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1.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(4): 1154-1158, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31418372

RESUMO

OBJECTIVE: To investigate the expression and pathogenesis of IL-17 in bone marrow blood of multiple myeloma (MM) patients. METHODS: Expression levels of IL-6, TNF-α and IL-17 in bone marrow serum of 20 MM patients and 20 control subjects were detected by ELISA, and correlation analysis was performed to analyze the correlation IL-17 with IL-6 and TNF-α. The effect of IL-17 on the proliferation of MM cells treated with different concentration of IL-17 was detected by cell prollferation and toxicity tesis. The morphological changes of RAW264.7 cells treated with IL-17 were observed by tartrate resistant acid phosphatase (TRAP) staining. RESULTS: The levels of IL-17, IL-6 and TNF- in the bone marrow of MM patients were all higher than those of the normal control group (P<0.05). The IL-17 level positively correlated with IL-6 and TNF-α levels (r=0.6045, P<0.01 and r=0.627, P<0.01). Cell proliferation and toxicity tests confirmed that IL-17 can promote the proliferation of multiple myeloma cells. TRAP staining revealed that IL-17 could induce differentiate of RAW264.7 cells into multinuclear giant cells. CONCLUSION: IL-17 may be involved in the pathogenesis of MM and promotes the proliferation of tumor cells, and induces the activation of osteoclasts leading to increased bone destruction.


Assuntos
Mieloma Múltiplo , Medula Óssea , Células da Medula Óssea , Humanos , Interleucina-17 , Osteoclastos , Fator de Necrose Tumoral alfa
2.
Mar Drugs ; 16(12)2018 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-30572615

RESUMO

Five new oxygenated sesquiterpenes, molestins A⁻D (1, 3⁻5) and epi-gibberodione (2), three new cyclopentenone derivatives, ent-sinulolides C, D, and F ((+)-9⁻(+)-11), one new butenolide derivative, ent-sinulolide H ((+)-13), and one new cembranolide, molestin E (14), together with 14 known related metabolites (6⁻8, (⁻)-9⁻(⁻)-11, (±)-12, (⁻)-13, 15⁻19) were isolated from the Paracel Islands soft coral Sinularia cf. molesta. The structures and absolute configurations were elucidated based on comprehensive spectroscopic analyses, quantum chemical calculations, and comparison with the literature data. Compound 5 is the first example of a norsesquiterpene with a de-isopropyl guaiane skeleton isolated from the genus Sinularia. Molestin E (14) exhibited cytotoxicities against HeLa and HCT-116 cell lines with IC50 values of 5.26 and 8.37 µM, respectively. Compounds 4, 5, and 8 showed significant inhibitory activities against protein tyrosine phosphatase 1B (PTP1B) with IC50 values of 218, 344, and 1.24 µM, respectively.


Assuntos
Antozoários/química , Citotoxinas/química , Sesquiterpenos/química , 4-Butirolactona/análogos & derivados , 4-Butirolactona/química , 4-Butirolactona/isolamento & purificação , 4-Butirolactona/farmacologia , Animais , Linhagem Celular Tumoral , Ciclopentanos/química , Ciclopentanos/isolamento & purificação , Ciclopentanos/farmacologia , Células HCT116 , Células HeLa , Humanos , Conformação Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/farmacologia
3.
JBMR Plus ; 2(4): 235-239, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30283904

RESUMO

The heritable disorder osteogenesis imperfecta (OI) is characterized by bone fragility and low bone mass. OI type VI is an autosomal recessive form of the disorder with moderate to severe bone fragility. OI type VI is caused by mutations in the serpin peptidase inhibitor, clade F, member 1 (SERPINF1), the gene coding for pigment epithelium-derived factor (PEDF). Here, we report a patient with OI type VI caused by a novel homozygous intronic variant in SERPINF1 identified by whole-exome sequencing (WES). The mutation was not identified using a low bone mass gene panel based on next-generation sequencing. This variant creates a novel consensus splice donor site (AGGC to AGGT) in intron 4. Analysis of cDNA generated from fibroblasts revealed retention of a 32-bp intronic fragment between exons 4 and 5 in the cDNA, a result of alternative splicing from the novel splice-donor site. As a result, the aberrant insertion of this intronic fragment generated a frameshift pathogenic variant and induced nonsense-mediated decay. Furthermore, gene expression by quantitative PCR showed SERPINF1 expression was dramatically reduced in patient fibroblasts, and PEDF level was also significantly reduced in the patient's plasma. In conclusion, we report a novel homozygous variant that generates an alternative splice-donor in intron 4 of SERPINF1 which gives rise to severe bone fragility. The work also demonstrates clinical utility of WES analysis, and consideration of noncoding variants, in the diagnostic setting of rare bone diseases. © 2018 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

4.
Am J Hum Genet ; 103(2): 276-287, 2018 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-30075114

RESUMO

Primary hypertension is a major risk factor for ischemic heart disease, stroke, and chronic kidney disease. Insights obtained from the study of rare Mendelian forms of hypertension have been invaluable in elucidating the mechanisms causing primary hypertension and development of antihypertensive therapies. Endothelial cells play a key role in the regulation of blood pressure; however, a Mendelian form of hypertension that is primarily due to endothelial dysfunction has not yet been described. Here, we show that the urea cycle disorder, argininosuccinate lyase deficiency (ASLD), can manifest as a Mendelian form of endothelial-dependent hypertension. Using data from a human clinical study, a mouse model with endothelial-specific deletion of argininosuccinate lyase (Asl), and in vitro studies in human aortic endothelial cells and induced pluripotent stem cell-derived endothelial cells from individuals with ASLD, we show that loss of ASL in endothelial cells leads to endothelial-dependent vascular dysfunction with reduced nitric oxide (NO) production, increased oxidative stress, and impaired angiogenesis. Our findings show that ASLD is a unique model for studying NO-dependent endothelial dysfunction in human hypertension.

5.
Hum Gene Ther ; 2018 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-30070147

RESUMO

Osteoarthritis (OA) is a degenerative disease of synovial joints characterized by progressive loss of articular cartilage, subchondral bone remodeling, and intra-articular inflammation with synovitis that results in chronic pain and motor impairment. Despite the economic and health impacts, current medical therapies are targeted at symptomatic relief of OA and fail to alter its progression. Given the complexity of OA pathogenesis, we hypothesized that a combinatorial gene therapy approach, designed to inhibit inflammation with interleukin-1 receptor antagonist (IL-1Ra) while promoting chondroprotection using lubricin (PRG4), would improve preservation of the joint compared to monotherapy alone. Employing two surgical techniques to model mild, moderate and severe posttraumatic OA, we found that combined delivery of helper-dependent adenoviruses (HDVs), expressing IL-1Ra and PRG4, preserved articular cartilage better than either monotherapy in both models as demonstrated by preservation of articular cartilage volume and surface area. This improved protection was associated with increased expression of proanabolic and cartilage matrix genes together with decreased expression of catabolic genes and inflammatory mediators. In addition to improvements in joint tissues, this combinatorial gene therapy prolonged protection against thermal hyperalgesia compared to either monotherapy. Taken together, our results show that a combinatorial strategy is superior to monotherapeutic approaches for treatment of posttraumatic OA.

6.
Mol Genet Metab ; 125(1-2): 112-117, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30055993

RESUMO

Arginine is a semi-essential amino acid which serves as a substrate for nitric oxide (NO) production by nitric oxide synthase (NOS) and a precursor for various metabolites including ornithine, creatine, polyamines, and agmatine. Arginase competes with nitric oxide synthase for substrate arginine to produce orthinine and urea. There is contradictory evidence in the literature on the role of nitric oxide in the pathophysiology of traumatic brain injury (TBI). These contradictory perspectives are likely due to different NOS isoforms - endothelial (eNOS), inducible (iNOS) and neuronal (nNOS) which are expressed in the central nervous system. Of these, the role of nNOS in acute injury remains less clear. This study aimed to employ a genetic approach by overexpressing arginase isoforms specifically in neurons using a Thy-1 promoter to manipulate cell autonomous NO production in the context of TBI. The hypothesis was that increased arginase would divert arginine from pathological NO production. We generated 2 mouse lines that overexpress arginase I (a cytoplasmic enzyme) or arginase II (a mitochondrial enzyme) in neurons of FVB mice. We found that two-weeks after induction of controlled cortical injury, overexpressing arginase I but not arginase II in neurons significantly reduced contusion size and contusion index compared to wild-type (WT) mice. This study establishes enhanced neuronal arginase levels as a strategy to affect the course of TBI and provides support for the potential role of neuronal NO production in this condition.

7.
Nanoscale ; 10(20): 9602-9607, 2018 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-29748685

RESUMO

Van der Waals heterostructures (vdWHs) have opened new avenues for fundamental scientific studies and design of novel devices. Although numerous reports have demonstrated vdWH optoelectronic devices, no report on vdWH lasers can be found to date. In this paper we demonstrated electrically driven vdWH lasers for the first time, and the lasers were realized from ZnO microwire/MgO/p-GaN structures. By coating Ag films on the top surfaces of the ZnO microwires, the current injection and lasing directionality of the vdWH lasers have been improved significantly, and this improvement can be attributed to the high conductivity and reflectivity of the Ag film. The output power of the device can reach 2.41 µW under 14 mA drive current, which is among the highest values ever reported for ZnO based lasers. Our results may provide a promising way to electrically pumped lasers based on micro/nano-structures.

8.
Chin Med J (Engl) ; 131(2): 151-155, 2018 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-29336362

RESUMO

BACKGROUND: SH3TC2, PMP2, and BSCL2 genes are related to autosomal recessive (AR) Charcot-Marie-Tooth (CMT) disease type 1, autosomal dominant (AD)-CMT1, and AD-CMT2, respectively. Pathogenic variants in these three genes were not well documented in Chinese CMT patients. Therefore, this study aims to detect SH3TC2, PMP2, and BSCL2 pathogenic variants in a cohort of 315 unrelated Chinese CMT families. METHODS: A total of 315 probands from 315 unrelated Chinese CMT families were recruited from the Department of Neurology of Third Xiangya Hospital and Xiangya Hospital. We screened for SH3TC2 pathogenic variants in 84 AR or sporadic CMT probands, PMP2 pathogenic variants in 39 AD or sporadic CMT1 probands, and BSCL2 pathogenic variants in 50 AD or sporadic CMT2 probands, using polymerase chain reaction and Sanger sequencing. All these patients were out of 315 unrelated Chinese CMT families and genetically undiagnosed after exclusion of pathogenic variants of PMP22, MFN2, MPZ, GJB1, GDAP1, HSPB1, HSPB8, EGR2, NEFL, and RAB7. Candidate variants were analyzed based on the standards and guidelines of American College of Medical Genetics and Genomics (ACMG). Clinical features were reevaluated. RESULTS: We identified three novel heterozygous variants such as p.L95V (c.283C>G), p.L1048P (c.3143T>C), and p.V1105M (c.3313G>A) of SH3TC2 gene and no pathogenic variants of PMP2 and BSCL2 genes. Although evaluation in silico and screening in the healthy control revealed that the three SH3TC2 variants were likely pathogenic, no second allele variants were discovered. According to the standards and guidelines of ACMG, the heterozygous SH3TC2 variants such as p.L95V, p.L1048P, and p.V1105M were considered to be of uncertain significance. CONCLUSIONS: SH3TC2, PMP2, and BSCL2 pathogenic variants might be rare in Chinese CMT patients. Further studies to confirm our findings are needed.


Assuntos
Doença de Charcot-Marie-Tooth/genética , Subunidades gama da Proteína de Ligação ao GTP/genética , Mutação , Proteína P2 de Mielina/genética , Proteínas/genética , Adolescente , Adulto , Estudos de Coortes , Feminino , Humanos , Masculino
9.
J Cancer Res Clin Oncol ; 144(4): 667-674, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29372377

RESUMO

OBJECTIVE: Circular RNAs (circRNAs) are a novel class of non-protein-coding RNA. Emerging evidence indicates that circRNAs participate in the regulation of many pathophysiological processes. This study aims to explore the expression profiles and pathological effects of circRNAs in non-small cell lung cancer (NSCLC). METHODS: Human circRNAs microarray analysis was performed to screen the expression profile of circRNAs in NSCLC tissue. Expressions of circRNA and miRNA in NSCLC tissues and cells were quantified by qRTPCR. Functional experiments were performed to investigate the biological functions of circRNA, including CCK-8 assay, colony formation assay, transwell assay and xenograft in vivo assay. RESULTS: Human circRNAs microarray revealed a total 957 abnormally expressed circRNAs (> twofold, P < 0.05) in NSCLC tissue compared with adjacent normal tissue. In further studies, hsa_circ_0007385 was significantly up regulated in NSCLC tissue and cells. In vitro experiments with hsa_circ_0007385 knockdown resulted in significant suppression of the proliferation, migration and invasion of NSCLC cells. In vivo xenograft assay using hsa_circ_0007385 knockdown, significantly reduced tumor growth. Bioinformatics analysis and luciferase reporter assay verified the potential target miR-181, suggesting a possible regulatory pathway for hsa_circ_0007385. CONCLUSION: In summary, results suggest hsa_circ_0007385 plays a role in NSCLC tumorigenesis, providing a potential therapeutic target for NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , RNA/genética , Células A549 , Animais , Carcinogênese/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Técnicas de Silenciamento de Genes , Células HEK293 , Xenoenxertos , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Análise em Microsséries , Oncogenes
10.
Biochem Biophys Res Commun ; 495(1): 20-26, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29079188

RESUMO

Pulmonary fibrosis (PF) is a chronic, fibrosing interstitial pneumonia and devastating disease. Here we investigated the potential roles of Kruppel-like factor 2 (KLF2) on pulmonary fibrosis and inflammation response. A mouse model of pulmonary fibrosis was established by intratracheal injection of bleomycin (BLM). The mRNA and protein levels of KLF2 were assayed by RT-PCR and Western blotting respectively. The extent of lung fibrosis was determined using hematoxylin and eosin (HE) staining and Masson's trichrome staining, and the hydroxyproline content was quantified. RT-PCR was used to evaluate the mRNA expression of collagen type 1a1 (col1a1), col3a1, α-SMA, TNF-α, IL-1ß and IL-6. The concentrations of TNF-α, IL-1ß, and IL-6 in bronchoalveolar lavage fluid (BALF) and lung tissue were examined by ELISA. Also, the effects of KLF2 on activator protein-1 (AP-1) were evaluated by measuring the c-Jun and c-Fos protein levels. We found that KLF2 was remarkably downregulated in BLM-treated rats, both in mRNA and protein levels. Additionally, overexpression of KLF2 attenuated the destruction of the alveolar space and pulmonary interstitial collagen hyperplasia, and deposition reduced the expression of col1a1, col3a1, and α-SMA, and blocked the production of TNF-α, IL-1ß, and IL-6 in BALF and lung tissue in vivo. Moreover, adenoviral transduction of KLF2 inhibited TGF-ß1-induced expression of col1a1, col3a1, and α-SMA in vitro. Mechanically, BLM up-regulated c-Jun and c-Fos expression, which was impeded by KLF2 overexpression. Taken together, our data indicate that KLF2 attenuates pulmonary fibrosis and inflammation, possibly through the regulation of AP-1.


Assuntos
Fatores de Transcrição Kruppel-Like/metabolismo , Fibrose Pulmonar/metabolismo , Fator de Transcrição AP-1/metabolismo , Actinas/genética , Animais , Bleomicina/toxicidade , Linhagem Celular , Colágeno Tipo I/genética , Colágeno Tipo III/genética , Citocinas/biossíntese , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta1/metabolismo
11.
Sci Rep ; 7(1): 17175, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29215029

RESUMO

Tendons transmit contractile forces between musculoskeletal tissues. Whereas the biomechanical properties of tendons have been studied extensively, the molecular mechanisms regulating postnatal tendon development are not well understood. Here we examine the role of mTORC1 signaling in postnatal tendon development using mouse genetic approaches. Loss of mTORC1 signaling by removal of Raptor in tendons caused severe tendon defects postnatally, including decreased tendon thickness, indicating that mTORC1 is necessary for postnatal tendon development. By contrast, activation of mTORC1 signaling in tendons increased tendon cell numbers and proliferation. In addition, Tsc1 conditional knockout mice presented severely disorganized collagen fibers and neovascularization in the tendon midsubstance. Interestingly, collagen fibril diameter was significantly reduced in both Raptor and Tsc1 conditional knockout mice, albeit with variations in severity. We performed RNA-seq analysis using Achilles tendons to investigate the molecular changes underlying these tendon phenotypes. Raptor conditional knockout mice showed decreased extracellular matrix (ECM) structure-related gene expression, whereas Tsc1 conditional knockout mice exhibited changes in genes regulating TGF-ß/BMP/FGF signaling, as well as in genes controlling ECM structure and disassembly. Collectively, our studies suggest that maintaining physiological levels of mTORC1 signaling is essential for postnatal tendon development and maturation.

12.
Oncol Lett ; 14(1): 733-736, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28693227

RESUMO

We studied the relationship between the polymorphisms of -800G/A and +915G/C in transforming growth factor-ß1 (TGF-ß1) gene and lung cancer susceptibility. The sequence-specific primer polymerase chain reaction (PCR-SSP) technique was used to test 156 non-small cell lung cancer (NSCLC) patients that were selected as the observation group and 156 patients with pneumonia and tuberculosis that were selected as the control group (age and gender 1:1 proximal matching principle) and the polymorphisms of the first exon -800G/A and +915G/C TGF-ß1 genes. The expression of TGF-ß1 levels in peripheral blood was detected using ELISA. The proportion of -800G/A gene AA subtype and A allelic gene in the observation group was significantly higher than that in the control group, while the proportion of +915G/C gene CC subtype and C allelic gene was also significantly higher than that in the control group (P<0.05). The cancer risk [odds ratio (OR)] of patients with A allelic gene in -800G/A gene was 4.8 (95% CI=2.563-6.537, P<0.05), while the cancer risk (OR) of patients with C allelic gene in +915G/C gene was 4.7 (95% CI=2.317-5.864, P<0.05). The serum TGF-ß1 expression levels of -800G/A gene AA subtype in the observation group was significantly higher than the GG type, GA type and the control group, while the TGF-ß1 level of +915G/C gene CC subtype was significantly higher than the GG type, GC type and the control group (P<0.05). Therefore, the polymorphisms of -800G/A and +915G/C in TGF-ß1 gene are closely related to the lung cancer susceptibility.

13.
Mol Cancer ; 16(1): 111, 2017 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-28659173

RESUMO

BACKGROUND: Recent evidences showed that long noncoding RNAs (lncRNAs) are frequently dysregulated and play important roles in various cancers. Clear cell renal cell carcinoma (ccRCC) is one of the leading cause of cancer-related death, largely due to the metastasis of ccRCC. However, the clinical significances and roles of lncRNAs in metastatic ccRCC are still unknown. METHODS: lncRNA expression microarray analysis was performed to search the dysregulated lncRNA in metastatic ccRCC. quantitative real-time PCR was performed to measure the expression of lncRNAs in human ccRCC samples. Gain-of-function and loss-of-function experiments were performed to investigate the biological roles of lncRNAs on ccRCC cell proliferation, migration, invasion and in vivo metastasis. RNA pull-down, RNA immunoprecipitation, chromatin immunoprecipitation, and western blot were performed to explore the molecular mechanisms underlying the functions of lncRNAs. RESULTS: The microarray analysis identified a novel lncRNA termed metastatic renal cell carcinoma-associated transcript 1 (MRCCAT1), which is highly expressed in metastatic ccRCC tissues and associated with the metastatic properties of ccRCC. Multivariate Cox regression analysis revealed that MRCCAT1 is an independent prognostic factor for ccRCC patients. Overexpression of MRCCAT1 promotes ccRCC cells proliferation, migration, and invasion. Depletion of MRCCAT1 inhibites ccRCC cells proliferation, migration, and invasion in vitro, and ccRCC metastasis in vivo. Mechanistically, MRCCAT1 represses NPR3 transcription by recruiting PRC2 to NPR3 promoter, and subsequently activates p38-MAPK signaling pathway. CONCLUSIONS: MRCCAT1 is a critical lncRNA that promotes ccRCC metastasis via inhibiting NPR3 and activating p38-MAPK signaling. Our results imply that MRCCAT1 could serve as a prognostic biomarker and therapeutic target for ccRCC.


Assuntos
Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , RNA Longo não Codificante/genética , Receptores do Fator Natriurético Atrial/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Idoso , Animais , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/mortalidade , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Neoplasias Renais/mortalidade , Masculino , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Prognóstico , Regiões Promotoras Genéticas , Receptores do Fator Natriurético Atrial/genética , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas Quinases p38 Ativadas por Mitógeno/genética
14.
J Clin Invest ; 127(7): 2678-2688, 2017 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-28628032

RESUMO

Mutations in WNT1 cause osteogenesis imperfecta (OI) and early-onset osteoporosis, identifying it as a key Wnt ligand in human bone homeostasis. However, how and where WNT1 acts in bone are unclear. To address this mechanism, we generated late-osteoblast-specific and osteocyte-specific WNT1 loss- and gain-of-function mouse models. Deletion of Wnt1 in osteocytes resulted in low bone mass with spontaneous fractures similar to that observed in OI patients. Conversely, Wnt1 overexpression from osteocytes stimulated bone formation by increasing osteoblast number and activity, which was due in part to activation of mTORC1 signaling. While antiresorptive therapy is the mainstay of OI treatment, it has limited efficacy in WNT1-related OI. In this study, anti-sclerostin antibody (Scl-Ab) treatment effectively improved bone mass and dramatically decreased fracture rate in swaying mice, a model of global Wnt1 loss. Collectively, our data suggest that WNT1-related OI and osteoporosis are caused in part by decreased mTORC1-dependent osteoblast function resulting from loss of WNT1 signaling in osteocytes. As such, this work identifies an anabolic function of osteocytes as a source of Wnt in bone development and homoeostasis, complementing their known function as targets of Wnt signaling in regulating osteoclastogenesis. Finally, this study suggests that Scl-Ab is an effective genotype-specific treatment option for WNT1-related OI and osteoporosis.


Assuntos
Fraturas Ósseas/metabolismo , Homeostase , Osteócitos/metabolismo , Osteogênese Imperfeita/metabolismo , Osteoporose/metabolismo , Via de Sinalização Wnt , Proteína Wnt1/metabolismo , Animais , Anticorpos/farmacologia , Fraturas Ósseas/tratamento farmacológico , Fraturas Ósseas/genética , Fraturas Ósseas/patologia , Glicoproteínas/antagonistas & inibidores , Glicoproteínas/genética , Glicoproteínas/metabolismo , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Transgênicos , Complexos Multiproteicos/genética , Complexos Multiproteicos/metabolismo , Osteócitos/patologia , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/genética , Osteogênese Imperfeita/patologia , Osteoporose/tratamento farmacológico , Osteoporose/genética , Osteoporose/patologia , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Proteína Wnt1/genética
15.
J Clin Invest ; 127(4): 1475-1484, 2017 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-28263186

RESUMO

Shohat-type spondyloepimetaphyseal dysplasia (SEMD) is a skeletal dysplasia that affects cartilage development. Similar skeletal disorders, such as spondyloepiphyseal dysplasias, are linked to mutations in type II collagen (COL2A1), but the causative gene in SEMD is not known. Here, we have performed whole-exome sequencing to identify a recurrent homozygous c.408+1G>A donor splice site loss-of-function mutation in DDRGK domain containing 1 (DDRGK1) in 4 families affected by SEMD. In zebrafish, ddrgk1 deficiency disrupted craniofacial cartilage development and led to decreased levels of the chondrogenic master transcription factor sox9 and its downstream target, col2a1. Overexpression of sox9 rescued the zebrafish chondrogenic and craniofacial phenotype generated by ddrgk1 knockdown, thus identifying DDRGK1 as a regulator of SOX9. Consistent with these results, Ddrgk1-/- mice displayed delayed limb bud chondrogenic condensation, decreased SOX9 protein expression and Col2a1 transcript levels, and increased apoptosis. Furthermore, we determined that DDRGK1 can directly bind to SOX9 to inhibit its ubiquitination and proteasomal degradation. Taken together, these data indicate that loss of DDRGK1 decreases SOX9 expression and causes a human skeletal dysplasia, identifying a mechanism that regulates chondrogenesis via modulation of SOX9 ubiquitination.


Assuntos
Proteínas de Transporte/fisiologia , Osteocondrodisplasias/genética , Fatores de Transcrição SOX9/metabolismo , Ubiquitinação , Animais , Cartilagem/crescimento & desenvolvimento , Células Cultivadas , Condrogênese , Colágeno Tipo II/genética , Colágeno Tipo II/metabolismo , Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Homozigoto , Humanos , Camundongos Knockout , Mutação , Osteocondrodisplasias/metabolismo , Linhagem , Isoformas de Proteínas/fisiologia , Estabilidade Proteica , Sítios de Splice de RNA , Peixe-Zebra
16.
Medicine (Baltimore) ; 96(9): e6139, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28248867

RESUMO

To investigate structural and functional brain changes in patients with primary open-angle glaucoma (POAG) by using voxel-based morphometry based on diffeomorphic anatomical registration through exponentiated Lie algebra (VBM-DARTEL) and blood oxygenation level dependent functional magnetic resonance imaging (BOLD-fMRI), respectively.Thirteen patients diagnosed with POAG and 13 age- and sex-matched healthy controls were enrolled in the study. For each participant, high-resolution structural brain imaging and blood flow imaging were acquired on a 3.0-Tesla magnetic resonance imaging (MRI) scanner. Structural and functional changes between the POAG and control groups were analyzed. An analysis was carried out to identify correlations between structural and functional changes acquired in the previous analysis and the retinal nerve fiber layer (RNFL).Patients in the POAG group showed a significant (P < 0.001) volume increase in the midbrain, left brainstem, frontal gyrus, cerebellar vermis, left inferior parietal lobule, caudate nucleus, thalamus, precuneus, and Brodmann areas 7, 18, and 46. Moreover, significant (P < 0.001) BOLD signal changes were observed in the right supramarginal gyrus, frontal gyrus, superior frontal gyrus, left inferior parietal lobule, left cuneus, and left midcingulate area; many of these regions had high correlations with the RNFL.Patients with POAG undergo widespread and complex changes in cortical brain structure and blood flow. (ClinicalTrials.gov number: NCT02570867).


Assuntos
Encéfalo/diagnóstico por imagem , Glaucoma de Ângulo Aberto/diagnóstico por imagem , Imagem por Ressonância Magnética , Adulto , Encéfalo/patologia , Estudos de Casos e Controles , Circulação Cerebrovascular , Feminino , Glaucoma de Ângulo Aberto/patologia , Glaucoma de Ângulo Aberto/fisiopatologia , Humanos , Masculino , Adulto Jovem
17.
J Bone Miner Res ; 32(2): 347-359, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27649409

RESUMO

Osteogenesis imperfecta (OI) is a group of genetic disorders characterized by brittle bones that are prone to fracture. Although previous studies in animal models investigated the mechanical properties and material composition of OI bone, little work has been conducted to statistically correlate these parameters to identify key compositional contributors to the impaired bone mechanical behaviors in OI. Further, although increased TGF-ß signaling has been demonstrated as a contributing mechanism to the bone pathology in OI models, the relationship between mechanical properties and bone composition after anti-TGF-ß treatment in OI has not been studied. Here, we performed follow-up analyses of femurs collected in an earlier study from OI mice with and without anti-TGF-ß treatment from both recessive (Crtap-/- ) and dominant (Col1a2+/P.G610C ) OI mouse models and WT mice. Mechanical properties were determined using three-point bending tests and evaluated for statistical correlation with molecular composition in bone tissue assessed by Raman spectroscopy. Statistical regression analysis was conducted to determine significant compositional determinants of mechanical integrity. Interestingly, we found differences in the relationships between bone composition and mechanical properties and in the response to anti-TGF-ß treatment. Femurs of both OI models exhibited increased brittleness, which was associated with reduced collagen content and carbonate substitution. In the Col1a2+/P.G610C femurs, reduced hydroxyapatite crystallinity was also found to be associated with increased brittleness, and increased mineral-to-collagen ratio was correlated with increased ultimate strength, elastic modulus, and bone brittleness. In both models of OI, regression analysis demonstrated that collagen content was an important predictor of the increased brittleness. In summary, this work provides new insights into the relationships between bone composition and material properties in models of OI, identifies key bone compositional parameters that correlate with the impaired mechanical integrity of OI bone, and explores the effects of anti-TGF-ß treatment on bone-quality parameters in these models. © 2016 American Society for Bone and Mineral Research.


Assuntos
Osso e Ossos/fisiopatologia , Genes Dominantes , Genes Recessivos , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/fisiopatologia , Fator de Crescimento Transformador beta/antagonistas & inibidores , Animais , Fenômenos Biomecânicos , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Fêmur/diagnóstico por imagem , Fêmur/patologia , Fêmur/fisiopatologia , Camundongos Endogâmicos C57BL , Osteogênese Imperfeita/diagnóstico por imagem , Proteínas/metabolismo , Análise de Regressão , Análise Espectral Raman , Microtomografia por Raio-X
18.
Opt Lett ; 41(4): 685-8, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26872163

RESUMO

Photovoltaic cells have been fabricated from p-GaN/MgO/n-ZnO structures. The photovoltaic cells are transparent to visible light and can transform ultraviolet irradiation into electrical signals. The efficiency of the photovoltaic cells is 0.025% under simulated AM 1.5 illumination conditions, while it can reach 0.46% under UV illumination. By connecting several such photovoltaic cells in a series, light-emitting devices can be lighting. The photovoltaic cells reported in this Letter may promise the applications in glass of buildings to prevent UV irradiation and produce power for household appliances in the future.

19.
Mol Genet Metab ; 117(3): 378-82, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26693895

RESUMO

Osteogenesis imperfecta (OI) is a group of genetic disorders characterized by bone fragility and deformity. OI type VI is unique owing to the mineralization defects observed in patient biopsies. Furthermore, it has been reported to respond less well to standard therapy with bisphosphonates [1]. Others and we have previously identified SERPINF1 mutations in patients with OI type VI. SERPINF1 encodes pigment epithelium derived factor (PEDF), a secreted collagen-binding glycoprotein that is absent in the sera of patients with OI type VI. Serpinf1 null mice show increased osteoid and decreased bone mass, and thus recapitulate the OI type VI phenotype. We tested whether restoration of circulating PEDF in the blood could correct the phenotype of OI type VI in the context of protein replacement. To do so, we utilized a helper-dependent adenoviral vector (HDAd) to express human SERPINF1 in the mouse liver and assessed whether PEDF secreted from the liver was able to rescue the bone phenotype observed in Serpinf1(-/-) mice. We confirmed that expression of SERPINF1 in the liver restored the serum level of PEDF. We also demonstrated that PEDF secreted from the liver was biologically active by showing the expected metabolic effects of increased adiposity and impaired glucose tolerance in Serpinf1(-/-) mice. Interestingly, overexpression of PEDF in vitro increased mineralization with a concomitant increase in the expression of bone gamma-carboxyglutamate protein, alkaline phosphatase and collagen, type I, alpha I, but the increased serum PEDF level did not improve the bone phenotype of Serpinf1(-/-) mice. These results suggest that PEDF may function in a context-dependent and paracrine fashion in bone homeostasis.


Assuntos
Osso e Ossos/fisiologia , Proteínas do Olho/sangue , Proteínas do Olho/genética , Fígado/metabolismo , Fatores de Crescimento Neural/sangue , Fatores de Crescimento Neural/genética , Osteogênese Imperfeita/fisiopatologia , Osteogênese Imperfeita/terapia , Serpinas/sangue , Serpinas/genética , Ácido 1-Carboxiglutâmico/genética , Adenoviridae/genética , Fosfatase Alcalina/genética , Animais , Densidade Óssea , Colágeno Tipo I/genética , Técnicas de Transferência de Genes , Intolerância à Glucose , Células HEK293 , Homeostase , Humanos , Camundongos , Camundongos Knockout , Mutação , Fatores de Crescimento Neural/deficiência , Fenótipo , Serpinas/deficiência
20.
J Bone Miner Res ; 31(5): 1030-40, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26716893

RESUMO

Osteogenesis imperfecta (OI) is characterized by low bone mass, poor bone quality, and fractures. Standard treatment for OI patients is limited to bisphosphonates, which only incompletely correct the bone phenotype, and seem to be less effective in adults. Sclerostin-neutralizing antibodies (Scl-Ab) have been shown to be beneficial in animal models of osteoporosis, and dominant OI resulting from mutations in the genes encoding type I collagen. However, Scl-Ab treatment has not been studied in models of recessive OI. Cartilage-associated protein (CRTAP) is involved in posttranslational type I collagen modification, and its loss of function results in recessive OI. In this study, we treated 1-week-old and 6-week-old Crtap(-/-) mice with Scl-Ab for 6 weeks (25 mg/kg, s.c., twice per week), to determine the effects on the bone phenotype in models of "pediatric" and "young adult" recessive OI. Vehicle-treated Crtap(-/-) and wild-type (WT) mice served as controls. Compared with control Crtap(-/-) mice, micro-computed tomography (µCT) analyses showed significant increases in bone volume and improved trabecular microarchitecture in Scl-Ab-treated Crtap(-/-) mice in both age cohorts, in both vertebrae and femurs. Additionally, Scl-Ab improved femoral cortical parameters in both age cohorts. Biomechanical testing showed that Scl-Ab improved parameters of whole-bone strength in Crtap(-/-) mice, with more robust effects in the week 6 to 12 cohort, but did not affect the increased bone brittleness. Additionally, Scl-Ab normalized the increased osteoclast numbers, stimulated bone formation rate (week 6 to 12 cohort only), but did not affect osteocyte density. Overall, our findings suggest that Scl-Ab treatment may be beneficial in the treatment of recessive OI caused by defects in collagen posttranslational modification. © 2015 American Society for Bone and Mineral Research.


Assuntos
Anticorpos/farmacologia , Genes Recessivos , Glicoproteínas/antagonistas & inibidores , Osteoclastos/metabolismo , Osteogênese Imperfeita , Osteogênese , Proteínas/genética , Animais , Camundongos , Camundongos Knockout , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/genética , Osteogênese Imperfeita/metabolismo , Osteogênese Imperfeita/patologia
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