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1.
Commun Biol ; 4(1): 95, 2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33479483

RESUMO

GABAergic neurons of the hypothalamus regulate many innate behaviors, but little is known about the mechanisms that control their development. We previously identified hypothalamic neurons that express the LIM homeodomain transcription factor Lhx6, a master regulator of cortical interneuron development, as sleep-promoting. In contrast to telencephalic interneurons, hypothalamic Lhx6 neurons do not undergo long-distance tangential migration and do not express cortical interneuronal markers such as Pvalb. Here, we show that Lhx6 is necessary for the survival of hypothalamic neurons. Dlx1/2, Nkx2-2, and Nkx2-1 are each required for specification of spatially distinct subsets of hypothalamic Lhx6 neurons, and that Nkx2-2+/Lhx6+ neurons of the zona incerta are responsive to sleep pressure. We further identify multiple neuropeptides that are enriched in spatially segregated subsets of hypothalamic Lhx6 neurons, and that are distinct from those seen in cortical neurons. These findings identify common and divergent molecular mechanisms by which Lhx6 controls the development of GABAergic neurons in the hypothalamus.

2.
PLoS One ; 15(12): e0244457, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33382787

RESUMO

BACKGROUND: Plasmodium falciparum histidine-rich protein 2 (HRP2)-based rapid diagnostic tests (RDTs) are exclusively recommended for malaria diagnosis in Uganda; however, their functionality can be affected by parasite-related factors that have not been investigated in field settings. METHODS: Using a cross-sectional design, we analysed 219 RDT-/microscopy+ and 140 RDT+/microscopy+ dried blood spots obtained from symptomatic children aged 2-10 years from 48 districts in Uganda between 2017 and 2019. We aimed to investigate parasite-related factors contributing to false RDT results by molecular characterization of parasite isolates. ArcGIS software was used to map the geographical distribution of parasites. Statistical analysis was performed using chi-square or Fisher's exact tests, with P ≤ 0.05 indicating significance. Odds ratios (ORs) were used to assess associations, while logistic regression was performed to explore possible factors associated with false RDT results. RESULTS: The presence of parasite DNA was confirmed in 92.5% (332/359) of the blood samples. The levels of agreement between the HRP2 RDT and PCR assay results in the (RDT+/microscopy+) and (RDT-/microscopy+) sample subsets were 97.8% (137/140) and 10.9% (24/219), respectively. Factors associated with false-negative RDT results in the (RDT-/microscopy+) samples were parasite density (<1,000/µl), pfhrp2/3 gene deletion and non-P. falciparum species (aOR 2.65, 95% CI: 1.62-4.38, P = 0.001; aOR 4.4, 95% CI 1.72-13.66, P = 0.004; and aOR 18.65, 95% CI: 5.3-38.7, P = 0.001, respectively). Overall, gene deletion and non-P. falciparum species contributed to 12.3% (24/195) and 19.0% (37/195) of false-negative RDT results, respectively. Of the false-negative RDTs results, 80.0% (156/195) were from subjects with low-density infections (< 25 parasites per 200 WBCs or <1,000/µl). CONCLUSION: This is the first evaluation and report of the contributions of pfhrp2/3 gene deletion, non-P. falciparum species, and low-density infections to false-negative RDT results under field conditions in Uganda. In view of these findings, the use of HRP2 RDTs should be reconsidered; possibly, switching to combination RDTs that target alternative antigens, particularly in affected areas, may be beneficial. Future evaluations should consider larger and more representative surveys covering other regions of Uganda.

3.
Clin Exp Pediatr ; 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33147910

RESUMO

Background: Complementary food in infancy is necessary for human growth, neurodevelopment, and health. However, the role of allergen consumption in early infancy and its effects on the development of food allergy or tolerance remain unclear. Purpose: To investigate the influence of age at the time of complementary food introduction on the development of asthma and atopic dermatitis in Korean children aged 1-3 years. Methods: We combined data from the Korea National Health and Nutrition Examination Survey collected from 2010 to 2014 and analyzed 1619 children aged 1-3 years who were included in the survey. Multivariate regression analysis was used to identify associations among type of feeding, age at the time of complementary food introduction, and doctor-diagnosed AD and asthma. Results: Age at the time of complementary food introduction was not significantly associated with doctor-diagnosed atopic dermatitis and asthma in children aged 1-3 years. In the univariate analysis, children with asthma showed higher water and sodium intake levels than non-asthmatic children. However, this relationship was not significant in the multivariate regression analysis. Conclusion: The present study revealed no statistically significant relationship between age at the time of complementary food introduction and the risk of atopic dermatitis and asthma in young Korean children. A national prospective study is needed to clarify the influence of age at the time of complementary food introduction on the development of allergic diseases.

4.
Eur Radiol ; 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33185751

RESUMO

OBJECTIVES: To establish a prognostic nomogram for patients undergoing R0 resection for gallbladder cancer based on preoperative CT. METHODS: A total of 151 patients (64 males, 87 females; mean age, 73.26 years) with gallbladder cancer who underwent CT and surgery with margin-negative resection were retrospectively collected at two tertiary institutions. The demographic and radiologic parameters were analyzed using univariate and multivariate Cox regression analyses to identify independent prognostic factors. The final CT-based nomogram was constructed to predict prognosis after curative resection of gallbladder cancer. Calibration curves for the survival probabilities were obtained for internal validation. RESULTS: Mass-forming type (hazard ratio [HR], 28.80), bile duct invasion (HR, 4.76), duodenal invasion (HR, 6.32), colon invasion (HR, 4.37), gallstones (HR, 0.09), and cholecystitis (HR, 2.56) were significant independent predictors for recurrence-free survival (p < .05). Mass-forming type (HR, 8.16, p < .001), bile duct invasion (HR, 2.92, p = .013), duodenal invasion (HR, 3.72, p = .012), and regional lymph node metastasis (HR, 2.07, p = .043) were independent predictors of poor cancer-specific survival (CSS) and were used to construct the nomogram. The nomogram showed a good predictive ability for the probabilities of survival on the calibration curves, and the concordance index of the model in predicting CSS was .768. CONCLUSION: Preoperative CT findings could predict the prognosis of gallbladder cancer, and the CT-based nomogram accurately predicted CSS in patients with gallbladder cancer after attempted curative resection. KEY POINTS: • Among the preoperative imaging features, mass-forming type, bile duct invasion, duodenal invasion, and regional lymph node metastasis were independent predictors of poor cancer-specific survival. • The nomogram constructed using preoperative CT findings showed a good predictive ability for the survival on calibration curves, and the concordance index of the model in predicting cancer-specific survival was 0.768.

5.
Sci Rep ; 10(1): 15853, 2020 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-32985539

RESUMO

Perioperative anaemia increases postoperative morbidity and mortality, and iron deficiency is anaemia's most common cause in surgical patients. Preoperative intravenous iron increases postoperative haemoglobin; however, data regarding intraoperative intravenous iron's effectiveness are inadequate. This study examined intraoperative intravenous iron's effects on postoperative haemoglobin levels in adults. Fifty-seven healthy subjects (aged 19-40 years) scheduled for bimaxillary orthognathic surgery were assigned randomly to the iron (n = 28) or control (n = 29) groups. The iron group received intravenous ferric derisomaltose (1,000 mg) after anaesthetic induction. The control group received an identical volume of intravenous normal saline. The primary outcome was postoperative haemoglobin level. Secondary outcomes included other postoperative haematologic and iron parameters. Laboratory data were obtained preoperatively and at 1 day, 2 weeks, and 4 weeks postoperatively. Haemoglobin was higher in the iron group 2 weeks postoperatively (12.9 g/dL vs. 12.2 g/dL), but the between-group difference was not significant after adjustment for multiple testing. However, the reticulocyte production index was significantly higher in the iron group 2 weeks postoperatively. Intraoperative intravenous iron maintains postoperative haemoglobin values in patients undergoing bimaxillary orthognathic surgery by increasing haematopoietic function and iron bioavailability and therefore appears to be a useful strategy for blood management.

6.
J Clin Endocrinol Metab ; 105(12)2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32772088

RESUMO

CONTEXT: Crosstalk through receptor ligand interactions at the maternal-fetal interface is impacted by fetal sex. This affects placentation in the first trimester and differences in outcomes. Sexually dimorphic signaling at early stages of placentation are not defined. OBJECTIVE: Investigate the impact of fetal sex on maternal-fetal crosstalk. DESIGN: Receptors/ligands at the maternal-fetal surface were identified from sexually dimorphic genes between fetal sexes in the first trimester placenta and defined in each cell type using single-cell RNA-Sequencing (scRNA-Seq). SETTING: Academic institution. SAMPLES: Late first trimester (~10-13 weeks) placenta (fetal) and decidua (maternal) from uncomplicated ongoing pregnancies. MAIN OUTCOME MEASURES: Transcriptomic profiling at tissue and single-cell level; immunohistochemistry of select proteins. RESULTS: We identified 91 sexually dimorphic receptor-ligand pairs across the maternal-fetal interface. We examined fetal sex differences in 5 major cell types (trophoblasts, stromal cells, Hofbauer cells, antigen-presenting cells, and endothelial cells). Ligands from the CC family chemokine ligand (CCL) family were most highly representative in females, with their receptors present on the maternal surface. Sexually dimorphic trophoblast transcripts, Mucin-15 (MUC15) and notum, palmitoleoyl-protein carboxylesterase (NOTUM) were also most highly expressed in syncytiotrophoblasts and extra-villous trophoblasts respectively. Gene Ontology (GO) analysis using sexually dimorphic genes in individual cell types identified cytokine mediated signaling pathways to be most representative in female trophoblasts. Upstream analysis demonstrated TGFB1 and estradiol to affect all cell types, but dihydrotestosterone, produced by the male fetus, was an upstream regulator most significant for the trophoblast population. CONCLUSIONS: Maternal-fetal crosstalk exhibits sexual dimorphism during placentation early in gestation.

7.
Chem Asian J ; 15(19): 3059-3081, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32749069

RESUMO

Syntheses of a range of chemically well-defined oligopyrrole/benzenoid hybrids are described using tandem Suzuki-Miyaura cross-coupling/bromo-desilyation reaction sequences for linking borylated pyrroles, halogenated pyrroles and/or dibromobenzenes to one another. By such means, including iterative variants, a range of all α-linked, all ß-linked oligopyrroles as well as certain combinations thereof have been assembled, some of them for the first time. The conductivities of iodine-treated thin films formed from certain such systems have been determined.

8.
Clin Nutr Res ; 9(3): 182-194, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32789148

RESUMO

The prevalence and progression of non-alcoholic fatty liver disease (NAFLD) is mediated via several factors correlating with hepatic necroinflammation (adipokines/cytokines). This study was performed to analyze the level of inflammatory markers according to the presence of NAFLD and to identify related nutritional factors. A total of 80 adults were classified into 2 groups (healthy and NAFLD), and their body composition, blood tests, and eating habits were evaluated. In addition, inflammatory markers (adiponectin, high-sensitivity C-reactive protein [CRP], and tumor necrosis factor-alpha [TNF-α]), nutrient intake status, and dietary quality were compared. The quality of diet was assessed according to the nutrient adequacy ratio and the mean adequacy ratio (MAR). The NAFLD group had a higher body mass index (p < 0.001) than the healthy group and also carried significantly higher CRP levels (p < 0.001) but lower adiponectin (p = 0.001). TNF-α levels increased significantly with fatty liver grade (p = 0.023). The NAFLD group showed significantly higher intake of energy, carbohydrates, iron, sodium, vitamin A and saturated fatty acids, but significantly lower intake of zinc and vitamin E than the healthy group. The MAR values were slightly higher in the NAFLD group but without any significant difference. The levels of adiponectin and vitamin E showed a significant inverse correlation (p < 0.05). Nutritional management of NAFLD patients is important, and the intake of antioxidant and anti-inflammatory nutrients such as zinc and vitamin E should be emphasized.

9.
Microorganisms ; 8(9)2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32825401

RESUMO

Environmental factors can influence the composition of gut microbiota, but understanding the combined effect of lifestyle factors on adult gut microbiota is limited. Here, we investigated whether changes in the modifiable lifestyle factors, such as cigarette smoking, alcohol consumption, sleep duration, physical exercise, and body mass index affected the gut microbiota of Korean navy trainees. The navy trainees were instructed to stop smoking and alcohol consumption and follow a sleep schedule and physical exercise regime for eight weeks. For comparison, healthy Korean civilians, who had no significant change in lifestyles for eight weeks were included in this study. A total of 208 fecal samples were collected from navy trainees (n = 66) and civilians (n = 38) at baseline and week eight. Gut flora was assessed by sequencing the highly variable region of the 16S rRNA gene. The α-and ß -diversity of gut flora of both the test and control groups were not significantly changed after eight weeks. However, there was a significant difference among individuals. Smoking had a significant impact in altering α-diversity. Our study showed that a healthy lifestyle, particularly cessation of smoking, even in short periods, can affect the gut microbiome by enhancing the abundance of beneficial taxa and reducing that of harmful taxa.

10.
Malar J ; 19(1): 300, 2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32843041

RESUMO

BACKGROUND: Histidine-rich protein-2 (HRP2)-based rapid diagnostic tests (RDTs) are the only RDTs recommended for malaria diagnosis in Uganda. However, the emergence of Plasmodium falciparum histidine rich protein 2 and 3 (pfhrp2 and pfhrp3) gene deletions threatens their usefulness as malaria diagnostic and surveillance tools. The pfhrp2 and pfhrp3 gene deletions surveillance was conducted in P. falciparum parasite populations in Uganda. METHODS: Three-hundred (n = 300) P. falciparum isolates collected from cross-sectional malaria surveys in symptomatic individuals in 48 districts of eastern and western Uganda were analysed for the presence of pfhrp2 and pfhrp3 genes. Presence of parasite DNA was confirmed by PCR amplification of the 18s rRNA gene, msp1 and msp2 single copy genes. Presence or absence of deletions was confirmed by amplification of exon1 and exon2 of pfhrp2 and pfhrp3 using gene specific PCR. RESULTS: Overall, pfhrp2 and pfhrp3 gene deletions were detected in 29/300 (9.7%, 95% CI 6.6-13.6%) parasite isolates. The pfhrp2 gene was deleted in 10/300 (3.3%, 95% CI 1.6-6.0%) isolates, pfhrp3 in 9/300 (3.0%, 95% CI 1.4-5.6%) while both pfhrp2 and pfhrp3 were deleted in 10/300 (3.3%, 95% CI 1.6-6.0%) parasite isolates. Proportion of pfhrp2/3 deletions was higher in the eastern 14.7% (95% CI 9.7-20.0%) compared to the western region 3.1% (95% CI 0.8-7.7%), p = 0.001. Geographical location was associated with gene deletions aOR 6.25 (2.02-23.55), p = 0.003. CONCLUSIONS: This is the first large-scale survey reporting the presence of pfhrp2/3 gene deletions in P. falciparum isolates in Uganda. Roll out of RDTs for malaria diagnosis should take into consideration the existence of pfhrp2/3 gene deletions particularly in areas where they were detected. Periodic pfhrp2/3 surveys are recommended to inform future decisions for deployment of alternative RDTs.

11.
PLoS One ; 15(7): e0236506, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32730287

RESUMO

BACKGROUND: Few studies report the effects of tamoxifen intake and the occurrence of de novo fatty liver and the deterioration of existing fatty liver. The aim of this study was to investigate the effects of tamoxifen on fatty change of liver over time and also the impact of fatty liver on the prognosis of patients with breast cancer. METHODS: This was a single-center, retrospective study of patients who were diagnosed with primary breast cancer from January 2007 to July 2017. 911 consecutive patients were classified into three groups according to treatment method: tamoxifen group, aromatase inhibitor (AI) group, and control group. RESULTS: Median treatment duration was 49 months (interquartile range, IQR; 32-58) and median observational period was 85 months (IQR; 50-118). Long-term use of tamoxifen significantly aggravated fatty liver status compared to AI or control groups [hazard ratio (HR): 1.598, 95% confidence interval (CI): 1.173-2.177, P = 0.003] after adjusting other factors. When analyzed separately depending on pre-existing fatty liver at baseline, tamoxifen was involved in the development of de novo fatty liver [HR: 1.519, 95% CI: 1.100-2.098, P = 0.011) and had greater effect on fatty liver worsening (HR: 2.103, 95% CI: 1.156-3.826, P = 0.015). However, the progression of fatty liver did not significantly affect the mortality of breast cancer patients. CONCLUSIONS: Tamoxifen had a significant effect on the fatty liver status compared to other treatment modalities in breast cancer patients. Although fatty liver did not affect the prognosis of breast cancer, meticulous attention to cardiovascular disease or other metabolic disease should be paid when used for a long time.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Fígado Gorduroso/diagnóstico , Tamoxifeno/efeitos adversos , Adulto , Antineoplásicos Hormonais/efeitos adversos , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Duração da Terapia , Fígado Gorduroso/etiologia , Fígado Gorduroso/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pontuação de Propensão , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Taxa de Sobrevida , Tamoxifeno/uso terapêutico
12.
Proc Natl Acad Sci U S A ; 117(29): 17142-17150, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32636256

RESUMO

Gut microbes play diverse roles in modulating host fitness, including longevity; however, the molecular mechanisms underlying their mediation of longevity remain poorly understood. We performed genome-wide screens using 3,792 Escherichia coli mutants and identified 44 E. coli mutants that modulated Caenorhabditis elegans longevity. Three of these mutants modulated C. elegans longevity via the bacterial metabolite methylglyoxal (MG). Importantly, we found that low MG-producing E. coli mutants, Δhns E. coli, extended the lifespan of C. elegans through activation of the DAF-16/FOXO family transcription factor and the mitochondrial unfolded protein response (UPRmt). Interestingly, the lifespan modulation by Δhns did not require insulin/insulin-like growth factor 1 signaling (IIS) but did require TORC2/SGK-1 signaling. Transcriptome analysis revealed that Δhns E. coli activated novel class 3 DAF-16 target genes that were distinct from those regulated by IIS. Taken together, our data suggest that bacteria-derived MG modulates host longevity through regulation of the host signaling pathways rather than through nonspecific damage on biomolecules known as advanced glycation end products. Finally, we demonstrate that MG enhances the phosphorylation of hSGK1 and accelerates cellular senescence in human dermal fibroblasts, suggesting the conserved role of MG in controlling longevity across species. Together, our studies demonstrate that bacteria-derived MG is a novel therapeutic target for aging and aging-associated pathophysiology.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans , Fatores de Transcrição Forkhead/metabolismo , Longevidade/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Aldeído Pirúvico , Animais , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/microbiologia , Escherichia coli/metabolismo , Microbioma Gastrointestinal/fisiologia , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Modelos Biológicos , Aldeído Pirúvico/metabolismo , Aldeído Pirúvico/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transcriptoma/genética
13.
Cell Syst ; 11(2): 186-195.e9, 2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32710834

RESUMO

Cancer is driven by genomic alterations, but the processes causing this disease are largely performed by proteins. However, proteins are harder and more expensive to measure than genes and transcripts. To catalyze developments of methods to infer protein levels from other omics measurements, we leveraged crowdsourcing via the NCI-CPTAC DREAM proteogenomic challenge. We asked for methods to predict protein and phosphorylation levels from genomic and transcriptomic data in cancer patients. The best performance was achieved by an ensemble of models, including as predictors transcript level of the corresponding genes, interaction between genes, conservation across tumor types, and phosphosite proximity for phosphorylation prediction. Proteins from metabolic pathways and complexes were the best and worst predicted, respectively. The performance of even the best-performing model was modest, suggesting that many proteins are strongly regulated through translational control and degradation. Our results set a reference for the limitations of computational inference in proteogenomics. A record of this paper's transparent peer review process is included in the Supplemental Information.

14.
Nutrients ; 12(7)2020 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-32605036

RESUMO

After a gastrectomy, the nutritional status of patients with gastric cancer has great effect on the treatment outcome and patients' quality of life. We investigated the changes in body composition and nutrient intake after gastrectomy in 288 gastric cancer patients. A multiple linear regression analysis was used for each time period to verify the effects of nutritional and clinical factors on weight and fat-free mass loss rates. Gastric cancer patients who underwent a gastrectomy continued to experience weight and fat-free mass loss until three months after surgery and became stagnant at six months. The marginal mean of calorie intake per weight was 24.5, 26.8, and 29.4 kcal at one, three, and six months. The protein intake per kg lean mass was 1.14, 1.14, and 1.16 g at one, three, and six months, respectively. One month after surgery, the rate of weight loss increased significantly in females who received chemotherapy (p < 0.001). At one to three months postoperative, females who had undergone chemotherapy tended to significantly lose weight (p = 0.016). Females with a history of chemotherapy also showed a reduction in fat-free mass for one to three months (p = 0.036). Calorie intake was a significant factor in preventing fat-free mass weight loss at one month after surgery. Chemotherapy was an independent factor affecting the weight and fat-free mass loss rate up to six months after gastrectomy. Careful monitoring of weight and muscle mass changes following active nutritional intervention for sufficient nutrition support could be helpful for patients after gastrectomy.

15.
Obstet Gynecol Sci ; 63(3): 278-285, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32489972

RESUMO

Objective: To prove the efficacy of determining the abnormal fetal cardiac axis for screening congenital heart defects (CHDs) and predicting fetal aneuploidy at 11.0 to 13.6 weeks of pregnancy. Methods: This retrospective study was performed at a single high-risk pregnancy center. The fetal cardiac axis was evaluated between 11.0 and 13.6 weeks of gestation in 142 fetuses. The cardiac axis in a 4-chamber view was measured as the angle between the line tracing the long axis of the heart and the line bisecting the thorax in the anteroposterior direction. A CHD was confirmed based on the second- to third-trimester fetal status or postnatal imaging. Aneuploidy was diagnosed using chorionic villus sampling, amniocentesis, or genetic testing after birth. Fisher's exact test was performed to assess the association between the fetal cardiac axis and the abnormal fetal status. A 2-way contingence table analysis was performed to confirm the efficacy of the fetal cardiac axis as a screening tool. Results: Among the 142 fetuses, 10 had a CHD while 17 had aneuploidy. The abnormal fetal cardiac axis was significantly associated with CHDs (P=0.013) and aneuploidy (P=0.010). None of the fetuses with CHDs or aneuploidy had an isolated abnormal cardiac axis alone without other sonographic findings. The sensitivity of the fetal cardiac axis was 50.0% for CHDs and 41.2% for aneuploidy. Conclusion: The fetal cardiac axis can be an additional helpful tool for prenatal screening of CHDs and aneuploidy in the first trimester.

16.
Autophagy ; : 1-18, 2020 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-32579471

RESUMO

The uterus undergoes vascular changes during the reproductive cycle and pregnancy. Steroid hormone deprivation induces macroautophagy/autophagy in major uterine cell types. Herein, we explored the functions of uterine autophagy using the Amhr2-Cre-driven atg7 deletion model. Deletion of Atg7 was confirmed by functional deficit of autophagy in uterine stromal, myometrial, and vascular smooth muscle cells, but not in endothelial cells. atg7d/d uteri exhibited enhanced stromal edema accompanied by dilation of blood vessels. Ovariectomized atg7d/d uteri showed decreased expression of endothelial junction-related proteins, such as CTNNB1/beta-catenin, with increased vascular permeability, and increased expression of VEGFA and NOS1. Nitric oxide (NO) was shown to mediate VEGFA-induced vascular permeability by targeting CTNNB1. NO involvement in maintaining endothelial junctional stability in atg7d/d uteri was confirmed by the reduction in extravasation following treatment with a NOS inhibitor. We also showed that atg7d/d uterine phenotype improved the fetal weight:placental weight ratio, which is one of the indicators of assessing the status of preeclampsia. We showed that autophagic deficit in the uterine vessel microenvironment provokes hyperpermeability through the deregulation of VEGFA, NOS1, and CTNNB1. ABBREVIATIONS: ACTA2: actin, alpha 2, smooth muscle, aortic; Amhr2: anti-Mullerian hormone type 2 receptor; ANGPT1: angiopoietin 1; ATG: autophagy-related; CDH5: cadherin 5; CLDN5: claudin 5; COL1A1: collagen, type I, alpha 1; CSPG4/NG2: chondroitin sulfate proteoglycan 4; CTNNB1: catenin (cadherin associated protein), beta 1; DES: desmin; EDN1: endothelin 1; EDNRB: endothelin receptor type B; F3: coagulation factor III; KDR/FLK1/VEGFR2: kinase insert domain protein receptor; LYVE1: lymphatic vessel endothelial hyaluronan receptor 1; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MCAM/CD146: melanoma cell adhesion molecule; MYL2: myosin, light polypeptide 2, regulatory, cardiac, slow; MYLK: myosin, light polypeptide kinase; NOS1/nNOS: nitric oxide synthase 1, neuronal; NOS2/iNOS: nitric oxide synthase 2, inducible; NOS3/eNOS: nitric oxide synthase 3, endothelial cell; OVX: ovariectomy; PECAM1/CD31: platelet/endothelial cell adhesion molecule 1; POSTN: periostin, osteoblast specific factor; SQSTM1: sequestosome 1; TEK/Tie2: TEK receptor tyrosine kinase; TJP1/ZO-1: tight junction protein 1; TUBB1, tubulin, beta 1 class VI; USC: uterine stromal cell; VEGFA: vascular endothelial growth factor A; VSMC: vascular smooth muscle cell.

17.
J Cachexia Sarcopenia Muscle ; 11(5): 1336-1350, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32495509

RESUMO

BACKGROUND: The microRNAs (miRNAs) down-regulated in aged mouse skeletal muscle were mainly clustered within the delta-like homologue 1 and the type III iodothyronine deiodinase (Dlk1-Dio3) genomic region. Although clustered miRNAs are coexpressed and regulate multiple targets in a specific signalling pathway, the function of miRNAs in the Dlk1-Dio3 cluster in muscle aging is largely unknown. We aimed to ascertain whether these miRNAs play a common role to regulate age-related muscle atrophy. METHODS: To examine anti-atrophic effect of miRNAs, we individually transfected 42 miRNA mimics in fully differentiated myotubes and analysed their diameters. The luciferase reporter assay using target 3' untranslated region (UTR) and RNA pull-down assay were employed to ascertain the target predicted by the TargetScan algorithm. To investigate the therapeutic potential of the miRNAs in vivo, we generated adeno-associated virus (AAV) serotype 9 expressing green fluorescent protein (GFP) (AAV9-GFP) bearing miR-376c-3p and infected it into the tibialis anterior muscle of old mice. We performed morphometric analysis and measured ex vivo isometric force using a force transducer. Human gluteus maximus muscle tissues (ages ranging from 25 to 80 years) were used to investigate expression levels of the conserved miRNAs in the Dlk1-Dio3 cluster. RESULTS: We found that the majority of miRNAs (33 out of 42 tested) in the cluster induced anti-atrophic phenotypes in fully differentiated myotubes with increasing their diameters. Eighteen of these miRNAs, eight of which are conserved in humans, harboured predicted binding sites in the 3' UTR of muscle atrophy gene-1 (Atrogin-1) encoding a muscle-specific E3 ligase. Direct interactions were identified between these miRNAs and the 3' UTR of Atrogin-1, leading to repression of Atrogin-1 and thereby induction of eIF3f protein content, in both human and mouse skeletal muscle cells. Intramuscular delivery of AAV9 expressing miR-376c-3p, one of the most effective miRNAs in myotube thickening, dramatically ameliorated skeletal muscle atrophy and improved muscle function, including isometric force, twitch force, and fatigue resistance in old mice. Consistent with our findings in mice, the expression of miRNAs in the cluster was significantly down-regulated in human muscle from individuals > 50 years old. CONCLUSIONS: Our study suggests that genetic intervention using a muscle-directed miRNA delivery system has therapeutic efficacy in preventing Atrogin-1-mediated muscle atrophy in sarcopenia.

18.
Nutrients ; 12(6)2020 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-32545878

RESUMO

Although bariatric surgery is the best treatment modality for morbidly obese patients, a 10-30% rate of weight recidivism has been reported in various specialized centers. We examined changes in energy and macronutrients after bariatric surgery and performed analysis to establish appropriate nutritional guidelines for reaching the target percentage of weight loss after surgery. A total of 189 subjects who underwent bariatric surgery were classified into success and failure groups depending on whether or not they reached 50% loss of excess weight at 12 months after bariatric surgery. Physical examinations and dietary surveys were completed before and 1, 6, and 12 months after surgery. Using receiver operating characteristic (ROC) analysis, the optimal cutoff points for nutrient intakes for determining success after bariatric surgery were computed based on maximal Youden's index. At 6 and 12 months after surgery, the success group had significantly lower carbohydrate and fat intakes than the failure group. The cutoff calorie intake for success in weight loss was <835.0, <1132.5, and <1523.0 kcal/day at 1, 6, and 12 months post operation, respectively. With regard to protein, the cutoff intakes were >44.5, >41.5, and >86.5 g/day at 1, 6, and 12 months post operation, respectively. At 12 months, the cutoff ratio for energy obtained from carbohydrates, protein, and fat was <49.0, >24.5, and <28.0%, respectively. Our findings confirm that the level of diet control and nutrition restriction affect the achievement of target weight loss, emphasizing that long-term weight loss is related to compliance with nutrient recommendations.

19.
Harmful Algae ; 96: 101820, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32560838

RESUMO

Species belonging to the toxic dinoflagellate genus Ostreopsis are widespread, occurring from tropical to temperate waters. As mainly benthic/epiphytic species, they would be expected to show distinct geographical patterns. In this study, ribosomal DNA (rDNA) sequences from partial nuclear LSU D8-D10, 5.8S, and ITS regions were determined for 169 isolates of Ostreopsis species collected from three coastal sites (i.e., Jeju Island, Chuja Island, and Pohang) within Korea. The phylogenetic tree inferred from the LSU rDNA D8-D10 sequences showed that Korean Ostreopsis species corresponded to either Ostreopsis sp. 1 or sp. 6, with Ostreopsis sp. 1 being relatively predominant regarding their distribution. While Ostreopsis sp. 1 occurred throughout all the three sampling sites within Korea, Ostreopsis sp. 6 was confined to the northern part of Jeju Island. When further investigated, the genetic diversity of Ostreopsis sp. 1 in Korea based on ITS sequences showed a total of 21 haplotypes. The presumed ancestral haplotype H3, was also present in the Japanese and Russian populations of Ostreopsis sp. 1. Although the overall demographic history of all the Korean populations of Ostreopsis sp. 1 could not be clearly identified, probably due to a mixture of different regional demographic patterns within Korea, each Ostreopsis sp. 1 population showed a characteristic demographic pattern at a regional scale. While the Jeju Island Ostreopsis sp. 1 population showed a signal in agreement with population equilibrium, the Chuja Island and Pohang Ostreopsis sp. 1 populations showed distribution patterns that are expected in a sudden population expansion model. The results from this study provide a basis for a better understanding of the distribution and genetic structure of the Asian Ostreopsis sp. 1 populations.

20.
Clin Nutr Res ; 9(2): 90-96, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32395439

RESUMO

Calcium intake is essential for bone health, but young Korean women have low calcium intakes. Seaweeds have high calcium content, which may affect calcium metabolism. Twenty nine females aged 18-39 years with low calcium intake (< 400 mg/day) participated in a 19-day open-label randomized controlled trial. During the first five days, participants adhered to a controlled-feeding protocol followed by a two-week supplementation period in free-living conditions. The treatment group (n = 14) received an additional 200 mg Ca/day through Undaria pinnatifida and Porphyra in meals during the controlled-feeding period, and as U. pinnatifida noodles during days 6-19. Mineral intake (Ca, P, Mg, Na, and K) was assessed from diet composites and three 24-hour recalls during the controlled-feeding and free-living periods, respectively. Fasting serum levels of calcium, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D (1,25[OH]D), phosphorus, parathyroid hormone (PTH), and alkaline phosphatase (ALP) were assessed at baseline, day 6, and day 19. Statistical analyses were performed by Student's t-test and mixed ANOVA. Mean intakes of all minerals during days 1-5 and mean Ca and Mg intakes during days 6-19 were greater in the treatment group compared to the control group. No group effect or group and time interaction was observed in serum biomarkers. Serum 1,25(OH)D increased while PTH and ALP tended to decrease on day 6 but returned to baseline values on day 20. Short-term intake of U. pinnatifida and Porphyra does not affect calcium metabolism in young Korean women with low calcium intakes. Trial Registration: Clinical Research Information Service Identifier: KCT0003307.

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