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1.
Sci Rep ; 11(1): 19476, 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34593925

RESUMO

Variant prioritization of exome sequencing (ES) data for molecular diagnosis of sensorineural hearing loss (SNHL) with extreme etiologic heterogeneity poses a significant challenge. This study used an automated variant prioritization system ("EVIDENCE") to analyze SNHL patient data and assess its diagnostic accuracy. We performed ES of 263 probands manifesting mild to moderate or higher degrees of SNHL. Candidate variants were classified according to the 2015 American College of Medical Genetics guidelines, and we compared the accuracy, call rates, and efficiency of variant prioritizations performed manually by humans or using EVIDENCE. In our in silico panel, 21 synthetic cases were successfully analyzed by EVIDENCE. In our cohort, the ES diagnostic yield for SNHL by manual analysis was 50.19% (132/263) and 50.95% (134/263) by EVIDENCE. EVIDENCE processed ES data 24-fold faster than humans, and the concordant call rate between humans and EVIDENCE was 97.72% (257/263). Additionally, EVIDENCE outperformed human accuracy, especially at discovering causative variants of rare syndromic deafness, whereas flexible interpretations that required predefined specific genotype-phenotype correlations were possible only by manual prioritization. The automated variant prioritization system remarkably facilitated the molecular diagnosis of hearing loss with high accuracy and efficiency, fostering the popularization of molecular genetic diagnosis of SNHL.

3.
Cereb Cortex ; 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34613359

RESUMO

Medial prefrontal cortex (MPFC) and other regions like the occipital cortex (OC) exhibit abnormal neural activity in major depressive disorder (MDD). Their relationship to specific biochemical, psychophysical, and psychopathological changes remains unclear, though. For that purpose, we focus on a particular subregion in OC, namely middle temporal (MT) visual area that is known to mediate the perception of visual motion. Using high-field 7 T magnetic resonance imaging (MRI), including resting state functional MRI and proton magnetic resonance spectroscopy, the amplitude of low-frequency fluctuations (ALFF) of the blood oxygen level-dependent signal in MT, MT-seeded functional connectivity (FC), and gamma-aminobutyric acid (GABA) in MT were investigated. Applying the vision motion psychophysical task, the motion suppression index of subjects was also examined. We demonstrate significantly elevated neural variability (as measured by ALFF) in MT together with decreases in both MT GABA and motion suppression in our MDD sample. Unlike in healthy subjects, MT neural variability no longer modulates the relationship of MT GABA and motion suppression in MDD. MT also exhibits reduction in global inter-regional FC to MPFC in MDD. Finally, elevated MT ALFF relates to specifically retardation in behavior as measured by the Hamilton subscore. Together, MT provides a strong candidate for biomarker in MDD.

4.
EMBO Rep ; : e52728, 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34605607

RESUMO

During central nervous system development, neurogenesis and gliogenesis occur in an orderly manner to create precise neural circuitry. However, no systematic dataset of neural lineage development that covers both neurogenesis and gliogenesis for the human spinal cord is available. We here perform single-cell RNA sequencing of human spinal cord cells during embryonic and fetal stages that cover neuron generation as well as astrocytes and oligodendrocyte differentiation. We also map the timeline of sensory neurogenesis and gliogenesis in the spinal cord. We further identify a group of EGFR-expressing transitional glial cells with radial morphology at the onset of gliogenesis, which progressively acquires differentiated glial cell characteristics. These EGFR-expressing transitional glial cells exhibited a unique position-specific feature during spinal cord development. Cell crosstalk analysis using CellPhoneDB indicated that EGFR glial cells can persistently interact with other neural cells during development through Delta-Notch and EGFR signaling. Together, our results reveal stage-specific profiles and dynamics of neural cells during human spinal cord development.

5.
Assessment ; : 10731911211051281, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34643095

RESUMO

Early maladaptive schemas (EMSs) are proposed to be maladaptive ways of thinking and feeling that develop from adverse experiences and basic needs not being met in childhood or adolescence. Once developed, EMSs increase vulnerability to psychopathology. Psychometric evaluations of EMS measures in children are scarce. This study aimed to evaluate the psychometric properties of the English version of the Schema Inventory for Children (SIC) in a community sample of youth aged 8 to 13 years. The SIC and measures of positive and negative automatic thoughts, social phobia symptoms, and depressed mood were administered to participants. Although a correlated 11-factor model was expected for the SIC, the optimal factor structure was a correlated six-factor model. EMS subscales corresponding to these six factors had acceptable internal consistency, and they had positive associations with the measures of negative automatic thoughts, social phobia symptoms, and depressive mood, as well as negative associations with the measure of positive automatic thoughts. These results indicate that EMSs in children may not be as differentiated as they are in adults. The results provide evidence for the reliability and validity of the English version of the SIC, justifying its use in contexts requiring the assessment of EMSs in children.

6.
Sci Rep ; 11(1): 19171, 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34580346

RESUMO

Autoimmune and autoinflammatory inner ear diseases (AIED/AID) are characterized by the symptom of sensorineural hearing loss (SNHL). To date, standardized diagnostic tools for AIED/AID are lacking, and clinically differentiating AIED/AID from chronic otitis media (COM) with SNHL is challenging. This retrospective study aimed to construct a magnetic resonance imaging (MRI)-based decision tree using classification and regression tree (CART) analysis to distinguish AIED/AID from COM. In total, 67 patients were enrolled between January 2004 and October 2019, comprising AIED/AID (n = 18), COM (n = 24), and control groups (n = 25). All patients underwent 3 T temporal bone MRI, including post-contrast T1-weighted images (postT1WI) and post-contrast FLAIR images (postFLAIR). Two radiologists evaluated the presence of otomastoid effusion and inner ear contrast-enhancement on MRI. A CART decision tree model was constructed using MRI features to differentiate AIED/AID from COM and control groups, and diagnostic performance was analyzed. High-intensity bilateral effusion (61.1%) and inner ear enhancement (postFLAIR, 93.8%; postT1WI, 61.1%) were the most common findings in the AIED/AID group. We constructed two CART decision tree models; the first used effusion amount as the first partitioning node and postT1WI-inner ear enhancement as the second node, whereas the second comprised two partitioning nodes with the degree of postFLAIR-enhancement of the inner ear. The first and second models enabled distinction of AIED/AID from COM with high specificity (100% and 94.3%, respectively). The amount of effusion and the degree of inner ear enhancement on MRI may facilitate the distinction between AIED/AID and COM with SNHL using decision tree models, thereby contributing to early diagnosis and intervention.

7.
Eur J Cancer Prev ; 2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34519691

RESUMO

Consensus remains lack regarding whether sleep-disordered breathing (SDB) is an independent risk factor for lung cancer. We therefore conducted a meta-analysis to clarify the relationship of SDB and lung cancer. Longitudinal follow-up studies investigating the association between SDB and incidence of lung cancer were included by search of electronic databases including PubMed, Embase, and Cochrane's Library. A random-effects model was adopted to combine the results. Seven studies were included. Pooled results showed that presence of SDB was independently associated with higher incidence of lung cancer [adjusted risk ratio (RR): 1.28; 95% confidence interval (CI), 1.11-1.47; P < 0.001; I2 = 37%]. Sensitivity analysis limited to studies with adjustment of smoking showed consistent results (three studies, RR: 1.34; 95% CI, 1.22-1.48; P < 0.001; I2 = 8%). Subgroup analysis suggested that the association between SDB and higher risk of lung cancer was not significantly affected by study characteristics such as study design, source of population, sample size, evaluation methods for SDB, follow-up duration, methods for validation of lung cancer, or score of study quality (P values for subgroup difference all >0.05). No significant publication bias was observed (P for Egger's regression test = 0.258). These results suggested that SDB may be an independent risk factor of lung cancer in adult population. Intensive screening and prevention of lung cancer in subjects with SDB should be considered.

8.
Pflugers Arch ; 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34553266

RESUMO

Cereblon (CRBN) is a substrate recognition protein in the E3-ligase ubiquitin complex. The binding target of CRBN varies according to tissues and cells, and the protein regulates various biological functions by regulating tissue-specific targets. As new endogenous targets of CRBN have been identified over the past decade, the physiological and pathological functions of CRBN and its potential as a therapeutic target in various diseases have greatly expanded. For this purpose, in this review article, we introduce the basic principle of the ubiquitin-proteasome system, the regulation of physiological/pathological functions related to the endogenous substrate of CRBN, and the discovery of immunomodulatory imide drug-mediated neo-substrates of CRBN. In addition, the development of CRBN-based proteolysis-targeting chimeras, which has been actively researched recently, and strategies for developing therapeutic agents using them are introduced. These recent updates on CRBN will be useful in the establishment of strategies for disease treatment and utilization of CRBNs in biomedical engineering and clinical medicine.

9.
Circ Cardiovasc Qual Outcomes ; : CIRCOUTCOMES121007956, 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34555929

RESUMO

BACKGROUND: We conducted a secondary analysis of changes in the Kansas City Cardiomyopathy Questionnaire (KCCQ)-12 over 30 days in a randomized trial of self-care coaching versus structured usual care in patients with acute heart failure who were discharged from the emergency department. METHODS: Patients in 15 emergency departments completed the KCCQ-12 at emergency department discharge and at 30 days. We compared change in KCCQ-12 scores between the intervention and usual care arms, adjusted for enrollment KCCQ-12 and demographic characteristics. We used linear regression to describe changes in KCCQ-12 summary scores and logistic regression to characterize clinically meaningful KCCQ-12 subdomain changes at 30 days. RESULTS: There were 350 patients with both enrollment and 30-day KCCQ summary scores available; 166 allocated to usual care and 184 to the intervention arm. Median age was 64 years (interquartile range, 55-70), 37% were female participants, 63% were Black, median KCCQ-12 summary score at enrollment was 47 (interquartile range, 33-64). Self-care coaching resulted in significantly greater improvement in health status compared with structured usual care (5.4-point greater improvement, 95% CI, 1.12-9.68; P=0.01). Improvements in health status in the intervention arm were driven by improvements within the symptom frequency (adjusted odds ratio, 1.62 [95% CI, 1.01-2.59]) and quality of life (adjusted odds ratio, 2.39 [95% CI, 1.46-3.90]) subdomains. CONCLUSIONS: In this secondary analysis, patients with acute heart failure who received a tailored, self-care intervention after emergency department discharge had clinically significant improvements in health status at 30 days compared with structured usual care largely due to improvements within the symptom frequency and quality of life subdomains of the KCCQ-12. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02519283.

10.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(9): 900-906, 2021 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-34487541

RESUMO

OBJECTIVE: To investigate the application value of whole exome sequencing technology in fetuses with congenital structural abnormalities. METHODS: The chromosomal abnormalities of 1147 families were analyzed. According to the follow-up results, the data of fetuses with new phenotypes in late pregnancy or after birth were reanalyzed. Subgroups were divided according to the organs involved and whether single malformation or not. The gene regulatory network map was drawn by using string database and Cytoscape software. Fisher exact probability method was used to compare the difference of the diagnostic rate of pathogenic genes among the groups. RESULTS: A total of 160 fetal cases received positive molecular diagnosed, involving 178 variant sites of 125 pathogenic genes, including 8 cases (4.9%, 8/163) by data reanalysis, and the overall positive diagnosis rate was 13.9%. Diagnostic rate was highest in the group of skeletal malformation (31.5%, 39/124) and lowest in that with thoracic malformation (0, 0/32). The gene clusters of fetal edema and intrauterine growth restriction were independent, and were not associated with the major structural malformations. The probability of each parent carrying the same recessive gene variant was 0.03 (39/1146) and 0.08 (4/53) with positive family history. CONCLUSION: For fetuses with congenital structural abnormalities that are negative for conventional genetic tests, 13.9% of phenotypic associated pathogenic/likely pathogenic genetic variants can be detected by whole exome sequencing technology. Its application value for prenatal diagnosis varies in fetus with different organs involved. Reanalysis of sequencing data for cases with new phenotypes in late pregnancy or after birth can further improve the molecular diagnosis rate. Further investigations are needed to explore the related genetic mechanisms.


Assuntos
Doenças Fetais , Feto , Feminino , Feto/diagnóstico por imagem , Humanos , Gravidez , Diagnóstico Pré-Natal , Tecnologia , Ultrassonografia Pré-Natal , Sequenciamento Completo do Exoma
11.
Stem Cell Res ; 56: 102524, 2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34481189

RESUMO

Alpha-smooth muscle actin (α-SMA) is encoded by ACTA2 and is a key protein in the cellular contractile system of various mesodermal cell types, including hepatic stellate cells (HSCs), smooth muscle cells, and cardiomyocytes. α-SMA, which is a key protein in the development of hepatic fibrosis, is widely used as a reliable marker of HSC activation. Here, we generated an ACTA2-EGFP reporter human induced pluripotent stem cell line, KITi001-C-41, using a CRISPR/Cas9-based knock-in system. These reporter hiPSC lines can be used for lineage tracing of mesodermal cells and for screening of HSC activation factors.

12.
Immunol Invest ; : 1-15, 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34490837

RESUMO

BACKGROUND: Peritoneal fibrosis (PF) can reduce the efficiency of peritoneal dialysis and eventually lead to ultrafiltration failure. Epithelial-mesenchymal transition (EMT) of peritoneal mesothelial cells (PMCs) is the start of PF. Macrophages are involved in the process. This study was to investigate the effect of macrophage polarization on EMT of PMCs. METHODS: Monocyte-macrophage cells (THP-1) were treated to induce macrophage subsets (M1, M2a, M2c). The inducing was assessed by detecting protein and mRNA expression of cytokines using ELISA and RT-PCR. Subsequently, PMCs were co-cultured with M1, M2a and M2c, respectively, in Transwell chambers for 48 h and then expressions of E-cadherin and α-SMA were determined in PMCs. The PMCs that were not co-cultured with macrophages served as control PMCs. One-way ANOVA and SNK-q test were used to conduct statistics and P < .05 as significant. RESULTS: Detection of the cytokines, including IL-6, IL-10, IL-12, TGF-ß1, CCL17 and CXCL13, verified that the inducting of macrophage subtypes was successful. Compared to control, E-cadherin protein expression was significantly decreased and α-SMA protein expression increased in M1-treated PMCs (P < .05); M2a-treated PMCs had an increased gene expression of α-SMA (P < .05); E-cadherin protein and gene expression were decreased and α-SMA protein and gene expression increased significantly in M2c-treated PMCs (P < .05 or P < .01). CONCLUSIONS: EMT of PMCs is enhanced by M2c macrophage polarization; meanwhile, M1 and M2a polarization may have the effect to some extent, but not as definite as M2c.

13.
Phytomedicine ; 91: 153674, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34333327

RESUMO

BACKGROUND: Physciosporin (PHY) is one of the potent anticancer lichen compound. Recently, PHY was shown to suppress colorectal cancer cell proliferation, motility, and tumorigenesis through novel mechanisms of action. PURPOSE: We investigated the effects of PHY on energy metabolism and tumorigenicity of the human breast cancer (BC) cells MCF-7 (estrogen and progesterone positive BC) and MDA-MB-231 (triple negative BC). METHODS: The anticancer effect of PHY on cell viability, motility, cancer metabolism and tumorigenicity was evaluated by MTT assay, migration assay, clonogenic assay, anchorage-independent colony formation assay, glycolytic and mitochondrial metabolism analysis, qRT-PCR, flow cytometric analysis, Western blotting, immunohistochemistry in vitro; and by tumorigenicity study with orthotopic breast cancer xenograft model in vivo. RESULTS: PHY markedly inhibited BC cell viability. Cell-cycle profiling and Annexin V-FITC/PI double staining showed that a toxic dosage of PHY triggered apoptosis in BC cell lines by regulating the B-cell lymphoma-2 (Bcl-2) family proteins and the activity of caspase pathway. At non-toxic concentrations, PHY potently decreased migration, proliferation, and tumorigenesis of BC cells in vitro. Metabolic studies revealed that PHY treatment significantly reduced the bioenergetic profile by decreasing respiration, ATP production, and glycolysis capacity. In addition, PHY significantly altered the levels of mitochondrial (PGC-1α) and glycolysis (GLUT1, HK2 and PKM2) markers, and downregulated transcriptional regulators involved in cancer cell metabolism, including ß-catenin, c-Myc, HIF-1α, and NF-κB. An orthotopic implantation mouse model of BC confirmed that PHY treatment suppressed BC growth in vivo and target genes were consistently suppressed in tumor specimens. CONCLUSION: The findings from our in vitro as well as in vivo studies exhibit that PHY suppresses energy metabolism as well as tumorigenesis in BC. Especially, PHY represents a promising therapeutic effect against hormone-insensitive BC (triple negative) by targeting energy metabolism.


Assuntos
Neoplasias da Mama , Oxepinas/farmacologia , Neoplasias de Mama Triplo Negativas , Animais , Apoptose , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica , Feminino , Glicólise , Humanos , Camundongos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
14.
Phytomedicine ; 91: 153690, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34438229

RESUMO

BACKGROUND: Cortex Phellodendri amurensis (CPA) has high medicinal value in the treatment of kidney-yin deficiency diseases. However, due to the lack of research on the therapeutic material basis of CPA, the current quality control standard for CPA is defective, and the effect of the nourishing kidney-yin of CPA was limited. PURPOSE: Based on the principle of correspondence between the syndrome and prescriptions, we studied the CPA in ZhibaiDihuang pill (ZBDH) to identify quality markers (Q-markers) of CPA in ZBDH for treating kidney-yin deficiency and seek the potential Q-markers of CPA under nourishing kidney-yin effect combined with the analysis of single CPA. METHODS: Taking Chinmedomics as the core strategy, metabonomics analysis and effective component identification were performed by UPLC-MS. RESULTS: A total of 121 chemical components of ZBDH were identified, among which the contents of berberine, palmatine, jatrorrhizine and magnoflorine changed the most obviously with the addition of CPA. Forty-five components were identified in the blood in the markedly effective state, including berberine, palmatine, jatrorrhizine and magnoflorine. The therapeutic material basis of ZBDH in the treatment of kidney-yin deficiency was found, and 6 components were found to derive from CPA, including magnoflorine and jatrorrhizine. In addition, seventeen components were identified in the blood in the single CPA treatment, including berberine, palmatine, jatrorrhizine and magnoflorine. CONCLUSIONS: Magnoflorine and jatrorrhizine were the Q-markers of CPA for treating kidney-yin deficiency in the formula of ZBDH and they were also potential Q-markers of the nourishing kidney-yin of CPA.


Assuntos
Medicamentos de Ervas Chinesas , Rim/efeitos dos fármacos , Phellodendron/química , Animais , Cromatografia Líquida , Medicamentos de Ervas Chinesas/farmacologia , Masculino , Metabolômica , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem
15.
Sensors (Basel) ; 21(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34372469

RESUMO

Sea fog is a natural phenomenon that reduces the visibility of manned vehicles and vessels that rely on the visual interpretation of traffic. Fog clearance, also known as fog dissipation, is a relatively under-researched area when compared with fog prediction. In this work, we first analyzed meteorological observations that relate to fog dissipation in Incheon port (one of the most important ports for the South Korean economy) and Haeundae beach (the most populated and famous resort beach near Busan port). Next, we modeled fog dissipation using two separate algorithms, classification and regression, and a model with nine machine learning and three deep learning techniques. In general, the applied methods demonstrated high prediction accuracy, with extra trees and recurrent neural nets performing best in the classification task and feed-forward neural nets in the regression task.


Assuntos
Aprendizado Profundo , Algoritmos , Aprendizado de Máquina
16.
Nat Biomed Eng ; 2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34341534

RESUMO

The understanding of the foreign-body responses to implanted biomaterials would benefit from the reconstruction of intracellular and intercellular signalling networks in the microenvironment surrounding the implant. Here, by leveraging single-cell RNA-sequencing data from 42,156 cells collected from the site of implantation of either polycaprolactone or an extracellular-matrix-derived scaffold in a mouse model of volumetric muscle loss, we report a computational analysis of intercellular signalling networks reconstructed from predictions of transcription-factor activation. We found that intercellular signalling networks can be clustered into modules associated with specific cell subsets, and that biomaterial-specific responses can be characterized by interactions between signalling modules for immune, fibroblast and tissue-specific cells. In a Il17ra-/- mouse model, we validated that predicted interleukin-17-linked transcriptional targets led to concomitant changes in gene expression. Moreover, we identified cell subsets that had not been implicated in the responses to implanted biomaterials. Single-cell atlases of the cellular responses to implanted biomaterials will facilitate the design of implantable biomaterials and the understanding of the ensuing cellular responses.

17.
Life Sci ; 283: 119868, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34358551

RESUMO

AIMS: In this study, we investigated the vasodilatory effects of trelagliptin (a dipeptidyl peptidase-4 inhibitor) and its related mechanisms using rabbit aortic rings. MAIN METHODS: Arterial tone measurement was performed in rabbit thoracic aortic rings. KEY FINDINGS: Trelagliptin induced vasodilation in a dose-dependent manner. Pretreatment with the ATP-sensitive K+ channel inhibitor glibenclamide, large-conductance Ca2+-activated K+ channel inhibitor paxilline, and inwardly rectifying K+ channel inhibitor Ba2+ did not affect the vasodilatory effect of trelagliptin. However, pretreatment with the voltage-dependent K+ (Kv) channel inhibitors 4-aminopyridine and tetraethylammonium significantly attenuated the vasodilatory effect of trelagliptin, suggesting that the vasodilatory effect of trelagliptin is associated with Kv channel activation. Although pretreatment with Kv1.5 and Kv2.1 subtype inhibitors did not affect the response to trelagliptin, pretreatment with a Kv7.X subtype inhibitor effectively reduced the vasodilatory effect of trelagliptin. Furthermore, sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pump inhibitors also significantly attenuated the vasodilatory effect of trelagliptin. These effects, however, were not affected by pretreatment with Ca2+ channel inhibitors, adenylyl cyclase/PKA inhibitors, guanylyl cyclase/PKG inhibitors, or removal of the endothelium. SIGNIFICANCE: From these results, we concluded that the vasodilatory effect of trelagliptin was associated with the activation of Kv channels (primary the Kv7.X subtype) and SERCA pump regardless of other K+ channels, Ca2+ channels, cAMP/PKA-related or cGMP/PKG-related signaling pathways, and the endothelium. Therefore, caution is required when prescribing trelagliptin to the patients with hypotension and diabetes.


Assuntos
Aorta/metabolismo , Endotélio Vascular/metabolismo , Hipoglicemiantes/farmacologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Uracila/análogos & derivados , Vasodilatação/efeitos dos fármacos , Animais , Masculino , Coelhos , Uracila/farmacologia
18.
Artigo em Inglês | MEDLINE | ID: mdl-34423586

RESUMO

BACKGROUND: Sarcopenia and osteoporosis frequently co-occur in the elderly and have common pathophysiological determinants. Slit guidance ligand 3 (SLIT3) has been recently discovered as a novel therapeutic factor against osteoporosis, and a SLIT3 fragment containing the second leucine-rich repeat domain (LRRD2) had a therapeutic efficacy against osteoporosis. However, a role of SLIT3 in the skeletal muscle is unknown. METHODS: Skeletal muscle mass, strength, and/or physical activity were evaluated in Slit3-/- , ovariectomized, and aged mice, based on the measurements of muscle weight and grip strength, Kondziella's inverted hanging test, and/or wheel-running test. Skeletal muscles were also histologically evaluated by haematoxylin and eosin staining and/or immunofluorescence. The ovariectomized and aged mice were intravenously injected with recombinant SLIT3 LRRD2 for 4 weeks. C2C12 cells were used to know cellular effects of SLIT3, such as in vitro myogenesis, fusion, cell viability, and proliferation, and also used to evaluate its molecular mechanisms by immunocytochemistry, immunoprecipitation, western blotting, real-time PCR, siRNA transfection, and receptor-ligand binding ELISA. RESULTS: Slit3-deficient mice exhibited decreased skeletal muscle mass, muscle strength, and physical activity. The relative masses of gastrocnemius and soleus were lower in the Slit3-/- mice (0.580 ± 0.039% and 0.033 ± 0.003%, respectively) than those in the WT littermates (0.622 ± 0.043% and 0.038 ± 0.003%, respectively) (all, P < 0.05). Gastrocnemius of Slit3-/- mice showed the reduced number of Type I and Type IIa fibres (all, P < 0.05), but not of Type IIb and Type IIx fibres. SLIT3 activated ß-catenin signalling by promoting its release from M-cadherin, thereby increasing myogenin expression to stimulate myoblast differentiation. In vitro experiments involving ROBO2 expression, knockdown, and interaction with SLIT3 indicated that ROBO2 functions as a SLIT3 receptor to aid myoblast differentiation. SLIT3 LRRD2 dissociated M-cadherin-bound ß-catenin and up-regulated myogenin expression to increase myoblast differentiation, in a manner similar to full-length SLIT3. Systemic treatment with SLIT3 LRRD2 increased skeletal muscle mass in both ovariectomized and aged mice (all, P < 0.05). The relative masses of gastrocnemius and soleus were higher in the treated aged mice (0.548 ± 0.045% and 0.033 ± 0.005%, respectively) than in the untreated aged mice (0.508 ± 0.016% and 0.028 ± 0.003%, respectively) (all, P < 0.05). SLIT3 LRRD2 treatment increased the hanging duration of the aged mice by approximately 1.7-fold (P < 0.05). CONCLUSIONS: SLIT3 plays a sarcoprotective role by activating ß-catenin signalling. SLIT3 LRRD2 can potentially be used as a therapeutic agent against muscle loss.

19.
Int J Stroke ; : 17474930211041213, 2021 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-34427481

RESUMO

RATIONALE: Very early stage blood pressure (BP) levels may affect outcome in stroke patients who have successfully undergone recanalization following intra-arterial treatment, but the optimal target of BP management remains uncertain. AIM: We hypothesized that the clinical outcome after intensive BP-lowering is superior to conventional BP control after successful recanalization by intra-arterial treatment. SAMPLE-SIZE ESTIMATES: We aim to randomize 668 patients (334 per arm), 1:1. METHODS AND DESIGN: We initiated a multicenter, prospective, randomized, open-label trial with a blinded end-point assessment (PROBE) design. After successful recanalization (thrombolysis in cerebral infarction score ≥ 2 b), patients with elevated systolic BP level, defined as the mean of two readings ≥ 140 mmHg, will be randomly assigned to the intensive BP-lowering (systolic BP < 140 mm Hg) group or the conventional BP-lowering (systolic BP, 140-180 mm Hg) group. STUDY OUTCOMES: The primary efficacy outcomes are from dichotomized analysis of modified Rankin Scale (mRS) scores at three months (mRS scores: 0-2 vs. 3-6). The primary safety outcomes are symptomatic intracerebral hemorrhage and death within three months. DISCUSSION: The OPTIMAL-BP trial will provide evidence for the effectiveness of active BP control to achieve systolic BP < 140 mmHg during 24 h in patients with successful recanalization after intra-arterial treatment. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04205305.

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