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BACKGROUND: Haloxylon ammodendron holds significance as an ecological plant, showcasing remarkable adaptability to desert conditions, halophytic environments, and sand fixation. With its potential for carbon sequestration, it emerges as a promising candidate for environmental sustainability. Furthermore, it serves as a valuable C4 plant model, offering insights into the genetic foundations of extreme drought tolerance. Despite the availability of plastid and nuclear genomes, the absence of a mitochondrial genome (mitogenome or mtDNA) hinders a comprehensive understanding of its its mtDNA structure, organization, and phylogenetic implications. RESULTS: In the present study, the mitochondrial genome of H. ammodendron was assembled and annotated, resulting in a multi-chromosomal configuration with two circular chromosomes. The mtDNA measured 210,149 bp in length and contained 31 protein-coding genes, 18 tRNA and three rRNA. Our analysis identified a total of 66 simple sequence repeats along with 27 tandem repeats, 312 forward repeats, and 303 palindromic repeats were found. Notably, 17 sequence fragments displayed homology between the mtDNA and chloroplast genome (cpDNA), spanning 5233 bp, accounting for 2.49% of the total mitogenome size. Additionally, we predicted 337 RNA editing sites, all of the C-to-U conversion type. Phylogenetic inference confidently placed H. ammodendron in the Amaranthacea family and its close relative, Suaeda glacum. CONCLUSIONS: H. ammodendron mtDNA showed a multi-chromosomal structure with two fully circularized molecules. This newly characterized mtDNA represents a valuable resource for gaining insights into the basis of mtDNA structure variation within Caryophyllales and the evolution of land plants, contributing to their identification, and classification.
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Chenopodiaceae , Genoma Mitocondrial , Plantas Tolerantes a Sal/genética , Filogenia , Chenopodiaceae/genética , DNA Mitocondrial/genéticaRESUMO
BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease, and its morbidity and mortality are increasing. At present, there is no specific therapy available. An exacerbated IFN-I response and cytokine storm are related to the mortality of patients with SFTS. Ruxolitinib is a Janus kinase (JAK) 1/2 inhibitor that can block proinflammatory cytokines and inhibit the type I IFN pathway. We aimed to explore the use of ruxolitinib plus standard of care for severe SFTS. METHODS: We conducted a prospective, single-arm study of severe SFTS. We recruited participants aged 18 years or older who were admitted to the hospital with laboratory-confirmed severe SFTS and whose clinical score exceeded 8 points within 6 days of symptom onset. Participants received oral ruxolitinib (10 mg twice a day) for up to 10 days. The primary endpoint was 28-day overall survival. The secondary endpoints included the proportion of participants who needed intensive care unit (ICU) admission, total cost, changes in neurologic symptoms and clinical laboratory parameters, and adverse events (AEs) within 28 days. A historical control group (HC group, n = 26) who met the upper criteria for inclusion and hospitalized from April 1, 2021, to September 16, 2022, was selected and 1:1 matched for baseline characteristics by propensity score matching. RESULTS: Between Sep 16, 2022, and Sep 16, 2023, 26 participants were recruited into the ruxolitinib treatment group (RUX group). The 28-day overall mortality was 7.7% in the RUX group and 46.2% in the HC group (P = 0.0017). There was a significantly lower proportion of ICU admissions (15.4% vs 65.4%, p < 0.001) and total hospitalization cost in the RUX group. Substantial improvements in neurologic symptoms, platelet counts, hyperferritinemia, and an absolute decrease in the serum SFTS viral load were observed in all surviving participants. Treatment-related adverse events were developed in 6 patients (23.2%) and worsened in 8 patients (30.8%), and no treatment-related serious adverse events were reported. CONCLUSIONS: Our findings indicate that ruxolitinib has the potential to increase the likelihood of survival as well as reduce the proportion of ICU hospitalization and being tolerated in severe SFTS. Further trials are needed. TRAIL REGISTRATION: ChiCTR2200063759, September 16, 2022.
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Nitrilas , Pirazóis , Pirimidinas , Febre Grave com Síndrome de Trombocitopenia , Humanos , Pirazóis/uso terapêutico , Nitrilas/uso terapêutico , Masculino , Feminino , Pirimidinas/uso terapêutico , Pessoa de Meia-Idade , Estudos Prospectivos , Idoso , Febre Grave com Síndrome de Trombocitopenia/tratamento farmacológico , Padrão de Cuidado , Adulto , Hospitalização , Resultado do TratamentoRESUMO
BACKGROUND: Oligoribonuclease (orn) of P. aeruginosa is a highly conserved exonuclease, which can regulate the global gene expression levels of bacteria through regulation of both the nanoRNA and c-di-GMP. NanoRNA can regulate the expression of the bacterial global genome as a transcription initiator, and c-di-GMP is the most widely second messenger in bacterial cells. OBJECTIVE: This study seeks to elucidate on the regulation by orn on pathogenicity of P. aeruginosa. METHODS: P. aeruginosa with orn deletion was constructed by suicide plasmid homologous recombination method. The possible regulatory process of orn was analyzed by TMT quantitative labeling proteomics. Then experiments were conducted to verify the changes of Δorn on bacterial motility, virulence and biofilm formation. Bacterial pathogenicity was further detected in cell and animal skin trauma models. ELISA detection c-di-GMP concentration and colony aggregation and biofilm formation were observed by scanning electron microscope. RESULTS: orn deletion changed the global metabolism of P. aeruginosa and reduced intracellular energy metabolism. It leads to the disorder of the quorum sensing system, the reduction of bacterial motility and virulence factors pyocyanin and rhamnolipids. But, orn deletion enhanced pathogenicity in vitro and in vivo, a high level of c-di-GMP and biofilm development of P. aeruginosa. CONCLUSION: orn regulates the ability of P. aeruginosa to adapt to the external environment.
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Proteínas de Bactérias , Exorribonucleases , Pseudomonas aeruginosa , Humanos , Animais , Pseudomonas aeruginosa/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , GMP Cíclico/metabolismo , Sistemas do Segundo Mensageiro , Biofilmes , Regulação Bacteriana da Expressão GênicaRESUMO
BACKGROUND: Chronic total occlusion percutaneous coronary intervention (CTO-PCI) is an available means of revascularization in patients with ischemic heart failure (IHF). However, the prognosis of IHF patients undergoing CTO-PCI remains unclear due to the lack of reliable clinical predictive tools. AIM: This study aimed to establish a nomogram for major adverse cardiovascular events (MACE) after CTO-PCI in IHF patients. METHODS: Sixty-seven potential predictive variables for MACE in 560 IHF patients undergoing CTO-PCI were screened using least absolute shrinkage and selection operator regression. A nomogram was constructed based on multivariable Cox regression to visualize the risk of MACE, and then evaluation was carried out using the concordance index (C-index), time-independent receiver operating characteristic (timeROC) curves, calibration curves, and decision curve analysis (DCA). RESULTS: During a median follow-up of 32.0 months, there were 208 MACE occurrences. Seven variables were selected for nomogram construction: age, left ventricular ejection fraction, left ventricular end-diastolic diameter, N-terminal precursor B-type diuretic peptide, bending, and use of intravascular ultrasound and beta-blockers. The C-index was 0.715 (0.680-0.750) and the internal validation result was 0.715 (0.676-0.748). The timeROC area under the curve at 6 months, 1 year, and 2 years was 0.750 (0.653-0.846), 0.747 (0.690-0.804), and 0.753 (0.708-0.798), respectively. The calibration curves and DCA showed the nomogram had acceptable calibration and clinical applicability. CONCLUSIONS: We developed a simple and efficient nomogram for MACE after CTO-PCI in IHF patients, which helps in early risk stratification and postoperative management optimization.
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Chemoresistance largely hampers the clinical use of chemodrugs for cancer patients, combination or sequential drug treatment regimens have been designed to minimize chemotoxicity and resensitize chemoresistance. In this work, the cytotoxic effect of cisplatin was found to be enhanced by palbociclib pretreatment in HeLa cells. With the integration of liquid chromatography-mass spectrometry-based proteomic and N-glycoproteomic workflow, we found that palbociclib alone mainly enhanced the N-glycosylation alterations in HeLa cells, while cisplatin majorly increased the different expression proteins related to apoptosis pathways. As a result, the sequential use of two drugs induced a higher expression level of apoptosis proteins BAX and BAK. Those altered N-glycoproteins induced by palbociclib were implicated in pathways that were closely associated with cell membrane modification and drug sensitivity. Specifically, the top four frequently glycosylated proteins FOLR1, L1CAM, CD63, and LAMP1 were all associated with drug resistance or drug sensitivity. It is suspected that palbociclib-induced N-glycosylation on the membrane protein allowed the HeLa cell to become more vulnerable to cisplatin treatment. Our study provides new insights into the mechanisms underlying the sequential use of target drugs and chemotherapy drugs, meanwhile suggesting a high-efficiency approach that involves proteomic and N-glycoproteomic to facilitate drug discovery.
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BACKGROUND: Talaromyces marneffei is endemic to eastern India, Southeast Asia, and Guangdong and Guangxi provinces in China. It is common in immunocompromised individuals, especially in HIV-infected patients. CASE PRESENTATION: A 66-year-old male who had a history of hypertension and resided in Shandong Province (Northern China) was admitted for recurrent fever for one month. The patient had recurrent fever, multiple lymphadenopathies, hepatosplenomegaly, a back rash, and a progressive decrease in white blood cells and platelets. Talaromyces marneffei was isolated from peripheral blood and bone marrow after admission, and suspected fungal cells were found via lymph node pathology. The patient's infection secondary to haemophagocytic syndrome continued to worsen despite antifungal, anti-inflammatory, and symptomatic treatment, leading to death due to multiple-organ failure. CONCLUSION: Although rare, infection due to Talaromyces marneffei in HIV-negative patients has been increasing in recent years, and we should be vigilant about "new" infections in nonendemic areas.
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Infecções por HIV , Linfo-Histiocitose Hemofagocítica , Masculino , Humanos , Idoso , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/diagnóstico , ChinaRESUMO
BACKGROUND: Timely and accurate identification of pathogens is crucial for appropriate treatment and prognosis of infectious diseases. As an increasingly popular pathogen detection method, the performance of metagenomic next-generation sequencing (mNGS) in detecting pathogens in febrile patients with suspected infection requires further exploration. METHODS: This study included 368 febrile patients with suspected infections who were admitted to the Infectious Disease Department of Qilu Hospital, Shandong University between January 5, 2021 and April 14, 2023. Both mNGS testing and conventional culture were performed in all patients. Clinical data of enrolled patients were collected, and the diagnostic performances of mNGS and culture were compared. RESULTS: Of the 368 enrolled patients, 231 were finally diagnosed with infection and 137 were with diseases other than infection. The sensitivity (58.01% vs. 21.65%, p < 0.001) and negative predictive value (54.67% vs. 42.9%) of mNGS were superior to those of culture. In contrast, the culture exhibited higher specificity (99.27% vs. 85.40%, p < 0.001) and positive predictive value (98.84% vs. 87.01%) than mNGS. Among infected patients with positive mNGS results, 64 received adjusted antibiotic therapy including treatment transitions, antibiotic downgrading, and combination therapy. Among them, 9 had additional antifungal drugs and 21 patients had a treatment turning point based on the mNGS results and these patients recovered and discharged due to timely antibiotic adjustment. Both positive rates of puncture fluid mNGS and tissue mNGS were higher than those of culture in the patients who had prior antibiotic use, and this difference was statistically significant (p = 0.000). CONCLUSION: mNGS is more sensitive and accurate than traditional culture, making it ideal for identifying pathogens and screening infectious diseases, especially for those with uncultivated or difficult-to-cultivate species. Early diagnosis allows for prompt treatment with targeted antibiotics, and mNGS is recommended when samples are limited.
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Doenças Transmissíveis , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Antibacterianos , Antifúngicos , Terapia Combinada , Febre , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: The association between obesity, metabolic dysregulation, and the aggressive pathological traits of papillary thyroid carcinoma (PTC) continues to be a contentious issue. To date, no investigations have examined the impact of metabolic status on the malignant pathological features of PTC in relation to obesity. METHODS: This research involved 855 adult patients with PTC from Shandong Provincial Hospital, classified into 4 groups based on metabolic and obesity status: metabolically healthy nonobese, metabolically unhealthy nonobese (MUNO), metabolically healthy obese, and metabolically unhealthy obese. We employed logistic regression to investigate the relationship between these metabolic obesity phenotypes and PTC's pathological characteristics. Mediation analysis was also performed to determine metabolic abnormalities' mediating role in the nexus between obesity and these characteristics. RESULTS: Relative to metabolically healthy nonobese individuals, the metabolically unhealthy obese group was significantly associated with an elevated risk of larger tumor sizes and a greater number of tumor foci in PTC. Mediation analysis indicated that obesity directly influences tumor size, whereas its effect on tumor multifocality is mediated through metabolic dysfunctions. Specifically, high-density lipoprotein cholesterol levels were notably associated with tumor multifocality within obese subjects, serving as a mediator in obesity's impact on this trait. CONCLUSION: The concurrent presence of obesity and metabolic dysregulation is often connected to more aggressive pathological features in PTC. The mediation analysis suggests obesity directly affects tumor size and indirectly influences tumor multifocality via low high-density lipoprotein cholesterol levels.
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Obesidade , Fenótipo , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Câncer Papilífero da Tireoide/patologia , Câncer Papilífero da Tireoide/metabolismo , Adulto , Obesidade/metabolismo , Obesidade/complicações , Obesidade/patologia , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/epidemiologia , IdosoRESUMO
OBJECTIVES: Interferon (IFN)-induced lung injury is a rare but severe complication. Studies are needed to elucidate the demographic characteristics, clinical manifestations, and prognostic features of IFN-induced interstitial lung disease (ILD). CASE REPORT: We report a patient with chronic hepatitis who developed ILD after interferon monotherapy. To further clarify the clinical characteristics of such patients, we searched for cases in which lung injury was documented as a side effect of hepatitis treatment and systematically analyzed all case reports for clinical manifestations, type of treatment, and outcomes. RESULTS: This is a 61-year-old male with a previous medical history of chronic hepatitis B. After 2 months of pegylated-interferon alpha (PEG-IFNα) application, he gradually developed cough and exertional dyspnea. Repeated chest images suggested progressive ILD, and lung biopsy revealed subacute lung injury. The diagnosis of PEG-IFNα-induced ILD was made. Including our case, 35 articles containing 45 patients were involved in our review. IFN-induced ILDs, often with a subacute onset, are characterized by nonproductive cough, dyspnea, and pulmonary infiltrates on chest radiograph. Most patients(62%, 28/45) required additional systemic steroid, and 5 (11%) patients who were co-administered ribavirin died of ILD progression despite steroid treatment. CONCLUSION: Although rare, IFN-induced ILD can lead to decreased lung function, and sometimes become fatal despite intensive treatment. Most previously reported cases were with chronic hepatitis C, and most of the medication was in combination with ribavirin. IFN-induced ILD should be monitored during IFN therapy, and appropriate steroid is recommended in patients with progressive manifestations.
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Antivirais , Hepatite B Crônica , Interferon-alfa , Doenças Pulmonares Intersticiais , Polietilenoglicóis , Proteínas Recombinantes , Humanos , Masculino , Doenças Pulmonares Intersticiais/induzido quimicamente , Interferon-alfa/efeitos adversos , Pessoa de Meia-Idade , Polietilenoglicóis/efeitos adversos , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/complicações , Antivirais/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Proteínas Recombinantes/efeitos adversosRESUMO
BACKGROUND: Despite being a prognostic predictor, cardiac autonomic dysfunction (AD) has not been well investigated in chronic obstructive pulmonary disease (COPD). We aimed to characterise computed tomography (CT), spirometry, and cardiopulmonary exercise test (CPET) features of COPD patients with cardiac AD and the association of AD with CT-derived vascular and CPET-derived ventilatory efficiency metrics. METHODS: This observational cohort study included stable, non-severe COPD patients. They underwent clinical evaluation, spirometry, CPET, and CT. Cardiac AD was determined based on abnormal heart rate responses to exercise, including chronotropic incompetence (CI) or delayed heart rate recovery (HRR) during CPET. RESULTS: We included 49 patients with FEV1 of 1.2-5.0 L (51.1-129.7%), 24 (49%) had CI, and 15 (31%) had delayed HRR. According to multivariate analyses, CI was independently related to reduced vascular volume (VV; VV ≤ median; OR [95% CI], 7.26 [1.56-33.91]) and low ventilatory efficiency (nadir VE/VCO2 ≥ median; OR [95% CI], 10.67 [2.23-51.05]). Similar results were observed for delayed HRR (VV ≤ median; OR [95% CI], 11.46 [2.03-64.89], nadir VE/VCO2 ≥ median; OR [95% CI], 6.36 [1.18-34.42]). CONCLUSIONS: Cardiac AD is associated with impaired pulmonary vascular volume and ventilatory efficiency. This suggests that lung blood perfusion abnormalities may occur in these patients. Further confirmation is required in a large population-based cohort.
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Pneumopatias , Doença Pulmonar Obstrutiva Crônica , Humanos , Frequência Cardíaca/fisiologia , Pneumopatias/complicações , Teste de Esforço/métodos , Espirometria , Tolerância ao Exercício/fisiologiaRESUMO
The saponin-enriched extract from Celosiae Semen is a promising resource owing to its lipid-lowering activity. However, triterpenoid saponins are difficult to extract owing to their high molecular weight and strong water solubility. The aim of this paper was to explore an eco-friendly and effective technology of extraction and enrichment of total triterpenoid saponins to obtain high lipid-lowering fractions. Initially, Box-Behnken design experiments were employed to optimize the heat reflux extraction process on the basic of mono-factor experiments. Afterwards, the crude extract was further purified using D-101 resin, and the purification parameters were investigated based on adsorption/desorption experiments and biological activity assay. Under optimal conditions, the purity of the finally obtained total triterpenoid saponins was increased by 7.28-fold. The lipid-lowering activities of the six main triterpenoid saponins were evaluated in HepG2 cells induced by palmitic acid. The results of Oil Red O staining showed that the compounds all exhibited potential lipid-lowering activity. The structure-activity relationship analysis suggested that the oligosaccharide chain at C-28 played an essential role in their lipid-lowering activity and the substituent group at C-23 site also showed important effects. The optimal extraction and purification methods may facilitate the utilization of Celosiae Semen for the industrial production as a functional food and drug.
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Amaranthaceae , Metabolismo dos Lipídeos , Saponinas/química , Saponinas/farmacologia , Triterpenos/química , Amaranthaceae/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Humanos , Células Hep G2 , Etanol/químicaRESUMO
AIM: Knowledge of how circadian rhythm influences brain health remains limited. We aimed to investigate the associations of accelerometer-measured circadian rest-activity rhythm (CRAR) with incident dementia, cognitive dysfunction, and structural brain abnormalities in the general population and underlying biological mechanisms. METHODS: Fifty-seven thousand five hundred and two participants aged over 60 years with accelerometer data were included to investigate the association of CRAR with incidental dementia. Non-parametric CRAR parameters were utilized, including activity level during active periods of the day (M10), activity level during rest periods of the day (L5), and the relative difference between the M10 and L5 (relative amplitude, RA). Associations of CRAR with cognitive dysfunction and brain structure were studied in a subset of participants. Neuroimaging-transcriptomics analysis was utilized to identify the underlying molecular mechanisms. RESULTS: Over 6.86 (4.94-8.78) years of follow-up, 494 participants developed dementia. The risk of incident dementia was associated with decreasing M10 (hazard ratio [HR] 1.45; 95% conference interval [CI], 1.28-1.64) and RA (HR 1.37; 95% CI, 1.28-1.64), increasing L5 (HR 1.14, 95% CI 1.07-1.21) and advanced L5 onset time (HR 1.12; 95% CI, 1.02-1.23). The detrimental associations were exacerbated by APOE ε4 status and age (>65 years). Decreased RA was associated with lower processing speed (Beta -0.04; SE 0.011), predominantly mediated by abnormalities in subcortical regions and white matter microstructure. The genes underlying CRAR-related brain regional structure variation were enriched for synaptic function. CONCLUSIONS: Our study underscores the potential of intervention targeting at maintaining a healthy CRAR pattern to prevent dementia risk.
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Acelerometria , Encéfalo , Ritmo Circadiano , Demência , Humanos , Masculino , Feminino , Demência/genética , Demência/fisiopatologia , Demência/diagnóstico por imagem , Idoso , Ritmo Circadiano/fisiologia , Pessoa de Meia-Idade , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Encéfalo/patologia , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/diagnóstico por imagem , Idoso de 80 Anos ou mais , Descanso/fisiologia , Imageamento por Ressonância MagnéticaRESUMO
Exosomes participate in intercellular communication by carrying proteins, messenger RNA, microRNAs, and non-coding RNA. Fatty liver is a common phenomenon in farmed fish, but there has been little study of fatty hepatocytes-derived exosomes. Here, we successfully isolated exosomes from hepatocytes of grass carp, named Exos (hepatocytes-derived exosomes) and OA-Exos (fatty hepatocytes-derived exosomes), from which 617 differentially expressed proteins were identified using liquid chromatography tandem mass spectrometry. Of these, 320 proteins were promoted and 297 proteins were restrained, which were gathered in biological processes and cellular components (cellular processes, cells, and intracellular structures). The results of kyoto encyclopedia of genes and genomes (KEGG) analysis revealed that the differential expression proteins were gathered in "carbohydrate transport and metabolism", "translation, ribosomal structure and biogenesis", "posttranslational modification, protein turnover, chaperones", and "intracellular trafficking, secretion, and vesicular transport". In addition, five differentially expressed exosomal proteins were further confirmed by parallel reaction monitoring, including 2-phospho-D-glycerate hydrolyase, cytochrome b5, fatty acid-binding protein domain-containing protein, metallothionein, and malate dehydrogenas, which were downregulated. These findings provided evidence that exosomes derived from fatty hepatocytes of grass carp may be biomarkers for the early diagnosis, treatment, and prevention of fatty liver in fishery development.
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Exosomes regulate lipid metabolism by carrying miRNAs, nucleic acids, and proteins, thereby influencing the function of receptor cells. Glucose-regulated protein 78 (GRP78) is also involved in the regulation of lipid metabolism. However, it remains unclear whether exosomes derived from fatty hepatocytes (OA-Exo) regulate lipid metabolism through the enrichment of GRP78. In this study, we observed the expression of GRP78 was significantly increased in fatty hepatocytes (incubating hepatocytes with oleic acid (OA) for 24 h) and OA-Exo (P < 0.05). In addition, OA-Exo (50 µg/mL) and GRP78 protein (1 µg/mL) significant increased the content of triacylglycerol (TG) and total cholesterol (TC), as well as up-regulated the expression of GRP78 and inositol-requiring enzyme-1alpha (IRE1α) protein (P < 0.05). We further used YUM70 (an inhibitor of GRP78) to inhibit endogenous GRP78, and compared with the YUM70 group, OA-Exo reversed the effect of YUM70 and increased the content of TG, TC, and the expression of GRP78 protein in hepatocytes (P < 0.05). Furthermore, the inhibition of the IRE1α pathway with 4µ8C resulted in a significant decrease in TG content compared to the control group (P < 0.05). However, when compared with the 4µ8C group, OA-Exo and GRP78 reversed the effect of 4µ8C and significantly increased TG content (P < 0.05). Taken together, these results indicated that OA-Exo activated IRE1α to promote lipid accumulation in hepatocytes through the enrichment of GRP78. This study provided a new perspective for further exploration of exosomal lipid metabolism in fish.
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BACKGROUND AND AIMS: NAFLD is considered as the hepatic manifestation of the metabolic syndrome, which includes insulin resistance, obesity and hyperlipidemia. NASH is a progressive stage of NAFLD with severe hepatic steatosis, hepatocyte death, inflammation, and fibrosis. Currently, no pharmacological interventions specifically tailored for NASH are approved. Ovarian tumor domain, ubiquitin aldehyde binding 1 (OTUB1), the founding member of deubiquitinases, regulates many metabolism-associated signaling pathways. However, the role of OTUB1 in NASH is unclarified. METHODS AND RESULTS: We demonstrated that mice with Otub1 deficiency exhibited aggravated high-fat diet-induced and high-fat high-cholesterol (HFHC) diet-induced hyperinsulinemia and liver steatosis. Notably, hepatocyte-specific overexpression of Otub1 markedly alleviated HFHC diet-induced hepatic steatosis, inflammatory responses, and liver fibrosis. Mechanistically, we identified apoptosis signal-regulating kinase 1 (ASK1) as a key candidate target of OTUB1 through RNA-sequencing analysis and immunoblot analysis. Through immunoprecipitation-mass spectrometry analysis, we further found that OTUB1 directly bound to tumor necrosis factor receptor-associated factor 6 (TRAF6) and suppressed its lysine 63-linked polyubiquitination, thus inhibiting the activation of ASK1 and its downstream pathway. CONCLUSIONS: OTUB1 is a key suppressor of NASH that inhibits polyubiquitinations of TRAF6 and attenuated TRAF6-mediated ASK1 activation. Targeting the OTUB1-TRAF6-ASK1 axis may be a promising therapeutic strategy for NASH.
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Cisteína Endopeptidases/metabolismo , Hepatopatia Gordurosa não Alcoólica , Animais , Dieta Hiperlipídica , Modelos Animais de Doenças , Fígado , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Transdução de Sinais , Fator 6 Associado a Receptor de TNFRESUMO
BACKGROUND: Pulmonary sequestration (PS) is a rare congenital lower airway malformation. This study presents the clinical and imaging features and surgical outcomes of PS in adults, and compare the safety and feasibility of minimally invasive surgery versus open thoracotomy for PS. METHODS: Adult patients with PS treated at our center from July 2011 to September 2021 were included. Information regarding the patient demographics, clinical and CT features, arterial supply and venous drainage, and surgical outcomes were collected. RESULTS: Ninety seven patients were included. The most common CT findings were mass lesions (50.5%) and cystic lesions (20.6%). The vast majority of the lesions (96 out of 97) were located close to the spine in the lower lobes (left vs. right: 3.6 vs. 1). Arterial supply was mainly provided by the thoracic aorta (87.4%) and abdominal aorta (10.5%). Intralobar and extralobar PS accounted for 90.7% and 9.3% of the patients, respectively. Three (4.5%) patients who underwent minimally invasive surgery were converted to open thoracotomy due to dense adhesions. Though no significant differences regarding operative time (P = 0.133), the minimally invasive surgery group was significantly better than the open thoracotomy group regarding intraoperative blood loss (P = 0.001), drainage volume (P = 0.004), postoperative hospital days (P = 0.017) and duration of chest drainage (P = 0.001). There were no cases of perioperative mortality. Only four (4.1%) patients developed postoperative complications, and no significant difference existed between the two groups. CONCLUSION: Our study revealed PS can present with a variety of different clinical and radiologic manifestations. Clinicians should consider the possibility of PS when diagnosing a lesion in the lower lobes close to the spine. Moreover, minimally invasive surgery is a safe and effective treatment modality for the treatment of PS in an experienced center.
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Sequestro Broncopulmonar , Humanos , Adulto , Sequestro Broncopulmonar/diagnóstico por imagem , Sequestro Broncopulmonar/cirurgia , Sequestro Broncopulmonar/complicações , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Pulmão/patologia , Resultado do TratamentoRESUMO
A phosphine-catalyzed ring-opening addition reaction of cyclopropenones with a variety of nucleophiles (NuH), including oxygen-, nitrogen-, sulfur-, and carbon-based ones, has been investigated, which produces potentially useful α,ß-unsaturated carbonyl derivatives in high yields (up to 99%), high regioselectivity, and exclusive E-selectivity. The reaction proceeds in high efficiency under very mild conditions using only 1 mol % PPh3 as the catalyst at room temperature. The method is also amenable for the synthesis of deuterated alkenes when deuterated nucleophiles (NuD) are employed. The mechanism is investigated by experiments and DFT calculations, which suggests an α-ketenyl phosphorus ylide as a key intermediate in the catalytic cycle that captures the nucleophiles in a stereoselective manner.
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Fosfinas , Estrutura Molecular , CatáliseRESUMO
Epimedii folium (EF) is an effective herbal medicine in osteoporosis treatment, but the clinical utilization of EF has been limited due to potential hepatotoxicity. The previous studies identified that baohuoside I (BI), the main active component of EF, was relevant to EF-induced liver injury. However, the mechanisms of BI causing direct injury to hepatocytes remain unclear. Here, we reveal that BI inhibits FXR-mediated signaling pathway via targeting estrogen receptor α (ER α), leading to the accumulation of bile acids (BAs). Targeted bile acid analyses show BI alters the BA composition and distribution, resulting in impaired BA homeostasis. Mechanistically, BI induces FXR-dependent hepatotoxicity at transcriptional level. Additionally, ER α is predicted to bind to the FXR promoter region based on transcription factor binding sites databases and we further demonstrate that ER α positively regulates FXR promoter activity and affects the expression of target genes involved in BA metabolism. Importantly, we discover that ER α and its mediated FXR transcription regulation might be involved in BI-induced liver injury via ligand-dependent ER α degradation. Collectively, our findings indicate that FXR is a newly discovered target gene of ER α mediated BI-induced liver injury, and suggest BI may be responsible for EF-induced liver injury.
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Doença Hepática Crônica Induzida por Substâncias e Drogas , Receptores Citoplasmáticos e Nucleares , Humanos , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/farmacologia , Ácidos e Sais Biliares/metabolismo , Ácidos e Sais Biliares/farmacologia , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Fígado , Homeostase , Transdução de SinaisRESUMO
BACKGROUND: A prognostic assessment method with good sensitivity and specificity plays an important role in the treatment of pancreatic cancer patients. Finding a way to evaluate the prognosis of pancreatic cancer is of great significance for the treatment of pancreatic cancer. METHODS: In this study, GTEx dataset and TCGA dataset were merged together for differential gene expression analysis. Univariate Cox regression and Lasso regression were used to screen variables in the TCGA dataset. Screening the optimal prognostic assessment model is then performed by gaussian finite mixture model. Receiver operating characteristic (ROC) curves were used as an indicator to assess the predictive ability of the prognostic model, the validation process was performed on the GEO datasets. RESULTS: Gaussian finite mixture model was then used to build 5-gene signature (ANKRD22, ARNTL2, DSG3, KRT7, PRSS3). Receiver operating characteristic (ROC) curves suggested the 5-gene signature performed well on both the training and validation datasets. CONCLUSIONS: This 5-gene signature performed well on both our chosen training dataset and validation dataset and provided a new way to predict the prognosis of pancreatic cancer patients.
Assuntos
Aprendizado de Máquina , Neoplasias Pancreáticas , Humanos , Prognóstico , Curva ROC , Tripsina , Neoplasias PancreáticasRESUMO
BACKGROUND: The occurrence and development of developmental dysplasia of the hip (DDH) are related to a variety of factors, which have been reported in the literature, but the literature does not mention factors related to the severity of DDH. The purpose of this study is to analyze the related factors of the occurrence and severity of DDH in combination with the Graf ultrasonic diagnostic classification. METHODS: This study was a monocentric retrospective study describing the factors associated with DDH in a large hospital of northwest China. A total of 3046 infants (6092 hips) within 6 months after birth using the Graf method were admitted to our department between 2014 and 2018. We analyzed data of DDH. After reviewing medical charts and diagnostic examination results, we assessed whether factors such as ethnicity, gender, gestational age, birth weight, diagnosis age, maternal age, mode of delivery, fetal presentation, amniotic fluid volume and birth order, had any effect on development of hip. RESULT: â Analysis showed that DDH mostly occurs in female and left hip joint, related to intrauterine fetal presentation, amniotic fluid volume, gestational age, mode of delivery, prenatal weight, and diagnosis age after birth, and the occurrence of DDH is also related to maternal age (All Pï¼0.05). Ethnicity and first born showed have no obvious correlation with DDH incidence (p = 0.718, 0.147, respectively). â¡ The strongest correlation was found with amniotic fluid, followed by birth weight. ⢠The severity of DDH was correlated with ethnicity, births, prenatal weight, gestational age, diagnosis age and maternal age (All Pï¼0.05, respectively). ⣠There were significant differences in treatment methods, duration and prognosis among different types of DDH. CONCLUSIONS: The occurrence and development of DDH are related to a variety of factors. Ultrasound examination can provide an early assessment of the hip development status of infants and may play an important role in establishing an early clinical diagnosis treatment and monitoring and prognosis.