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The reciprocal coordination between cholesterol absorption in the intestine and de novo cholesterol synthesis in the liver is essential for maintaining cholesterol homeostasis, yet the mechanisms governing the opposing regulation of these processes remain poorly understood. Here, we identify a hormone, Cholesin, which is capable of inhibiting cholesterol synthesis in the liver, leading to a reduction in circulating cholesterol levels. Cholesin is encoded by a gene with a previously unknown function (C7orf50 in humans; 3110082I17Rik in mice). It is secreted from the intestine in response to cholesterol absorption and binds to GPR146, an orphan G-protein-coupled receptor, exerting antagonistic downstream effects by inhibiting PKA signaling and thereby suppressing SREBP2-controlled cholesterol synthesis in the liver. Therefore, our results demonstrate that the Cholesin-GPR146 axis mediates the inhibitory effect of intestinal cholesterol absorption on hepatic cholesterol synthesis. This discovered hormone, Cholesin, holds promise as an effective agent in combating hypercholesterolemia and atherosclerosis.
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Colesterol , Hormonas , Proteínas de Unión al ARN , Animales , Humanos , Ratones , Colesterol/metabolismo , Hormonas/genética , Hormonas/metabolismo , Hipercolesterolemia/metabolismo , Hígado/metabolismo , Transducción de Señal , Proteínas de Unión al ARN/metabolismoRESUMEN
PURPOSE: The aim of the study was to evaluate the feasibility of a bioabsorbable cage consisting of magnesium and magnesium phosphate cement (MPC) in a porcine lumbar interbody fusion model. METHODS: Twelve male Ba-Ma mini pigs underwent lumbar discectomy and fusion with an Mg-MPC cage or a PEEK cage at the L3/L4 and L4/L5 level. Computed tomography (CT) scans were made to evaluate the distractive property by comparing average disc space height (DSH) before and at 6, 12, and 24 weeks after the operation. After the lumbar spines were harvested at 6 or 24 weeks after the operation, micro-CT examination was conducted to analyze the fusion rate, and stiffness of motion segments was investigated through mechanical tests. A histological study was performed to evaluate the tissue type, inflammation, and osteolysis in the intervertebral space. RESULTS: CT scans showed no significant difference between the two groups in average DSH at each time point. Micro-CT scans revealed an equal fusion rate in both groups (0% at 6 weeks, 83.3% at 24 weeks). Both groups showed time-dependent increases in stability, the Mg-MPC cages achieved an inferior stiffness at 6 weeks and a comparable stiffness at 24 weeks. Histologic evaluation showed the presence of newly formed bone in both groups. However, empty spaces were observed at the interface or around the Mg-MPC cages. CONCLUSION: Compared with the PEEK cages, the Mg-MPC cages achieved comparable distraction, fusion rate, and spinal stability at 24 weeks after the operation. However, due to inferior stiffness at the early stage and fast degradation, further modification of material composition and design are necessary.
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Since biomolecules change dynamically with tumor evolution and drug treatment, it is necessary to confirm target molecule expression in real time for effective guidance of subsequent chemotherapy treatment. However, current methods to confirm target proteins require complex processing steps and invasive tissue biopsies, limiting their clinical utility for targeted treatment monitoring. Here, CTCs, as a promising liquid biopsy source, were used to molecularly characterize the target protein HER2. To accurately identify CTCs, we specifically proposed a combined molecular and morphological imaging method, rather than using specific biomarker alone or morphology analysis, we identified CTCs as CK19+/CD45-/HE+. On the basis of the accurate identification of CTCs, we further analyzed the target protein HER2 in clinical patients at the single-CTC level. Comparative analysis of the clinical results of patient pathological tissue and paired blood samples showed that CTCs had a heterogeneous HER2 expression at the single-cell level and showed results inconsistent with the immunohistochemistry results in some cases. CTC-based analysis could help clinicians have a more comprehensive understanding of patient target protein expression. We believe that CTC-based target protein studies are of great significance for the precise management of targeted therapy.
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Diagnóstico por Imagen , Humanos , Biopsia , Biopsia LíquidaRESUMEN
Abnormal accumulation of triglycerides in the liver, caused in part by increased de novo lipogenesis, results in non-alcoholic fatty liver disease and insulin resistance. Sterol regulatory element-binding protein 1 (SREBP1), an important transcriptional regulator of lipogenesis, is synthesized as an inactive precursor that binds to the endoplasmic reticulum (ER). In response to insulin signalling, SREBP1 is transported from the ER to the Golgi in a COPII-dependent manner, processed by proteases in the Golgi, and then shuttled to the nucleus to induce lipogenic gene expression; however, the mechanisms underlying enhanced SREBP1 activity in insulin-resistant obesity and diabetes remain unclear. Here we show in mice that CREB regulated transcription coactivator 2 (CRTC2) functions as a mediator of mTOR signalling to modulate COPII-dependent SREBP1 processing. CRTC2 competes with Sec23A, a subunit of the COPII complex, to interact with Sec31A, another COPII subunit, thus disrupting SREBP1 transport. During feeding, mTOR phosphorylates CRTC2 and attenuates its inhibitory effect on COPII-dependent SREBP1 maturation. As hepatic overexpression of an mTOR-defective CRTC2 mutant in obese mice improved the lipogenic program and insulin sensitivity, these results demonstrate how the transcriptional coactivator CRTC2 regulates mTOR-mediated lipid homeostasis in the fed state and in obesity.
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Metabolismo de los Lípidos , Hígado/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Factores de Transcripción/metabolismo , Animales , Unión Competitiva , Vesículas Cubiertas por Proteínas de Revestimiento/química , Vesículas Cubiertas por Proteínas de Revestimiento/metabolismo , Homeostasis , Resistencia a la Insulina , Lipogénesis , Masculino , Ratones , Ratones Obesos , Obesidad/metabolismo , Fosforilación , Procesamiento Proteico-Postraduccional , Transporte de Proteínas , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Factores de Transcripción/deficiencia , Factores de Transcripción/genética , Proteínas de Transporte Vesicular/metabolismoRESUMEN
Circulating tumor cell (CTC) analysis has been approved for cancer diagnosis and monitoring. However, efficient sorting and high-through phenotypic counting of CTCs from peripheral blood is still a challenge. In this manuscript, we propose an optofluidic flow cytometer (OFCM), which integrates a multistage microfluidic chip and a four-color fluorescence detection system. The OFCM can automatically complete CTC separation, 3D focusing in the microchannel, single-cell phenotypic analysis, and counting at 1.2 mL of whole blood/hour. A high recovery greater than 95% was obtained. Using the OFCM, we analyzed the epithelial-to-mesenchymal transition (EMT) phenotype of CTCs in patients with breast cancer and patients with nonsmall cell lung cancer, which proved that the OFCM is adaptable for phenotypic counting of various CTCs based on the fluorescence labeling of varied biomarkers. We believe that this OFCM will provide a convenient and efficient device for clinical liquid biopsy of tumors.
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Neoplasias de la Mama/patología , Citometría de Flujo , Neoplasias Pulmonares/patología , Células Neoplásicas Circulantes/patología , Transición Epitelial-Mesenquimal , Citometría de Flujo/instrumentación , Humanos , Técnicas Analíticas Microfluídicas/instrumentación , Imagen Óptica , Fenotipo , Células Tumorales CultivadasRESUMEN
Single-cell phenotypic profiling of circulating tumor cells (CTCs) in the blood of cancer patients can reveal vital tumor biology information. Even though various approaches have been provided to enrich and detect CTCs, it remains challenging for consecutive CTC sorting, enumeration, and single-cell characterizations. Here, we report an integrated microfluidic device (IMD) for single-cell phenotypic profiling of CTCs that enables automated CTCs sorting from whole blood following continuous single-cell phenotypic analysis while satisfying the requirements of both high purity (92 ± 3%) of cell sorting and high-throughput processing capacity (5 mL whole blood/3 h). Using this new technique we test the phenotypes of individual CTCs collected from xenograft tumor-bearing mice and colorectal (CRC) patients at different tumor stages. We obtained a correlation between CTC characterization and clinical tumor stage and treatment response. The developed IMD offers a high-throughput, convenient, and rapid strategy to study individual CTCs toward minimally invasive cancer therapy prediction and disease monitoring and has the potential to be translated to clinic for liquid biopsy.
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Antígenos CD/sangre , Biomarcadores de Tumor/sangre , Cadherinas/sangre , Neoplasias Colorrectales/sangre , Molécula de Adhesión Celular Epitelial/sangre , Dispositivos Laboratorio en un Chip , Células Neoplásicas Circulantes/metabolismo , Análisis de la Célula Individual/métodos , Animales , Antígenos CD/genética , Biomarcadores de Tumor/genética , Cadherinas/genética , Recuento de Células , Línea Celular Tumoral , Separación Celular/instrumentación , Separación Celular/métodos , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Molécula de Adhesión Celular Epitelial/genética , Femenino , Fluoresceína-5-Isotiocianato/química , Colorantes Fluorescentes/química , Glicoconjugados/química , Xenoinjertos , Humanos , Biopsia Líquida , Ratones , Ratones Endogámicos BALB C , Estadificación de Neoplasias , Células Neoplásicas Circulantes/patologíaRESUMEN
1-Deoxynojirimycin (DNJ), the main alkaloid in mulberry leaves, was recognized to treat patients with type 2 diabetes mellitus (T2DM). However, the regulatory mechanism of DNJ on glucose homeostasis was still unclear. In the present study, a safe concentration of 0.1-10 µmol/L for DNJ was incubated with mature 3T3-L1 adipocytes. The results demonstrated that the genes/proteins expression of insulin receptor (IR), phosphatidylinositol-3-kinase (PI3K), protein kinase B (AKt/PkB), and adiponectin (ADIPO) increased with the increasing of DNJ concentration from 0.1-10 µmol/L. However the mRNA expression of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), glucose transporter 4 (GLUT4) and glucose absorption increased to the maximum at concentration of 5 µmol/L then decreased with further increase of DNJ concentration to 10 µmol/L. Both IR and ADIPO signaling pathways simultaneously affect the glucose homeostasis regulation effect of DNJ, whereas the key response target located in AMPK and its effect on subsequent GLUT4 mRNA expression.
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1-Desoxinojirimicina/farmacología , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Adiponectina/metabolismo , Transportador de Glucosa de Tipo 4/metabolismo , Glucosa/metabolismo , Homeostasis/efectos de los fármacos , Receptor de Insulina/metabolismo , Transducción de Señal/efectos de los fármacos , Células 3T3-L1 , Animales , Ratones , Modelos BiológicosRESUMEN
In the fasted state, increases in circulating glucagon promote hepatic glucose production through induction of the gluconeogenic program. Triggering of the cyclic AMP pathway increases gluconeogenic gene expression via the de-phosphorylation of the CREB co-activator CRTC2 (ref. 1). Glucagon promotes CRTC2 dephosphorylation in part through the protein kinase A (PKA)-mediated inhibition of the CRTC2 kinase SIK2. A number of Ser/Thr phosphatases seem to be capable of dephosphorylating CRTC2 (refs 2, 3), but the mechanisms by which hormonal cues regulate these enzymes remain unclear. Here we show in mice that glucagon stimulates CRTC2 dephosphorylation in hepatocytes by mobilizing intracellular calcium stores and activating the calcium/calmodulin-dependent Ser/Thr-phosphatase calcineurin (also known as PP3CA). Glucagon increased cytosolic calcium concentration through the PKA-mediated phosphorylation of inositol-1,4,5-trisphosphate receptors (InsP(3)Rs), which associate with CRTC2. After their activation, InsP(3)Rs enhanced gluconeogenic gene expression by promoting the calcineurin-mediated dephosphorylation of CRTC2. During feeding, increases in insulin signalling reduced CRTC2 activity via the AKT-mediated inactivation of InsP(3)Rs. InsP(3)R activity was increased in diabetes, leading to upregulation of the gluconeogenic program. As hepatic downregulation of InsP(3)Rs and calcineurin improved circulating glucose levels in insulin resistance, these results demonstrate how interactions between cAMP and calcium pathways at the level of the InsP(3)R modulate hepatic glucose production under fasting conditions and in diabetes.
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Glucemia/metabolismo , Diabetes Mellitus/metabolismo , Ayuno/metabolismo , Gluconeogénesis , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Hígado/metabolismo , Animales , Calcineurina/metabolismo , Calcio/metabolismo , Señalización del Calcio , Células Cultivadas , AMP Cíclico/metabolismo , Diabetes Mellitus/sangre , Diabetes Mellitus/genética , Ayuno/sangre , Regulación de la Expresión Génica/efectos de los fármacos , Glucagón/farmacología , Gluconeogénesis/genética , Células HEK293 , Hepatocitos/metabolismo , Humanos , Resistencia a la Insulina , Hígado/citología , Ratones , Fosforilación/efectos de los fármacos , Transactivadores/metabolismo , Factores de TranscripciónRESUMEN
Energy metabolism follows a diurnal pattern responding to the cycles of light and food exposures. Although food availability is a potent synchronizer of peripheral circadian clock in mammals, the underlying mechanism remains elusive. Here, we found that the temporal signals of fasting and refeeding hormones regulate the transcription of Bmal1, a key transcription activator of molecular clock, in the liver. During fasting, glucagon, a major fasting hormone, activates CREB/CRTC2 transcriptional complex that is recruited to Bmal1 promoter to induce its expression. Furthermore, we showed that CRTC2 is required for basal transcriptional regulation of Bmal1 by experiments using either adenovirus-mediated CRTC2 RNAi knockdown or primary Crtc2 null hepatocytes. On the other hand, insulin suppresses fasting-induced Bmal1 expression by inhibiting CRTC2 activity after refeeding. Taken together, our results indicate CRTC2 as a key component of the circadian oscillator that integrates the mammalian clock and energy metabolism.
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Factores de Transcripción ARNTL/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Glucagón/metabolismo , Hígado/metabolismo , Factores de Transcripción/fisiología , Animales , Línea Celular , Ritmo Circadiano , Glucocorticoides/metabolismo , Gluconeogénesis , Células HEK293 , Hepatocitos/metabolismo , Humanos , Insulina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Oscilometría , Regiones Promotoras Genéticas , Interferencia de ARN , Transducción de Señal/genética , Transcripción GenéticaRESUMEN
In fasted mammals, circulating pancreatic glucagon stimulates hepatic gluconeogenesis in part through the CREB regulated transcription coactivator 2 (CRTC2, also referred to as TORC2). Hepatic glucose production is increased in obesity, reflecting chronic increases in endoplasmic reticulum (ER) stress that promote insulin resistance. Whether ER stress also modulates the gluconeogenic program directly, however, is unclear. Here we show that CRTC2 functions as a dual sensor for ER stress and fasting signals. Acute increases in ER stress triggered the dephosphorylation and nuclear entry of CRTC2, which in turn promoted the expression of ER quality control genes through an association with activating transcription factor 6 alpha (ATF6alpha, also known as ATF6)--an integral branch of the unfolded protein response. In addition to mediating CRTC2 recruitment to ER stress inducible promoters, ATF6alpha also reduced hepatic glucose output by disrupting the CREB-CRTC2 interaction and thereby inhibiting CRTC2 occupancy over gluconeogenic genes. Conversely, hepatic glucose output was upregulated when hepatic ATF6alpha protein amounts were reduced, either by RNA interference (RNAi)-mediated knockdown or as a result of persistent stress in obesity. Because ATF6alpha overexpression in the livers of obese mice reversed CRTC2 effects on the gluconeogenic program and lowered hepatic glucose output, our results demonstrate how cross-talk between ER stress and fasting pathways at the level of a transcriptional coactivator contributes to glucose homeostasis.
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Retículo Endoplásmico/metabolismo , Ayuno/fisiología , Gluconeogénesis/fisiología , Hígado/metabolismo , Estrés Fisiológico/fisiología , Transactivadores/metabolismo , Factores de Transcripción/metabolismo , Factor de Transcripción Activador 6 , Animales , Núcleo Celular/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Regulación de la Expresión Génica , Masculino , Proteínas de la Membrana/metabolismo , Ratones , Obesidad/fisiopatología , Transporte de ProteínasRESUMEN
OBJECTIVE: To screen and summarize evaluation indexes for symptom changes in Chinese medicine (CM). METHODS: A case database was established based on information from subsequent patient visits from the case records of famous doctors since 1866. Symptom change descriptions in the database were regarded as research materials. The evaluation indexes of the symptom changes were screened and summarized. RESULTS: In total, 243 evaluation indexes for 256 symptoms were summarized. Among them, common symptoms were frequency, quantity, degree, mobility, color, and correlation with fatigue. CONCLUSION: There are many aspects to evaluating the changes in a symptom. Some symptoms occur with other simultaneous symptoms. The alleviation or aggravation of simultaneous symptoms could reflect the corresponding changes in a symptom. The changes of inducing factors are important to judging changes in symptoms.
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Medicina Tradicional China/métodos , Evaluación de Síntomas/métodos , Bases de Datos Factuales/estadística & datos numéricos , Diagnóstico Diferencial , HumanosRESUMEN
The aim of this study was to investigate the expression of recombinant Hepatitis B virus (HBV) in normal human glomerular mesangial cells (NHMC) and its effect on cell apoptosis. Cell transfection was conducted by the liposome method. The levels of HBsAg and HBeAg in the culture supernatant were detected by electrochemiluminescence. Morphological changes were observed by light and fluorescence microscopy. Cell proliferation was analysed by the methyl thiazole tetrazolium (MTT) assay and cell apoptosis, by flow cytometry. The expression level of Bax and Bcl-2 mRNA was measured by semi-quantitative reverse-transcription polymerase chain reaction (RT-PCR). Caspase-3 activity was detected by a Caspase-3 activity detection kit. The results showed high expression levels of HBsAg and HBeAg in NHMC cells transfected with recombinant full-length C genotype HBV (PHY106-CHBV). Typical apoptotic morphology was observed at 48 h after PHY106-CHBV transfection. Cell proliferation was inhibited. The percentage of apoptotic cells and the expression level of Bax mRNA were significantly higher in the PHY106-CHBV group than those in the blank control group and the PHY106 group. There was no significant difference in the expression level of Bcl-2 mRNA among the three groups. Caspase-3 was significantly activated after PHY106-CHBV transfection. The results demonstrate that recombinant HBV can be expressed in NHMC and its expression induces NHMC apoptosis.
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Background: Dl-3-n-Butylphthalide (NBP) has emerged as a potential therapeutic agent for cerebral hemorrhage, despite not being included in current guideline recommendations. Investigating the underlying physiological and pathological mechanisms of Dl-3-n-Butylphthalide in cerebral hemorrhage treatment remains a critical area of research. Objective: This review aims to evaluate the efficacy of Dl-3-n-Butylphthalide in cerebral hemorrhage treatment and elucidate its potential biological mechanisms, thereby providing evidence to support treatment optimization. Methods: A comprehensive search of seven electronic databases (PubMed, Web of Science, Embase, Cochrane Library, China National Knowledge Infrastructure, VIP, and Wanfang Database) was conducted for studies published up to September 2023. Screening and data extraction were performed by a team of researchers. The Cochrane collaboration tool was utilized for risk bias assessment, and Revman 5.3 along with Stata 17.0 were employed for statistical analysis. Outcomes: We searched 254 literature, and 19 were included in this meta-analysis. The results showed that Dl-3-n-Butylphthalide improved the clinical efficacy rate (RR = 1.25, 95% CI 1.19-1.31; p = 0.00), quality of life (MD = 13.93, 95% CI: 11.88-15.98; p = 0.000), increased cerebral blood flow and velocity, reduced cerebral edema volume, Hcy concentration, and did not have obvious adverse reactions (RR = 0.68, 95% CI: 0.39-1.18; p = 0.10). Conclusion: This meta-analysis is the first to demonstrate the potential of Dl-3-n-Butylphthalide in treating cerebral hemorrhage. It suggests that Dl-3-n-Butylphthalide may alleviate clinical symptoms by modulating neurological function and improving hemodynamics. Our findings provide robust evidence for incorporating Dl-3-n-Butylphthalide into cerebral hemorrhage treatment strategies, potentially guiding future clinical practice and research. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/ display_record.php?RecordID=355114, Identifier CRD42022355114.
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Renal dysfunction can lead to insulin resistance and increase the incidence of type 2 diabetes mellitus (T2DM). The blood urea nitrogen to creatinine ratio (NCR) is a frequently used indicator to assess renal dysfunction and differentiate between prerenal and intrinsic renal injury. However, the association between NCR and T2DM in the Chinese population remains unclear. Hence, this study aimed to investigate the association between NCR and the incidence of T2DM in the Chinese population. The relationship between NCR and T2DM was examined using the Cox proportional hazards model and curve fitting techniques. In addition, a comprehensive set of sensitivity and subgroup analyses were performed. All results were presented as hazard ratios (HRs) and 95% confidence intervals (CIs). Between 2010 and 2016, 189,416 Chinese people were recruited from the Rich Healthcare Group for this retrospective cohort study. Of the participants, 3755 (19.8%) were diagnosed with T2DM during the follow-up period. After full adjustment, the Cox proportional hazards model revealed a positive connection between NCR and the incidence of T2DM (HRâ =â 1.03, 95% CI: 1.02-1.04, Pâ <â .001). Compared with individuals with lower NCR Q1 (≤13.536), the multivariate HR for NCR and T2DM in Q2 (13.536-16.256), Q3 (16.256-19.638), Q4 (>19.638) were 1.08 (0.98-1.19), 1.16 (1.05-1.28), 1.39 (1.26-1.53). The higher NCR groups (≥20) had a higher ratio of T2DM (HRâ =â 1.28, 95% CI: 1.18-1.38, Pâ <â .001) than the lowest NCR group (<20). These findings were validated using sensitivity and subgroup analyses. In conclusion, this study found a positive and independent association between NCR and the incidence of T2DM after adjusting for confounding variables.
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Nitrógeno de la Urea Sanguínea , Creatinina , Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/sangre , Masculino , Estudios Retrospectivos , Femenino , Persona de Mediana Edad , China/epidemiología , Creatinina/sangre , Incidencia , Modelos de Riesgos Proporcionales , Anciano , Adulto , Biomarcadores/sangre , Factores de Riesgo , Pueblos del Este de AsiaRESUMEN
Methylation of microRNAs (miRNAs) is a post-transcriptional modification that affects miRNA activity by altering the specificity of miRNAs to target mRNAs. Abnormal methylation of miRNAs in cancer suggests their potential as a tumor marker. However, the traditional methylated miRNA detection mainly includes mass spectrometry, sequencing and others; complex procedures and reliance on large instruments greatly limit their application in point-of-care testing (POCT). Based on this, we developed DNAzyme-RCA-based gold nanoparticle (AuNP) colorimetric and lateral flow dipstick (LFD) assays to achieve convenient detection of exosomal 5-methylcytosine miRNA-21 (m5C-miRNA-21) for the first time. The two assays achieved specific recognition and linear amplification of m5C-miRNA-21 through the DNAzyme triggered RCA reaction and color output with low background interference through AuNP aggregation induced by base complementary pairing. The lowest concentration of m5C-miRNA-21 visible to the naked eye of the two assays can reach 1 pM and 0.1 pM, respectively. Detection of exosomal m5C-miRNA-21 in clinical blood samples showed that the expression level of m5C-miRNA-21 in colorectal cancer patients was significantly higher than that in healthy individuals. This approach not only demonstrates a new strategy for the detection of colorectal cancer but also provides a reference for the development of novel diagnostic tools for other miRNA methylation-related diseases.
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Hepatocellular carcinoma (HCC) typically originates from HBV or HCV associated liver cirrhosis. Primary Sjögren's syndrome (pSS) is a kind of autoimmune disease. A sixty-two year old female patient with mild liver damage was diagnosed with pSS after excluding viral, alcoholic and drug-induced hepatitis according to serum immunological detection and liver biopsy. But when she was hospitalized for a second time two years later, a CT scan revealed liver neoplasm. Surgery confirmed HCC and liver cirrhosis by pathology. The elevated level of AFP recovered to normal after tumorectomy. In conclusion, HCC might be a candidate outcome in patients with pSS; it is the doctors' responsibility to keep this kind of patient under surveillance.
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Carcinoma Hepatocelular/etiología , Neoplasias Hepáticas/etiología , Síndrome de Sjögren/complicaciones , Biopsia , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/cirugía , Quimioterapia Adyuvante , Femenino , Hepatectomía , Humanos , Cirrosis Hepática/etiología , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/cirugía , Persona de Mediana Edad , Síndrome de Sjögren/diagnóstico , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , alfa-Fetoproteínas/metabolismoRESUMEN
The plant homeodomain (PHD) finger is identified in many chromatin-binding proteins, and functions as a 'reader' that recognizes specific epigenetic marks on histone tails, bridging transcription factors and their associated complexes to chromatin, and regulating gene expression. PHD finger-containing proteins perform many biological functions and are involved in many human diseases including cancer. PHF14 is predicted to code for a protein with multiple PHD fingers. However, its function is unidentified. The aim of this study is to characterize PHF14 and investigate its biological significance by employing multiple approaches including mouse gene-targeting knockout, and molecular cloning and characterization. Three transcripts of PHF14 in human cell lines were identified by reverse transcriptase polymerase chain reaction. Two isoforms of PHF14 (PHF14α and PHF14ß) were cloned in this study. It was found that PHF14 was ubiquitously expressed in mouse tissues and human cell lines. PHF14α, the major isoform of PHF14, was localized in the nucleus and also bound to chromatin during cell division. Interestingly, co-immunoprecipitation results suggested that PHF14α bound to histones via its PHD fingers. Strikingly, gene-targeting knockout of PHF14 in mice resulted in a neonatal lethality due to respiratory failure. Pathological analysis revealed severe disorders of tissue and cell structures in multiple organs, particularly in the lungs. These results indicated that PHF14 might be an epigenetic regulator and play an important role in the development of multiple organs in mouse.
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Genes Letales , Insuficiencia Respiratoria/genética , Factores de Transcripción/genética , Secuencia de Aminoácidos , Animales , Animales Recién Nacidos , Secuencia de Bases , Cartilla de ADN , Células HEK293 , Humanos , Ratones , Ratones Noqueados , Datos de Secuencia Molecular , Reacción en Cadena en Tiempo Real de la Polimerasa , Homología de Secuencia de Aminoácido , Factores de Transcripción/químicaRESUMEN
Under fasting conditions, increases in circulating concentrations of pancreatic glucagon maintain glucose homeostasis through induction of gluconeogenic genes by the CREB coactivator CRTC2. Hepatic CRTC2 activity is elevated in obesity, although the extent to which this cofactor contributes to attendant increases in insulin resistance is unclear. Here we show that mice with a knockout of the CRTC2 gene have decreased circulating glucose concentrations during fasting, due to attenuation of the gluconeogenic program. CRTC2 was found to stimulate hepatic gene expression in part through an N-terminal CREB binding domain that enhanced CREB occupancy over relevant promoters in response to glucagon. Deletion of sequences encoding the CREB binding domain in CRTC2 (-/-) mice lowered circulating blood glucose concentrations and improved insulin sensitivity in the context of diet-induced obesity. Our results suggest that small molecules that attenuate the CREB-CRTC2 pathway may provide therapeutic benefit to individuals with type 2 diabetes.
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Diabetes Mellitus Tipo 2/metabolismo , Regulación de la Expresión Génica/genética , Gluconeogénesis/genética , Transactivadores/deficiencia , Animales , Glucemia/metabolismo , Inmunoprecipitación de Cromatina , Cartilla de ADN/genética , Electroforesis en Gel de Poliacrilamida , Ensayo de Cambio de Movilidad Electroforética , Silenciador del Gen , Glucagón/sangre , Gluconeogénesis/fisiología , Immunoblotting , Luciferasas , Ratones , Ratones Noqueados , Reacción en Cadena de la Polimerasa , Transactivadores/genética , Transactivadores/metabolismo , Factores de TranscripciónRESUMEN
BACKGROUND: Acute cerebral infarction (ACI) is a common medical emergency. This study is the first systematic review of the use of Dl-3-n-butylphthalide (NBP) injection in the treatment of ACI. The purpose of this study was to systematically evaluate the effects of NBP injection on the inflammatory response, oxidative stress response and vascular endothelial function in patients with acute ACI. The objective is to provide reference for clinical application. METHODS: From the establishment of the database until August 2022, we systematically searched EMbase, PubMed, Cochrane Library, Web of Science, CNKI, VIP, and Wanfang Database. RCTs and retrospective studies were included in this study, and the results that qualified for inclusion were screened by 2 researchers and cross-checked. After the relevant data were extracted, a meta-analysis was performed using RevMan5.3 software. RESULTS: A total of 3307 patients with ACI from 34 studies were analyzed. The meta-analysis showed that the C-reactive protein levels in the NBP combined group were effectively reduced compared with those in the control group (MDâ =â -3.75, 95% confidence intervals [95% CI] [-4.95, -2.56], Pâ <â .00001). Based on comparison with the control group, it is evident that combination treatment with NBP is more effective than control group in reducing the oxidative stress response of ACI (MD[superoxide dismutase levels]â =â 22.16, 95% CI [14.20,30.11], Pâ <â .00001; MD[malondialdehyde levels]â =â -1.97, 95% CI [-2.62, -1.32], Pâ <â .00001). Comparison with the control group shows that combination treatment with NBP is more effective in improving vascular endothelial function in ACI patients (MD[vascular endothelial growth factor levels]â =â 71.44, 95% CI [41.22, 101.66], Pâ <â .00001; MD[endothelin-1 levels]â =â -11.47, 95% CI [-17.39, -5.55], Pâ =â .0001; MD[nitric oxide levels]â =â 9.54, 95% CI [8.39, 10.68], Pâ <â .00001) than control group. The NBP combined group also showed a greater reduction in cerebral infarct volume (CIV) and cerebral infarct size (CIS) of ACI (MD[CIV]â =â -1.52, 95% CI [-2.23, -0.81], Pâ <â .0001; MD[CIS]â =â -2.79, 95% CI [-3.65, -1.94], Pâ <â .00001). The NBP combined group did not show an increase in the incidence of adverse reactions compared with the control group (odds ratioâ =â 1.06, 95% CI [0.73, 1.53], Pâ =â .77). CONCLUSION: In summary, the use of NBP in combination with control group for ACI can reduce the degree of nerve damage, reduce inflammation and oxidative stress, improve vascular endothelial function, and reduce CIS and CIV in ACI patients, without increasing the incidence of clinical adverse events.