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Lipid transfer protein (LTP) has been documented as the dominant protein involved in food-induced anaphylaxis and food-dependent exercise-induced anaphylaxis (FDEIA) patients from Mediterranean European countries. To date, there is no report of FDEIA triggering by LTP in China. A 12-year-old Chinese boy experienced recurrent anaphylaxis during intense exercise for 3 months. Specific immunoglobulin E was performed using ImmunoCAP (Thermo Fisher Scientific, Sweden) and Euroline (EUROIMMUN, Germany). He was sensitized to several pollens, mainly mugwort (62 KUA/L), and was found to have detectable immunoglobulin E in multiple foods: cereal (wheat, barley, oat maize, rice, buckwheat, and common millet), fruits (peach, apple, grape, cherry, and orange), vegetables (lettuce, cabbage, broccoli, cauliflower, tomato, and celery), and legumes and nuts (soybean, peanut, and walnut). He also showed sensitization to LTP components from mugwort Art v3 (79.7 KUA/L) and wheat Tri a14 (12.4 KUA/L), but negative to gluten, gliadin, and omega-5 gliadin. We advised our patient to carry an epinephrine auto-injector, not to exercise alone, and to avoid wheat and fruit/vegetable ingestion for at least 4 hours before exercise or when taking non-steroidal anti-inflammatory drugs. After a 6-month follow-up, the patient has experienced no episode of anaphylaxis. We reported the first documented FDEIA case suspected triggered by LTP in a Chinese child. Clinicians should be aware of LTP sensitization when anaphylaxis occurs during exercise in individuals with multiple pollen and food sensitization.
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BACKGROUND: The imaging manifestations of oral and maxillofacial myofibroma/myofibromatosis can vary among patients. Although many clinical cases have been reported, a consensus on the clinicopathological features of and treatment principles for this disease is lacking. PURPOSE: This study aimed to summarize the clinicopathological features of solitary myofibroma of the oral and maxillofacial regions in pediatric patients. METHODS: The clinical data, histological features, and immunohistochemical characteristics of ten pediatric patients who underwent surgical removal and subsequent pathological diagnosis of myofibroma were collected and retrospectively and cross-sectionally analyzed. RESULTS: Seven patients were male, and 3 were female, with ages ranging from 3 months to 6 years (mean: 2.6 years). The patients presented with solitary lesions involving the mandibular gingiva and adjacent mandible (4 patients), mandible (2 patients), oral floor and submandibular area and adjacent mandible (1 patient), gingiva (1 patient), maxilla (1 patient), and oropharynx (1 patient). Light microscopy revealed spindle-shaped tumor cells organized in bundles or vortex patterns, forming a hemangiopericytoma-like perivascular pattern, whereas immunohistochemical staining revealed diffuse smooth muscle actin (SMA) positivity. All patients underwent surgical resection, and none experienced recurrence over the 12- to 82-month follow-up. CONCLUSIONS: Solitary myofibroma in the oral and maxillofacial regions is predominantly observed in infants and young children, with a higher incidence among males. The prognosis is favorable following localized lesion resection or curettage of jawbone lesions. Accurate recognition of the clinical, radiological, and pathological features of the disease will reduce the misdiagnosis rate.
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Background: Global budget payment is currently the prevailing payment strategy internationally. In China, the concept of multi-hospital global budget payment has been proposed with the aims of achieving cost control effects while also encouraging hospital collaboration and optimising allocation of healthcare resources. This study seeks to analyse the impact of multi-hospital global budget payment in China on healthcare expenditure and service volume. Materials and Methods: A retrospective comparative study was carried out in Dangyang County, China. The exposure cases were migrants who were not locally registered in the residence registration system. The study period encompassed January 1, 2017, to December 31, 2019. Including 3,246,164 outpatient medical records and 242,685 inpatient medical records. The key variables are medical expenditure and service volume indicators. Continuous variables were reported as mean and tested by t-test. We used interrupted time series analysis models to estimate the changes in the level and trend of each outcome measure after the policy. Results: After the outpatient global budget payment reform, the monthly medical expenditure of the hospital alliance has transitioned from a discernible upward trajectory to a deceleration in the rate of growth. The outpatient volume in public and private high-level hospitals decreased at a rate of -419.26 person/month and -137.04 person/month, respectively. In terms of inpatient service volume, only private high-level hospitals reported a decrease, with a reduction rate of -15.38 individuals per month. Conclusion: This study presents new evidence demonstrating that the multi-hospital global budget payment can effectively control costs and promote resource reallocation when implemented jointly with hospital alliance policies. However, overly lenient budget caps risk counterproductive effects.
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BACKGROUND: Since 2020, China has piloted an innovative payment method known as the Diagnosis-Intervention Packet (DIP). This study aimed to assess the impact of the DIP on inpatient volume and bed allocation and their regional distribution. This study investigated whether the DIP affects the efficiency of regional health resource utilization and contributes to disparities in health equity among regions. METHODS: We collected data from a central province in China from 2019 to 2022. The treatment group included 508 hospitals in the pilot area (Region A, where the DIP was implemented in 2021), whereas the control group consisted of 3,728 hospitals from non-pilot areas within the same province. We employed the difference-in-differences method to analyze inpatient volume and bed resources. Additionally, we conducted a stratified analysis to examine whether the effects of DIP implementation varied across urban and rural areas or hospitals of different levels. RESULTS: Compared with the non-pilot regions, Region A experienced a statistically significant reduction in inpatient volume of 14.3% (95% CI 0.061-0.224) and a notable decrease of 9.1% in actual available bed days (95% CI 0.041-0.141) after DIP implementation. The study revealed no evidence of patient consultations shifting from inpatient to outpatient services due to the reduction in hospital admissions in Region A after DIP implementation. Stratified analysis revealed that inpatient volume decreased by 12.4% (95% CI 0.006-0.243) in the urban areas and 14.7% in the rural areas of Region A (95% CI 0.051-0.243). At the hospital level, primary hospitals experienced the greatest impact, with a 19.0% (95% CI 0.093-0.287) decline in inpatient volume. Furthermore, primary and tertiary hospitals experienced significant reductions of 11.0% (95% CI 0.052-0.169) and 8.2% (95% CI 0.002-0.161), respectively, in actual available bed days. CONCLUSIONS: Despite efforts to curb excessive medical service expansion in the region following DIP implementation, large hospitals continue to attract a large number of patients from primary hospitals. This weakening of primary hospitals and the subsequent influx of patients to urban areas may further limit rural patients' access to medical services. The implementation of the DIP may raise concerns about its impact on health care equality and accessibility, particularly for underserved rural populations.
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Pacientes Internos , Humanos , China , Pacientes Internos/estadística & datos numéricos , Hospitalización/estadística & datos numéricos , Hospitalización/economíaRESUMEN
BACKGROUND: The transcription factor POU2F1 regulates the expression levels of microRNAs in neoplasia. However, the miR-29b1/a cluster modulated by POU2F1 in gastric cancer (GC) remains unknown. METHODS: Gene expression in GC cells was evaluated using reverse-transcription polymerase chain reaction (PCR), western blotting, immunohistochemistry, and RNA in situ hybridization. Co-immunoprecipitation was performed to evaluate protein interactions. Transwell migration and invasion assays were performed to investigate the biological behavior of GC cells. MiR-29b1/a cluster promoter analysis and luciferase activity assay for the 3'-UTR study were performed in GC cells. In vivo tumor metastasis was evaluated in nude mice. RESULTS: POU2F1 is overexpressed in GC cell lines and binds to the miR-29b1/a cluster promoter. POU2F1 is upregulated, whereas mature miR-29b-3p and miR-29a-3p are downregulated in GC tissues. POU2F1 promotes GC metastasis by inhibiting miR-29b-3p or miR-29a-3p expression in vitro and in vivo. Furthermore, PIK3R1 and/or PIK3R3 are direct targets of miR-29b-3p and/or miR-29a-3p, and the ectopic expression of PIK3R1 or PIK3R3 reverses the suppressive effect of mature miR-29b-3p and/or miR-29a-3p on GC cell metastasis and invasion. Additionally, the interaction of PIK3R1 with PIK3R3 promotes migration and invasion, and miR-29b-3p, miR-29a-3p, PIK3R1, and PIK3R3 regulate migration and invasion via the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway in GC cells. In addition, POU2F1, PIK3R1, and PIK3R3 expression levels negatively correlated with miR-29b-3p and miR-29a-3p expression levels in GC tissue samples. CONCLUSIONS: The POU2F1-miR-29b-3p/miR-29a-3p-PIK3R1/PIK3R1 signaling axis regulates tumor progression and may be a promising therapeutic target for GC.
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The trail making test (TMT) is a commonly used tool for evaluating executive functions, and the activation of cerebral oxygenation in the prefrontal cortex (PFC) during the test can reflect the participation of executive function. This study aimed to compare the differences in cerebral oxygenation in the PFC between the computer- and paper-based versions of the TMT and provide a theoretical basis for the optimization and clinical application of the computer-based version. A total of 32 healthy adult participants completed the computer- and paper-based TMT Types A and B. Cerebral oxygenation changes in the PFC were monitored during the experiment using near-infrared spectroscopy. Moreover, average changes in oxyhemoglobin (Δoxy-Hb) levels at the baseline and during activation periods in different types of testing were compared and analyzed. The number of correct connections in the computer-based version Type B was less than that in the paper-based version Type B (p < .001). The task time of the computer-based version was longer than that of the paper-based version (p < .001). The B/A ratio of the number of correct connections in the computer-based version was lower than that in the paper-based version (p < .001). The Δoxy-Hb in the PFC of the paper-based version was higher than that of the computer-based version (p < .001). Significant differences in oxygenation in the PFC were observed between the paper- and computer-based versions of TMT. After further improvement and correction in the subsequent development of the computer-based TMT, and taking into account the psychological feelings and preferences of the participants when performing different versions of the TMTs, the computer-based TMT is expected to play a good auxiliary role in clinical evaluation.
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Corteza Prefrontal , Espectroscopía Infrarroja Corta , Prueba de Secuencia Alfanumérica , Humanos , Corteza Prefrontal/metabolismo , Masculino , Femenino , Espectroscopía Infrarroja Corta/métodos , Adulto Joven , Adulto , Oxígeno/metabolismo , Oxígeno/sangre , Función Ejecutiva/fisiología , Oxihemoglobinas/metabolismo , Oxihemoglobinas/análisisRESUMEN
The classic Astragalus-Cassia twig drug pair has a long history of proven efficacy. However, a fewer studies on material basis of the Astragalus and Cassia twig decoction (ACD) was researched at present. The method of UPLC-Q-TOF-MS for classifying and identifying the main chemical components of ACD was established and the differences in composition between single decoction and co-decoction were compared by using HPLC-UV. The therapeutic role of ACD on type 2 diabetes (T2D) rats was investigated. Thirty-five compounds were resolved from the ACD. Fifteen compounds were deduced from the decoction of Astragalus, whereas nine compounds were identified from Cassia twig. Pairing of herbs make a significant effect on the chemical composition of herbal decoction. ACD can play a more obvious role in alleviating the symptoms of T2D rats, compared to the application of single herb.
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Planta del Astrágalo , Animales , Cromatografía Líquida de Alta Presión , Ratas , Planta del Astrágalo/química , Masculino , Ratas Sprague-Dawley , Cassia/química , Medicamentos Herbarios Chinos/química , Espectrometría de Masas , Estructura Molecular , Fitoquímicos/farmacología , Fitoquímicos/aislamiento & purificación , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológicoRESUMEN
N6-methyladenosine (m6A) serves as the most abundant posttranscription modification. However, the role of m6A in tumorigenesis and chemotherapeutic drugs sensitivity remains largely unclear. Present research focuses on the potential function of the m6A writer KIAA1429 in tumor development and sorafenib sensitivity in liver cancer. We found that the level of KIAA1429 was significantly elevated in liver cancer tissues and cells and was closely associated with poorer prognosis. Functionally, KIAA1429 promoted the proliferation and Warburg effect of liver cancer cells in vitro and in vivo. RNA-seq and MeRIP-seq analysis revealed the glycolysis was one of the most affected pathways by KIAA1429, and m6A-modified HK1 was the most likely targeted gene to regulate the Warburg effect. KIAA1429 depletion decreased Warburg effect and increased sorafenib sensitivity in liver cancer. Mechanistically, KIAA1429 could affect the m6A level of HK1 mRNA through directly binding with it. Moreover, KIAA1429 cooperated with the m6A reader HuR to enhance HK1 mRNA stability, thereby upregulating its expression. These findings demonstrated that KIAA1429/HK1 axis decreases the sensitivity of liver cancer cells to sorafenib by regulating the Warburg effect, which may provide a novel therapeutic target for liver cancer treatment.
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Antineoplásicos , Hexoquinasa , Neoplasias Hepáticas , Sorafenib , Efecto Warburg en Oncología , Animales , Humanos , Masculino , Ratones , Antineoplásicos/farmacología , Línea Celular Tumoral , Hexoquinasa/metabolismo , Hexoquinasa/genética , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genética , Ratones Endogámicos BALB C , Ratones Desnudos , Sorafenib/farmacología , Efecto Warburg en Oncología/efectos de los fármacosRESUMEN
BACKGROUND: Chronic obstructive pulmonary disease (COPD), a common respiratory disease, can be effectively treated by traditional Chinese medicine (TCM). Qingfei Huatan, a TCM formula, has been reported to effectively alleviate the clinical symptoms of COPD patients. However, there is a lack of multi-centre, randomised, double-blind, controlled clinical trials documenting the clinical efficacy and safety of this formula in the treatment of acute exacerbation of COPD (AECOPD). OBJECTIVE: This study evaluated the efficacy and safety of Qingfei Huatan formula in the treatment of AECOPD, thereby providing high-quality clinical evidence. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: A total of 276 patients with AECOPD were included in this multi-centre, randomised, double-blind, placebo-controlled trial and were randomised into treatment and control groups at a ratio of 1:1. Patients in the treatment and control groups took Qingfei Huatan granules or simulated Qingfei Huatan granules twice a day, for 14 days, in addition to Western medicine treatment. All patients were followed up for 3 months. MAIN OUTCOME MEASURES: The primary outcome was time taken to symptom stabilisation. The secondary outcomes included duration of antibiotic use, clinical symptom and sign score, TCM syndrome score, dyspnoea score, and quality of life (QOL) score. Meanwhile, the safety of the formula was assessed through routine urine and stool tests, electrocardiograms, liver and kidney function tests, and the observation of adverse events throughout the trial. RESULTS: The time taken for effective stabilisation (P < 0.05) and obvious stabilisation (P < 0.01), and the duration of antibiotic use (P < 0.05) were significantly shorter in the treatment group than in the control group. On days 6, 9, 12 and 14 of treatment, clinical symptom and sign score decreased in both groups, particularly in the treatment group (P < 0.01). On days 9, 12 and 14 of treatment, the TCM syndrome scores of both groups were reduced (P < 0.01), with more significant reductions in the treatment group. At 3 months after the end of treatment, the treatment group continued to have lower clinical symptom and sign score and TCM syndrome score than the control group (P < 0.01). On days 6, 9, 12 and 14 of treatment, dyspnoea and QOL scores were markedly reduced in the two groups (P < 0.05 and P < 0.01, respectively), especially in the treatment group. At 3 months after the end of treatment, dyspnoea and QOL scores were lower in the treatment group than those in the control group (P < 0.01). No serious adverse events were observed in either group. CONCLUSION: The Qingfei Huatan formula can effectively shorten the duration of AECOPD and antibiotic use, significantly relieve clinical symptoms, and increase QOL for AECOPD patients, with a favourable safety profile. These results suggest that this formula can be used as a complementary treatment for AECOPD patients. TRIAL REGISTRATION: The protocol was registered at the Chinese Clinical Trial Registry (ChiCTR1900026576). Please cite this article as: Zhu HZ, Li CY, Liu LJ, Tong JB, Lan ZH, Tian SG, Li Q, Tong XL, Wu JF, Zhu ZG, Li SY, Li JS. Efficacy and safety of Qingfei Huatan formula in the treatment of acute exacerbation of chronic obstructive pulmonary disease: A multi-centre, randomised, double-blind, placebo-controlled trial. J Integr Med. 2024; Epub ahead of print.
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ETHNOPHARMACOLOGICAL RELEVANCE: Treatment options for hepatic fibrosis, a prevalent liver condition closely linked to cirrhosis, are currently limited. While Guizhi Fuling Wan (GFW), a pill derived from traditional Chinese herbs, has been reported to possess hepatoprotective properties, its therapeutic effect and mechanism in hepatic fibrosis remain elusive. AIM OF THE STUDY: This study aimed to evaluate the anti-fibrotic impact of GFW and its underlying mechanisms in both in vivo and in vitro settings. MATERIALS AND METHODS: Tetrachloromethane (CCl4) was used to induce hepatic fibrosis in male rats. In vitro, activation of hepatic stellate cells (HSCs) was triggered by platelet-derived growth factor-BB (PDGF-BB). In vivo, liver function, pathological alterations, and HSC activation were evaluated. Additionally, the impact of GFW on the activated phenotypes of Lieming Xu-2 (LX-2) cells was examined in vitro. Network pharmacology was employed to identify the potential targets of GFW in hepatic fibrosis. Lastly, the impact of GFW on the PTEN/AKT/mTOR pathway and PTEN ubiquitination in HSCs was investigated. RESULTS: GFW alleviated CCl4-induced liver damage and scarring in rats in a dose-dependent manner and suppressed HSC activation in vivo. Moreover, GFW inhibited the proliferation, migration, differentiation, and extracellular matrix (ECM) production of activated HSCs in vitro. GFW also promoted autophagy and apoptosis of HSCs. Meanwhile, network pharmacology and in vitro studies suggested that GFW inhibits the AKT/mTOR pathway by preventing PTEN degradation by suppressing ubiquitination. CONCLUSION: GFW attenuates Ccl4-induced hepatic fibrosis in male rats by regulating the PTEN/AKT/mTOR signaling pathway, positioning it as a potential candidate for the treatment of hepatic fibrosis.
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Medicamentos Herbarios Chinos , Células Estrelladas Hepáticas , Cirrosis Hepática , Fosfohidrolasa PTEN , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Serina-Treonina Quinasas TOR , Animales , Humanos , Masculino , Ratas , Tetracloruro de Carbono , Línea Celular , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfohidrolasa PTEN/metabolismo , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Previous studies have reported a high occurrence of contrast-associated acute kidney injury (CA-AKI) in myocardial infarction (MI) patients undergoing primary percutaneous coronary intervention (PCI). However, the data on CA-AKI in MI patients who underwent elective PCI are limited. To evaluate the incidence of CA-AKI in MI patients undergoing elective PCI. The data were sourced from the Iodixanol-AKI Registry of MI patients scheduled to undergo elective PCI in 8 medical centers from May 2020 to November 2021. The participants were divided into three groups: acute, prior, and multiple MI. The outcomes measured were CA-AKI and the composite endpoint of major adverse renal and cardiovascular events (MARCE). The incidence of CA-AKI was 4.46% (37/830) in the MI patients, 4.40% (7/159) in the acute MI patients, 4.41% (22/499) in the prior MI patients, and 4.65% (8/172) in the multiple MI patients. Of note, 36 patients (97.30%) at AKI stage 1, and only 1 patient at AKI stage 2. There was no difference in the incidence of CA-AKI (P = 0.991) among the three groups. Multivariate regression analysis revealed that the independent risk factors for CA-AKI were diabetes and an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2. MARCE occurred in 3.4% (28/830) of the total patients and was not associated with either any subgroup of patients with MI or AKI. The incidence of CA-AKI was low and mainly limited to mildly impaired renal function in MI patients undergoing elective PCI.
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BACKGROUND: CDD-2103 is an herbal prescription used to treat ulcerative colitis (UC). This study aimed to uncover its mechanism by integrating metabolomics and serum-feces pharmacochemistry-based network pharmacology. METHODS: A DSS-induced chronic colitis mice model was used to evaluate the anti-colitis effect of CDD-2103. Serum and feces metabolomics were conducted to identify differential metabolites and pathways. In the serum-feces pharmacochemistry study, biological samples were collected from rats treated with CDD-2103. Then, network pharmacology was utilized to predict the targets of the identified compounds. Critical genes were extracted through the above-integrated analysis. The interactions between targets, CDD-2103, and its compounds were validated through molecular docking, immunoblotting, and enzyme activity assays. RESULTS: CDD-2103 alleviated ulcerous symptoms and colonic injuries in colitis mice. Metabolomics study identified differential metabolites associated with tryptophan, glycerophospholipid, and linoleic acid metabolisms. The serum-feces pharmacochemistry study revealed twenty-three compounds, which were subjected to network pharmacology analysis. Integration of these results identified three key targets (AHR, PLA2, and PTGS2). Molecular docking showed strong affinities between the compounds and targets. PTGS2 was identified as a hub gene targeted by most CDD-2103 compounds. Immunoblotting and enzyme activity assays provided further evidence that CDD-2103 alleviates UC, potentially through its inhibitory effect on cyclooxygenase-2 (COX-2, encoded by PTGS2), with alkaloids and curcuminoids speculated as crucial anti-inflammatory compounds. CONCLUSION: This integrated strategy reveals the mechanism of CDD-2103 and provides insights for developing herbal medicine-based therapies for UC.
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Colitis Ulcerosa , Medicamentos Herbarios Chinos , Metabolómica , Simulación del Acoplamiento Molecular , Farmacología en Red , Animales , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/metabolismo , Ratones , Masculino , Ratas , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Heces/química , Modelos Animales de Enfermedad , Metaboloma/efectos de los fármacosRESUMEN
BACKGROUND: Nuclear erythroid 2-related factor 2 (Nrf2), a transcription factor, is critically involved in the regulation of oxidative stress and inflammation. However, the role of endothelial Nrf2 in atherogenesis has yet to be defined. In addition, how endothelial Nrf2 is activated and whether Nrf2 can be targeted for the prevention and treatment of atherosclerosis is not explored. METHODS: RNA-sequencing and single-cell RNA sequencing analysis of mouse atherosclerotic aortas were used to identify the differentially expressed genes. In vivo endothelial cell (EC)-specific activation of Nrf2 was achieved by injecting adeno-associated viruses into ApoE-/- mice, while EC-specific knockdown of Nrf2 was generated in Cdh5CreCas9floxed-stopApoE-/- mice. RESULTS: Endothelial inflammation appeared as early as on day 3 after feeding of a high cholesterol diet (HCD) in ApoE-/- mice, as reflected by mRNA levels, immunostaining and global mRNA profiling, while the immunosignal of the end-product of lipid peroxidation (LPO), 4-hydroxynonenal (4-HNE), started to increase on day 10. TNF-α, 4-HNE, and erastin (LPO inducer), activated Nrf2 signaling in human ECs by increasing the mRNA and protein expression of Nrf2 target genes. Knockdown of endothelial Nrf2 resulted in augmented endothelial inflammation and LPO, and accelerated atherosclerosis in Cdh5CreCas9floxed-stopApoE-/- mice. By contrast, both EC-specific and pharmacological activation of Nrf2 inhibited endothelial inflammation, LPO, and atherogenesis. CONCLUSIONS: Upon HCD feeding in ApoE-/- mice, endothelial inflammation is an earliest event, followed by the appearance of LPO. EC-specific activation of Nrf2 inhibits atherosclerosis while EC-specific knockdown of Nrf2 results in the opposite effect. Pharmacological activators of endothelial Nrf2 may represent a novel therapeutic strategy for the treatment of atherosclerosis.
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Apolipoproteínas E , Aterosclerosis , Células Endoteliales , Inflamación , Peroxidación de Lípido , Factor 2 Relacionado con NF-E2 , Animales , Humanos , Masculino , Ratones , Apolipoproteínas E/genética , Apolipoproteínas E/deficiencia , Apolipoproteínas E/metabolismo , Aterosclerosis/metabolismo , Aterosclerosis/genética , Aterosclerosis/patología , Modelos Animales de Enfermedad , Células Endoteliales/metabolismo , Inflamación/metabolismo , Inflamación/genética , Ratones Noqueados , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Estrés OxidativoRESUMEN
Hypermucoviscosity (HMV) is a phenotype that is commonly associated with hypervirulence in Klebsiella pneumoniae. The factors that contribute to the emergence of HMV subpopulations remain unclear. In this study, eight K. pneumoniae strains were recovered from an inpatient who had been hospitalized for 20 days. Three of the isolates exhibited a non-HMV phenotype, which was concomitant with higher biofilm formation than the other five HMV isolates. All eight isolates were highly susceptible to serum killing, albeit HMV strains were remarkably more infective than non-HMV counterparts in a mouse model of infection. Whole genome sequencing (WGS) showed that the eight isolates belonged to the K57-ST412 lineage. Average nucleotide identity (FastANIb) analysis indicated that eight isolates share 99.96% to 99.99% similarity and were confirmed to be the same clone. Through comparative genomics analysis, 12 non-synonymous mutations were found among these isolates, eight of which in the non-HMV variants, including rmpA (c.285delG) and wbaP (c.1305T > A), which are assumed to be associated with the non-HMV phenotype. Mutations in manB (c.1318G > A), dmsB (c.577C > T) and tkt (c.1928C > A) occurred in HMV isolates only. RNA-Seq revealed transcripts of genes involved in energy metabolism, carbohydrate metabolism and membrane transport, including cysP, cydA, narK, tktA, pduQ, aceB, metN, and lsrA, to be significantly dysregulated in the non-HMV strains, suggesting a contribution to HMV phenotype development. This study suggests that co-occurrence of HMV and non-HMV phenotypes in the same clonal population may be mediated by mutational mechanisms as well as by certain genes involved in membrane transport and central metabolism. IMPORTANCE: K. pneumoniae with a hypermucoviscosity (HMV) phenotype is a community-acquired pathogen that is associated with increased invasiveness and pathogenicity, and underlying diseases are the most common comorbid risk factors inducing metastatic complications. HMV was earlier attributed to the overproduction of capsular polysaccharide, and more data point to the possibility of several causes contributing to this bacterial phenotype. Here, we describe a unique event in which the same clonal population showed both HMV and non-HMV characteristics. Studies have demonstrated that this process is influenced by mutational processes and genes related to transport and central metabolism. These findings provide fresh insight into the mechanisms behind co-occurrence of HMV and non-HMV phenotypes in monoclonal populations as well as potentially being critical in developing strategies to control the further spread of HMV K. pneumoniae.
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Infecciones por Klebsiella , Klebsiella pneumoniae , Fenotipo , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/aislamiento & purificación , Humanos , Infecciones por Klebsiella/microbiología , Infecciones por Klebsiella/epidemiología , Ratones , Animales , Secuenciación Completa del Genoma , Biopelículas/crecimiento & desarrollo , Virulencia/genética , Genoma Bacteriano/genética , Masculino , Mutación , FemeninoRESUMEN
BACKGROUND: Since 2020, China has implemented an innovative payment method called Diagnosis-Intervention Packet (DIP) in 71 cities nationwide. This study aims to assess the impact of DIP on medical expenditure, efficiency, and quality for inpatients covered by the Urban Employee Basic Medical Insurance (UEBMI) and Urban and Rural Residents Basic Medical Insurance (URRBMI). It seeks to explore whether there are differences in these effects among inpatients of the two insurance types, thereby further understanding its implications for health equity. MATERIALS AND METHODS: We conducted interrupted time series analyses on outcome variables reflecting medical expenditure, efficiency, and quality for both UEBMI and URRBMI inpatients, based on a dataset comprising 621,125 inpatient reimbursement records spanning from June 2019 to June 2023 in City A. This dataset included 110,656 records for UEBMI inpatients and 510,469 records for URRBMI inpatients. RESULTS: After the reform, the average expenditure per hospital admission for UEBMI inpatients did not significantly differ but continued to follow an upward pattern. In contrast, for URRBMI inpatients, the trend shifted from increasing before the reform to decreasing after the reform, with a decline of 0.5%. The average length of stay for UEBMI showed no significant changes after the reform, whereas there was a noticeable downward trend in the average length of stay for URRBMI. The out-of-pocket expenditure (OOP) per hospital admission, 7-day all-cause readmission rate and 30-day all-cause readmission rate for both UEBMI and URRBMI inpatients showed a downward trend after the reform. CONCLUSION: The DIP reform implemented different upper limits on budgets based on the type of medical insurance, leading to varying post-treatment prices for UEBMI and URRBMI inpatients within the same DIP group. After the DIP reform, the average expenditure per hospital admission and the average length of stay remained unchanged for UEBMI inpatients, whereas URRBMI inpatients experienced a decrease. This trend has sparked concerns about hospitals potentially favoring UEBMI inpatients. Encouragingly, both UEBMI and URRBMI inpatients have seen positive outcomes in terms of alleviating patient financial burdens and enhancing the quality of care.
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Gastos en Salud , Pacientes Internos , Seguro de Salud , Humanos , Gastos en Salud/estadística & datos numéricos , China , Seguro de Salud/economía , Pacientes Internos/estadística & datos numéricos , Calidad de la Atención de Salud/normas , Proyectos Piloto , Análisis de Series de Tiempo Interrumpido , Masculino , FemeninoRESUMEN
As a vital energy source for cellular metabolism and tissue survival, the mitochondrion can undergo morphological or positional change and even shuttle between cells in response to various stimuli and energy demands. Multiple human diseases are originated from mitochondrial dysfunction, but the curative succusses by traditional treatments are limited. Mitochondrial transplantation therapy (MTT) is an innovative therapeutic approach that is to deliver the healthy mitochondria either derived from normal cells or reassembled through synthetic biology into the cells and tissues suffering from mitochondrial damages and finally replace their defective mitochondria and restore their function. MTT has already been under investigation in clinical trials for cardiac ischemia-reperfusion injury and given an encouraging performance in animal models of numerous fatal critical diseases including central nervous system disorders, cardiovascular diseases, inflammatory conditions, cancer, renal injury, and pulmonary damage. This review article summarizes the mechanisms and strategies of mitochondrial transfer and the MTT application for types of mitochondrial diseases, and discusses the potential challenge in MTT clinical application, aiming to exhibit the good therapeutic prospects of MTTs in clinics.
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Mitocondrias , Enfermedades Mitocondriales , Humanos , Animales , Enfermedades Mitocondriales/terapia , Mitocondrias/metabolismo , Mitocondrias/trasplante , Terapia de Reemplazo Mitocondrial/métodosRESUMEN
Objective: Microfold cells (M cells) are specific intestinal epithelial cells for monitoring and transcytosis of antigens, microorganisms, and pathogens in the intestine. However, the mechanism for M-cell development remained elusive. Materials and Methods: Real-time polymerase chain reaction, immunofluorescence, and western blotting were performed to analyze the effect of sorbitol-regulated M-cell differentiation in vivo and in vitro, and luciferase and chromatin Immunoprecipitation were used to reveal the mechanism through which sorbitol-modulated M-cell differentiation. Results: Herein, in comparison to the mannitol group (control group), we found that intestinal M-cell development was inhibited in response to sorbitol treatment as evidenced by impaired enteroids accompanying with decreased early differentiation marker Annexin 5, Marcksl1, Spib, sox8, and mature M-cell marker glycoprotein 2 expression, which was attributed to downregulation of receptor activator of nuclear factor kappa-Ð ligand (RANKL) expression in vivo and in vitro. Mechanically, in the M-cell model, sorbitol stimulation caused a significant upregulation of phosphodiesterase 4 (PDE4) phosphorylation, leading to decreased protein kinase A (PKA)/cAMP-response element binding protein (CREB) activation, which further resulted in CREB retention in cytosolic and attenuated CREB binds to RANKL promoter to inhibit RANKL expression. Interestingly, endogenous PKA interacted with CREB, and this interaction was destroyed by sorbitol stimulation. Most importantly, inhibition of PDE4 by dipyridamole could rescue the inhibitory effect of sorbitol on intestinal enteroids and M-cell differentiation and mature in vivo and in vitro. Conclusion: These findings suggested that sorbitol suppressed intestinal enteroids and M-cell differentiation and matured through PDE4-mediated RANKL expression; targeting to inhibit PDE4 was sufficient to induce M-cell development.
Asunto(s)
Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , Células M , Ligando RANK , Sorbitol , Animales , Masculino , Ratones , Diferenciación Celular/efectos de los fármacos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Mucosa Intestinal/metabolismo , Células M/efectos de los fármacos , Ratones Endogámicos C57BL , Ligando RANK/metabolismo , Sorbitol/farmacologíaRESUMEN
Phage therapy has shown great promise in the treatment of bacterial infections. However, the effectiveness of phage therapy is compromised by the inevitable emergence of phage-resistant strains. In this study, a phage-resistant carbapenem-resistant Klebsiella pneumoniae strain SWKP1711R, derived from parental carbapenem-resistant K. pneumoniae strain SWKP1711 was identified. The mechanism of bacteriophage resistance in SWKP1711R was investigated and the molecular determinants causing altered growth characteristics, antibiotic resistance, and virulence of SWKP1711R were tested. Compared to SWKP1711, SWKP1711R showed slower growth, smaller colonies, filamentous cells visible under the microscope, reduced production of capsular polysaccharide (CPS) and lipopolysaccharide, and reduced resistance to various antibiotics accompanied by reduced virulence. Adsorption experiments showed that phage vB_kpnM_17-11 lost the ability to adsorb onto SWKP1711R, and the adsorption receptor was identified to be bacterial surface polysaccharides. Genetic variation analysis revealed that, compared to the parental strain, SWKP1711R had only one thymine deletion at position 78 of the open reading frame of the lpcA gene, resulting in a frameshift mutation that caused alteration of the bacterial surface polysaccharide and inhibition of phage adsorption, ultimately leading to phage resistance. Transcriptome analysis and quantitative reverse transcriptase PCR revealed that genes encoding lipopolysaccharide synthesis, ompK35, blaTEM-1, and type II and Hha-TomB toxin-antitoxin systems, were all downregulated in SWKP1711R. Taken together, the evidence presented here indicates that the phenotypic alterations and phage resistance displayed by the mutant may be related to the frameshift mutation of lpcA and altered gene expression. While evolution of phage resistance remains an issue, our study suggests that the reduced antibiotic resistance and virulence of phage-resistant strain derivatives might be beneficial in alleviating the burden caused by multidrug-resistant bacteria.