RESUMEN
OBJECTIVES: To investigate the role of cell cycle protein-dependent kinase regulatory subunit 1B (CKS1B) in driving the aggressive and rapid proliferation observed in pancreatic cancer. METHODS: A comprehensive analysis was carried out using raw mRNA information and data from 2 databases: the cancer genome atlas and gene expression omnibus. The differential expression of CKS1B at the mRNA and tissue levels in cancer and adjacent paracancerous tissues were assessed. Additionally, the relationship of CKS1B expression and overall survival (OS) rate was investigated using Kaplan-Meier survival curves. Potential molecular mechanisms by which CKS1B may influence the biological characteristics of pancreatic cancer were explored using resources available within the encyclopedia of RNA interactomes database. RESULTS: The CKS1B exhibited significant differential expression at the mRNA as well as protein levels. A correlation with statistical significance between CKS1B expression and N stage, age, and alcohol consumption was observed. Notably, high CKS1B expression was determined as a predictive factor for worse OS. Furthermore, the analysis revealed a potential synergistic role between CKS1B and the molecule PKMYT1, which could impact the ATR-Chk1-Cdc25 signaling pathway and disrupt the G2/M checkpoint within the cell cycle, ultimately promoting abnormal tumor proliferation. CONCLUSION: The CKS1B may serve as a novel potential prognostic factor in pancreatic cancer and is involved in the abnormal proliferation biology phenotype by mediating cell cycle signaling pathways.
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Quinasas CDC2-CDC28 , Neoplasias Pancreáticas , Humanos , Quinasas CDC2-CDC28/genética , Ciclo Celular/genética , Proliferación Celular/genética , Proteínas de la Membrana/genética , Neoplasias Pancreáticas/genética , Fenotipo , Pronóstico , Proteínas Serina-Treonina Quinasas/genética , Proteínas Tirosina Quinasas/genética , ARN Mensajero/genética , Transducción de Señal/genéticaRESUMEN
This meta-analysis analyzed the clinical pregnancy outcomes of repeated implantation failure (RIF) patients treated with immunomodulatory therapies. Publications (published by August 16, 2021) were identified by searching the PubMed, Embase, and Web of Science databases. The quality of the studies was evaluated with the Cochrane bias risk assessment tool, and a network meta-analysis was performed with Stata 14.0. The outcomes were clinical pregnancy rate (CPR), live birth rate (LBR), and implantation rate (IR). The results of our network meta-analysis of 16 RCTs (including 2,008 participants) show that PBMCs, PRP, and SC-GCSF can significantly improve the CPR compared with LMWH (PBMCs: OR 2.15; 95% CI 1.21-3.83; PRP: OR 2.38; 95% CI 1.08-5.24; SC-GCSF: OR 2.46; 95% CI 1.05-5.72). The LBR of PRP was significantly higher than those of IU-GCSF (OR 3.81; 95% CI 1.22-11.86), LMWH (OR 4.38; 95% CI 1.50-12.90), and intralipid (OR 3.85; 95% CI 1.03-14.29), and the LBR of PBMCs was also significantly better than that of LMWH (OR 2.35; 95% CI 1.14-4.85). Furthermore, PRP treatment significantly improved the IR compared with LMWH treatment (OR 2.81; 95% CI 1.07-7.4). The limited evidence from existing RCTs suggests that PBMCs and PRP are the best therapeutic options for RIF patients. However, owing to the quantity limitation, more top-quality research is required to obtain additional high-level evidence.
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Implantación del Embrión , Heparina de Bajo-Peso-Molecular , Embarazo , Femenino , Humanos , Metaanálisis en Red , Índice de Embarazo , Inmunomodulación , Nacimiento VivoRESUMEN
BACKGROUND: Obstructive sleep apnea (OSA) is associated with cardiovascular diseases and increased sympathetic tone. We previously demonstrated that patients with OSA have increased skin sympathetic nerve activity (SKNA). OBJECTIVE: The purpose of this study was to test the hypothesis that continuous positive airway pressure (CPAP) treatment reduces SKNA. METHODS: The electrocardiogram, SKNA, and polysomnographic recording were recorded simultaneously in 9 patients with OSA. After baseline recording, CPAP titration was performed and the pressure was adjusted gradually for the optimal treatment, defined by reducing the apnea-hypopnea index (AHI) to ≤5/h. Otherwise the treatment was considered suboptimal (AHI > 5/h). Fast Fourier transform analyses were performed to investigate the frequency spectrum of SKNA. RESULTS: There were very low frequency (VLF), low frequency (LF), and high frequency (HF) oscillations in SKNA. The HF oscillation matched the frequency of respiration. OSA episodes were more frequently associated with the VLF and LF than with the HF oscillations of SKNA. Compared with baseline, CPAP significantly decreased the arousal index and AHI and increased the minimal and mean oxyhemoglobin levels. Optimal treatment significantly increased the dominant frequency and reduced the heart rate, average SKNA (aSKNA), SKNA burst duration, and total burst area. The dominant frequency negatively correlated with aSKNA. CONCLUSION: VLF, LF, and HF oscillations are observed in human SKNA recordings. Among them, VLF and LF oscillations are associated with OSA while HF oscillations are associated with normal breathing. CPAP therapy reduces aSKNA and shifts the frequency of SKNA oscillation from VLF or LF to HF.
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Presión de las Vías Aéreas Positiva Contínua , Piel/inervación , Apnea Obstructiva del Sueño/fisiopatología , Sistema Nervioso Simpático/fisiopatología , Adulto , Anciano , Electrocardiografía , Femenino , Análisis de Fourier , Humanos , Masculino , Persona de Mediana Edad , PolisomnografíaRESUMEN
BACKGROUND: To investigate the association between phosphatase and tension homologue deleted on chromosome ten (PTEN) gene polymorphisms and non-small-cell lung cancer (NSCLC) and further identify whether these polymorphisms influence serum PTEN levels. METHODS: A total of 152 NSCLC patients and 124 healthy controls were included in the study. PTEN gene rs11202586 (T > C) and rs1903858 (A > G) polymorphisms were detected using the multiple single-base extension technique (SNaPshot). The serum PTEN levels were determined using an enzyme-linked immunosorbent assay (ELISA) kit. RESULTS: The rs1903858 AG, GG genotypes, and G allele were associated with a higher risk of NSCLC (odds ratio (OR) =2.079, 95% confidence interval (CI) = 1.087-3.974, P = .027; OR = 1.897, 95%CI = 1.053-3.419, P = .033; OR = 1.505, 95%CI = 1.065-2.126, P = .020). Stratified analysis reveal that the rs1903858 GG genotype and G allele were associated with an increased risk of squamous cell carcinoma (SCC) (OR = 3.226, 95%CI = 1.075-9.678, P = .037; OR = 1.873, 95%CI = 1.092-3.212, P = .023). Among smokers, the rs1903858 G allele carriers have an increased risk of NSCLC (OR = 1.916, 95%CI = 1.023-3.589, P = .042), but a decreased risk of NSCLC was found with the AT haplotype. With respect to the serum PTEN levels, no significant difference was noted between NSCLC patients and healthy controls in this study. CONCLUSIONS: The study indicated that the rs1903858 gene polymorphism is associated with increased risk of NSCLC, particularly in SCC and smoker, and the haplotype AT was a protective factor for NSCLC. The serum PTEN levels were not associated with NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Fosfohidrolasa PTEN , Polimorfismo de Nucleótido Simple/genética , Anciano , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/epidemiología , Carcinoma de Pulmón de Células no Pequeñas/genética , Estudios de Casos y Controles , Femenino , Haplotipos/genética , Humanos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Fosfohidrolasa PTEN/sangre , Fosfohidrolasa PTEN/genéticaRESUMEN
BACKGROUND: Obstructive sleep apnea (OSA) is associated with increased cardiac arrhythmia and sudden cardiac death. We recently developed a new method (neuECG) to noninvasively measure electrocardiogram and skin sympathetic nerve activity (SKNA). OBJECTIVE: The purpose of this study was to test the hypothesis that SKNA measured during sleep study is higher in patients with OSA than in those without OSA. METHODS: We prospectively recorded neuECG and polysomnography in 26 patients undergoing a sleep study. Sleep stages were scored into rapid eye movement (REM), and non-REM sleep stages 1 (N1), 2 (N2), and 3 (N3). Average voltage of skin sympathetic nerve activity (aSKNA) and SKNA burst area were calculated for quantification. Apnea/hypopnea index (AHI) >5 per hour was used to diagnose OSA. RESULTS: There was a positive correlation (r = 0.549; P = .018) between SKNA burst area and the arousal index in OSA but not in the control group. aSKNA during sleep was 0.61 ± 0.09 µV in OSA patients (n = 18) and 0.53 ± 0.04 µV in control patients (n = 8; P = .025). Burst area was 3.26 (1.90-4.47) µV·s/min in OSA patients and 1.31 (0.67-1.94) µV·s/min in control (P = .047). More apparent differences were found during N2, when the burst area in OSA (3.06 [1.46-5.52] µV·s/min) was much higher than that of the control (0.89 [0.79-1.65] µV·s/min; P = .03). CONCLUSION: OSA patients have higher SKNA activity than control patients, with the most pronounced differences observed during N2. Arousal at the end of apnea episodes is associated with large SKNA bursts. Overlaps of aSKNA and SKNA burst area between groups suggest that not all OSA patients have increased sympathetic tone.
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Vías Autónomas/fisiopatología , Electrocardiografía/métodos , Frecuencia Cardíaca/fisiología , Piel/inervación , Apnea Obstructiva del Sueño/fisiopatología , Fases del Sueño/fisiología , Sistema Nervioso Simpático/fisiopatología , Adulto , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Polisomnografía , Estudios Prospectivos , Apnea Obstructiva del Sueño/diagnósticoRESUMEN
BACKGROUND AND OBJECTIVE: Leptin receptor (LEPR) signaling inhibits apoptosis, promotes angiogenesis and proliferation, and plays a critical role in carcinogenesis. Variants of the LEPR gene may be key factors in the growth of human malignant tumors. However, the relationship between LEPR polymorphisms and hepatocellular carcinoma (HCC) has not been thoroughly investigated. Therefore, we further investigated the association between LEPR polymorphisms and the risk of chronic hepatitis B (CHB), hepatitis B virus (HBV)-related liver cirrhosis (LC), and HCC in a southern Guangxi Chinese population. METHOD: Two LEPR polymorphisms (rs1137100 and rs1137101) were genotyped in 138 CHB patients, 136 patients with LC, 149 HCC patients, and 146 healthy controls using the SNaPshot method. RESULTS: We did not observe any significant difference in the LEPR rs1137100 and rs1137101 polymorphisms between the groups of healthy controls and patients (all p > 0.05), regardless of genotypes, alleles, or haplotypes. CONCLUSIONS: Our data suggest that the genetic variants of the LEPR gene are not associated with the risk of HBV-related liver diseases (CHB, LC, and HCC) in the Guangxi population. Further studies are necessary to validate these results.
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Carcinoma Hepatocelular/virología , Hepatitis B Crónica/genética , Cirrosis Hepática/virología , Neoplasias Hepáticas/virología , Receptores de Leptina/genética , Adulto , Pueblo Asiatico/genética , Carcinoma Hepatocelular/genética , Estudios de Casos y Controles , China , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Haplotipos , Virus de la Hepatitis B/patogenicidad , Hepatitis B Crónica/virología , Humanos , Cirrosis Hepática/genética , Neoplasias Hepáticas/genética , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: The full complement of DNA mutations that are responsible for the pathogenesis of acute myeloid leukemia (AML) is not yet known. METHODS: We used massively parallel DNA sequencing to obtain a very high level of coverage (approximately 98%) of a primary, cytogenetically normal, de novo genome for AML with minimal maturation (AML-M1) and a matched normal skin genome. RESULTS: We identified 12 acquired (somatic) mutations within the coding sequences of genes and 52 somatic point mutations in conserved or regulatory portions of the genome. All mutations appeared to be heterozygous and present in nearly all cells in the tumor sample. Four of the 64 mutations occurred in at least 1 additional AML sample in 188 samples that were tested. Mutations in NRAS and NPM1 had been identified previously in patients with AML, but two other mutations had not been identified. One of these mutations, in the IDH1 gene, was present in 15 of 187 additional AML genomes tested and was strongly associated with normal cytogenetic status; it was present in 13 of 80 cytogenetically normal samples (16%). The other was a nongenic mutation in a genomic region with regulatory potential and conservation in higher mammals; we detected it in one additional AML tumor. The AML genome that we sequenced contains approximately 750 point mutations, of which only a small fraction are likely to be relevant to pathogenesis. CONCLUSIONS: By comparing the sequences of tumor and skin genomes of a patient with AML-M1, we have identified recurring mutations that may be relevant for pathogenesis.
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Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/genética , Mutación , Adulto , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes , Genoma Humano , Humanos , Masculino , Persona de Mediana Edad , Nucleofosmina , Mutación Puntual , Análisis de Secuencia de ADN/métodosRESUMEN
Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers--including NF1, APC, RB1 and ATM--and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.
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Adenocarcinoma Bronquioloalveolar/genética , Neoplasias Pulmonares/genética , Mutación/genética , Femenino , Dosificación de Gen , Regulación Neoplásica de la Expresión Génica , Genes Supresores de Tumor , Humanos , Masculino , Proto-Oncogenes/genéticaRESUMEN
Following the loss of functional small bowel surface area, the intestine undergoes a compensatory adaptive response. The observation that adaptation is inhibited in vitamin A-deficient rats following submassive intestinal resection suggested that vitamin A is required for this response and raised the possibility that exogenous vitamin A could augment adaptation. Therefore, to directly assess whether chronically administered retinoic acid could stimulate gut adaptation in a model of short bowel syndrome and to address the mechanisms of any such effects, Sprague-Dawley rats were implanted with controlled release retinoic acid or control pellets and then subjected to mid-small bowel or sham resections. At 2 wk postoperation, changes in gut morphology, crypt cell proliferation and apoptosis, enterocyte migration, the extracellular matrix, and gene expression were assessed. Retinoic acid had significant trophic effects in resected and sham-resected rats. Retinoic acid markedly inhibited apoptosis and stimulated crypt cell proliferation and enterocyte migration postresection. Data presented indicate that these proadaptive effects of retinoic acid may be mediated via changes in the extracellular matrix (e.g., by increasing collagen IV synthesis, decreasing E-cadherin expression, and reducing integrin beta(3) levels), via affects on Hedgehog signaling (e.g., by reducing expression of the Hedgehog receptors Ptch and Ptch2 and the Gli1 transcription factor), by increasing expression of Reg1 and Pap1, and by modulation of retinoid and peroxisome proliferator-activated receptor signaling pathways. These studies are the first to demonstrate that retinoic acid can significantly enhance intestinal adaptation and suggest it may be beneficial in patients with short bowel syndrome.
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Adaptación Fisiológica/efectos de los fármacos , Intestino Delgado/efectos de los fármacos , Receptores de Ácido Retinoico/agonistas , Síndrome del Intestino Corto/tratamiento farmacológico , Tretinoina/farmacología , Adaptación Fisiológica/genética , Animales , Apoptosis/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Implantes de Medicamentos , Enterocitos/efectos de los fármacos , Enterocitos/patología , Proteínas de la Matriz Extracelular/metabolismo , Expresión Génica/efectos de los fármacos , Proteínas Hedgehog/metabolismo , Intestino Delgado/metabolismo , Intestino Delgado/patología , Intestino Delgado/fisiopatología , Intestino Delgado/cirugía , Masculino , Proteínas Asociadas a Pancreatitis , Receptores Activados del Proliferador del Peroxisoma/efectos de los fármacos , Receptores Activados del Proliferador del Peroxisoma/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Ácido Retinoico/genética , Receptores de Ácido Retinoico/metabolismo , Síndrome del Intestino Corto/genética , Síndrome del Intestino Corto/metabolismo , Síndrome del Intestino Corto/patología , Síndrome del Intestino Corto/fisiopatología , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Tretinoina/administración & dosificación , Tretinoina/uso terapéutico , Proteínas Wnt/metabolismo , beta Catenina/metabolismoRESUMEN
Dynamic and reciprocal epithelial-mesenchymal interactions are critical for the normal morphogenesis and maintenance of epithelia. Epimorphin has been identified as a unique molecule expressed by mesenchymal cells and myofibroblasts and has putative morphogenetic effects in multiple epithelial tissues, including intestine, skin, mammary gland, lung, gallbladder, and liver. To define the in vivo role of epimorphin, we created epimorphin-null mice by targeted inactivation of the epimorphin gene. Male epimorphin-/- mice are sterile due to abnormal testicular development and impaired spermatogenesis. Intestinal growth is increased in epimorphin-/- mice due to augmented crypt cell proliferation and crypt fission during the neonatal (suckling) period, mediated at least in part by changes in bone morphogenetic protein (Bmp) and Wnt/beta-catenin signaling pathways. Colonic mucosal injury and colitis induced by dextran sodium sulfate (DSS) are ameliorated in epimorphin-/- mice, probably due to the increased proliferative capacity of the epimorphin-/- colon. These in vivo findings support the notion that epimorphin is a key stromal regulator of epithelial cell proliferation and growth in the intestine. In addition, our studies demonstrate a novel and critical role for epimorphin in regulating testicular development and growth as well as spermatogenesis.
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Colitis/inducido químicamente , Sulfato de Dextran/toxicidad , Intestinos/crecimiento & desarrollo , Glicoproteínas de Membrana/metabolismo , Espermatogénesis/fisiología , Animales , Proteínas Morfogenéticas Óseas/genética , Proteínas Morfogenéticas Óseas/metabolismo , Línea Celular , Colitis/patología , Femenino , Marcación de Gen , Indicadores y Reactivos/toxicidad , Intestinos/citología , Intestinos/patología , Masculino , Glicoproteínas de Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Desnudos , Morfogénesis , Testículo/citología , Testículo/patología , Testículo/fisiología , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , beta Catenina/metabolismoRESUMEN
The intestinal epithelium undergoes a marked adaptive response following loss of functional small bowel surface area characterized by increased crypt cell proliferation and increased enterocyte migration from crypt to villus tip, resulting in villus hyperplasia and enhanced nutrient absorption. Hedgehog (Hh) signaling plays a critical role in regulating epithelial-mesenchymal interactions during morphogenesis of the embryonic intestine. Our previous studies showed that blocking Hh signaling in neonatal mice results in increased small intestinal epithelial crypt cell proliferation and altered enterocyte fat absorption and morphology. Hh family members are also expressed in the adult intestine, but their role in the mature small bowel is unclear. With the use of a model of intestinal adaptation following partial small bowel resection, the role of Hh signaling in the adult gut was examined by determining the effects of blocking Hh signaling on the regenerative response following loss of functional surface area. Hh-inactivating monoclonal antibodies or control antibodies were administered to mice that sustained a 50% intestinal resection. mRNA analyses of the preoperative ileum by quantitative real-time PCR revealed that Indian hedgehog was the most abundant Hh family member. The Hh receptor Patched was more abundant than Patched 2. Analyses of downstream targets of Hh signaling demonstrated that Gli3 was twofold more abundant than Gli1 and Gli2 and that bone morphogenetic protein (BMP)2 was most highly expressed compared with BMP1, -4, and -7. Following intestinal resection, the expression of Hh, Patched, Gli, and most BMP genes was markedly downregulated in the remnant ileum, and, in anti-Hh antibody-treated mice, expression of Patched 2 and Gli 1 was further suppressed. In Hh antibody-treated mice following resection, the enterocyte migration rate from crypt to villus tip was increased, and by 2 wk postoperation, apoptosis was increased in the adaptive gut. However, crypt cell proliferation, villus height, and crypt depth were not augmented. These data indicate that Hh signaling plays a role in adult gut epithelial homeostasis by regulating epithelial cell migration from crypt to villus tip and by enhancing apoptosis.
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Células Epiteliales/metabolismo , Mucosa Intestinal/fisiopatología , Intestino Delgado/fisiopatología , Síndrome del Intestino Corto/fisiopatología , Transducción de Señal , Transactivadores/metabolismo , Adaptación Fisiológica , Animales , Apoptosis , Movimiento Celular , Células Epiteliales/patología , Proteínas Hedgehog , Mucosa Intestinal/patología , Ratones , Ratones Endogámicos BALB C , Síndrome del Intestino Corto/patologíaRESUMEN
Hedgehog (Hh) signaling plays an important role in embryonic development of many tissues, including the gastrointestinal tract. Sonic Hh-and Indian Hh-deficient mice die before or soon after birth, precluding further study of this signaling pathway in the mature intestine. Maternal transfer of inactivating monoclonal antibodies to Hh proteins (anti-Hh moAb) during late stages of embryogenesis or to early postnatal mice produced intestinal villous abnormalities, progressive runting, and severe malabsorption of dietary fat. In the present study, we sought to determine the effect of inhibiting Hh signaling on weight gain and lipid absorption in adult mice. Anti-Hh moAb was administered to adult Balb/c mice fed either a low-fat, nonpurified diet or a high-fat, semipurified diet, and to adult ob/ob mice fed the low-fat, nonpurified diet. Weight gain was significantly inhibited by anti-Hh moAb treatment in Balb/C mice fed the high-fat, but not the low-fat diet and in ob/ob mice. Further analysis of adult Balb/c mice fed the high-fat diet demonstrated that although total lipid absorption was normal, the rate of triglyceride absorption was significantly delayed in mice treated with anti-Hh moAb and they had significantly increased fecal FFA excretion. Hepatic steatosis, found in high-fat fed Balb/c mice treated with the control moAb, was abrogated by anti-Hh moAb administration. These findings point to a potential role for Hh signaling pathways in diet-induced abnormalities of lipid metabolism.
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Transducción de Señal/fisiología , Transactivadores/antagonistas & inhibidores , Transactivadores/fisiología , Aumento de Peso/fisiología , Animales , Anticuerpos Monoclonales/farmacología , Dieta con Restricción de Grasas , Grasas de la Dieta/administración & dosificación , Enterocitos/química , Hígado Graso/prevención & control , Expresión Génica , Proteínas Hedgehog , Absorción Intestinal , Metabolismo de los Lípidos , Lípidos/genética , Ratones , Ratones Endogámicos BALB C , Ratones Obesos , ARN Mensajero/análisis , Transducción de Señal/efectos de los fármacos , Transactivadores/inmunología , Triglicéridos/metabolismoRESUMEN
BACKGROUND AND AIMS: To define better the homeostatic mechanisms contributing to small intestinal adaptation following partial resection, the relative contributions of apoptosis, cell proliferation, and enterocyte migration and the comparative roles of the intrinsic (mitochondrial) and extrinsic (death receptor-mediated) apoptotic pathways were assessed. METHODS: After 50% jejunoileal resections or transections, adaptation was analyzed in duodenal-jejunal and ileal segments from C57BL/6 Bax(+/+) (16, 48, and 168 hours postoperative) and Bax(-/-) mice (168 hours). RESULTS: Basal apoptotic rates were equivalent in all mice. By 1-week postresection, villus heights and crypt depths were increased in the duodenal-jejunal and ileal remnants of both genotypes. In Bax(+/+) mice, adaptation occurred in concert with increased crypt proliferative and apoptotic indices. Bax(-/-) mice did not show increases in proliferation or apoptosis, yet adaptive increases in villus height were enhanced relative to Bax(+/+) mice. Enterocyte migration increased in both genotypes. Postresection, the expression of caspases and genes involved in death receptor-mediated apoptosis was decreased in Bax(-/-) compared with Bax(+/+) mice. CONCLUSIONS: Postresection adaptation involves parallel changes in crypt proliferation and apoptosis, but, as observed in Bax(-/-) mice, it can occur without increased proliferation. These studies demonstrate that spontaneous gut apoptosis is Bax independent, whereas adaptation-related apoptosis is Bax-dependent. Differences between resected Bax(+/+) and Bax(-/-) mice suggest that apoptosis in the adapting gut utilizes the extrinsic pathway, but this requires linkage to the mitochondrial pathway via Bax. The increased adaptive response in Bax(-/-) mice indicates that modulation of apoptosis may be useful for enhancing adaptation.
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Apoptosis , Intestino Delgado/fisiopatología , Intestino Delgado/cirugía , Proteínas Proto-Oncogénicas c-bcl-2 , Proteínas Proto-Oncogénicas/metabolismo , Receptores del Factor de Necrosis Tumoral/metabolismo , Adaptación Fisiológica , Animales , Apoptosis/genética , División Celular , Movimiento Celular , Expresión Génica , Intestino Delgado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Microvellosidades/patología , Periodo Posoperatorio , Factores de Tiempo , Proteína X Asociada a bcl-2RESUMEN
In a prior study, vitamin A-deficient rats subjected to submassive small bowel resections did not mount a normal intestinal adaptive response by 10 days postoperatively, although adaptive increases in crypt cell proliferation were not attenuated and there were no differences in apoptotic indexes. The present study was designed to address the mechanisms by which vitamin A status effects adaptation by analyzing proliferation, apoptosis, and enterocyte migration in the early postoperative period (16 and 48 h) in vitamin A-sufficient, -deficient, and partially replenished sham-resected and resected rats. At 16 h postresection, apoptosis was significantly greater in the remnant ileum of resected vitamin A-deficient rats compared with the sufficient controls. Crypt cell proliferation was increased by resection in all dietary groups at both timepoints. However, at 48 h postresection, proliferation was significantly decreased in the vitamin A-deficient and partially replenished rats. By 48 h after resection, vitamin A deficiency also reduced enterocyte migration rates by 44%. This occurred in conjunction with decreased immunoreactive collagen IV at 48 h and 10 days postoperation. Laminin expression was also reduced by deficiency at 10 days postresection, whereas fibronectin and pancadherin were unchanged at 48 h and 10 days. These studies indicate that vitamin A deficiency inhibits intestinal adaptation following partial small bowel resection by reducing crypt cell proliferation, by enhancing early crypt cell apoptosis, and by markedly reducing enterocyte migration rates, which may be related to changes in the expression of collagen IV and other extracellular matrix components.