RESUMEN
Mycoplasma pneumoniae can cause respiratory infections and pneumonia, posing a serious threat to the health of children and adolescents. Early diagnosis of Mycoplasma pneumoniae infection is crucial for clinical treatment. Currently, diagnostic methods for Mycoplasma pneumoniae infection include pathogen detection, molecular biology techniques, and bacterial culture, all of which have certain limitations. Here, we developed a rapid, simple, and accurate detection method for Mycoplasma pneumoniae that does not rely on large equipment or complex operations. This technology combines the CRISPR-Cas12a system with recombinase polymerase amplification (RPA), allowing the detection results to be observed through fluorescence curves and immunochromatographic lateral flow strips.It has been validated that RPA-CRISPR/Cas12a fluorescence analysis and RPA-CRISPR/Cas12-immunochromatographic exhibit no cross-reactivity with other common pathogens, and The established detection limit was ascertained to be as low as 102 copies/µL.Additionally, 49 clinical samples were tested and compared with fluorescence quantitative polymerase chain reaction, demonstrating a sensitivity and specificity of 100%. This platform exhibits promising clinical performance and holds significant potential for clinical application, particularly in settings with limited resources, such as clinical care points or resource-constrained areas.
Asunto(s)
Sistemas CRISPR-Cas , Mycoplasma pneumoniae , Mycoplasma pneumoniae/genética , Mycoplasma pneumoniae/aislamiento & purificación , Humanos , Sistemas CRISPR-Cas/genética , Técnicas de Amplificación de Ácido Nucleico/métodos , Neumonía por Mycoplasma/diagnóstico , Neumonía por Mycoplasma/microbiologíaRESUMEN
Surgical resection, the mainstay for melanoma treatment, faces challenges due to high tumor recurrence rates and complex postoperative wound healing. Chronic inflammation from residual disease and the risk of secondary infections impede healing. We introduce an innovative, injectable hydrogel system that integrates a multifaceted therapeutic approach. The hydrogel, crosslinked by calcium ions with sodium alginate, encapsulates a blood clot rich in dendritic cells (DCs) chemoattractants and melanoma cell-derived nanovesicles (NVs), functioning as a potent immunostimulant. This in situ recruitment strategy overcomes the limitations of subcutaneous tumor vaccine injections and more effectively achieves antitumor immunity. Additionally, the hydrogel incorporates Chlorella extracts, enhancing its antimicrobial properties to prevent wound infections and promote healing. One of the key findings of our research is the dual functionality of Chlorella extracts; they not only expedite the healing process of infected wounds but also increase the hydrogel's ability to stimulate an antitumor immune response. Given the patient-specific nature of the blood clot and NVs, our hydrogel system offers customizable solutions for individual postoperative requirements. This personalized approach is highlighted by our study, which demonstrates the synergistic impact of the composite hydrogel on preventing melanoma recurrence and hastening wound healing, potentially transforming postsurgical melanoma management.
Asunto(s)
Células Dendríticas , Hidrogeles , Melanoma , Cicatrización de Heridas , Hidrogeles/química , Animales , Células Dendríticas/inmunología , Células Dendríticas/efectos de los fármacos , Melanoma/terapia , Melanoma/patología , Cicatrización de Heridas/efectos de los fármacos , Humanos , Recurrencia Local de Neoplasia/prevención & control , Ratones Endogámicos C57BL , Antiinfecciosos/uso terapéutico , Antiinfecciosos/farmacología , Ratones , Línea Celular Tumoral , FemeninoRESUMEN
Gliomas, the most prevalent malignant brain tumors in the central nervous system, are marked by rapid growth, high recurrence rates, and poor prognosis. Glioblastoma (GBM) stands out as the most aggressive subtype, characterized by significant heterogeneity. The etiology of gliomas remains elusive. RNA modifications, particularly reversible methylation, play a crucial role in regulating transcription and translation throughout the RNA lifecycle. Increasing evidence highlights the prevalence of RNA methylation in primary central nervous system malignancies, underscoring its pivotal role in glioma pathogenesis. This review focuses on recent findings regarding changes in RNA methylation expression and their effects on glioma development and progression, including N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), and N7-methylguanosine (m7G). Given the extensive roles of RNA methylation in gliomas, the potential of RNA methylation-related regulators as prognostic markers and therapeutic targets was also explored, aiming to enhance clinical management and improve patient outcomes.
RESUMEN
To know the influence of lauric acid (LA) on wheat flour fresh noodles (WFN) quality and the latent mechanism, the effect of LA on cooking properties, digestibility and structure of WFN with/without sodium bicarbonate (SB) and the properties of wheat flour (WF) with/without SB were studied. The results indicated that LA reduced cooking loss and digestibility of WFN with SB and slightly decreased water adsorption and increased the free water binding ability and hardness of WFN without SB. Furthermore, LA increased the degree of short- and long-range order and molecular weight of starch in cooked WFN with/without SB and it had greater effect on the degree of short- and long-range order and molecular weight of starch in cooked WFN with SB than that without SB. Differential scanning calorimeter (DSC) and rapid viscosity analysis (RVA) displayed that WFN with LA and SB formed more starch-LA or/and starch-LA-protein complexes than WFN with LA. Additionally, the impact of LA on WFN quality and WF properties was influenced by SB concentration. This study will provide theoretical basis and new thoughts for the design of high-quality fresh noodles with low digestibility, low cooking loss and high hardness.
RESUMEN
Copper (Cu) is recognized as an essential trace elements for the body; However, excessive levels of Cu can lead to toxic effects. We investigated the effects of Cu2+(75⯵g/L, 150⯵g/L, and 300⯵g/L) on the rainbow trout liver. Combination of transcriptome and metabolome analyses, the regulatory mechanisms of the liver under Cu stress were elucidated. The results showed that Cu affected the antioxidant levels, leading to disruptions in the normal tissue structure of the liver. Combined transcriptome and metabolome analyses revealed significant enrichment of the insulin signaling pathway and the adipocytokine signaling pathway. Additionally, Cu2+ stress altered the amino acid metabolism in rainbow trout by reducing serine and arginine levels while increasing proline content. Apoptosis is inhibited and autophagy and lipid metabolism are suppressed; In summary, Cu2+ stress affects energy and lipid metabolism, and the reduction of serine and arginine represents a decrease in the antioxidant capacity, whereas the increase in proline and the promotion of apoptosis potentially serving as crucial strategies for Cu2+ resistance in rainbow trout. These findings provided insights into the regulatory mechanisms of rainbow trout under Cu2+ stress and informed the prevention of heavy metal pollution and the selection of biomarkers under Cu pollution.
RESUMEN
Antisense long non-coding RNA (AS-lncRNA) represents a novel class of RNA molecules. In recent years, it has been discovered that AS-lncRNAs play crucial roles in various biological processes, particularly in the onset and progression of tumors. Skull base tumors, originating from the base of the brain, exhibit specific expression patterns of AS-lncRNA which correlate significantly with clinical characteristics. This makes AS-lncRNA a promising candidate as a tumor marker. Functional studies have revealed that AS-lncRNAs can regulate gene expression by acting as miRNA sponges and interacting with RBPs. Consequently, they play pivotal roles in tumor cell cycle, apoptosis, angiogenesis, invasion, and metastasis processes. Further exploration into the mechanisms of AS-lncRNA in tumors holds substantial theoretical significance for deeper insights into the etiology, pathogenesis, and RNA dynamics of skull base tumors. Moreover, AS-lncRNA could serve as molecular markers or potential targets for early diagnosis. Their potential extends to efficacy assessment, prognosis prediction, and gene therapy, suggesting broad clinical applications. In summary, AS-lncRNA emerges as a promising molecular marker implicated in the onset and progression of skull base tumors.
RESUMEN
The aim of this study was to explore the effects of low-frequency ultrasound (US) combined with microbubbles (MBs) on breast cancer xenografts and explain its underlying mechanisms. A total of 20 xenografted nude mice were randomly divided into four groups: a group treated with US plus MBs (the US + MBs group), a group treated with US alone (the US group), a group treated with MBs alone (the MBs group), and a control group. In different groups, mice were treated with different US and injection regimens on an alternate day, three times in total. Histological changes, apoptosis of cells, microvascular changes, and the apoptosis index (AI) and microvascular density (MVD) of the breast cancer xenograft were analyzed after the mice were sacrificed. Results indicated that the tumor volume in the US + MBs group was smaller than that in the other three groups (p < 0.001 for all). The rate of tumor growth inhibition in the US + MBs group was significantly higher than that in the US and MBs groups (p < 0.001 for both). There were no significant differences in histological changes among the four groups. However, the AI was higher in the US + MBs group than that in the other three groups while the MVD was lower (p < 0.001 for all). All in all, low-frequency US combined with MBs can effectively slow down the growth of breast cancer in nude mice. In summary, low-frequency US combined with MBs has a significant effect on breast cancer treatment. Cavitation, thermal effects, and mechanical effects all play a vital role in the inhibition of tumor growth.
RESUMEN
Background: Ventricular septal defect (VSD) is one of the most common congenital heart diseases. This study aims to evaluate the clinical value and benefit of transesophageal echocardiography (TEE) in transthoracic minimally invasive closure of VSDs using a completely biodegradable occluders, summarize the main points of surgical procedures, and analyze the follow-up results of short-term and medium-term treatment. Methods: We conducted a retrospective analysis of 24 pediatric cases of VSD, successfully treated with TEE-guided minimally invasive closure using fully biodegradable occluders between June 2019 and June 2022. The preoperative TEE meticulously examined the defect's location, size, and surrounding anatomical relationships, aiding in the selection of appropriate occluders and guiding the entire closure process. All patients were followed up for 1 year. Results: In our cohort, 13 cases were perimembranous inlet VSDs, and 11 involved VSDs with membranous aneurysm formation. The effective shunt size of VSD measured by TEE preoperatively ranged from 2.8 to 4.9 mm, with the defect located 2-6 mm from the aortic valve. Occluders used were 6-8 mm in diameter. All 24 procedures were successful. TEE confirmed that the occluders were tightly fitted at the edges of the VSDs. Twenty-three cases had no residual shunt post-surgery, while one case exhibited a small left-to-right shunt (<1.5 mm) at the occluder's edge. Follow-up was conducted on postoperative day 3, and in months 1, 3, 6, and 12, showing that the occluder's position remained normal in all patients. Except for one child who had a 1.2 mm left-to-right shunt at the edge of the occluder, no residual shunts were observed in the others. The occluder started to degrade from month 6, and the sizes of the left and right occluder discs were significantly smaller compared to those on postoperative day 3 (P=0.003). Conclusions: TEE-guided minimally invasive VSD occlusion using fully biodegradable occluders has the advantages of minimal trauma, high safety, and few complications, with satisfactory recent efficacy, and good prospects for clinical safety applications.
RESUMEN
Rationale: An impairment of plasma membrane repair has been implicated in various diseases such as muscular dystrophy and ischemia/reperfusion injury. MOTS-c, a short peptide encoded by mitochondria, has been shown to pass through the plasma membrane into the bloodstream. This study determined whether this biological behavior was involved in membrane repair and its underlying mechanism. Methods and Results: In human participants, the level of MOTS-c was positively correlated with the abundance of mitochondria, and the membrane repair molecule TRIM72. In contrast to high-intensity eccentric exercise, moderate-intensity exercise improved sarcolemma integrity and physical performance, accompanied by an increase of mitochondria beneath the damaged sarcolemma and secretion of MOTS-c. Furthermore, moderate-intensity exercise increased the interaction between MOTS-c and TRIM72, and MOTS-c facilitated the trafficking of TRIM72 to the sarcolemma. In vitro studies demonstrated that MOTS-c attenuated membrane damage induced by hypotonic solution, which could be blocked by siRNA-TRIM72, but not AMPK inhibitor. Co-immunoprecipitation study showed that MOTS-c interacted with TRIM72 C-terminus, but not N-terminus. The dynamic membrane repair assay revealed that MOTS-c boosted the trafficking of TRIM72 to the injured membrane. However, MOTS-c itself had negligible effects on membrane repair, which was recapitulated in TRIM72-/- mice. Unexpectedly, MOTS-c still increased the fusion of vesicles with the membrane in TRIM72-/- mice, and dot blot analysis revealed an interaction between MOTS-c and phosphatidylinositol (4,5) bisphosphate [PtdIns (4,5) P2]. Finally, MOTS-c blunted ischemia/reperfusion-induced membrane disruption, and preserved heart function. Conclusions: MOTS-c/TRIM72-mediated membrane integrity improvement participates in mitochondria-triggered membrane repair. An interaction between MOTS-c and plasma lipid contributes to the fusion of vesicles with membrane. Our data provide a novel therapeutic strategy for rescuing organ function by facilitating membrane repair with MOTS-c.
Asunto(s)
Membrana Celular , Mitocondrias , Sarcolema , Animales , Humanos , Ratones , Membrana Celular/metabolismo , Masculino , Mitocondrias/metabolismo , Sarcolema/metabolismo , Transporte de Proteínas , Proteínas Mitocondriales/metabolismo , Proteínas de Motivos Tripartitos/metabolismo , Proteínas de Motivos Tripartitos/genética , Ratones Endogámicos C57BL , Músculo Esquelético/metabolismo , Adulto , Ejercicio Físico/fisiología , Ratones Noqueados , Femenino , Proteínas Portadoras/metabolismo , Proteínas de la MembranaRESUMEN
The excessive inflammation caused by the prolonged activation of Toll-like receptor 4 (TLR4) and its downstream signaling pathways leads to sepsis. CD14-mediated endocytosis of TLR4 is the key step to control the amount of TLR4 on cell membrane and the activity of downstream pathways. The actin cytoskeleton is necessary for receptor-mediated endocytosis, but its role in TLR4 endocytosis remains elusive. Here we show that Tropomodulin 1 (Tmod1), an actin capping protein, inhibited lipopolysaccharide (LPS)-induced TLR4 endocytosis and intracellular trafficking in macrophages. Thus it resulted in increased surface TLR4 and the upregulation of myeloid differentiation factor 88 (MyD88)-dependent pathway and the downregulation of TIR domain-containing adaptor-inducing interferon-ß (TRIF)-dependent pathway, leading to the enhanced secretion of inflammatory cytokines, such as TNF-α and IL-6, and the reduced secretion of cytokines, such as IFN-ß. Macrophages deficient with Tmod1 relieved the inflammatory response in LPS-induced acute lung injury mouse model. Mechanistically, Tmod1 negatively regulated LPS-induced TLR4 endocytosis and inflammatory response through modulating the activity of CD14/Syk/PLCγ2/IP3/Ca2+ signaling pathway, the reorganization of actin cytoskeleton, and the membrane tension. Therefore, Tmod1 is a key regulator of inflammatory response and immune functions in macrophages and may be a potential target for the treatment of excessive inflammation and sepsis.
Asunto(s)
Endocitosis , Inflamación , Lipopolisacáridos , Macrófagos , Ratones Endogámicos C57BL , Transducción de Señal , Receptor Toll-Like 4 , Tropomodulina , Animales , Receptor Toll-Like 4/metabolismo , Lipopolisacáridos/farmacología , Ratones , Macrófagos/metabolismo , Macrófagos/inmunología , Inflamación/metabolismo , Inflamación/patología , Tropomodulina/metabolismo , Tropomodulina/genética , Citocinas/metabolismo , Células RAW 264.7 , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Receptores de Lipopolisacáridos/metabolismo , Masculino , Ratones Noqueados , Citoesqueleto de Actina/metabolismo , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Proteínas Adaptadoras del Transporte Vesicular/genética , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/patologíaRESUMEN
Background: Stomach adenocarcinoma (STAD) is one of the most common malignancies. Infection of helicobacter pylori (H. pylori) is a major risk factor that leads to the development of STAD. This study constructed a risk model based on the H. pylori-related macrophages for predicting STAD prognosis. Methods: The single-cell RNA sequencing (scRNA-seq) dataset and the clinic information and RNA-seq datasets of STAD patients were collected for establishing a prognostic model and for validation. The "Seurat" and "harmony" packages were used to process the scRNA-seq data. Key gene modules were sectioned using the "limma" package and the "WGCNA" package. Kaplan-Meier (KM) and Receiver Operating Characteristic Curve (ROC) analyses were performed with "survminer" package. The "GSVA" package was employed for single sample gene set enrichment analysis (ssGSEA). Cell migration and invasion were measured by carrying out wound healing and trans-well assays. Results: A total of 17397 were screened and classified into 8 cell type clusters, among which the macrophage cluster was closely associated with the H. pylori infection. Macrophages were further categorized into four subtypes (including C1, C2, C3, and C4), and highly variable genes of macrophage subtype C4 could serve as an indicator of the prognosis of STAD. Subsequently, we developed a RiskScore model based on six H. pylori -associated genes (TNFRSF1B, CTLA4, ABCA1, IKBIP, AKAP5, and NPC2) and observed that the high-risk patients exhibited poor prognosis, higher suppressive immune infiltration, and were closely associated with cancer activation-related pathways. Furthermore, a nomogram combining the RiskScore was developed to accurately predict the survival of STAD patients. AB CA 1 in the RiskScore model significantly affected the migration and invasion of tumor cells. Conclusion: The gene expression profile served as an indicator of the survival for patients with STAD and addressed the clinical significance of using H. pylori-associated genes to treat STAD. The current findings provided novel understandings for the clinical evaluation and management of STAD.
RESUMEN
Objective: In this study, the impact of inhibiting the PI3K/AKT/NF-κB pathway on lung oxidative damage induced by Echinococcus granulosus cyst fluid was investigated. Methods: Twenty-four mice were randomly assigned to four groups. Three months after inoculation with hydatid cyst segments, mice in group A were treated with intraperitoneal and intratracheal saline injections; mice in group B were administered a caudal vein injection of a PI3K inhibitor, followed by cyst fluid sensitization; mice in group C received an AKT inhibitor via caudal vein, followed by cyst fluid sensitization; and mice in group D were subjected to cyst fluid sensitization without any inhibitor treatment. Cellular changes in lung tissues across all groups were evaluated, including pathological section analysis. Analysis of pulmonary tissue and serum from these mice included the assessment of PI3K/AKT/NF-κB pathway proteins, inflammatory factors, and related mRNA levels. Results: Mice in groups B and C exhibited a higher proportion of M2-type macrophages and significantly lower levels of PI3K/AKT/NF-κB pathway proteins, inflammatory factors (interleukin-6 [IL-6]/tumor necrosis factor-α [TNF-α]), and oxidative markers in lung tissues compared to mice in group D (P < 0.05). Conclusion: Our results in this study indicate that activation of the PI3K/AKT/NF-κB pathway contributed to an increase in the M1 macrophage phenotype, leading to enhanced secretion of peroxidases and inflammatory factors. This mechanism plays a crucial role in the oxidative and inflammatory lung damage associated with allergic reactions to E. granulosus cyst fluid.
Asunto(s)
Echinococcus granulosus , FN-kappa B , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Animales , Echinococcus granulosus/inmunología , Ratones , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , FN-kappa B/metabolismo , Transducción de Señal , Lesión Pulmonar/inmunología , Lesión Pulmonar/etiología , Lesión Pulmonar/parasitología , Macrófagos/inmunología , Pulmón/inmunología , Pulmón/patología , Pulmón/parasitología , Equinococosis/inmunología , Modelos Animales de Enfermedad , Femenino , Citocinas/metabolismo , Estrés OxidativoRESUMEN
BACKGROUND: Breast cancer (BC) is the most common malignant tumor in women worldwide, and further elucidation of the molecular mechanisms involved in BC pathogenesis is essential to improve the prognosis of BC patients. RNA Binding Motif Protein 8 A (RBM8A), with high affinity to a myriad of RNA transcripts, has been shown to play a crucial role in genesis and progression of multiple cancers. We attempted to explore its functional significance and molecular mechanisms in BC. METHODS: Bioinformatics analysis was performed on publicly available BC datasets. qRT-PCR was used to determine the expression of RBM8A in BC tissues. MTT assay, clone formation assay and flow cytometry were employed to examine BC cell proliferation and apoptosis in vitro. RNA immunoprecipitation (RIP) and RIP-seq were used to investigate the binding of RBM8A/EIF4A3 to the mRNA of IGF1R/IRS-2. RBM8A and EIF4A3 interactions were determined by co-immunoprecipitation (Co-IP) and immunofluorescence. Chromatin immunoprecipitation (Ch-IP) and dual-luciferase reporter assay were carried out to investigate the transcriptional regulation of RBM8A by TEAD4. Xenograft model was used to explore the effects of RBM8A and TEAD4 on BC cell growth in vivo. RESULTS: In this study, we showed that RBM8A is abnormally highly expressed in BC and knockdown of RBM8A inhibits BC cell proliferation and induces apoptosis in vitro. EIF4A3, which phenocopy RBM8A in BC, forms a complex with RBM8A in BC. Moreover, EIF4A3 and RBM8A complex regulate the expression of IGF1R and IRS-2 to activate the PI3K/AKT signaling pathway, thereby promoting BC progression. In addition, we identified TEAD4 as a transcriptional activator of RBM8A by Ch-IP, dual luciferase reporter gene and a series of functional rescue assays. Furthermore, we demonstrated the in vivo pro-carcinogenic effects of TEAD4 and RBM8A by xenograft tumor experiments in nude mice. CONCLUSION: Collectively, these findings suggest that TEAD4 novel transcriptional target RBM8A interacts with EIF4A3 to increase IGF1R and IRS-2 expression and activate PI3K/AKT signaling pathway, thereby further promoting the malignant phenotype of BC cells.
Asunto(s)
Neoplasias de la Mama , Proteínas de Unión al ADN , Regulación Neoplásica de la Expresión Génica , Proteínas Musculares , Proteínas de Unión al ARN , Receptor IGF Tipo 1 , Factores de Transcripción de Dominio TEA , Animales , Femenino , Humanos , Ratones , Apoptosis/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Proliferación Celular , Progresión de la Enfermedad , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Ratones Desnudos , Proteínas Musculares/metabolismo , Proteínas Musculares/genética , Unión Proteica , Receptor IGF Tipo 1/metabolismo , Receptor IGF Tipo 1/genética , Receptores de Somatomedina/metabolismo , Receptores de Somatomedina/genética , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Transducción de Señal , Factores de Transcripción de Dominio TEA/metabolismoRESUMEN
The lungs, as vital organs in the human body, continuously engage in gas exchange with the external environment. The lung microbiota, a critical component in maintaining internal homeostasis, significantly influences the onset and progression of diseases. Beneficial interactions between the host and its microbial community are essential for preserving the host's health, whereas disease development is often linked to dysbiosis or alterations in the microbial community. Evidence has demonstrated that changes in lung microbiota contribute to the development of major chronic lung diseases, including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), asthma, and lung cancer. However, in-depth mechanistic studies are constrained by the small scale of the lung microbiota and its susceptibility to environmental pollutants and other factors, leaving many questions unanswered. This review examines recent research on the lung microbiota and lung diseases, as well as methodological advancements in studying lung microbiota, summarizing the ways in which lung microbiota impacts lung diseases and introducing research methods for investigating lung microbiota.
Asunto(s)
Disbiosis , Enfermedades Pulmonares , Pulmón , Microbiota , Humanos , Pulmón/microbiología , Enfermedades Pulmonares/microbiología , Disbiosis/microbiología , Enfermedad Crónica , Animales , Enfermedad Pulmonar Obstructiva Crónica/microbiologíaRESUMEN
Obesity is acknowledged as a significant risk factor for various metabolic diseases, and the inhibition of human pancreatic lipase (hPL) can impede lipid digestion and absorption, thereby offering potential benefits for obesity treatment. Anthraquinones is a kind of natural and synthetic compounds with wide application. In this study, the inhibitory effects of 31 anthraquinones on hPL were evaluated. The data shows that AQ7, AQ26, and AQ27 demonstrated significant inhibitory activity against hPL, and exhibited selectivity towards other known serine hydrolases. Then the structure-activity relationship between anthraquinones and hPL was further analysed. AQ7 was found to be a mixed inhibition of hPL through inhibition kinetics, while AQ26 and AQ27 were effective non-competitive inhibition of hPL. Molecular docking data revealed that AQ7, AQ26, and AQ27 all could associate with the site of hPL. Developing hPL inhibitors for obesity prevention and treatment could be simplified with this novel and promising lead compound.
Asunto(s)
Antraquinonas , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Inhibidores Enzimáticos , Lipasa , Páncreas , Relación Estructura-Actividad , Antraquinonas/farmacología , Antraquinonas/química , Antraquinonas/síntesis química , Lipasa/antagonistas & inhibidores , Lipasa/metabolismo , Humanos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Estructura Molecular , Páncreas/enzimología , Simulación del Acoplamiento Molecular , Productos Biológicos/farmacología , Productos Biológicos/química , Productos Biológicos/síntesis químicaRESUMEN
Acquired resistance is inevitable in the treatment of non-small cell lung cancer (NSCLC) with osimertinib, and one of the primary mechanisms responsible for this resistance is the epithelial-mesenchymal transition (EMT). We identify upregulation of the proviral integration site for Moloney murine leukemia virus 1 (PIM1) and functional inactivation of glycogen synthase kinase 3ß (GSK3ß) as drivers of EMT-associated osimertinib resistance. Upregulation of PIM1 promotes the growth, invasion, and resistance of osimertinib-resistant cells and is significantly correlated with EMT molecules expression. Functionally, PIM1 suppresses the ubiquitin-proteasome degradation of snail family transcriptional repressor 1 (SNAIL) and snail family transcriptional repressor 2 (SLUG) by deactivating GSK3ß through phosphorylation. The stability and accumulation of SNAIL and SLUG facilitate EMT and encourage osimertinib resistance. Furthermore, treatment with PIM1 inhibitors prevents EMT progression and re-sensitizes osimertinib-resistant NSCLC cells to osimertinib. PIM1/GSK3ß signaling is activated in clinical samples of osimertinib-resistant NSCLC, and dual epidermal growth factor receptor (EGFR)/PIM1 blockade synergistically reverse osimertinib-resistant NSCLC in vivo. These data identify PIM1 as a driver of EMT-associated osimertinib-resistant NSCLC cells and predict that PIM1 inhibitors and osimertinib combination therapy will provide clinical benefit in patients with EGFR-mutant NSCLC.
Asunto(s)
Acrilamidas , Compuestos de Anilina , Carcinoma de Pulmón de Células no Pequeñas , Resistencia a Antineoplásicos , Transición Epitelial-Mesenquimal , Receptores ErbB , Glucógeno Sintasa Quinasa 3 beta , Neoplasias Pulmonares , Proteínas Proto-Oncogénicas c-pim-1 , Transducción de Señal , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Acrilamidas/farmacología , Acrilamidas/uso terapéutico , Proteínas Proto-Oncogénicas c-pim-1/metabolismo , Proteínas Proto-Oncogénicas c-pim-1/genética , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Compuestos de Anilina/farmacología , Compuestos de Anilina/uso terapéutico , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Glucógeno Sintasa Quinasa 3 beta/genética , Receptores ErbB/metabolismo , Receptores ErbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Animales , Ratones , Línea Celular Tumoral , Mutación/genética , Ratones Desnudos , Factores de Transcripción de la Familia Snail/metabolismo , Factores de Transcripción de la Familia Snail/genética , Indoles , PirimidinasRESUMEN
Barrier membranes have been used for the treatment of alveolar bone loss caused by periodontal diseases or trauma. However, an optimal barrier membrane must satisfy multiple requirements simultaneously, which are challenging to combine into a single material. We herein report the design of a bioinspired membrane consisting of three functional layers. The primary layer is composed of clay nanosheets and chitin, which form a nacre-inspired laminated structure. A calcium phosphate mineral layer is deposited on the inner surface of the nacre-inspired layer, while a poly(lactic acid) layer is coated on the outer surface. The composite membrane integrates good mechanical strength and deformability because of the nacre-inspired structure, facilitating operations during the implant surgery. The mineral layer induces the osteogenic differentiation of bone marrow mesenchymal stem cells and increases the stiffness of the membrane, which is an important factor for the regeneration process. The poly(lactic acid) layer can prevent unwanted mineralization on the outer surface of the membrane in oral environments. Cell experiments reveal that the membrane exhibits good biocompatibility and anti-infiltration capability toward connective tissue/epithelium cells. Furthermore, in vitro analyses show that the membrane does not degrade too fast, allowing enough time for bone regeneration. In vivo experiments prove that the membrane can effectively induce better bone regeneration and higher trabecular bone density in alveolar bone defects. This study demonstrates the potential of this bioinspired triple-layered membrane with hierarchical structures as a promising barrier material for periodontal guided tissue regeneration.
RESUMEN
OBJECTIVES: The purpose of this study was to demonstrate the discriminating predictive indicators in peripheral blood and left atrium blood for predicting the risk of left atrial spontaneous echo contrast (LASEC) in atrial fibrillation patients underwent catheter ablation. METHODS: A total of 108 consecutive AF patients treated with radiofrequency ablation between July 2022 and July 2023 were enrolled and divided into two groups based on preprocedural transesophageal echocardiography: the non LASEC group (n = 71) and the LASEC group (n = 37). Circulating platelet and endothelial- derived MPs (PMPs and EMPs) in peripheral blood and left atrial blood were detected. Plasma soluble P-selectin (sP-selectin) and von Willebrand factor (vWF) were observed. Diagnostic efficiency was measured using receiver operating characteristic (ROC) curve. RESULTS: Peripheral sP-selectin, vWF and EMPs expressions elevated in all subjects when compared to those in left atrium blood. Levels of sP-selectin and vWF were significantly higher in peripheral blood of LASEC group than those of non LASEC group (p = 0.0018,p = 0.0271). Significant accumulations of peripheral PMPs and EMPs were documented in LASEC group by comparison with non LASEC group (p = 0.0395,p = 0.018). The area under curve(AUC) of combined PMPs and sP-selectin in predicting LASEC was 0.769 (95%CI: 0.678-0.845, sensitivity: 86.49%, specificity: 59.15%), significantly larger than PMPs or sP-selectin alone. CONCLUSIONS: Expressions of PMPs, sP-selectin, EMPs and vWF Increased in NVAF patients with LASEC and that might be potential biomarkers for LASEC prediction.
Asunto(s)
Fibrilación Atrial , Biomarcadores , Ablación por Catéter , Ecocardiografía Transesofágica , Atrios Cardíacos , Selectina-P , Valor Predictivo de las Pruebas , Factor de von Willebrand , Humanos , Fibrilación Atrial/sangre , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/diagnóstico por imagen , Fibrilación Atrial/cirugía , Masculino , Femenino , Persona de Mediana Edad , Atrios Cardíacos/diagnóstico por imagen , Selectina-P/sangre , Factor de von Willebrand/metabolismo , Factor de von Willebrand/análisis , Biomarcadores/sangre , Anciano , Resultado del Tratamiento , Función del Atrio Izquierdo , Factores de Riesgo , Medición de RiesgoRESUMEN
BACKGROUND: Bone regeneration is a well-regulated dynamic process, of which the prominent role of the immune system on bone homeostasis is more and more revealed by recent research. Before fully activation of the bone remodeling cells, the immune system needs to clean up the microenvironment in facilitating the bone repair initiation. Furthermore, this microenvironment must be maintained properly by various mechanisms over the entire bone regeneration process. OBJECTIVE: This review aims to summarize the role of the T-helper 17/Regulatory T cell (Th17/Treg) balance in bone cell remodeling and discuss the relevant progress in bone tissue engineering. RESULTS: The role of the immune response in the early stages of bone regeneration is crucial, especially the impact of the Th17/Treg balance on osteoclasts, mesenchymal stem cells (MSCs), and osteoblasts activity. By virtue of these knowledge advancements, innovative approaches in bone tissue engineering, such as nano-structures, hydrogel, and exosomes, are designed to influence the Th17/Treg balance and thereby augment bone repair and regeneration. CONCLUSION: Targeting the Th17/Treg balance is a promising innovative strategy for developing new treatments to enhance bone regeneration, thus offering potential breakthroughs in bone injury clinics.
Asunto(s)
Regeneración Ósea , Huesos , Linfocitos T Reguladores , Células Th17 , Ingeniería de Tejidos , Humanos , Linfocitos T Reguladores/inmunología , Ingeniería de Tejidos/métodos , Regeneración Ósea/inmunología , Animales , Células Th17/inmunología , Huesos/inmunología , Células Madre Mesenquimatosas/inmunología , Células Madre Mesenquimatosas/metabolismo , Remodelación Ósea/inmunología , Osteoblastos/inmunología , Osteoclastos/inmunología , Osteoclastos/metabolismoRESUMEN
INTRODUCTION: Amomum fruit, also known as Sharen, serves as both a functional food and a traditional Chinese medicine with significant pharmacological activities. However, there are three botanical origins of Amomum fruit: Amomum villosum Lour. (AVL), Amomum villosum Lour. var. xanthioides T. L. (AVX), and Amomum longiligulare T. L. Wu (ALW). OBJECTIVE: Conducting a comprehensive chemical composition analysis of Amomum fruit from three botanical origins aims to identify potential differences in metabolic characteristics. METHODS: To annotate the metabolic characteristic ions of multi-origin Amomum fruit, we employed metabolomic techniques, including ultra-high-performance liquid chromatography (LC) coupled with linear ion trap-Orbitrap-tandem mass spectrometry (MS) and gas chromatography-MS, in conjunction with feature-based molecular networking technology. Additionally, chemometrics was utilized to examine the correlations between the various botanical origins. RESULTS: A total of 201 non-volatile and 151 volatile metabolites were annotated, and most of the proanthocyanidins and flavonoids were identified by feature-based molecular networking. Additionally, 61 non-volatile and 45 volatile feature ions were screened out for classification. Principal component analysis, orthogonal projection to latent structures discrimination analysis, and heat map analysis were employed to clearly distinguish the metabolite profiles of Amomum fruit from different origins. Hierarchical clustering analysis indicated that proanthocyanidins C1 and C2, as well as proanthocyanins oligomers, show significant differential expression between AVX and AVL, which could be the new quality markers for the classification. CONCLUSION: Classification of the botanical origin of Amomum fruit based on LC-MS characteristic ions proved to be more advantageous. This study introduces new strategies and technical support for the quality control of Amomum fruit and facilitates the identification of unknown compounds for future research.