RESUMEN

This study investigates the enhancement of ozone adsorption on diverse TiO2 crystal interfaces through an innovative electrochemical modulation approach. The research focuses on the effects of applied electric field strength and reaction sites on ozone interfacial adsorption energies for Ti/Anatase TiO2 (0 0 1) and Ti/Rutile TiO2 (1 1 0) interfaces. The findings reveal that positive electric fields significantly enhance ozone adsorption on both interfaces, with adsorption energies increasing by up to 18% for Ti/Anatase TiO2 (0 0 1) and 15% for Ti/Rutile TiO2 (1 1 0). Notably, double water molecule sites (≡(H2O)2) play a crucial role in this enhancement process. The study demonstrates that the applied electric field alters the charge distribution at the TiO2 catalytic interface, thereby increasing interfacial charge density and promoting charge migration to ozone. Furthermore, this process leads to enhanced overlap and hybridization between ≡(H2O)2 sites and the s and p orbitals of ozone molecules, resulting in the formation of chemical bonds with lower Fermi levels. These comprehensive results demonstrate the broad applicability of the electrochemical interfacial ozone adsorption enhancement method across different crystal types and surfaces. Consequently, this study provides essential data to support the advancement of greener and more energy-efficient heterogeneous catalytic ozonation processes, potentially contributing to significant improvements in ozone-based water treatment technologies.

RESUMEN

Reversibility of metallic Zn anode serves as the corner stone for the development of aqueous Zn metal battery, which motivates scrutinizing the electrolyte-Zn interface. As the representative organic zinc salt, zinc trifluorosulfonate (Zn(OTf)2) facilitates a broad class of aqueous electrolytes, however, the stability issue of Zn anode remains crucial. The great challenge lies in the lack of Zn anode protection by the pristinely formed surface structure in aqueous Zn(OTf)2 electrolytes. Accordingly, an electrochemical route was developed to grow a uniform zinc trifluorosulfonate hydroxide (ZTH) layer on Zn anode as an artificial SEI, via regulation on metal dissolution and strong coordination ability of zinc ions. Co-precipitation was proposed to be the formation mechanism for the artificial SEI, where the reduction stability of OTf‾ anion and the low-symmetry layer structure of ZTH was unmasked. This artificial SEI favors interfacial kinetics, depresses side reactions, and well maintains its integrity during cycling, leading to a prolonged lifespan of Zn stripping/plating with a high DOD of ~85%, and an improved cycling stability of ~92% retention rate for V2O5/Zn cell at 1 A g-1. The unveiled role of anion on Zn anode drives the contemplation on the surface chemistry for the blooming aqueous rechargeable battery.

RESUMEN

Calcineurin is a serine/threonine protein phosphatase that is highly conserved from yeast to human and plays a critical role in many physiological processes. Regulators of calcineurin (RCANs) are a family of endogenous calcineurin regulators, which are capable of inhibiting the catalytic activity of calcineurin in vivo and in vitro. In this study, we first characterized the biochemical properties of yeast calcineurin and its endogenous regulator Rcn1, a yeast homolog of RCAN1. Our data show that Rcn1 inhibits yeast calcineurin toward pNPP substrate with a noncompetitive mode; and Rcn1 binds cooperatively to yeast calcineurin through multiple low-affinity interactions at several docking regions. Next, we reinvestigated the mechanism underlying the inhibition of mammalian calcineurin by RCAN1 using a combination of biochemical, biophysical, and computational methods. In contrast to previous observations, RCAN1 noncompetitively inhibits calcineurin phosphatase activity toward both pNPP and phospho-RII peptide substrates by targeting the enzyme active site in part. Re-analysis of previously reported kinetic data reveals that the RCAN1 concentrations used were too low to distinguish between the inhibition mechanisms [Chan B et al. (2005) Proc Natl Acad Sci USA 102, 13075]. The results presented in this study provide new insights into the interaction between calcineurin and RCAN1/Rcn1.

RESUMEN

Nerve invasion (NI) is a characteristic feature of pancreatic cancer. Traditional dichotomous statements on the presence of NI are unreasonable because almost all cases exhibit NI when sufficient pathological sections are examined. The critical implications of NI in pancreatic cancer highlight the need for a more effective criterion. This study included 511 patients, who were categorized into a training group and a testing group at a ratio of 7:3. According to the traditional definition, NI was observed in 91.2 % of patients using five pathological slides in our study. The prevalence of NI increased as more pathological slides were used. The criterion of 'two points of intraneural (endoneural) invasion in the case of four pathological slides' has the highest receiver operating characteristic (ROC) score. Based on this new criterion, NI was proved to be an independent prognostic factor for overall survival (OS) and disease-free survival (DFS) and was also correlated with tumor recurrence (P = 0.004). Interestingly, gemcitabine-based chemotherapy regimen is an independent favorable factor for patients with high NI. In the high NI group, patients who received a gemcitabine-based regimen exhibited a better prognosis than those who did not receive the gemcitabine-based regimen for OS (P = 0.000) and DFS (P = 0.001). In conclusion, this study establishes assessment criteria to evaluate the severity of NI in order to predict patient outcomes.

Asunto(s)

Invasividad Neoplásica , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/cirugía , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Adulto , Supervivencia sin Enfermedad , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Gemcitabina , Curva ROC , Anciano de 80 o más Años , Pronóstico

RESUMEN

The anti-inflammatory effects of plant polysaccharides are well known. However, the stimulatory effects of polysaccharides under immunosuppressive conditions and their link with the polysaccharide structure is underexplored. In this work, the immune modulatory effects of a garlic polysaccharide (GP) are investigated via in vitro and vivo methods. It is observed that GP enhance the immune response of macrophages (RAW264.7) as indicated by the elevated levels of nitric oxide, TNF-α and IL-6. The observation that GP are able to stimulate the immune response in vitro was then explored with the use of an immunosuppressed mouse model. Surprisingly, GP exhibited dose-dependent up-regulatory impacts on the cyclophosphamide (CTX) suppressed levels of cytokines such as IFN-γ and IL-6 and immunoglobulins (e.g. IgA and IgG). The GP intervention reversed histopathological damage to the small intestine and spleen and increased fecal short-chain fatty acid levels. Moreover, GP modulates the gut microbiota dysbiosis by increasing the abundance of immunogenic bacteria such as g__norank_f__Erysipelotrichaceae, while inhibiting the over-abundance of g_Bacteroides. Functional predictions indicated that gut biomarkers of GP possessed the functions of glycoside hydrolase family 32 (GH32) and ß-fructofuranosidase. It is concluded that GP is a promising immunostimulant for immune-compromised individuals.

Asunto(s)

Ajo , Macrófagos , Polisacáridos , Animales , Ratones , Ajo/química , Células RAW 264.7 , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Polisacáridos/farmacología , Polisacáridos/química , Fructanos/farmacología , Fructanos/química , Ciclofosfamida/farmacología , Inmunosupresores/farmacología , Inmunosupresores/química , Citocinas/metabolismo , Microbioma Gastrointestinal/efectos de los fármacos , Masculino , Óxido Nítrico/metabolismo , Ratones Endogámicos BALB C , Regulación hacia Arriba/efectos de los fármacos

RESUMEN

OBJECTIVE: Colorectal cancer (CRC), specifically colon adenocarcinoma, is the third most prevalent and the second most lethal form of cancer. Anoikis is found to be specialized form of programmed cell death (PCD), which plays a pivotal role in tumor progression. This study aimed to investigate the role of the anoikis related genes (ARGs) in colon cancer. METHODS: Consensus unsupervised clustering, differential expression analysis, tumor mutational burden analysis, and analysis of immune cell infiltration were utilized in the study. For the analysis of RNA sequences and clinical data of COAD patients, data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) were obtained. A prognostic scoring system for overall survival (OS) prediction was developed using Cox regression and LASSO regression analysis. Furthermore, loss-of-function assay was utilized to explore the role of RAD9A played in the progression of colon cancer. RESULTS: The prognostic value of a risk score composed of NTRK2, EPHA2, RAD9A, CDC25C, and SNAI1 genes was significant. Furthermore, these findings suggested potential mechanisms that may influence prognosis, supporting the development of individualized treatment plans and management of patient outcomes. Further experiments confirmed that RAD9A could promote proliferation and metastasis of colon cancer cells. These effects may be achieved by affecting the phosphorylation of AKT. CONCLUSION: Differences in survival time and the tumor immune microenvironment (TIME) were observed between two gene clusters associated with ARGs. In addition, a prognostic risk model was established and confirmed as an independent risk factor. Furthermore, our data indicated that RAD9A promoted tumorigenicityby activating AKT in colon cancer.

Asunto(s)

Anoicis , Neoplasias del Colon , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias del Colon/genética , Neoplasias del Colon/mortalidad , Neoplasias del Colon/patología , Neoplasias del Colon/inmunología , Anoicis/genética , Pronóstico , Línea Celular Tumoral , Masculino , Proliferación Celular , Animales , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Femenino

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) features substantial matrix stiffening and reprogrammed glucose metabolism, particularly the Warburg effect. However, the complex interplay between these traits and their impact on tumor advancement remains inadequately explored. Here, we integrated clinical, cellular, and bioinformatics approaches to explore the connection between matrix stiffness and the Warburg effect in PDAC, identifying CLIC1 as a key mediator. Elevated CLIC1 expression, induced by matrix stiffness through Wnt/ß-catenin/TCF4 signaling, signifies poorer prognostic outcomes in PDAC. Functionally, CLIC1 serves as a catalyst for glycolytic metabolism, propelling tumor proliferation. Mechanistically, CLIC1 fortifies HIF1α stability by curbing hydroxylation via reactive oxygen species (ROS). Collectively, PDAC cells elevate CLIC1 levels in a matrix-stiffness-responsive manner, bolstering the Warburg effect to drive tumor growth via ROS/HIF1α signaling. Our insights highlight opportunities for targeted therapies that concurrently address matrix properties and metabolic rewiring, with CLIC1 emerging as a promising intervention point.

Asunto(s)

Carcinoma Ductal Pancreático , Proliferación Celular , Canales de Cloruro , Subunidad alfa del Factor 1 Inducible por Hipoxia , Neoplasias Pancreáticas , Efecto Warburg en Oncología , Humanos , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Canales de Cloruro/metabolismo , Canales de Cloruro/genética , Línea Celular Tumoral , Animales , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Ratones , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/genética , Especies Reactivas de Oxígeno/metabolismo , Glucólisis , Ratones Desnudos , Matriz Extracelular/metabolismo , Regulación Neoplásica de la Expresión Génica

RESUMEN

Long noncoding RNAs (lncRNAs) are strongly associated with glucose homeostasis, but their roles remain largely unknown. In this study, the potential role of lncRNA-Snhg3 in glucose metabolism was evaluated both in vitro and in vivo. Here, we found a positive relationship between Snhg3 and hepatic glycogenesis. Glucose tolerance improved in hepatocyte-specific Snhg3 knock-in (Snhg3-HKI) mice, while it worsened in hepatocyte-specific Snhg3 knockout (Snhg3-HKO) mice. Furthermore, hepatic glycogenesis had shown remarkable increase in Snhg3-HKI mice and reduction in Snhg3-HKO mice, respectively. Mechanistically, Snhg3 increased mRNA and protein expression levels of PPP1R3B through inducing chromatin remodeling and promoting the phosphorylation of protein kinase B. Collectively, these results suggested that lncRNA-Snhg3 plays a critical role in hepatic glycogenesis.

Asunto(s)

Hígado , ARN Largo no Codificante , Animales , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Ratones , Hígado/metabolismo , Ratones Noqueados , Glucosa/metabolismo , Masculino , Hepatocitos/metabolismo , Ratones Endogámicos C57BL , Glucógeno Hepático/metabolismo

RESUMEN

Carbapenems and colistin are vital antimicrobials used to treat Enterobacteriaceae-caused infections. The present study aimed to characterize the coexistence mechanism of carbapenem and colistin resistance in an Escherichia coli isolated from retail chicken meat. A total of 4 E. coli isolates co-harboring carbapenem resistance gene blaNDM (2 E. coli isolates with blaNDM-5 and 2 with blaNDM-9) and colistin resistance gene mcr-1. Antimicrobial susceptibility testing exhibited that all the 4 E. coli strains had multidrug resistance profile and consistent with the resistance genes they carried. MLST showed that 3 E. coli isolates belonged to a pathogenic E. coli lineage ST354, which is closely associated with human infections and pose a serious threat to public health. Whole genome sequencing (WGS) showed that 4 mcr-1-positive plasmids with sizes of 60.4 kb to 67.4 kb all belonged to the IncI2 type. A total of 5 blaNDM-harboring plasmids ranged from 99.0 kb to 138.3 kb, among which 4 plasmids belonged to unknow type and only pCS5L-NDM belonged to IncFIA/IncFIB group of hybrid plasmids, a novel carrier for blaNDM. Comparative analysis exhibited that the mcr-1 or blaNDM-carrying plasmids of E. coli strains from chicken meat showed high identity with that from Enterobacteriaceae of human origin, which indicated the risk of mcr-1 or blaNDM dissemination from retail meat to human. The simultaneous occurrence of mcr-1 and blaNDM in E. coli emphasizes the significant of antimicrobial resistance surveillance in retail meat.

RESUMEN

Nitrogen oxides are inevitable hazardous components in coal-fired flue gas. This study designed a series of experiments and combined theoretical calculations to systematically investigate the effect of NOx on the removal of element mercury (Hg0) by nano-amorphous selenium (nano-a-Se). It was found that the impact of NOx on the removal of Hg0 by nano-a-Se primarily involves two mechanisms: competitive adsorption between NOx and Hg0, and the induced reduction effect of NOx on chemisorbed mercury (HgSe). NO inhibits the removal of Hg0 by nano-a-Se, and competitive adsorption is identified as the main influencing factor. Whereas the inhibitory effect of NO2 on the adsorption of Hg0 by nano a-Se can be counteracted due to its oxidizing effect on Hg0. Therefore, although NO2 presents stronger competitiveness than NO in the competitive adsorption with Hg0, it still shows a promoting effect on Hg0 removal, with 50 ppm NO2 restoring 5.7 % of the Hg0 removal efficiency. Additionally, the mechanism of NOx-induced reduction of HgSe was investigated in detail. NO2 is more capable of inducing the reduction of Hg(II) from HgSe to Hg0. This study presents new insights into the underlying influence mechanism, which could provide valuable references for the application of other selenium-based adsorbents.

RESUMEN

BACKGROUND: The impact of acrylamide (ACR) on learning and memory has garnered considerable attention. However, the targets and mechanisms are still unclear. RESULTS: Elongation factor 2 (eEF2) was significantly upregulated in the results of serum proteomics. Results from in vitro and in vivo experiments indicated a notable upregulation of Eukaryotic elongation factor 2 kinase (eEF2K), the sole kinase responsible for eEF2 phosphorylation, following exposure to ACR (P < 0.05). Subsequent in vitro experiments using eEF2K siRNA and in vivo experiments with eEF2K-knockout mice demonstrated significant improvements in abnormal indicators related to ACR-induced learning and memory deficits (P < 0.05). Proteomic analysis of the hippocampus revealed Lpcat1 as a crucial downstream protein regulated by eEF2K. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses indicated that eEF2K may play a role in the process of ACR-induced learning and memory impairment by affecting ether lipid metabolism. CONCLUSIONS: In summary, eEF2K as a pivotal treatment target in the mechanisms underlying ACR-induced learning and memory impairment, and studies have shown that it provides robust evidence for potential clinical interventions targeting ACR-induced impairments.

RESUMEN

BACKGROUND: As a medicinal and food homologous plant, Rosa damascena is not only highly ornamental, but also rich in a variety of active ingredients such as polyphenols and flavonoids. It is widely used in cosmetics, food and pharmaceutical industries. OBJECTIVE: To study the in vitro efficacy of Rosa damascena solid state fermentation liquid (RDF) and water extract (RDE). METHODS: Firstly, the effect of RDF and RDE on the proliferation rate of B16F10 cells was detected by CCK-8 method, and the melanin content was measured by sodium hydroxide lysis method to evaluate the whitening effect of them. Finally, the antioxidant, anti-wrinkling and soothing effects of RDF and RDE were evaluated by biochemical methods in vitro. RESULTS: RDF and RDE within a certain concentration range (0.05%-0.5%) had no effect on the proliferation of B16F10 cells. Compared with Rosa damascena extract (RDE), RDF showed significant effects on bleaching, antioxidant, anti-wrinkling and soothing, among which 0.5% RDF showed the best effect. CONCLUSION: Both RDF and RDE at a certain concentration have effect on skin care in vitro, but the effect of RDF is more significant than that of RDE.

Asunto(s)

Antioxidantes , Proliferación Celular , Fermentación , Extractos Vegetales , Rosa , Rosa/química , Extractos Vegetales/farmacología , Ratones , Animales , Proliferación Celular/efectos de los fármacos , Antioxidantes/farmacología , Cuidados de la Piel/métodos , Agua/química , Envejecimiento de la Piel/efectos de los fármacos , Melaninas , Línea Celular Tumoral , Humanos , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/patología

RESUMEN

Water-soluble fluorescent chemosensors for lead ion are highly desirable in environmental detection and bioimagery. Based on a water-soluble pillar[5]arene WP5 and imidazolium terminal functionalized 2,2'-bibenzimidazole derivative BIHB, we report a host-guest charge transfer assembly BIHB-2WP5 for sensitive and selective detection of Pb2+ in pure aqueous media. As a result of its high electron-rich cavity, WP5 can bind electron-deficiency guest BIHB with various host/guest stoichiometry to easily tune the microtopography of assembly from nanoparticle to nanocube. In view of the good biocompatibility and sensitivity, the supramolecular assembly BIHB-2WP5 was used as a fluorescent probe for the detection of Pb2+ in living cells and a smartphone Pb2+ detection device was constructed for the in situ test.

RESUMEN

Increasing evidence has demonstrated that oxidative phosphorylation (OXPHOS) is closely associated with the progression of pancreatic cancer (PC). Given its central role in mitochondrial transcription, the human mitochondrial RNA polymerase (POLRMT) is a promising target for developing PC treatments. Herein, structure-activity relationship exploration led to the identification of compound S7, which was the first reported POLRMT inhibitor possessing single-digit nanomolar potency of inhibiting PC cells proliferation. Mechanistic studies showed that compound S7 exerted antiproliferative effects without affecting the cell cycle, apoptosis, mitochondrial membrane potential (MMP), or intracellular reactive oxygen species (ROS) levels specifically in MIA PaCa-2 cells. Notably, compound S7 inhibited tumor growth in MIA PaCa-2 xenograft tumor model with a tumor growth inhibition (TGI) rate of 64.52% demonstrating significant improvement compared to the positive control (44.80%). In conclusion, this work enriched SARs of POLRMT inhibitors, and compound S7 deserved further investigations of drug-likeness as a candidate for PC treatment.

Asunto(s)

Antineoplásicos , Proliferación Celular , Cumarinas , ARN Polimerasas Dirigidas por ADN , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Animales , Relación Estructura-Actividad , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Cumarinas/farmacología , Cumarinas/química , Cumarinas/síntesis química , Cumarinas/uso terapéutico , Proliferación Celular/efectos de los fármacos , ARN Polimerasas Dirigidas por ADN/antagonistas & inhibidores , ARN Polimerasas Dirigidas por ADN/metabolismo , Línea Celular Tumoral , Ratones , Ratones Desnudos , Flúor/química , Apoptosis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/uso terapéutico , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones Endogámicos BALB C , Ensayos de Selección de Medicamentos Antitumorales

RESUMEN

Volatile-char interaction is an important phenomenon in biomass thermal conversion process, which significantly contributes to the decomposition, deoxygenation and upgrading of biomass. However, the deep insight into volatile-char interaction mechanisms between hemicellulose, cellulose and lignin is currently unclear. In this work, above mechanism was studied through systematic single-/bi-component torrefactions and the follow-up char analysis. Results demonstrate that only hemicellulose volatile and cellulose char interaction exists during torrefaction at 250 °C, causing over 19.9 wt% of mass loss and 27.3 wt% of O removal for cellulose. This volatile-char interaction causes significant depolymerization and amorphization of cellulose by hydrolysis, acid hydrolysis and esterification reactions. The depolymerized and amorphous cellulose partly thermally decomposes to dehydrated sugars and aromatic compounds through dehydroxylation and aromatization reactions. A volatile-char interaction mechanism model is thus developed. This work provides theoretical insight into biomass thermal conversion and provides basis for the development of new thermochemical method.

Asunto(s)

Biomasa , Celulosa , Celulosa/química , Celulosa/metabolismo , Hidrólisis , Carbón Orgánico/química , Polisacáridos/metabolismo , Polisacáridos/química , Lignina/química , Lignina/metabolismo , Compuestos Orgánicos Volátiles/metabolismo , Volatilización

RESUMEN

PURPOSE: Patients in the intensive care unit (ICU) commonly receive stress ulcer prophylaxis drugs, either proton pump inhibitors (PPIs) or histamine-2 receptor blockers (H2RBs). The goal of this research was to evaluate the impact of these drugs on mortality among ICU patients hospitalized for major adverse cardiovascular and cerebrovascular events (MACCEs). METHODS: ICU patients hospitalized for MACCEs were sourced from the Medical Information Mart for Intensive Care-III database. We performed a propensity score matching analysis to match patients treated with PPIs to those treated with H2RBs for stress ulcer prophylaxis. The outcome was 90-day mortality. We used multivariable Cox regression analyses to compare the effect. Hazard ratio (HR), 95% CIs, and P values were reported from the model. FINDINGS: From 2001 to 2012, a total of 3577 patients hospitalized for MACCEs (1997 received PPIs and 1580 received H2RBs) were admitted. The 90-day mortality was 23.7% (848/3577); it was 27% (540/1997) and 19.5% (308/1580) for PPIs and H2RBs users, respectively. The PPI group exhibited a greater 90­day mortality in comparison to the H2RBs group (relative risk = 1.17; P = 0.036), after conditioning on potential confounder. The results remained robust in propensity score matching, sensitivity analyses, and subgroup analyses. IMPLICATIONS: PPIs for stress ulcer prophylaxis were linked to an increased risk of in-hospital mortality than H2RBs in patients hospitalized for MACCEs. Further investigation of this association and validation of its clinical significance is needed.

Asunto(s)

Enfermedades Cardiovasculares , Trastornos Cerebrovasculares , Antagonistas de los Receptores H2 de la Histamina , Mortalidad Hospitalaria , Unidades de Cuidados Intensivos , Inhibidores de la Bomba de Protones , Humanos , Inhibidores de la Bomba de Protones/uso terapéutico , Inhibidores de la Bomba de Protones/administración & dosificación , Inhibidores de la Bomba de Protones/efectos adversos , Masculino , Antagonistas de los Receptores H2 de la Histamina/uso terapéutico , Antagonistas de los Receptores H2 de la Histamina/efectos adversos , Femenino , Estudios Retrospectivos , Unidades de Cuidados Intensivos/estadística & datos numéricos , Anciano , Persona de Mediana Edad , Trastornos Cerebrovasculares/mortalidad , Trastornos Cerebrovasculares/prevención & control , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/prevención & control , Úlcera Péptica/prevención & control , Úlcera Péptica/mortalidad , Puntaje de Propensión , Anciano de 80 o más Años

RESUMEN

Herein, a series of novel arylpiperazine (piperidine) derivatives were designed, synthesized, and evaluated for mechanisms of action through in vitro and in vivo studies. The most promising compound, II-13 (later named as MT-1207), is a potent α1 and 5-HT2A receptor antagonist with remarkable IC50 in the picomolar level. Importantly, in the in vivo assay, II-13 achieved an effective blood pressure (BP) reduction in the 2K2C rat model without damaging renal function. Compound II-13, with its significant advantages in terms of pharmacological effects, pharmacokinetic parameters, and a large safety window, was extensively investigated. Moreover, data also showed that compound II-13 had fewer side effects in a postural BP assay and could prevent the onset of postural hypotension. Together, these results suggested that compound II-13 is a highly potent antihypertensive drug candidate with multitarget mechanisms of action in preclinical models. Currently, MT-1207 is in phase II hypertensive clinical trials in China.

RESUMEN

BACKGROUND: Managing non-functioning pituitary adenomas (NFPAs) is difficult due to limited drug treatments. Cabergoline's (CAB) effectiveness for NFPAs is debated. This study explores the role of HTR2B in NFPAs and its therapeutic potential. METHODS: We conducted screening of bulk RNA-sequencing data to analyze HTR2B expression levels in NFPA samples. In vitro and in vivo experiments were performed to evaluate the effects of HTR2B modulation on tumor growth and cell cycle regulation. Mechanistic insights into the HTR2B-mediated signaling pathway were elucidated using pharmacological inhibitors and molecular interaction assays. RESULTS: Elevated HTR2B expression was detected in NFPA samples, which was associated with increased tumor survival. Inhibition of HTR2B activity resulted in the suppression of tumor growth through modulation of the G2M cell cycle. The inhibition of HTR2B with PRX-08066 was found to block STAT3 phosphorylation and nuclear translocation by interfering with the Gαq/PLC/PKC pathway. A direct interaction between PKC-γ and STAT3 was critical for STAT3 activation. CAB was shown to activate pSTAT3 via HTR2B, reducing its therapeutic potential. However, the combination of an HTR2B antagonist with CAB significantly inhibited tumor cell proliferation in HTR2B-expressing pituitary tumor cell lines, a xenografted pituitary tumor model, and patient-derived samples. Analysis of patient-derived data indicated that a distinct molecular pattern characterized by upregulated HTR2B/PKC-γ and downregulated BTG2/GADD45A may benefit from combination treatment with CAB and PRX-08066. CONCLUSIONS: HTR2B is a potential therapeutic target for NFPAs, and its inhibition could improve CAB efficacy. A dual therapy approach may be beneficial for NFPA patients with high HTR2B expression.

RESUMEN

OBJECTIVES: Aggressive driving behavior can lead to potential traffic collision risks, and abnormal weather conditions can exacerbate this behavior. This study aims to develop recognition models for aggressive driving under various climate conditions, addressing the challenge of collecting sufficient data in abnormal weather. METHODS: Driving data was collected in a virtual environment using a driving simulator under both normal and abnormal weather conditions. A model was trained on data from normal weather (source domain) and then transferred to foggy and rainy weather conditions (target domains) for retraining and fine-tuning. The K-means algorithm clustered driving behavior instances into three styles: aggressive, normal, and cautious. These clusters were used as labels for each instance in training a CNN model. The pre-trained CNN model was then transferred and fine-tuned for abnormal weather conditions. RESULTS: The transferred models showed improved recognition performance, achieving an accuracy score of 0.81 in both foggy and rainy weather conditions. This surpassed the non-transferred models' accuracy scores of 0.72 and 0.69, respectively. CONCLUSIONS: The study demonstrates the significant application value of transfer learning in recognizing aggressive driving behaviors with limited data. It also highlights the feasibility of using this approach to address the challenges of driving behavior recognition under abnormal weather conditions.

RESUMEN

Background: Ginsenoside Rg1 (Rg1) is one of the main active components in Chinese medicines, Panax ginseng and Panax notoginseng. Research has shown that Rg1 has a protective effect on the cardiovascular system, including anti-myocardial ischemia-reperfusion injury, anti-apoptosis, and promotion of myocardial angiogenesis, suggesting it a potential cardiovascular agent. However, the protective mechanism involved is still not fully understood. Methods: Based on network pharmacology, ligand-based protein docking, proteomics, Western blot, protein recombination and spectroscopic analysis (UV-Vis and fluorescence spectra) techniques, potential targets and pathways for Rg1 against myocardial ischemia (MI) were screened and explored. Results: An important target set containing 19 proteins was constructed. Two target proteins with more favorable binding activity for Rg1 against MI were further identified by molecular docking, including mitogen-activated protein kinase 1 (MAPK1) and adenosine kinase (ADK). Meanwhile, Rg1 intervention on H9c2 cells injured by H2O2 showed an inhibitory oxidative phosphorylation (OXPHOS) pathway. The inhibition of Rg1 on MAPK1 and OXPHOS pathway was confirmed by Western blot assay. By protein recombination and spectroscopic analysis, the binding reaction between ADK and Rg1 was also evaluated. Conclusion: Rg1 can effectively alleviate cardiomyocytes oxidative stress injury via targeting MAPK1 and ADK, and inhibiting oxidative phosphorylation (OXPHOS) pathway. The present study provides scientific basis for the clinical application of the natural active ingredient, Rg1, and also gives rise to a methodological reference to the searching of action targets and pathways of other natural active ingredients.