RESUMEN
Among arthropod vectors, ticks transmit the most diverse human and animal pathogens, leading to an increasing number of new challenges worldwide. Here we sequenced and assembled high-quality genomes of six ixodid tick species and further resequenced 678 tick specimens to understand three key aspects of ticks: genetic diversity, population structure, and pathogen distribution. We explored the genetic basis common to ticks, including heme and hemoglobin digestion, iron metabolism, and reactive oxygen species, and unveiled for the first time that genetic structure and pathogen composition in different tick species are mainly shaped by ecological and geographic factors. We further identified species-specific determinants associated with different host ranges, life cycles, and distributions. The findings of this study are an invaluable resource for research and control of ticks and tick-borne diseases.
Asunto(s)
Variación Genética/genética , Enfermedades por Picaduras de Garrapatas/microbiología , Garrapatas/genética , Animales , Línea Celular , Vectores de Enfermedades , Especificidad del Huésped/genéticaRESUMEN
Hexavalent chromium (Cr(VI)) exposure has been linked with gastrointestinal toxicity, whereas the molecular pathways and key targets remain elusive. Computational toxicology analysis predicted the correlation between protein phosphatase 2A (PP2A) and genes regarding Cr(VI)-induced intestinal injury. Here, we generated a mouse model with intestinal epithelium-specific knock-out of Ppp2r1a (encoding PP2A Aα subunit) to investigate the mechanisms underlying Cr(VI)-induced small intestinal toxicity. Heterozygous mice (HE) and matched wild-type (WT) littermates were administrated with Cr(VI) at 0, 5, 20, 80 mg/L for 28 successive days. Cr(VI) treatment led to crypt hyperplasia, epithelial cell apoptosis, and intestinal barrier dysfunction, accompanied by the decline of goblet cell counts and Occludin expression in WT mice. Notably, these effects were aggravated in HE mice, indicating that PP2A Aα deficiency conferred mice with susceptibility to Cr(VI)-induced intestinal injury. Integrated data analysis and biological experiments revealed Cr(VI) exposure could decrease YAP1 phosphorylation at Ser127 but increase protein expression and activity, together with elevated TAZ protein driving epithelial crypt cells proliferation following damage, suggesting the involvement of Hippo/YAP1 signaling pathway in Cr(VI)-induced intestinal toxicity. Nevertheless, the enhanced phosphorylation of YAP1 in HE mice resulted in proliferation/repair defects in intestinal epithelium, thereby exacerbating Cr(VI)-induced gut barrier dysfunction. Notably, by molecular docking and further studies, we identified Urolithin A, a microbial metabolite, attenuated Cr(VI)-induced disruption of intestinal barrier function, partly by modulating YAP1 expression and activity. Our findings reveal the novel molecular pathways participated in Cr(VI)-caused small intestinal injury and urolithin A could potentially protect against environmental hazards-induced intestinal diseases.
RESUMEN
µ-Conotoxin KIIIA, a selective blocker of sodium channels, has strong inhibitory activity against several Nav isoforms, including Nav1.7, and has potent analgesic effects, but it contains three pairs of disulfide bonds, making structural modification difficult and synthesis complex. To circumvent these difficulties, we designed and synthesized three KIIIA analogues with one disulfide bond deleted. The most active analogue, KIIIA-1, was further analyzed, and its binding pattern to hNav1.7 was determined by molecular dynamics simulations. Guided by the molecular dynamics computational model, we designed and tested 32 second-generation and 6 third-generation analogues of KIIIA-1 on hNav1.7 expressed in HEK293 cells. Several analogues showed significantly improved inhibitory activity on hNav1.7, and the most potent peptide, 37, was approximately 4-fold more potent than the KIIIA Isomer I and 8-fold more potent than the wildtype (WT) KIIIA in inhibiting hNav1.7 current. Intraperitoneally injected 37 exhibited potent in vivo analgesic activity in a formalin-induced inflammatory pain model, with activity reaching â¼350-fold of the positive control drug morphine. Overall, peptide 37 has a simplified disulfide-bond framework and exhibits potent in vivo analgesic effects and has promising potential for development as a pain therapy in the future.
Asunto(s)
Analgésicos , Conotoxinas , Canal de Sodio Activado por Voltaje NAV1.7 , Bloqueadores del Canal de Sodio Activado por Voltaje , Humanos , Analgésicos/farmacología , Analgésicos/química , Conotoxinas/química , Conotoxinas/farmacología , Disulfuros/metabolismo , Células HEK293 , Simulación de Dinámica Molecular , Dolor/inducido químicamente , Dolor/tratamiento farmacológico , Péptidos/farmacología , Péptidos/metabolismo , Bloqueadores del Canal de Sodio Activado por Voltaje/química , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacologíaRESUMEN
The effects of COVID-19 vaccination on short-term and long-term cerebrovascular risks among COVID-19 survivors remained unknown. We conducted a national multi-center retrospective cohort study with 151 597 vaccinated and 151 597 unvaccinated COVID-19 patients using the TriNetX database, from January 1, 2020 to December 31, 2023. Patients baseline characteristics were balanced with propensity score matching (PSM). The outcomes were incident cerebrovascular diseases occurred between 1st and 30th days (short-term) after COVID-19 diagnosis. Nine subgroup analyses were conducted to explore potential effect modifications. We performed six sensitivity analyses, including evaluation of outcomes between 1st to 180th days, accounting for competing risk, and incorporating different variant timeline to test the robustness of our results. Kaplan-Meier curves and Log-Rank tests were performed to evaluate survival difference. Cox proportional hazards regressions were adopted to estimate the PSM-adjusted hazard ratios (HR). The overall short-term cerebrovascular risks were lower in the vaccinated group compared to the unvaccinated group (HR: 0.66, 95% CI: 0.56-0.77), specifically cerebral infarction (HR: 0.62, 95% CI: 0.48-0.79), occlusion and stenosis of precerebral arteries (HR: 0.74, 95% CI: 0.53-0.98), other cerebrovascular diseases (HR: 0.57, 95% CI: 0.42-0.77), and sequelae of cerebrovascular disease (HR: 0.39, 95% CI:0.23-0.68). Similarly, the overall cerebrovascular risks were lower in those vaccinated among most subgroups. The long-term outcomes, though slightly attenuated, were consistent (HR: 0.80, 95% CI: 0.73-0.87). Full 2-dose vaccination was associated with a further reduced risk of cerebrovascular diseases (HR: 0.63, 95% CI: 0.50-0.80) compared to unvaccinated patients. Unvaccinated COVID-19 survivors have significantly higher cerebrovascular risks than their vaccinated counterparts. Thus, clinicians are recommended to monitor this population closely for stroke events during postinfection follow-up.
Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Trastornos Cerebrovasculares , Vacunación , Humanos , Trastornos Cerebrovasculares/epidemiología , Trastornos Cerebrovasculares/etiología , COVID-19/prevención & control , COVID-19/epidemiología , Femenino , Masculino , Estudios Retrospectivos , Persona de Mediana Edad , Vacunas contra la COVID-19/administración & dosificación , Vacunas contra la COVID-19/efectos adversos , Anciano , Vacunación/estadística & datos numéricos , Sobrevivientes/estadística & datos numéricos , Adulto , SARS-CoV-2/inmunología , Factores de Riesgo , Modelos de Riesgos ProporcionalesRESUMEN
STUDY QUESTION: Does the change in endometrial thickness (EMT) from the end of the follicular/estrogen phase to the day of embryo transfer (ET) determine subsequent pregnancy outcomes? SUMMARY ANSWER: Endometrial compaction from the late-proliferative to secretory phase is not associated with live birth rate (LBR) and other pregnancy outcomes. WHAT IS KNOWN ALREADY: Endometrial compaction has been suggested to be indicative of endometrial responsiveness to progesterone, and its association with ET outcome has been investigated but is controversial. STUDY DESIGN, SIZE, DURATION: A systematic review with meta-analysis was carried out. PubMed, EMBASE, and Web of Science were searched to identify relevant studies from inception to 18 November 2022. The reference lists of included studies were also manually screened for any additional publications. PARTICIPANTS/MATERIALS, SETTING, METHODS: Cohort studies comparing ET pregnancy outcomes between patients with and without endometrial compaction were included. A review of the studies for inclusion, data extraction, and quality assessment was performed by two independent reviewers. The effect size was synthesized as odds ratio (OR) with 95% CI using a random-effects model. Heterogeneity and publication bias were assessed by the I2 statistic and Egger's test, respectively. The primary outcome was LBR. Secondary outcomes included biochemical pregnancy rate (BPR), clinical pregnancy rate (CPR), miscarriage rate (MR), ongoing pregnancy rate (OPR), and ectopic pregnancy rate (EPR). MAIN RESULTS AND THE ROLE OF CHANCE: Seventeen cohort studies involving 18 973 ET cycles fulfilled the eligibility criteria. The pooled results revealed that there were no significant differences between endometrial compaction and non-compaction groups in LBR (crude OR (cOR) = 0.95, 95% CI 0.87-1.04; I2 = 0%; adjusted OR (aOR) = 1.02, 95% CI 0.87-1.19, I2 = 79%), BPR (cOR = 0.93, 95% CI 0.81-1.06; I2 = 0%; aOR = 0.88, 95% CI 0.75-1.03, I2 = 0%), CPR (cOR = 0.98, 95% CI 0.81-1.18; I2 = 70%; aOR = 0.86, 95% CI 0.72-1.02, I2 = 13%), MR (cOR = 1.09, 95% CI 0.90-1.32; I2 = 0%; aOR = 0.91, 95% CI 0.64-1.31; I2 = 0%), and EPR (cOR = 0.70, 95% CI 0.31-1.61; I2 = 61%). The OPR was marginally higher in crude analysis (cOR = 1.48, 95% CI 1.01-2.16; I2 = 81%) among women with compacted endometrium, but was not evident in adjusted results (aOR = 1.36, 95% CI 0.86-2.14; I2 = 84%). Consistently, the pooled estimate of LBR remained comparable in further subgroup and sensitivity analyses according to the degree of compaction (0%, 5%, 10%, 15%, or 20%), type of ET (fresh, frozen, or euploid only), and endometrial preparation protocol (natural or artificial). No publication bias was observed based on Egger's test. LIMITATIONS, REASONS FOR CAUTION: Although the number of included studies is sufficient, data on certain measures, such as EPR, are limited. The inherent bias and residual confounding were also inevitable owing to the observational study design. Furthermore, inconsistent definitions of pregnancy outcomes may affect the accuracy of our pooled analysis. WIDER IMPLICATIONS OF THE FINDINGS: Given the lack of prognostic value, assessing endometrial compaction or repeated EMT measurement on the day of ET may not be necessary or warranted. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Natural Science Foundation of Jiangxi Province (20224BAB216025), National Natural Science Foundation of China (82260315), and Central Funds Guiding the Local Science and Technology Development (20221ZDG020071). The authors have no conflicts of interest to declare. REGISTRATION NUMBER: CRD42022384539 (PROSPERO).
Asunto(s)
Transferencia de Embrión , Endometrio , Resultado del Embarazo , Índice de Embarazo , Humanos , Femenino , Embarazo , Transferencia de Embrión/métodos , Nacimiento VivoRESUMEN
The transcriptional regulation of skeletal muscle (SKM) development (myogenesis) has been documented for over 3 decades and served as a paradigm for tissue-specific cell type determination and differentiation. Myogenic stem cells (MuSC) in embryos and adult SKM are regulated by the transcription factors Pax3 and Pax7 for their stem cell characteristics, while their lineage determination and terminal differentiation are both dictated by the myogenic regulatory factors (MRF) that comprise Mrf4, Myf5, Myogenin, and MyoD. The myocyte enhancer factor Mef2c is activated by MRF during terminal differentiation and collaborates with them to promote myoblast fusion and differentiation. Recent studies have found critical regulation of these myogenic transcription factors at mRNA level, including subcellular localization, stability, and translational regulation. Therefore, the regulation of Pax3/7, MRFs and Mef2c mRNAs by RNA-binding factors and non-coding RNAs (ncRNA), including microRNAs and long non-coding RNAs (lncRNA), will be the focus of this review and the impact of this regulation on myogenesis will be further addressed. Interestingly, the stem cell characteristics of MuSC has been found to be critically regulated by ncRNAs, implying the involvement of ncRNAs in SKM homeostasis and regeneration. Current studies have further identified that some ncRNAs are implicated in the etiology of some SKM diseases and can serve as valuable tools/indicators for prediction of prognosis. The roles of ncRNAs in the MuSC biology and SKM disease etiology will also be discussed in this review.
Asunto(s)
Músculo Esquelético , Proteína MioD , Proteína MioD/genética , Músculo Esquelético/metabolismo , Regulación de la Expresión Génica , Factor de Transcripción PAX3/genética , Factor de Transcripción PAX3/metabolismo , Diferenciación Celular/genética , Desarrollo de Músculos/genéticaRESUMEN
Micro/nanostructured metal surfaces fabricated by laser direct writing (LDW) have been widely used in wettability-related fields. Previous studies focused on the effects of surface structural patterns or chemical composition on wettability, while the coupling mechanism and respective contributions of the two are not distinct. This paper reveals the coupling effect of micro/nanoscale characteristics on the wettability of LDW aluminum surfaces and elucidates the transition mechanism between wetting states on the surfaces with linear laser energy density. Through the contact angle experiments, a wetting state transition of the LDW surface is found from a more hydrophilic than pristine rose petal effect to lotus effect. Based on the bionic analysis method of the superhydrophobicity factors of lotus leaves, the contributions to the wettability of LDW surfaces are divided into the micro/nanoscale characteristics. The theoretical model for identifying the wetting state of a rough surface is proposed. Based on this model, the average Young's contact angle, Î¸Ì Y, is calculated, which indicates the contribution of the nanoscale characteristics. During the transition process from rose petal effect to lotus effect, Î¸Ì Y > 90° is a necessary condition for detachment from the rose petal effect, which is contributed by the high specific surface organic adsorption at the nanoscale. What is more, the wetting state determined by the microscale characteristics further enhances its hydrophobicity, leading to the lotus effect. Based on the wetting state identification model and the Cassie-Baxter equation, the change of micro/nanoscale characteristics on aluminum surfaces after LDW treatment is presented, and the influence of micro/nanoscale characteristics on the wetting state is decoupled and quantified. This research helps to coordinate the effects of surface structure and chemical composition on wettability in the design of specific wettability functional surfaces and can also be applied to other high heat density surface processing fields.
RESUMEN
BACKGROUND: Accumulating evidence has shown that disorders in the gut microbiota and derived metabolites affect the development of atherosclerotic cardiovascular disease (ASCVD). However, which and how specific gut microbial metabolites contribute to the progression of atherosclerosis and the clinical relevance of their alterations remain unclear. METHODS: We performed integrated microbiome-metabolome analysis of 30 patients with coronary artery disease (CAD) and 30 age- and sex-matched healthy controls to identify CAD-associated microbial metabolites, which were then assessed in an independent population of patients with ASCVD and controls (n=256). We further investigate the effect of CAD-associated microbial metabolites on atherosclerosis and the mechanisms of the action. RESULTS: Indole-3-propionic acid (IPA), a solely microbially derived tryptophan metabolite, was the most downregulated metabolite in patients with CAD. Circulating IPA was then shown in an independent population to be associated with risk of prevalent ASCVD and correlated with the ASCVD severity. Dietary IPA supplementation alleviates atherosclerotic plaque development in ApoE-/- mice. In murine- and human-derived macrophages, administration of IPA promoted cholesterol efflux from macrophages to ApoA-I through an undescribed miR-142-5p/ABCA1 (ATP-binding cassette transporter A1) signaling pathway. Further in vivo studies demonstrated that IPA facilitates macrophage reverse cholesterol transport, correlating with the regulation of miR-142-5p/ABCA1 pathway, whereas reduced IPA production contributed to the aberrant overexpression of miR-142-5p in macrophages and accelerated the progression of atherosclerosis. Moreover, the miR-142-5p/ABCA1/reverse cholesterol transport axis in macrophages were dysregulated in patients with CAD, and correlated with the changes in circulating IPA levels. CONCLUSIONS: Our study identify a previously unknown link between specific gut microbiota-derived tryptophan metabolite and ASCVD. The microbial metabolite IPA/miR-142-5p/ABCA1 pathway may represent a promising therapeutic target for ASCVD.
Asunto(s)
Aterosclerosis , Enfermedades Cardiovasculares , MicroARNs , Placa Aterosclerótica , Transportador 1 de Casete de Unión a ATP/genética , Transportador 1 de Casete de Unión a ATP/metabolismo , Animales , Aterosclerosis/metabolismo , Colesterol/metabolismo , Humanos , Indoles/farmacología , Ratones , MicroARNs/metabolismo , Placa Aterosclerótica/metabolismo , Propionatos , TriptófanoRESUMEN
Depression is a major global health issue that urgently requires innovative and precise treatment options. In this context, saikosaponin has emerged as a promising candidate, offering a variety of therapeutic benefits that may be effective in combating depression. This review delves into the multifaceted potential of saikosaponins in alleviating depressive symptoms. We summarized the effects of saikosaponins on structural and functional neuroplasticity, elaborated the regulatory mechanism of saikosaponins in modulating key factors that affect neuroplasticity, such as inflammation, the hypothalamic-pituitary-adrenal (HPA) axis, oxidative stress, and the brain-gut axis. Moreover, this paper highlights existing gaps in current researches and outlines directions for future studies. A detailed plan is provided for the future clinical application of saikosaponins, advocating for more targeted researches to speed up its transition from preclinical trials to clinical practice.
Asunto(s)
Ácido Oleanólico , Ácido Oleanólico/análogos & derivados , Saponinas , Depresión/tratamiento farmacológico , Saponinas/farmacología , Saponinas/uso terapéutico , Ácido Oleanólico/farmacología , Ácido Oleanólico/uso terapéutico , Plasticidad NeuronalRESUMEN
Zeolitic Imidazolate (metal organic) Frameworks (ZIFs) and Prussian Blue Analogues (PBAs) are promising materials in electrochemical sensing due to their unique properties. In this study, a composite material comprising NiFe-PBA and ZIF-67 was synthesized and made to form a uniform layer onto a glassy carbon electrode (GCE) to enhance electrochemical performance for furazolidone (FZD) detection. The synthesized NiFe-PBA/ZIF-67 composite exhibited excellent sensitivity, selectivity, and stability towards FZD detection, with a low limit of detection (LOD). The electrochemical behaviour of FZD on the NiFe-PBA/ZIF-67/GCE electrode was investigated, revealing a diffusion-controlled process. Differential pulse voltammetry (DPV) analysis demonstrated the synergetic effect of the PBA/MOF core-shell structure in enhancing FZD electro-reduction. The sensor exhibited exceptional LOD of 0.007 µM. Selectivity studies confirmed the sensor's ability to distinguish FZD from potential interferents. Extensive evaluations demonstrated the sensor's reproducibility, repeatability, and long-term stability, affirming its practical utility. Real sample analysis further validated the sensor's excellent analytical capabilities in diverse matrices.
RESUMEN
INTRODUCTION: Diabetic kidney disease (DKD) is one of the prominent microvascular complications of diabetes and the leading cause of end-stage renal disease. Inflammation plays a crucial role in the development and progression of DKD. Currently, only a few studies depict the landscape of infiltrating immune cells and their potential regulatory network in DKD. To gain a better understanding of the role of immune cells in the renal microenvironment, we sought to reveal the profile of infiltrating immune cells and their potential regulatory network in DKD. METHODS: We obtained the transcriptomes and the corresponding clinical data of 19 DKD and 25 control samples from the Gene Expression Omnibus and Nephroseq databases, respectively. Thereafter, we conducted an analysis on the infiltrating immune cells and identified immune-related differentially expressed genes through bioinformatics. Finally, correlation analyses among immune cells, immune genes, and clinical manifestations were performed, and differentially infiltrating immune cell subsets were verified through multiplex immunofluorescence staining. RESULTS: We demonstrated the landscape of infiltrating immune cells in patients with DKD and identified the top five hub immune regulatory genes (C3, IL7R, TYROBP, BMP2, and CXCL6). Three of the core genes (C3, BMP2, and CXCL6) were significantly correlated with the estimated glomerular filtration rate. Through multiplex immunofluorescence staining, we verified that macrophage numbers were remarkably elevated, whereas Treg cells were remarkably reduced in diabetic kidney tissues. Th2 cells were scarce in the kidney tissue. CONCLUSION: Collectively, our findings shed light on new, possible therapeutic strategies for DKD, from an immune microenvironment perspective.
Asunto(s)
Diabetes Mellitus , Nefropatías Diabéticas , Fallo Renal Crónico , Humanos , Riñón , Fallo Renal Crónico/metabolismo , Biología Computacional , Tasa de Filtración GlomerularRESUMEN
The high incidence of colorectal cancer (CRC) is closely associated with environmental pollutant exposure. To identify potential intestinal carcinogens, we developed a cell transformation assay (CTA) using mouse adult stem cell-derived intestinal organoids (mASC-IOs) and assessed the transformation potential on 14 representative chemicals, including Cd, iPb, Cr-VI, iAs-III, Zn, Cu, PFOS, BPA, MEHP, AOM, DMH, MNNG, aspirin, and metformin. We optimized the experimental protocol based on cytotoxicity, amplification, and colony formation of chemical-treated mASC-IOs. In addition, we assessed the accuracy of in vitro study and the human tumor relevance through characterizing interdependence between cell-cell and cell-matrix adhesions, tumorigenicity, pathological feature of subcutaneous tumors, and CRC-related molecular signatures. Remarkably, the results of cell transformation in 14 chemicals showed a strong concordance with epidemiological findings (8/10) and in vivo mouse studies (12/14). In addition, we found that the increase in anchorage-independent growth was positively correlated with the tumorigenicity of tested chemicals. Through analyzing the dose-response relationship of anchorage-independent growth by benchmark dose (BMD) modeling, the potent intestinal carcinogens were identified, with their carcinogenic potency ranked from high to low as AOM, Cd, MEHP, Cr-VI, iAs-III, and DMH. Importantly, the activity of chemical-transformed mASC-IOs was associated with the degree of cellular differentiation of subcutaneous tumors, altered transcription of oncogenic genes, and activated pathways related to CRC development, including Apc, Trp53, Kras, Pik3ca, Smad4 genes, as well as WNT and BMP signaling pathways. Taken together, we successfully developed a mASC-IO-based CTA, which might serve as a potential alternative for intestinal carcinogenicity screening of chemicals.
Asunto(s)
Pruebas de Carcinogenicidad , Transformación Celular Neoplásica , Neoplasias Colorrectales , Contaminantes Ambientales , Organoides , Animales , Transformación Celular Neoplásica/inducido químicamente , Transformación Celular Neoplásica/efectos de los fármacos , Pruebas de Carcinogenicidad/métodos , Organoides/efectos de los fármacos , Organoides/patología , Ratones , Contaminantes Ambientales/toxicidad , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/inducido químicamente , Humanos , Carcinógenos/toxicidad , Intestinos/efectos de los fármacos , Intestinos/patología , Neoplasias Intestinales/inducido químicamente , Neoplasias Intestinales/patología , Relación Dosis-Respuesta a DrogaRESUMEN
Daqu is used as the fermentation starter of Baijiu and contributes diversified functional microbes for saccharifying grains and converting sugars into ethanol and aroma components in Baijiu products. Daqu is mainly classified into three types, namely low (LTD), medium (MTD) and high (HTD) temperature Daqu, according to the highest temperatures reached in their fermentation processes. In this study, we used the PacBio small-molecule real-time (SMRT) sequencing technology to determine the full-length 16 S rRNA gene sequences from the metagenomes of 296 samples of different types of Daqu collected from ten provinces in China, and revealed the bacterial diversity at the species level in the Daqu samples. We totally identified 310 bacteria species, including 78 highly abundant species (with a relative abundance >0.1% each) which accounted for 91.90% of the reads from all the Daqu samples. We also recognized the differentially enriched bacterial species in different types of Daqu, and in the Daqu samples with the same type but from different provinces. Specifically, Lactobacillales, Enterobacterales and Bacillaceae were significantly enriched in the LTD, MTD and HTD groups, respectively. The potential co-existence and exclusion relationships among the bacteria species involved in all the Daqu samples and in the LTD, MTD and HTD samples from a specific region were also identified. These results provide a better understanding of the bacterial diversity in different types of Daqu at the species level.
Asunto(s)
Bacterias , Fermentación , ARN Ribosómico 16S , ARN Ribosómico 16S/genética , Bacterias/genética , Bacterias/clasificación , Bacterias/aislamiento & purificación , Bacterias/metabolismo , China , Microbiota , Filogenia , ADN Bacteriano/genética , Biodiversidad , Bebidas Alcohólicas/microbiología , Bebidas Alcohólicas/análisis , Microbiología de Alimentos , Metagenoma , Alimentos Fermentados/microbiologíaRESUMEN
5-hydroxymethyl-2-furfural (5-HMF) is a by-product of Maillard reaction and widely exists in food and environment, which may lead to lung cancer. However, the relevant mechanism is unknown. This study aims to predict the key targets of 5-HMF-induced lung cancer through network toxicology, analyze the relationship between the key targets and lung cancer through network informatics, and further validate them through in vitro experiments. By using ChEMBL, STITCH, GeneCards, and OMIM databases, 51 toxic targets were identified. GO and KEGG enrichment analyses indicated a strong correlation between toxic targets and lung cancer. Through protein-protein interaction (PPI) analysis, MAPK3, MAPK1, and SRC were identified as key targets implicated in 5-HMF-induced lung cancer. The HPA database showed high expression of these three key targets in lung cancer tissues. Kaplan-Meier database demonstrated that the higher expression of these key targets in lung cancer patients was associated with a poorer prognosis. The TIMER database revealed that the high expression of these key targets had a significant impact on the level of immune cell infiltration in lung cancer, particularly impacting CD4+ T cells and macrophages. Finaly, in In vitro experiments demonstrated that prolonged exposure to 5-HMF induced malignant transformation of BEAS-2B cells and the upregulation of key targets. The findings suggest that 5-HMF is a contributing factor in the development of lung cancer, with MAPK3, MAPK1, and SRC potentially playing crucial roles in this process.
RESUMEN
AIM: The chin-down posture is a widely used compensatory manoeuvre for patients with dysphagia. The aim of this study was designed to systematically measure the effectiveness of chin-down manoeuvre application. METHODOLOGY: We retrieved the PubMed, Web of Science, Embase, Cochrane Library, EBSCO, Medline, CNKI, WANFANG, VIP and SinoMed databases from inception to 30 August 2022. Raters independently screened literature according to inclusion and exclusion criteria. The quality of the included literature was evaluated, and data were extracted. The software Review Manager software 5.3 was used for statistical analysis. RESULTS: Fourteen studies with a total of 571 patients were included in this meta-analysis. The meta-analysis indicated that chin-down manoeuvre could significantly reduce the risk of aspiration (MD = -1.35, 95% CI [-2.25, -0.44], Z = 2.92, p < .01), decrease the chin angle (MD = -12.20, 95% CI [-14.61, -9.79], Z = 9.91, p < .001), shorten oral transit time (MD = -0.81, 95% CI [-1.20, -0.43], Z = 4.17, p < .001), reduce the maximum swallowing pressure at upper oesophageal sphincter (MD = -82.07, 95% CI [-112.77, -51.37], Z = 5.24, p < .001) and decrease pharyngeal residue. CONCLUSIONS: Existing evidence indicated that chin-down manoeuvre could reduce the risk of aspiration and pharyngeal residue, decrease the maximum swallowing pressure at UES. More large-sample, high-quality clinical trials are still needed in the future to further ascertain the results of this research.
Asunto(s)
Trastornos de Deglución , Humanos , Trastornos de Deglución/terapia , Mentón , Deglución , Bases de Datos Factuales , Esfínter Esofágico SuperiorRESUMEN
During embryogenesis, basic fibroblast growth factor (bFGF) is released from neural tube and myotome to promote myogenic fate in the somite, and is routinely used for the culture of adult skeletal muscle (SKM) stem cells (MuSC, called satellite cells). However, the mechanism employed by bFGF to promote SKM lineage and MuSC proliferation has not been analyzed in detail. Furthermore, the question of if the post-translational modification (PTM) of bFGF is important to its stemness-promoting effect has not been answered. In this study, GST-bFGF was expressed and purified from E.coli, which lacks the PTM system in eukaryotes. We found that both GST-bFGF and commercially available bFGF activated the Akt-Erk pathway and had strong cell proliferation effect on C2C12 myoblasts and MuSC. GST-bFGF reversibly compromised the myogenesis of C2C12 myoblasts and MuSC, and it increased the expression of Myf5, Pax3/7, and Cyclin D1 but strongly repressed that of MyoD, suggesting the maintenance of myogenic stemness amid repressed MyoD expression. The proliferation effect of GST-bFGF was conserved in C2C12 over-expressed with MyoD (C2C12-tTA-MyoD), implying its independence of the down-regulation of MyoD. In addition, the repressive effect of GST-bFGF on myogenic differentiation was almost totally rescued by the over-expression of MyoD. Together, these evidences suggest that (1) GST-bFGF and bFGF have similar effects on myogenic cell proliferation and differentiation, and (2) GST-bFGF can promote MuSC stemness and proliferation by differentially regulating MRFs and Pax3/7, (3) MyoD repression by GST-bFGF is reversible and independent of the proliferation effect, and (4) GST-bFGF can be a good substitute for bFGF in sustaining MuSC stemness and proliferation.
Asunto(s)
Proliferación Celular , Factor 2 de Crecimiento de Fibroblastos , Desarrollo de Músculos , Proteína MioD , Mioblastos , Desarrollo de Músculos/genética , Animales , Ratones , Proteína MioD/metabolismo , Proteína MioD/genética , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Factor 2 de Crecimiento de Fibroblastos/farmacología , Factor 2 de Crecimiento de Fibroblastos/genética , Mioblastos/metabolismo , Mioblastos/citología , Línea Celular , Factor de Transcripción PAX7/metabolismo , Factor de Transcripción PAX7/genética , Factor de Transcripción PAX3/metabolismo , Factor de Transcripción PAX3/genética , Factor 5 Regulador Miogénico/metabolismo , Factor 5 Regulador Miogénico/genética , Ciclina D1/metabolismo , Ciclina D1/genética , Células Satélite del Músculo Esquelético/metabolismo , Células Satélite del Músculo Esquelético/citología , Diferenciación Celular , Proteínas Proto-Oncogénicas c-akt/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/citologíaRESUMEN
AIMS: Dehydration is one of the common complications of dysphagia and poses significant risks including hospitalization and mortality, but the relationship between dysphagia and dehydration has received little attention. This study aims to determine the prevalence and risk factors for dehydration of patients with dysphagia in eastern China, and to provide reference for early identification and prevention of dehydration. METHODS: A descriptive, cross-sectional design was conducted. Three hundred and thirty-seven (n = 337) patients with dysphagia participated in the study between August and December 2022. Information relating to participants' demographic variables, nutrition, cognition, functional, hydration status and fluid intake was collected. Univariate analysis was used to examine related impact factors, and then binary logistic regression analysis was conducted to determine reliable impact factors. RESULTS: Among 337 patients with dysphagia, the average age was 63.47 ± 16.96, most participants were male (72.1%) and married (91.7%). The prevalence of dehydration was calculated to be 43.9%, the mean plasma osmolality score was 293.53 mmol/L. Diseases with the highest prevalence were stroke (78.3%), followed by hypertension (63.5%). The risk for dehydration increased with older age, usage of more medicines such as diuretics and beta-blockers, worse functional status and lower fluid intake. CONCLUSION: This study found a high percentage of dehydration in patients with dysphagia. Findings can provide a basis for targeted nursing interventions for clinical prevention and treatment of dehydration.
Asunto(s)
Trastornos de Deglución , Deshidratación , Humanos , Trastornos de Deglución/epidemiología , Estudios Transversales , Masculino , Deshidratación/epidemiología , Femenino , China/epidemiología , Persona de Mediana Edad , Factores de Riesgo , Prevalencia , Anciano , Anciano de 80 o más Años , AdultoRESUMEN
PURPOSE: Compared to Shack-Hartmann wavefront sensor (SHWS), the parameters of virtual SHWS (vSHWS) can be easily adjusted to obtain the optimal performance of aberration measurement. Its current optimal parameters are obtained with only a set of statistical aberrations and not statistically significant. Whether the above parameters are consistent with the statistical results of the optimal parameters corresponding to each set of aberrations, and which performance is better if not? The purpose of this study was to answer these questions. METHODS: The optimal parameters to reconstruct 624 sets of clinical ocular aberrations in the highest accuracy, including the numbers of sub-apertures (NSAs) and the expansion ratios (ERs) of electric field zero-padding, were determined sequentially in this work. By using wavefront-reconstruction accuracy as an evaluation index, the statistical optimal parameter configuration was selected from some possible configurations determined by the optimal NSAs and ERs. RESULTS: The statistical optimal parameters are consistent for normal and abnormal eyes. They are different from the optimal parameters obtained with a set of statistical aberrations from the same 624 sets of aberrations, and the performance using the former is better than that using the latter. The performance using a fixed set of statistical optimal parameters is even close to that using the respective optimal parameters corresponding to each set of aberrations. CONCLUSION: The vSHWS configured with a fixed set of statistical optimal parameters can be used for high-precision aberration measurement of both normal and abnormal eyes. The statistical optimal parameters are more suitable for vSHWS than the parameters obtained with a set of statistical aberrations. These conclusions are significant for the designs of vSHWS and also SHWS.
Asunto(s)
Aberración de Frente de Onda Corneal , Humanos , Aberración de Frente de Onda Corneal/diagnóstico , Aberración de Frente de Onda Corneal/fisiopatología , Topografía de la Córnea/métodos , Aberrometría/métodos , Refracción Ocular/fisiología , Agudeza Visual/fisiologíaRESUMEN
BACKGROUND & AIMS: While it is recognized that non-alcoholic fatty liver disease (NAFLD) is associated with cardiovascular disease (CVD), how NAFLD affects the development and progression of CVD remains unclear and debatable. Hence, we aimed to determine the role of steatotic hepatocyte-derived small extracellular vesicles (sEVs) in foam cell formation and atherosclerosis progression. METHODS: sEVs from steatotic hepatocytes were isolated and characterized. MicroRNA (miRNA) deep sequencing was utilized to identify functional miRNA in sEVs. Lastly, we conducted a cross-sectional study on patients with NAFLD to validate these findings. RESULTS: Treatment of sEVs from steatotic hepatocytes promoted macrophage-derived foam cell formation and atherosclerosis progression via inhibition of ABCA1-mediated cholesterol efflux. Macrophage-specific deletion of Abca1 in ApoE-/- mice abolished the role of steatotic hepatocyte-derived sEVs in atherosclerosis progression. In addition, hepatocyte-specific deletion of Rab27a, which is the key GTPase regulating sEV release, significantly ameliorated high-fat, high-cholesterol diet-induced atherosclerosis progression in ApoE-/- mice. The miRNA deep sequencing results showed that miR-30a-3p was enriched in sEVs from steatotic hepatocytes. miR-30a-3p directly targeted the 3' untranslated region of ABCA1 to inhibit ABCA1 expression and cholesterol efflux. Treatment with antagomiR-30a-3p significantly attenuated atherosclerosis progression in high-fat, high-cholesterol diet-fed ApoE-/- mice. Moreover, serum sEVs from patients with NAFLD and sEV-miR-30a-3p expression were associated with decreased cholesterol efflux levels in foam cells. CONCLUSION: Steatotic hepatocyte-derived sEVs promote foam cell formation and facilitate atherogenesis via the miR-30a-3p/ABCA1 axis. Reducing sEV secretion by steatotic hepatocytes or targeting miR-30a-3p may be potential therapeutic approaches to slow the progression of NAFLD-driven atherosclerosis. IMPACT AND IMPLICATIONS: The presence of hepatic steatosis is strongly correlated with the risk of cardiovascular disease and cardiovascular events, yet the molecular mechanisms linking steatosis to progression of atherosclerosis are unclear. Herein, we identified small extracellular vesicles from steatotic hepatocytes as a trigger that accelerated the progression of atherosclerosis. Steatotic hepatocyte-derived small extracellular vesicles promoted foam cell formation via the miR-30a-3p/ABCA1 axis. Our findings not only provide mechanistic insight into non-alcoholic fatty liver disease-driven atherosclerosis but also provide potential therapeutic targets for patients with atherosclerosis.
Asunto(s)
Aterosclerosis , Enfermedades Cardiovasculares , Vesículas Extracelulares , MicroARNs , Enfermedad del Hígado Graso no Alcohólico , Humanos , Animales , Ratones , Enfermedad del Hígado Graso no Alcohólico/etiología , Estudios Transversales , Aterosclerosis/etiología , Aterosclerosis/metabolismo , MicroARNs/metabolismo , Colesterol/metabolismo , Vesículas Extracelulares/metabolismo , Apolipoproteínas E/genéticaRESUMEN
An electrocatalyst with a large active site is critical for the development of a high-performance electrochemical sensor. This work demonstrates the fabrication of an iron diselenide (FeSe2)-modified screen-printed carbon electrode (SPCE) for the electrochemical determination of furaltadone (FLD). It has been prepared by the facile method and systematically characterized with various microscopic/spectroscopic approaches. Due to advantageous physiochemical properties, the FeSe2/SPCE showed a low charge-transfer resistance value of 200 Ω in 5.0 mM [Fe(CN)6]3-/4- containing 0.1 M KCl. More importantly, the FeSe2/SPCE exhibited superior catalytic performance compared to the bare SPCE for FLD sensing based on the electrochemical response in terms of a peak potential of -0.44 V (vs Ag/AgCl (sat. KCl)) and cathodic response current of -22.8 µA. Operating at optimal conditions, the FeSe2-modified electrode showed wide linearity from 0.01 to 252.2 µM with a limit of detection of 0.002 µM and sensitivity of 1.15 µA µM-1 cm-2. The analytical performance of the FeSe2-based platform is significantly higher than many previously reported FLD electrochemical sensors. Furthermore, the FeSe2/SPCE also has a promising platform for FLD detection with high sensitivity, good selectivity, excellent stability, and robust reproducibility. Thus, the finding above shows that the FeSe2/SPCE is a highly suitable candidate for the electrochemical determination of glucose levels for real-time applications such as in human urine and river water samples.