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Red blood cells (RBCs) are the primary mediators of oxygen transport in the human body, and their function is mainly achieved through conformational changes of hemoglobin (Hb). Hb is a tetramer composed of four subunits, with HbA being the predominant Hb in healthy adults, existing in two forms: tense state (T state) and relaxed state (R state). Endogenous regulators of Hb conformation include 2,3-diphosphoglyceric acid, carbon dioxide, protons, and chloride ions, while exogenous regulators include inositol hexaphosphate, inositol tripyrophosphate, benzabate, urea derivative L35, and vanillin, each with different mechanisms of action. The application of Hb conformational regulators provides new insights into the study of hypoxia oxygen supply issues and the treatment of sickle cell disease.
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Hemoglobinas , Oxígeno , Conformación Proteica , Humanos , Oxígeno/metabolismo , Hemoglobinas/metabolismo , Hemoglobinas/química , Transporte Biológico , Eritrocitos/metabolismo , Ácido Fítico/metabolismo , Ácido Fítico/farmacología , 2,3-Difosfoglicerato/metabolismoRESUMEN
Fruit flies cause substantial economic damage, and their management relies primarily on chemical insecticides. However, pesticide resistance has been reported in several fruit fly species, the mitigation of which is crucial to enhancing fruit fly control. Here, we assess the toxicity of a novel insecticide (fluralaner) and a common insecticide (dinotefuran) against three fruit fly species, Bactrocera dorsalis (Hendel), Bactrocera cucurbitae (Coquillett), and Bactrocera tau (Walker). Both pesticides exhibit robust lethal and sublethal effects against all three fruit fly species, with fluralaner being more potent. Fluralaner and dinotefuran suppress the reproductive capacities and survival rates of fruit flies. However, at the 50% lethal concentration, fluralaner stimulates the reproductive capacity of B. dorsalis and the survival rate of B. tau. Fluralaner also causes significant transgenerational effects, impacting the offspring hatching rate of B. cucurbitae and B. tau and reducing the proportion of female offspring. Thus, both pesticides exhibit high potential for controlling fruit flies. However, their application should be tailored according to species variations and the diverse effects they may induce. Collectively, the findings of this study outline the sublethal effects of two insecticides against fruit flies, helping to optimize their application to ensure the effective management of insecticide resistance.
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Entomopathogenic fungi (EPF) are economical and environmentally friendly, forming an essential part of integrated pest management strategies. We screened six strains of Beauveria bassiana (B1-B6) (Hypocreales: Cordycipitaceae), of which B4 was the most virulent to Bactrocera dorsalis (Hendel) (Diptera: Tephritidae). We further assessed the biological characteristics of strain B4 and the environmental factors influencing its ability to infect B. dorsalis. We also evaluated the effects of B4 on two of the natural predators of B. dorsalis. We found that strain B4 was the most virulent to 3rd instar larvae, pupae, and adult B. dorsalis, causing mortality rates of 52.67, 61.33, and 90.67%, respectively. B4 was not toxic to B. dorsalis eggs. The optimum B4 effects on B. dorsalis were achieved at a relative humidity of 91-100% and a temperature of 25°C. Among the six insecticides commonly used for B. dorsalis control, 1.8% abamectin emulsifiable concentrate had the strongest inhibitory effect on B4 strain germination. B4 spraying affected both natural enemies (Amblyseius cucumeris and Anastatus japonicus), reducing the number of A. cucumeris and killing A. japonicus adults. We found a valuable strain of EPF (B4) that is virulent against many life stages of B. dorsalis and has great potential for the biological control of B. dorsalis. We also provide an important theoretical and practical base for developing a potential fungicide to control B. dorsalis.
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BACKGROUND & AIMS: Ultra-processed food (UPF) intake has increased sharply over the last few decades and has been consistently asserted to be implicated in the development of non-communicable diseases. We aimed to evaluate and update the existing observational evidence for associations between ultra-processed food (UPF) consumption and human health. METHODS: We searched Medline and Embase from inception to March 2023 to identify and update meta-analyses of observational studies examining the associations between UPF consumption, as defined by the NOVA classification, and a wide spectrum of health outcomes. For each health outcome, we estimated the summary effect size, 95% confidence interval (CI), between-study heterogeneity, evidence of small-study effects, and evidence of excess-significance bias. These metrics were used to evaluate evidence credibility of the identified associations. RESULTS: This umbrella review identified 39 meta-analyses on the associations between UPF consumption and health outcomes. We updated all meta-analyses by including 122 individual articles on 49 unique health outcomes. The majority of the included studies divided UPF consumption into quartiles, with the lowest quartile being the reference group. We identified 25 health outcomes associated with UPF consumption. For observational studies, 2 health outcomes, including renal function decline (OR: 1.25; 95% CI: 1.18, 1.33) and wheezing in children and adolescents (OR: 1.42; 95% CI: 1.34, 1.49), showed convincing evidence (Class I); and five outcomes were reported with highly suggestive evidence (Class II), including diabetes mellitus, overweight, obesity, depression, and common mental disorders. CONCLUSIONS: High UPF consumption is associated with an increased risk of a variety of chronic diseases and mental health disorders. At present, not a single study reported an association between UPF intake and a beneficial health outcome. These findings suggest that dietary patterns with low consumption of UPFs may render broad public health benefits.
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Comida Rápida , Estudios Observacionales como Asunto , Humanos , Comida Rápida/estadística & datos numéricos , Comida Rápida/efectos adversos , Manipulación de Alimentos , Dieta/estadística & datos numéricos , Metaanálisis como Asunto , Femenino , Alimentos ProcesadosRESUMEN
BACKGROUND: Chidamide is a selective histone deacetylase inhibitor approved for patients with hormone receptor (HoR)-positive and HER2-negative metastatic breast cancer (MBC). We aimed to investigate the efficacy, safety, and treatment patterns of chidamide and identify clinicopathological factors that predict the efficacy of chidamide in real-world scenarios. METHODS: Consecutive MBC patients treated with chidamide from January 2020 to August 2021 across 11 institutions were enrolled in this multicenter, retrospective study. Eligible patients were pre- and postmenopausal women who had clinically or histologically confirmed ER-positive, HER2-negative MBC, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients with multiple primary malignancies or missing baseline characteristics were excluded. Patients received 30 mg chidamide orally twice a week, combined with aromatase inhibitors (AIs) or non-AIs. Efficacy analyses included progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR). Univariate and multivariate Cox regression analyses were performed to identify the potential efficacy predictors. RESULTS: A total of 157 patients were finally included for analysis. The median number of lines prior to chidamide was four. In the whole cohort, the median PFS was 4.2 months (95% confidence interval [CI] 3.8-4.5). The ORR was 7.5% and the CBR was 31.3%. The efficacy of chidamide was consistent in patients pretreated with CDK4/6 inhibitors and patients treated with different endocrine combinations. Multivariate analysis indicated that patients who had liver metastases (adjusted HR = 1.66, 95% CI 1.14-2.43, adjusted p = 0.008) or ≥3 prior lines of treatment (adjusted HR = 1.80, 95% CI 1.17-2.77, adjusted p = 0.008) had significantly worse PFS. The most common AEs with chidamide were thrombocytopenia, leucopenia, neutropenia, and anemia. CONCLUSION: This study provided real-world data for the use of chidamide in patients with HoR-positive and HER2-negative MBC. Our data endorsed the use of chidamide in patients pretreated with CDK4/6 inhibitors and patients treated with different endocrine combinations.
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Aminopiridinas , Benzamidas , Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/patología , Receptor ErbB-2 , Estudios Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
The process of drug development is expensive and time-consuming. In contrast, drug repurposing can be introduced to clinical practice more quickly and at a reduced cost. Over the last decade, there has been a significant expansion of large biobanks that link genomic data to electronic health record data, public availability of various databases containing biological and clinical information and rapid development of novel methodologies and algorithms in integrating different sources of data. This review aims to provide a thorough summary of different strategies that utilize genomic data to seek drug-repositioning opportunities. We searched MEDLINE and EMBASE databases to identify eligible studies up until 1 May 2023, with a total of 102 studies finally included after two-step parallel screening. We summarized commonly used strategies for drug repurposing, including Mendelian randomization, multi-omic-based and network-based studies and illustrated each strategy with examples, as well as the data sources implemented. By leveraging existing knowledge and infrastructure to expedite the drug discovery process and reduce costs, drug repurposing potentially identifies new therapeutic uses for approved drugs in a more efficient and targeted manner. However, technical challenges when integrating different types of data and biased or incomplete understanding of drug interactions are important hindrances that cannot be disregarded in the pursuit of identifying novel therapeutic applications. This review offers an overview of drug repurposing methodologies, providing valuable insights and guiding future directions for advancing drug repurposing studies.
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Reposicionamiento de Medicamentos , Genómica , Humanos , Algoritmos , Desarrollo de Medicamentos , Descubrimiento de Drogas/métodos , Reposicionamiento de Medicamentos/métodosRESUMEN
Many species of the Tephritidae family are invasive and cause huge damage to agriculture and horticulture, owing to their reproductive characteristics. In this review, we have summarized the existing studies on the reproductive behavior of Tephritidae, particularly those regarding the genes and external factors that are associated with courtship, mating, and oviposition. Furthermore, we outline the issues that still need to be addressed in fruit fly reproduction research. The review highlights the implications for understanding the reproductive behavior of fruit flies and discusses methods for their integrated management and biological control. © 2023 Society of Chemical Industry.
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Oviposición , Tephritidae , Animales , Femenino , Cortejo , Conducta Sexual Animal , Reproducción , DrosophilaRESUMEN
Lycium barbarum polysaccharides (LBPs) have been shown to exert an antiglycemic effect. Emerging evidence suggests that patients with hyperglycemia have a hypercontractility of duodenum, and targeting duodenal contraction of duodenum can be beneficial to glucose metabolism. However, it is unknown whether LBPs can improve glucose metabolism by regulating the hypercontractility of the duodenum. Our aim was to explore the effect of LBPs on duodenal contraction in prediabetic mice and also preliminarily investigate the mechanism. The results showed that LBPs improved glucose homeostasis by decreasing the duodenal amplitude of contraction rather than frequency. Moreover, LBPs ameliorated the gut microbiota composition and the levels of short-chain fatty acids, especially acetic acid, which might bind to the receptor on neurons to regulate the contraction of the duodenum. Acetic acid was hypothesized to play a key role in the above process. Then, acetic acid was determined to exert an antiglycemic effect as expected. In conclusion, LBPs may rely on acetic acid to regulate duodenal contraction to ameliorate glucose metabolism in prediabetic mice, which provides a new therapeutic strategy to treat dysglycemia.
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Medicamentos Herbarios Chinos , Lycium , Estado Prediabético , Ratones , Humanos , Animales , Estado Prediabético/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Acetatos , Polisacáridos/farmacología , GlucosaRESUMEN
BACKGROUND: Studies reporting the effects of metabolic surgery, lifestyle intervention, and intensive insulin therapy for the remission of type 2 diabetes (T2DM) has been increasing, with fruitful results better conducted and yielded. However, there are only a few studies on the remission of T2DM using oral hypoglycemic drugs. Therefore, this study aims to investigate the remission effect of canagliflozin and metformin on participants with newly diagnosed T2DM and its possible underlying mechanism(s) through which these two medications elicit diabetes remission. METHOD: To this end, we performed a multicenter, parallel-group, randomized, controlled, and open-label trial. A total of 184 participants with a ≤ 3-year course of T2DM will be enrolled and randomly assigned to the canagliflozin or metformin treatment group in a ratio of 1:1. Participants in each group will maintain their medication for 3 months after achieving the target blood glucose level and then stop it. These participants will be followed up for one year to determine remission rates in both groups. DISCUSSION: In this study, we will establish that whether canagliflozin is superior to metformin in terms of remission rate in participants with newly diagnosed T2DM. The results of this trial may provide robust evidence regarding the efficacy and mechanisms of the action of sodium-glucose cotransporter-2 inhibitors (SGLT2is) in T2DM remission. TRIAL REGISTRATION: ChiCTR2100043770(February 28, 2021).
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Diabetes Mellitus Tipo 2 , Metformina , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Canagliflozina/uso terapéutico , Hipoglucemiantes/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Glucemia/metabolismo , Hemoglobina Glucada , Resultado del Tratamiento , Metformina/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Multicéntricos como AsuntoRESUMEN
Background: A bidirectional association between atopic dermatitis and chronic kidney disease (CKD) has been revealed in observational studies, whereas the causality of this association was unclear. We conducted a Mendelian randomization study to determine the bidirectional causal association between atopic dermatitis and CKD. Methods: Independent genetic instruments associated with atopic dermatitis and CKD at the genome-wide significance level were chosen from corresponding meta-analyses of genome-wide association studies. Summary-level data for atopic dermatitis were obtained from the EAGLE Eczema consortium (30,047 cases and 40,835 controls) and FinnGen consortium (7,024 cases and 198,740 controls). Summary-level data for CKD were derived from CKDGen consortium (64,164 cases and 625,219 controls) and FinnGen consortium (3,902 cases and 212,841 controls). The inverse-variance weighted method was used in the main analysis and supplemented with three sensitivity analyses. Results: Genetic predisposition to atopic dermatitis was associated with an increased risk of CKD. For a one-unit increase in the prevalence of atopic dermatitis, the odds ratio of CKD was 1.07 (95% confidence interval: 1.01-1.12). In the reverse Mendelian randomization analysis, the odds ratio of atopic dermatitis was 1.14 (95% confidence interval: 1.03-1.26) for a one-unit increase in the prevalence of CKD. The associations persisted in sensitivity analyses and no pleiotropy was detected. Conclusion: This Mendelian randomization study suggests a bidirectional positive association between atopic dermatitis and CKD.
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Introduction: Fine roots are the critical functional organs of plants to absorb water and nutrients from the soil environment, while the relation between fine root morphological characteristics and yield & quality has received less attention for medicinal plants. Methods: Therefore, we investigated the relationship between fine root morphological characteristics and biomass & gypenosides content. We explored the primary environmental drivers of fine root indicators for Gynostemma longipes from three provenances cultivated at two altitude habitats. Results: At the end of the growing season, compared with the low-altitude habitat, the underground biomass of G. longipes in the high-altitude habitat increased significantly by 200%~290% for all three provenances. The response of gypenosides content to different altitude habitats varied with provenance and plant organs. The biomass of G. longipes strongly depended on the fine root characteristic indicators (P < 0.001), fine root length density, and fine root surface area. Our results also showed that the harvest yield of G. longipes could be effectively increased by promoting the growth of fine roots per unit leaf weight (P < 0.001, R2 = 0.63). Both fine root length density and fine root surface area had strong positive correlations with soil nutrient factors (R2 > 0.55) and a strong negative correlation with soil pH (R2 > 0.48). In a word, the growth of G. longipes is strongly controlled by the fine root morphological characteristics through the response of fine roots to soil nutrient factors and pH. Discussion: Our findings will help to deepen the understanding of the root ecophysiological basis driven by soil factors for the growth and secondary metabolites formation of G. longipes and other medicinal plants under changing habitat conditions. In future research, we should investigate how environmental factors drive plant morphological characteristics (e.g., fine roots) to affect the growth & quality of medicinal plants over a longer time scale.
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BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous tumor with diverse molecular pathological profiles. Recent studies have suggested the vital role of pyroptosis in tumor microenvironment. However, the expression patterns of pyroptosis in HPV-positive HNSCC are still unclear. METHODS: Unsupervised clustering analysis was used to identify the pyroptosis patterns based on the RNA-sequencing data of 27 pyroptosis-related genes (PRGs) in HPV-positive HNSCC samples. Random forest classifier and artificial neural network were performed to screen the signature genes associated with pyroptosis, which were verified in two independent external cohorts and qRT-PCR experiment. Principal component analysis was used to develop a scoring system, namely Pyroscore. RESULTS: The expression variations of 27 PRGs in HPV-positive HNSCC patients were analyzed from genomic and transcriptional domains. Two pyroptosis-related subtypes with distinct clinical outcomes, enrichment pathways and immune characteristics were identified. Next, six signature genes (GZMB, LAG3, NKG7, PRF1, GZMA and GZMH) associated with pyroptosis were selected for prognostic prediction. Further, a Pyroscore system was constructed to determine the level of pyroptosis in each patient. A low Pyroscore was featured by better survival time, increased immune cell infiltration, higher expression of immune checkpoint molecules and T cell-inflamed genes, as well as elevated mutational burden. The Pyroscore was also related to the sensitivity of chemotherapeutic agents. CONCLUSIONS: The pyroptosis-related signature genes and Pyroscore system may be reliable predictors of prognosis and serve as mediators of immune microenvironment in patients with HPV-positive HNSCC.
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Gynostemma is an important medicinal and food plant of the Cucurbitaceae family. The phylogenetic position of the genus Gynostemma in the Cucurbitaceae family has been determined by morphology and phylogenetics, but the evolutionary relationships within the genus Gynostemma remain to be explored. The chloroplast genomes of seven species of the genus Gynostemma were sequenced and annotated, of which the genomes of Gynostemma simplicifolium, Gynostemma guangxiense and Gynostemma laxum were sequenced and annotated for the first time. The chloroplast genomes ranged from 157,419 bp (Gynostemma compressum) to 157,840 bp (G. simplicifolium) in length, including 133 identical genes: 87 protein-coding genes, 37 tRNA genes, eight rRNA genes and one pseudogene. Phylogenetic analysis showed that the genus Gynostemma is divided into three primary taxonomic clusters, which differs from the traditional morphological classification of the genus Gynostemma into the subgenus Gynostemma and Trirostellum. The highly variable regions of atpH-atpL, rpl32-trnL, and ccsA-ndhD, the repeat unilts of AAG/CTT and ATC/ATG in simple sequence repeats (SSRs) and the length of overlapping regions between rps19 and inverted repeats(IRb) and between ycf1 and small single-copy (SSC) were found to be consistent with the phylogeny. Observations of fruit morphology of the genus Gynostemma revealed that transitional state species have independent morphological characteristics, such as oblate fruit and inferior ovaries. In conclusion, both molecular and morphological results showed consistency with those of phylogenetic analysis.
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Genoma del Cloroplasto , Gynostemma , Filogenia , Gynostemma/genética , Genoma del Cloroplasto/genética , Secuencia de BasesRESUMEN
BACKGROUND: Fruit flies are internationally important quarantine or invasive pests of many fruits and vegetables and can cause serious economic losses. Long-term reliance on insecticides for controlling these pests has led to increasing resistance to multiple insecticides; hence, a new agent is needed. In this study, the acute toxicity and sublethal effects of the novel insecticide broflanilide on four adult fruit fly species, Bactrocera dorsalis, Bactrocera cucurbitae, Bactrocera tau, and Bactrocera correcta, were evaluated. RESULTS: Broflanilide was effective against B. dorsalis and B. correcta, with lethal concentration values (amount required to kill 50% of animals; LC50 ) of 0.390 and 1.716 mg/L. However, for B. cucurbitae (19.673 mg/L) and B. tau (24.373 mg/L), the LC50 was 50-60 times higher than that of B. dorsalis. The survival rates of B. correcta and B. cucurbitae were significantly lower under LC50 treatment than those of the control (corrected for mortality rate). Sublethal concentrations of broflanilide stimulated fecundity in all species except B. tau. The hatching rate at LC50 was significantly lower for B. correcta and B. tau compared with the control and even more so for B. correcta, which was zero. CONCLUSION: Broflanilide is potentially an effective insecticide for controlling B. dorsalis and B. correcta. However, the variation in toxicity of broflanilide to the four fruit flies suggests that species variation needs to be carefully considered. Our results highlight the importance of clarifying the sublethal effects of insecticides on target insects to ensure the comprehensive evaluation and rational use of insecticides. © 2023 Society of Chemical Industry.
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Insecticidas , Tephritidae , Animales , Insecticidas/toxicidad , Benzamidas/farmacología , Dosificación Letal Mediana , DrosophilaRESUMEN
BACKGROUND: Increasingly, studies have discovered that different fatty acids (Fas) are linked to colorectal cancer (CRC) risk. METHODS: We systematically searched Embase and Medline databases to identify eligible studies that examined the associations of different types of Fas with CRC risk. The effect estimates and their 95% confidence intervals (Cis) were pooled using a random-effects model. Subgroup and sensitivity analyses were performed to examine the robustness of the study findings. RESULTS: This study evaluated the associations of 28 dietary and 18 blood Fas with CRC risk by summarizing the most updated evidence from 54 observational and four Mendelian Randomization (MR) studies. The present findings suggested that high dietary intake of eicosapentaenoic acid (EPA), docosahexanoic acid (DHA), and docosapentaenoic acid (DPA) are related to low risk of CRC, while the n-6/n-3 PUFA ratio and trans-FA are related to high risk of CRC. The summary of all cohort studies found that a high intake of SFA and DHA was a protective factor for CRC, and a high intake of the n-6/n-3 PUFA ratio was a risk factor for CRC. In the subgroup analysis of cancer subsites, we found that the dietary intake of linoleic acid (LA) and trans-FA are risk factors, while DPA is a protective factor for colon cancer. High dietary DHA intake was associated with a lower risk of rectal cancer, while the dietary n-6/n-3 PUFA ratio was associated with a higher risk of rectal cancer. Meta-analysis of blood FA levels showed a significant reverse association between blood pentadecanoic acid and CRC risk, whilst other blood Fas showed no significant association with CRC risk. All included MR studies showed that high plasma arachidonic acid (AA) is associated with increased CRC risk. CONCLUSIONS: Current evidence on the dietary intake and blood levels of Fas in relation to CRC risk is less consistent. Future studies are needed to investigate how the metabolism of Fas contributes to CRC development.
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Neoplasias Colorrectales , Ácidos Grasos Omega-3 , Neoplasias del Recto , Humanos , Ácidos Grasos , Ingestión de Alimentos , Factores de Riesgo , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/etiología , Estudios Observacionales como AsuntoRESUMEN
BACKGROUND: Diverticular disease has been inconsistently associated with colorectal cancer risk. We conducted a bidirectional Mendelian randomization study to assess this association. METHODS: Forty-three and seventy single-nucleotide polymorphisms associated with diverticular disease and colorectal cancer at the genome-wide significance level (p < 5 × 10- 8) were selected as instrumental variables from large-scale genome-wide association studies of European descent, respectively. Summary-level data for colon cancer, rectum cancer, and colorectal cancer were obtained from genome-wide association analyses of the FinnGen consortium and the UK Biobank study. Summary-level data for diverticular disease was derived from a genome-wide association study conducted in the UK Biobank population. The random effect inverse-variance weighted Mendelian randomization approach was used as the primary method and MR-Egger, weighted-median, and MR-PRESSO approaches were conducted as sensitivity analyses. RESULTS: Genetically determined diverticular disease was associated with a higher risk of colorectal cancer (beta = 0.441, 95%CI: 0.081-0.801, P = 0.016) in the FinnGen population, but the association was not found in the UK Biobank (beta = 0.208, 95%CI: -0.291,0.532, P = 0.207). The positive association remained consistent direction in the three sensitivity analyses. In the stratified analysis in the FinnGen consortium, an association was found to exist between genetically predicted diverticular disease and colon cancer (beta = 0.489, 95%CI: 0.020-0.959, P = 0.041), rather than rectum cancer (beta = 0.328, 95%CI: -0.119-0.775, P = 0.151). Besides, we found a slight association between colorectal cancer and diverticular disease (beta = 0.007, 95%CI: 0.004-0.010, P < 0.001) when using colorectal cancer as exposome and diverticular disease as outcome. However, there is a large sample overlap in this step of analysis. CONCLUSION: This Mendelian randomization study suggests that diverticular disease may be a possible risk factor for colorectal cancer and colon cancer rather than rectum cancer in the FinnGen population.
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Neoplasias del Colon , Enfermedades Diverticulares , Neoplasias del Recto , Humanos , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido SimpleRESUMEN
Prenylated flavonol glycosides in Epimedium plants, as key medicinal components, are known to have great pharmaceutical activities for human health. Among the main prenylated flavonol glycosides, the modification mechanism of different sugar moieties is still not well understood. In the current study, a novel prenylated flavonol rhamnoside xylosyltransferase gene (EpF3R2â³XylT) was cloned from E. pubescens, and the enzymatic activity of its decoding proteins was examined in vitro with different prenylated flavonol rhamnoside substrates and different 3-O-monosaccharide moieties. Furthermore, the functional and structural domains of EpF3R2â³XylT were analyzed by bioinformatic approaches and 3-D protein structure remodeling. In summary, EpF3R2â³XylT was shown to cluster with GGT (glycosyltransferase that glycosylates sugar moieties of glycosides) through phylogenetic analysis. In enzymatic analysis, EpF3R2â³XylT was proven to transfer xylose moiety from UDP-xylose to prenylated flavonol rhamnoside at the 2â³-OH position of rhamnose. The analysis of enzymatic kinetics showed that EpF3R2â³XylT had the highest substrate affinity toward icariin with the lowest Km value of 75.96 ± 11.91 mM. Transient expression of EpF3R2â³XylT in tobacco leaf showed functional production of EpF3R2â³XylT proteins in planta. EpF3R2â³XylT was preferably expressed in the leaves of E. pubescens, which is consistent with the accumulation levels of major prenylflavonol 3-O-triglycoside. The discovery of EpF3R2â³XylT will provide an economical and efficient alternative way to produce prenylated flavonol trisaccharides through the biosynthetic approach.
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Epimedium , Glicósidos , Flavonoides , Flavonoles/química , Glicósidos/química , Filogenia , Azúcares , Xilosa , UDP Xilosa Proteína XilosiltransferasaRESUMEN
BACKGROUND: We performed phenome-wide Mendelian randomization analysis (MR-PheWAS), two-sample MR analysis, and systemic review to comprehensively explore the health effects of milk consumption in the European population. METHODS: Rs4988235 located upstream of the LCT gene was used as the instrumental variable for milk consumption. MR-PheWAS analysis was conducted to map the association of genetically predicted milk consumption with 1081 phenotypes in the UK Biobank study (n=339,197). The associations identified in MR-PheWAS were examined by two-sample MR analysis using data from the FinnGen study (n=260,405) and international consortia. A systematic review of MR studies on milk consumption was further performed. RESULTS: PheWAS and two-sample MR analyses found robust evidence in support of inverse associations of genetically predicted milk consumption with risk of cataract (odds ratio (OR) per 50 g/day increase in milk consumption, 0.89, 95% confidence interval (CI), 0.84-0.94; p=3.81×10-5), hypercholesterolemia (OR, 0.91, 95% CI 0.86-0.96; p=2.97×10-4), and anal and rectal polyps (OR, 0.85, 95% CI, 0.77-0.94; p=0.001). An inverse association for type 2 diabetes risk (OR, 0.92, 95% CI, 0.86-0.97; p=0.003) was observed in MR analysis based on genetic data with body mass index adjustment but not in the corresponding data without body mass index adjustment. The systematic review additionally found evidence that genetically predicted milk consumption was inversely associated with asthma, hay fever, multiple sclerosis, colorectal cancer, and Alzheimer's disease, and positively associated with Parkinson's disease, renal cell carcinoma, metabolic syndrome, overweight, and obesity. CONCLUSIONS: This study suggests several health effects of milk consumption in the European population.
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Diabetes Mellitus Tipo 2 , Neoplasias Renales , Humanos , Animales , Análisis de la Aleatorización Mendeliana , Leche , Diabetes Mellitus Tipo 2/epidemiología , Polimorfismo de Nucleótido SimpleRESUMEN
While therapies such as chemotherapy combined with immunotherapy, sacituzumab govitecan, and PARP inhibitors are available for metastatic TNBC, on disease progression after these therapies, the mainstay of therapy is chemotherapy. Apatinib is a small-molecule tyrosine kinase inhibitor that has promising anti-angiogenesis and antitumor activity for TNBC. We aimed to evaluate the safety and efficacy of adding apatinib to chemotherapy in patients with advanced TNBC with failed first/second-line treatment. A total of 66 patients were randomly assigned, in a 1:1 ratio, to receive vinorelbine or vinorelbine with apatinib in 28-day cycles. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR) and safety. 33 received apatinib plus vinorelbine and 32 received vinorelbine (1 was withdrawal). Median PFS was significantly longer in the apatinib plus vinorelbine group than in the vinorelbine group (3.9 months vs. 2.0 months; hazard ratio, 1.82; 95% confidence interval [CI], 1.06 to 3.11; P = 0.026). Median OS was 11.5 months with apatinib plus vinorelbine and 9.9 months with vinorelbine (HR,1.01; 95% CI, 0.51 to 1.97; P = 0.985). The ORR was 9.1% in the apatinib plus vinorelbine group and 6.3% in the vinorelbine group (P = 0.667). The most common treatment-related hematologic grade 3-4 adverse events in apatinib plus vinorelbine group, were leukopenia, granulocytopenia, anemia, and thrombocytopenia. no treatment-related nonhematologic grade 4 adverse events or treatment-related deaths were observed. Collectively, adding apatinib to vinorelbine shows a promising benefit in PFS compared to vinorelbine monotherapy, with an excellent toxicity profile, warranting further exploration.
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Background: Primary breast diffuse large B-cell lymphoma (PB-DLBCL) is a rare subtype of non-Hodgkin lymphoma (NHL) with limited data on the clinical features and prognostic factors. Patients and Methods: A consecutive cohort of patients with PB-DLBCL was retrospectively analyzed in our hospital from February 1997 through July 2018. The primary endpoint is overall survival (OS) contributing to any cause. Results: A total of 76 patients were diagnosed with PB-DLBCL. The median age at diagnosis was 51 years (range: 25-80 years), with female prevalence (98.7%). Forty (52.6%) patients had right-sided breast involvement but no bilateral breast involvement at diagnosis. Overall, disease stages IE and IIE were seen in 55 (72.4%) and 21 (27.6%) patients, respectively. According to the stage-modified International Prognostic Index (IPI), 37 (48.7%) patients were classified in the very good risk group (IPI 0). Of the 72 patients available, the non-germinal center B-cell (non-GCB) subtype of DLBCL was observed in 66 (91.6%) patients. All patients received anthracycline-based chemotherapy, 56 (73.7%) with rituximab, 31 (40.8%) also with additional radiation therapy, and 14 (18.4%) patients received a prophylactic intrathecal injection. Seven (9.2%) patients had refractory disease. With a median follow-up of 6.8 years (range 0.4-25.0 years), 10 (13.2%) patients had a relapse in the central nervous system (CNS) site. The 5-year and 10-year OS of all the patients was 97.2% (95% CI: 99.3-89.5) and 84.8% (95% CI: 70.0-93.5), respectively. The median OS was not reached. The median progression-free survival (PFS) was 10.3 years for patients with PB-DLBCL. The 5-year PFS of all the patients was 76.3% (95% CI: 64.6-84.6). Univariate analysis revealed several prognostic factors, including stage-modified IPI, breast surgery, refractory disease, and CNS relapse. Multivariate analyses produced two independent prognostic factors for patients with PB-DLBCL, including stage-modified IPI score (2-3 versus 0) (hazard ratio: 19.114, 95% CI 1.841 to 198.451, p=0.013) and CNS relapse (hazard ratio: 5.522, 95% CI 1.059 to 28.788, p=0.043). Conclusion: In our cohort, PB-DLBCL clinical features are similar to prior literature reports. Stage-modified IPI score and CNS relapse were associated with overall survival.