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CRISPR mutagenesis screens conducted with SpCas9 and other nucleases have identified certain cis-regulatory elements and genetic variants but at a limited resolution due to the absence of protospacer adjacent motif (PAM) sequences. Here, leveraging the broad targeting scope of the near-PAMless SpRY variant, we have demonstrated that saturated SpRY mutagenesis and base editing screens can faithfully identify functional regulatory elements and essential genetic variants for target gene expression at single-base resolution. We further extended this methodology to investigate a genome-wide association study (GWAS) locus at 10q22.1 associated with a red blood cell trait, where we identified potential enhancers regulating HK1 gene expression, despite not all of these enhancers exhibiting typical chromatin signatures. More importantly, our saturated base editing screens pinpoint multiple causal variants within this locus that would otherwise be missed by Bayesian statistical fine-mapping. Our approach is generally applicable to functional interrogation of all non-coding genomic elements while complementing other high-coverage CRISPR screens.
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Sistemas CRISPR-Cas , Estudio de Asociación del Genoma Completo , Humanos , Estudio de Asociación del Genoma Completo/métodos , Sistemas CRISPR-Cas/genética , Edición Génica/métodos , Mutagénesis , Elementos de Facilitación Genéticos/genéticaRESUMEN
In situ depot gel is a type of polymeric long-acting injectable (pLAI) drug delivery system; compared to microsphere technology, its preparation process is simpler and more conducive to industrialization. To ensure the chemical stability of peptide ACTY116, we avoided the use of harsh conditions such as high temperatures, high shear mixing, or homogenization; maintaining a water-free and oxygen-free environment was also critical to prevent hydrolysis and oxidation. Molecular dynamics (MDs) simulations were employed to assess the stability mechanism between ACTY116 and the pLAI system. The initial structure of ACTY116 with an alpha helix conformation was constructed using SYBYL-X, and the copolymer PLGA was generated by AMBER 16; results showed that PLGA-based in situ depot gel improved conformational stability of ACTY116 through hydrogen bonds formed between peptide ACTY116 and the components of the pLAI formulation, while PLGA (Poly(DL-lactide-co-glycolide)) also created steric hindrance and shielding effects to prevent conformational changes. As a result, the chemical and conformational stability and in vivo long-acting characteristics of ACTY116 ensure its enhanced efficacy. In summary, we successfully achieved our objective of developing a highly stable peptide-loaded long-acting injectable (LAI) in situ depot gel formulation that is stable for at least 3 months under harsh conditions (40 °C, above body temperature), elucidating the underlying stabilisation mechanism, and the high stability of the ACTY116 pLAI formulation creates favourable conditions for its in vivo pharmacological activity lasting for weeks or even months.
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BACKGROUND: Heart failure (HF) has been reported to affect cerebral cortex structure, but the underlying cause has not been determined. This study used Mendelian randomization (MR) to reveal the causal relationship between HF and structural changes in the cerebral cortex. METHODS: HF was defined as the exposure variable, and cerebral cortex structure was defined as the outcome variable. Inverse-variance weighted (IVW), MR-Egger regression and weighted median (WME) were performed for MR analysis; MR-PRESSO and Egger's intercept was used to test horizontal pleiotropy; and "leave-one-out" was used for sensitivity analysis. RESULTS: Fifty-two single nucleotide polymorphisms (SNPs) were defined as instrumental variables (IVs), and there was no horizontal pleiotropy in the IVs. According to the IVW analysis, the OR and 95% CI of cerebral cortex thickness were 0.9932 (0.9868-1.00) (P=0.0402), and the MR-Egger intercept was -15.6× 10-5 (P = 0.7974) and the Global test pval was 0.078. The P-value of the cerebral cortex surface was 0.2205, and the MR-Egger intercept was -34.69052 (P= 0.6984) and the Global Test pval was 0.045. HF had a causal effect on the surface area of the caudal middle frontal lobule (P=0.009), insula lobule (P=0.01), precuneus lobule (P=0.049) and superior parietal lobule (P=0.044). CONCLUSIONS: HF was potentially associated with changes in cortical thickness and in the surface area of the caudal middle frontal lobule, insula lobule, precuneus lobule and superior parietal lobule.
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Corteza Cerebral , Insuficiencia Cardíaca , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Humanos , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/genética , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Imagen por Resonancia Magnética , MasculinoRESUMEN
Neutrophil membrane-coated nanoparticles (NM-NPs) are nanomedicines with traits of mimicking the surface properties and functions of neutrophils, which are the most abundant type of white blood cells in the human body. NM-NPs have been widely used as targeted drug delivery systems for various inflammatory diseases, but their intrinsic effects on inflammation are not fully characterized yet. This study found that NM-NPs could modulate inflammation by multiple mechanisms without drug loading. NM-NPs could inhibit the recruitment of neutrophils and macrophages to the inflamed site by capturing chemokines and blocking their adhesion to inflamed endothelial cells. After internalized by macrophages and other phagocytic cells, NM-NPs could alter their phenotype by phosphatidylserine and simultaneously degrade the sequestered and neutralized cytokines and chemokines by lysosomal degradation. Under these effects, NM-NPs exhibited significant anti-inflammatory effects on LPS-induced inflammatory liver injury in vivo without drug loading. Our study unveiled the anti-inflammatory effects and mechanisms of NM-NPs without drug loading, and provided new insights and evidence for understanding their biological effects and safety, as well as developing more effective and safe targeted drug delivery systems.
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Antiinflamatorios , Inflamación , Macrófagos , Nanopartículas , Neutrófilos , Nanopartículas/administración & dosificación , Animales , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacología , Humanos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Inflamación/tratamiento farmacológico , Citocinas/metabolismo , Masculino , Ratones , Membrana Celular/metabolismo , Membrana Celular/efectos de los fármacos , Ratones Endogámicos C57BL , Lipopolisacáridos , Células RAW 264.7 , Sistemas de Liberación de Medicamentos , Células Endoteliales de la Vena Umbilical HumanaRESUMEN
Purpose: This study aimed to elucidate the protective mechanism of Traditional Chinese Medicine (TCM) Qifu Yixin formula (QFYXF) to improve heart failure (HF) by promoting ß-arrestin2 (ß-arr2)-mediated SERCA2a SUMOylation. Materials and Methods: The transverse aortic constriction (TAC)-induced HF mice were treated with QFYXF or carvedilol for 8 weeks. ß-arr2-KO mice and their littermate wild-type (WT) mice were used as controls. Neonatal rat cardiomyocytes (NRCMs) were used in vitro. Cardiac function was evaluated by echocardiography and serum NT-proBNP. Myocardial hypertrophy and myocardial fibrosis were assessed by histological staining. ß-arr2, SERCA2a, SUMO1, PLB and p-PLB expressions were detected by Western blotting, immunofluorescence and immunohistochemistry. SERCA2a SUMOylation was detected by Co-IP. The molecular docking method was used to predict the binding ability of the main active components of QFYXF to ß-arr2, SERCA2a, and SUMO1, and the binding degree of SERCA2a to SUMO1 protein. Results: The HF model was constructed 8 weeks after TAC. QFYXF ameliorated cardiac function, inhibiting myocardial hypertrophy and fibrosis. QFYXF promoted SERCA2a expression and SERCA2a SUMOylation. Further investigation showed that QFYXF promoted ß-arr2 expression, whereas Barbadin (ß-arr2 inhibitor) or ß-arr2-KO reduced SERCA2a SUMOylation and attenuated the protective effect of QFYXF improved HF. Molecular docking showed that the main active components of QFYXF had good binding activities with ß-arr2, SERCA2a, and SUMO1, and SERCA2a had a high binding degree with SUMO1 protein. Conclusion: QFYXF improves HF by promoting ß-arr2 mediated SERCA2a SUMOylation and increasing SERCA2a expression.
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Insuficiencia Cardíaca , Sumoilación , Ratas , Ratones , Animales , Simulación del Acoplamiento Molecular , Miocitos Cardíacos , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/metabolismoRESUMEN
Hypokalemia and hyponatremia are common but easily ignored adverse events in treatment with voriconazole (VCZ) that can lead to serious consequences. We intend to investigate the incidence of VCZ-induced hypokalemia and hyponatremia and their risk factors based on real-world data. A prospective study was conducted. A total of 272 patients with 414 VCZ plasma trough concentrations (C0) and VCZ N-oxide concentrations (CN) were included. The incidence of hypokalemia was 18.0% (48/266). A total of 81.2% (39/48) of patients developed hypokalemia within 14 days, whereas 56.2% (27/48) of patients developed hypokalemia within 1 week. The proportion of female patients in the hypokalemia group was higher than that in the nonhypokalemia group, as was the proportion of patients receiving intravenous VCZ. In the multivariate analysis, the independent risk factors for hypokalemia were sex, combined use of antibiotics, and VCZ CN/C0. The incidence of hyponatremia was 7.9% (21/266). The proportion of patients over 47 years of age in the hyponatremia group was 71.4% (15/21). The number of days of VCZ use in the hyponatremia group was greater than that in the nonhyponatremia group. A total of 47.6% (10/21) of patients in the hyponatremia group had supratherapeutic VCZ C0 (>5.0 µg/mL). In conclusion, hypokalemia is more likely to occur in females, in patients receiving intravenous VCZ, and in patients with the combined use of antibiotics. Hyponatremia is more likely to occur in patients older than 47 years who have been using VCZ for a long time and have higher VCZ C0 values.
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Hipopotasemia , Hiponatremia , Adulto , Humanos , Femenino , Voriconazol , Antifúngicos , Estudios Prospectivos , Monitoreo de Drogas , Hipopotasemia/tratamiento farmacológico , Estudios Retrospectivos , Antibacterianos/uso terapéuticoRESUMEN
Autistic spectrum disorder (ASD) is a male-biased, heterogeneous neurodevelopmental disorder that affects approximately 1%-2% of the population. Prenatal exposure to valproic acid (VPA) is a recognized risk factor for ASD, but the cellular and molecular basis of VPA-induced ASD at the single-cell resolution is unclear. Here, we aim to compare the cellular and molecular differences in the hippocampus between male and female prenatal mice with ASD at the single-cell transcriptomic level. The transcriptomes of more than 45,000 cells are assigned to 12 major cell types, including neurons, glial cells, vascular cells, and immune cells. Cell type-specific genes with altered expression after prenatal VPA exposure are analyzed, and the largest number of differentially expressed genes (DEGs) are found in neurons, choroid plexus epithelial cells, and microglia. In microglia, several pathways related to inflammation are found in both males and females, including the tumor necrosis factor (TNF), nuclear factor kappa B (NF-κB), toll-like receptor (TLR), and mitogen-activated protein kinase (MAPK) signaling pathways, which are important for the induction of autistic-like behavior. Additionally, we note that several X-linked genes, including Bex1, Bex3, and Gria3, were among the male-specific DEGs of neurons. This pioneering study describes the landscape of the transcriptome in the hippocampus of autistic mice. The elucidation of sexual differences could provide innovative strategies for the prevention and treatment of ASD.
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Trastorno del Espectro Autista , Trastorno Autístico , Embarazo , Ratones , Animales , Masculino , Femenino , Trastorno del Espectro Autista/inducido químicamente , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/metabolismo , Ácido Valproico/efectos adversos , Ácido Valproico/metabolismo , Neuronas/metabolismo , Inflamación/metabolismo , Modelos Animales de Enfermedad , Conducta AnimalRESUMEN
BACKGROUND: Schwannomas are benign tumors that arise from Schwann cells. Rare cases are shown to arise from the olfactory nerve. The genesis of Olfactory groove schwannoma (OGSs) is still puzzling. Yusda et al hypothesized that olfactory ensheathing cell tumors (OECTs) might be the origin of OGSs. CLINICAL PRESENTATION: Here, the authors report the case of a 59-year-old woman who presented with a paroxysmal headache for 1 year. The tumor appeared as hypointensity on T1-weighted images, hyperintensity on T2-weighted, and exhibited strong, heterogeneous enhancement. The tumor was removed through a lateral supraorbital approach. The final pathologic diagnosis was schwannoma. The postoperative period was uneventful after 4 months, and the headache disappeared. DISSCUSSION AND CONCLUSION: OGSs and OECTs are extremely rare. There are many similarities in clinical manifestations, images, and pathologic findings. OGSs are difficult to distinguish from OECTs.
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Fosa Craneal Anterior , Neurilemoma , Femenino , Humanos , Persona de Mediana Edad , Imagen por Resonancia Magnética , Neurilemoma/diagnóstico por imagen , Neurilemoma/cirugía , CefaleaRESUMEN
Background: The plasma concentrations of the four most commonly used first-line anti-tuberculosis (TB) drugs, isoniazid (INH), rifampicin (RMP), ethambutol (EMB), and pyrazinamide (PZA), are often not within the therapeutic range. Insufficient drug exposure could lead to drug resistance and treatment failure, while excessive drug levels may lead to adverse reactions. The purpose of this study was to identify the physiological parameters influencing anti-TB drug concentrations. Methods: A retrospective cohort study was conducted. The 2-h plasma concentrations of the four drugs were measured by using the high-performance liquid chromatography-tandem mass spectrometry method. Results: A total of 317 patients were included in the study. The proportions of patients with INH, RMP, EMB, and PZA concentrations within the therapeutic range were 24.3%, 31.5%, 27.8%, and 18.6%, respectively. There were positive associations between the concentrations of INH and PZA and RMP and EMB, but negative associations were observed between the concentrations of INH and RMP, INH and EMB, RMP and PZA, and EMB and PZA. In the multivariate analysis, the influencing factors of the INH concentration were the PZA concentration, total bile acid (TBA), serum potassium, dose, direct bilirubin, prealbumin (PA), and albumin; those of the RMP concentration were PZA and EMB concentrations, weight, α-l-fucosidase (AFU), drinking, and dose; those of the EMB concentration were the RMP and PZA concentrations, creatinine, TBA and indirect bilirubin; and those of the PZA concentration were INH, RMP and EMB concentrations, sex, weight, uric acid and drinking. Conclusion: The complex correlations between the concentrations of the four first-line anti-TB drugs lead to a major challenge in dose adjustment to maintain all drugs within the therapeutic window. Levels of TBA, PA, AFU, and serum potassium should also be considered when adjusting the dose of the four drugs.
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Immune checkpoint therapies (ICT) have achieved unprecedented efficacy in multiple cancer treatments, but are still limited by low clinical response rates. Identification of immunogenic cell death (ICD)-inducing drugs that can induce tumor cell immunogenicity and reprogram the tumor microenvironment is an attractive approach to enhance antitumor immunity. In the present study, Raddeanin A (RA), an oleanane class triterpenoid saponin isolated from Anemone raddeana Regel, is uncovered as a potent ICD inducer through an ICD reporter assay combined with a T cell activation assay. RA significantly increases high-mobility group box 1 release in tumor cells and promotes dendritic cell (DC) maturation and CD8+ T cell activation for tumor control. Mechanistically, RA directly binds to transactive responsive DNA-binding protein 43 (TDP-43) and induces TDP-43 localization to mitochondria and mtDNA leakage, leading to cyclic GMP-AMP synthase/stimulator of interferon gene-dependent upregulation of nuclear factor κB and type I interferon signaling, thereby potentiating the DC-mediated antigen cross-presentation and T cell activation. Moreover, combining RA with anti-programmed death 1 antibody effectively enhances the efficacy of ICT in animals. These findings highlight the importance of TDP-43 in ICD drug-induced antitumor immunity and reveal a potential chemo-immunotherapeutic role of RA in enhancing the efficacy of cancer immunotherapy.
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ADN Mitocondrial , Neoplasias , Animales , Neoplasias/tratamiento farmacológico , Proteínas de Unión al ADN , Mitocondrias/genética , Nucleotidiltransferasas/genética , Microambiente TumoralRESUMEN
Recent publications regarding the role of mesencephalic astrocyte-derived neurotrophic factor (MANF) in various metabolic and degenerative disorders suggest that MANF is both a marker of disease and a possible therapeutic agent. We investigate the role of plasma MANF levels in patients in intensive care units (ICUs) receiving voriconazole (VCZ) therapy while also comparing MANF levels in healthy individuals. A single-center prospective study was conducted. The plasma MANF level in patients in ICU was found to have high interindividual variability and was significantly higher than that in healthy controls (P < .01). Compared with patients using VCZ only, patients using both VCZ and amikacin had 3-fold lower MANF concentrations (P < .05). The MANF concentrations also decreased when alkaline phosphatase (ALP) and serum creatinine levels were above the upper limits of the normal range (P < .05) and the estimated glomerular filtration rate (eGFR) was below the lower limit of the normal range (P < .01). Receiver operating characteristic curve analysis indicated that low MANF levels were associated with high ALP levels, high creatinine levels, and low eGFR. The cut-off value of MANF for ALP levels higher than 126 U/L was 0.35 ng/mL (area under curve, AUC = 0.62, 95%CI = 0.50-0.74, P = .044); for serum creatinine levels higher than 104 µmol/L, the cut-off value was 0.41 ng/mL (AUC = 0.74, 95%CI = 0.62-0.87, P = .001); and for eGFR below 80 mL/min, the cut-off value was 0.75 ng/mL (AUC = 0.70, 95%CI = 0.59-0.81, P = .002). Monitoring plasma MANF levels may be of value for clinical decision-making regarding the choice of antibiotics and the prediction of impaired liver function and renal function in patients admitted to an ICU.
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Astrocitos , Factores de Crecimiento Nervioso , Humanos , Voriconazol/uso terapéutico , Astrocitos/metabolismo , Creatinina , Estudios Prospectivos , Factores de Crecimiento Nervioso/metabolismoRESUMEN
Acid mine drainage (AMD) is a significant environmental problem caused by the oxidation of pyrite and other metal sulfide ores. Organosilane passivation is an effective strategy to inhibit pyrite oxidation. However, synthetic organic silane passivation agents generally require temperatures of 50-80 °C, resulting in high energy consumption and high synthesis cost. In this study, a 3-aminopropyltrimethoxysilane -methyltrimethoxysilane (APS-MTMS) coatings was successfully prepared at ambient temperatures of 15-40 °C as a passivation agent to inhibit pyrite oxidation. Chemical leaching tests were used to study the inhibition performance of APS-MTMS for pyrite oxidation. The experimental results showed that the release of the total Fe from APS-MTMS-coated pyrite was 11.31 mg/L after chemical oxidation for 7 hours, and the passivation rate can reach 77.78%. The contact angle of the APS-MTMS-coated pyrite was significantly larger (140.4°) than that of the bare pyrite (58.8°), indicating that APS-MTMS prompted the formation of a superhydrophobic surface of pyrite, improving the oxidation resistance. Fourier transform infrared (FTIR) spectroscopy and X-ray photoelectron spectroscopy (XPS) were applied to probe the interaction mechanism of APS-MTMS with pyrite. The results indicated that APS accelerated the Si-O-Si formation by amino protonation and enriched a crosslinked network of Si-O-Si and Fe-O-Si on the pyrite surface to prevent pyrite oxidation. This study provides a novel method for preparing organosilane passivation materials at ambient temperatures for AMD control.
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Hierro , Compuestos de Organosilicio , Ácidos/química , Hierro/química , Oxidación-Reducción , Sulfuros/química , TemperaturaRESUMEN
OBJECTIVE: Acute myeloid leukemia (AML) is an aggressive hematological malignancy with a poor prognosis. This study aimed to investigate the action of PARP14 in the growth and glycolysis of AML. METHODS: The clinical samples of AML patients were collected, and the expression of PARP14 was detected. AML cells were transfected with PARP14, HIF-1α or treated with NF-KB inhibitor (BAY11-7082) or PARP14 inhibitor (RBN012759). Cell proliferation was detected by CCK-8 and colony formation assays, apoptosis by flow cytometry, glucose consumption and lactate production by glucose and lactate kits, ECAR and OCR by XF96 bioenergy analyzer, and related protein levels by Western blot. A mouse xenograft tumor model was established to evaluate the effect of PARP14 on tumor formation. RESULTS: Significant upregulation of PARP14 expression was observed in AML. PARP14 promoted AML cell proliferation and glycolysis and inhibited apoptosis, while PARP14 deficiency had the opposite effect. PARP14 promoted HIF-1α expression by activating NF-κB. HIF-1α silencing reversed the cancer-promoting effect of PARP14. In vivo results suggested that PARP14 promoted tumor formation. CONCLUSION: PARP14 induces AML cell growth and glycolysis by activating NF-κB and promoting HIF-1α expression, which may suggest new insights into the pathogenesis of AML.
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Subunidad alfa del Factor 1 Inducible por Hipoxia , Leucemia Mieloide Aguda , FN-kappa B , Poli(ADP-Ribosa) Polimerasas , Animales , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Glucosa , Glucólisis , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Lactatos/metabolismo , Leucemia Mieloide Aguda/genética , Ratones , FN-kappa B/metabolismo , Poli(ADP-Ribosa) Polimerasas/genética , Poli(ADP-Ribosa) Polimerasas/metabolismoRESUMEN
Long noncoding RNAs (lncRNAs) are critical regulators of inflammation with great potential as new therapeutic targets. However, the role of lncRNAs in early atherosclerosis remains poorly characterized. This study aimed to identify the key lncRNA players in activated endothelial cells (ECs). The lncRNAs in response to pro-inflammatory factors in ECs were screened through RNA sequencing. ICAM-1-related non-coding RNA (ICR) was identified as the most potential candidate for early atherosclerosis. ICR is essential for intercellular adhesion molecule-1 (ICAM1) expression, EC adhesion and migration. In a high fat diet-induced atherosclerosis model in mice, ICR is upregulated in the development of atherosclerosis. After intravenous injection of adenovirus carrying shRNA for mouse ICR, the atherosclerotic plaque area was markedly reduced with the declined expression of ICR and ICAM1. Mechanistically, ICR stabilized the mRNA of ICAM1 in quiescent ECs; while under inflammatory stress, ICR upregulated ICAM1 in a nuclear factor kappa B (NF-κB) dependent manner. RNA-seq analysis showed pro-inflammatory targets of NF-κB were regulated by ICR. Furthermore, the chromatin immunoprecipitation assays showed that p65 binds to ICR promoter and facilitates its transcription. Interestingly, ICR, in turn, promotes p65 accumulation and activity, forming a positive feedback loop to amplify NF-κB signaling. Preventing the degradation of p65 using proteasome inhibitors rescued the expression of NF-κB targets suppressed by ICR. Taken together, ICR acts as an accelerator to amplify NF-κB signaling in activated ECs and suppressing ICR is a promising early intervention for atherosclerosis through ICR/p65 loop blockade.
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Aterosclerosis , ARN Largo no Codificante , Animales , Aterosclerosis/genética , Células Endoteliales/metabolismo , Molécula 1 de Adhesión Intercelular/genética , Ratones , FN-kappa B/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismoRESUMEN
Background: The inner association of inflammation with voriconazole (VCZ) metabolism has not been fully investigated. We intend to investigate the effects of inflammation on liver function, VCZ trough concentration (C0), C0/dose ratio and the ratio of VCZ to VCZ-N-oxide concentration (C0/CN) in adult and elderly patients. Methods: A single-center retrospective study was conducted among patients who were treated in our hospital between January 2018 and December 2021. For each eligible patient, demographic details, medical history, laboratory parameters, procalcitonin (PCT), C reactive protein (CRP), and interleukin-6 (IL-6) were collected from the medical chart. VCZ CN, TNF-α, IL-1ß, IL-8, and IL-10 concentrations were detected in blood samples. Results: A total of 356 patients were included in our study, with 195 patients in the adult cohort (<60 years) and 161 patients in the elderly cohort (≥60 years). In adult patients, CRP and IL-8 levels showed moderate association with VCZ C0/CN ratio (CRP: r = 0.512, p < 0.001; IL-8: r = 0.476, p = 0.002). IL-6 level shallowly associated with VCZ C0/CN ratio both in adult and elderly patients (r = 0.355, p = 0.003; r = 0.386, p = 0.001). A significantly higher VCZ C0, C0/dose ratio and C0/CN ratio was observed in adult patients with severe inflammation compared with patients with moderate inflammation and no to mild inflammation, as reflected by PCT levels (p < 0.05). However, there was no significant difference observed among different inflammation degrees in elderly patients. Lower albumin (AL) and higher total bilirubin (TBIL) were observed along with the degree of inflammation in both adult and elderly patients, as reflected by CRP and PCT levels (p < 0.05). Conclusion: Inflammation may affect the metabolism of VCZ to VCZ-N-oxide both in adult and elderly patients, and decreased plasma AL levels and increased TBIL levels under inflammatory conditions may also alter VCZ metabolism.
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Hyperglycemia is reported to accelerate endothelial cell senescence that contributes to diabetic complications. The underlying mechanism, however, remains elusive. We previously demonstrated AQR as a susceptibility gene for type 2 diabetes mellitus (T2DM) and showed that it was increased in multiple tissues in models with T2DM or metabolic syndrome. This study aimed to investigate the role of AQR in hyperglycemia-induced senescence and its underlying mechanism. Here, we retrieved several datasets of the aging models and found the expression of AQR was increased by high glucose and by aging across species, including C. elegans (whole-body), rat (cardiac tissues), and monkey (blood). we validated the increased AQR expression in senescent human umbilical vein endothelial cells (HUVECs). When overexpressed, AQR promoted the endothelial cell senescence, confirmed by an increased number of cells stained with senescence-associated beta-galactosidase and upregulation of CDKN1A (P21) as well as the prohibited cellular colony formation and G2/M phase arrest. To explore the mechanism by which AQR regulated the cellular senescence, transcriptomic analyses of HUVECs with the overexpression and knockdown of the AQR were performed. We identified 52 co-expressed genes that were enriched, in the terms of plasminogen activation, innate immunity, immunity, and antiviral defense. Among co-expressed genes, PLAU was selected to evaluate its contribution to senescence for its highest strength in the enrichment of the biological process. We demonstrated that the knockdown of PLAU rescued senescence-related phenotypes, endothelial cell activation, and inflammation in models induced by AQR or TNF-α. These findings, for the first time, indicate that AQR/PLAU is a critical signaling axis in the modulation of endothelial cell senescence, revealing a novel link between hyperglycemia and vascular dysfunction. The study may have implications in the prevention of premature vascular aging associated with T2DM.
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Fenómenos Biológicos , Diabetes Mellitus Tipo 2 , Hiperglucemia , Animales , Caenorhabditis elegans , Células Cultivadas , Senescencia Celular/genética , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Hiperglucemia/genética , Hiperglucemia/metabolismo , RatasRESUMEN
Background: ABCG2 and ABCB1 are genes related to the pharmacokinetics of sunitinib and have been associated with its toxicity and efficacy. However, the results have been controversial. This study aimed to evaluate the associations of ABCG2 and ABCB1 polymorphisms with sunitinib-induced toxicity and efficacy in renal cell carcinoma (RCC) by meta-analysis. Methods: PubMed, EMBASE, Cochrane Library, and Web of Science were systematically searched for studies investigating the associations of the ABCG2 rs2231142 polymorphism with sunitinib-induced toxicity and the associations of the ABCB1 rs1128503 and ABCB1 rs2032582 polymorphisms with sunitinib-induced toxicity and clinical outcomes. The associations were evaluated by effect size (ES) with 95% confidence intervals (CIs). Results: Eight and five studies were included in the toxicity and efficacy analysis, respectively, including a total of 1081 RCC patients. The ABCG2 rs2231142 A allele was associated with an increased risk of sunitinib-induced thrombocytopenia and hand-foot syndrome (HFS) in Asians (ES = 1.65, 95% CI = 1.15-2.36, p = 0.006; ES = 1.52, 95% CI = 1.02-2.27, p = 0.041). However, the ABCG2 rs2231142 polymorphism was not associated with sunitinib-induced hypertension or neutropenia (ES = 1.09, 95% CI = 0.69-1.73, p = 0.701; ES = 0.87, 95% CI = 0.57-1.31, p = 0.501). Compared with the C allele, the ABCB1 rs1128503 T allele was associated with a decreased risk of sunitinib-induced hypertension but worse progression-free survival (PFS) (ES = 0.44, 95% CI = 0.26-0.77, p = 0.004; ES = 1.36, 95% CI = 1.07-1.73, p = 0.011). There was no significant association between the T allele or C allele of ABCB1 rs1128503 and overall survival (OS) (ES = 0.82, 95% CI = 0.61-1.10, p = 0.184). The ABCB1 rs2032582 T allele was associated with worse PFS than the other alleles (ES = 1.46, 95% CI = 1.14-1.87, p = 0.003), while there was no significant association between the T allele or other alleles and sunitinib-induced hypertension, HFS, or OS (ES = 0.77, 95% CI = 0.46-1.29, p = 0.326; ES = 1.02, 95% CI = 0.65-1.62, p = 0.919; ES = 1.32, 95% CI = 0.85-2.05, p = 0.215). Conclusion: The results indicate that the ABCG2 rs2231142 polymorphism may serve as a predictor of sunitinib-induced thrombocytopenia and HFS in Asians, while the ABCB1 rs1128503 polymorphism may serve as a predictor of sunitinib-induced hypertension, and both the ABCB1 rs1128503 and rs2032582 polymorphisms may serve as predictors of PFS in RCC. These results suggest a possible application of individualized use of sunitinib according to the genetic background of patients.
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The black-bellied hornet Vespa basalis is responsible for the large quantity of accidents and severe wasp envenomation in China. This study aims to identify the rat pain responses induced by experimental V. basalis sting and related-components in the venom. It was observed that unilateral intraplantar injection of crude V. basalis venom could induce several kinds of pain related behaviors in a dose-dependent manner including spontaneous pain, unilateral thermal and unilateral mechanical hypersensitivity at different time courses. Fourteen main fractions were separated from the crude venom of V. basalis using high performance liquid chromatography, among them, five components (1, 3, 4, 9 and 12) could absolutely mimic the crude venom-induced pain behaviors. According to the molecular mass and N-terminal sequence, the component 3 and 4 were identified as Mastoparan B and HP-1 respectively, the component 9 was speculated as a novel variant of HP-1/2. In addition, the other two sub-components (1-1 and 1-2) purified from component 1 cannot be determined. The results offered the key information about six active polypeptides from V. basalis contributing to pain responses, which might provide a basis for exploring mechanisms of wasp sting injury.
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Venenos de Avispas/toxicidad , Avispas , Animales , China , Cromatografía Líquida de Alta Presión , Péptidos y Proteínas de Señalización Intercelular/toxicidad , Dolor , Péptidos , Ratas , Toxinas BiológicasRESUMEN
BACKGROUND: Ventricular arrhythmias (VAs) arising from the origin above pulmonary valve lack comprehensive investigation. This study aimed to disclose the characteristics and radiofrequency catheter ablation (RFCA) outcomes for those VAs. METHODS: One hundred six VAs arising from the region above pulmonary valve treated with RFCA were included in this study. RESULTS: Seventy-five cases were identified in the pulmonary sinus cusps (PSCs, 32 in left sinus cusp (PLC), 15 in right (PRC), 28 in anterior (PAC)) and 31 cases were in the main stem of pulmonary artery (MSPA, 18 above PLC (LMSPA), 3 above PRC (RMSPA), 10 above PAC (AMSPA)). Compared with PSCs VAs, MSPA VAs exhibited a higher R wave amplitude in the inferior leads, a total inferior R amplitude > 5.1 mV predicting MSPA origins. LMSPA, RMSPA and AMSPA VAs resembled PLC, PRC and PAC VAs in electrocardiographic characteristics respectively. No electrophysiological differences were found between PSCs and MSPA VAs. The irrigated-up catheter and R0 Swartz long sheath were more utilized for ablation of PSCs VAs than for MSPA VAs. All these VAs were successfully eliminated by RFCA. CONCLUSION: VAs arising from the origin above pulmonary valve were common. Based on certain electrocardiographic characteristics, they could be roughly located, which contributed to an effective RFCA.
Asunto(s)
Ablación por Catéter , Arteria Pulmonar/cirugía , Válvula Pulmonar , Taquicardia Ventricular/cirugía , Complejos Prematuros Ventriculares/cirugía , Adulto , Ablación por Catéter/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Arteria Pulmonar/diagnóstico por imagen , Arteria Pulmonar/fisiopatología , Válvula Pulmonar/diagnóstico por imagen , Estudios Retrospectivos , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/fisiopatología , Resultado del Tratamiento , Complejos Prematuros Ventriculares/diagnóstico , Complejos Prematuros Ventriculares/fisiopatologíaRESUMEN
Nanomedicine with programmed drug release can give full play to the synergistic effect of multi-component system in complicated tumor environment. However, the construction of these programmed drug delivery systems often depends on the sophisticated materials design and synthesis. In this study, we successfully designed an indomethacin (IND)-mediated ternary complex system based on a PEG cleavable polyethyleneimine (PEI), indomethacin (IND) and benzene ring containing chemotherapeutic drugs (such as paclitaxel (PTX), doxorubicin and docetaxel). Based on the difference of hydrophobicity in these components, these components were one-pot self-assembled into drug-loaded IND mediated PEGylation cleavable nanoassemblies (IPCNs) in multilayer structure. In drug-loaded IPCNs, PEG fragments, PEI/IND, and chemotherapeutic drug were respectively distributed from the out layer to core of nanomedicine. When drug-loaded IPCNs reached tumor site through EPR effect, the PEG fragment would firstly responsively release to the acidic tumor microenvironment to expose the intermediate layer of drug-loaded IPCNs that composed by mixture of PEI and IND for increasing the surface potential to promote the uptake by tumor cells. After entering cells, IND would be released faster than chemotherapeutic drug encapsulated in core to efficiently inhibit the expression of multidrug resistance protein 1 to reverse MDR of tumor cells before chemotherapeutic drug releasing. Contributed by the staged responsively releasing of PEG fragments, IND and encapsulated chemotherapeutic drug, the drug-loaded IPCNs exhibited a superior antitumor efficacy against A549/MDR tumor cells both in vitro and in vivo. STATEMENT OF SIGNIFICANCE: The way to develop programmed released drug delivery system is commonly relied on complicated material design and synthesis. Herein, under the computer-assist design, we successfully designed a ternary complex derived from indomethacin (IND), paclitaxel (PTX) and a pH-responsive PEGylated polyethyleneimine (PEG-s-PEI), and employed this ternary complex to successfully prepare a high drug loading and multilayer structured nanomedicine of PTX (PTX IPCNs). Contribute by the different location of PTX, IND and PEG-s-PEI in PTX IPCNs, PEG fragments, IND and PTX molecules could programmed release after reaching tumor for perfectly realizing the synergistic anti-tumor effect of tumor targeting, reversal of MDR and chemotherapy. Based on a fusion of these multiple mechanisms, PTX IPCNs showed a superior antitumor efficacy in mice loading A549/MDR tumor.