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Kagome lattice AV3Sb5 has attracted tremendous interest because it hosts correlated and topological physics. However, an in-depth understanding of the temperature-driven electronic states in AV3Sb5 is elusive. Here we use scanning tunneling microscopy to directly capture the rotational symmetry-breaking effect in KV3Sb5. Through both topography and spectroscopic imaging of defect-free KV3Sb5, we observe a charge density wave (CDW) phase transition from an a0 × a0 atomic lattice to a robust 2a0 × 2a0 superlattice upon cooling the sample to 60 K. An individual Sb-atom vacancy in KV3Sb5 further gives rise to the local Friedel oscillation (FO), visible as periodic charge modulations in spectroscopic maps. The rotational symmetry of the FO tends to break at the temperature lower than 40 K. Moreover, the FO intensity shows an obvious competition against the intensity of the CDW. Our results reveal a tantalizing electronic nematicity in KV3Sb5, highlighting the multiorbital correlation in the kagome lattice framework.
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A kagome lattice hosts a plethora of quantum states arising from the interplay between nontrivial topology and electron correlations. The recently discovered kagome magnet RMn6Sn6 (R represents a rare-earth element) is believed to showcase a kagome band closely resembling textbook characteristics. Here, we report the characterization of local electronic states and their magnetization response in YMn6Sn6 via scanning tunneling microscopy measurements under vector magnetic fields. Our spectroscopic maps reveal a spontaneously trimerized kagome electronic order in YMn6Sn6, where the 6-fold rotational symmetry is disrupted while translational symmetry is maintained. Further application of an external magnetic field demonstrates a strong coupling of the YMn6Sn6 kagome band to the field, which exhibits an energy shift discrepancy under different field directions, implying the existence of magnetization-response anisotropy and anomalous g factors. Our findings establish YMn6Sn6 as an ideal platform for investigating kagome-derived orbital magnetic moment and correlated magnetic topological states.
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The prevalence of chronic kidney disease (CKD) is highly increasing. Renal fibrosis is a common pathological feature in various CKD. Previous studies showed tubular cell senescence is highly involved in the pathogenesis of renal fibrosis. However, the inducers of tubular senescence and the underlying mechanisms have not been fully investigated. C-X-C motif chemokine receptor 4 (CXCR4), a G-protein-coupled seven-span transmembrane receptor, increases renal fibrosis and plays an important role in tubular cell injury. Whereas, whether CXCR4 could induce tubular cell senescence and the detailed mechanisms have not studied yet. In this study, we adopted adriamycin nephropathy and 5/6 nephrectomy models, and cultured tubular cell line. Overexpression or knockdown of CXCR4 was obtained by injection of related plasmids. We identified CXCR4 increased in injury tubular cells. CXCR4 was expressed predominantly in renal tubular epithelial cells and co-localized with adipose differentiation-related protein (ADRP) as well as the senescence-related protein P16INK4A . Furthermore, we found overexpression of CXCR4 greatly induced the activation of ß-catenin, while knockdown of CXCR4 inhibited it. We also found that CXCR4 inhibited fatty acid oxidation and triggered lipid deposition in tubular cells. To inhibit ß-catenin by ICG-001, an inhibitor of ß-catenin, could significantly block CXCR4-suppressed fatty acid oxidation. Taken together, our results indicate that CXCR4 is a key mediator in tubular cell senescence and renal fibrosis. CXCR4 promotes tubular cell senescence and renal fibrosis by inducing ß-catenin and inhibiting fatty acid metabolism. Our findings provide a new theory for tubular cell injury in renal fibrosis.
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Rim , Receptores CXCR4 , Insuficiência Renal Crônica , beta Catenina , beta Catenina/metabolismo , Senescência Celular , Células Epiteliais/metabolismo , Ácidos Graxos/metabolismo , Fibrose , Rim/patologia , Insuficiência Renal Crônica/patologia , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Animais , CamundongosRESUMO
Brassinosteroid activated kinase 1 (BAK1) is a cell-surface coreceptor which plays multiple roles in innate immunity of plants. HopF2 is an effector secreted by the bacterial pathogen Pseudomonas syringae pv. tomato DC3000 into Arabidopsis and suppresses host immune system through interaction with BAK1 as well as its downstream kinase MKK5. The association mechanism of HopF2 to BAK1 remains unclear, which prohibits our understanding and subsequent interfering of their interaction for pathogen management. Herein, we found the kinase domain of BAK1 (BAK1-KD) is sufficient for HopF2 association. With a combination of hydrogen/deuterium exchange mass spectrometry and mutational assays, we found a region of BAK1-KD N-lobe and a region of HopF2 head subdomain are critical for intermolecular interaction, which is also supported by unbiased protein-protein docking with ClusPro and kinase activity assay. Collectively, this research presents the interaction mechanism between Arabidopsis BAK1 and P. syringae HopF2, which could pave the way for bactericide development that blocking the functioning of HopF2 toward BAK1.
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Proteínas de Arabidopsis , Arabidopsis , Pseudomonas syringae/fisiologia , Brassinosteroides , Proteínas de Bactérias/química , Proteínas de Arabidopsis/fisiologia , Doenças das Plantas/microbiologia , Proteínas Serina-Treonina Quinases/químicaRESUMO
The morbidity of polycystic ovary syndrome (PCOS) is in highly increasing rate nowadays. PCOS not only affects the fertility in women, but also threatens the health of whole life. Hence, to find the prognostic risk factors is of great value. However, the effective predictors in clinical practice of PCOS are still in blackness. In this study, we found Klotho was increased in FF (Follicular Fluid) and primary luteinized granulosa cells (GCs) from PCOS patients with hyperandrogenism. Furthermore, we found follicular Klotho was negatively correlated with numbers of mature oocytes, and positively correlated with serum testosterone, LH, and LH/FSH levels menstrual cycle and number of total antral follicles in PCOS patients. In primary luteinized GCs, the increased Klotho was accompanied with upregulation of cell apoptosis and inflammation-related genes. In ovaries of PCOS mice and cultured human KGN cell line, Klotho was up-regulated and accompanied by apoptosis, inflammation and mitochondrial dysfunction. Therefore, our findings suggest new mechanisms for granulosa cell injury and revealed to target inhibit Klotho maybe a new therapeutic strategy for treatment of PCOS.
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BACKGROUND: IDH1-wildtype glioblastoma multiforme (IDHwt-GBM) is a highly heterogeneous and aggressive brain tumour characterised by a dismal prognosis and significant challenges in accurately predicting patient outcomes. To address these issues and personalise treatment approaches, we aimed to develop and validate robust multiomics molecular subtypes of IDHwt-GBM. Through this, we sought to uncover the distinct molecular signatures underlying these subtypes, paving the way for improved diagnosis and targeted therapy for this challenging disease. METHODS: To identify stable molecular subtypes among 184 IDHwt-GBM patients from TCGA, we used the consensus clustering method to consolidate the results from ten advanced multiomics clustering approaches based on mRNA, lncRNA, and mutation data. We developed subtype prediction models using the PAM and machine learning algorithms based on mRNA and MRI data for enhanced clinical utility. These models were validated in five independent datasets, and an online interactive system was created. We conducted a comprehensive assessment of the clinical impact, drug treatment response, and molecular associations of the IDHwt-GBM subtypes. RESULTS: In the TCGA cohort, two molecular subtypes, class 1 and class 2, were identified through multiomics clustering of IDHwt-GBM patients. There was a significant difference in survival between Class 1 and Class 2 patients, with a hazard ratio (HR) of 1.68 [1.15-2.47]. This difference was validated in other datasets (CGGA: HR = 1.75[1.04, 2.94]; CPTAC: HR = 1.79[1.09-2.91]; GALSS: HR = 1.66[1.09-2.54]; UCSF: HR = 1.33[1.00-1.77]; UPENN HR = 1.29[1.04-1.58]). Additionally, class 2 was more sensitive to treatment with radiotherapy combined with temozolomide, and this sensitivity was validated in the GLASS cohort. Correspondingly, class 2 and class 1 exhibited significant differences in mutation patterns, enriched pathways, programmed cell death (PCD), and the tumour immune microenvironment. Class 2 had more mutation signatures associated with defective DNA mismatch repair (P = 0.0021). Enriched pathways of differentially expressed genes in class 1 and class 2 (P-adjust < 0.05) were mainly related to ferroptosis, the PD-1 checkpoint pathway, the JAK-STAT signalling pathway, and other programmed cell death and immune-related pathways. The different cell death modes and immune microenvironments were validated across multiple datasets. Finally, our developed survival prediction model, which integrates molecular subtypes, age, and sex, demonstrated clinical benefits based on the decision curve in the test set. We deployed the molecular subtyping prediction model and survival prediction model online, allowing interactive use and facilitating user convenience. CONCLUSIONS: Molecular subtypes were identified and verified through multiomics clustering in IDHwt-GBM patients. These subtypes are linked to specific mutation patterns, the immune microenvironment, prognoses, and treatment responses.
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Neoplasias Encefálicas , Glioblastoma , Isocitrato Desidrogenase , Imageamento por Ressonância Magnética , RNA Mensageiro , Humanos , Análise por Conglomerados , Glioblastoma/genética , Glioblastoma/diagnóstico por imagem , Glioblastoma/patologia , Glioblastoma/terapia , Prognóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/terapia , Isocitrato Desidrogenase/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Mutação/genética , Reprodutibilidade dos Testes , Estudos de Coortes , Resultado do Tratamento , MultiômicaRESUMO
OBJECTIVE: In this study, we retrospectively analysed the efficacy and safety of three treatment models, namely, short-course radiotherapy sequential XELOX chemotherapy, neoadjuvant mFOLFOX6 concurrent radiotherapy and long-course concurrent radiotherapy with total mesorectal excision (TME) after treatment of locally advanced rectal cancer with high-risk factors. METHODS: We collected clinical data on 177 patients with locally advanced rectal cancer (cT3-4 and/or cN+) who were treated at the Department of Abdominal Oncology of the Affiliated Cancer Hospital of Guizhou Medical University from December 2017 to December 2022. All patients were associated with 2-3 risk factors [T4b, N2, Extramural Vascular Invasion (EMVI), Mesorectal Fascia (MRF) positivity], positive lateral lymph nodes. Among them, there were 45 cases in the short course radiotherapy sequential XELOX chemotherapy group (RT + XELOX group); 64 cases in the neoadjuvant mFOLFOX6 concurrent radiotherapy group (mFOLFOX6 + CRT group); and 68 cases in the long course concurrent radiotherapy group (CRT group). The RT + XELOX group and mFOLFOX6 + CRT group completed radiotherapy and 4 cycles of neoadjuvant chemotherapy, respectively, and then rested for 1-2 weeks before TME surgery; the CRT group completed concurrent radiotherapy and then rested for 6-8 weeks before TME surgery.Adjuvant chemotherapy was conducted after surgery in each of the three groups: 2 cycles of adjuvant chemotherapy with XELOX regimen in the RT + XELOX group, 4-6 cycles of adjuvant chemotherapy with mFOLFOX6 in the mFOLFOX6 + CRT group, and 8-12 cycles of adjuvant chemotherapy with mFOLFOX6 in the CRT group.The pathological complete response rate (pCR rate), tumour downstage rate, tumour complete resection rate (R0 resection rate), local recurrence rate, distant metastasis rate, overall survival rate, incidence of adverse reactions, surgical complications and completion rate of perioperative systemic chemotherapy were compared among patients in the three groups of cases after TME. RESULTS: The pCR rate (21.95% vs 17.24% vs 5.00%, p = 0.034) and and tumour downstage rate (78.05% vs 68.97% vs 53.33%, p = 0.029) were higher in the RT + XELOX group and mFOLFOX6 + CRT group compared to the CRT group. The RT + XELOX group had a lower 3-year distant metastasis rate (14.63% vs 36.67%, p = 0.048) and improved 3-year overall survival (76.57% vs 48.56%, p < 0.001) compared to the CRT group. There was no significant reduction in the 3-year distant metastasis rate in the mFOLFOX6 + CRT group versus the CRT group (27.59% vs 36.67%, p = 0.719), and the 3-year overall survival was similar (51.23% vs 48.56%, p = 0.35). Multi-logistic regression analysis and stratified analysis showed that patients in the RT + XELOX group and mFOLFOX6 + CRT group were more likely to achieve pCR than the CRT group (RT + XELOX group: OR 7.3, 95% CI [2.6-20.8], p < 0.001; mFOLFOX6 + CRT group OR 2.9, 95% CI [1.1-7.9], p = 0.036). The completion rates of perioperative systemic chemotherapy in the RT + XELOX, mFOLFOX6 + CRT, and CRT groups were 82.93% vs. 84.48% vs. 61.67% (χ2=9.95, p = 0.007), respectively. And there were significant differences in grade 3-4 leukopenia and thrombocytopenia (incidence of leukopenia: 15.50% vs. 7.81% vs. 1.47%, p = 0.045; incidence of thrombocytopenia: 13.33% vs 7.81% vs 1.47%, p = 0.027). There was no significant difference in the incidence of intraoperative and postoperative complications among the three groups (p > 0.05). CONCLUSIONS: RT + XELOX group and mFOLFOX6 + CRT group significantly improved the near-term outcome (e.g., pCR rate) in patients with locally advanced rectal cancer with high-risk factors compared with CRT group. The RT + XELOX group also reduced the 3-year distant metastasis rate, increased the 3-year overall survival rate, and did not increase the incidence of perioperative surgical complications. It provides an effective means for the comprehensive treatment of locally advanced rectal cancer and has important clinical guidance and application value.
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Protocolos de Quimioterapia Combinada Antineoplásica , Capecitabina , Leucovorina , Terapia Neoadjuvante , Neoplasias Retais , Humanos , Neoplasias Retais/terapia , Neoplasias Retais/patologia , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/mortalidade , Masculino , Feminino , Terapia Neoadjuvante/métodos , Pessoa de Meia-Idade , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina/administração & dosagem , Capecitabina/uso terapêutico , Idoso , Leucovorina/administração & dosagem , Leucovorina/uso terapêutico , Adulto , Fluoruracila/administração & dosagem , Fluoruracila/uso terapêutico , Compostos Organoplatínicos/uso terapêutico , Compostos Organoplatínicos/administração & dosagem , Oxaloacetatos , Resultado do TratamentoRESUMO
BACKGROUND: DEAD-box RNA helicase 19 A (DDX19A) is overexpressed in cervical squamous cell carcinoma. However, its role in gastric cancer remains unclear. The present study aimed to explore the role and underlying mechanism of DDX19A in the development of gastric cancer. METHODS: The expression of DDX19A in gastric cancer and paracancerous tissues was evaluated through quantitative polymerase chain reaction, western blotting, and immunohistochemical staining. The biological functions of DDX19A in gastric cancer were determined using CCK8, plate colony-forming, and Transwell migration assays. The specific mechanism of DDX19A in gastric cancer cells was studied using western blotting, RNA-binding protein immunoprecipitation, mRNA half-life detection, and nuclear and cytoplasmic RNA isolation. RESULTS: DDX19A was highly expressed in gastric cancer and positively associated with malignant clinicopathological features and poor prognosis. Additionally, DDX19A promoted gastric cancer cell proliferation, migration, and epithelial-mesenchymal transition phenotypes. Mechanistically, DDX19A activated the PI3K/AKT pathway by upregulating phosphatidylinositol-3-kinase (PIK3CA) expression. Furthermore, DDX19A interacted with PIK3CA mRNA, stabilized it, and facilitated its export from the nucleus. CONCLUSIONS: Our study reveals a novel mechanism whereby DDX19A promotes the proliferation and migration of gastric cancer cells by enhancing the stability and nuclear export of PIK3CA mRNA, thereby activating the PI3K/AKT pathway.
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BACKGROUND: The pathogenesis of amyotrophic lateral sclerosis (ALS) involves both genetic and environmental factors. This study investigates associations between metal measures in plasma and urine, ALS risk and survival and exposure sources. METHODS: Participants with and without ALS from Michigan provided plasma and urine samples for metal measurement via inductively coupled plasma mass spectrometry. ORs and HRs for each metal were computed using risk and survival models. Environmental risk scores (ERS) were created to evaluate the association between exposure mixtures and ALS risk and survival and exposure source. ALS (ALS-PGS) and metal (metal-PGS) polygenic risk scores were constructed from an independent genome-wide association study and relevant literature-selected single-nucleotide polymorphisms. RESULTS: Plasma and urine samples from 454 ALS and 294 control participants were analysed. Elevated levels of individual metals, including copper, selenium and zinc, significantly associated with ALS risk and survival. ERS representing metal mixtures strongly associated with ALS risk (plasma, OR=2.95, CI=2.38-3.62, p<0.001; urine, OR=3.10, CI=2.43-3.97, p<0.001) and poorer ALS survival (plasma, HR=1.37, CI=1.20-1.58, p<0.001; urine, HR=1.44, CI=1.23-1.67, p<0.001). Addition of the ALS-PGS or metal-PGS did not alter the significance of metals with ALS risk and survival. Occupations with high potential of metal exposure associated with elevated ERS. Additionally, occupational and non-occupational metal exposures were associated with measured plasma and urine metals. CONCLUSION: Metals in plasma and urine associated with increased ALS risk and reduced survival, independent of genetic risk, and correlated with occupational and non-occupational metal exposures. These data underscore the significance of metal exposure in ALS risk and progression.
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Severe acute pancreatitis (SAP) is an inflammatory disease of the pancreas with a high mortality rate. Macrophages play a crucial role in the pathogenesis of pancreatitis. Tectoridin (Tec) is a highly active isoflavone with anti-inflammatory pharmacological activity. However, the role of Tec in the SAP process is not known. The purpose of this study was to investigate the therapeutic effect and potential mechanism of Tec on SAP. To establish SAP mice by intraperitoneal injection of caerulein and Lipopolysaccharide (LPS), the role of Tec in the course of SAP was investigated based on histopathology, biochemical indicators of amylase and lipase and inflammatory factors. The relationship between Tec and macrophage polarization was verified by immunofluorescence, real-time quantitative PCR and Western blot analysis. We then further predicted the possible targets and signal pathways of action of Tec by network pharmacology and molecular docking, and validated them by in vivo and in vitro. In this study, we demonstrated that Tec significantly reduced pancreatic injury in SAP mice, and decreased serum levels of amylase and lipase. The immunofluorescence and Western blot analysis showed that Tec promoted macrophage M2 polarization. Network pharmacology and molecular docking predicted that Tec may target ERK2 for the treatment of SAP, and in vivo and in vitro experiments proved that Tec inhibited the ERK MAPK signal pathway. In summary, Tec can target ERK2, promote macrophage M2 polarization and attenuate pancreatic injury, Tec may be a potential drug for the treatment of SAP.
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Isoflavonas , Pancreatite , Camundongos , Animais , Pancreatite/induzido quimicamente , Pancreatite/tratamento farmacológico , Pancreatite/metabolismo , Ceruletídeo/efeitos adversos , Doença Aguda , Simulação de Acoplamento Molecular , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Macrófagos/metabolismo , Amilases , LipaseRESUMO
Tuberculosis (TB) is one of the infectious diseases caused by the pathogen Mycobacterium tuberculosis that continuously threatens the global human health. Bacillus Calmette-Guérin (BCG) vaccine is the only vaccine that has been used clinically to prevent tuberculosis in recent centuries, but its limitations in preventing latent infection and reactivation of tuberculosis do not provide full protection. In this study, we selected the membrane-associated antigen Rv1513 of Mycobacterium. In order to achieve stable expression and function of the target gene, the prokaryotic expression recombinant vector pET30b-Rv1513 was constructed and expressed and purified its protein. Detection of IFN- γ levels in the peripheral blood of TB patients stimulated by whole blood interferon release assay (WBIA) and multi-microsphere flow immunofluorescence luminescence (MFCIA) revealed that the induced production of cytokines, such as IFN-γ and IL-6, was significantly higher than that in the healthy group. Rv1513 combined with adjuvant DMT (adjuvant system liposomes containing dimethyldioctadecylammonium bromide (DDA), monophospholipid A (MPL), and trehalose-660-dibenzoic acid (TDB)) was used to detect serum specific antibodies, cytokine secretion from splenic suprasplenic cell supernatants, and multifunctional T-cell levels in splenocytes in immunised mice. The levels of IFN-γ, TNF-α, and IL-2 secreted by mouse splenocytes were found in the Rv1513+DMT group and the BCG+Rv1513+DMT group. The serum levels of IgG and its subclasses and the number of IFN-γ+T cells, TNF-α+T and IFN-γ+TNF-α+T cells in the induced CD4+/CD8+T cells in mice were significantly higher than those in the BCG group, and the highest levels were found in the BCG+Rv1513+DMT group. These findings suggest that Rv1513/DMT may serve as a potential subunit vaccine candidate that may be effective as a booster vaccine after the first BCG vaccination.
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Mycobacterium tuberculosis , Células Th1 , Vacinas contra a Tuberculose , Tuberculose , Animais , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/genética , Camundongos , Humanos , Células Th1/imunologia , Vacinas contra a Tuberculose/imunologia , Vacinas contra a Tuberculose/genética , Vacinas contra a Tuberculose/administração & dosagem , Tuberculose/imunologia , Tuberculose/prevenção & controle , Tuberculose/microbiologia , Feminino , Antígenos de Bactérias/imunologia , Antígenos de Bactérias/genética , Citocinas/metabolismo , Citocinas/imunologia , Proteínas de Bactérias/imunologia , Proteínas de Bactérias/genética , Interferon gama/imunologia , Interferon gama/metabolismo , Camundongos Endogâmicos BALB C , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/imunologia , Adjuvantes Imunológicos/administração & dosagem , AdultoRESUMO
BACKGROUND: The combined procedure of left atrial appendage closure (LAAC) with concomitant pulmonary vein isolation (PVI) has demonstrated its efficacy and safety. However, there is still a lack of comparative investigations regarding the long-term benefits of the combined procedure when compared to LAAC alone. Our study aims to assess the long-term outcomes of combined procedure of LAAC with concomitant PVI in comparison with a propensity matched LAAC alone group. METHODS: Propensity score matching (PSM) was employed to rectify covariate imbalances, resulting in the inclusion of 153 comparable patients from the initial cohort of 333 non-valvular atrial fibrillation (AF) patients. Clinical outcomes, encompassing thrombotic events, major cardiocerebrovascular adverse events (MACCE), re-hospitalization due to cardiovascular disease (CVD), and atrial tachycardia (AT), were juxtaposed between the two groups. Bleeding events and peri-device complications, such as residual flow, device-related thrombus, and device replacement, were also compared. Additionally, a patients group underwent PVI alone was included for comparing AF recurrence rates between the PVI alone group and the combined group. RESULTS: Following PSM, 153 patients (mean age 70.3 ± 8.9, 62.7% men) were included, with 102 undergoing the combined procedure and 51 undergoing LAAC alone. No significant differences were found in baseline characteristics between the two groups. The mean follow-up time was 37.6 ± 7.9 months, and two patients were lost to follow-up in the combined procedure group. Thrombotic events were observed in 4 (7.8%) patients in the LAAC alone group and 4 (4.0%) in the combined group (Log-rank p = 0.301). The proportion of patients experiencing MACCE, re-hospitalization due to CVD, and AT between the two groups was comparable, as were bleeding events and peri-device complications. Among patients from the combined procedure group without AF recurrence, a significant difference was noted in prior-procedure left ventricular ejection fraction (LVEF) and LVEF at the 12th month after the procedure (57.2% ± 7.1% vs. 60.5% ± 6.5%, p = 0.002). CONCLUSION: The concomitant PVI and LAAC procedure did not increase procedure-related complications, nor did it confer significant benefits in preventing thrombotic events or reducing other cardiovascular events. However, the combined procedure improved heart function, suggesting potential long-term benefits.
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Apêndice Atrial , Fibrilação Atrial , Ablação por Cateter , Veias Pulmonares , Acidente Vascular Cerebral , Masculino , Humanos , Feminino , Oclusão do Apêndice Atrial Esquerdo , Veias Pulmonares/cirurgia , Pontuação de Propensão , Volume Sistólico , Resultado do Tratamento , Função Ventricular Esquerda , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/cirurgia , Fibrilação Atrial/complicações , Hemorragia/etiologia , Apêndice Atrial/diagnóstico por imagem , Apêndice Atrial/cirurgia , Ablação por Cateter/efeitos adversos , Ablação por Cateter/métodos , Acidente Vascular Cerebral/prevenção & controle , Acidente Vascular Cerebral/complicaçõesRESUMO
Renal tubular epithelial cell senescence plays a critical role in promoting and accelerating kidney aging and age-related renal fibrosis. Senescent cells not only lose their self-repair ability, but also can transform into senescence-associated secretory phenotype (SASP) to trigger inflammation and fibrogenesis. Recent studies show that mitochondrial dysfunction is critical for renal tubular cell senescence and kidney aging, and calcium overload and abnormal calcium-dependent kinase activities are involved in mitochondrial dysfunction-associated senescence. In this study we investigated the role of mitochondrial calcium overload and mitochondrial calcium uniporter (MCU) in kidney aging. By comparing the kidney of 2- and 24-month-old mice, we found calcium overload in renal tubular cells of aged kidney, accompanied by significantly elevated expression of MCU. In human proximal renal tubular cell line HK-2, pretreatment with MCU agonist spermine (10 µM) significantly increased mitochondrial calcium accumulation, and induced the production of reactive oxygen species (ROS), leading to renal tubular cell senescence and age-related kidney fibrosis. On the contrary, pretreatment with MCU antagonist RU360 (10 µM) or calcium chelator BAPTA-AM (10 µM) diminished D-gal-induced ROS generation, restored mitochondrial homeostasis, retarded cell senescence, and protected against kidney aging in HK-2 cells. In a D-gal-induced accelerated aging mice model, administration of BAPTA (100 µg/kg. i.p.) every other day for 8 weeks significantly alleviated renal tubuarl cell senescence and fibrosis. We conclude that MCU plays a key role in promoting renal tubular cell senescence and kidney aging. Targeting inhibition on MCU provides a new insight into the therapeutic strategy against kidney aging.
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BACKGROUND: Racial disparities exist in access to health care and management of multiple health conditions including chronic pain; however, racial disparities in pre- and postoperative pain management in lower extremity amputation are not well-studied. Our objective was to examine the association between different racial and ethnic groups and prescription opioid and other analgesics use before and after lower extremity amputation. We hypothesize prescription opioid and other analgesic use among Black, Hispanic, and Native American US Medicare beneficiaries undergoing lower extremity amputations will be lower compared to White US Medicare beneficiaries. METHODS: This retrospective cohort study included a 5% national sample of all Medicare beneficiaries from 2011 to 2015 and 15% national sample of fee-for-service Medicare beneficiaries from 2016 to 2018 undergoing nontraumatic, lower extremity amputations. The exposure of interest was racial and ethnic group membership (ie, Black, Hispanic, Native American, White, and others-with others being the combination of the categories Asian and other) as provided in Medicare claims data. Using multivariable generalized estimating equations with a logistic link to account for repeated measurements over time, we estimated the odds of prescription opioid use within 6 months before and after lower extremity amputation across different racial and ethnic groups separately, adjusting for sociodemographic and health status factors (eg, Elixhauser index). Adjusted odds ratios (aORs) and 95% confidence intervals (95% CI) were reported. RESULTS: Among 16,068 eligible beneficiaries who underwent major and minor amputations (mean age = 65.1 ± 12.7 years; female = 36.1%), 10,107 (62.9%) were White, 3462 (21.5%) were Black, 1959 (12.2%) were Hispanic, 247 (1.5%) were Native American, and 151 (2.9%) were beneficiaries of other races. During the 6 months before lower extremity amputation, Hispanic beneficiaries (aOR, 0.71, 95% CI, 0.65-0.78) and beneficiaries of other races (aOR, 0.60, 95% CI, 0.47-0.76) had significantly lower odds of using prescription opioids compared to White beneficiaries. Similarly, Hispanic beneficiaries (aOR, 0.78, 95% CI, 0.71-0.84) and beneficiaries of other races (aOR, 0.63, 95% CI, 0.51-0.78) were associated with lower odds of opioid use in the 6 months after amputation compared to White beneficiaries. CONCLUSIONS: Among fee-for-service Medicare beneficiaries, Hispanic and other (eg, Asian) fee-for-service Medicare beneficiaries had lower odds of prescription opioid use than their White counterparts before and after nontraumatic, lower extremity amputations. Efforts to determine the underlying reasons are needed to ensure equitable health care access.
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KEY MESSAGE: The transcription factor AmCBF1 deepens the leaf colour of transgenic cotton by binding to the promoter of the chloroplast development-related protein GhClpR1 to promote photosynthesis. The ATP-dependent caseinolytic protease (Clp protease) family plays a crucial role within chloroplasts, comprising several Clp proteins to maintain chloroplast homeostasis. At present, research on Clp proteins mainly focuses on Arabidopsis, leaving its function in other plants, particularly in crops, less explored. In this study, we overexpressed AmCBF1 from Ammopiptanthus mongolicus (A. mongolicus) in wild type (R15), and found a significant darkening of leaf colour in transgenic plants (L28 and L30). RNA-seq analysis showed an enrichment of pathways associated with photosynthesis. Subsequent screening of differentially expressed genes revealed a significant up-regulation of GhClpR1, a gene linked to chloroplast development, in the transgenic strain. In addition, GhClpR1 was consistently expressed in upland cotton, with the highest expression observed in leaves. Subcellular localization analysis revealed that the protein encoded by GhClpR1 was located in chloroplasts. Yeast one hybrid and dual luciferase experiments showed that the AmCBF1 transcription factor positively regulates the expression of GhClpR1. VIGs-mediated silencing of GhClpR1 led to a significant yellowing phenotype in the leaves. This was accompanied by a reduction in chlorophyll content, and microscopic examination of chloroplast ultrastructure revealed severe developmental impairment. Finally, yeast two-hybrid assays showed that GhClpR1 interacts with the Clp protease complex accessory protein GhClpT2. Our study provides a foundation for studying the function of the Clp protease complex and a new strategy for cultivating high-light-efficiency cotton resources.
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Arabidopsis , Gossypium , Gossypium/genética , Endopeptidase Clp/genética , Cloroplastos , Fotossíntese , Arabidopsis/genética , Fatores de Transcrição/genéticaRESUMO
Polymyxin B (PMB) is considered a last-line treatment for multidrug-resistant (MDR) gram-negative bacterial infections. Model-informed precision dosing with population pharmacokinetics (PopPK) models could help to individualize PMB dosing regimens and improve therapy. However, the external prediction ability of the established PopPK models has not been fully elaborated. This study aimed to systemically evaluate eleven PMB PopPK models from ten published literature based on a new independent population, which was divided into four different populations, patients with liver dysfunction, kidney dysfunction, liver and kidney dysfunction, and normal liver and kidney function. The whole data set consisted of 146 patients with 391 PMB concentrations. The prediction- and simulation-based diagnostics and Bayesian forecasting were conducted to evaluate model predictability. In the overall evaluation process, none of the models exhibited satisfactory predictive ability in both prediction- and simulation-based diagnostic simultaneously. However, the evaluation of the models in the subgroup of patients with normal liver and kidney function revealed improved predictive performance compared to those with liver and/or kidney dysfunction. Bayesian forecasting demonstrated enhanced predictability with the incorporation of two to three prior observations. The external evaluation highlighted a lack of consistency between the prediction results of published models and the external validation dataset. Nonetheless, Bayesian forecasting holds promise in improving the predictive performance of the models, and feedback from therapeutic drug monitoring is crucial in optimizing individual dosing regimens.
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BACKGROUND: Systemic inflammatory response syndrome (SIRS) is an uncontrolled systemic inflammatory response. Proanthocyanidins (PC) is a general term of polyphenol compounds widely existed in blueberry fruits and can treat inflammation-related diseases. This study aimed to explore the regulatory effect of PC on lipopolysaccharide (LPS)-induced systemic inflammation and its potential mechanism, providing effective strategies for the further development of PC. METHODS: Here, RAW264.7 macrophages were stimulated with LPS to establish an inflammation model in vitro, while endotoxin shock mouse models were constructed by LPS in vivo. The function of PC was investigated by MTT, ELISA kits, H&E staining, immunohistochemistry, and Western blot analysis. RESULTS: Functionally, PC could demonstrate the potential to mitigate mortality in mice with endotoxin shock, as well as attenuated the levels of inflammatory cytokines (IL-6, TNF-α) and biochemical indicators (AST, ALT, CRE and BUN). Moreover, it had a significant protective effect on lung and kidney tissues damage. Mechanistically, PC exerted anti-inflammatory effects by inhibiting the activation of the NF-κB/NLRP3 signaling pathway. CONCLUSION: PC might have the potential ability of anti-inflammatory effects via modulation of the NF-κB/NLRP3 signaling pathway.
Assuntos
Anti-Inflamatórios , Mirtilos Azuis (Planta) , NF-kappa B , Proteína 3 que Contém Domínio de Pirina da Família NLR , Proantocianidinas , Transdução de Sinais , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proantocianidinas/farmacologia , Camundongos , Transdução de Sinais/efeitos dos fármacos , NF-kappa B/metabolismo , Mirtilos Azuis (Planta)/química , Células RAW 264.7 , Anti-Inflamatórios/farmacologia , Masculino , Lipopolissacarídeos/toxicidade , Lipopolissacarídeos/farmacologia , Choque Séptico/tratamento farmacológico , Choque Séptico/metabolismo , Choque Séptico/induzido quimicamenteRESUMO
OBJECTIVES: We explore patient-reported behaviors and activities within 30-days post-stroke hospitalization and their role in reducing death or readmissions within 90-days post-stroke. METHODS: We constructed the adequate transitions of care (ATOC) composite score, measuring patient-reported participation in eligible behaviors and activities (diet modification, weekly exercise, follow-up medical appointment attendance, medication adherence, therapy use, and toxic habit cessation) within 30 days post-stroke hospital discharge. We analyzed ATOC scores in ischemic and intracerebral hemorrhage stroke patients discharged from the hospital to home or rehabilitation facilities and enrolled in the NIH-funded Transitions of Care Stroke Disparities Study (TCSD-S). We utilized Cox regression analysis, with the progressive adjustment for sociodemographic variables, social determinants of health, and stroke risk factors, to determine the associations between ATOC score within 30-days and death or readmission within 90-days post-stroke. RESULTS: In our sample of 1239 stroke patients (mean age 64 +/- 14, 58 % male, 22 % Hispanic, 22 % Black, 52 % White, 76 % discharged home), 13 % experienced a readmission or death within 90 days (3 deaths, 160 readmissions, 3 readmissions with subsequent death). Seventy percent of participants accomplished a ≥75 % ATOC score. A 25 % increase in ATOC was associated with a respective 20 % (95 % CI 3-33 %) reduced risk of death or readmission within 90-days. CONCLUSION: ATOC represents modifiable behaviors and activities within 30-days post-stroke that are associated with reduced risk of death or readmission within 90-days post-stroke. The ATOC score should be validated in other populations, but it can serve as a tool for improving transitions of stroke care initiatives and interventions.
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PURPOSE: This study aimed to assess the predictive value of macrophage colony-stimulating factor (M-CSF) in the first trimester for hypertensive disorders complicating pregnancy (HDCP) and its association with disease severity and adverse pregnancy outcomes. HDCP pose significant risks to both maternal health and fetal health. M-CSF is implicated in the pathogenesis of HDCP by promoting inflammation and endothelial damage. METHODS: Serum levels of M-CSF were measured using an enzyme-linked immunosorbent assay, and clinical characteristics and pregnancy outcomes were compared between groups. RESULTS: Pregnant women with HDCP had significantly higher levels of proteinuria, systolic blood pressure, and diastolic blood pressure compared to those with normal pregnancy. Among patients with HDCP, the severity of disease correlated positively with serum levels of M-CSF. Furthermore, M-CSF levels in the first trimester were significantly associated with adverse pregnancy outcomes. The findings suggest that M-CSF may serve as a potential biomarker for predicting HDCP and its severity, as well as adverse pregnancy outcomes. CONCLUSIONS: Early detection and monitoring of M-CSF levels could aid in identifying high-risk pregnancies and implementing appropriate interventions to improve maternal and fetal outcomes.
RESUMO
BACKGROUND: The repair of bone defects caused by periodontal diseases is a difficult challenge in clinical treatment. Dental pulp stem cells (DPSCs) are widely studied for alveolar bone repair. The current investigation aimed to examine the specific mechanisms underlying the role of Zinc finger DHHC-type palmitoyl transferases 16 (ZDHHC16) in the process of osteogenic differentiation (OD) of DPSCs. METHODS: The lentiviral vectors ZDHHC16 or si-ZDHHC16 were introduced in the DPSCs and then the cells were induced by an odontogenic medium for 21 days. Subsequently, Quantitate Polymerase Chain Reaction (PCR), immunofluorescent staining, proliferation assay, ethynyl deoxyuridine (EdU) staining, and western blot analysis were used to investigate the specific details of ZDHHC16 contribution in OD of DPSCs. RESULTS: Our findings indicate that ZDHHC16 exhibited a suppressive effect on cellular proliferation and oxidative phosphorylation, while concurrently inducing ferroptosis in DPSCs. Moreover, the inhibition of ZDHHC16 promoted cell development and OD and reduced ferroptosis of DPSCs. The expression of p-CREB was suppressed by ZDHHC16, and immunoprecipitation (IP) analysis revealed that ZDHHC16 protein exhibited interconnection with cAMP-response element binding protein (CREB) of DPSCs. The CREB suppression reduced the impacts of ZDHHC16 on OD and ferroptosis of DPSCs. The activation of CREB also reduced the influences of si-ZDHHC16 on OD and ferroptosis of DPSCs. CONCLUSIONS: These findings provide evidences to support a negative association between ZDHHC16 and OD of DPSCs, which might be mediated by ferroptosis of DPSCs via CREB.