical screening assay and a chromatin immunoprecipitation assay were performed. NNMT inhibition was achieved via both genetic (adenoviral short hairpin RNA delivery) and pharmacological approaches. RESULTS: Chronic alcohol consumption induces endoplasmic reticulum (ER) stress and upregulates NNMT expression in the liver. ER stress inducers upregulated NNMT expression in both AML12 hepatocytes and mice. PERK-ATF4 pathway activation is the main contributor to ER stress-mediated NNMT upregulation in the liver. Alcohol consumption fails to upregulate NNMT in liver-specific Atf4 knockout mice. Both adenoviral NNMT knockdown and NNMT inhibitor administration prevented fatty liver development in response to chronic alcohol feeding; this was also associated with the downregulation of an array of genes involved in de novo lipogenesis, including Srebf1, Acaca, Acacb and Fasn. Further investigations revealed that activation of the lipogenic pathway by NNMT was independent of its NAD+-enhancing action; however, increased cellular NAD+, resulting from NNMT inhibition, was associated with marked liver AMPK activation. CONCLUSIONS: ER stress, specifically PERK-ATF4 pathway activation, is mechanistically involved in hepatic NNMT upregulation in response to chronic alcohol exposure. Overexpression of NNMT in the liver plays an important role in the pathogenesis of ALD. LAY SUMMARY: In this study, we show that nicotinamide methyltransferase (NNMT) - the enzyme that catalyzes nicotinamide degradation - is a pathological regulator of alcohol-related fatty liver development. NNMT inhibition protects against alcohol-induced fatty liver development and is associated with suppressed de novo lipogenic activity and enhanced AMPK activation. Thus, our data suggest that NNMT may be a potential therapeutic target for the treatment of alcohol-related liver disease.
Assuntos
Estresse do Retículo Endoplasmático/genética , Fígado Gorduroso Alcoólico/genética , Regulação da Expressão Gênica , Hepatócitos/metabolismo , Nicotinamida N-Metiltransferase/genética , RNA/genética , Regulação para Cima , Animais , Células Cultivadas , Modelos Animais de Doenças , Fígado Gorduroso Alcoólico/metabolismo , Fígado Gorduroso Alcoólico/patologia , Hepatócitos/patologia , Camundongos , Camundongos Knockout , Nicotinamida N-Metiltransferase/biossínteseRESUMO
B vitamins (including folate, vitamin B2, vitamin B6 and vitamin B12) and methionine are essential for methylation reactions, nucleotide synthesis, DNA stability and DNA repair. However, epidemiological evidence among Chinese populations is limited. The objective of this study was to evaluate B vitamins and methionine in relation to colorectal cancer risk in a Chinese population. A case-control study was conducted from July 2010 to April 2019. A total of 2502 patients with colorectal cancer were recruited along with 2538 age- (5-year interval) and sex-matched controls. Dietary data were collected using a validated FFQ. Multivariable logistic regression was used to assess OR and 95 % CI. The intake of folate, vitamin B2, vitamin B6 and vitamin B12 was inversely associated with colorectal cancer risk. The multivariable OR for the highest quartile v. the lowest quartile were 0·62 (95 % CI 0·51, 0·74; Ptrend < 0·001) for folate, 0·46 (95 % CI 0·38, 0·55; Ptrend < 0·001) for vitamin B2, 0·55 (95 % CI 0·46, 0·76; Ptrend < 0·001) for vitamin B6 and 0·72 (95 % CI 0·60, 0·86; Ptrend < 0·001) for vitamin B12. No statistically significant association was found between methionine intake and colorectal cancer risk. Stratified analysis by sex showed that the inverse associations between vitamin B12 and methionine intake and colorectal cancer risk were found only among women. This study indicated that higher intake of folate, vitamin B2, vitamin B6 and vitamin B12 was associated with decreased risk of colorectal cancer in a Chinese population.
Assuntos
Neoplasias Colorretais/epidemiologia , Dieta Saudável/estatística & dados numéricos , Dieta/efeitos adversos , Metionina/análise , Complexo Vitamínico B/análise , Adulto , Idoso , Estudos de Casos e Controles , China , Neoplasias Colorretais/etiologia , Inquéritos sobre Dietas , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
The effects of dietary vitamin D, Ca and dairy products intakes on colorectal cancer risk remain controversial. The present study investigated the association between these dietary intakes and the risk of colorectal cancer in Guangdong, China. From July 2010 to December 2018, 2380 patients with colorectal cancer and 2389 sex- and age-matched controls were recruited. Dietary intake data were collected through face-to-face interviews using a validated FFQ. Unconditional multivariable logistic regression models were used to calculate the OR and 95 % CI after adjusting for various confounders. Higher dietary vitamin D and Ca intakes were associated with 43 and 52 % reductions in colorectal cancer risk, with OR of 0·57 (95 % CI 0·46, 0·70) and 0·48 (95 % CI 0·39, 0·61), respectively, for the highest quartile (v. the lowest quartile) intakes. A statistically significant inverse association was observed between total dairy product intake and colorectal cancer risk, with an adjusted OR of 0·32 (95 % CI 0·27, 0·39) for the highest v. the lowest tertile. Subjects who drank milk had a 48 % lower risk of colorectal cancer than those who did not (OR 0·52, 95 % CI 0·45, 0·59). The inverse associations of dietary vitamin D, Ca, total dairy products and milk intakes with the risk of colorectal cancer were independent of sex and cancer site. Our study supports the protective effects of high dietary vitamin D, Ca and dairy products intakes against colorectal cancer in a Chinese population.
Assuntos
Cálcio da Dieta/administração & dosagem , Neoplasias Colorretais/prevenção & controle , Laticínios , Vitamina D/administração & dosagem , Idoso , Estudos de Casos e Controles , China/epidemiologia , Neoplasias Colorretais/epidemiologia , Dieta , Comportamento Alimentar , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Blood-retinal barrier breakdown is the main pathological characteristics of diabetic retinopathy (DR). Asymmetric dimethylarginine (ADMA) was reported to be elevated in DR patients. In this study, we observed the dynamic profile of ADMA, retinal morphology and permeability of BRB at 2, 4 or 8 week of diabetic rats induced by a single intraperitoneal injection of streptozocin (60 mg/kg) and in cultured rat retinal pericytes pretreated with D-glucose (30 mM) for 1, 3, 5 and 7 days or ADMA (3, 10, 30 µM) for 24, 48 and 72 h, trying to explore the effects of ADMA on blood-retinal barrier in DR. Gap junction intercellular communication (GJIC) and the expression of blood-retinal barrier-specific component connexin 43 (Cx43) were examined in diabetic rats or cultured retinal pericytes to elucidate whether ADMA impacted blood-retinal barrier function via damaging Cx43-GJIC. The results showed that with increasing duration of diabetes, the ultrastructure of blood-retinal barrier of diabetic rats appeared cell junction damage, apoptosis of retinal pericytes and breakdown of barrier successively. The increases in retinal permeability, ADMA levels and Cx43 expression, and abnormal GJIC were observed in diabetic rats and retinal pericytes exposed to D-glucose (30 mM). A glucose-like effect was seen using ADMA or another L-arginine analogue NG-monomethyl-L-arginine or dimethylarginine dimethylaminohydrolases (DDAHs) siRNA, implicating that ADMA aggravated the breakdown of blood-retinal barrier via damaging Cx43-GJIC.
Assuntos
Arginina/análogos & derivados , Barreira Hematorretiniana/patologia , Diabetes Mellitus Experimental/patologia , Retinopatia Diabética/patologia , Pericitos/patologia , Animais , Apoptose , Arginina/metabolismo , Barreira Hematorretiniana/metabolismo , Comunicação Celular , Permeabilidade da Membrana Celular , Células Cultivadas , Conexina 43/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Retinopatia Diabética/induzido quimicamente , Retinopatia Diabética/metabolismo , Junções Comunicantes/patologia , Glucose/metabolismo , Masculino , Pericitos/metabolismo , Ratos , Ratos Sprague-Dawley , Estreptozocina/administração & dosagem , Estreptozocina/toxicidadeRESUMO
BACKGROUND: Early hematoma expansion in intracerebral hemorrhage (ICH) patients is associated with poor outcome. We aimed to investigate whether the minimal computed tomography (CT) attenuation value predicted hematoma expansion and poor outcome. METHODS: This study involved spontaneous ICH patients of two cohorts who underwent baseline CT scan within 6 h after ICH onset and follow-up CT scan within 24 h after initial CT scan. We determined the critical value of the minimal CT attenuation value via retrospective analysis of the data from a derivation cohort. Then, a prospective study on the validation cohort of three clinical centers was performed for determining the association between the minimal CT attenuation value and hematoma expansion as well as poor outcome (modified Rankin Scale scores > 3) at 90 days by using univariate and multivariate logistic regression analyses. RESULTS: One hundred and forty eight ICH patients were included in the derivation cohort. Minimal CT attenuation value ≤ 31 Hounsfield units (HU) was demonstrated as the critical value to predict hematoma expansion by using receiver operating characteristic analysis. A total of 311 ICH patients were enrolled in the validation cohort, 86 (27.7%) and 133 (42.8%) of which were found hematoma expansion and poor outcome. Minimal CT attenuation value ≤ 31 HU was positive in 73 patients (23.5%). The multivariate logistic regression analysis demonstrated minimal CT attenuation value and minimal CT attenuation value ≤ 31 HU independently predicted hematoma expansion (p < 0.001) and poor outcome (p < 0.001). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of minimal CT attenuation value ≤ 31 HU for hematoma expansion and poor outcome prediction were 64.0, 92.0, 75.3, 87.0, 84.2 and 45.1%, 92.7%, 82.2%, 69.3%, 72.3%, respectively. CONCLUSIONS: The minimal CT attenuation value independently predicts early hematoma expansion and poor outcome in patients with ICH.
Assuntos
Hemorragia Cerebral/diagnóstico por imagem , Hematoma/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Idoso , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Curva ROC , Estudos RetrospectivosRESUMO
BACKGROUND: Apelin-13 has been found to have protective effects on many neurological diseases, including cerebral ischemia. However, whether Apelin-13 acts on blood-brain barrier (BBB) disruption following cerebral ischemia is largely unknown. Aquaporin-4 (AQP4) has a close link with BBB due to the high concentration in astrocyte foot processes and regulation of astrocytes function. Here, we aimed to test Apelin-13's effects on ischemic BBB injury and examine whether the effects were dependent on AQP4. METHODS: We detected the expression of AQP4 induced by Apelin-13 injection at 1, 3, and 7 days after middle cerebral artery occlusion. Meanwhile, we examined the effects of Apelin-13 on neurological function, infarct volume, and BBB disruption owing to cerebral ischemia in wild type mice, and tested whether such effects were AQP4 dependent by using AQP4 knock-out mice. Furthermore, we assessed the possible signal transduction pathways activated by Apelin-13 to regulate AQP4 expression via astrocyte cultures. RESULTS: It was found that Apelin-13 highly increased AQP4 expression as well as reduced neurological scores and infarct volume. Importantly, Apelin-13 played a role of BBB protection in both types of mice by reducing BBB permeability, increased vascular endothelial growth factor, upregulated endothelial nitric oxide synthase, and downregulated inducible NOS. In morphology, we demonstrated Apelin-13 suppressed tight junction opening and endothelial cell swelling via electron microscopy detection. Meanwhile, Apelin-13 also alleviated apoptosis of astrocytes and promoted angiogenesis. Interestingly, effects of AQP4 on neurological function and infarct volume varied with time course, while AQP4 elicited protective effects on BBB at all time points. Statistical analysis of 2-way analysis of variance with replication indicated that AQP4 was required for these effects. In addition, Apelin-13 upregulated phosphorylation of extracellular signal-regulated kinase (ERK) and Akt as well as AQP4 protein in cultured astrocytes. The latter was inhibited by ERK and phosphatidylinositol 3'-kinase (PI3K) inhibitors. CONCLUSION: Our data suggest that Apelin-13 protects BBB from disruption after cerebral ischemia both morphologically and functionally, which is highly associated with the increased levels of AQP4, possibly through the activation of ERK and PI3K/Akt pathways. This study provides double targets to protection of ischemic BBB damage, which can present new insights to drugs development.
Assuntos
Aquaporina 4/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Fármacos Neuroprotetores/farmacologia , Animais , Apoptose/efeitos dos fármacos , Aquaporina 4/deficiência , Aquaporina 4/genética , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/fisiopatologia , Barreira Hematoencefálica/ultraestrutura , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/ultraestrutura , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Camundongos Knockout , Neovascularização Fisiológica/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Junções Íntimas/ultraestrutura , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Paeoniflorin (PF) and astragaloside IV (AS-IV) have protective effects on cerebral ischemia. We aimed to test the effects of combined use of PF and AS-IV on ischemic brain edema and investigate whether the effects were dependent on connexin43 (Cx43). We detected the expression of Cx43 induced by PF and AS-IV after cerebral ischemia. We also examined the effects of combined use of PF and AS-IV on ischemic edema and further investigated the related pathways. We demonstrated PF and AS-IV decreased Cx43 and aquaporin4 (AQP4) associating with reduction of brain edema by dry-wet weight and brain-specific gravity methods after cerebral ischemia. Administration of PF and AS-IV displayed a further attenuation of brain edema with lower Cx43 levels. Meanwhile, Cx43 blockade inhibited AQP4 down-regulation by the two drugs. Moreover, phosphorylation of C-Jun amino-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) were increased by PF and AS-IV, respectively. The effects of PF and AS-IV to down-regulate Cx43 were suppressed by JNK and ERK inhibitors, respectively. Our data indicate that PF and AS-IV alleviate ischemic brain edema, which has close relation to Cx43 down-regulation causing decrease of AQP4 via JNK and ERK pathways activation, respectively. Combined administration elicits synergistic effects on brain edema reduction. Copyright © 2017 John Wiley & Sons, Ltd.
Assuntos
Edema Encefálico/tratamento farmacológico , Conexina 43/metabolismo , Glucosídeos/farmacologia , Monoterpenos/farmacologia , Saponinas/farmacologia , Triterpenos/farmacologia , Animais , Aquaporina 4/metabolismo , Isquemia Encefálica/tratamento farmacológico , Regulação para Baixo , Sinergismo Farmacológico , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacosRESUMO
Herein we present a new structural design of hole-transporting material, Trux-OMeTAD, which consists of a C3h Truxene-core with arylamine terminals and hexyl side-chains. This planar, rigid, and fully conjugated molecule exhibits excellent hole mobility and desired surface energy to the perovskite uplayer. Perovskite solar cells fabricated using the p-i-n architecture with Trux-OMeTAD as the p-layer, show a high PCE of 18.6% with minimal hysteresis.
RESUMO
The objective of this study is to find if co-transfecting microRNA-338 and microRNA-21 into the neurons in the spinal cord can promote functional recovery after peripheral nerve injury in rats. Animals were divided into three groups: 20 animals in the GFP control vector group (group A), 20 animals in the GFP experimental vector group (group B) and ten animals in the normal control group. Right sciatic nerves of animals in groups A and B were transected and were bridged with collagen nerve conduits with 10 mm distance between the stumps. 3 µl GFP control vector or 3 µl lentiviral vectors encoding the sequence of microRNA-338 and microRNA-21 were injected in the conduit. 8 weeks after the surgery, the treatment effect was evaluated by functional analysis, electrophysiological analysis, immunohistochemical analysis as well as transmitting electronic microscope observations in all the rats. Animals treated with microRNA-338 and microRNA-21 showed significantly better recovery than GFP control group animals by means of functional analysis (Sciatic nerve index -47.7 ± 2.5 vs -59.4 ± 3.7), electrophysiological analysis (Conduction velocity 20.5 ± 2.8 vs 10.5 ± 1.4 m/s), ratio of wet weight of the gastrocnemius muscles (0.83 ± 0.03 vs 0.55 ± 0.06), axon diameter (5.0 ± 1.8 µm vs 4.0 ± 2.2), myelin sheath thickness (1.4 ± 0.43 vs 0.80 ± 0.31 µm) and G-ratio (0.80 ± 0.06 vs 0.75 ± 0.04). Lentiviral vectors encoding microRNA 338 and 21 might be explored in the future as potential therapeutic intervention to promote nerve regeneration.
Assuntos
MicroRNAs/uso terapêutico , Neuropatia Ciática/terapia , Transfecção , Acetilcolinesterase/metabolismo , Animais , Axônios/patologia , Axônios/ultraestrutura , Modelos Animais de Doenças , Potenciais Evocados/fisiologia , Seguimentos , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Microscopia Eletrônica de Transmissão , Músculo Esquelético/patologia , Proteínas de Neurofilamentos/metabolismo , Tamanho do Órgão/fisiologia , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/genética , Nervo Isquiático/patologia , Nervo Isquiático/ultraestrutura , Neuropatia Ciática/genética , Neuropatia Ciática/patologia , Índice de Gravidade de DoençaRESUMO
Bilateral hemifacial spasm and Meige syndrome can be easily confused due to their similar clinical manifestation. Here, we aimed to investigate the application of electrophysiological methods and magnetic resonance tomographic angiography (MRTA) in the differentiation between hemifacial spasm and Meige syndrome. 10 patients with bilateral hemifacial spasm and 9 patients with Meige syndrome received electrophysiological monitoring of nerves. There were two males and eight females with bilateral hemifacial spasm, aged 16-58 years with a course of 5-54 months. For the patients with Meige syndrome, there were three males and six females, aged 51-68 years with a course of 12-36 months. All patients received conventional MRTA of the brain blood vessels before decompression. We found that all patients with Meige syndrome showed synchronous contraction of bilateral orbicularis oculi muscles and (or) burst discharge from orbicularis oris muscles in surface electromyography (sEMG). However, those with hemifacial spasm presented with bilaterally asynchronous burst discharge. Electromyography for patients with Meige syndrome did not record abnormal muscle response (AMR), but recorded AMR for those with bilateral hemifacial spasm. The offending vessels were compressed in patients with hemifacial spasm in MRTA, while MRTA results were generally negative for those with Meige syndrome. Combining sEMG and AMR detection in EMG and MRTA, bilateral hemifacial spasm can be differentiated from Meige syndrome with a reduction of misdiagnosis rate.
Assuntos
Potencial Evocado Motor/fisiologia , Espasmo Hemifacial/diagnóstico por imagem , Espasmo Hemifacial/fisiopatologia , Angiografia por Ressonância Magnética , Síndrome de Meige/diagnóstico por imagem , Síndrome de Meige/fisiopatologia , Adolescente , Adulto , Idoso , Eletromiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
Cerebrovascular diseases are conditions caused by problems with brain vasculature, which have a high morbidity and mortality. Aquaporin-4 (AQP4) is the most abundant water channel in the brain and crucial for the formation and resolution of brain edema. Considering brain edema is an important pathophysiological change after stoke, AQP4 is destined to have close relation with cerebrovascular diseases. However, this relation is not limited to brain edema due to other biological effects elicited by AQP4. Till now, multiple studies have investigated roles of AQP4 in cerebrovascular diseases. This review focuses on expression of AQP4 and the effects of AQP4 on brain edema and neural cells injuries in cerebrovascular diseases including cerebral ischemia, intracerebral hemorrhage and subarachnoid hemorrhage. In the current review, we pay more attention to the studies of recent years directly from cerebrovascular diseases animal models or patients, especially those using AQP4 gene knockout mice. This review also elucidates the potential of AQP4as an excellent therapeutic target.
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Aquaporina 4/metabolismo , Transtornos Cerebrovasculares/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Edema Encefálico/metabolismo , Edema Encefálico/patologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/patologia , Transtornos Cerebrovasculares/patologia , HumanosRESUMO
Alzheimer's disease (AD) is characterized by beta-amyloid plaques and neurofibrillary tangles that cause devastating cognitive and memory deficits. AD is known to be associated with neuronal death and synaptic loss. Thus, methods to retard the progression of the disease and to promote neuro-regeneration are vital for the prevention of advancement of AD. The recent trend is to decipher the molecular mechanisms of AD, and further aim at neuro-restorative mechanisms such as neuro-protection, neuro-modulation, and neuro-regeneration. In this review, we provide an overview of the recent studies describing various neuro-restorative strategies for AD and mainly focus on stem cell and neuro-modulation therapies. Furthermore, we briefly refer to the other neurorestorative treatments including medications, bioengineering, and gene therapies for AD. Although most of them remain in an experimental phase, neuro-restorative strategies may have the potential for clinical use in the management of this debilitative disease.
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BACKGROUND & AIMS: It has been revealed good nutritional status and no physical frailty, which are modifiable lifestyle factors, are linked to less cognitive decline and a lower risk of Alzheimer's disease (AD). We aimed to investigate the associations between nutritional status and physical frailty and plasma AD biomarkers, especially the Tau-associated biomarkers in older cognitively unimpaired (CU) adults with higher ß-amyloid (Aß) burden. METHODS: The nutritional status and physical frailty were assessed via Mini-Nutritional Assessment Short-Form (MNA-SF) and Fried frailty index. The participants underwent the examination of plasma AD biomarkers and 18F-florbetapir PET scan as well as 18F-MK6240 PET in the validation cohort. Correlation and multiple linear regression analyses were used to investigate the associations between nutritional status and frailty and AD biomarkers. RESULTS: Two cohorts were included in our study. A total of 129 participants with Aß-PET positive were enrolled in the development cohort. Multiple linear regression analysis showed MNA-SF scores, normal nutritional status, Fried frailty index scores, frailty and some domains of frailty including weight loss, maximal grip strength and exhaustion were associated with plasma p-Tau-181. Furthermore, weight loss, Fried frailty index scores and frailty were associated with higher Aß-PET standard uptake value ratio. We further performed subgroup analyses stratified by age, sex and apolipoprotein E ε4 genotype to investigate the beneficial characteristics of nutrition and frailty in the special subgroups. Validation cohort contained 38 Aß-PET positive participants. MNA-SF scores, normal nutritional status, Fried frailty index scores and frailty were associated with Tau burden evaluated by 18F-MK6240 PET Braak-like stages. CONCLUSIONS: Our data indicates that normal nutritional status and no physical frailty may be associated with expected trend of plasma AD biomarkers, especially less Tau pathology in older CU adults with Aß deposition. Adjusting to these characteristics of nutrition and physical frailty may help reduce the risk of AD development.
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Doença de Alzheimer , Peptídeos beta-Amiloides , Biomarcadores , Fragilidade , Estado Nutricional , Tomografia por Emissão de Pósitrons , Humanos , Masculino , Feminino , Idoso , Biomarcadores/sangue , Doença de Alzheimer/sangue , Fragilidade/sangue , Peptídeos beta-Amiloides/sangue , Tomografia por Emissão de Pósitrons/métodos , Proteínas tau/sangue , Idoso de 80 Anos ou mais , Avaliação Nutricional , Estudos de Coortes , Idoso Fragilizado , Cognição/fisiologia , Avaliação Geriátrica/métodos , Força da Mão/fisiologiaRESUMO
Despite pharmaceuticals being widely detected in water-bodies worldwide, what remain unclear are the effects of high pharmaceutical concentrations on the treatment efficiency of biological wastewater treatment processes, such as membrane bioreactor (MBR) systems. This study investigated the efficiency of MBR technology in the treatment of synthetic wastewater containing a mixture of five typical pharmaceuticals (ofloxacin, sulfamethoxazole, sulfamethylthiadiazole, carbamazepine and naproxen) with a total concentration of 500 µg/L. Both the control MBR (MBRc) without pharmaceutical dosing and the MBR operated with high influent pharmaceutical concentrations (MBRe) were operated under room temperature with the same hydraulic retention time of 11 h and the same sludge retention time of 30 d. The removal efficiency rates of total nitrogen and total phosphorus were 83.2% vs. 90.1% and 72.6% vs. 57.8% in the MBRc vs. MBRe systems, and both MBRs achieved >98% removal of organics for a 180-day period. The floc size decreased, and membrane fouling became more severe in the MBRe system. Microbial diversity increased in the MBRe system and the relative abundances of functional microbe differed between the two MBRs. Furthermore, the total relative abundances of genes involved in glycolysis, assimilating nitrate reduction and nitrification processes increased in the MBRe system, which could account for the higher organics and nitrogen removal performance. This work provides insights for MBR operation in wastewater treatment with high pharmaceutical concentrations.
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BACKGROUND: The roles of gut microbiota in the pathogenesis of SLE have been receiving much attention during recent years. However, it remains unknown how fecal microbiota transplantation (FMT) and microbial metabolites affect immune responses and lupus progression. METHODS: We transferred fecal microbiota from MRL/lpr (Lpr) mice and MRL/Mpj (Mpj) mice or PBS to pristane-induced lupus mice and observed disease development. We also screened gut microbiota and metabolite spectrums of pristane-induced lupus mice with FMT via 16S rRNA sequencing, metagenomic sequencing, and metabolomics, followed by correlation analysis. RESULTS: FMT from MRL/lpr mice promoted the pathogenesis of pristane-induced lupus and affected immune cell profiles in the intestine, particularly the plasma cells. The structure and composition of microbial communities in the gut of the FMT-Lpr mice were different from those of the FMT-Mpj mice and FMT-PBS mice. The abundances of specific microbes such as prevotella taxa were predominantly elevated in the gut microbiome of the FMT-Lpr mice, which were positively associated with functional pathways such as cyanoamino acid metabolism. Differential metabolites such as valine and L-isoleucine were identified with varied abundances among the three groups. The abundance alterations of the prevotella taxa may affect the phenotypic changes such as proteinuria levels in the pristane-induced lupus mice. CONCLUSION: These findings further confirm that gut microbiota play an important role in the pathogenesis of lupus. Thus, altering the gut microbiome may provide a novel way to treat lupus.