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1.
Sci Rep ; 14(1): 13206, 2024 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-38851806

RESUMO

Chronic obstructive pulmonary disease (COPD) is often associated with lung squamous cell carcinoma (LUSC), which has the same etiology (smoking, inflammation, oxidative stress, microenvironmental changes, and genetics). Smoking, inflammation, and airway remodeling are the most important and classical mechanisms of COPD comorbidity in LUSC patients. Cancer can occur during repeated airway damage and repair (airway remodeling). Changes in the inflammatory and immune microenvironments, which can cause malignant transformation of some cells, are currently being revealed in both LUSC and COPD patients. We obtained the GSE76925 dataset from the Gene Expression Omnibus database. Screening for possible COPD biomarkers was performed using the LASSO regression model and a random forest classifier. The compositional patterns of the immune cell fraction in COPD patients were determined using CIBERSORT. HTR2B expression was analyzed using validation datasets (GSE47460, GSE106986, and GSE1650). HTR2B expression in COPD cell models was determined via real-time quantitative PCR. Epithelial-mesenchymal transition (EMT) marker expression levels were determined after knocking down or overexpressing HTR2B. HTR2B function and mechanism in LUSC were analyzed with the Kaplan‒Meier plotter database. HTR2B expression was inhibited to detect changes in LUSC cell proliferation. A total of 1082 differentially expressed genes (DEGs) were identified in the GSE76925 dataset (371 genes were significantly upregulated, and 711 genes were significantly downregulated). Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis indicated that the DEGs were mainly enriched in the p53 signaling and ß-alanine metabolism pathways. Gene Ontology enrichment analysis indicated that the DEGs were largely related to transcription initiation from the RNA polymerase I promoter and to the regulation of mononuclear cell proliferation. The LASSO regression model and random forest classifier results revealed that HTR2B, DPYS, FRY, and CD19 were key COPD genes. Immune cell infiltration analysis indicated that these genes were closely associated with immune cells. Analysis of the validation sets suggested that HTR2B was upregulated in COPD patients. HTR2B was significantly upregulated in COPD cell models, and its upregulation was associated with increased EMT marker expression. Compared with that in bronchial epithelial cells, HTR2B expression was upregulated in LUSC cells, and inhibiting HTR2B expression led to the inhibition of LUSC cell proliferation. In conclusions, HTR2B might be a new biomarker and therapeutic target in COPD patients with LUSC.


Assuntos
Biomarcadores Tumorais , Carcinoma de Células Escamosas , Transição Epitelial-Mesenquimal , Neoplasias Pulmonares , Doença Pulmonar Obstrutiva Crônica , Humanos , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/metabolismo , Transição Epitelial-Mesenquimal/genética , Receptor 5-HT2B de Serotonina/genética , Receptor 5-HT2B de Serotonina/metabolismo , Regulação Neoplásica da Expressão Gênica , Proliferação de Células/genética , Linhagem Celular Tumoral
2.
Front Microbiol ; 15: 1410504, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38912347

RESUMO

The potentially lethal zoonotic disease alveolar echinococcosis (AE) is caused by the metacestode larval stages of the tapeworm Echinococcus multilocularis. Metacestode growth and proliferation occurs within the inner organs of mammalian hosts, which is associated with complex molecular parasite-host interactions. The host has developed various ways to resist a parasitic infection, and the production of reactive oxygen species (ROS) is one of the most important strategies. Here, we found that scavenging of ROS reduced metacestode larval growth and germinative cell proliferation in in vivo models. Furthermore, using in vitro-cultured metacestode vesicles, we found that increased ROS levels enhanced metacestode growth and germinative cell proliferation, which was achieved by positively activating the ROS-EmERK-EmHIF1α axis. These results indicate that, beside its capacity to damage the parasite, ROS also play critical roles in metacestode growth and germinative cell proliferation. This study suggests that the effects of ROS on parasite may be bidirectional during AE infection, reflecting the parasite's adaptation to the oxidative stress microenvironment.

4.
JCI Insight ; 9(9)2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38592784

RESUMO

Recent studies have uncovered that noncoding sequence variants may relate to Axenfeld-Rieger syndrome (ARS), a rare developmental anomaly with genetic heterogeneity. However, how these genomic regions are functionally and structurally associated with ARS is still unclear. In this study, we performed genome-wide linkage analysis and whole-genome sequencing in a Chinese family with ARS and identified a heterozygous deletion of about 570 kb (termed LOH-1) in the intergenic sequence between paired-like homeodomain transcription factor 2 (PITX2) and family with sequence similarity 241 member A. Knockout of LOH-1 homologous sequences caused ARS phenotypes in mice. RNA-Seq and real-time quantitative PCR revealed a significant reduction in Pitx2 gene expression in LOH-1-/- mice, while forkhead box C1 expression remained unchanged. ChIP-Seq and bioinformatics analysis identified a potential enhancer region (LOH-E1) within LOH-1. Deletion of LOH-E1 led to a substantial downregulation of the PITX2 gene. Mechanistically, we found a sequence (hg38 chr4:111,399,594-111,399,691) that is on LOH-E1 could regulate PITX2 by binding to RAD21, a critical component of the cohesin complex. Knockdown of RAD21 resulted in reduced PITX2 expression. Collectively, our findings indicate that a potential enhancer sequence that is within LOH-1 may regulate PITX2 expression remotely through cohesin-mediated loop domains, leading to ARS when absent.


Assuntos
Segmento Anterior do Olho , Anormalidades do Olho , Oftalmopatias Hereditárias , Proteína Homeobox PITX2 , Proteínas de Homeodomínio , Fatores de Transcrição , Animais , Feminino , Humanos , Masculino , Camundongos , Segmento Anterior do Olho/anormalidades , Segmento Anterior do Olho/metabolismo , DNA Intergênico/genética , Elementos Facilitadores Genéticos/genética , Anormalidades do Olho/genética , Oftalmopatias Hereditárias/genética , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Camundongos Knockout , Linhagem , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
5.
Acc Chem Res ; 57(9): 1398-1410, 2024 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-38652467

RESUMO

Electrical neuromodulation has achieved significant translational advancements, including the development of deep brain stimulators for managing neural disorders and vagus nerve stimulators for seizure treatment. Optoelectronics, in contrast to wired electrical systems, offers the leadless feature that guides multisite and high spatiotemporal neural system targeting, ensuring high specificity and precision in translational therapies known as "photoelectroceuticals". This Account provides a concise overview of developments in novel optoelectronic nanomaterials that are engineered through innovative molecular, chemical, and nanostructure designs to facilitate neural interfacing with high efficiency and minimally invasive implantation.This Account outlines the progress made both within our laboratory and across the broader scientific community, with particular attention to implications in materials innovation strategies, studying bioelectrical activation with spatiotemporal methods, and applications in regenerative medicine. In materials innovation, we highlight a nongenetic, biocompatible, and minimally invasive approach for neuromodulation that spans various length scales, from single neurons to nerve tissues using nanosized particles and monolithic membranes. Furthermore, our discussion exposes the critical unresolved questions in the field, including mechanisms of interaction at the nanobio interface, the precision of cellular or tissue targeting, and integration into existing neural networks with high spatiotemporal modulation. In addition, we present the challenges and pressing needs for long-term stability and biocompatibility, scalability for clinical applications, and the development of noninvasive monitoring and control systems.In addressing the existing challenges in the field of nanobio interfaces, particularly for neural applications, we envisage promising strategic directions that could significantly advance this burgeoning domain. This involves a deeper theoretical understanding of nanobiointerfaces, where simulations and experimental validations on how nanomaterials interact spatiotemporally with biological systems are crucial. The development of more durable materials is vital for prolonged applications in dynamic neural interfaces, and the ability to manipulate neural activity with high specificity and spatial resolution, paves the way for targeting individual neurons or specific neural circuits. Additionally, integrating these interfaces with advanced control systems, possibly leveraging artificial intelligence and machine learning algorithms and programming dynamically responsive materials designs, could significantly ease the implementation of stimulation and recording. These innovations hold the potential to introduce novel treatment modalities for a wide range of neurological and systemic disorders.


Assuntos
Nanoestruturas , Humanos , Nanoestruturas/química , Nanotecnologia/métodos , Animais , Eletrônica
6.
Foods ; 13(8)2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38672905

RESUMO

The functional components in tartary buckwheat leaf powder can give flour products higher nutritional value. To comprehensively realize the high-value utilization of tartary buckwheat and its by-products, electric stone mill powder (EMP), ultra-fine mill powder (UMP), steel mill powder (SMP), and grain mill powder (GMP) from tartary buckwheat leaves were used in the preparation of wheat dough, and this was used to explore their effects on dough properties and protein microstructure. With an increase in tartary buckwheat leaf powder, the hydration characteristics, protein weakening rate, and starch gelatinization characteristics of the dough changed, and the water holding capacity and swelling capacity decreased. The retrogradation value increased, which could prolong the shelf life of related products. The water solubility of the dough showed an upward trend and was the lowest at 10% UMP. The addition of UMP produced a more uniform dough stability time and the lowest degree of protein weakening, which made the dough more resistant to kneading. An increasing amount of tartary buckwheat leaf powder augmented the free sulfhydryl content of the dough and decreased the disulfide bond content. The disulfide bond content of the dough containing UMP was higher than that of the other doughs, and the stability of the dough was better. The peaks of the infrared spectrum of the dough changed after adding 10% UMP and 20% EMP. The content of α-helical structures was the highest at 10% UMP, and the content of ordered structures was enhanced. The polymerization of low molecular weight proteins to form macromolecular polymers led to a reduction in surface hydrophobic regions and the aggregation of hydrophobic groups. The SEM results also demonstrated that at 10% tartary buckwheat leaf powder, the addition of UMP was significantly different from that of the other three leaf powders, and at 20%, the addition of EMP substantially altered the structure of the dough proteins. Considering the effects of different milling methods and different added amounts of tartary buckwheat leaf powder on various characteristics of dough, 10% UMP is the most suitable amount to add to the dough.

7.
Neurotherapeutics ; : e00365, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38658264

RESUMO

Despite advances in intravenous thrombolysis and endovascular thrombectomy, numerous acute ischemic stroke survivors continue to experience various disability levels. The nitric oxide (NO) donor, Glyceryl Trinitrate (GTN), has been identified as a potential neuroprotective agent against ischemic damage. We evaluated the safety and feasibility of intravenous GTN in AIS patients. Subsequently, we conducted a secondary analysis to assess for possible efficacy of GTN as a neuroprotectant. We conducted a prospective, double-blind, randomized controlled trial in the Stroke Intervention & Translational Center (SITC) in Beijing Luhe Hospital, Capital Medical University (ChiCTR2100046271). AIS patients within 24 h of stroke onset were evenly divided into GTN or control groups (n = 20 each). The GTN group received intravenous GTN (5 mg in 50 ml saline at a rate of 0.4 mg/h for 12.5 h/day over 2 days), while controls were administered an equivalent volume of 0.9% saline. Both groups followed standard Stroke Guidelines for treatment. Safety measures focused on SBP<110 mmHg and headache occurrence. Efficacy was assessed via the 90-day modified rankin score (mRS) and the national institutes of health stroke score (NIHSS). Of the 40 AIS patients, baseline characteristics such as age, gender, risk factors, and pre-mRS scores showed no significant difference between the groups. Safety measures of SBP<110 mmHg and headache occurrence were comparable. Overall, 90-day mRS (1 vs. 1) and NIHSS (1 vs. 1) did not significantly differ between groups. However, the GTN-treated group had a benefit in enhancing NIHSS recovery (△NIHSS 4.5 vs. 3, p = 0.028), indicating that GTN may augment recovery. Subgroup analyses revealed a benefit in the GTN group at the 90-day NIHSS score and △NIHSS follow up for non-thrombolysis patients (1 vs. 2, p = 0.016; 5 vs. 2, p = 0.001). Moreover, the GTN group may benefit mild stroke patients in NIHSS score at 90 day and △NIHSS observed at 90 days (1 vs. 1, p = 0.025; 3 vs. 2 p = 0.002). Overall, while preliminary data suggest GTN might aid recovery in NIHSS improvement, the evidence is tempered due to sample size limitations. The RIGID study confirms the safety and feasibility of intravenous GTN administration for AIS patients. Preliminary data also suggest that the GTN group may provide improvement in NIHSS recovery compared to the control group. Furthermore, a potential benefit for non-thrombolysis patients and those with mild stroke symptoms was identified, suggesting a possible potential role as a tailored intervention in specific AIS subgroups. Due to the limited sample size, further larger RCT will be necessary to replicate these results. TRIAL REGISTRATION: www.chictr.org.cn, identifier: ChiCTR2100046271.

8.
Int J Mol Sci ; 25(6)2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38542268

RESUMO

Recently, artificial exosomes have been developed to overcome the challenges of natural exosomes, such as production scalability and stability. In the production of artificial exosomes, the incorporation of membrane proteins into lipid nanostructures is emerging as a notable approach for enhancing biocompatibility and treatment efficacy. This study focuses on incorporating HEK293T cell-derived membrane proteins into liposomes to create membrane-protein-bound liposomes (MPLCs), with the goal of improving their effectiveness as anticancer therapeutics. MPLCs were generated by combining two key elements: lipid components that are identical to those in conventional liposomes (CLs) and membrane protein components uniquely derived from HEK293T cells. An extensive comparison of CLs and MPLCs was conducted across multiple in vitro and in vivo cancer models, employing advanced techniques such as cryo-TEM (tramsmission electron microscopy) imaging and FT-IR (fourier transform infrared spectroscopy). MPLCs displayed superior membrane fusion capabilities in cancer cell lines, with significantly higher cellular uptake. Additionally, MPLCs maintained their morphology and size better than CLs when exposed to FBS (fetal bovine serum), suggesting enhanced serum stability. In a xenograft mouse model using HeLa and ASPC cancer cells, intravenous administration of MPLCs MPLCs accumulated more in tumor tissues, highlighting their potential for targeted cancer therapy. Overall, these results indicate that MPLCs have superior tumor-targeting properties, possibly attributable to their membrane protein composition, offering promising prospects for enhancing drug delivery efficiency in cancer treatments. This research could offer new clinical application opportunities, as it uses MPLCs with membrane proteins from HEK293T cells, which are known for their efficient production and compatibility with GMP (good manufacturing practice) standards.


Assuntos
Lipossomos , Nanoestruturas , Humanos , Camundongos , Animais , Lipossomos/química , Células HEK293 , Espectroscopia de Infravermelho com Transformada de Fourier , Proteínas de Membrana , Lipídeos/química
9.
Nat Commun ; 15(1): 2365, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38491012

RESUMO

It remains a challenge to obtain biocompatible afterglow materials with long emission wavelengths, durable lifetimes, and good water solubility. Herein we develop a photooxidation strategy to construct near-infrared afterglow carbon nanodots with an extra-long lifetime of up to 5.9 h, comparable to that of the well-known rare-earth or organic long-persistent luminescent materials. Intriguingly, size-dependent afterglow lifetime evolution from 3.4 to 5.9 h has been observed from the carbon nanodots systems in aqueous solution. With structural/ultrafast dynamics analysis and density functional theory simulations, we reveal that the persistent luminescence in carbon nanodots is activated by a photooxidation-induced dioxetane intermediate, which can slowly release and convert energy into luminous emission via the steric hindrance effect of nanoparticles. With the persistent near-infrared luminescence, tissue penetration depth of 20 mm can be achieved. Thanks to the high signal-to-background ratio, biological safety and cancer-specific targeting ability of carbon nanodots, ultralong-afterglow guided surgery has been successfully performed on mice model to remove tumor tissues accurately, demonstrating potential clinical applications. These results may facilitate the development of long-lasting luminescent materials for precision tumor resection.


Assuntos
Nanopartículas , Neoplasias , Animais , Camundongos , Luminescência
10.
Small ; 20(26): e2308861, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38372029

RESUMO

The anabolism of tumor cells can not only support their proliferation, but also endow them with a steady influx of exogenous nutrients. Therefore, consuming metabolic substrates or limiting access to energy supply can be an effective strategy to impede tumor growth. Herein, a novel treatment paradigm of starving-like therapy-triple energy-depleting therapy-is illustrated by glucose oxidase (GOx)/dc-IR825/sorafenib liposomes (termed GISLs), and such a triple energy-depleting therapy exhibits a more effective tumor-killing effect than conventional starvation therapy that only cuts off one of the energy supplies. Specifically, GOx can continuously consume glucose and generate toxic H2O2 in the tumor microenvironment (including tumor cells). After endocytosis, dc-IR825 (a near-infrared cyanine dye) can precisely target mitochondria and exert photodynamic and photothermal activities upon laser irradiation to destroy mitochondria. The anti-angiogenesis effect of sorafenib can further block energy and nutrition supply from blood. This work exemplifies a facile and safe method to exhaust the energy in a tumor from three aspects and starve the tumor to death and also highlights the importance of energy depletion in tumor treatment. It is hoped that this work will inspire the development of more advanced platforms that can combine multiple energy depletion therapies to realize more effective tumor treatment.


Assuntos
Glucose Oxidase , Lipossomos , Sorafenibe , Lipossomos/química , Humanos , Glucose Oxidase/metabolismo , Glucose Oxidase/química , Animais , Sorafenibe/farmacologia , Linhagem Celular Tumoral , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Metabolismo Energético , Peróxido de Hidrogênio/metabolismo , Peróxido de Hidrogênio/química , Indóis
11.
Eur J Intern Med ; 124: 46-53, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38350784

RESUMO

BACKGROUND: The performance of existing prognostic scores including the simplified Pulmonary Embolism Severity Index (sPESI) for short-term mortality of non-high-risk PE in Chinese population has not been widely validated. METHODS: Non-high-risk patients were included from the prospective cohort of the China pUlmonary Thromboembolism REgistry Study (CURES). The sPESI, RIETE, Geneva, modified FAST, and Bova score were validated. The discriminatory performance was measured by the area under the curve (AUC). We also compared the sensitivity, odds ratio, specificity, positive predictive value and negative predictive value of these scores. RESULTS: A total of 6,873 non-high-risk patients with acute PE were included and 241 (3.5 %) patients died within 30 days. Compared to the Geneva, modified FAST, and Bova score, the AUCs for predicting 30-day death of sPESI and RIETE score were higher at 0.712 (95 % CI, 0.680, 0.743) and 0.723 (95 % CI, 0.691, 0.755) respectively. The sPESI demonstrated the highest sensitivity at 0.809, while the RIETE score, Geneva, Modified FAST and BOVA score showed sensitivities of 0.622, 0.568, 0.477 and 0.502 respectively. A sPESI ⩾1 point was associated with a 4.7-fold increased risk of 30-day all-cause mortality (95 % CI, 3.427, 6.563, p < 0.001), while a RIETE score of ⩾1 point was associated with a 4.5-fold increased risk (95 % CI, 3.127, 6.341, p < 0.001). The Geneva score, modified FAST and Bova score showed inferior performance. CONCLUSIONS: The implementation of the fewer-parameter, easier-to-calculate sPESI in Chinese patients with PE can help to discriminate patients with extremely low risk of short-term mortality for home treatment or early discharge.


Assuntos
Embolia Pulmonar , Sistema de Registros , Índice de Gravidade de Doença , Humanos , Embolia Pulmonar/mortalidade , Embolia Pulmonar/diagnóstico , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Estudos Prospectivos , China/epidemiologia , Prognóstico , Área Sob a Curva , Medição de Risco/métodos , Valor Preditivo dos Testes , Curva ROC , Doença Aguda
12.
Cell Death Discov ; 10(1): 71, 2024 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-38341418

RESUMO

Abnormal lipid metabolism is an essential hallmark of glioblastoma. Hormone sensitive lipase (HSL), an important rate-limiting enzyme contributed to lipolysis, which was involved in aberrant lipolysis of glioblastoma, however, its definite roles and the relevant regulatory pathway have not been fully elucidated. Our investigations disclosed high expression of HSL in glioblastoma. Knock-down of HSL restrained proliferation, migration, and invasion of glioblastoma cells while adding to FAs could significantly rescue the inhibitory effect of si-HSL on tumor cells. Overexpression of HSL further promoted tumor cell proliferation and invasion. Bioinformatics analysis and dual-luciferase reporter assay were performed to predict and verify the regulatory role of ncRNAs on HSL. Mechanistically, hsa_circ_0021205 regulated HSL expression by sponging miR-195-5p, which further promoted lipolysis and drove the malignant progression of glioblastoma. Besides, hsa_circ_0021205/miR-195-5p/HSL axis activated the epithelial-mesenchymal transition (EMT) signaling pathway. These findings suggested that hsa_circ_0021205 promoted tumorigenesis of glioblastoma through regulation of HSL, and targeting hsa_circ_0021205/miR-195-5p/HSL axis can serve as a promising new strategy against glioblastoma.

13.
Phytomedicine ; 126: 155283, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38422652

RESUMO

BACKGROUND: Portulacae Herba and Granati Pericarpium pair (PGP) is a traditional Chinese herbal medicine treatment for colitis, clinically demonstrating a relatively favorable effect on relieving diarrhea and abnormal stools. However, the underlying mechanism remain uncertain. PURPOSE: The present study intends to evaluate the efficacy of PGP in treating colitis in mice and investigate its underlying mechanism. METHODS: The protective effect of PGP against colitis was determined by monitoring body weight, colon length, colon weight, and survival rate in mice. Colonic inflammation was assessed by serum cytokine levels, colonic H&E staining, and local neutrophil infiltration. The reversal of intestinal epithelial barrier damage by PGP was subsequently analyzed with Western blot and histological staining. Furthermore, RNA-seq analysis and molecular docking were performed to identify potential pathways recruited by PGP. Following the hints of the transcriptomic results, the role of PGP through the IL-6/STAT3/SOCS3 pathway in DSS-induced colitis mice was verified by Western blot. RESULTS: DSS-induced colitis in mice was significantly curbed by PGP treatment. PGP treatment significantly mitigated DSS-induced colitis in mice, as evidenced by improvements in body weight, DAI severity, survival rate, and inflammatory cytokines levels in serum and colon. Moreover, PGP treatment up-regulated the level of Slc26a3, thereby increasing the expressions of the tight junction/adherens junction proteins ZO-1, occludin and E-cadherin in the colon. RNA-seq analysis revealed that PGP inhibits the IL-6/STAT3/SOCS3 pathway at the transcriptional level. Molecular docking indicated that the major components of PGP could bind tightly to the proteins of IL-6 and SOCS3. Meanwhile, the result of Western blot revealed that the IL-6/STAT3/SOCS3 pathway was inhibited at the protein level after PGP administration. CONCLUSION: PGP could alleviate colonic inflammation and reverse damage to the intestinal epithelial barrier in DSS-induced colitis mice. The underlying mechanism involves the inhibition of the IL-6/STAT3/SOCS3 pathway.


Assuntos
Colite Ulcerativa , Colite , Extratos Vegetais , Punica granatum , Animais , Camundongos , Interleucina-6/metabolismo , Simulação de Acoplamento Molecular , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Inflamação/metabolismo , Colo/patologia , Citocinas/metabolismo , Peso Corporal , Sulfato de Dextrana/efeitos adversos , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Colite Ulcerativa/tratamento farmacológico , Transportadores de Sulfato/metabolismo , Transportadores de Sulfato/farmacologia , Transportadores de Sulfato/uso terapêutico , Antiporters/efeitos adversos , Antiporters/metabolismo
14.
Obesity (Silver Spring) ; 32(5): 840-856, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38413012

RESUMO

OBJECTIVE: This network meta-analysis evaluates the efficacy and safety of tirzepatide compared to glucagon-like peptide-1 receptor agonists (GLP-1 RA) and other weight loss drugs in the treatment of overweight and obesity. METHODS: MEDLINE, Embase, and Cochrane CENTRAL were searched for randomized controlled trials on tirzepatide, GLP-1 RA, and weight loss drugs approved by the US Food and Drug Administration. A network meta-analysis was performed, drawing direct and indirect comparisons between treatment groups. Network diagrams and surface under the cumulative ranking curve analysis were performed for primary (≥5%, ≥10%, ≥15%, absolute weight loss) and secondary outcomes and adverse effects. RESULTS: Thirty-one randomized controlled trials, involving more than 35,000 patients, were included in this study. Tirzepatide 15 mg ranked in the top three across weight-related parameters, glycemic profile (glycated hemoglobin), lipid parameters (total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides), and blood pressure. Tirzepatide 15 mg had the highest efficacy compared with placebo for achieving ≥15% weight loss (risk ratio 10.24, 95% CI: 6.42-16.34). As compared to placebo, tirzepatide and GLP-1 RA across all doses had significant increases in gastrointestinal adverse effects. CONCLUSIONS: The superiority of tirzepatide and GLP-1 RA in inducing weight loss and their ability to target multiple metabolic parameters render them promising candidates in the treatment of patients with overweight and obesity.

15.
Phys Chem Chem Phys ; 26(8): 6708-6716, 2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38321982

RESUMO

The coupled transport of charge and heat provide fundamental insights into the microscopic thermodynamics and kinetics of materials. We describe a sensitive ac differential resistance bridge that enables measurements of the temperature difference on two sides of a coin cell with a resolution of better than 10 µK. We use this temperature difference metrology to determine the ionic Peltier coefficients of symmetric Li-ion electrochemical cells as a function of Li salt concentration, solvent composition, electrode material, and temperature. The Peltier coefficients Π are negative, i.e., heat flows in the direction opposite to the drift of Li ions in the applied electric field, large, -Π > 30 kJ mol-1, and increase with increasing temperature at T > 300 K. The Peltier coefficient is approximately constant on time scales that span the characteristic time for mass diffusion across the thickness of the electrolyte, suggesting that heat of transport plays a minor role in comparison to the changes in partial molar entropy of Li at the interface between the electrode and electrolyte. Our work demonstrates a new platform for studying the non-equilibrium thermodynamics of electrochemical cells and provides a window into the transport properties of electrochemical materials through measurements of temperature differences and heat currents that complement traditional measurements of voltages and charge currents.

16.
Angew Chem Int Ed Engl ; 63(13): e202319489, 2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38308123

RESUMO

Alveolar echinococcosis (AE) is a zoonotic parasitic disease, resulting from being infected with the metacestode larvae of the tapeworm Echinococcus multilocularis (E. multilocularis). Novel prophylactic and therapeutic interventions are urgently needed since the current chemotherapy displays limited efficiency in AE treatment. Bioengineered nano cellular membrane vesicles are widely used for displaying the native conformational epitope peptides because of their unique structure and biocompatibility. In this study, four T-cells and four B-cells dominant epitope peptides of E. multilocularis with high immunogenicity were engineered into the Vero cell surface to construct a membrane vesicle nanovaccine for the treatment of AE. The results showed that the nanovesicle vaccine can efficiently activate dendritic cells, induce specific T/B cells to form a mutually activated circuit, and inhibit E. multilocularis infection. This study presents for the first time a nanovaccine strategy that can completely eliminate the burden of E. multilocularis.


Assuntos
Equinococose , Echinococcus multilocularis , Vacinas , Animais , Imunoterapia , Nanovacinas , Epitopos , Peptídeos
17.
J Imaging Inform Med ; 37(1): 347-362, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38343233

RESUMO

Lung cancer is one of the leading causes of death worldwide and early detection is crucial to reduce the mortality. A reliable computer-aided diagnosis (CAD) system can help facilitate early detection of malignant nodules. Although existing methods provide adequate classification accuracy, there is still room for further improvement. This study is dedicated to investigating a new CAD scheme for predicting the malignant likelihood of lung nodules in computed tomography (CT) images in light of a deep learning strategy. Conceived from the residual learning and selective kernel, we investigated an efficient residual selective kernel (RSK) block to handle the diversity of lung nodules with various shapes and obscure structures. Founded on this RSK block, we established a multiview RSK network (MRSKNet), to which three anatomical planes in the axial, coronal, and sagittal directions were fed. To reinforce the classification efficiency, seven handcrafted texture features with a filter-like computation strategy were explored, among which the homogeneity (HOM) feature maps are combined with the corresponding intensity CT images for concatenation input, leading to an improved network architecture. Evaluated on the public benchmark Lung Image Database Consortium and Image Database Resource Initiative (LIDC-IDRI) challenge database with ten-fold cross validation of binary classification, our experimental results indicated high area under receiver operating characteristic (AUC) and accuracy scores. A better compromise between recall and specificity was struck using the suggested concatenation strategy comparing to many state-of-the-art approaches. The proposed pulmonary nodule classification framework exhibited great efficacy and achieved a higher AUC of 0.9711. The association of handcrafted texture features with deep learning models is promising in advancing the classification performance. The developed pulmonary nodule CAD network architecture is of potential in facilitating the diagnosis of lung cancer for further image processing applications.

18.
Lipids Health Dis ; 23(1): 50, 2024 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-38368351

RESUMO

Steatotic liver disease poses a serious threat to human health and has emerged as one of the most significant burdens of chronic liver disease worldwide. Currently, the research mechanism is not clear, and there is no specific targeted drug for direct treatment. Phosphorylation is widely regarded as the most common type of protein modification, closely linked to steatotic liver disease in previous studies. However, there is no systematic review to clarify the relationship and investigate from the perspective of phosphorylation. Phosphorylation has been found to mainly regulate molecule stability, affect localization, transform molecular function, and cooperate with other protein modifications. Among them, adenosine 5'-monophosphate-activated protein kinase (AMPK), serine/threonine kinase (AKT), and nuclear factor kappa-B (NF-kB) are considered the core mechanisms in steatotic liver disease. As to treatment, lifestyle changes, prescription drugs, and herbal ingredients can alleviate symptoms by influencing phosphorylation. It demonstrates the significant role of phosphorylation as a mechanism occurrence and a therapeutic target in steatotic liver disease, which could be a new star for future exploration.


Assuntos
Fígado Gorduroso , Humanos , Fosforilação , Fígado Gorduroso/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Fígado/metabolismo
19.
J Adv Res ; 2024 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-38346487

RESUMO

INTRODUCTION: Despite the high morbidity and mortality, the effective therapies for heart failure with preserved fraction (HFpEF) are limited as the poor understand of its pathophysiological basis. OBJECTIVE: This study was aimed to characterize the cellular heterogeneity and potential mechanisms of HFpEF at single-cell resolution. METHODS: An HFpEF mouse model was induced by a high-fat diet with N-nitro-L-arginine methyl ester. Cells from the hearts were subjected to single-cell sequencing. The key protein expression was measured with Immunohistochemistry and immunofluorescence staining. RESULTS: In HFpEF hearts, myocardial fibroblasts exhibited higher levels of fibrosis. Furthermore, an increased number of fibroblasts differentiated into high-metabolism and high-fibrosis phenotypes. The expression levels of genes encoding certain pro-angiogenic secreted proteins were decreased in the HFpEF group, as confirmed by bulk RNA sequencing. Additionally, the proportion of the endothelial cell (EC) lineages in the HFpEF group was significantly downregulated, with low angiogenesis and high apoptosis phenotypes observed in these EC lineages. Interestingly, the fibroblasts in the HFpEF heart might cross-link with the EC lineages via over-secretion of ANGPTL4, thus displaying an anti-angiogenic function. Immunohistochemistry and immunofluorescence staining then revealed the downregulation of vascular density and upregulation of ANGPTL4 expression in HFpEF hearts. Finally, we predicted ANGPTL4as a potential druggable target using DrugnomeAI. CONCLUSION: In conclusion, this study comprehensively characterized the angiogenesis impairment in HFpEF hearts at single-cell resolution and proposed that ANGPTL4 secretion by fibroblasts may be a potential mechanism underlying this angiogenic abnormality.

20.
ACS Appl Mater Interfaces ; 16(6): 8109-8118, 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38315970

RESUMO

Heat dissipation plays a crucial role in the performance and reliability of high-power GaN-based electronics. While AlN transition layers are commonly employed in the heteroepitaxial growth of GaN-on-SiC substrates, concerns have been raised about their impact on thermal transport across GaN/SiC interfaces. In this study, we present experimental measurements of the thermal boundary conductance (TBC) across GaN/SiC interfaces with varying thicknesses of the AlN transition layer (ranging from 0 to 73 nm) at different temperatures. Our findings reveal that the addition of an AlN transition layer leads to a notable increase in the TBC of the GaN/SiC interface, particularly at elevated temperatures. Structural characterization techniques are employed to understand the influence of the AlN transition layer on the crystalline quality of the GaN layer and its potential effects on interfacial thermal transport. To gain further insights into the trend of TBC, we conduct molecular dynamics simulations using high-fidelity deep learning-based interatomic potentials, which reproduce the experimentally observed enhancement in TBC even for atomically perfect interfaces. These results suggest that the enhanced TBC facilitated by the AlN intermediate layer could result from a combination of improved crystalline quality at the interface and the "phonon bridge" effect provided by AlN that enhances the overlap between the vibrational spectra of GaN and SiC.

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