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BACKGROUND: Intracellular Ca2+ cycling determines myocardial contraction and relaxation in response to physiological demands. SERCA2a (sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2a) is responsible for the sequestration of cytosolic Ca2+ into intracellular stores during cardiac relaxation, and its activity is reversibly inhibited by PLN (phospholamban). However, the regulatory hierarchy of SERCA2a activity remains unclear. METHODS: Cardiomyocyte-specific ZBTB20 knockout mice were generated by crossing ZBTB20flox mice with Myh6-Cre mice. Echocardiography, blood pressure measurements, Langendorff perfusion, histological analysis and immunohistochemistry, quantitative reverse transcription-PCR, Western blot analysis, electrophysiological measurements, and chromatin immunoprecipitation assay were performed to clarify the phenotype and elucidate the molecular mechanisms. RESULTS: Specific ablation of ZBTB20 in cardiomyocyte led to a significant increase in basal myocardial contractile parameters both in vivo and in vitro, accompanied by an impairment in cardiac reserve and exercise capacity. Moreover, the cardiomyocytes lacking ZBTB20 showed an increase in sarcoplasmic reticular Ca2+ content and exhibited a remarkable enhancement in both SERCA2a activity and electrically stimulated contraction. Mechanistically, PLN expression was dramatically reduced in cardiomyocytes at the mRNA and protein levels by ZBTB20 deletion or silencing, and PLN overexpression could largely restore the basal contractility in ZBTB20-deficient cardiomyocytes. CONCLUSIONS: These data point to ZBTB20 as a fine-tuning modulator of PLN expression and SERCA2a activity, thereby offering new perspective on the regulation of basal contractility in the mammalian heart.
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Miocardio , Retículo Sarcoplasmático , Animales , Ratones , Calcio/metabolismo , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Mamíferos , Ratones Noqueados , Contracción Miocárdica/fisiología , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Retículo Sarcoplasmático/metabolismo , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/genética , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismoRESUMEN
Non-alcoholic fatty liver disease (NAFLD), a chronic liver condition and metabolic disorder, has emerged as a significant health issue worldwide. D-mannose, a natural monosaccharide widely existing in plants and animals, has demonstrated metabolic regulatory properties. However, the effect and mechanism by which D-mannose may counteract NAFLD have not been studied. In this study, network pharmacology followed by molecular docking analysis was utilized to identify potential targets of mannose against NAFLD, and the leptin receptor-deficient, genetically obese db/db mice was employed as an animal model of NAFLD to validate the regulation of D-mannose on core targets. As a result, 67 targets of mannose are predicted associated with NAFLD, which are surprisingly centered on the mechanistic target of rapamycin (mTOR). Further analyses suggest that mTOR signaling is functionally enriched in potential targets of mannose treating NAFLD, and that mannose putatively binds to mTOR as a core mechanism. Expectedly, repeated oral gavage of supraphysiological D-mannose ameliorates liver steatosis of db/db mice, which is based on suppression of hepatic mTOR signaling. Moreover, daily D-mannose administration reduced hepatic expression of lipogenic regulatory genes in counteracting NAFLD. Together, these findings reveal D-mannose as an effective and potential NAFLD therapeutic through mTOR suppression, which holds translational promise.
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Manosa , Farmacología en Red , Enfermedad del Hígado Graso no Alcohólico , Serina-Treonina Quinasas TOR , Animales , Ratones , Hígado/metabolismo , Hígado/efectos de los fármacos , Manosa/farmacología , Manosa/metabolismo , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
OBJECTIVE: Accurate prediction of survival prognosis is helpful to guide clinical decision-making. The aim of this study was to develop a model using machine learning techniques to predict the occurrence of composite thromboembolic events (CTEs) in elderly patients with atrial fibrillation(AF). These events encompass newly diagnosed cerebral ischemia events, cardiovascular events, pulmonary embolism, and lower extremity arterial embolism. METHODS: This retrospective study included 6,079 elderly hospitalized patients (≥ 75 years old) with AF admitted to the People's Liberation Army General Hospital in China from January 2010 to June 2022. Random forest imputation was used for handling missing data. In the descriptive statistics section, patients were divided into two groups based on the occurrence of CTEs, and differences between the two groups were analyzed using chi-square tests for categorical variables and rank-sum tests for continuous variables. In the machine learning section, the patients were randomly divided into a training dataset (n = 4,225) and a validation dataset (n = 1,824) in a 7:3 ratio. Four machine learning models (logistic regression, decision tree, random forest, XGBoost) were trained on the training dataset and validated on the validation dataset. RESULTS: The incidence of composite thromboembolic events was 19.53%. The Least Absolute Shrinkage and Selection Operator (LASSO) method, using 5-fold cross-validation, was applied to the training dataset and identified a total of 18 features that exhibited a significant association with the occurrence of CTEs. The random forest model outperformed other models in terms of area under the curve (ACC: 0.9144, SEN: 0.7725, SPE: 0.9489, AUC: 0.927, 95% CI: 0.9105-0.9443). The random forest model also showed good clinical validity based on the clinical decision curve. The Shapley Additive exPlanations (SHAP) showed that the top five features associated with the model were history of ischemic stroke, high triglyceride (TG), high total cholesterol (TC), high plasma D-dimer, age. CONCLUSIONS: This study proposes an accurate model to stratify patients with a high risk of CTEs. The random forest model has good performance. History of ischemic stroke, age, high TG, high TC and high plasma D-Dimer may be correlated with CTEs.
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Fibrilación Atrial , Técnicas de Apoyo para la Decisión , Aprendizaje Automático , Valor Predictivo de las Pruebas , Tromboembolia , Humanos , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/epidemiología , Femenino , Masculino , Anciano , Estudios Retrospectivos , Medición de Riesgo , China/epidemiología , Tromboembolia/epidemiología , Tromboembolia/diagnóstico , Tromboembolia/etiología , Factores de Riesgo , Anciano de 80 o más Años , Incidencia , Pronóstico , Factores de Edad , Reproducibilidad de los Resultados , Pueblos del Este de AsiaRESUMEN
Among the thirteen leukocyte Ig-like receptor (LILR) loci located at 19q13.4, LILRA3 is unique in that it encodes a soluble protein lacking the transmembrane and cytoplasmic domains, and a 6.7 kb deletion spanning the first seven exons has been detected in some human individuals. Presently, there is a lack of data about the distribution of LILRA3 gene deletion in more diverse ethnic groups. Also, no previous studies have investigated the correlation between copy number variation (CNV) of LILRA3 and nasopharyngeal carcinoma (NPC). In this study, five populations from China mainland: two Southern Han populations, Hunan (N = 1478) and Guandong (N = 107); one Southeastern Han population, Fujian (N = 439); and two Northern populations, Inner Mongolia Han (N = 104) and Mongol population from Inner Mongolia (N = 158) were investigated for CNV of LILRA3 using polymerase chain reaction-sequence-specific priming (PCR-SSP) method. LILRA3 variants were also examined in a cohort of NPC cases (N = 1142) in Hunan Han population. The five Chinese populations demonstrated northward increase in frequency of the deleted form of LILRA3 gene (LILRA3*Del) (all corrected p values < 0.05). Inter-population comparison also uncovered significant differentiation in the distribution of CNV of LILRA3 among modern human populations. LILRA3*Del was found to confer significantly reduced risk to NPC in Hunan Han population (at allelic level: OR = 0.79, 95% CI = 0.71-0.89, p < 0.0001; at genotype level: OR = 0.63, 95% CI = 0.51-0.79, p < 0.0001). No interaction was found between LILRA3 variants and HLA-A*02:07, HLA-A*11:01, HLA-B*13 and HLA-B*46:01 alleles in susceptibility to NPC. Our study constitutes the first demonstration of LILRA3 gene as a locus linked to NPC susceptibility in a southern Chinese population. Future independent studies in other populations are warranted to confirm the findings reported in this study.
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Variaciones en el Número de Copia de ADN , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/genética , Eliminación de Gen , Frecuencia de los Genes , Variaciones en el Número de Copia de ADN/genética , Antígenos HLA-B/genética , Neoplasias Nasofaríngeas/genética , Antígenos HLA-A/genética , Inmunoglobulinas/genética , China/epidemiología , Receptores Inmunológicos/genéticaRESUMEN
Polygonatum cyrtonema Hua is a perennial herb of the Asparagaceae family that is used for both dietary and medicinal purposes in China. In September 2019, a new leaf spot disease on Polygonatum cyrtonema was detected and is currently widespread in Huaihua, Hunan Province, China. Pathogenic fungi were isolated and purified from samples of diseased tissue that were collected for morphological and molecular phylogenetic studies. The pathogen was identified using multilocus (ITS, TEF-1, and TUB2) phylogenies, as well as morphological characters, and was found to be clustered but separately divergent from species of Pestalotiopsis. However, there were significant morphological differences between the pathogen and similar species. The pathogen was finally identified as a new species that was designated Pestalotiopsis xuefengensis. This is the first report of Pestalotiopsis xuefengensis serving as the causal agent of gray leaf spot on Polygonatum cyrtonema. This study will provide useful information for the diagnosis and management of this disease.
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Filogenia , Enfermedades de las Plantas , Polygonatum , Enfermedades de las Plantas/microbiología , China , Polygonatum/microbiología , Xylariales/genética , Xylariales/clasificación , Xylariales/aislamiento & purificación , Hojas de la Planta/microbiologíaRESUMEN
Understanding the optimal extraction methods for flavonoids from Abelmoschus manihot flowers (AMF) is crucial for unlocking their potential benefits. This study aimed to optimize the efficiency of flavonoid extraction from AMF. After comparing extraction methods, the ultrasonic cell crusher demonstrated superior performance over conventional techniques. Four key factors-solid-to-liquid ratio (1:10 to 1:50 g·mL-1), ethanol concentration (55% to 95%), ultrasonic time (10 to 50 min), and ultrasonic power (5% to 25% of 900 W)-were investigated and normalized using the entropy weight method. This led to a comprehensive evaluation (CE). Optimization of extraction conditions for the ultrasonic cell crusher was achieved through response surface methodology and a deep neural network model, resulting in optimal parameters: ethanol volume fraction of 66%, solid-to-liquid ratio of 1:21 g/mL, extraction efficiency of 9%, and extraction duration of 35 min, yielding a CE value of 23.14 (RSD < 1%). Additionally, the inhibitory effects of the optimized extracts against Streptococcus mutans (S. mutans) were assessed. The results revealed that AMF extract (AMFE) exhibits inhibitory effects on S. mutans, with concomitant inhibition of sucrase and lactate dehydrogenase (LDH). The MIC of AMFE against planktonic S. mutans is 3 mg/mL, with an MBC of 6 mg/mL. Within the concentration range of 1/8 MIC to 2 MIC of AMFE, the activities of sucrase and LDH decreased by 318.934 U/mg prot and 61.844 U/mg prot, respectively. The antioxidant activity of AMFE was assessed using the potassium ferricyanide reduction and phosphomolybdenum methods. Additionally, the effect of AMFE on DPPH, ABTS, and ·OH free radical scavenging abilities was determined. The concentrations at which AMFE exhibited over 90% scavenging rate for ABTS and DPPH free radicals were found to be 0.125 mg/mL and 2 mg/mL, respectively.
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Abelmoschus , Antioxidantes , Flavonoides , Flores , Redes Neurales de la Computación , Extractos Vegetales , Flavonoides/química , Flavonoides/farmacología , Flavonoides/aislamiento & purificación , Abelmoschus/química , Flores/química , Extractos Vegetales/química , Extractos Vegetales/farmacología , Antioxidantes/farmacología , Antioxidantes/química , Ondas UltrasónicasRESUMEN
Precisely controlling the selectivity of nanocatalysts has always been a hot topic in heterogeneous catalysis but remains difficult owing to their complex and inhomogeneous catalytic sites. Herein, an effective strategy to regulate the chemoselectivity of Pd nanocatalysts for selective hydrogenation reactions by inserting single-atom Zn into Pd nanoparticles is reported. Taking advantage of the tannic acid coating-confinement strategy, small-sized Pd nanoparticles with inserted single-atom Zn are obtained on the O-doped carbon-coated alumina. Compared with the pure Pd nanocatalyst, the Pd nanocatalyst with single-atom Zn insertion exhibits prominent selectivity for the hydrogenation of p-iodonitrobenzene to afford the hydrodeiodination product instead of nitro hydrogenation ones. Further computational studies reveal that the single-atom Zn on Pd nanoparticles strengthens the adsorption of the nitro group to avoid its reduction and increases the d-band center of Pd atoms to facilitate the reduction of the iodo group, which leads to enhanced selectivity. This work provides new guidelines to tune the selectivity of nanocatalysts with guest single-atom sites.
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Streptococcus mutans (S. mutans) is the main cariogenic pathogen associated with dental caries. Orientin-2''-O-ß-L-galactoside, orientin and vitexin are natural flavonoids compound. In this study, the antibacterial ability of these flavonoids and their mechanisms in inhibiting S. mutans biofilm formation were investigated. Inhibition zone and 2-fold-dilution tests showed that these flavonoids exerted inhibitory effects on S. mutans. Phenol sulfuric acid method and lactate dehydrogenase (LDH) test revealed that they could reduce EPS formation and stimulate S. mutans to release LDH. Moreover, crystal violet and live/dead bacterial staining test showed that they inhibited biofilm formation. Finally, qRT-PCR test indicated that the down-regulated the transcription levels of spaP, srtA, brpA, gtfB and luxS genes of S. mutans. In conclusion, orientin-2''-O-ß-L-galactoside, orientin and vitexin had antibacterial and anti-biofilm activities.
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Caries Dental , Streptococcus mutans , Humanos , Biopelículas , Antibacterianos/farmacología , Flavonoides/farmacologíaRESUMEN
PURPOSE: Studies show that patients with obstructive sleep apnea (OSA) are more likely than the general population to have psychological disorders such as depression. However, it is less clear how OSA treatment affects this association. This meta-analysis aimed to assess whether or not continuous positive airway pressure (CPAP) and mandibular advancement devices (MADs) reduce depression symptoms in patients with OSA. METHODS: We searched Pubmed, Embase, Web of Science, and Cochrane Library from creating the databases until November 2022. Our analysis included RCTs that examined CPAP and MAD treatment effectiveness for depression in patients with OSA. RESULTS: We identified 17 CPAP studies comprising 1,931 patients for inclusion in the meta-analysis. The results of the meta-analysis using a fixed effects model found that CPAP improved depressed mood in patients with OSA relative to controls (SMD = 0.27;95% CI:0.18,0.36), with small heterogeneity among trials (I2 = 8.1% < 50%, P = 0.359). We performed subgroup analyses on three factors: the length of trial follow-up, patient adherence data, and depression assessment scales. The meta-analysis also identified six MAD studies involving 315 patients. According to this analysis, there was no heterogeneity between studies (I2 = 0%, P = 0.748). MADs did not significantly improve depression symptoms compared to controls, indicating a combined effect of SMD = 0.07 (95% CI: - 0.15,0.29), P > 0.05. CONCLUSION: The present findings confirm that CPAP may improve depressive symptoms in patients with OSA. However, the review results suggest that MADs have no significant effect on depressive symptoms in patients with OSA, a finding that is different from the results of previous meta-analyses.
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Avance Mandibular , Apnea Obstructiva del Sueño , Humanos , Depresión/terapia , Ferulas Oclusales , Avance Mandibular/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto , Apnea Obstructiva del Sueño/terapiaRESUMEN
Y-box binding protein-1 (YB-1) is upregulated in glioma and plays an important role in its occurrence and drug resistance. However, the involved regulatory processes and downstream pathways are still unclear. Since various circular RNAs (circRNAs) and microRNAs (miRNAs) also play roles in the pathogenesis of glioma, we hypothesize that YB-1 may exert its function through a circRNA-miRNA-protein interaction network. In this study, we use the RNA binding protein immunoprecipitation assay and quantitative reverse transcription polymerase chain reaction to determine the circRNAs involved in the regulation of YB-1 and further elucidate their biological functions. The level of circSPECC1 (hsa_circ_0000745) modulated by YB-1 is significantly upregulated in the U251 and U87 glioma cell lines. Downregulation of circSPECC1 markedly inhibits the proliferation and invasiveness of U251 and U87 cells by inducing apoptosis. Bioinformatics analysis reveals that miR-615-5p could interact with circSPECC1 and huntingtin-interacting protein-1 (HIP-1). Then we determine the interactions between miR-615-5p, circSPECC1, and HIP1 using dual luciferase reporter system and pull-down assays. Mechanistic analysis indicates that the downregulation of circSPECC1 results in a decreased HIP1 expression. This study demonstrates that circSPECC1 modulated by YB-1 is increased in glioma cell lines. In addition, circSPECC1 promotes glioma growth through the upregulation of HIP1 by sponging miR-615-5p and targeting the HIP1/AKT pathway. This indicates that YB-1 and circSPECC1 may both be promising targets for glioma treatment.
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Glioma , MicroARNs , Humanos , Proteínas Proto-Oncogénicas c-akt/genética , ARN Circular/genética , ARN Circular/metabolismo , Proteína 1 de Unión a la Caja Y/genética , Glioma/patología , MicroARNs/genética , MicroARNs/metabolismo , Carcinogénesis/genética , Transformación Celular Neoplásica , Proliferación Celular/genética , Línea Celular Tumoral , Proteínas de Unión al ADN/genéticaRESUMEN
Strawflower (Helichrysum bracteatum, Asteraceae) , an annual or biennial herb, is one of the most popular flowers in the world because of the colorful flowers and the long flowering period. However, the ornamental plants belonging to Asteraceae are susceptible to numerous viruses such as cucumber mosaic virus (CMV) (Cucumovirus, Bromoviridae) , potato virus Y (Potyvirus, Potyviridae), tomato mosaic virus (ToMV) (Tobamovirus, Virgaviridae), tobacco mosaic virus (TMV) (Tobamovirus, Virgaviridae), chrysanthemum virus B (CVB) (Carlavirus, Betaflexiviridae), tomato aspermy virus (TAV) (Cucumovirus, Bromoviridae), tomato spotted wilt virus (TSWV) (Orthotospovirus tomatomaculae, Tospoviridae), and impatiens necrotic spot virus (INSV) (Orthotospovirus impatiensnecromaculae, Orthotospovirus) resulting in severe yield loss (Verma et al. 2003; Raj et al. 2007; Kondo et al. 2011; Liu et al. 2014; Marys et al. 2014; Min et al. 2020; Gautam et al. 2021; Read et al. 2022; Supakitthanakorn et al. 2022). Among these viruses, the TSWV, a thrips-transmitted negative-stranded RNA virus, is well known to cause viral disease in several plant species while is less reported in Helichrysum, especially in China. In April 2021, viral attack symptoms were detected on the leaves of H. bracteatum during our routine checks in the greenhouse located at Shunyi District, Beijing, China, such as wilting, shrinking, chlorotic blotches, chlorotic ring spots. To investigate the virus infecting H. bracteatum, in total of 25 symptomatic and 5 asymptomatic leaves were sampled and tested by the effective double antibody sandwich enzyme-linked immunosorbent assay (DAS-ELISA) using antisera against CMV, PVY/PVX, ToMV, TMV, CVB, TAV, TSWV, INSV, separately (Agdia, USA). Only the TSWV showed positive in symptomatic samples, and asymptomatic samples were all negative, which implied TSWV infection. To further confirm the virus type of TSWV isolated from H. bracteatum samples, the genomic RNA of the virus was isolated using reverse transcription and polymerase chain reaction (RT-PCR), and then was cloned, sequenced and analyzed. Total RNA of five symptomatic leaves (ELISA-positive) were extracted using the FastPure Plant Total RNA Isolation Kit (Vazyme, China), and then were reverse transcribed by HiScript II Reverse Transcriptase (Vazyme, China). Each genome segments were amplified using Phanta Max Super-Fidelity DNA Polymerase (Vazyme, China) with TSWV-specific primers newly designed and listed in Table S1. The PCR setup was as follow: 95°C for 30 s, followed by 35 cycles at 95°C for 30 s, 55°C for 30 s, and 72°C for 1.5 min, with a final extension at 72°C for 10 min. All PCR products were cloned into the TA/Blunt-Zero vector (Vazyme, China) and sequenced (GENEWIZ, Inc.). We assembled and then analyzed the evolutionary relationship of three genomic fragments, that is, TSWV-BJFC-Hb S (2923 bp), M (4785 bp) and L (8971 bp) using the BLAST tools. The results showed high similarity with TSWV-henan isolated from pepper in China (99.6% to TSWV-S (MT799179.1), 99.8 % to TSWV-M (MT799178.1) and 99.8 % TSWV-L (MT799177.1)). These sequences have been submitted to the GenBank (OM982910, OM982911 and OM937131). Taking all of these evidences together, the viral disease observed in H. bracteatum was closely associated with TSWV. TSWV is currently widespread in China, infecting Nasturtium, Chrysanthemum and cowpea (Xiao et al. 2015; Hu et al. 2018; Yu et al. 2021). Epidemics of TSWV have also been reported in several other countries such as Korea, North Carolina, Turkey and India (Renukadevi et al. 2015; Koehler et al. 2016; Kwak et al. 2021; Erilmez, S. 2022). This is the first report of TSWV infection on H. bracteatum in China. Due to the fast spread and serious economic losses of TSWV, the rapid detection may be the essential way to prevent this viral disease among crops (Macharia et al. 2014).
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Polygonatum cyrtonema Hua, a perennial plant of the Asparagaceae family, is an important herb in Chinese medicine and is mainly grown in the Chinese provinces of Guizhou, Hunan, Yunnan, Anhui, and Zhejiang (Chen et al. 2021). In June 2021, a new case of leaf spot disease was detected in an 80 m2 plantation of P. cyrtonema on Xuefeng Mountain, Huaihua City, Hunan Province (27°17'30â³N, 110°24'20â³E). It infected almost 40% of the total planted area. Initially, irregular light brown spots appeared on the leaves, gradually turning dark brown and coalescing to form large necrotic areas, after which the affected plant turned yellow and eventually died. Ten disease samples were collected from ten plants in the plantation area. The leading edge of necrotic tissues were rinsed with sterile water and then disinfected with 3% hydrogen peroxide for 30 s, followed by 75% ethanol for 90 s, and rinsed three times with sterile water. Samples were then placed on water agar plates and incubated in the dark in a constant temperature incubator at 28 â for 3-5 days. After mycelial growth was observed in the media, the hyphae were transferred to potato dextrose agar plates and incubated for 3-5 days at 28 â in the dark. Ultimately, 12 purified fungal isolates were obtained, some of which were morphologically similar, including 10 that were Alternaria (83.3% isolation rate). Three representative isolates (HJYB1, HJYB2, and HJYB3) were selected for further study. The initial colonies were grayish green with white fluffy mycelia on the surface and a prominent white rim, which became brown with dense, cottony aerial mycelia as the colonies matured. The conidia were obpyriform or ellipsoidal, pale to dark brown, with 0-4 transverse and 0-3 longitudinal septa, some with a short cylindrical beak at the tip. They measured 11.826-28.873 × 6.231-26.018 µm (n = 100). To further confirm the identity of the isolates, their rDNA internal transcribed spacer region (ITS), ß-microtubulin (TUB2) and translation elongation factor-1 (TEF-1) genes were amplified and sequenced using the ITS4/ITS5, TUB2F/R and EF-526F/1567R primers, respectively (Hong et al. 2006). The sequences were submitted to GenBank (ITS: OR513924, OR513964, OR519874; TUB2: OR526928, OR533421, OR526929; TEF: OR526926, OR533420, OR526927). A concatenated phylogenetic tree of the three genes showed that the isolate clustered significantly with Alternaria alternata. Based on morphological identification and phylogenetic tree analysis, the isolate was identified as A. alternata. We carried out pathogenicity tests on four uniformly growing P. cyrtonema plants. Three of these plants were used as experimental plants and one as a control. For each plant, three young leaves were selected and inoculated with 6 × 6 mm PDA blocks, while sterile PDA blocks were used as controls. The treated plants were subjected to 10 days of stable temperature in a climatic chamber set at 28°C, 80% constant relative humidity and 12 hours of light per day. The pathogenic lesions appeared and the pathogens re-isolated from the diseased leaves showed similar morphological characteristics to representative isolates and were confirmed as A. alternata by DNA sequencing, thus fulfilling Koch's postulates. A. alternata is the major causal agent of leaf spot on P. sibiricum (Zou et al. 2023) and Agrimonia pilosa (Jiang et al. 2023). As far as we know, leaf necrosis caused by A. tenuissima has been found on P. cyrtonema (Li et al. 2020). To our knowledge, this is the first report of A. alternata causing leaf spot disease in P. cyrtonema. These findings form the basis for the management of this leaf spot disease.
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Objective: To examine the in vitro inhibitory effect of flower extracts from Salvia deserta Schang (SFE) on Streptococcu smutans ( S. mutans). Methods: The inhibitory effect of SFE on planktonic S. mutans and the effect of SFE on the growth process of planktonic S. mutans were determined by the agar drilling method and the microdilution method. Crystal violet staining and MTT reduction assay were conducted to determine the effect of SFE on S. mutans biofilm formation. The effect of SFE on the production of exopolysaccharides (EPS) in S. mutans biofilm was determined by anthrone-sulfuric acid method. The intracellular lactate dehydrogenase (LDH) activity in S. mutans was determined by LDH colorimetric assay. The effects of SFE on the acid-producing capacity of S. mutans was determined by pH meter. Results: The minimum inhibitory concentration (MIC) of SFE against S. mutans was 14 µg/µL. SFE of the the concentration between 1/8 MIC and MIC could inhibit the growth rate of S. mutans within 30 h and it could significantly inhibit the LDH activity compared with the control group ( P<0.0001). SFE of the concentration between 4 MIC and 1/4 MIC had an inhibitory effect on the acid production of S. mutans ( P<0.001). Moreover, it could effectively restrain the formation of S. mutans biofilm and significantly reduce the amount of EPS produced by biofilm ( P<0.01). Conclusion: SFE can effectively inhibit the activity of S. mutans and its biofilm. The mechanism of inhibiting S. mutans by SFE was preliminarily discussed as follows, it interferes with microbial adhesion and aggregation by reducing the production of bacterial EPS, thus inhibiting the formation of bacterial biofilms. In addition, it interferes with glycolysis of S. mutans by reducing the LDH activity of bacteria, thus inhibiting the acid production of S. mutans.
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Biopelículas , Streptococcus mutans , Pruebas de Sensibilidad Microbiana , Extractos Vegetales/farmacología , Antibacterianos/farmacologíaRESUMEN
INTRODUCTION: Immune checkpoint inhibitors (ICIs) are effective in the treatment of advanced esophageal squamous cell carcinoma (ESCC); however, their efficacy in locally advanced resectable ESCC and the potential predictive biomarkers have limited data. METHODS: In this study, locally advanced resectable ESCC patients were enrolled and received neoadjuvant toripalimab (240 mg, day 1) plus paclitaxel (135 mg/m2, day 1) and carboplatin (area under the curve 5 mg/mL per min, day 1) in each 3-week cycle for 2 cycles, followed by esophagectomy planned 4-6 weeks after preoperative therapy. The primary endpoints were safety, feasibility, and the major pathological response (MPR) rate; the secondary endpoints were the pathological complete response (pCR) rate, disease-free survival (DFS), and overall survival (OS). Association between molecular signatures/tumor immune microenvironment and treatment response was also explored. RESULTS: Twenty resectable ESCC patients were enrolled. Treatment-related adverse events (AEs) occurred in all patients (100%), and 4 patients (22.2%) experienced grade 3 or higher treatment-related AEs. Sixteen patients underwent surgery without treatment-related surgical delay, and the R0 resection rate was 87.5% (14/16). Among the 16 patients, the MPR rate was 43.8% (7/16) and the pCR rate was 18.8% (3/16). The abundance of CD8+ T cells in surgical specimens increased (P = .0093), accompanied by a decreased proportion of M2-type tumor-associated macrophages (P = .036) in responders upon neoadjuvant therapy. Responders were associated with higher baseline gene expression levels of CXCL5 (P = .03) and lower baseline levels of CCL19 (P = .017) and UMODL1 (P = .03). CONCLUSIONS: The combination of toripalimab plus paclitaxel and carboplatin is safe, feasible, and effective in locally advanced resectable ESCC, indicating its potential as a neoadjuvant treatment for ESCC. CLINICAL TRIAL REGISTRATION: NCT04177797.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/farmacología , Carboplatino/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/cirugía , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/cirugía , Humanos , Terapia Neoadyuvante/efectos adversos , Paclitaxel , Microambiente TumoralRESUMEN
BACKGROUND: Pulmonary hypertension (PH) is a progressive and fatal cardiopulmonary disease characterized by pulmonary vascular remodeling and increased pulmonary vascular resistance and artery pressure. Vascular remodeling is associated with the excessive cell proliferation and migration of pulmonary artery smooth muscle cells (PASMCs). In this paper, the effects of heat shock protein-110 (HSP110) on PH were investigated. METHODS: The C57BL/6 mice and human PASMCs (HPASMCs) were respectively exposed to hypoxia to establish and simulate PH model in vivo and cell experiment in vitro. To HSP110 knockdown, the hypoxia mice and HPASMCs were infected with adeno-associated virus or adenovirus carring the shRNAs (short hairpin RNAs) for HSP110 (shHSP110). For HSP110 and yes-associated protein (YAP) overexpression, HPASMCs were infected with adenovirus vector carring the cDNA of HSP110 or YAP. The effects of HSP110 on PH development in mice and cell proliferation, migration and autophagy of PASMCs under hypoxia were assessed. Moreover, the regulatory mechanisms among HSP110, YAP and TEA domain transcription factor 4 (TEAD4) were investigated. RESULTS: We demonstrated that expression of HSP110 was significantly increased in the pulmonary arteries of mice and HPASMCs under hypoxia. Moreover, knockdown of HSP110 alleviated hypoxia-induced right ventricle systolic pressure, vascular wall thickening, right ventricular hypertrophy, autophagy and proliferation of PASMCs in mice. In addition, knockdown of HSP110 inhibited the increases of proliferation, migration and autophagy of HPASMCs that induced by hypoxia in vitro. Mechanistically, HSP110 knockdown inhibited YAP and transcriptional co-activator with PDZ-binding motif (TAZ) activity and TEAD4 nuclear expression under hypoxia. However, overexpression of HSP110 exhibited the opposite results in HPASMCs. Additionally, overexpression of YAP partially restored the effects of shHSP110 on HPASMCs. The interaction of HSP110 and YAP was verified. Moreover, TEAD4 could promote the transcriptional activity of HSP110 by binding to the HSP110 promoter under hypoxia. CONCLUSIONS: Our findings suggest that HSP110 might contribute to the development of PH by regulating the proliferation, migration and autophagy of PASMCs through YAP/TAZ-TEAD4 pathway, which may help to understand deeper the pathogenic mechanism in PH development.
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Hipertensión Pulmonar , Animales , Movimiento Celular/genética , Proliferación Celular/genética , Células Cultivadas , Proteínas de Unión al ADN , Proteínas del Choque Térmico HSP110/metabolismo , Proteínas del Choque Térmico HSP110/farmacología , Humanos , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/prevención & control , Hipoxia/metabolismo , Ratones , Ratones Endogámicos C57BL , Proteínas Musculares/metabolismo , Miocitos del Músculo Liso/metabolismo , Arteria Pulmonar/metabolismo , Factores de Transcripción de Dominio TEA , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Remodelación VascularRESUMEN
Circadian rhythm disorder is a significant risk factor for mental diseases, and the recovery of circadian rhythm function has gradually become a signal of effective antidepressant therapy. Sini powder (SNP) is a classical, traditional Chinese formula for depression treatment. However, few clinical reports have been recorded. This randomized, double-blinded, controlled trial (ChiCTR1900022700) aimed to explore the efficacy of SNP on depression via regulating circadian rhythm. In total, 36 patients with major depressive disorder (MDD) were enrolled for 4-weeks medication and 6-weeks follow-up. HAMD-24 score and circadian rhythm index, including dim light melatonin onset (DLMO) and phase angle difference (PAD), were included in the assessment. DLMO and PAD were statistically significant in the SNP group after 4 weeks of treatment (p < .05) and with greater improvement in DLMO (p = .03). In addition, DLMO and the HAMD-24 score showed a positive correlation (p < .05); the HAMD-24 score degree decreased significantly over time (p < .001). Similarly, interaction effects were shown significantly between group and time (p = .049). The duration of SNP supplementation was relatively short, and the sample size was relatively small. SNP granules combined with paroxetine tablets have definite efficacy in improving the circadian rhythms of MDD patients, reflecting the therapeutic advantages of traditional Chinese medicine as antidepressants.
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Trastorno Depresivo Mayor , Medicamentos Herbarios Chinos , Melatonina , Humanos , Antidepresivos/uso terapéutico , Ritmo Circadiano/fisiología , Trastorno Depresivo Mayor/tratamiento farmacológico , Melatonina/metabolismo , Paroxetina/uso terapéutico , Polvos/uso terapéutico , Sueño/fisiología , Comprimidos/uso terapéutico , Medicamentos Herbarios Chinos/uso terapéuticoRESUMEN
To search for novel focal adhesion kinase (FAK) inhibitors for intervention of metastatic triple-negative breast cancer (TNBC), a series of hybrids 7a-s from chloropyramine and cinnamic acid analogs were designed, synthesized and biologically evaluated. The most active compound 7d could potently inhibit the proliferation, invasion and migration of TNBC cells in vitro. The docking analysis of 7d was performed to elucidate its possible binding modes to focal adhesion targeting (FAT) domain of FAK scaffold. Further mechanism studies indicated the ability of 7d in disrupting Y925 autophosphorylation of FAK, reducing formation of focal adhesions (FAs) and stress fibers (SFs) as well as inducing apoptosis of TNBC cells. Together, 7d is a novel FAK inhibitor to inhibit the essential nonkinase scaffolding function of FAK via binding FAT domain and may be worth studying further for intervention of TNBC.
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Neoplasias de la Mama Triple Negativas , Línea Celular Tumoral , Movimiento Celular , Cinamatos , Etilenodiaminas , Proteína-Tirosina Quinasas de Adhesión Focal , Humanos , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
BACKGROUND INFORMATION: In many cellular processes including cell division, the synergistic dynamics of actin filaments and microtubules play vital roles. However, the regulatory mechanisms of these synergistic dynamics are not fully understood. Proteins such as formins are involved in actin filament-microtubule interactions and Arabidopsis thaliana formin 14 (AtFH14) may function as a crosslinker between actin filaments and microtubules in cell division, but the molecular mechanism underlying such crosslinking remains unclear. RESULTS: Without microtubules, formin homology (FH) 1/FH2 of AtFH14 nucleated actin polymerisation from actin monomers and capped the barbed end of actin filaments. However, in the presence of microtubules, quantitative analysis showed that the binding affinity of AtFH14 FH1FH2 to microtubules was higher than that to actin filaments. Moreover, microtubule-bound AtFH14 FH1FH2 neither nucleated actin polymerisation nor inhibited barbed end elongation. In contrast, tubulin did not affect AtFH14 FH1FH2 to nucleate actin polymerisation and inhibit barbed end elongation. Nevertheless, microtubule-bound AtFH14 FH1FH2 bound actin filaments and the bound actin filaments slid and elongated along the microtubules or elongated away from the microtubules, which induced bundling or crosslinking of actin filaments and microtubules. Pharmacological analyses indicated that AtFH14 FH1FH2 promoted crosslinking of actin filaments and microtubules in vivo. Additionally, co-sedimentation and fluorescent dye-labelling experiments of AtFH14 FH2-truncated proteins in vitro revealed the essential motifs of bundling actin filaments or microtubules, which were 63-92 aa and 42-62 aa in the AtFH14 FH2 N-terminal, respectively, and 42-62 aa was the essential motif to crosslink actin filaments and microtubules. CONCLUSIONS AND SIGNIFICANCE: Our results aid in explaining how AtFH14 functions as a crosslinker between actin filaments and microtubules to regulate their dynamics via different manners during cell division. They also facilitate further understanding of the molecular mechanisms of the interactions between actin filaments and microtubules.
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Citoesqueleto de Actina/metabolismo , Actinas/metabolismo , Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Forminas/metabolismo , Microtúbulos/metabolismo , Animales , División Celular , Unión Proteica , ConejosRESUMEN
AIM: This study was conducted to investigate the effects of dietary tributyrin (TB) and physterol ester (PSE) supplementation on the growth performance and intestinal health of weaned piglets. METHODS AND RESULTS: Ninety-six piglets were randomly allocated to one of four groups, including a control group (basal diet), TB group (basal diet + 1500 g t-1 TB), PSE group (basal diet + 300 g t-1 PSE) and TB + PSE group (basal diet + 1500 g t-1 TB + 300 g t-1 PSE). All groups had eight replicates with three piglets per replicate. The experiment lasted for 28 days. The results showed that dietary TB supplementation increased (p < 0.05) average daily feed intake and average daily gain, as well as the acetate and butyrate concentration in ileum, and dietary PSE supplementation decreased (p < 0.05) the ratio of feed to gain (F/G) on days 1-14 of the trial. Dietary TB or PSE alone supplementation improved the ratio of villus height to crypt depth (VH/CD) and the expression level of Occludin in ileum. The linear discriminant analysis effect size analysis identified eight biomarkers in the control group, 18 in the TB + PSE group, two in the PSE group in ileum respectively. Correlation analysis showed that the relative abundances of Enterococcus, and Streptococcus were positively correlated (p < 0.05) with propionate concentration, while the relative abundance of Clostridium_sensu_stricto_1 was negatively correlated (p < 0.05) with acetate concentration in ileum. CONCLUSION: These findings suggest that dietary TB or PSE alone supplementation could alter the growth performance, intestinal morphology, microbiota community and metabolites of weaned piglets. SIGNIFICANCE AND IMPACT OF THE STUDY: Weaning stress is a major cause of slow growth and increased diarrhoea in piglets. This study demonstrated that dietary TB and PSE presented a beneficial role in growth performance and gut health via regulating intestinal morphology, microbiota composition and metabolites.
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Microbioma Gastrointestinal , Microbiota , Alimentación Animal/análisis , Animales , Dieta/veterinaria , Suplementos Dietéticos/análisis , Ésteres , Porcinos , Triglicéridos , DesteteRESUMEN
Retroperitoneal liposarcoma (RLPS) is one of the most common subtypes of retroperitoneal soft tissue sarcomas. It is characterized by poor sensitivity to radiotherapy and chemotherapy and a low success rate of complete surgical resection. However, there are few reliable preclinical RLPS models for target discovery and therapy research. In this study, we aimed to establish RLPS patient-derived xenograft (PDX) models that are useful for biological research and preclinical drug trials. A total of 56 freshly resected RLPS tissues were subcutaneously transplanted into non-obese diabetic-severe combined immune deficient (NOD-SCID) mice, with subsequent xenotransplantation into second-generation mice. The tumor engraftment rate of first generation PDXs was 44.64%, and higher success rates were obtained from implantations of dedifferentiated, myxous, pleomorphic, high-grade liposarcomas and those with retroperitoneal organ infiltration. The first- and second- generation PDX models preserved the histopathological morphology, gene mutation profiles and MDM2 amplification of the primary tissues. PDX models can also provide the benefit of retaining original tumor biology and microenvironment characteristics, such as abnormal adipose differentiation, elevated Ki67 levels, high microvessel density, cancer-associated fibroblast presence, and tumor-associated macrophage infiltration. Overall survival (OS) and disease-free survival (DFS) of patients with successful first-generation PDX engraftment were significantly poorer than those with failed engraftment. Treatment with MDM2 inhibitor RG7112 significantly suppressed tumor growth of DDLPS PDX in mice. In conclusion, we successfully established RLPS PDX models that were histologically, genetically, and molecularly consistent with the original tissues. These models might provide opportunities for advancing RLPS tumor biology research, facilitating the development of novel drugs, particularly those targeting MDM2 amplification, adipose differentiation process, angiogenesis, cancer-associated fibroblasts, and so on.