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ObjectiveTo investigate the effect of circSLC8A1_005 on the fibrotic phenotype of cardiac fibroblasts and the potential mechanism involved. MethodsThe effect of adenovirus-mediated overexpression of circSLC8A1_005 on the expression of fibrosis-related genes， collagen type I alpha 1 chain （Col1a1）， collagen type Ⅲ alpha 1 chain （Col3a1） and smooth muscle actin alpha 2 （Acta2）， in mouse cardiac fibroblasts （mCFs） were detected. The proliferation and migration activities of mCFs were detected by EdU and wound-healing assay， respectively. Dual luciferase reporter gene assay was performed to detect the activity of potential internal ribozyme entry site （IRES） in circSLC8A1_005. CircSLC8A1_005-translated protein， SLC8A1-605aa， and its intracellular distribution was identified by Western blot assay. The effect of SLC8A1-605aa protein on transcription activity of Sod2 gene was detected by the dual luciferase reporter gene assay. RNA binding protein immunoprecipitation （RIP） was utilized to verify the interaction between SLC8A1-605aa and superoxide dismutase 2 （Sod2） mRNA. Actinomycin D treatment was used to detect the effect of SLC8A1-605aa on Sod2 mRNA stability in mCFs. ResultsAn efficient adenovirus-mediated overexpression of circSLC8A1_005 was achieved in mCFs. The enforced expression of circSLC8A1_005 suppressed proliferation and migration of mCFs， and inhibited the expression of fibrosis-related genes in mCFs. The dual luciferase reporter gene assay revealed the activities of 2 IRES in circSLC8A1_005. Results of Western blot assay showed that circSLC8A1_005 could translate protein SLC8A1-605aa with the prospected molecular weight of 70 ku， which is predominantly distributed in the nucleus. Overexpression of the circSLC8A1_005 and SLC8A1-605aa could consistently inhibit the fibrotic phenotype of mCFs. SLC8A1-605aa could up-regulate superoxide dismutase 2 （Sod2） expression， but not at the transcriptional level. RIP assay indicated that SLC8A1-605aa could specifically interact with Sod2 mRNA， and the results of actinomycin D assay showed that SLC8A1-605aa could enhance the stability of Sod2 mRNA in mCFs. ConclusionCircSLC8A1_005 inhibits the fibrotic phenotype of cardiac fibroblasts via translating SLC8A1-605aa protein， and SLC8A1-605aa may be a potential target for the treatment of myocardial fibrosis.
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Age-related macular degeneration(ARMD)is a neurodegenerative disease associated with oxidative stress. It is characterized by progressive death of photoreceptors and retinal pigment epithelium(RPE), and is one of the leading causes of irreversible loss of central vision in patients over the age of 65 years old. MicroRNA(miRNA)is a class of regulatory short-chain non-coding RNA that can bind and inhibit multiple gene targets in the same biological pathway. This unique property makes microRNA an ideal target for exploring the pathogenesis, diagnosis and treatment of non-exudative ARMD. Previous studies have found that the pathogenesis of non-exudative ARMD involves age, genetics, environment, oxidative stress, lipid metabolism, autophagy and immunity. However, the exact mechanisms have not been fully clarified. As biomarkers of non-exudative ARMD, miRNA play a role in oxidative stress and lipid metabolism. This article summarizes the role of various miRNA in targeting Nrf2 and HIF-1α to inhibit hypoxia-related angiogenesis signaling, thereby affecting oxidative stress. Additionally, miRNA regulate lipid uptake and the expression of ABCA1 in RPE and macrophages, thereby influencing lipid metabolism. This deepens the understanding of the role of miRNA in oxidative stress and lipid metabolism in non-exudative ARMD, and provides directions for further improving the understanding of the pathogenesis and prevention of non-exudative ARMD.
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Current research highlighted the importance to recognize feasible biomarkers for early diagnoses and treatment in oral cancer. Our study analyzed the expression and spatial distribution of ALDH1A1, FGFR2, caspase-3, and CD44 in Oral Squamous Cell Carcinoma (OSCC) and leukoplakia with and without oral mucosal dysplasia. Paraffin-embedded samples of OSCC (n=5), leukoplakia with (n=5) and without (n=5) dysplasia obtained by incisional biopsies were processed using conventional histochemical techniques. Immunohistochemistry was performed using antibodies against ALDH1A1, FGFR2, caspase-3, and CD44. Images of the immunohistochemically stained tissue sections were analyzed according to the intensity of the immunostaining of each marker and classified in Scores. The Kruskal- Wallis test was performed (p≤0.05). Our results demonstrated a statically difference in the expression of all immunomarkers between OSCC and leukoplakia without dysplasia, being more significant in FGFR2 and ALDH1A1. Within the limitations of this study, our data showed that all biomarkers were overexpressed in OSCC and leukoplakia with oral mucosa dysplasia, suggesting that the presence of dysplasia is a significant clinic-pathologic predictor for malignant transformation.
La actual evidencia científica enfatiza la importancia de reconocer biomarcadores viables para el diagnóstico y tratamiento temprano del cáncer oral. Nuestro estudio piloto analizó la expresión y distribución espacial de ALDH1A1, FGFR2, caspasa-3 y CD44 en carcinoma oral de células escamosas (COCE) y en leucoplasia con o sin displasia de la mucosa oral. Las muestras incluidas en parafina de COCE (n=5), con (n=5) y sin (n=5) displasia fueron obtenidas mediante biopsias incisionales, las cuales se procesaron utilizando técnicas histoquímicas convencionales. El análisis inmunohistoquímico se realizó utilizando anticuerpos contra ALDH1A1, FGFR2, caspasa-3 y CD44. Las imágenes de las secciones de cada muestra fueron analizadas según la intensidad de inmunoexpresión de cada marcador y se clasificaron en diferentes escalas (scores). Se realizó la prueba de Kruskal-Wallis (valores de p<0,05). Nuestros resultados demostraron una diferencia estadística en la expresión de todos los inmunomarcadores entre COCE y las muestras con leucoplasia sin displasia, siendo más significativa en FGFR2 y ALDH1A1. Considerando las limitaciones de este estudio, los datos sugieren que la presencia de displasia en la mucosa oral es un importante predictor clínico-patológico de transformación maligna.
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El síndrome de deficiencia del transportador de glucosa tipo 1 es una enfermedad de causa genética, que involucra el gen SLC2A1. En general, se presenta durante los primeros años de vida con retraso en la adquisición de pautas madurativas, epilepsia farmacorresistente y desórdenes del movimiento. La clínica y la disminución de glucosa en líquido cefalorraquídeo permiten sospechar el diagnóstico, el cual debe ser confirmado mediante el estudio molecular del gen SLC2A1. Debido a que se trata de una enfermedad poco frecuente y de expresión clínica variable, el diagnóstico precoz suele representar un desafío para los equipos de salud. Este es importante, ya que la implementación de la terapia cetogénica logra controlar las manifestaciones clínicas y mejora el pronóstico a largo plazo. Presentamos una revisión sobre el déficit del transportador de glucosa tipo 1, que abarca sus características clínicas, bioquímicas, moleculares y terapéuticas.
Glucose transporter type 1 deficiency with a typical onset is a genetic disorder associated with the SLC2A1 gene. Usually appears during the first years of life with severe developmental delay, drugresistant epilepsy, and movement disorders. Diagnosis is suspected based on clinical manifestations and a low glucose level in cerebrospinal fluid, and should be confirmed by the molecular genetic study of the SLC2A1 gene. As it is a rare disease with variable clinical expression, early diagnosis is often challenging for the healthcare team. Nevertheless, this is important because early implementation of ketogenic therapy will lead to control of the clinical manifestations and a better long-term prognosis. Here we review the glucose transporter type 1 deficiency syndrome focusing on its clinical, biochemical, molecular, and therapeutic characteristics.
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Humans , Carbohydrate Metabolism, Inborn Errors/diagnosis , Carbohydrate Metabolism, Inborn Errors/genetics , Carbohydrate Metabolism, Inborn Errors/therapy , Monosaccharide Transport Proteins/genetics , Epilepsy/diagnosis , Epilepsy/genetics , MutationABSTRACT
La estandarización de la hemoglobina A1c (HbA1c) permitió en algunos países su uso para el diagnóstico de la diabetes mellitus (DM) y la prediabetes, además de su empleo en el seguimiento del paciente con DM. Es importante recordar que se trata de una medida indirecta del promedio glucémico durante el tiempo de vida media del eritrocito, pudiendo verse afectada por variables no glucémicas, como también por interferencias analíticas según la metodología empleada para su determinación. A continuación, se describen las recomendaciones y consideraciones a tener en cuenta para la determinación de la HbA1c cuando se emplea como criterio diagnóstico de la DM, teniendo en cuenta que al utilizarla para tal fin es necesario que la medida se realice con métodos certificados y estandarizados al ensayo utilizado en el Diabetes Control and Complications Trial (DCCT).
The standardization of hemoglobin A1c (HbA1c) allowed in some countries its use for the diagnosis of diabetes mellitus (DM) and prediabetes, in addition to its use in the follow-up of patients with DM. It is important to highlight that it is an indirect measurement of the glycemic average during the halflife of the erythrocyte, and may be affected by non-glycemic variables, as well as by analytical interferences depending on the methodology used for its determination. The recommendations and considerations to take into account for the determination of HbA1c when it is used as a diagnostic criterion for diabetes are described below. In addition, it is important to emphasize that it is essential that the HbA1c measurement be performed with certified and standardized methods to the Diabetes Control and Complications Trial (DCCT)results.
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Prediabetic State , Diabetes MellitusABSTRACT
Abstract Aims Although reduced life expectancy in Parkinson's Disease (PD) patients has been related to severe cardiac arrhythmias due to autonomic dysfunctions, its molecular mechanisms remain unclear. To investigate the role of cardiac β1-Adrenergic (β1AR) and A1-Adenosine (A1R) receptors in these dysfunctions, the pharmacological effects of stimulation of cardiac β1AR (isoproterenol, ISO), in the absence and presence of cardiac β1AR (atenolol, AT) or A1R (1,3-dipropyl-8-cyclopentyl xanthine, DPCPX) blockade, on the arrhythmias induced by Ischemia/Reperfusion (CIR) in an animal PD model were studied. Methods PD was produced by dopaminergic lesions (confirmed by immunohistochemistry analysis) caused by the injection of 6-hydroxydopamine (6-OHDA, 6 μg) in rat striatum. CIR was produced by a surgical interruption for 10 min followed by reestablishment of blood circulation in the descendent left coronary artery. On the incidence of CIR-Induced Ventricular Arrhythmias (VA), Atrioventricular Block (AVB), and Lethality (LET), evaluated by Electrocardiogram (ECG) analysis, the effects of intravenous treatment with ISO, AT and DPCPX (before CIR) were studied. Results VA, AVB and LET incidences were significantly higher in 6-OHDA (83%, 92%, 100%, respectively) than in control rats (58%, 67% and 67%, respectively). ISO treatment significantly reduced these incidences in 6-OHDA (33%, 33% and 42%, respectively) and control rats (25%, 25%, 33%, respectively), indicating that stimulation of cardiac β1AR induced cardioprotection. This response was prevented by pretreatment with AT and DPCPX, confirming the involvement of cardiac β1AR and A1R. Conclusion Pharmacological modulation of cardiac β1AR and A1R could be a potential therapeutic strategy to reduce severe arrhythmias and increase life expectancy in PD patients.
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@#Objective To predict and analyze the physical and chemical properties,structure,function,protein interaction and homology of SLC33A1 gene based on bioinformatics so as to provide a reference for further study on the function of SLC33A1.Methods A variety of bioinformatics tools were used to predict the physical and chemical properties,hydrophilicity,hydrophobicity,signal peptide structure,transmembrane structure,subcellular localization,three dimensional spatial structure,post-translational modification sites and protein-protein interaction of SLC33A1.Results SLC33A1 was a neutral,stable and hydrophobic protein without signal peptide sequence,which was mainly distributed in cell membrane and membrane structural organelle,with a probability of 13. 0% in vesicle membrane. There were 11 transmembrane domains,6 extracellular domains and 6 intracellular domains in SLC33A1 sequence. The tertiary structure of SLC33A1 was elastic and stable,which had 2 N-glycosylation sites,2 O-glycosylation sites and 13 potential protein phosphorylation sites. SLC33A1 interacted with 7 proteins such as ATM with high confidence,which was mainly involved in the negative regulation of inositol-requiring enyzme 1(IRE1)-mediated unfolded protein response,the respon-ses of glycosphingolipid,sialylation and cells to γ ray as well as the negative regulation of endoplasmic reticulum stress response.Conclusion The nature and function of SLC33A1 were investigated by various software,which provided theoretical references and ideas for further research on new anticancer targets in the future.
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Objective To explore the improvements of high-fat intake on lung injury induced by Paragonimus proliferus infection in rats, and to preliminarily explore the mechanisms underlying the role of cytochrome P450 4A1 (CYP 4A1) in the improve ments. Methods SD rats were randomly assigned into three groups, including the normal control group (n = 10), the infection and normal diet group (n = 12) and the infection and high-fat diet group (n = 12). Rats in the normal control group were fed with normal diet and without any other treatments, and animals in the infection and normal diet group were subcutaneously injected with 8 excysted metacercariae of P. proliferus via the abdominal wall, followed by feeding with normal diet, while rats in the infection and high-fat diet group were subcutaneously injected with 8 excysted metacercariae of P. proliferus via the abdominal wall, followed by feeding with high-fat diet. All rats were sacrificed 28 weeks post-infection, and serum samples and lung specimens were collected. Following hematoxylin-eosin (HE) staining of rat lung specimens, the rat lung injury was observed under an optical microscope, and alveolitis was evaluated using semi-quantitative scoring. Serum interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNF-α) levels were measured using enzyme-linked immunosorbent assay (ELISA), and the cytochrome P450 4A1 (CYP 4A1) expression was quantified in rat lung specimens at transcriptional and translational levels using quantitative real-time PCR (qPCR) and Western blotting assays. Results Alveolar wall thickening, edema and inflammatory cell infiltration were alleviated 28 weeks post-infection with P. proliferus in rats in the infection and high-fat diet group relative to the infection and normal diet group, and no alveolar consolidation was seen in the infection and high-fat diet group. The semi-quantitative score of alveolitis was significantly higher in the infection and normal diet group [(2.200 ± 0.289) points] than in the normal control group [(0.300 ± 0.083) points] and the infection and high-fat diet group [(1.300 ± 0.475) points] (both P values < 0.05), and higher serum IL-1β [(151.586 ± 20.492)] pg/mL and TNF-α levels [(180.207 ± 23.379) pg/mL] were detected in the infection and normal diet group than in the normal control group [IL-1β: (103.226 ± 3.366) pg/mL; TNF-α: (144.807 ± 1.348) pg/mL] and the infection and high-fat diet group [IL-1β: (110.131 ± 12.946) pg/mL; TNF-α: (131.764 ± 27.831) pg/mL] (all P values < 0.05). In addition, lower CYP 4A1 mRNA (3.00 ± 0.81) and protein expression (0.40 ± 0.02) was quantified in lung specimens in the infection and normal diet group than in the normal control group [(5.03 ± 2.05) and (0.84 ± 0.14)] and the infection and high-fat diet group [(11.19 ± 3.51) and (0.68 ± 0.18)] (all P values < 0.05). Conclusion High-fat intake may alleviate lung injuries caused by P. proliferus infection in rats through up-regulating CYP 4A1 expression in lung tissues at both translational and transcriptional levels.
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Abstract Consuming a high-fat diet causes a harmful accumulation of fat in the liver, which may not reverse even after switching to a healthier diet. Different reports dealt with the role of purslane as an extract against high-fat diet; meanwhile, it was necessary to study the potential role of fresh purslane as a hypolipidemic agent. This study is supposed to investigate further the potential mechanism in the hypolipidemic effect of fresh purslane, by measuring cholesterol 7a-hydroxylase (CYP7A1) and low-density lipoprotein receptor (Ldlr). Rats were divided into two main groups: the first one is the normal control group (n=7 rats) and the second group (n=28 rats) received a high fat diet for 28 weeks to induce obesity. Then the high fat diet group was divided into equal four subgroups. As, the positive control group still fed on a high fat diet only. Meanwhile, the other three groups were received high-fat diet supplemented with a different percent of fresh purslane (25, 50 and 75%) respectively. At the end of the experiment, rats were sacrificed and samples were collected for molecular, biochemical, and histological studies. Current study reported that, supplementation of fresh purslane especially at a concentration of 75% play an important role against harmful effects of high-fat diet at both cellular and organ level, by increasing CYP7A1 as well as Ldlr mRNA expression. Also, there were an improvement on the tested liver functions, thyroid hormones, and lipid profile. Fresh purslane plays the potential role as a hypolipidemic agent via modulation of both Ldlr and Cyp7A, which will point to use fresh purslane against harmful effects of obesity.
Resumo O consumo de uma dieta rica em gordura causa um acúmulo prejudicial de gordura no fígado, que pode não reverter mesmo após a mudança para uma dieta mais saudável. Diferentes relatórios trataram do papel da beldroega como um extrato contra uma dieta rica em gordura; entretanto, foi necessário estudar o papel potencial da beldroega fresca como agente hipolipemiante. Este estudo pretende investigar mais profundamente o mecanismo potencial no efeito hipolipidêmico da beldroega fresca, medindo o colesterol 7a-hidroxilase (CYP7A1) e o receptor de lipoproteína de baixa densidade (Ldlr). Os ratos foram divididos em dois grupos principais: o primeiro é o grupo controle normal (n = 7 ratos) e o segundo grupo (n = 28 ratos) recebeu dieta rica em gorduras por 28 semanas para induzir a obesidade. Em seguida, o grupo de dieta rica em gordura foi dividido em quatro subgrupos iguais. Como, o grupo de controle positivo ainda se alimentava apenas com dieta rica em gordura. Enquanto isso, os outros três grupos receberam dieta rica em gordura suplementada com diferentes porcentagens de beldroegas frescas (25%, 50% e 75%), respectivamente. Ao final do experimento, os ratos foram sacrificados e amostras coletadas para estudos moleculares, bioquímica e histológicos. O estudo atual relatou que a suplementação de beldroegas frescas, especialmente a uma concentração de 75%, desempenha papel importante contra os efeitos prejudiciais da dieta rica em gordura em nível celular e orgânico, aumentando a expressão de CYP7A1 e Ldlr mRNA. Além disso, houve melhora nas funções hepáticas testadas, nos hormônios tireoidianos e no perfil lipídico. Beldroegas frescas desempenham papel potencial como agente hipolipemiante por meio da modulação de Ldlr e Cyp7A, o que apontará para o uso de beldroegas frescas contra os efeitos nocivos da obesidade.
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Animals , Rats , Portulaca , Diet, High-Fat/adverse effects , Hypolipidemic Agents , Cholesterol 7-alpha-Hydroxylase , Rats, Sprague-Dawley , LiverABSTRACT
Most prostate cancers initially respond to androgen deprivation therapy (ADT). With the long-term application of ADT, localized prostate cancer will progress to castration-resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), and neuroendocrine prostate cancer (NEPC), and the transcriptional network shifted. Forkhead box protein A1 (FOXA1) may play a key role in this process through multiple mechanisms. To better understand the role of FOXA1 in prostate cancer, we review the interplay among FOXA1-targeted genes, modulators of FOXA1, and FOXA1 with a particular emphasis on androgen receptor (AR) function. Furthermore, we discuss the distinct role of FOXA1 mutations in prostate cancer and clinical significance of FOXA1. We summarize possible regulation pathways of FOXA1 in different stages of prostate cancer. We focus on links between FOXA1 and AR, which may play different roles in various types of prostate cancer. Finally, we discuss FOXA1 mutation and its clinical significance in prostate cancer. FOXA1 regulates the development of prostate cancer through various pathways, and it could be a biomarker for mCRPC and NEPC. Future efforts need to focus on mechanisms underlying mutation of FOXA1 in advanced prostate cancer. We believe that FOXA1 would be a prognostic marker and therapeutic target in prostate cancer.
Subject(s)
Humans , Male , Androgen Antagonists/therapeutic use , Androgens/metabolism , Hepatocyte Nuclear Factor 3-alpha/metabolism , Mutation , Prostatic Neoplasms, Castration-Resistant/drug therapy , Receptors, Androgen/metabolismABSTRACT
Objective:To analyze the clinical phenotype and genotype characteristics of children with pyridoxine-dependent epilepsy (PDE) and provide evidence for diagnosis.Methods:Clinical data of 3 children with PDE enrolled in the Department of Neurology of Hunan Children′s Hospital from July 2016 to December 2020 were collected, and whole-exome sequencing (WES) was used for analysis. Pathogenic variants were analyzed and screened using bioinformatics tools combined with clinical phenotype. Sanger sequencing was used to analyze the source of mutations in children′s core family members.Results:Cases 1 (female) and 2 (male) were siblings, both of whom had convulsions within 24 hours after birth. WES results showed that the siblings carried compound heterozygous mutations of c.796C>T (p.R266 *) and c.1553G>C (p.R518T) in the ALDH7A1 gene, coming from the father and mother of the siblings respectively. Both of the mutations have been reported as pathogenic. Case 3, female, developed convulsions at the age of 1. WES results revealed that she carried compound heterozygous mutations of c.1094-109T>A and c.7C>T (p.R3C) in the ALDH7A1 gene, coming from her father and mother respectively. After searching HGMDPro, PubMed, 1000 Genomes, and dbSNP databases, both of the 2 mutations of c.1094-109T>A and c.7C>T (p.R3C) were not reported. The pathogenicity predictions of the 2 mutations were carried out by different biological information analysis software. The results showed that both of the mutations were harmful. All the 3 children had no epileptic seizures after treatment with increased doses of vitamin B6. Conclusions:When infants have unexplained convulsions, especially in the neonatal stage, PDE caused by ALDH7A1 gene mutation should be considered. Pyridoxine precision treatment has a good effect. The 2 de novo mutations of c.1094-109T>A and c.7C>T (p.R3C) enrich the mutation spectrum in the ALDH7A1 gene. WES has the auxiliary significance in the diagnosis of epilepsy.
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Objective:Congenital hyperinsulinemia is a heterogeneous disorder characterized by severe hypoglycemia due to dysregulated insulin secretion. Sixteen genes have been reported to be associated with congenital hyperinsulinemia. In this study, whole exome sequencing was performed on a patient with obesity, hyperinsulinemia, and postprandial hypoglycemia to further explore its genetic etiology.Methods:The clinical data and peripheral blood of a patient with hyperinsulinemia and his family members were collected. Genomic DNA was extracted from the peripheral blood. Sanger sequencing and pedigree verification were performed on the pathogenic variants filtered by whole-exome sequencing. The function of the mutation sites was analyzed by bioinformatics software.Results:The proband presented with obesity, hyperinsulinemia, and postprandial hypoglycemia, but without exercise-induced hypoglycemia. A heterozygous SCL16A1 gene c. 1259A>G(p.K420R) mutation was identified in the proband. Co-segregated analysis showed that the c. 1259A>G mutation was also found in his father and brother, who had obesity and hyperinsulinemia, which was consistent with autosomal dominant inheritance. The mutation c. 1259A>G was predicted to be pathogenic by the MutationTaster, FATHMM-MKL, PolyPhen2, and CADD programs, and has not been reported in HGDM database yet, which was considered to be a novel mutation.Conclusion:This study reported a patient with hyperinsulinemia caused by a new mutation of SCL16A1 gene, which expanded our understanding of the pathogenic mutation spectrum of hyperinsulinemia.
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Objective:To investigate the impact of short-term variability in fasting blood glucose (FPG) on the recent major cardiovascular adverse events (MACE) in patients with ST segment elevation myocardial infarction (STEMI) with different levels of glycated hemoglobin (HbA 1c) . Methods:Retrospective analysis was made on the patients with type 2 diabetes mellitus who underwent emergency percutaneous coronary intervention (PCI) due to STEMI from January 2016 to March 2020 in Shenzhen Hospital, Fuwai Hospital, Chinese Academy of Medical Sciences. The patients were divided into HbA 1c compliant group (<6.5%) and non-compliant group (≥6.5%). The blood glucose variability indexes defined included FPG variability score (FPG-VS), variability index independent of FPG mean (VIM) and mean fast plasma glucose (FPG-M). The logistic regression model was used to evaluate the relationship between different HbA 1c levels, blood glucose variability risk indicators, and MACE. Results:A total of 612 patients were ultimately included in the analysis. The blood glucose variability indicators (FPG-VS, VIM) of the HbA 1c non-compliant group (302 cases) were higher than those of the compliant group (310 cases): [FPG-VS: (0.7±0.3) vs (0.4±0.4), P<0.001, VIM: (0.4±0.2) vs (0.3±0.2), P<0.001], while there was no statistically significant difference in FPG-M between the two groups [(7.9±3.2) vs (8.0±3.9), P=0.221]. In the HbA 1c non-compliant group, the correlation between FPG-VS, VIM, and FPG-M and the risk of MACE within 30 days was 0.89(95% CI: 0.69-1.15), 1.21(95% CI: 0.65-2.25), and 1.06(95% CI: 0.97-1.16), respectively (all P>0.05). In the HbA 1c compliant group, FPG-VS was associated with an increase in MACE risk within 30 days ( P=0.04): for each increase in FPG variation ≥1 mmol/L, after multiple factor adjustment, the risk of MACE increased by 8% within 30 days ( OR=1.08, 95% CI: 0.71-1.65); Compared with FPG-VS<20%, FPG-VS≥80% increased the risk of MACE within 30 days by 33% ( OR=1.33, 95% CI: 0.21-8.25, P<0.01), while the correlation between VIM and FPG-M and the risk of MACE within 30 days was 1.65(95% CI: 0.96-2.83) and 1.15(95% CI: 0.98-1.35), respectively (all P>0.05). Conclusions:High FPG-VS is associated with the recent MACE risk in STEMI patients who do not meet HbA 1c standards. After reaching HbA 1c standards, FPG-VS remains an independent MACE risk factor.
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Objective:To investigate the serum levels and clinical significance of Fc fragment of the IgG-binding protein (FCGBP), serum amyloid protein A1 (SAA1), and CXC chemokine ligand 10 (CXCL10) in children with mycoplasma pneumoniae pneumonia (MPP) and their relationship with prognosis.Methods:A prospective study was conducted on 122 children with MPP admitted to the department of pediatrics of the 970th Hospital of the Joint Logistics Support Force of the Chinese People′s Liberation Army from January 2019 to December 2021. According to the severity and prognosis of MPP, they were divided into mild and severe groups, good prognosis group, and poor prognosis group. Forty healthy children who underwent physical examination during the same period were set as the control group. Enzyme-linked immunosorbent assay (ELISA) was used to detect the serum levels of FCGBP, SAA1, and CXCL10 in each subject, and to compare the differences in serum levels of FCGBP, SAA1, and CXCL10 among different groups. Multivariate logistic regression analysis was used to investigate the influencing factors of poor prognosis in MPP patients. The diagnostic value of individual and combined detection of serum procalcitonin (PCT), FCGBP, SAA1, and CXCL10 for poor prognosis in MPP children by analyzing the receiver operating characteristic (ROC) curve.Results:The levels of serum FCGBP [(115.68±10.57)ng/ml, (78.41±6.73)ng/ml, (12.55±3.25)ng/ml], SAA1 [(34.18±3.72)mg/L, (25.54±2.63)mg/L, (6.74±0.82)mg/L], and CXCL10 [(714.26±55.64)ng/L, (353.74±42.67)ng/L, (106.25±12.92)ng/L] in the severe MPP group were significant higher than those in the mild MPP group and the control group, with statistical significance (all P<0.05). The white blood cell (WBC), neutrophil percentage, C reactive protein (CRP), erythrocyte sedimentation rate (ESR), PCT, lactate dehydrogenase (LDH), D-dimer (D-D), FCGBP, SAA1, CXCL10 of the children in the poor prognosis group were significantly higher than those in the good prognosis group, and the differences were statistically significant (all P<0.05). Multivariate logistic regression analysis showed that increased PCT ( OR=1.603, 95% CI: 1.190-2.160), FCGBP ( OR=1.757, 95% CI: 1.115-2.770), SAA1 ( OR=1.900, 95% CI: 1.327-2.720) and CXCL10 ( OR=1.704, 95% CI: 1.212-2.397) were independent risk factors for poor prognosis of MPP children (all P<0.05). The combined detection of serum PCT, FCGBP, SAA1, and CXCL10 had a significantly higher diagnostic value for the risk of poor prognosis in children with MPP than a single indicator. Conclusions:The elevated levels of serum FCGBP, SAA1, and CXCL10 in children with MPP are associated with the severity of MPP and are independent risk factors for poor prognosis in MPP patients.
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Objective:To explore the effect and mechanism of cytochrome P450 1A1 (CYP1A1) on regulating phagocytosis of macrophage treated with Escherichia coli ( E.coli). Methods:① The mouse leukemia cells lines of monocyte macrophage RAW264.7 (RAW) were cultured in vitro and treated with 30 multiplicity of infection (MOI) dosages of E.coli for 40 minutes, glycerin control group was set up to observe the change of CYP1A1 during infection. ② The RAW cells with CYP1A1 overexpression (CYP1A1/RAW) and knock out (CYP1A1 KO/RAW) were cultured in vitro and treated with 30 MOI E. coli for 40 minutes, while the negative controlled RAW cells (NC/RAW) were established as control to observe the relationship between cell phagocytosis and CYP1A1 expression, and the effect of CYP1A1 on phagocytic receptor [scavenger receptor-A (SR-A)] and its signal pathway [mitogen-activated protein kinase (MAPK) pathway]. ③ NC/RAW and CYP1A1 KO/RAW cells were cultured in vitro and pretreated with 1 μmol/L extracellular signal-regulated kinase (ERK) inhibitor (U0126) for 2 hours, and then treated with 30 MOI E.coli for 40 minutes, phosphate buffered solution (PBS) control group was set up to observe whether the effect of CYP1A1 on phagocytosis through controlled the MAPK pathway. ④ The RAW cells were cultured in vitro and pretreated with 100 nmol/L CYP1A1 hydroxylase active product 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE] for 2 hours, and then treated with 30 MOI E.coli for 40 minutes, and PBS control group was set up to observe whether the effect of CYP1A1 on phagocytosis was related to CYP1A1 hydroxylating metabolite. ⑤ The RAW cells with overexpression CYP1A1 hydroxylase-activity mutation (CYP1A1m/RAW) were cultured in vitro and treated with 30 MOI E.coli for 40 minutes, the CYP1A1/RAW cells were set up as control group to observe whether the effect of CYP1A1 on phagocytosis was related to CYP1A1 hydroxylase-activity. Results:① Compared with glycerin control group, CYP1A1 mRNA expression was significantly increased by E.coli stimulation (2 -ΔΔCt: 7.79±0.71 vs. 1.00±0.00, P < 0.05), indicating that CYP1A1 might participate in regulating infection progress. ② Compared with NC/RAW cells, the number of E.coli colonies phagocytized by CYP1A1/RAW cells was significantly decreased after 40 minutes of E.coli stimulation (×10 3 CFU/mL: 4.67±3.06 vs. 15.67±5.03, P < 0.05), while CYP1A1 KO/RAW cells had a significant increase in the number of E.coli colonies phagocytized (×10 3 CFU/mL: 46.00±5.29 vs. 15.67±5.03, P < 0.05), suggesting that CYP1A1 might negatively control macrophage phagocytosis function. Meanwhile, compared with NC/RAW cells, the expression of SR-A mRNA in CYP1A1/RAW cells was significantly down-regulated (2 -ΔΔCt: 0.31±0.03 vs. 1.00±0.00, P < 0.05), and the activation level of ERK was significantly reduced. However, the expression of SR-A mRNA in CYP1A1 KO/RAW cells was significantly up-regulated (2 -ΔΔCt: 3.74±0.25 vs. 1.00±0.00, P < 0.05), and the activation of ERK was enhanced, indicating that CYP1A1 could negatively regulate phagocytic receptors and their signaling pathways.③ Compared with PBS, U0126 pretreatment significantly inhibited the CYP1A1 knockout induced upregulation of SR-A mRNA expression (2 -ΔΔCt: 0.62±0.05 vs. 4.38±0.39, P < 0.05) and ERK activation, and inhibited the enhancement of phagocytosis in macrophages induced by CYP1A1 knock out [ E.coli colonies phagocytized by cells (×10 3 CFU/mL): 12.67±1.15 vs. 45.33±4.16, P < 0.05], suggesting that CYP1A1 inhibited macrophage phagocytosis function by regulating ERK activation. ④ Compared with PBS, the phagocytosis of RAW cells pretreated with 12(S)-HETE did not change significantly [ E.coli colonies phagocytized by cells (×10 3 CFU/mL): 17.00±1.00 vs. 16.33±2.52, P > 0.05], suggesting that CYP1A1 might not control phagocytosis function by its hydroxylase-activity metabolism 12(S)-HETE. ⑤ Compared with CYP1A1/RAW cells, there was no significant change in the phagocytic function of CYP1A1m/RAW cells [ E.coli colonies phagocytized by cells (×10 3 CFU/mL): 3.67±1.15 vs. 3.33±0.58, P > 0.05], suggesting that CYP1A1 might not control phagocytosis function by its hydroxylase-activity. Conclusion:CYP1A1 can negatively regulate the phagocytosis of macrophages by inhibiting the activation of ERK and reducing the expression of SR-A, but this regulatory effect is not related to the activity of CYP1A1 hydroxylase and its pro-inflammatory metabolism 12(S)-HETE.
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Objective:To explore the association between the G71R polymorphism of the UGT1A1 gene and neonatal hyperbilirubinemia. Methods:DNA was extracted from blood samples of 61 neonates with severe neonatal hyperbilirubinemia(severe neonatal hyperbilirubinemia group), 60 neonates with hyperbilirubinemia(hyperbilirubinemia group) and 62 healthy neonates(control group), the G71R mutation of UGT1A1 gene was analyzed by direct sequencing. Results:In severe neonatal hyperbilirubinemia group, there were 17 cases of homozygous mutation(A/A), 23 cases of heterozygous mutation(A/G) , and 21 cases of wild type(G/G) , with 28.87% homozygous mutation rate and 37.70% heterozygous mutation rate.In neonatal hyperbilirubinemia group, there were ten cases of homozygous mutation(A/A), 28 cases of heterozygous mutation(A/G) and 22 cases of wild type(G/G), with 16.67% homozygous mutation rate and 46.67% heterozygous mutation rate.In the control group, there were nine cases of homozygous mutation (A/A), 28 cases of heterozygous mutation(A/G) and 25 cases of wild type(G/G), among which the homozygous mutation rate was 14.52% and the heterozygous mutation rate was 45.16%.The genotype frequency( χ2=4.14, P=0.38)and allele frequency( χ2=2.47, P=0.29)of G71R in severe neonatal hyperbilirubinemia group, neonatal hyperbilirubinemia group and control group were not statistically significant. Conclusion:The G71R polymorphism of the UGT1A1 gene may not be significantly correlated with the prevalence of neonatal hyperbilirubinemia.
ABSTRACT
Chronic enteropathy associated with solute carrier organic anion transporter family member 2A1 gene(CEAS)is an autosomal recessive disease caused by SLCO2A1 gene mutation.Characterized by Persistent, intractable, nonspecific intestinal ulcers that lead to chronic loss of blood and protein.At present, pathogenesis of CEAS is still unclear.Endoscopic examination shows specific intestinal ulcers and intestinal stenosis, which mainly involves ileum.Due to its rare occurrence and similar clinical manifestations with Crohn′s disease and non-steroidal anti-inflammatory drug related bowel disease, it is easy to be confused clinically.No effective treatment has been established, and iron supplementation, blood transfusion and parenteral or enteral nutrition can be given symptomatic treatment.Surgical treatment is feasible in serious condition, however, all of them can only get a temporary effect.Usually, after the end of treatment, the disease relapses, and the life prognosis is not clear.
ABSTRACT
Consuming a high-fat diet causes a harmful accumulation of fat in the liver, which may not reverse even after switching to a healthier diet. Different reports dealt with the role of purslane as an extract against high-fat diet; meanwhile, it was necessary to study the potential role of fresh purslane as a hypolipidemic agent. This study is supposed to investigate further the potential mechanism in the hypolipidemic effect of fresh purslane, by measuring cholesterol 7a-hydroxylase (CYP7A1) and low-density lipoprotein receptor (Ldlr). Rats were divided into two main groups: the first one is the normal control group (n=7 rats) and the second group (n=28 rats) received a high fat diet for 28 weeks to induce obesity. Then the high fat diet group was divided into equal four subgroups. As, the positive control group still fed on a high fat diet only. Meanwhile, the other three groups were received high-fat diet supplemented with a different percent of fresh purslane (25, 50 and 75%) respectively. At the end of the experiment, rats were sacrificed and samples were collected for molecular, biochemical, and histological studies. Current study reported that, supplementation of fresh purslane especially at a concentration of 75% play an important role against harmful effects of high-fat diet at both cellular and organ level, by increasing CYP7A1 as well as Ldlr mRNA expression. Also, there were an improvement on the tested liver functions, thyroid hormones, and lipid profile. Fresh purslane plays the potential role as a hypolipidemic agent via modulation of both Ldlr and Cyp7A, which will point to use fresh purslane against harmful effects of obesity.
O consumo de uma dieta rica em gordura causa um acúmulo prejudicial de gordura no fígado, que pode não reverter mesmo após a mudança para uma dieta mais saudável. Diferentes relatórios trataram do papel da beldroega como um extrato contra uma dieta rica em gordura; entretanto, foi necessário estudar o papel potencial da beldroega fresca como agente hipolipemiante. Este estudo pretende investigar mais profundamente o mecanismo potencial no efeito hipolipidêmico da beldroega fresca, medindo o colesterol 7a-hidroxilase (CYP7A1) e o receptor de lipoproteína de baixa densidade (Ldlr). Os ratos foram divididos em dois grupos principais: o primeiro é o grupo controle normal (n = 7 ratos) e o segundo grupo (n = 28 ratos) recebeu dieta rica em gorduras por 28 semanas para induzir a obesidade. Em seguida, o grupo de dieta rica em gordura foi dividido em quatro subgrupos iguais. Como, o grupo de controle positivo ainda se alimentava apenas com dieta rica em gordura. Enquanto isso, os outros três grupos receberam dieta rica em gordura suplementada com diferentes porcentagens de beldroegas frescas (25%, 50% e 75%), respectivamente. Ao final do experimento, os ratos foram sacrificados e amostras coletadas para estudos moleculares, bioquímica e histológicos. O estudo atual relatou que a suplementação de beldroegas frescas, especialmente a uma concentração de 75%, desempenha papel importante contra os efeitos prejudiciais da dieta rica em gordura em nível celular e orgânico, aumentando a expressão de CYP7A1 e Ldlr mRNA. Além disso, houve melhora nas funções hepáticas testadas, nos hormônios tireoidianos e no perfil lipídico. Beldroegas frescas desempenham papel potencial como agente hipolipemiante por meio da modulação de Ldlr e Cyp7A, o que apontará para o uso de beldroegas frescas contra os efeitos nocivos da obesidade.
Subject(s)
Animals , Rats , Diet, High-Fat , Fatty Liver/drug therapy , Fatty Liver/veterinary , Obesity/drug therapy , Portulaca , Mice, ObeseABSTRACT
Abstract Consuming a high-fat diet causes a harmful accumulation of fat in the liver, which may not reverse even after switching to a healthier diet. Different reports dealt with the role of purslane as an extract against high-fat diet; meanwhile, it was necessary to study the potential role of fresh purslane as a hypolipidemic agent. This study is supposed to investigate further the potential mechanism in the hypolipidemic effect of fresh purslane, by measuring cholesterol 7a-hydroxylase (CYP7A1) and low-density lipoprotein receptor (Ldlr). Rats were divided into two main groups: the first one is the normal control group (n=7 rats) and the second group (n=28 rats) received a high fat diet for 28 weeks to induce obesity. Then the high fat diet group was divided into equal four subgroups. As, the positive control group still fed on a high fat diet only. Meanwhile, the other three groups were received high-fat diet supplemented with a different percent of fresh purslane (25, 50 and 75%) respectively. At the end of the experiment, rats were sacrificed and samples were collected for molecular, biochemical, and histological studies. Current study reported that, supplementation of fresh purslane especially at a concentration of 75% play an important role against harmful effects of high-fat diet at both cellular and organ level, by increasing CYP7A1 as well as Ldlr mRNA expression. Also, there were an improvement on the tested liver functions, thyroid hormones, and lipid profile. Fresh purslane plays the potential role as a hypolipidemic agent via modulation of both Ldlr and Cyp7A, which will point to use fresh purslane against harmful effects of obesity.
Resumo O consumo de uma dieta rica em gordura causa um acúmulo prejudicial de gordura no fígado, que pode não reverter mesmo após a mudança para uma dieta mais saudável. Diferentes relatórios trataram do papel da beldroega como um extrato contra uma dieta rica em gordura; entretanto, foi necessário estudar o papel potencial da beldroega fresca como agente hipolipemiante. Este estudo pretende investigar mais profundamente o mecanismo potencial no efeito hipolipidêmico da beldroega fresca, medindo o colesterol 7a-hidroxilase (CYP7A1) e o receptor de lipoproteína de baixa densidade (Ldlr). Os ratos foram divididos em dois grupos principais: o primeiro é o grupo controle normal (n = 7 ratos) e o segundo grupo (n = 28 ratos) recebeu dieta rica em gorduras por 28 semanas para induzir a obesidade. Em seguida, o grupo de dieta rica em gordura foi dividido em quatro subgrupos iguais. Como, o grupo de controle positivo ainda se alimentava apenas com dieta rica em gordura. Enquanto isso, os outros três grupos receberam dieta rica em gordura suplementada com diferentes porcentagens de beldroegas frescas (25%, 50% e 75%), respectivamente. Ao final do experimento, os ratos foram sacrificados e amostras coletadas para estudos moleculares, bioquímica e histológicos. O estudo atual relatou que a suplementação de beldroegas frescas, especialmente a uma concentração de 75%, desempenha papel importante contra os efeitos prejudiciais da dieta rica em gordura em nível celular e orgânico, aumentando a expressão de CYP7A1 e Ldlr mRNA. Além disso, houve melhora nas funções hepáticas testadas, nos hormônios tireoidianos e no perfil lipídico. Beldroegas frescas desempenham papel potencial como agente hipolipemiante por meio da modulação de Ldlr e Cyp7A, o que apontará para o uso de beldroegas frescas contra os efeitos nocivos da obesidade.
ABSTRACT
tRNA-derived small RNAs (tsRNAs) are novel non-coding RNAs that are involved in the occurrence and progression of diverse diseases. However, their exact presence and function in hepatocellular carcinoma (HCC) remain unclear. Here, differentially expressed tsRNAs in HCC were profiled. A novel tsRNA, tRNAGln-TTG derived 5'-tiRNA-Gln, is significantly downregulated, and its expression level is correlated with progression in patients. In HCC cells, 5'-tiRNA-Gln overexpression impaired the proliferation, migration, and invasion in vitro and in vivo, while 5'-tiRNA-Gln knockdown yielded opposite results. 5'-tiRNA-Gln exerted its function by binding eukaryotic initiation factor 4A-I (EIF4A1), which unwinds complex RNA secondary structures during translation initiation, causing the partial inhibition of translation. The suppressed downregulated proteins include ARAF, MEK1/2 and STAT3, causing the impaired signaling pathway related to HCC progression. Furthermore, based on the construction of a mutant 5'-tiRNA-Gln, the sequence of forming intramolecular G-quadruplex structure is crucial for 5'-tiRNA-Gln to strongly bind EIF4A1 and repress translation. Clinically, 5'-tiRNA-Gln expression level is negatively correlated with ARAF, MEK1/2, and STAT3 in HCC tissues. Collectively, these findings reveal that 5'-tiRJNA-Gln interacts with EIF4A1 to reduce related mRNA binding through the intramolecular G-quadruplex structure, and this process partially inhibits translation and HCC progression.