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PURPOSE: Although there is a growing emphasis on supportive care for cancer patients, those with colorectal cancer (CRC) who have ostomies require special attention in terms of their physical, psychological, spiritual, and social needs. However, there has been a lack of significant progress in meeting the supportive care needs of CRC survivors with ostomies. To bridge this gap, we conducted a prospective longitudinal study to track the trends in supportive care needs among CRC survivors with ostomies and identify any predictors over 6-month period. METHODS: A prospective longitudinal study was conducted at the wound and stoma clinic of Dalian University Affiliated Xinhua Hospital, focusing on CRC survivors with ostomies. A total of 143 participants completed self-report questionnaires on the 34-item Short-Form Supportive Care Needs Survey (SCNS-SF34-C (Mandarin)) and stoma complications at the first, third, and sixth month after surgery. ANOVA with repeated measure was utilized to assess the course of supportive care needs, with Generalized Estimating Equation (GEE) applied to identify predictors of SCNS. RESULTS: The supportive care needs and five dimensions scores were statistically significant at three time points (P < 0.05). The ratings of patients at the first, third, and sixth month after surgery revealed a decreasing trend in the scores for patient care and support, psychological needs, physical and daily living needs, and health system and information needs. However, the score for sexual needs showed an increased tendency. Higher levels supportive care needs were generally connected with a short duration after ostomy, high income level, resident medical insurance, spouse caregiver, other chronic disease, and stoma complications. CONCLUSIONS: Survivors' supportive care needs showed a dynamic trend over 6 months after surgery. Through three rounds, the primary needs were health system and information needs. It is recommended to integrate interdisciplinary health professionals and establish a comprehensive support and care system to effectively meet the diverse needs at different stages. Priority should be given to individuals with ostomies during the first and third month after surgery, particularly those with higher income levels, employee medical insurance, spouse caregivers, other chronic diseases, and stoma complications.
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Supervivientes de Cáncer , Neoplasias Colorrectales , Estomía , Humanos , Masculino , Estudios Longitudinales , Femenino , Neoplasias Colorrectales/cirugía , Persona de Mediana Edad , Supervivientes de Cáncer/psicología , Estudios Prospectivos , Anciano , Estomía/psicología , Encuestas y Cuestionarios , Apoyo Social , Evaluación de Necesidades , AdultoRESUMEN
The homeostasis of protein palmitoylation and depalmitoylation is essential for proper physiological functions in various tissues, in particular the central nervous system (CNS). The dysfunction of PPT1 (PPT1-KI, infantile neuronal ceroid lipofuscinosis [INCL] mouse model), which catalyze the depalmitoylation process, results in serious neurodegeneration accompanied by severe astrogliosis in the brain. Endeavoring to determine critical factors that might account for the pathogenesis in CNS by palm-proteomics, glial fibrillary acidic protein (GFAP) was spotted, indicating that GFAP is probably palmitoylated. Questions concerning if GFAP is indeed palmitoylated in vivo and how palmitoylation of GFAP might participate in neural pathology remain unexplored and are waiting to be investigated. Here we show that GFAP is readily palmitoylated in vitro and in vivo; specifically, cysteine-291 is the unique palmitoylated residue in GFAP. Interestingly, it was found that palmitoylated GFAP promotes astrocyte proliferation in vitro. Furthermore, we showed that PPT1 depalmitoylates GFAP, and the level of palmitoylated GFAP is overwhelmingly up-regulated in PPT1-knockin mice, which lead us to speculate that the elevated level of palmitoylated GFAP might accelerate astrocyte proliferation in vivo and ultimately led to astrogliosis in INCL. Indeed, blocking palmitoylation by mutating cysteine-291 into alanine in GFAP attenuate astrogliosis, and remarkably, the concurrent neurodegenerative pathology in PPT1-knockin mice. Together, these findings demonstrate that hyperpalmitoylated GFAP plays critical roles in regulating the pathogenesis of astrogliosis and neurodegeneration in the CNS, and most importantly, pinpointing that cysteine-291 in GFAP might be a valuable pharmaceutical target for treating INCL and other potential neurodegenerative diseases.
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Astrocitos/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Gliosis/metabolismo , Lipofuscinosis Ceroideas Neuronales/metabolismo , Tioléster Hidrolasas/genética , Animales , Astrocitos/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Técnicas de Sustitución del Gen , Técnicas de Inactivación de Genes , Proteína Ácida Fibrilar de la Glía/genética , Gliosis/genética , Humanos , Lipoilación , Ratones , Ratones Endogámicos C57BL , Lipofuscinosis Ceroideas Neuronales/genéticaRESUMEN
Oxygen regulates hypoxia-inducible factor (HIF) transcription factors to control cell metabolism, erythrogenesis, and angiogenesis. Whereas much has been elucidated about how oxygen regulates HIF, whether lipids affect HIF activity is un-known. Here, using cultured cells and two animal models, we demonstrate that lipoprotein-derived fatty acids are an independent regulator of HIF. Decreasing extracellular lipid supply inhibited HIF prolyl hydroxylation, leading to accumulation of the HIFα subunit of these heterodimeric transcription factors comparable with hypoxia with activation of downstream target genes. The addition of fatty acids to culture medium suppressed this signal, which required an intact mitochondrial respiratory chain. Mechanistically, fatty acids and oxygen are distinct signals integrated to control HIF activity. Finally, we observed lipid signaling to HIF and changes in target gene expression in developing zebrafish and adult mice, and this pathway operates in cancer cells from a range of tissues. This study identifies fatty acids as a physiological modulator of HIF, defining a mechanism for lipoprotein regulation that functions in parallel to oxygen.
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Ácidos Grasos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Lipoproteínas/química , Oxígeno/metabolismo , Animales , Perfilación de la Expresión Génica , Humanos , Hidroxilación , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Lipoproteínas/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal , Pez CebraRESUMEN
PURPOSE: We constructed a self-management program for rectal cancer survivors with colostomies and evaluated the effect of the program on self-efficacy, self-management ability, and incidence of stomal and peristomal complications. DESIGN: A prospective, nonrandomized clinical trial. SUBJECTS AND SETTING: Participants were recruited from 4 proctology departments in a tertiary hospital in northeast China. Fifty-five were assigned to the intervention group and 56 were assigned to the control group; 26 were lost to follow-up. Therefore, data analysis was based on 43 participants in the intervention group and 42 in the control group. METHODS: Control group patients received the standard care where guidance and stoma care manuals were given the day before hospital discharge, and regular telephone follow-up twice a month for 3 months. Participants in the experimental group received, in addition to standard care, a self-management program delivered via a multimedia messaging app initiated after discharge available over a 6-week period. Primary outcomes were self-efficacy and self-management ability; we also analyzed the incidence of stomal and peristomal complications as a secondary outcome. Between-groups outcomes were analyzed via a repeated-measures analysis of variance. RESULTS: Analysis indicated intervention group participants had higher levels of self-efficacy and self-management of their colostomies than did control group participants. Analysis also revealed intervention group participants had a lower incidence of peristomal complications; no differences in the incidence of stomal complications were found. CONCLUSIONS: Study findings suggest that use of the multimedia messaging app-based self-management program enhanced self-efficacy and self-management, while reducing the incidence of peristomal complications in rectal cancer survivors with colostomies.
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Neoplasias Colorrectales/cirugía , Colostomía , Educación del Paciente como Asunto , Neoplasias del Recto/cirugía , Automanejo , China , Humanos , Evaluación de Programas y Proyectos de Salud , Estudios ProspectivosRESUMEN
H19 is an imprinted long noncoding RNA abundantly expressed in embryonic liver and repressed after birth. We show that H19 serves as a lipid sensor by synergizing with the RNA-binding polypyrimidine tract-binding protein 1 (PTBP1) to modulate hepatic metabolic homeostasis. H19 RNA interacts with PTBP1 to facilitate its association with sterol regulatory element-binding protein 1c mRNA and protein, leading to increased stability and nuclear transcriptional activity. H19 and PTBP1 are up-regulated by fatty acids in hepatocytes and in diet-induced fatty liver, which further augments lipid accumulation. Ectopic expression of H19 induces steatosis and pushes the liver into a "pseudo-fed" state in response to fasting by promoting sterol regulatory element-binding protein 1c protein cleavage and nuclear translocation. Deletion of H19 or knockdown of PTBP1 abolishes high-fat and high-sucrose diet-induced steatosis. CONCLUSION: Our study unveils an H19/PTBP1/sterol regulatory element-binding protein 1 feedforward amplifying signaling pathway to exacerbate the development of fatty liver. (Hepatology 2018;67:1768-1783).
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Hígado Graso/metabolismo , Ribonucleoproteínas Nucleares Heterogéneas/metabolismo , Lipogénesis/genética , Proteína de Unión al Tracto de Polipirimidina/metabolismo , ARN Largo no Codificante/metabolismo , Animales , Western Blotting , Técnicas de Cultivo de Célula , Femenino , Hepatocitos/metabolismo , Homeostasis/genética , Humanos , Hígado/metabolismo , Masculino , Espectrometría de Masas , Metabolómica , Ratones , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismoRESUMEN
Based on our recent finding that disruption of bile acid (BA) homeostasis in mice results in the induction of hepatic long noncoding RNA H19 expression, we sought to elucidate the role of H19 in cholestatic liver fibrosis. Hepatic overexpression of H19RNA augmented bile duct ligation (BDL)-induced liver fibrosis, which was accompanied by the elevation of serum alanine aminotransferase, aspartate aminotransferase, bilirubin, and BA levels. Multiple genes related to liver fibrosis, inflammation, and biliary hyperplasia were increased in H19-BDL versus null-BDL mice, whereas genes in BA synthesis were decreased. Livers and spleens of H19-BDL mice showed significant enrichment of CD3+γδ+, interleukin-4, and interleukin-17 producing CD4+ and CD8+ immune cell populations. H19 down-regulated hepatic zinc finger E-box-binding homeobox 1 (ZEB1) but up-regulated epithelial cell adhesion molecule (EpCAM) and SRY (sex determining region Y)-box 9 expression. Mechanistically, ZEB1 repressed EpCAM promoter activity and gene transcription. H19RNA impeded ZEB1's inhibitory action by interacting with ZEB1 protein to prevent its binding to the EpCAM promoter. Hepatic overexpression of ZEB1 or knockdown of EpCAM diminished H19-induced fibrosis; the latter was also prevented in H19-/- mice. H19RNA was markedly induced by bile acids in mouse small cholangiocytes and to a lesser extent in mouse large cholangiocytes. The up-regulation of H19RNA and EpCAM correlated positively with the down-regulation of ZEB1 in primary sclerosing cholangitis and primary biliary cirrhosis liver specimens. CONCLUSION: The activation of hepatic H19RNA promoted cholestatic liver fibrosis in mice through the ZEB1/EpCAM signaling pathway. (Hepatology 2017;66:1183-1196).
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Colestasis/metabolismo , Molécula de Adhesión Celular Epitelial/metabolismo , Cirrosis Hepática/etiología , ARN Largo no Codificante/metabolismo , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismo , Adulto , Anciano , Animales , Ácidos y Sales Biliares , Colestasis/complicaciones , Femenino , Células HEK293 , Células Hep G2 , Humanos , Masculino , Ratones Endogámicos C57BL , Persona de Mediana Edad , Regulación hacia Arriba , Adulto JovenRESUMEN
The small heterodimer partner (SHP) nuclear receptor is an important regulator of nonalcoholic fatty liver disease. However, little is known about the role of SHP in alcoholic fatty liver. In this study, we used a modified chronic ethanol-binge model to examine cyclic alterations of lipid metabolism in wild-type (WT) and Shp-/- mice over a 24-hour period after binge. The serum and hepatic lipid profiles, as well as the expression of lipid synthesis genes and markers of endoplasmic reticulum stress, exhibited distinct variations in WT and Shp-/- mice in response to ethanol diet plus ethanol binge (ED+E) and control diet plus maltose binge. ED+E induced steatosis in WT mice, which correlated with a marked up-regulation of activating transcription factor 4 protein (ATF4) but down-regulation of C/EBP homologous protein (CHOP) and sterol regulatory element-binding transcription factor 1c protein (SREBP-1c). On the contrary, the control diet plus maltose binge caused lipid accumulation in Shp-/- mice, which was accompanied by a sharp elevation of CHOP, SREBP-1c, and REV-ERBα proteins but a diminished ATF4. REV-ERBα activated CHOP promoter activity and gene transcription, which were inhibited by SHP. Knockdown Rev-Erbα in Shp-/- mice prevented steatosis induced by ED+E. Our study revealed a critical role of SHP and REV-ERBα in controlling rhythmic CHOP expression in alcoholic fatty liver.
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Hígado Graso Alcohólico/etiología , Regulación de la Expresión Génica , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares/genética , Receptores Citoplasmáticos y Nucleares/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Factor de Transcripción CHOP/genética , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Regulación hacia Abajo , Etanol/efectos adversos , Hígado Graso Alcohólico/patología , Humanos , Metabolismo de los Lípidos , Lipogénesis , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares/metabolismo , Regiones Promotoras Genéticas/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Factor de Transcripción CHOP/metabolismo , Regulación hacia ArribaRESUMEN
Metabolic reprogramming is a necessary component of oncogenesis and cancer progression that solid tumors undergo when their growth outstrips local nutrient supply. The supply of lipids such as cholesterol and fatty acids is required for continued tumor cell proliferation, and oncogenic mutations stimulate de novo lipogenesis to support tumor growth. Sterol regulatory element-binding protein (SREBP) transcription factors control cellular lipid homeostasis by activating genes required for lipid synthesis and uptake. SREBPs have been implicated in the progression of multiple cancers, including brain, breast, colon, liver, and prostate. However, the role the SREBP pathway and its central regulator SREBP cleavage activating protein (SCAP) in pancreatic ductal adenocarcinoma (PDAC) has not been studied in detail. Here, we demonstrated that pancreas-specific knockout of Scap has no effect on mouse pancreas development or function, allowing for examination of the role for Scap in the murine KPC model of PDAC. Notably, heterozygous loss of Scap prolonged survival in KPC mice, and homozygous loss of Scap impaired PDAC tumor progression. Using subcutaneous and orthotopic xenograft models, we showed that S CAP is required for human PDAC tumor growth. Mechanistically, chemical or genetic inhibition of the SREBP pathway prevented PDAC cell growth under low serum conditions due to a lack of lipid supply. Highlighting the clinical importance of this pathway, the SREBP pathway is broadly required for cancer cell growth, SREBP target genes are upregulated in human PDAC tumors, and increased expression of SREBP targets genes is associated with poor survival in PDAC patients. Collectively, these results demonstrate that SCAP and the SREBP pathway activity are essential for PDAC cell and tumor growth in vitro and in vivo , identifying SCAP as a potential therapeutic target for PDAC. SIGNIFICANCE: Our findings demonstrate that SREBP pathway activation is a critical part of the metabolic reprogramming that occurs in PDAC development and progression. Therefore, targeting the SREBP pathway has significant therapeutic potential.
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PURPOSE: To examined the course and predictors of psychological distress among colorectal cancer survivors with ostomies. METHODS: 131 survivors were considered in this longitudinal study. Participants were measured at first month (T1), third month (T2), and sixth month (T3) post-operation. Psychological distress, peristomal skin complications and stomal complications were measured. All participants' sociodemographic data were collected one day before discharge. ANOVA with repeated measures was used to compare the course of psychological distress. Generalized Estimating Equations were used to determine the predictors. RESULTS: The prevalence of mild to severe psychological distress in colorectal cancer survivors undergoing colostomy at T1, T2 and T3 was 96.94%, 88.55%, and 29.77%ï¼respectively. The difference of psychological distress in survivors with ostomies at T1, T2 and T3 was statistically significant (F = 603.310, P < 0.001). Higher level psychological distress was generally differentiated by no religious belief, spouse caregiver, first and third month after ostomy, permanent enterostomy, peristomal skin complications and stomal complications. CONCLUSION: Survivors generally experience psychological distress, especially at first and third month after surgery. A multidisciplinary collaborative group comprised of Wound, Ostomy, and Continence/Enterostomal Therapy nurses and doctors, as well as psychological counselors, peer educators, and other participants, should be formed to conduct continuous assessments and management of psychological distress. Permanent enterostomies at first and third month after surgery, with spouse caregiver and no religious belief, with peristomal skin complications and stomal complications were being a priority for targeted attention.
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Neoplasias Colorrectales , Estomía , Distrés Psicológico , Enfermedades de la Piel , Neoplasias Colorrectales/complicaciones , Neoplasias Colorrectales/cirugía , Humanos , Estudios Longitudinales , Estomía/efectos adversos , Enfermedades de la Piel/complicaciones , SobrevivientesRESUMEN
This study aimed to investigate the effect of steam cooking on the proteolysis of Pacific oysters (Crassostrea gigas) using the simulated oral-gastrointestinal digestion model and a NCM460 cell monolayer. Steam cooking changed the peptide profile of the digests of oysters considerably and induced more thorough hydrolysis. However, the heat-stable allergen, Cra g 1, still had remnant fragments in the intestinal phase, which could be allergenic epitopes. Two regions of Cra g 1 (residues 224-228 and 245-248) were digestion-tolerant. Furthermore, more oligopeptides were derived from raw proteins than from steamed proteins. After molecular docking and in vitro determination, six novel angiotensin I-converting enzyme inhibitory (ACEi) peptides were finally identified in the hydrolysates (WIS, WLS, LSL, SGPF, LGPI, and IGLP). Among them, LSL exhibited the highest ACEi activity (IC50 = 107.17 nM). Our findings provide supportive information on the effective utilization of oyster proteins.
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Crassostrea , Alérgenos , Animales , Culinaria , Simulación del Acoplamiento Molecular , Proteolisis , VaporRESUMEN
Deltamethrin (DEL) can be introduced into the food chain through bioaccumulation in Pacific oysters, and then potentially threaten human health. The objective of this study was to investigate the bioaccessibility of DEL in oysters with different cooking methods after simulated digestion. DEL content in different tissues of oysters going from high to low were gills, mantle, viscera, and adductor muscle. Bioaccessibility of DEL in oysters decreased after steaming (65%) or roasting (51%) treatments compared with raw oysters (82%), which indicated that roasting can be used as a recommended cooking method for oysters. In the simulated digestion process, the concentration of DEL in the digestive juice and the bioaccessibility of DEL were affected by the pH in the gastric phase. And the transport efficiency of DEL through the monolayer molecular membrane of NCM460 cells ranged from 35 to 45%. These results can help assess the potential harm to consumers of DEL in shellfish. Furthermore, it provides a reference for the impact of lipophilic toxins in seafood.
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Adiponectin is a newly researched adipokine which participates in the regulation of energy homeostasis. AMP-activated protein kinase (AMPK) represents an energy sensor that responds to hormone and nutrition status in vivo and exerts a regulatory effect in the hypothalamus and multiple peripheral tissues. We investigated the possible mechanisms involved in appetite regulation by adiponectin in vitro with GT1-7 cells, a mouse immortalized hypothalamic neuron. The results showed that adiponectin increased the phosphorylation of AMPK, activated AMPK phosphorylated and inactivated acetyl-CoA carboxylase (ACC), and subsequently increased expression of agouti-related peptide (AgRP) mRNA. Our results also indicated that adiponectin had no effect on signal transducer and activator of transcription (STAT3). Together these findings suggest that adiponectin regulated energy homeostasis through the AMPK/ACC pathway but not the JAK/STAT3 pathway in the hypothalamus.
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Proteínas Quinasas Activadas por AMP/metabolismo , Acetil-CoA Carboxilasa/metabolismo , Adiponectina/fisiología , Metabolismo Energético , Homeostasis , Hipotálamo/metabolismo , Animales , Secuencia de Bases , Western Blotting , Línea Celular , Cartilla de ADN , Hipotálamo/enzimología , Ratones , Fosforilación , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción STAT3/metabolismoRESUMEN
OBJECTIVE: To compare clinical effect of Kirschner wire radial sector fixation and bilateral ulnar radial cross fixation in treating supracondylar fracture of humerus in children after closed reduction. METHODS: From March 2017 to December 2018, 60 children with supracondylar fracture of humerus treated with closed reduction and Kirschner wire fixation were analyzed retrospectively, and divided into two groups according to different needling methods. Thirty patients in radial three needles fan fixation group (group A), including 19 males and 11 females, aged from 2 to 10 years old with an average of (5.00±2.10) years old, 21 patients were typeâ ¡ and 9 patients were typeâ ¢ according to Gartland classification. Thirty patients in cross fixationwith 3 needles on both ulnar and radial side group(group B), including 22 males and 8 females, aged from 1 to 9 years old with an average of(5.13±2.08) years old, 19 patients were typeâ ¡and 11 patients were typeâ ¢. Healing time of fracture, postoperative complications, elbow flexion and extension activity, forearm rotation activity recovery, elbow carrying angle and angle loss after operation between two groups were observed and compared. Mayo Elbow function score at the final following up was used to evaluate clinical efficacy. RESULTS: All patients were followed up, while there were no significant difference in follow-up time and fracture healing time between two groups (P>0.05);there was 1 patient occurred iatrogenic ulnar nerve injury in group A, 9 patients in group B, and there was difference between two groups (P<0.01);2 patients in group A occurred mild displacement and 1 patient in group B, while no significant difference between two groups(P>0.05). No cubitus varus deformity, needle infection, osteofascial compartment syndrome and myositis ossificans occurred. There was no significant difference in elbow flexion, extension activity, and forearm rotation activity between two groups at 3 months after operation(P>0.05); there was no significant difference in elbow carrying angle and its loss angle between two groups at 3 and 6 months after operation (P>0.05);there was also no significant difference in Mayo Elbow function score and efficacy evaluation at the final follow-up (P>0.05). CONCLUSION: Closed reduction and Kirschner wire at the early stage of fracture has advantages of less trauma, easy reduction, stable fixation, and early functional exercise. The risk of iatrogenic ulnar nerve injury caused by fan-shaped fixation of three radial needles is less than that of cross fixation of three radial needles.
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Hilos Ortopédicos , Fracturas del Húmero , Niño , Preescolar , Femenino , Humanos , Fracturas del Húmero/cirugía , Húmero/cirugía , Lactante , Masculino , Rango del Movimiento Articular , Estudios RetrospectivosRESUMEN
In this study, the total concentration and bioaccessibility of four metals (Zn, Se, Cd, Cu) in sea cucumbers (Apostichopus japonicus) before and after cooking were measured. The concentration of Zn, Se, Cd, and Cu were 22.24 ± 0.75, 0.75 ± 0.06, 0.32 ± 0.07, and 1.88 ± 0.09 mg/kg in raw cucumber, respectively. The contents of Zn, Se, and Cu in high-pressured samples were significantly higher than that in the raw sea cumber (p < 0.01). The levels of Cd were all decreased after three thermal treatments. The intake of Zn and Cu increased in sea cucumber cooked by all thermal processes. While the bioaccessibility of Se and Cd decreased after cooking. A significant correlation was observed between the concentration and bioaccessibility of minerals. These data provide useful information for dietary risk assessments of minerals in sea cucumbers.
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Prostate cancer is the second most common cancer in men worldwide. This study focused to clarify the roles of Metadherin (MTDH) and miR-342-3p in prostate cancer. We identified that MTDH was up-regulated and miR-342-3p was down-regulated in the prostate tissues, and there is an inverse correlation between MTDH and miR-342-3p. Functional studies revealed that miR-342-3p directly targets MTDH via binding to the 3' untranslated regions (UTRs) in the prostate cancer cells. Moreover, we also found MTDH overexpression in DU145 and PC3 cells inhibited apoptosis. Subsequently, miR-342-3p has been revealed to reverse the MTDH effect on the cellular apoptosis in the further studies. Our results indicate that MTDH repress apoptosis of prostate cancer in vitro and provides a new strategy for human prostate cancer therapy in the future.
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Mesenchymal stem cells (MSC) are of interest for cell therapy since their secreted factors mediate immunomodulation and support tissue regeneration. This study investigated the direct humoral interactions between MSC and pancreatic ß-cells using human telomerase-immortalized MSC (hMSC-TERT) and rat insulinoma-derived INS-1E ß-cells. hMSC-TERT supported survival of cocultured INS-1E ß-cells during cellular stress by alloxan (ALX) and streptozotocin (STZ), but not in response to IL-1ß. Accordingly, hMSC-TERT had no effect on inflammatory cytokine-related signalling via NF-kB and p-JNK but maintained p-Akt and upregulated p-ERK1/2. Inhibition of either p-Akt or p-ERK1/2 did not abolish protection by hMSC-TERT but activated the respective non-inhibited pathway. This suggests that one pathway compensates for the other. Main results were confirmed in mouse islets except hMSC-TERT-mediated upregulation of p-ERK1/2. Therefore, MSC promote ß-cell survival by preservation of p-Akt signalling and further involve p-ERK1/2 activation in certain conditions such as loss of p-Akt or insulinoma background.
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Células Secretoras de Insulina/enzimología , Células Secretoras de Insulina/patología , Insulina/biosíntesis , Sistema de Señalización de MAP Quinasas , Células Madre Mesenquimatosas/citología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Estrés Fisiológico , Aloxano , Animales , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Citoprotección/efectos de los fármacos , Humanos , Interleucina-1beta/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Fosforilación/efectos de los fármacos , Poli(ADP-Ribosa) Polimerasas/metabolismo , Ratas Wistar , Estreptozocina , Estrés Fisiológico/efectos de los fármacos , Telomerasa/metabolismoRESUMEN
A hallmark of type 2 diabetes (T2DM) is the reduction in functional ß-cell mass, which is considered at least in part to result from an imbalance of ß-cell renewal and apoptosis, with the latter being accelerated during metabolic stress. More recent studies, however, suggest that the loss of functional ß-cell mass is not as much due to ß-cell death but rather to de-differentiation of ß-cells when these cells are exposed to metabolic stressors, opening the possibility to re-differentiate and restore functional ß-cell mass by therapeutic intervention. In parallel, clinical observations suggest that temporary intensive insulin therapy in early diagnosed humans with T2DM, so as to "rest" endogenous ß-cells, allows these patients to regain adequate insulin secretion and to maintain euglycemia for prolonged periods free of continued pharmacotherapy. Whether observations made in (mostly rodent) models of diabetes mellitus and in clinical trials are revealing identical mechanisms and therapeutic opportunities remains a tantalizing possibility. Our intention is for this review to serve as an overview of the field and commentary of this particularly exciting field of research.
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Diabetes Mellitus Tipo 2/metabolismo , Regulación hacia Abajo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Animales , Apoptosis/efectos de los fármacos , Desdiferenciación Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/patología , Humanos , Hipoglucemiantes/uso terapéutico , Insulina/biosíntesis , Insulina/uso terapéutico , Resistencia a la Insulina , Secreción de Insulina , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/patologíaRESUMEN
Bile acid (BA) metabolism is tightly controlled by nuclear receptor signaling to coordinate regulation of BA synthetic enzymes and transporters. Here we reveal a molecular cascade consisting of the antiapoptotic protein BCL2, nuclear receptor Shp, and long non-coding RNA (lncRNA) H19 to maintain BA homeostasis. Bcl2 was overexpressed in liver of C57BL/6J mice using adenovirus mediated gene delivery for two weeks. Hepatic overexpression of Bcl2 caused drastic accumulation of serum BA and bilirubin levels and dysregulated BA synthetic enzymes and transporters. Bcl2 reactivation triggered severe liver injury, fibrosis and inflammation, which were accompanied by a significant induction of H19. Bcl2 induced rapid SHP protein degradation via the activation of caspase-8 pathway. The induction of H19 in Bcl2 overexpressed mice was contributed by a direct loss of Shp transcriptional repression. H19 knockdown or Shp re-expression largely rescued Bcl2-induced liver injury. Strikingly different than Shp, the expression of Bcl2 and H19 was hardly detectable in adult liver but was markedly increased in fibrotic/cirrhotic human and mouse liver. We demonstrated for the first time a detrimental effect of Bcl2 and H19 associated with cholestatic liver fibrosis and an indispensable role of Shp to maintain normal liver function.
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Ácidos y Sales Biliares/metabolismo , Hepatopatías/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , ARN Largo no Codificante/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Animales , Ácidos y Sales Biliares/sangre , Caspasa 8/metabolismo , Línea Celular , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Células HT29 , Células HeLa , Células Hep G2 , Humanos , Hígado/metabolismo , Hepatopatías/patología , Ratones , Transducción de SeñalRESUMEN
Adiponectin secreted from adipose tissues plays a role in the regulation of energy homeostasis, food intake, and reproduction in the hypothalamus. We have previously demonstrated that adiponectin significantly inhibited GNRH secretion from GT1-7 hypothalamic GNRH neuron cells. In this study, we further investigated the effect of adiponectin on hypothalamic KISS1 gene transcription, which is the upstream signal of GNRH. We found that globular adiponectin (gAd) or AICAR, an artificial AMPK activator, decreased KISS1 mRNA transcription and promoter activity. Conversely, inhibition of AMPK by Compound C or AMPKα1-SiRNA augmented KISS1 mRNA transcription and promoter activity. Additionally, gAd and AICAR decreased the translocation of specificity protein-1 (SP1) from cytoplasm to nucleus; however, Compound C and AMPKα1-siRNA played an inverse role. Our experiments in vivo demonstrated that the expression of Kiss1 mRNA was stimulated twofold in the Compound C-treated rats and decreased about 60-70% in gAd- or AICAR-treated rats compared with control group. The numbers of kisspeptin immunopositive neurons in the arcuate nucleus region of Sprague Dawley rats mimicked the same trend seen in Kiss1 mRNA levels in animal groups with different treatments. In conclusion, our results provide the first evidence that adiponectin reduces Kiss1 gene transcription in GT1-7 cells through activation of AMPK and subsequently decreased translocation of SP1.
Asunto(s)
Adenilato Quinasa/fisiología , Adiponectina/farmacología , Hipotálamo/efectos de los fármacos , Kisspeptinas/genética , Neuronas/efectos de los fármacos , Factor de Transcripción Sp1/fisiología , Adenilato Quinasa/metabolismo , Adiponectina/fisiología , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacología , Animales , Células Cultivadas , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Femenino , Hipotálamo/citología , Hipotálamo/metabolismo , Kisspeptinas/metabolismo , Neuronas/metabolismo , Fosforilación/efectos de los fármacos , Transporte de Proteínas/efectos de los fármacos , Transporte de Proteínas/genética , Transporte de Proteínas/fisiología , Ratas , Ratas Sprague-Dawley , Ribonucleótidos/farmacología , Factor de Transcripción Sp1/metabolismo , Transcripción Genética/efectos de los fármacosRESUMEN
The aim of this study was to evaluate the associations of body mass index (BMI) with insulin resistance and ß-cell function in subjects with normal glucose tolerance. A cross-sectional study was carried out in Fujian province by multistratified sampling from July 2007 to May 2008. The sample consisted of 2931 subjects aged from 20 to 79 years. The questionnaires, physical examinations, and laboratory tests were obtained from all the participants. The homeostasis model assessment of insulin resistance (HOMA-IR) index was used to estimate insulin sensitivity, insulin secretion was assessed using the HOMA-ß index, and ß-cell function was quantified as the ratio of the incremental insulin to glucose responses over the first 30 minutes during the oral glucose tolerance test (ΔI30/ΔG30). Another measure was adjusted for insulin sensitivity as it modulates ß-cell function ([ΔI30/ΔG30]/HOMA-IR). Associations of BMI with morbidities were estimated using multiple logistic regression analysis. Relationships of BMI to insulin resistance and ß-cell function were assessed using multiple linear regression analysis and analysis of covariance. The age- and sex-adjusted prevalence of overweight and obesity was 23.04% (27.44% in men and 18.40% in women) and 2.65% (2.75% in men and 2.55% in women), respectively. After adjustment for covariables, BMI was independently associated with morbidity conditions; and there were increasing trend for odds ratios of morbidities across the BMI categories. There were independent differences for HOMA-IR, HOMA-ß, and ΔI30/ΔG30 between the normal-weight, overweight, and obese groups except for (ΔI30/ΔG30)/HOMA-IR. Body mass index was significantly and independently associated with HOMA-IR, HOMA-ß, and ΔI30/ΔG30 in the multiple linear regression analysis. Body mass index was an independent risk factor for hypertension, type 2 diabetes mellitus, dyslipidemia, metabolic syndrome, as well as the indexes of insulin resistance and ß-cell function. It is imperative that the whole society pay more attention to the identification and intervention of overweight and obesity to prevent obesity-related diseases at the very early stage.