RESUMO
Atherosclerosis treatments by gene regulation are garnering attention, yet delivery of gene cargoes to atherosclerotic plaques remains inefficient. Here, we demonstrate that assembly of therapeutic oligonucleotides into a three-dimensional spherical nucleic acid nanostructure improves their systemic delivery to the plaque and the treatment of atherosclerosis. This noncationic nanoparticle contains a shell of microRNA-146a oligonucleotides, which regulate the NF-κB pathway, for achieving transfection-free cellular entry. Upon an intravenous injection into apolipoprotein E knockout mice fed with a high-cholesterol diet, this nanoparticle naturally targets class A scavenger receptor on plaque macrophages and endothelial cells, contributing to elevated delivery to the plaques (â¼1.2% of the injected dose). Repeated injections of the nanoparticle modulate genes related to immune response and vascular inflammation, leading to reduced and stabilized plaques but without inducing severe toxicity. Our nanoparticle offers a safe and effective treatment of atherosclerosis and reveals the promise of nucleic acid nanotechnology for cardiovascular disease.
Assuntos
Aterosclerose , MicroRNAs , Nanopartículas , Placa Aterosclerótica , Animais , Aterosclerose/tratamento farmacológico , Aterosclerose/genética , Células Endoteliais/metabolismo , Camundongos , Camundongos Knockout , MicroRNAs/genética , MicroRNAs/uso terapêutico , NF-kappa B/genética , NF-kappa B/metabolismo , Nanopartículas/química , Nanopartículas/uso terapêutico , Oligonucleotídeos/uso terapêutico , Placa Aterosclerótica/metabolismo , Receptores Depuradores/metabolismoRESUMO
INTRODUCTION: Existing blood-based biomarkers for Alzheimer's disease (AD) mainly focus on its pathological features. However, studies on blood-based biomarkers associated with other biological processes for a comprehensive evaluation of AD status are limited. METHODS: We developed a blood-based, multiplex biomarker assay for AD that measures the levels of 21 proteins involved in multiple biological pathways. We evaluated the assay's performance for classifying AD and indicating AD-related endophenotypes in three independent cohorts from Chinese or European-descent populations. RESULTS: The 21-protein assay accurately classified AD (area under the receiver operating characteristic curve [AUC] = 0.9407 to 0.9867) and mild cognitive impairment (MCI; AUC = 0.8434 to 0.8945) while also indicating brain amyloid pathology. Moreover, the assay simultaneously evaluated the changes of five biological processes in individuals and revealed the ethnic-specific dysregulations of biological processes upon AD progression. DISCUSSION: This study demonstrated the utility of a blood-based, multi-pathway biomarker assay for early screening and staging of AD, providing insights for patient stratification and precision medicine. HIGHLIGHTS: The authors developed a blood-based biomarker assay for Alzheimer's disease. The 21-protein assay classifies AD/MCI and indicates brain amyloid pathology. The 21-protein assay can simultaneously assess activities of five biological processes. Ethnic-specific dysregulations of biological processes in AD were revealed.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/patologia , Etnicidade , Biomarcadores , Peptídeos beta-Amiloides , Proteínas tau , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/patologiaRESUMO
A Gram-stain-positive, facultatively anaerobic, non-motile, endospore-forming and rod-shaped bacterium, occurring singly or in pairs, designated TB2019T, was isolated from environmental monitoring samples of corridor air collected at the Tianjin Institute for Drug Control, Tianjin Province (PR China). The isolate was able to grow at 15-40 °C (optimum growth at 37 °C), pH 6.0-8.0 (pH 7.0) and in the presence of 0-2% (w/v) NaCl (0% NaCl). Comparison of 16S rRNA gene sequences indicated that TB2019T was most closely related to Paenibacillus typhae CGMCC 1.11012T (98.63%), Paenibacillus albidus Q4-3T (98.19%), Paenibacillus borealis DSM 13188T (97.55%), Paenibacillus helianthi P26ET (97.33%) and Paenibacillus odorifer DSM 15391T (97.19%). The digital DNA-DNA hybridization and the average nucleotide identity values between TB2019T and the five type strains mentioned above ranged from 20.7 to 25.0% and 75.2 to 81.3%, respectively, and the genomic DNA G+C content was 49.52 mol%. The diagnostic cell-wall sugar was ribose, and the diagnostic amino acid was meso-diaminopimelic acid. The polar lipids of TB2019T included diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, three unidentified aminophospholipids and one unidentified phospholipid. MK-7 was the predominant menaquinone, and anteiso-C15:0 (30.6%) was the major fatty acid. Based on the polyphasic taxonomic data, strain TB2019T represents a novel species of the genus Paenibacillus, for which the name Paenibacillus tianjinensis sp. nov. is proposed. The type strain is TB2019T (=CICC 25065T=JCM 34610T).
Assuntos
Microbiologia do Ar , Paenibacillus , Fosfolipídeos/química , Filogenia , Técnicas de Tipagem Bacteriana , Composição de Bases , China , DNA Bacteriano/genética , Ácidos Graxos/química , Hibridização de Ácido Nucleico , Paenibacillus/classificação , Paenibacillus/isolamento & purificação , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Vitamina K 2/análogos & derivados , Vitamina K 2/químicaRESUMO
BACKGROUND: Peel color is an economically relevant trait that influences the appearance and quality of red pear, whose red color is due to anthocyanin accumulation. Prohydrojasmon (PDJ), which has similar effects to endogenous jasmonates, was developed as a commercial bioregulator, particularly to improve fruits coloring. However, little information is available about the effect of PDJ on pears. This study investigated the effects of preharvest PDJ treatments on color development, phenolic compounds accumulation, and related gene expression in the red pear cultivar 'Nanhong'. The treatments were performed during the pre-color-change period by spraying 50 or 100 mg L-1 of PDJ on fruits. RESULTS: Preharvest PDJ treatments had a significant effect on color development, without affecting other quality parameters such as total soluble solids and fruit acidity. Liquid chromatography-mass spectrometry analysis showed that concentrations of anthocyanins and flavonols were enhanced in the peel after PDJ treatments, particularly when a concentration of 100 mg L-1 was used, whereas those of hydroxycinnamates and flavanols were decreased. After PDJ application, the transcription levels of anthocyanin biosynthesis genes PAL, CHS, CHI, ANS, F3H, and UFGT were enhanced, especially under the higher PDJ concentration tested. In addition, anthocyanin accumulation in the peels of PDJ-treated fruits was found to be positively correlated with the upregulation of the regulatory gene MYB114. CONCLUSION: Preharvest treatments with PDJ could be a useful tool to improve fruits coloring and increase phenolic content in pear. These findings also improve our understanding of the molecular mechanisms associated with PDJ-regulated anthocyanin accumulation in pear fruits.
Assuntos
Frutas/crescimento & desenvolvimento , Fenóis/metabolismo , Reguladores de Crescimento de Plantas/farmacologia , Proteínas de Plantas/genética , Pyrus/efeitos dos fármacos , Antocianinas/biossíntese , Cor , Frutas/química , Frutas/genética , Frutas/metabolismo , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Fenóis/química , Proteínas de Plantas/metabolismo , Pyrus/genética , Pyrus/crescimento & desenvolvimento , Pyrus/metabolismoRESUMO
Polycystic ovary syndrome (PCOS), known as a common endocrine disorder among females, plagues many PCOS patients. The current study aimed to explore the correlations of sex hormone-binding globulin (SHBG) polymorphisms with the outcome of in vitro fertilization-embryo transfer (IVF-ET) in PCOS patients. PCOS patients who underwent IVF-ET and patients with non-PCOS-related infertility were selected in the study. Correlations of SHBG rs6259 and rs727428 with the risk factors in PCOS were analyzed, followed by the evaluation of the effect of SHBG polymorphisms on the outcome of IVF-ET in PCOS patients. At last, unconditional logistic regression analysis was performed to study the risk factors for IVF-ET treatment outcome. Compared with SHBG rs6259 GG carriers, the incidence of PCOS was found to be elevated in SHBG rs6259 GA+AA carriers which indicated that the A allele was a risk factor for PCOS. Compared with SHBG rs6259 TT carriers, the number of retrieved oocytes and embryo as well as the fertility rate in SHBG rs6259 GA+AA carriers was found to be decreased, while the abortion rate, incidence of ovarian hyperstimulation syndrome, transplant rejection rate, estradiol, and testosterone in serum, as well as testosterone in follicular fluid were elevated. The luteal hormone, serum testosterone, and progesterone and GA+AA genotype of rs6259 were the risk factors for IVF-ET treatment outcome. Taken together, the study showed that SHBG rs6259 polymorphisms might be correlated with the risk of PCOS and the outcome of IVF-ET treatment.
Assuntos
Alelos , Transferência Embrionária , Fertilização in vitro , Síndrome do Ovário Policístico/genética , Polimorfismo Genético , Globulina de Ligação a Hormônio Sexual/genética , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Síndrome do Ovário Policístico/epidemiologia , Síndrome do Ovário Policístico/metabolismo , Fatores de Risco , Globulina de Ligação a Hormônio Sexual/metabolismoRESUMO
Objective: To investigate in vivo correlates of erectile dysfunction (ED) in male patients with acromegaly. Methods: Fifty-one male patients with acromegaly were assessed by the International Index of Erectile Function-5 and Acromegaly Quality of Life (Acro-QoL) questionnaires. The measurement of serum nitric oxide (NO) were performed in patients and age-matched nonacromegalic controls. Results: Among 51 patients analyzed, 32 (62.7%) had ED. Patients with ED showed lower Acro-QoL scores regarding global (69.8 ± 17.7 versus 79.4 ± 11.2; P = .035) and personal relationship dimensions (59.6 ± 22.1 versus 76.8 ± 17.6; P = .012) than non-ED patients. ED patients were older (44.5 ± 11.2 years versus 33.2 ± 8.5 years; P = .04) and showed higher growth hormone (GH) levels (15.5 µg/L [interquartile range of 9.5 to 34.5 µg/L] versus 5.9 µg/L [interquartile range of 3.4 to 13.9 µg/L]; P = .001) compared to non-ED patients. The cutoff values for identifying ED were 7.9 µg/L for random GH and 5.3 µg/L for GH nadir after oral administration of 75 g of glucose. There was no significant difference in total testosterone levels between the two groups (6.36 ± 4.24 nmol/L versus 9.54 ± 5.50 nmol/L; P = .299). The NO levels in patients with acromegaly were significantly lower than those in nonacromegalic controls (8.77 ± 1.78 µmol/L versus 19.19 ± 5.02 µmol/L, respectively; P = .049). Furthermore, the NO levels were even lower in ED patients than those in non-ED patients (5.14 ± 0.98 µmol/L versus 12.09 ± 3.44 µmol/L; P = .027). Conclusion: Our study showed that ED is prevalent in male acromegalic patients and may be associated with systemic endothelial dysfunction induced by excessive GH. Further studies investigating the mechanism of GH and ED are required. Abbreviations: Acro-QoL = Acromegaly Quality of Life; ED = erectile dysfunction; FSH = follicle-stimulating hormone; GH = growth hormone; IGF-1 = insulin-like growth factor 1; IIEF-5 = international index of erection function-5; LH = luteinizing hormone; MRI = magnetic resonance imaging; NO = nitric oxide; OGTT = oral glucose tolerance test; QoL = quality of life; ROC = receiver operating characteristic.
Assuntos
Acromegalia , Disfunção Erétil , Hormônio do Crescimento Humano , Humanos , Fator de Crescimento Insulin-Like I , Masculino , Qualidade de VidaRESUMO
Some microRNAs (miRs) are dysregulated in cancers, and aberrant miR expression has been reported to correlate with chemoresistance of cancer cells. Therefore, the present study aims at investigating the effects of microRNA-139-5p (miR-139-5p) on cisplatin resistance of ovarian cancer (OC) with involvement of ring finger protein 2 (RNF2) and the mitogen-activated protein kinase (MAPK) signaling pathway. OC tissues were obtained from 66 primary OC patients. The cisplatin-sensitive A2780 and cisplatin-resistant A2780/DDP cell lines were collected for construction of RNF2 silencing and overexpressed plasmids. Cell vitality and apoptosis were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and annexin V-FITC/propidium iodide double-staining, respectively. Next, expression of RNF2, extracellular signal-related kinase, and p38 was determined by quantitative reverse transcription-quantitative polymerase chain reaction and Western blot analysis. Finally, the volume of xenograft tumors in BALB/c nude mice was detected. RNF2 and miR-139-5p were identified to be involved in OC. In addition, MAPK activation and RNF2 were related to cisplatin resistance of OC. miR-139-5p was downregulated in cisplatin-resistant OC tissues, and miR-139-5p overexpression could inhibit cell vitality, reduce cisplatin resistance, and promote apoptosis of OC cells. Furthermore, miR-139-5p combined with MAPK inhibitors more obviously reduced cisplatin resistance of OC. Taken together, this study demonstrated that miR-139-5p overexpression combined with inactivation of the MAPK signaling pathway can reverse the cisplatin resistance of OC by suppressing RNF2. Thus, miR-139-5p overexpression might be a future therapeutic strategy for OC.
Assuntos
Cisplatino/farmacologia , Regulação para Baixo/genética , Resistencia a Medicamentos Antineoplásicos/genética , Sistema de Sinalização das MAP Quinases/genética , MicroRNAs/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Animais , Apoptose/genética , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Complexo Repressor Polycomb 1 , Transdução de Sinais/genéticaRESUMO
Cervical cancer (CC) remains a highly prevalent cancer and mortality globally among women globally. The aim of the present study was to assess the ability of miR-374b to regulate CC cells through JAM-2, whilst exploring whether the underlying mechanism and its relation to the p38/ERK signaling pathway. During the study, microRNA-374b (miR-374b) was observed to have been expressed at a low level among CC tissues. Hence, a series of miR-374b mimics, miR-374b inhibitors, siRNA against JAM-2, SB202190 (an inhibitor for p38), and PD98059 (an inhibitor for ERK) were introduced to treat CC Siha cells and normal cervical Ect1/E6E7 cells. MTT, flow cytometry, scratch test, and transwell assays were applied to determine cell viability, apoptosis, migration, and invasion. The inhibitory role of the p38/ERK signaling pathway was observed in the CC cells treated with miR-374b mimics or siRNA against JAM-2. miR-374b mimic exposure was found to reduce cell viability, migration, and invasion, but induce apoptosis. MiR-374b inhibitor exposure was observed to have induced effects on the CC cells in a contrary manner to those induced by that of the miR-374b mimics. The key findings of the study demonstrated that miR-374b significantly inhibits cell proliferation, migration, and invasion through the blockade of the p38/ERK signaling pathway activation, as well as negatively binding to JAM-2, highlighting its potential as a therapeutic target for CC.
Assuntos
Apoptose/genética , Moléculas de Adesão Celular/metabolismo , Sistema de Sinalização das MAP Quinases , MicroRNAs/metabolismo , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Adulto , Sequência de Bases , Moléculas de Adesão Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Regulação para Cima/genéticaRESUMO
BACKGROUND/AIMS: Free radical scavenger tempol is a protective antioxidant against ischemic injury. Tubular epithelial apoptosis is one of the main changes in the renal ischemia/reperfusion (I/R) injury. Meanwhile some proteins related with apoptosis and inflammation are also involved in renal I/R injury. We tested the hypothesis that tempol protects against renal I/R injury by activating protein kinase B/mammalian target of rapamycin (PKB, Akt/mTOR) and glycogen synthase kinase 3ß (GSK3ß) pathways as well as the coordinating apoptosis and inflammation related proteins. METHODS: The right renal pedicle of C57Bl/6 mouse was clamped for 30 minutes and the left kidney was removed in the study. The renal injury was assessed with serum parameters by an automatic chemistry analyzer. Renal expressions of Akt/mTOR and GSK3ß pathways were measured by western blot in I/R mice treated with saline or tempol (50mg/kg) and compared with sham-operated mice. RESULTS: The levels of blood urea nitrogen (BUN), creatinine and superoxide anion (O2.-) increased, and superoxide dismutase (SOD) and catalase (CAT) decreased significantly after renal I/R injury. However, tempol treatment prevented the changes. Besides, I/R injury reduced renal expression of p-Akt, p-GSK3ß, p-mTOR, Bcl2 and increased NF-κB, p-JNK and p53 in kidney, tempol significantly normalized these changes. In addition, renal I/R injury reduced the response of afferent arteriole to Angiotensin II (Ang II), while tempol treatment improved the activity of afferent arteriole. CONCLUSION: Tempol attenuates renal I/R injury. The protective mechanisms seem to relate with activation of PI3K/Akt/mTOR and GSK3ß pathways, inhibition of cellular damage markers and inflammation factors, as well as improvement of afferent arteriolar activity.
Assuntos
Injúria Renal Aguda/tratamento farmacológico , Arteríolas/metabolismo , Óxidos N-Cíclicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Arteríolas/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Marcadores de Spin , Serina-Treonina Quinases TOR/metabolismoRESUMO
BACKGROUND/AIMS: Canonical Wnt signaling is involved in oxidative stress, vasculopathy and diabetes mellitus but its role in diabetic renal microvascular dysfunction is unclear. We tested the hypothesis that enhanced canonical Wnt signaling in renal afferent arterioles from diabetic mice increases reactive oxygen species (ROS) and contractions to endothelin-1 (ET-1). METHODS: Streptozotocin-induced diabetes or control C57Bl/6 mice received vehicle or sulindac (40 mg·kg-1·day-1) to block Wnt signaling for 4 weeks. ET-1 contractions were measured by changes of afferent arteriolar diameter. Arteriolar H2O2, O2 -, protein expression and enzymatic activity were assessed using sensitive fluorescence probes, immunoblotting and colorimetric assay separately. RESULTS: Compared to control, diabetic mouse afferent arteriole had increased O2- (+ 84%) and H2O2 (+ 91%) and enhanced responses to ET-1 at 10-8 mol·l-1 (-72±4% of versus -43±4%, P< 0.05) accompanied by reduced protein expressions and activities for catalase and superoxide dismutase 2 (SOD2). Arteriolar O2 - was increased further by ET-1 and contractions to ET-1 reduced by PEG-SOD in both groups whereas H2O2 unchanged by ET-1 and contractions were reduced by PEG-catalase selectively in diabetic mice. The Wnt signaling protein ß-catenin was upregulated (3.3-fold decrease in p-ß-catenin/ß-catenin) while the glycogen synthase kinase-3ß (GSK-3ß) was downregulated (2.6-fold increase in p-GSK-3ß/ GSK-3ß) in preglomerular vessels of diabetic mice. Sulindac normalized the Wnt signaling proteins, arteriolar O2 -, H2O2 and ET-1 contractions while doubling microvascular catalase and SOD2 expression in diabetic mice. CONCLUSION: Increased ROS, notably H2O2 contributes to enhanced afferent arteriolar responses to ET-1 in diabetes, which is closely associated with Wnt signaling. Antioxidant pharmacological strategies targeting Wnt signaling may improve vascular function in diabetic nephropathy.
Assuntos
Arteríolas/efeitos dos fármacos , Diabetes Mellitus Experimental/metabolismo , Endotelina-1/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Vasoconstrição/efeitos dos fármacos , Via de Sinalização Wnt , Animais , Arteríolas/metabolismo , Peróxido de Hidrogênio , Rim/irrigação sanguínea , CamundongosRESUMO
BACKGROUND: The 12-item Short-Form Health Survey (SF-12) is the abridged practical version of SF-36. AIMS: This cross-sectional study was aimed to assess the reliability and validity of SF-12 for the health status of Chinese community elderly population. METHODS: The Chinese community elderly people in Xujiahui district of Shanghai were investigated. The internal consistency reliability was assessed using Cronbach's alpha and split-half reliability coefficients. Construct validity was analyzed using exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). Spearman's correlation coefficient (ρ) was used for the evaluation of criterion, convergent, and discriminant validity with Spearman's ρ ≥ 0.4 as satisfactory. Comparisons of the SF-12 summary scores among populations that differed in demographics were performed for discriminant validity. RESULTS: Total 1343 individuals aged ≥60 and <85 years old (response rate: 91.3 %) were analyzed. The Cronbach's α value (0.910) and the split-half reliability coefficient (0.812) reflected satisfactory internal consistency reliability of SF-12. EFA extracted a two-factor model (physical and mental health). About 60.7 % of the total variance was explained by the two factors. CFA showed that the two-factor solution provided a good fit to the data. Good convergent validity and discriminant validity of SF-12 were proved by the correction analyses (Spearman's ρ > 0.4) and the comparisons of the SF-12 summary scores among populations (P < 0.05). SF-12 summary scores were significantly correlated with the SF-36 summary scores (Spearman's ρ > 0.4, P < 0.05). CONCLUSIONS: In conclusion, SF-12 had satisfactory reliability and validity in measuring health status of Chinese community elderly population in Xujiahui district of Shanghai.
Assuntos
Qualidade de Vida , Idoso , Idoso de 80 Anos ou mais , Povo Asiático/psicologia , Povo Asiático/estatística & dados numéricos , China/epidemiologia , Estudos Transversais , Feminino , Avaliação Geriátrica/métodos , Disparidades nos Níveis de Saúde , Inquéritos Epidemiológicos , Humanos , Masculino , Saúde Mental/estatística & dados numéricos , Pessoa de Meia-Idade , Exame Físico , Reprodutibilidade dos TestesRESUMO
Asthma is the chronic pulmonary inflammatory response that could lead to respiratory failure when allergic reactions exacerbate. It is featured by type 2 immunity with eosinophilic inflammation, mucus, and IgE production, and Th2 cytokine secretion upon repeated challenge of allergens. The symptom severity of asthma displays an apparent circadian rhythm with aggravated airway resistance in the early morning in patients. Bmal1 is the core regulator of the circadian clock, while the regulatory role of Bmal1 in asthma remains unclear. Here, we investigate whether the myeloid Bmal1 is involved in the pathogenesis of house dust mite (HDM)-induced lung allergy. We found that knockdown of Bmal1 in macrophages suppressed the time-of-day variance of the eosinophil infiltration in the alveolar spaces in chronic asthmatic mice. This was accompanied by decreased bronchial mucus production, collagen deposition, and HDM-specific IgE production. However, the suppression effects of myeloid Bmal1 deletion did not alter the allergic responses in short-term exposure to HDM. The transcriptome profile of alveolar macrophages (AMs) showed that Bmal1-deficient AMs have enhanced phagocytosis and reduced production of allergy-mediating prostanoids thromboxane A2 and prostaglandin F2α synthesis. The attenuated thromboxane A2 and prostaglandin F2α may lead to less induction of the eosinophil chemokine Ccl11 expression in bronchial epithelial cells. In summary, our study demonstrates that Bmal1 ablation in macrophages attenuates eosinophilic inflammation in HDM-induced chronic lung allergy, which involves enhanced phagocytosis and reduced prostanoid secretion.
Assuntos
Asma , Eosinofilia , Hipersensibilidade , Humanos , Camundongos , Animais , Pyroglyphidae , Dinoprosta/metabolismo , Tromboxano A2/metabolismo , Pulmão , Alérgenos , Eosinofilia/metabolismo , Eosinofilia/patologia , Imunoglobulina E/metabolismo , Inflamação/patologia , Modelos Animais de DoençasRESUMO
Atherosclerosis is initiated with endothelial cell (EC) dysfunction and vascular inflammation under hyperlipidemia. Sirtuin 3 (SIRT3) is a mitochondrial deacetylase. However, the specific role of endothelial SIRT3 during atherosclerosis remains poorly understood. The present study aims to study the role and mechanism of SIRT3 in EC function during atherosclerosis. Wild-type Sirt3f/f mice and endothelium-selective SIRT3 knockout Sirt3f/f; Cdh5Cre/+ (Sirt3EC-KO) mice are injected with adeno-associated virus (AAV) to overexpress PCSK9 and fed with high-cholesterol diet (HCD) for 12 weeks to induce atherosclerosis. Sirt3EC-KO mice exhibit increased atherosclerotic plaque formation, along with elevated macrophage infiltration, vascular inflammation, and reduced circulating L-arginine levels. In human ECs, SIRT3 inhibition resulted in heightened vascular inflammation, reduced nitric oxide (NO) production, increased reactive oxygen species (ROS), and diminished L-arginine levels. Silencing of SIRT3 results in hyperacetylation and deactivation of Argininosuccinate Synthase 1 (ASS1), a rate-limiting enzyme involved in L-arginine biosynthesis, and this effect is abolished in mutant ASS1. Furthermore, L-arginine supplementation attenuates enhanced plaque formation and vascular inflammation in Sirt3EC-KO mice. This study provides compelling evidence supporting the protective role of endothelial SIRT3 in atherosclerosis and also suggests a critical role of SIRT3-induced deacetylation of ASS1 by ECs for arginine synthesis.
Assuntos
Aterosclerose , Sirtuína 3 , Humanos , Camundongos , Animais , Pró-Proteína Convertase 9 , Argininossuccinato Sintase , Arginina , Endotélio , InflamaçãoRESUMO
Malus 'Pinkspire' is regulated by abscisic acid (ABA), which results in a red colour, but the regulatory relationship between ABA and anthocyanin synthesis has not been determined. The key factors affecting the colour change of M. 'Pinkspire' peel were investigated during the periods of significant colour changes during fruit ripening. The results showed that the transcription factor MpbZIP9 associated with ABA was screened by transcriptomic analysis. MpbZIP9 expression was consistent with the trend of structural genes expression for anthocyanin synthesis in the peel during fruit ripening, as well as with changes in the content of ABA, which is a positive regulator. A yeast one-hybrid assay showed that MpbZIP9 can directly bind to the promoter of MpF3'H. Dual luciferase reporter gene assays and GUS staining experiments showed that MpbZIP9 significantly activate MpF3'H expression. In addition, overexpression of the MpbZIP9 significantly enhanced anthocyanin accumulation and the expression of genes involved in anthocyanin synthesis. In contrast, virus-induced silencing of the MpbZIP9 significantly reduced the expression of structural genes involved in anthocyanin synthesis. These results suggest that the MpbZIP9 transcription factor can regulate the synthesis of peel anthocyanin and is a positive regulator that promotes anthocyanin biosynthesis by activating MpF3'H expression.
Assuntos
Malus , Malus/genética , Frutas/genética , Frutas/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Antocianinas/metabolismo , Ácido Abscísico/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Regulação da Expressão Gênica de PlantasRESUMO
BACKGROUND: Surgical treatment of complex giant pituitary adenomas (GPAs) presents significant challenges. The efficacy and safety of combining transsphenoidal and transcranial approaches for these tumors remain controversial. In this largest cohort of patients with complex GPAs, we compared the surgical outcomes between those undergoing a combined regimen and a non-combined regimen. We also examined the differences in risks of complications, costs, and logistics between the two groups, which might offer valuable information for the appropriate management of these patients. PATIENTS AND METHODS: This was a multicenter retrospective cohort study conducted at 13 neurosurgical centers. Consecutive patients who received a combined or non-combined regimen for complex GPAs were enrolled. The primary outcome was gross total resection, while secondary outcomes included complications, surgical duration, and relapse. A propensity score-based weighting method was used to account for differences between the groups. RESULTS: Out of 647 patients [298 (46.1%) women, mean age: 48.5 ± 14.0 years] with complex GPAs, 91 were in the combined group and 556 were in the noncombined group. Compared with the noncombined regimen, the combined regimen was associated with a higher probability of gross total resection [50.5% vs. 40.6%, odds ratio (OR): 2.18, 95% confidence interval (CI): 1.30-3.63, P = 0.003]. The proportion of patients with life-threatening complications was lower in the combined group than in the non-combined group (4.4% vs. 11.2%, OR: 0.25, 95% CI: 0.08-0.78, P = 0.017). No marked differences were found between the groups in terms of other surgical or endocrine-related complications. However, the combined regimen exhibited a longer average surgery duration of 1.3 h ( P < 0.001) and higher surgical costs of 22,000 CNY (~ 3,000 USD, P = 0.022) compared with the noncombined approach. CONCLUSIONS: The combined regimen offered increased rates of total resection and decreased incidence of life-threatening complications, which might be recommended as the first-line choice for these patients.
Assuntos
Adenoma , Neoplasias Hipofisárias , Humanos , Estudos Retrospectivos , Feminino , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/cirurgia , Adulto , Adenoma/cirurgia , Adenoma/patologia , Resultado do Tratamento , Estudos Longitudinais , Procedimentos Neurocirúrgicos/métodos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Pontuação de PropensãoRESUMO
BACKGROUND: Intelligence is much important for brain tumor patients after their operation, while the reports about surgical related intelligence deficits are not frequent. It is not only theoretically important but also meaningful for clinical practice. METHODS: Wechsler Adult Intelligence Scale was employed to evaluate the intelligence of 103 patients with intracranial tumor and to compare the intelligence quotient (IQ), verbal IQ (VIQ), and performance IQ (PIQ) between the intracerebral and extracerebral subgroups. RESULTS: Although preoperative intelligence deficits appeared in all subgroups, IQ, VIQ, and PIQ were not found to have any significant difference between the intracerebral and extracerebral subgroups, but with VIQ lower than PIQ in all the subgroups. An immediate postoperative follow-up demonstrated a decline of IQ and PIQ in the extracerebral subgroup, but an improvement of VIQ in the right intracerebral subgroup. Pituitary adenoma resection exerted no effect on intelligence. In addition, age, years of education, and tumor size were found to play important roles. CONCLUSIONS: Brain tumors will impair IQ, VIQ, and PIQ. The extracerebral tumor resection can deteriorate IQ and PIQ. However, right intracerebral tumor resection is beneficial to VIQ, and transsphenoidal pituitary adenoma resection performs no effect on intelligence.
Assuntos
Neoplasias Encefálicas/complicações , Deficiência Intelectual/etiologia , Inteligência , Adolescente , Adulto , Idoso , Neoplasias Encefálicas/cirurgia , Estudos de Casos e Controles , China , Feminino , Seguimentos , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos/efeitos adversos , Período Pós-Operatório , Período Pré-OperatórioRESUMO
We examined the responses of physiological and leaf anatomic structural characteristics of six Helleborus orientalis cultivars to different degrees of drought stress. A membership function was used to evaluate drought resis-tance and identify physiological and leaf anatomical indicators that exhibited a stronger correlation with drought tolerance. The results showed that leaf thickness, leaf area per unit mass and soluble protein levels of the six cultivars significantly decreased with the increases of drought stress. Net photosynthetic rate, stomatal conductance, and transpiration rate of leaves increased first and then decreased, while the intercellular CO2 concentration decreased. The relative electrical conductivity, MDA, and H2O2 contents of leaves were increased. Soluble saccharide and proline contents, and antioxidant enzyme activities were first elevated and then decreased. With the increases of drought stress, the ratio of palisade tissue thickness to sponge tissue thickness and stomatal density increased. Key indicators and relativities in evaluating drought resistance of those cultivars were proline, soluble sugars, and the ratio of palisade tissue thickness to sponge tissue thickness. H. orientalis 'Anemone Red' and H. orientalis 'Ane-mone Red spotted' had better drought resistance, which could be the excellent parental materials for the cultivation of new drought-resistant cultivars in the future.
Assuntos
Secas , Helleborus , Resistência à Seca , Helleborus/metabolismo , Peróxido de Hidrogênio , Fotossíntese/fisiologia , Folhas de Planta/fisiologia , Antioxidantes/metabolismo , Prolina , Estresse Fisiológico , Água/fisiologiaRESUMO
Purpose: We aimed to describe and predict the risk of severe hypernatremia after surgical resection of craniopharyngioma and to identify the association of water intake, urine output, and sodium level change in the patients. Method: The outcome was postoperative severe hypernatremia. We identified risk factors associated with hypernatremia using multivariable regression. We trained machine learning models to predict the outcome. We compared serum sodium change, intravenous input, oral input, total input, urine output, and net fluid balance according to different nurse shifts. Results: Among 234 included patients, 125 developed severe hypernatremia after surgery. The peak incidence occurred during day 0 and day 6 after surgery. The risk was increased in patients with gross total resection (odds ratio (OR) 2.41, P < 0.001), high Puget classification (OR 4.44, P = 0.026), preoperative adrenal insufficiency (OR 2.01, P = 0.040), and preoperative hypernatremia (OR 5.55, P < 0.001). The random forest algorithm had the highest area under the receiver operating characteristic curve (0.770, 95% CI, 0.727-0.813) in predicting the outcome and was validated in the prospective validation cohort. Overnight shifts were associated with the highest serum sodium increase (P = 0.010), less intravenous input (P < 0.001), and less desmopressin use (P < 0.001). Conclusion: The overall incidence of severe hypernatremia after surgical resection of craniopharyngioma was significant, especially in patients with gross total resection, hypothalamus distortion, preoperative adrenal insufficiency, and preoperative severe hypernatremia. Less intravenous input and less desmopressin use were associated with serum sodium increases, especially during overnight shifts.
RESUMO
In recent years, the association between microRNAs (miRNAs) and autophagy in cerebral infarction (CI) has attracted increasingly more attention. The mammalian target of the rapamycin (mTOR) pathway is a key protein regulating the autophagy response. miR-100-5p can bind to the mTOR protein, but its role in CI remains unclear yet. This experiment aims to clarify the role of miR-100-5p in CI. Bioinformatics analysis was performed to screen differentiated expressed functional genes between CI tissue and normal tissue specimens. In vivo experiments: the mouse model of CI was established by middle cerebral artery occlusion (MCAO) methods, After being treated with miR-100-5p-overexpressing lentivirus, the amount of terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL)-positive fluorescence and the fluorescent expression level of mTOR protein were significantly inhibited in the CI region. Western blotting analysis showed that miR-100-5p inhibited the protein expression level of phosphorylated mTOR and total mTOR and enhanced the expression of autophagy-related proteins Beclin, microtubule-associated protein light chain 3II (LC-3II), and autophagy-related gene 7 (ATG-7). For in vitro experiment, after the BV-2 cells were successfully infected with the control lentivirus and miR-100-5p-overexpression lentivirus, they were stimulated with 1% hypoxia and low-glucose medium in a tri-gas incubator for 24 h. It was found that miR-100-5p could significantly lower the protein expression level of phosphorylated mTOR and total mTOR, and increase the expression of the Beclin, LC-3II, ATG-7 autophagy related proteins. miR-100-5p promotes the autophagy response through binding to mTOR protein, thereby inhibiting apoptosis and delaying the progression of CI.
Assuntos
Infarto Cerebral , MicroRNAs , Animais , Camundongos , Autofagia , Serina-Treonina Quinases TOR , Apoptose , Proteínas Relacionadas à Autofagia , MamíferosRESUMO
BACKGROUND: Craniopharyngioma is a common intracranial tumor located in the sellar-suprasellar region. Due to the involvement of adjacent structures, it can lead to increased intracranial pressure, visual impairment, and endocrine deficiencies. Surgical resection is the primary treatment, but it is a tough challenge to achieve total resection, which will led to the frequency of recurrences and progressions. Among them, distant spread is extremely rare, but important complication, identifying and providing proper therapy, is crucial. METHODS: We report two cases of ectopic recurrence craniopharyngioma and make a literature review for the published similar case reports. RESULTS: Our literature review revealed 63 cases (including our patient). The onset age in children group and adult group ranges from 2-14 years old (6.70 ± 3.33) to 17-73 years old (40.63 ± 15.58), while the interval year between tumor initiation and ectopic recurrence ranges from 0.17-20 (7.28 ± 6.76) years to 0.3-34 (6.85 ± 7.29). Achieving gross total resection seems not to prevent the ectopic recurrence. The major pathology of ectopic recurrence craniopharyngioma is adamantinomatous type. The most common site of ectopic recurrence is frontal lobe. According to the pathogenesis, 35 cases were seeding along the surgical approach, and 28 cases were seeding via the CSF pathway. CONCLUSION: Ectopic recurrence craniopharyngioma is rare, but it can lead to serious symptoms. Delicate surgical procedure can help to reduce the risk of ectopic recurrence, and standardized follow-up can provide valuable information for treatment.