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1.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(5): 1592-1597, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33067959

RESUMO

OBJECTIVE: To explore the role of interaction between osteoclast stimulator stromal derived factor 1 alpha (SDF-1α) and osteoblast inhibitor dickkopf-1 (DKK-1) in the development of multiple myeloma (MM) bone disease. METHODS: The serum samples of 51 patients with newly diagnosed MM, 30 age-matched healthy controls, and 35 non-Hodgkin lymphoma patients from June 2011 to May 2014 in Peking Union Medical College Hospital were collected. The serum SDF-1α and DKK-1 were detected by ELISA. Primary myeloma cells and human MM cell line RPMI 8226 were treated with SDF-1α, then DKK-1 mRNA expression was detected by real time PCR. Primary bone marrow stromal cells (BMSCs) were treated with Wnt-3a and/or DKK-1, and the transc-ription level of SDF-1α mRNA was assayed. RESULTS: Serum SDF-1α in MM patients was significantly higher than that in control group (3231.0±1269.5 pg/ml vs 2817.5±419.6 pg/ml)(P=0.036), so was serum DKK-1 (3057.4±1874.7 pg/ml vs 1867.7±1148.4 pg/ml)(P=0.01). There was a positive correlation between serum SDF-1α and DKK-1 in MM patients (r=0.301, P=0.032), but there was no correlation between control group (r=0.15, P=0.428) and non-Hodgkin lymphoma patients (r=0.227, P=0.095). After treated with SDF-1α (20 ng/ml) for 8 and 36 h, the DKK-1 mRNA transcription level in RPMI 8226 increased by 1.92 and 4.19-folds respectively(P=0.365, P=0.099). Moreover, the high transcription level of DKK-1 mRNA was observed in 5 out of 9 MM patients. The detection showed that after treatment with SDF-1α, the transcription level was up-regulated(P=0.043), the Wnt-3a (200 ng/ml) could decrease the expression of SDF-1α mRNA in primary BMSC to 29% of baseline(P=0.028), the adding DKK-1 could reverse the down-regulation effect. CONCLUSION: The serum SDF-1α and DKK-1 level in MM patients is high than normal leve, moreover shows the positive correlation between them. The SDF-1α and DKK-1 can interreact, therefore accerate the formation of MM bone disease.


Assuntos
Doenças Ósseas , Linfoma não Hodgkin , Mieloma Múltiplo , Quimiocina CXCL12 , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Osteoclastos
2.
Stomatologiia (Mosk) ; 99(5): 122-126, 2020.
Artigo em Russo | MEDLINE | ID: mdl-33034189

RESUMO

PRP-therapy - method, based on local application platelet rich plasma. Efficiency of this method is investigated and approved both in vitro and in vivo. PRP includes growth factors: platelet derived growth factor, transforming growth factor, epidermal growth factor, insulin-like growth factor, vascular endothelial growth factor, which significantly accelerate regenerative process. PRP-therapy reduces pain syndrome, accelerates tissue regeneration and has an anti-inflammatory effect.


Assuntos
Plasma Rico em Plaquetas , Fator A de Crescimento do Endotélio Vascular , Face , Peptídeos e Proteínas de Sinalização Intercelular , Cicatrização
3.
Nat Commun ; 11(1): 5357, 2020 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-33097721

RESUMO

Low-density lipoprotein receptor-related protein 6 (LRP6) is a coreceptor of the ß-catenin-dependent Wnt signaling pathway. The LRP6 ectodomain binds Wnt proteins, as well as Wnt inhibitors such as sclerostin (SOST), which negatively regulates Wnt signaling in osteocytes. Although LRP6 ectodomain 1 (E1) is known to interact with SOST, several unresolved questions remain, such as the reason why SOST binds to LRP6 E1E2 with higher affinity than to the E1 domain alone. Here, we present the crystal structure of the LRP6 E1E2-SOST complex with two interaction sites in tandem. The unexpected additional binding site was identified between the C-terminus of SOST and the LRP6 E2 domain. This interaction was confirmed by in vitro binding and cell-based signaling assays. Its functional significance was further demonstrated in vivo using Xenopus laevis embryos. Our results provide insights into the inhibitory mechanism of SOST on Wnt signaling.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Proteínas Wnt/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/química , Animais , Sítios de Ligação , Cristalografia por Raios X , Feminino , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/química , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/química , Modelos Moleculares , Peptídeos/metabolismo , Ligação Proteica , Conformação Proteica , Transcriptoma , Xenopus laevis/embriologia , Xenopus laevis/metabolismo , beta Catenina/metabolismo
4.
Cells ; 9(10)2020 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-32998369

RESUMO

The vitamin K-dependent factors protein S (PROS1) and growth-arrest-specific gene 6 (GAS6) and their tyrosine kinase receptors TYRO3, AXL, and MERTK, the TAM subfamily of receptor tyrosine kinases (RTK), are key regulators of inflammation and vascular response to damage. TAM signaling, which has largely studied in the immune system and in cancer, has been involved in coagulation-related pathologies. Because of these established biological functions, the GAS6-PROS1/TAM system is postulated to play an important role in SARS-CoV-2 infection and progression complications. The participation of the TAM system in vascular function and pathology has been previously reported. However, in the context of COVID-19, the role of TAMs could provide new clues in virus-host interplay with important consequences in the way that we understand this pathology. From the viral mimicry used by SARS-CoV-2 to infect cells, to the immunothrombosis that is associated with respiratory failure in COVID-19 patients, TAM signaling seems to be involved at different stages of the disease. TAM targeting is becoming an interesting biomedical strategy, which is useful for COVID-19 treatment now, but also for other viral and inflammatory diseases in the future.


Assuntos
Infecções por Coronavirus/complicações , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Pneumonia Viral/complicações , Proteína S/metabolismo , Trombose/etiologia , Imunidade Adaptativa , Animais , Infecções por Coronavirus/sangue , Infecções por Coronavirus/imunologia , Hemostasia , Humanos , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/imunologia , Trombose/sangue , Trombose/imunologia , c-Mer Tirosina Quinase/metabolismo
5.
Anticancer Res ; 40(11): 6017-6028, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33109540

RESUMO

BACKGROUND/AIM: R-spondins control WNT signaling and RSPO1 and LGR6, two of its receptors, are uniquely expressed at high levels in high-grade serous ovarian cancer (HGSOC). The aim of this study was to assess the interrelations between the expression of the RSPOs and LGRs in HGSOC and in the ovarian surface (OSE) and fallopian tube surface epithelium (FTSE) from which HGSOC arises. MATERIALS AND METHODS: Analysis of TCGA (HGSOC), CCLE (ovary), and other publicly accessed RNA-Seq data using UC San Diego Computational Cancer Analysis Library (CCAL) to perform differential expression analysis, association studies, and gene set inspection using the single-sample GSEA method. Additionally, we employed multiple publicly available databases including StringDB, Human Protein Atlas, and cBioPortal to aid the investigation. RESULTS: Among normal tissues, expression of RSPO1, LGR5 and LGR6 was highest in the fallopian tube. The relative levels of expression of the RSPOs and LGRs in the OSE and FTSE matched those in HGSOC. RSPO1 and LGR6 were highly co-expressed in all three tissues. Gene set enrichment analysis (GSEA) showed that expression of RSPO1 was strongly linked to the enrichment of three separate WNT-driven GO pathways. Analysis of genes that impacted overall survival identified two other immediately adjacent genes that control WNT signaling, KREMEN1 and ZNRF3 whose expression and copy number were coordinately linked. CONCLUSION: RSPO1 and LGR6 are coordinately expressed in HGSOC and the two normal tissues from which this tumor arises, and their expression is linked to WNT signaling pathways known the control cell fate and proliferation.


Assuntos
Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Receptores Acoplados a Proteínas-G/metabolismo , Trombospondinas/metabolismo , Via de Sinalização Wnt , Cistadenocarcinoma Seroso/genética , Tubas Uterinas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Gradação de Tumores , Neoplasias Ovarianas/genética , Ovário/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Acoplados a Proteínas-G/genética , Trombospondinas/genética , Via de Sinalização Wnt/genética
6.
Nat Commun ; 11(1): 5114, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33037205

RESUMO

Tissue growth in the adult is an orchestrated process that often requires biological clocks to time stem cell and progenitor activity. Here, we employed the hair follicle, which cycles between growth and regression in a timely-restricted mode, to show that some components of the hair cycle clock reside within the mesenchymal niche of the hair follicle, the dermal papilla (DP), and both Fgf and Wnt signaling pathways interact within the DP to regulate the expression of these components that include Wnt agonists (Rspondins) and antagonists (Dkk2 and Notum). The levels of Wnt agonists and antagonists in the DP are progressively reduced and elevated during the growth phase, respectively. Consequently, Wnt signaling activity in the overlying epithelial progenitor cells decreases, resulting in the induction of the regression phase. Remarkably, DP properties allow Wnt activity in the DP to persist despite the Wnt-inhibiting milieu and consequently synchronize the induction and progression of the regression phase. This study provides insight into the importance of signaling crosstalk in coupling progenitors and their niche to regulate tissue growth.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica , Folículo Piloso/citologia , Folículo Piloso/crescimento & desenvolvimento , Via de Sinalização Wnt/fisiologia , Animais , Esterases/genética , Esterases/metabolismo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Camundongos Knockout , Camundongos Mutantes , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Pele/citologia , Trombospondinas/genética , Trombospondinas/metabolismo
7.
Artigo em Russo | MEDLINE | ID: mdl-32929929

RESUMO

OBJECTIVE: To compare the effects of cortexin, cerebrolysin and actovegin on memory impairment, cerebral circulation and morphological changes in the hippocampus of rats with chronic brain ischemia. MATERIAL AND METHODS: The study was conducted using male rats with chronic brain ischemia caused by stenosis of the common carotid arteries by 50%. Animals received cortexin (0,3; 1 or 3 mg/kg), cerebrolysin (0,8; 2,5 or 7,5 ml/kg) and actovegin (5 ml/kg) in two 10-day courses with 10 days of treatment break. The severity of cognitive impairment was evaluated using the Morris water maze, passive and active avoidance tests. Cerebral circulation using laser flowmetry and brain hippocampus structures were studied in the end of treatment. RESULTS: Cognitive impairment in animals with chronic brain ischemia was accompanied by the development of pathological changes in the CA1 and CA4 regions of the hippocampus. Administration of cortexin (1 and 3 mg/kg) and cerebrolysin (2.5 and 7.5 ml/kg) to rats with chronic brain ischemia had almost no effect on cerebral blood flow, but contributed to the improvement in memory formation and retrieval processes in the Morris water maze. The treatment effect was comparable for both drugs and persisted after 10 days of treatment break. Morphological assessment showed a decrease in the severity of pathological changes in the hippocampal regions. CONCLUSION: The course-administration of cortexin and cerebrolysin lead to a decrease in the severity of memory impairment and pathomorphological changes in the hippocampus in rats with chronic brain ischemia.


Assuntos
Isquemia Encefálica , Aminoácidos , Animais , Circulação Cerebrovascular , Heme/análogos & derivados , Hipocampo , Peptídeos e Proteínas de Sinalização Intercelular , Masculino , Ratos , Ratos Wistar
8.
Georgian Med News ; (304-305): 43-48, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32965248

RESUMO

Aim of study - examine the association between circulating blood adipokine levels (adiponectin, resistin, irisin, nesfatin-1, apelin-12 and obestatin) and hypertension and obesity.; The study included a comprehensive survey of 98 patients, including 52 subjects with hypertension and 46 with hypertension and obesity. The levels of adiponectin, resistin, irisin, nesfatin-1, apelin-12, obestatin has been determined.; On conducting an analysis of the study population, the circulating level of resistin (19.32±0.53 ng/mL vs. 14.90±0.29 ng/mL, p=0.0024) was higher in obese subjects with hypertension than in those without obesity, whereas apelin-12 (1.51±0.09 ng/mL vs. 1.42±0.04 ng/mL, p=0.069) and obestatin (2.97±0.04 ng/mL vs. 3.06±0.04 ng/mL, p=0.073) levels were not different between the two groups. The circulating levels of adiponectin (6.83±0.10 ng/mL vs. 2.54±0.72 ng/mL, p=0.00038), irisin (1.91±0.06 ng/mL vs. 1.19±0.03 ng/mL, p=0.021) and nesfatin-1 (8.07±0.06 ng/mL vs. 6.95±0.04 ng/mL, p=0.0057) were higher in subjects with hypertension than in those with obesity.; Patients in the highest tertile of resistin were more likely to have obesity and subjects in the highest tertile of adiponectin and nesfatin-1 were more likely to have hypertension. Apelin-12 and obestatin levels in plasma did not differ according to the presence or absence of obesity. The fact that the level of resistin is highest in patients with hypertension and obesity in comparison with patients with hypertension without obesity, and the level of adipokines such as adiponectin, nesfatin-1 and irisin is higher in patients with hypertension without obesity in comparison with patients with hypertension and obesity may indicate a possible different pathogenetic role of the studied adipokines in the development of cardiovascular diseases. Since the cellular and molecular mechanisms of these changes are not definitively established and there are conflicting data in the literature, further research is needed to clarify the mechanisms of the pathogenetic role of the studied adipokines in the development of cardiovascular diseases.


Assuntos
Hipertensão , Resistina , Adiponectina , Apelina , Grelina , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Leptina , Obesidade
9.
Int J Nanomedicine ; 15: 6097-6111, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32884266

RESUMO

The development of biomaterials, stem cells and bioactive factors has led to cartilage tissue engineering becoming a promising tactic to repair cartilage defects. Various polymer three-dimensional scaffolds that provide an extracellular matrix (ECM) mimicking environment play an important role in promoting cartilage regeneration. In addition, numerous growth factors have been found in the regenerative process. However, it has been elucidated that the uncontrolled delivery of these factors cannot fully exert regenerative potential and can also elicit undesired side effects. Considering the complexity of the ECM, neither scaffolds nor growth factors can independently obtain successful outcomes in cartilage tissue engineering. Therefore, collectively, an appropriate combination of growth factors and scaffolds have great potential to promote cartilage repair effectively; this approach has become an area of considerable interest in recent investigations. Of late, an increasing trend was observed in cartilage tissue engineering towards this combination to develop a controlled delivery system that provides adequate physical support for neo-cartilage formation and also enables spatiotemporally delivery of growth factors to precisely and fully exert their chondrogenic potential. This review will discuss the role of polymer scaffolds and various growth factors involved in cartilage tissue engineering. Several growth factor delivery strategies based on the polymer scaffolds will also be discussed, with examples from recent studies highlighting the importance of spatiotemporal strategies for the controlled delivery of single or multiple growth factors in cartilage tissue engineering applications.


Assuntos
Cartilagem , Peptídeos e Proteínas de Sinalização Intercelular/administração & dosagem , Polímeros/química , Engenharia Tecidual/métodos , Tecidos Suporte/química , Animais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/metabolismo , Materiais Biocompatíveis/farmacologia , Cartilagem/citologia , Cartilagem/fisiologia , Condrogênese , Matriz Extracelular/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Células-Tronco
10.
J Endod ; 46(9S): S63-S70, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32950197

RESUMO

INTRODUCTION: Incorporating fully assembled microvascular networks into bioengineered dental pulp constructs can significantly enhance functional blood flow and tissue survival upon transplantation. Endothelial cells (ECs), cellular building blocks of vascular tissue, play an essential role in the process of prevascularization. However, obtaining sufficient ECs from a suitable source for translational application is challenging. Dental stem cells (DSCs), which exhibit a robust proliferative ability and immunocompatibility because of their autologous origin, could be a promising alternative cell source for the derivation of endothelial lineages. Under specific culture conditions, DSCs differentiate into osteo/odontogenic, adipogenic, chondrogenic, and neurogenic cell lineages. METHODS: Recently, a new approach has been developed to directly reprogram cells using chemical cocktails and growth factors. Compared with the traditional reprogramming approach based on the forced expression of exogenous transcription factors, the chemical strategy avoids the risk associated with lentiviral transduction while offering a more viable methodology to drive cell lineage switch. The aim of this review was to unveil the concept of the use of small-molecule compounds and growth factors modulating key signaling pathways to derive ECs from DSCs. RESULTS: In addition, our preliminary study showed that stem cells from the apical papilla could be induced into EC-like cells using small-molecule compounds and growth factors. These EC-like cells expressed endothelial specific genes (CD31 and VEGFR2) and proteins (CD31, VEGF receptor 2, and vascular endothelial cadherin) as well as gave rise to vessel-like tubular structures in vitro. CONCLUSIONS: Our preliminary results suggest that chemical reprogramming might offer a novel way to generate EC-like cells from dental stem cells.


Assuntos
Células Endoteliais , Células-Tronco , Diferenciação Celular , Peptídeos e Proteínas de Sinalização Intercelular , Odontogênese
11.
PLoS Genet ; 16(9): e1008916, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32877400

RESUMO

Some imprinted genes exhibit parental origin specific expression bias rather than being transcribed exclusively from one copy. The physiological relevance of this remains poorly understood. In an analysis of brain-specific allele-biased expression, we identified that Trappc9, a cellular trafficking factor, was expressed predominantly (~70%) from the maternally inherited allele. Loss-of-function mutations in human TRAPPC9 cause a rare neurodevelopmental syndrome characterized by microcephaly and obesity. By studying Trappc9 null mice we discovered that homozygous mutant mice showed a reduction in brain size, exploratory activity and social memory, as well as a marked increase in body weight. A role for Trappc9 in energy balance was further supported by increased ad libitum food intake in a child with TRAPPC9 deficiency. Strikingly, heterozygous mice lacking the maternal allele (70% reduced expression) had pathology similar to homozygous mutants, whereas mice lacking the paternal allele (30% reduction) were phenotypically normal. Taken together, we conclude that Trappc9 deficient mice recapitulate key pathological features of TRAPPC9 mutations in humans and identify a role for Trappc9 and its imprinting in controlling brain development and metabolism.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Microcefalia/genética , Obesidade/genética , Animais , Criança , Feminino , Regulação da Expressão Gênica , Frequência do Gene , Impressão Genômica , Heterozigoto , Homozigoto , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Herança Materna , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microcefalia/metabolismo , Mutação , Obesidade/metabolismo , Fenótipo
12.
Nat Commun ; 11(1): 3962, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32770059

RESUMO

Social context can dampen or amplify the perception of touch, and touch in turn conveys nuanced social information. However, the neural mechanism behind social regulation of mechanosensation is largely elusive. Here we report that fruit flies exhibit a strong defensive response to mechanical stimuli to their wings. In contrast, virgin female flies being courted by a male show a compromised defensive response to the stimuli, but following mating the response is enhanced. This state-dependent switch is mediated by a functional reconfiguration of a neural circuit labelled with the Tmc-L gene in the ventral nerve cord. The circuit receives excitatory inputs from peripheral mechanoreceptors and coordinates the defensive response. While male cues suppress it via a doublesex (dsx) neuronal pathway, mating sensitizes it by stimulating a group of uterine neurons and consequently activating a leucokinin-dependent pathway. Such a modulation is crucial for the balance between defense against body contacts and sexual receptivity.


Assuntos
Drosophila melanogaster/fisiologia , Vias Neurais/fisiologia , Comportamento Sexual Animal/fisiologia , Alelos , Animais , Corte , Proteínas de Ligação a DNA/metabolismo , Proteínas de Drosophila/metabolismo , Feminino , Neurônios GABAérgicos/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Mecanorreceptores/metabolismo , Mutação/genética , Neuropeptídeos/metabolismo , Útero/inervação , Asas de Animais/inervação
13.
DNA Cell Biol ; 39(10): 1862-1871, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32845709

RESUMO

Sepsis is a life-threatening disorder and leads to organ dysfunction and death. Therefore, searching for more alternative biomarkers is of great significance for sepsis assessment and surveillance. In our study, the gene expression profiles of 163 samples from healthy controls and septic patients were analyzed and 8 gene co-expression modules were identified by constructing weighted gene co-expression network. The blue and yellow modules showed close correlations with the phenotypic trait "days postsepsis." Besides, differentially expressed genes (DEGs) over time in septic patients were screened using Short Time-series Expression Miner (STEM) program. The intersection of genes in the blue and yellow modules and DEGs, which were significantly enriched in "HTLV-1 infection" pathway, was analyzed with protein-protein interaction network. The logistic regression model based on these eight mRNAs was constructed to determine the type of the sample reliably. Eight vital genes CECR1, ANXA2, ELANE, CTSG, AZU1, PRTN3, LYZ, and DEFA4 presented high scores and may be associated with sepsis, which provided candidate biomarkers for sepsis.


Assuntos
Sepse/genética , Transcriptoma , Adenosina Desaminase/genética , Adenosina Desaminase/metabolismo , Anexina A2/genética , Anexina A2/metabolismo , Biomarcadores/metabolismo , Catepsina G/genética , Catepsina G/metabolismo , Redes Reguladoras de Genes , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Elastase de Leucócito/genética , Elastase de Leucócito/metabolismo , Mieloblastina/genética , Mieloblastina/metabolismo , Sepse/metabolismo , Sepse/patologia , Análise de Sobrevida , alfa-Defensinas/genética , alfa-Defensinas/metabolismo
14.
Am J Hum Genet ; 107(3): 514-526, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32791035

RESUMO

Multiple morphological abnormalities of the sperm flagella (MMAF) is a severe form of asthenoteratozoospermia. Although recent studies have revealed several MMAF-associated genes and demonstrated MMAF to be a genetically heterogeneous disease, at least one-third of the cases are still not well understood for their etiology. Here, we identified bi-allelic loss-of-function variants in CFAP58 by using whole-exome sequencing in five (5.6%) unrelated individuals from a cohort of 90 MMAF-affected Chinese men. Each of the men harboring bi-allelic CFAP58 variants presented typical MMAF phenotypes. Transmission electron microscopy demonstrated striking flagellar defects with axonemal and mitochondrial sheath malformations. CFAP58 is predominantly expressed in the testis and encodes a cilia- and flagella-associated protein. Immunofluorescence assays showed that CFAP58 localized at the entire flagella of control sperm and predominantly concentrated in the mid-piece. Immunoblotting and immunofluorescence assays showed that the abundances of axoneme ultrastructure markers SPAG6 and SPEF2 and a mitochondrial sheath protein, HSP60, were significantly reduced in the spermatozoa from men harboring bi-allelic CFAP58 variants. We generated Cfap58-knockout mice via CRISPR/Cas9 technology. The male mice were infertile and presented with severe flagellar defects, consistent with the sperm phenotypes in MMAF-affected men. Overall, our findings in humans and mice strongly suggest that CFAP58 plays a vital role in sperm flagellogenesis and demonstrate that bi-allelic loss-of-function variants in CFAP58 can cause axoneme and peri-axoneme malformations leading to male infertility. This study provides crucial insights for understanding and counseling of MMAF-associated asthenoteratozoospermia.


Assuntos
Anormalidades Múltiplas/genética , Astenozoospermia/genética , Axonema/genética , Infertilidade Masculina/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Anormalidades Múltiplas/patologia , Alelos , Animais , Astenozoospermia/fisiopatologia , Axonema/patologia , Sistemas CRISPR-Cas/genética , Proteínas de Ciclo Celular/genética , Homozigoto , Humanos , Infertilidade Masculina/patologia , Mutação com Perda de Função/genética , Perda de Heterozigosidade/genética , Masculino , Camundongos , Camundongos Knockout , Proteínas dos Microtúbulos/genética , Mitocôndrias/genética , Cauda do Espermatozoide/metabolismo , Cauda do Espermatozoide/patologia , Testículo/metabolismo , Testículo/patologia , Sequenciamento Completo do Exoma
15.
Nat Commun ; 11(1): 4082, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32796832

RESUMO

The phytohormone ethylene has numerous effects on plant growth and development. Its immediate precursor, 1-aminocyclopropane-1-carboxylic acid (ACC), is a non-proteinogenic amino acid produced by ACC SYNTHASE (ACS). ACC is often used to induce ethylene responses. Here, we demonstrate that ACC exhibits ethylene-independent signaling in Arabidopsis thaliana reproduction. By analyzing an acs octuple mutant with reduced seed set, we find that ACC signaling in ovular sporophytic tissue is involved in pollen tube attraction, and promotes secretion of the pollen tube chemoattractant LURE1.2. ACC activates Ca2+-containing ion currents via GLUTAMATE RECEPTOR-LIKE (GLR) channels in root protoplasts. In COS-7 cells expressing moss PpGLR1, ACC induces the highest cytosolic Ca2+ elevation compared to all twenty proteinogenic amino acids. In ovules, ACC stimulates transient Ca2+ elevation, and Ca2+ influx in octuple mutant ovules rescues LURE1.2 secretion. These findings uncover a novel ACC function and provide insights for unraveling new physiological implications of ACC in plants.


Assuntos
Arabidopsis/metabolismo , Etilenos/metabolismo , Óvulo Vegetal/metabolismo , Tubo Polínico/metabolismo , Aminoácidos Cíclicos/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Cálcio/metabolismo , Regulação da Expressão Gênica de Plantas , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Liases/metabolismo , Reguladores de Crescimento de Planta/metabolismo
16.
Nat Commun ; 11(1): 4112, 2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32807784

RESUMO

Macropinocytosis is essential for myeloid cells to survey their environment and for growth of RAS-transformed cancer cells. Several growth factors and inflammatory stimuli are known to induce macropinocytosis, but its endogenous inhibitors have remained elusive. Stimulation of Roundabout receptors by Slit ligands inhibits directional migration of many cell types, including immune cells and cancer cells. We report that SLIT2 inhibits macropinocytosis in vitro and in vivo by inducing cytoskeletal changes in macrophages. In mice, SLIT2 attenuates the uptake of muramyl dipeptide, thereby preventing NOD2-dependent activation of NF-κB and consequent secretion of pro-inflammatory chemokine, CXCL1. Conversely, blocking the action of endogenous SLIT2 enhances CXCL1 secretion. SLIT2 also inhibits macropinocytosis in RAS-transformed cancer cells, thereby decreasing their survival in nutrient-deficient conditions which resemble tumor microenvironment. Our results identify SLIT2 as a physiological inhibitor of macropinocytosis and challenge the conventional notion that signals that enhance macropinocytosis negatively regulate cell migration, and vice versa.


Assuntos
Citoesqueleto/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Receptores Imunológicos/metabolismo , Animais , Quimiocina CXCL1/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Peptídeos e Proteínas de Sinalização Intercelular/genética , Macrófagos/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Proteínas do Tecido Nervoso/genética , Fagócitos/metabolismo , Pinocitose/genética , Pinocitose/fisiologia , Receptores Imunológicos/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Proteína rhoA de Ligação ao GTP/metabolismo
17.
Plast Reconstr Surg ; 146(2): 309-320, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32740581

RESUMO

BACKGROUND: Adipose-derived stem cells are considered as candidate cells for regenerative plastic surgery. Measures to influence cellular properties and thereby direct their regenerative potential remain elusive. Hyperbaric oxygen therapy-the exposure to 100% oxygen at an increased atmospheric pressure-has been propagated as a noninvasive treatment for a multitude of indications and presents a potential option to condition cells for tissue-engineering purposes. The present study evaluates the effect of hyperbaric oxygen therapy on human adipose-derived stem cells. METHODS: Human adipose-derived stem cells from healthy donors were treated with hyperbaric oxygen therapy at 2 and 3 atm. Viability before and after each hyperbaric oxygen therapy, proliferation, expression of surface markers and protein contents of transforming growth factor (TGF)-ß, tumor necrosis factor-α, hepatocyte growth factor, and epithelial growth factor in the supernatants of treated adipose-derived stem cells were measured. Lastly, adipogenic, osteogenic, and chondrogenic differentiation with and without use of differentiation-inducing media (i.e., autodifferentiation) was examined. RESULTS: Hyperbaric oxygen therapy with 3 atm increased viability, proliferation, and CD34 expression and reduced the CD31/CD34/CD45 adipose-derived stem cell subset and endothelial progenitor cell population. TGF-ß levels were significantly decreased after two hyperbaric oxygen therapy sessions in the 2-atm group and decreased after three hyperbaric oxygen therapy sessions in the 3-atm group. Hepatocyte growth factor secretion remained unaltered in all groups. Although the osteogenic and chondrogenic differentiation were not influenced, adipogenic differentiation and autodifferentiation were significantly enhanced, with osteogenic autodifferentiation significantly alleviated by hyperbaric oxygen therapy with 3 atm. CONCLUSION: Hyperbaric oxygen therapy with 3 atm increases viability and proliferation of adipose-derived stem cells, alters marker expression and subpopulations, decreases TGF-ß secretion, and skews adipose-derived stem cells toward adipogenic differentiation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.


Assuntos
Adipogenia/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Engenharia Celular/métodos , Células-Tronco Mesenquimais/efeitos dos fármacos , Oxigênio/administração & dosagem , Tecido Adiposo/citologia , Adulto , Biomarcadores/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Células-Tronco Mesenquimais/fisiologia , Pessoa de Meia-Idade , Pressão , Cultura Primária de Células/métodos
18.
Life Sci ; 259: 118208, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32763294

RESUMO

Cancer is the second leading cause of death worldwide, with prostate cancer, the second most commonly diagnosed cancer among men. Prostate cancer develops in the peripheral zone of the prostate gland, and the initial progression largely depends on androgens, the male reproductive hormone that regulates the growth and development of the prostate gland and testis. The currently available treatments for androgen dependent prostate cancer are, however, effective for a limited period, where the patients show disease relapse, and develop androgen-independent prostate cancer (AIPC). Studies have shown various intricate cellular processes such as, deregulation in multiple biochemical and signaling pathways, intra-tumoral androgen synthesis; AR over-expression and mutations and AR activation via alternative growth pathways are involved in progression of AIPC. The currently approved treatment strategies target a single cellular protein or pathway, where the cells slowly develop resistance and adapt to proliferate via other cellular pathways over a period of time. Therefore, an increased research aims to understand the efficacy of combination therapy, which targets multiple interlinked pathways responsible for acquisition of resistance and survival. The combination therapy is also shown to enhance efficacy as well as reduce toxicity of the drugs. Thus, the present review focuses on the signaling pathways involved in the progression of AIPC, comprising a heterogeneous population of cells and the advantages of combination therapy. Several clinical and pre-clinical studies on a variety of combination treatments have shown beneficial outcomes, yet further research is needed to understand the potential of combination therapy and its diverse strategies.


Assuntos
Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Receptores Androgênicos/metabolismo , Androgênios/metabolismo , Terapia Combinada/métodos , Progressão da Doença , Quimioterapia Combinada/métodos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Estudos Prospectivos , Próstata/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores Androgênicos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
19.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(4): 1167-1170, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32798393

RESUMO

OBJECTIVE: To investigate the effect of chidamide on the killing activity of NK (Natural killer cell, NK) cells targeting K562 cells and its related mechanism. METHODS: K562 cells were pretreated with chidamide at different concentrations and cocultured with NK cells at different effect-target ratios. The killing effect of chidamide on K562 cells by NK cells, the expression of natural killer group 2 member D (NKG2D) ligands and apoptosis rate of K562 cells were detected by flow cytometry. RESULTS: The killing sensitivity of NK cells to K562 cells could be enhanced by chidamide. The expression of ULBP2 on K562 cell surface could be up-regulate, however, the expression of ULBP1 and MICA/MICB showed no statistically difference as compared with control group. Chidamide showed no obvious cytotoxicity to K562 cells. CONCLUSION: Chidamide can significantly improve killing efficiency of NK cells on K562 cells, which may be related to the up-regulation of ULBP2 expression.


Assuntos
Antígenos de Histocompatibilidade Classe I , Células Matadoras Naturais/imunologia , Aminopiridinas , Benzamidas , Proteínas Ligadas por GPI , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Células K562 , Subfamília K de Receptores Semelhantes a Lectina de Células NK
20.
Placenta ; 99: 117-130, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32798764

RESUMO

The current challenge of the COVID-19 pandemic is complicated by the limited therapeutic options against the virus, with many being anecdotal or still undergoing confirmatory trials, underlining the urgent need for novel strategies targeting the virus. The pulmotropic virus causes loss of oxygenation in severe cases with acute respiratory distress syndrome (ARDS) and need for mechanical ventilation. This work seeks to introduce placental extract-derived biologically active components as a therapeutic option and highlights their mechanism of action relevant to COVID-19 virus. Human placenta has been used in clinical practice for over a century and there is substantial experience in clinical applications of placental extract for different indications. Aqueous extract of human placentacontains growth factors, cytokines/chemokines, natural metabolic and other compounds, anti-oxidants, amino acids, vitamins, trace elements and biomolecules, which individually or in combination show accelerated cellular metabolism, immunomodulatory and anti-inflammatory effects, cellular proliferation and stimulation of tissue regeneration processes. Placental extract treatment is proposed as a suitable therapeutic approach consideringthe above properties which could protect against initial viral entry and acute inflammation of alveolar epithelial cells, reconstitute pulmonary microenvironment and regenerate the lung. We reviewed useful therapeutic information of placental biomolecules in relation to COVID-19 treatment. We propose the new approach of using placental growth factors, chemokines and cytokine which will execute antiviral activity in coordination with innate and humoral immunity and improve patient's immunological responses to COVID-19. Executing a clinical trial using placental extract as preventive, protective and/or therapeutic approach for COVID-19treatment could advance the development of a most promising therapeutic candidate that can join the armamentaria against the COVID-19 virus.


Assuntos
Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Fator de Crescimento Placentário/uso terapêutico , Placenta/química , Pneumonia Viral/tratamento farmacológico , Anti-Inflamatórios , Antivirais , Betacoronavirus/patogenicidade , Quimiocinas/uso terapêutico , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/imunologia , Citocinas/uso terapêutico , Feminino , Humanos , Sistema Imunitário/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular , Pandemias , Peptidil Dipeptidase A , Pneumonia Viral/diagnóstico , Pneumonia Viral/imunologia , Gravidez , Receptores Virais
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