RESUMEN
In recent years, osteoarthritis of the knee, a common degenerative joint disease, often occurs in the elderly population. This disease has a significant impact on the quality of life of patients. For treating knee osteoarthritis, physical therapy is highly regarded as a very effective treatment method. This article delves deeply into commonly used physical therapy methods and analyzes their therapeutic effects, cost-effectiveness, and applicability, aiming to find treatments with broader applicability and better cost-effectiveness. The goal is to help a large number of patients effectively alleviate the discomfort caused by knee osteoarthritis, enhance the clinical therapeutic effects, and introduce home treatment methods to reduce financial burdens. The article also compares various physical therapy methods and finds that moxibustion and electrotherapy are more suitable for home use. Other treatment methods provide a reliable scientific basis for patient treatment.
Asunto(s)
Osteoartritis de la Rodilla , Modalidades de Fisioterapia , Humanos , Osteoartritis de la Rodilla/terapia , Análisis Costo-Beneficio , Calidad de Vida , Moxibustión/métodos , Terapia por Estimulación Eléctrica/métodosRESUMEN
The distinct pathological and molecular features of kidney cancer in adaptation to oxygen homeostasis render this malignancy an attractive model for investigating hypoxia signalling and potentially developing potent targeted therapies. Hypoxia signalling has a pivotal role in kidney cancer, particularly within the most prevalent subtype, known as renal cell carcinoma (RCC). Hypoxia promotes various crucial pathological processes, such as hypoxia-inducible factor (HIF) activation, angiogenesis, proliferation, metabolic reprogramming and drug resistance, all of which contribute to kidney cancer development, growth or metastasis formation. A substantial portion of kidney cancers, in particular clear cell RCC (ccRCC), are characterized by a loss of function of Von Hippel-Lindau tumour suppressor (VHL), leading to the accumulation of HIF proteins, especially HIF2α, a crucial driver of ccRCC. Thus, therapeutic strategies targeting pVHL-HIF signalling have been explored in ccRCC, culminating in the successful development of HIF2α-specific antagonists such as belzutifan (PT2977), an FDA-approved drug to treat VHL-associated diseases including advanced-stage ccRCC. An increased understanding of hypoxia signalling in kidney cancer came from the discovery of novel VHL protein (pVHL) targets, and mechanisms of synthetic lethality with VHL mutations. These breakthroughs can pave the way for the development of innovative and potent combination therapies in kidney cancer.
RESUMEN
In cutaneous wound healing, an overproduction of inflammatory chemokines and bacterial infections impedes the process. Hydrogels can maintain a physiologically moist microenvironment, absorb chemokines, prevent bacterial infection, inhibit bacterial reproduction, and facilitate wound healing at a wound site. The development of hydrogels provides a novel treatment strategy for the entire wound repair process. Here, a series of Fructus Ligustri Lucidi polysaccharide extracts loaded with polyvinyl alcohol (PVA) and pectin hydrogels were successfully fabricated through the freeze-thaw method. A hydrogel containing a 1% mixing weight ratio of FLL-E (named PVA-P-FLL-E1) demonstrated excellent physicochemical properties such as swellability, water retention, degradability, porosity, 00drug release, transparency, and adhesive strength. Notably, this hydrogel exhibited minimal cytotoxicity. Moreover, the crosslinked hydrogel, PVA-P-FLL-E1, displayed multifunctional attributes, including significant antibacterial properties, earlier re-epithelialization, production of few inflammatory cells, the formation of collagen fibers, deposition of collagen I, and faster remodeling of the ECM. Consequently, the PVA-P-FLL-E1 hydrogel stands out as a promising wound dressing due to its superior formulation and enhanced healing effects in wound care.
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Ligustrum , Pectinas , Pectinas/farmacología , Alcohol Polivinílico , Polisacáridos/farmacología , Cicatrización de Heridas , Antibacterianos/farmacología , Antiinflamatorios/farmacología , Colágeno Tipo I , Quimiocinas , HidrogelesRESUMEN
N6-Methyladenosine (m6A) is the most abundant posttranscriptional modification, and its contribution to cancer evolution has recently been appreciated. Renal cancer is the most common adult genitourinary cancer, approximately 85% of which is accounted for by the clear cell renal cell carcinoma (ccRCC) subtype characterized by VHL loss. However, it is unclear whether VHL loss in ccRCC affects m6A patterns. In this study, we demonstrate that VHL binds and promotes METTL3/METTL14 complex formation while VHL depletion suppresses m6A modification, which is distinctive from its canonical E3 ligase role. m6A RNA immunoprecipitation sequencing (RIP-Seq) coupled with RNA-Seq allows us to identify a selection of genes whose expression may be regulated by VHL-m6A signaling. Specifically, PIK3R3 is identified to be a critical gene whose mRNA stability is regulated by VHL in a m6A-dependent but HIF-independent manner. Functionally, PIK3R3 depletion promotes renal cancer cell growth and orthotopic tumor growth while its overexpression leads to decreased tumorigenesis. Mechanistically, the VHL-m6A-regulated PIK3R3 suppresses tumor growth by restraining PI3K/AKT activity. Taken together, we propose a mechanism by which VHL regulates m6A through modulation of METTL3/METTL14 complex formation, thereby promoting PIK3R3 mRNA stability and protein levels that are critical for regulating ccRCC tumorigenesis.
Asunto(s)
Adenina , Carcinoma de Células Renales , Neoplasias Renales , Adulto , Humanos , Carcinogénesis/genética , Carcinoma de Células Renales/genética , Transformación Celular Neoplásica , Expresión Génica , Neoplasias Renales/genética , Metiltransferasas/genética , Fosfatidilinositol 3-Quinasas/genéticaRESUMEN
TANK-binding kinase 1 (TBK1) is a potential therapeutic target in multiple cancers, including clear cell renal cell carcinoma (ccRCC). However, targeting TBK1 in clinical practice is challenging. One approach to overcome this challenge would be to identify an upstream TBK1 regulator that could be targeted therapeutically in cancer specifically. In this study, we perform a kinome-wide small interfering RNA (siRNA) screen and identify doublecortin-like kinase 2 (DCLK2) as a TBK1 regulator in ccRCC. DCLK2 binds to and directly phosphorylates TBK1 on Ser172. Depletion of DCLK2 inhibits anchorage-independent colony growth and kidney tumorigenesis in orthotopic xenograft models. Conversely, overexpression of DCLK2203, a short isoform that predominates in ccRCC, promotes ccRCC cell growth and tumorigenesis in vivo. Mechanistically, DCLK2203 elicits its oncogenic signaling via TBK1 phosphorylation and activation. Taken together, these results suggest that DCLK2 is a TBK1 activator and potential therapeutic target for ccRCC.
Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinogénesis/genética , Carcinoma de Células Renales/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Transformación Celular Neoplásica/genética , Quinasas Similares a Doblecortina , Regulación Neoplásica de la Expresión Génica , Neoplasias Renales/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismoRESUMEN
Histone post-translational modifications (PTMs) are important for regulating various DNA-templated processes. Here, we report the existence of a histone PTM in mammalian cells, namely histone H3 with hydroxylation of proline at residue 16 (H3P16oh), which is catalyzed by the proline hydroxylase EGLN2. We show that H3P16oh enhances direct binding of KDM5A to its substrate, histone H3 with trimethylation at the fourth lysine residue (H3K4me3), resulting in enhanced chromatin recruitment of KDM5A and a corresponding decrease of H3K4me3 at target genes. Genome- and transcriptome-wide analyses show that the EGLN2-KDM5A axis regulates target gene expression in mammalian cells. Specifically, our data demonstrate repression of the WNT pathway negative regulator DKK1 through the EGLN2-H3P16oh-KDM5A pathway to promote WNT/ß-catenin signaling in triple-negative breast cancer (TNBC). This study characterizes a regulatory mark in the histone code and reveals a role for H3P16oh in regulating mammalian gene expression.
Asunto(s)
Histonas , Prolina , Animales , Histonas/metabolismo , Metilación , Prolina/genética , Prolina/metabolismo , Hidroxilación , Expresión Génica , Mamíferos/genéticaRESUMEN
Characterized by intracellular lipid droplet accumulation, clear cell renal cell carcinoma (ccRCC) is resistant to cytotoxic chemotherapy and is a lethal disease. Through an unbiased siRNA screen of 2-oxoglutarate (2-OG)-dependent enzymes, which play a critical role in tumorigenesis, we identified Jumonji domain-containing 6 (JMJD6) as an essential gene for ccRCC tumor development. The downregulation of JMJD6 abolished ccRCC colony formation in vitro and inhibited orthotopic tumor growth in vivo. Integrated ChIP-seq and RNA-seq analyses uncovered diacylglycerol O-acyltransferase 1 (DGAT1) as a critical JMJD6 effector. Mechanistically, JMJD6 interacted with RBM39 and co-occupied DGAT1 gene promoter with H3K4me3 to induce DGAT1 expression. JMJD6 silencing reduced DGAT1, leading to decreased lipid droplet formation and tumorigenesis. The pharmacological inhibition (or depletion) of DGAT1 inhibited lipid droplet formation in vitro and ccRCC tumorigenesis in vivo. Thus, the JMJD6-DGAT1 axis represents a potential new therapeutic target for ccRCC.
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Carcinoma de Células Renales , Diacilglicerol O-Acetiltransferasa , Histona Demetilasas con Dominio de Jumonji , Neoplasias Renales , Carcinogénesis/genética , Carcinoma de Células Renales/genética , Diacilglicerol O-Acetiltransferasa/genética , Diacilglicerol O-Acetiltransferasa/metabolismo , Epigénesis Genética , Humanos , Histona Demetilasas con Dominio de Jumonji/genética , Histona Demetilasas con Dominio de Jumonji/metabolismo , Neoplasias Renales/genética , Gotas Lipídicas/metabolismoRESUMEN
Triple-negative breast cancer (TNBC) is an aggressive and highly lethal disease. Because of its heterogeneity and lack of hormone receptors or HER2 expression, targeted therapy is limited. Here, by performing a functional siRNA screening for 2-OG-dependent enzymes, we identified gamma-butyrobetaine hydroxylase 1 (BBOX1) as an essential gene for TNBC tumorigenesis. BBOX1 depletion inhibits TNBC cell growth while not affecting normal breast cells. Mechanistically, BBOX1 binds with the calcium channel inositol-1,4,5-trisphosphate receptor type 3 (IP3R3) in an enzymatic-dependent manner and prevents its ubiquitination and proteasomal degradation. BBOX1 depletion suppresses IP3R3-mediated endoplasmic reticulum calcium release, therefore impairing calcium-dependent energy-generating processes including mitochondrial respiration and mTORC1-mediated glycolysis, which leads to apoptosis and impaired cell-cycle progression in TNBC cells. Therapeutically, genetic depletion or pharmacologic inhibition of BBOX1 inhibits TNBC tumor growth in vitro and in vivo. Our study highlights the importance of targeting the previously uncharacterized BBOX1-IP3R3-calcium oncogenic signaling axis in TNBC. SIGNIFICANCE: We provide evidence from unbiased screens that BBOX1 is a potential therapeutic target in TNBC and that genetic knockdown or pharmacologic inhibition of BBOX1 leads to decreased TNBC cell fitness. This study lays the foundation for developing effective BBOX1 inhibitors for treatment of this lethal disease.This article is highlighted in the In This Issue feature, p. 1611.
Asunto(s)
gamma-Butirobetaína Dioxigenasa/metabolismo , Proliferación Celular , Femenino , Humanos , Transducción de SeñalRESUMEN
Clear cell renal cell carcinoma (ccRCC) is characterized by loss of tumor suppressor Von Hippel Lindau (VHL) function, which leads to accumulation of hypoxia inducible factor α (including HIF1α and HIF2α). HIF2α was previously reported to be one of the major oncogenic drivers in ccRCC, however, its therapeutic targets remain challenging. Here we performed a deubiquitinase (DUB) complementary DNA (cDNA) library binding screen and discovered that ubiquitin-specific peptidase 37 (USP37) is a DUB that binds HIF2α and promotes HIF2α deubiquitination. As a result, USP37 promotes HIF2α protein stability in an enzymatically dependent manner, and depletion of USP37 leads to HIF2α down-regulation in ccRCC. Functionally, USP37 depletion causes decreased cell proliferation measured by MTS, two-dimensional (2D) colony formation as well as three-dimensional (3D) anchorage- independent growth. USP37 is also essential for maintaining kidney tumorigenesis in an orthotopic xenograft model and its depletion leads to both decreased primary kidney tumorigenesis and spontaneous lung metastasis. Our results suggest that USP37 is a potential therapeutic target in ccRCC.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Carcinoma de Células Renales/patología , Endopeptidasas/metabolismo , Neoplasias Renales/patología , Animales , Carcinogénesis , Carcinoma de Células Renales/genética , Línea Celular Tumoral , Secuenciación de Inmunoprecipitación de Cromatina , Regulación hacia Abajo , Endopeptidasas/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Renales/genética , Ratones , Estabilidad Proteica , ARN Interferente Pequeño/metabolismo , RNA-Seq , Ubiquitinación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
von Hippel-Lindau (VHL) is a critical tumor suppressor in clear cell renal cell carcinomas (ccRCCs). It is important to identify additional therapeutic targets in ccRCC downstream of VHL loss besides hypoxia-inducible factor 2α (HIF2α). By performing a genome-wide screen, we identified Scm-like with four malignant brain tumor domains 1 (SFMBT1) as a candidate pVHL target. SFMBT1 was considered to be a transcriptional repressor but its role in cancer remains unclear. ccRCC patients with VHL loss-of-function mutations displayed elevated SFMBT1 protein levels. SFMBT1 hydroxylation on Proline residue 651 by EglN1 mediated its ubiquitination and degradation governed by pVHL. Depletion of SFMBT1 abolished ccRCC cell proliferation in vitro and inhibited orthotopic tumor growth in vivo. Integrated analyses of ChIP-seq, RNA-seq, and patient prognosis identified sphingosine kinase 1 (SPHK1) as a key SFMBT1 target gene contributing to its oncogenic phenotype. Therefore, the pVHL-SFMBT1-SPHK1 axis serves as a potential therapeutic avenue for ccRCC.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales/patología , Regulación Neoplásica de la Expresión Génica , Neoplasias Renales/patología , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Proteínas Represoras/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Animales , Apoptosis , Biomarcadores de Tumor/genética , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Ciclo Celular , Movimiento Celular , Proliferación Celular , Estudio de Asociación del Genoma Completo , Humanos , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Ratones , Ratones Endogámicos NOD , Ratones SCID , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Pronóstico , Prolil Hidroxilasas/genética , Prolil Hidroxilasas/metabolismo , Proteínas Represoras/genética , Células Tumorales Cultivadas , Ubiquitinación , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
TANK binding kinase 1 (TBK1) is an important kinase involved in the innate immune response. Here we discover that TBK1 is hyperactivated by von Hippel-Lindau (VHL) loss or hypoxia in cancer cells. Tumors from patients with kidney cancer with VHL loss display elevated TBK1 phosphorylation. Loss of TBK1 via genetic ablation, pharmacologic inhibition, or a new cereblon-based proteolysis targeting chimera specifically inhibits VHL-deficient kidney cancer cell growth, while leaving VHL wild-type cells intact. TBK1 depletion also significantly blunts kidney tumorigenesis in an orthotopic xenograft model in vivo. Mechanistically, TBK1 hydroxylation on Proline 48 triggers VHL as well as the phosphatase PPM1B binding that leads to decreased TBK1 phosphorylation. We identify that TBK1 phosphorylates p62/SQSTM1 on Ser366, which is essential for p62 stability and kidney cancer cell proliferation. Our results establish that TBK1, distinct from its role in innate immune signaling, is a synthetic lethal target in cancer with VHL loss. SIGNIFICANCE: The mechanisms that lead to TBK1 activation in cancer and whether this activation is connected to its role in innate immunity remain unclear. Here, we discover that TBK1, distinct from its role in innate immunity, is activated by VHL loss or hypoxia in cancer.See related commentary by Bakouny and Barbie, p. 348.This article is highlighted in the In This Issue feature, p. 327.
Asunto(s)
Carcinoma de Células Renales/genética , Neoplasias Renales/genética , Proteínas Serina-Treonina Quinasas/genética , Proteína Sequestosoma-1/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Inmunidad Innata/genética , Neoplasias Renales/inmunología , Neoplasias Renales/patología , FosforilaciónRESUMEN
Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark of clear cell renal cell carcinoma (ccRCC). Identifying how pathways affected by VHL loss contribute to ccRCC remains challenging. We used a genome-wide in vitro expression strategy to identify proteins that bind VHL when hydroxylated. Zinc fingers and homeoboxes 2 (ZHX2) was found as a VHL target, and its hydroxylation allowed VHL to regulate its protein stability. Tumor cells from ccRCC patients with VHL loss-of-function mutations usually had increased abundance and nuclear localization of ZHX2. Functionally, depletion of ZHX2 inhibited VHL-deficient ccRCC cell growth in vitro and in vivo. Mechanistically, integrated chromatin immunoprecipitation sequencing and microarray analysis showed that ZHX2 promoted nuclear factor κB activation. These studies reveal ZHX2 as a potential therapeutic target for ccRCC.
Asunto(s)
Carcinoma de Células Renales/genética , Proteínas de Homeodominio/metabolismo , Neoplasias Renales/genética , Oncogenes , Factores de Transcripción/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Animales , Carcinoma de Células Renales/tratamiento farmacológico , Inmunoprecipitación de Cromatina , Femenino , Regulación Neoplásica de la Expresión Génica , Proteínas de Homeodominio/genética , Humanos , Hidroxilación , Neoplasias Renales/tratamiento farmacológico , Ratones , Ratones SCID , Terapia Molecular Dirigida , Mutación , FN-kappa B/metabolismo , Especificidad por Sustrato , Factores de Transcripción/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genéticaRESUMEN
The centromere regulates proper chromosome segregation, and its dysfunction is implicated in chromosomal instability (CIN). However, relatively little is known about how centromere dysfunction occurs in cancer. Here, we define the consequences of phosphorylation by cyclin E1/CDK2 on a conserved Ser18 residue of centromere-associated protein CENP-A, an essential histone H3 variant that specifies centromere identity. Ser18 hyperphosphorylation in cells occurred upon loss of FBW7, a tumor suppressor whose inactivation leads to CIN. This event on CENP-A reduced its centromeric localization, increased CIN, and promoted anchorage-independent growth and xenograft tumor formation. Overall, our results revealed a pathway that cyclin E1/CDK2 activation coupled with FBW7 loss promotes CIN and tumor progression via CENP-A-mediated centromere dysfunction. Cancer Res; 77(18); 4881-93. ©2017 AACR.
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Autoantígenos/metabolismo , Neoplasias de la Mama/patología , Proteínas de Ciclo Celular/metabolismo , Transformación Celular Neoplásica/patología , Inestabilidad Cromosómica , Proteínas Cromosómicas no Histona/metabolismo , Neoplasias del Colon/patología , Ciclina E/metabolismo , Quinasa 2 Dependiente de la Ciclina/metabolismo , Proteínas F-Box/metabolismo , Proteínas Oncogénicas/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Apoptosis , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Ciclo Celular , Proliferación Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Centrómero , Proteína A Centromérica , Neoplasias del Colon/genética , Neoplasias del Colon/metabolismo , Proteína 7 que Contiene Repeticiones F-Box-WD , Femenino , Histonas/metabolismo , Humanos , Fosforilación , Células Tumorales CultivadasRESUMEN
Non-receptor tyrosine kinase activated cdc42 kinase was reported to participate in several types of cancers in mammals. It is also believed to have an anti-apoptotic function in Drosophila. Here, we report the identification of Drosophila activated cdc42 kinase as a growth promoter and a novel Hippo signaling pathway regulator. We find that activated cdc42 kinase promotes tissue growth through modulating Yorkie activity. Furthermore, we demonstrate that activated cdc42 kinase interacts with Expanded and induces tyrosine phosphorylation of Expanded on multiple sites. We propose a model that activated cdc42 kinase negatively regulates Expanded by changing its phosphorylation status to promote tissue growth. Moreover, we show that ack genetically interacts with merlin and expanded. Thus, we identify Drosophila activated cdc42 kinase as a Hippo pathway regulator.
RESUMEN
The Hippo signaling pathway controls organ size by orchestrating cell proliferation and apoptosis. When the Hippo pathway was inactivated, the transcriptional co-activator Yorkie translocates into the nucleus and forms a complex with transcription factor Scalloped to promote the expression of Hippo pathway target genes. Therefore, the nuclear translocation of Yorkie is a critical step in Hippo signaling. Here, we provide evidence that the N-terminal 1-55 amino acids of Yorkie, especially Arg-15, were essential for its nuclear localization. By mass spectrometry and biochemical analyses, we found that Importin α1 can directly interact with the Yorkie N terminus and drive Yorkie into the nucleus. Further experiments show that the upstream component Hippo can inhibit Importin α1-mediated Yorkie nuclear import. Taken together, we identified a potential nuclear localization signal at the N-terminal end of Yorkie as well as a critical role for Importin α1 in Yorkie nuclear import.
Asunto(s)
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Señales de Localización Nuclear , Proteínas Nucleares/metabolismo , Transactivadores/metabolismo , alfa Carioferinas/metabolismo , Transporte Activo de Núcleo Celular , Animales , Línea Celular , Proteínas de Drosophila/análisis , Drosophila melanogaster/química , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas Nucleares/análisis , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Transactivadores/análisis , Proteínas Señalizadoras YAP , alfa Carioferinas/análisisRESUMEN
OBJECTIVE: To analyze the trends of multiple births rates and their perinatal outcomes in Zhejiang province from 2008 to 2013. METHODS: Data were obtained from hospital-based perinatal mortality surveillance system in Zhejiang, including all the hospitals in 30 monitoring counties (districts). All births (28 or more weeks of gestation) born in the monitoring hospitals were included in our study within 7 days after delivery from 2008 to 2013. Chi-square test was performed for statistical analyses for comparisons between regions. Trends in the incidence of multiple births and causes of perinatal death were analyzed using chi-square test for trend. RESULTS: From 2008 to 2013, the multiple births rate in Zhejiang province was increased and the rates were 2.32% (5 551/239 636), 2.49% (6 053/243 452), 2.61% (6 549/250 594), 2.82% (7 758/275 105), 2.91% (8 803/302 447) and 3.06% (9 051/295 709), respectively. And the perinatal mortality rates for multiple births were 4.32% (240/5 551), 3.45% (209/6 053), 3.76% (246/6 549), 2.86% (222/7 758), 2.77% (244/8 803) and 2.11% (191/9 051), respectively. A significant drop in the perinatal mortality rates for multiple births was observed between 2008 and 2013 (χ(2) trend = 66.52, P < 0.001). There was a significantly greater risk for perinatal death to multiple births when compared with single birth (OR = 3.62, 95% CI: 3.42-3.83). The three leading causes of perinatal death for multiple births were birth defect, premature and/or low birth weight, and twin-twin transfusion syndrome. CONCLUSION: The multiple births rates in Zhejiang province showed an increasing trend. The perinatal mortality rates for multiple births were decreased annually, however, it was still higher than those in developed countries.
Asunto(s)
Progenie de Nacimiento Múltiple , Mortalidad Perinatal , China , Anomalías Congénitas , Femenino , Transfusión Feto-Fetal , Humanos , Incidencia , Lactante , Recién Nacido de Bajo Peso , Recién Nacido , Embarazo , Embarazo Múltiple , Nacimiento PrematuroRESUMEN
Pez functions as an upstream negative regulator of Yorkie (Yki) to regulate intestinal stem cell (ISC) proliferation and is essential for the activity of the Hippo pathway specifically in the Drosophila midgut epithelium. Here we report that Suppressor of Deltex (Su(dx)) acts as a negative regulator of Pez. We show that Su(dx) targets Pez for degradation both in vitro and in vivo. Overexpression of Su(dx) induces proliferation in the fly midgut epithelium, which can be rescued by overexpressed Pez. We also demonstrate that the interaction between Su(dx) and Pez, bridged by WW domains and PY/PPxY motifs, is required for Su(dx)-mediated Pez degradation. Furthermore, we find that Kibra, a binding partner of Pez, stabilizes Pez via WW-PY/PPxY interaction. Moreover, PTPN14, a Pez mammalian homolog, is degraded by overexpressed Su(dx) or Su(dx) homologue WWP1 in mammalian cells. These results reveal a previously unrecognized mechanism of Pez degradation in maintaining the homeostasis of Drosophila midgut.
Asunto(s)
Proteínas del Citoesqueleto/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Mucosa Intestinal/crecimiento & desarrollo , Proteínas Tirosina Fosfatasas no Receptoras/genética , Proteínas Tirosina Fosfatasas/genética , Proteínas Supresoras de Tumor/metabolismo , Ubiquitina-Proteína Ligasas/genética , Animales , Línea Celular , Proliferación Celular , Proteínas del Citoesqueleto/metabolismo , Drosophila , Células HEK293 , Homeostasis , Humanos , Técnicas In Vitro , Mucosa Intestinal/citología , Mucosa Intestinal/metabolismo , Intestinos/citología , Intestinos/crecimiento & desarrollo , Proteínas Tirosina Fosfatasas/metabolismo , Proteínas Tirosina Fosfatasas no Receptoras/metabolismo , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Drosophila Hippo signaling regulates Wts activity to phosphorylate and inhibit Yki in order to control tissue growth. CK2 is widely expressed and involved in a variety of signaling pathways. In this study we report that Drosophila CK2 promotes Wts activity to phosphorylate and inhibit Yki activity, which is independent of Hpo-induced Wts promotion. In vivo, CK2 overexpression suppresses hpo mutant-induced expanded (Ex) up-regulation and overgrowth phenotype, whereas it cannot affect wts mutant. Consistent with this, knockdown of CK2 up-regulates Hpo pathway target expression. We also found that Drosophila CK2 is essential for tissue growth as a cell death inhibitor as knockdown of CK2 in the developing disc induces severe growth defects as well as caspase3 signals. Taken together, our results uncover a dual role of CK2; although its major role is promoting cell survive, it may potentially be a growth inhibitor as well.
Asunto(s)
Quinasa de la Caseína II/metabolismo , Proteínas de Drosophila/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Quinasas/metabolismo , Transducción de Señal/fisiología , Transactivadores/metabolismo , Animales , Quinasa de la Caseína II/genética , Proteínas de Drosophila/genética , Drosophila melanogaster , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Mutación , Proteínas Nucleares/genética , Proteínas Quinasas/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Transactivadores/genética , Proteínas Señalizadoras YAPRESUMEN
The Drosophila midgut has emerged as an attractive model system to study stem cell biology. Extensive studies have been carried out to investigate the mechanisms of how the signaling pathways integrate to regulate intestinal stem cells (ISCs), yet, whether the microRNAs are involved in ISC self-renewal and maintenance is unknown. Here we demonstrate that the bantam microRNA is expressed specifically at high levels in Drosophila midgut precursor cells (including ISCs and enteroblasts) and secretory enteroendocrine cells while at extremely low levels in enterocytes. Furthermore, overexpression of bantam microRNA results in increase of the division of the midgut precursor cells, whereas loss of bantam microRNA decreases their proliferation. The mechanical studies show that bantam microRNA is essential for the Hpo pathway induced cell-autonomous ISC self-renewal, while it is disposable for EGFR and Notch pathways mediated ISC proliferation. More interestingly, we find that bantam microRNA is not required for the Hpo pathway mediated non-cell-autonomous ISC proliferation, revealing a novel mechanism by which the Hpo signaling pathway specifies its transcriptional targets in specific tissue to exhibit its biological functions.
Asunto(s)
Proliferación Celular , Proteínas de Drosophila/fisiología , Drosophila/citología , Intestinos/citología , Péptidos y Proteínas de Señalización Intracelular/fisiología , MicroARNs/fisiología , Proteínas Serina-Treonina Quinasas/fisiología , Transducción de Señal/fisiología , Células Madre/citología , Animales , Diferenciación Celular , Linaje de la CélulaRESUMEN
Chromatin remodeling processes are among the most important regulatory mechanisms in controlling cell proliferation and regeneration. Drosophila intestinal stem cells (ISCs) exhibit self-renewal potentials, maintain tissue homeostasis, and serve as an excellent model for studying cell growth and regeneration. In this study, we show that Brahma (Brm) chromatin-remodeling complex is required for ISC proliferation and damage-induced midgut regeneration in a lineage-specific manner. ISCs and enteroblasts exhibit high levels of Brm proteins; and without Brm, ISC proliferation and differentiation are impaired. Importantly, the Brm complex participates in ISC proliferation induced by the Scalloped-Yorkie transcriptional complex and that the Hippo (Hpo) signaling pathway directly restricted ISC proliferation by regulating Brm protein levels by inducing caspase-dependent cleavage of Brm. The cleavage resistant form of Brm protein promoted ISC proliferation. Our findings highlighted the importance of Hpo signaling in regulating epigenetic components such as Brm to control downstream transcription and hence ISC proliferation. DOI:http://dx.doi.org/10.7554/eLife.00999.001.