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1.
Front Cell Infect Microbiol ; 14: 1385562, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38846353

RESUMEN

Background: Lower respiratory tract infections represent prevalent ailments. Nonetheless, current comprehension of the microbial ecosystems within the lower respiratory tract remains incomplete and necessitates further comprehensive assessment. Leveraging the advancements in metagenomic next-generation sequencing (mNGS) technology alongside the emergence of machine learning, it is now viable to compare the attributes of lower respiratory tract microbial communities among patients across diverse age groups, diseases, and infection types. Method: We collected bronchoalveolar lavage fluid samples from 138 patients diagnosed with lower respiratory tract infections and conducted mNGS to characterize the lung microbiota. Employing various machine learning algorithms, we investigated the correlation of key bacteria in patients with concurrent bronchiectasis and developed a predictive model for hospitalization duration based on these identified key bacteria. Result: We observed variations in microbial communities across different age groups, diseases, and infection types. In the elderly group, Pseudomonas aeruginosa exhibited the highest relative abundance, followed by Corynebacterium striatum and Acinetobacter baumannii. Methylobacterium and Prevotella emerged as the dominant genera at the genus level in the younger group, while Mycobacterium tuberculosis and Haemophilus influenzae were prevalent species. Within the bronchiectasis group, dominant bacteria included Pseudomonas aeruginosa, Haemophilus influenzae, and Klebsiella pneumoniae. Significant differences in the presence of Pseudomonas phage JBD93 were noted between the bronchiectasis group and the control group. In the group with concomitant fungal infections, the most abundant genera were Acinetobacter and Pseudomonas, with Acinetobacter baumannii and Pseudomonas aeruginosa as the predominant species. Notable differences were observed in the presence of Human gammaherpesvirus 4, Human betaherpesvirus 5, Candida albicans, Aspergillus oryzae, and Aspergillus fumigatus between the group with concomitant fungal infections and the bacterial group. Machine learning algorithms were utilized to select bacteria and clinical indicators associated with hospitalization duration, confirming the excellent performance of bacteria in predicting hospitalization time. Conclusion: Our study provided a comprehensive description of the microbial characteristics among patients with lower respiratory tract infections, offering insights from various perspectives. Additionally, we investigated the advanced predictive capability of microbial community features in determining the hospitalization duration of these patients.


Asunto(s)
Bacterias , Líquido del Lavado Bronquioalveolar , Secuenciación de Nucleótidos de Alto Rendimiento , Aprendizaje Automático , Metagenómica , Microbiota , Infecciones del Sistema Respiratorio , Humanos , Metagenómica/métodos , Persona de Mediana Edad , Infecciones del Sistema Respiratorio/microbiología , Infecciones del Sistema Respiratorio/virología , Anciano , Masculino , Femenino , Adulto , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Líquido del Lavado Bronquioalveolar/microbiología , Microbiota/genética , Adulto Joven , Bronquiectasia/microbiología , Anciano de 80 o más Años , Metagenoma , Adolescente , Pulmón/microbiología , Pulmón/virología , Hospitalización
2.
NPJ Precis Oncol ; 8(1): 99, 2024 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-38831114

RESUMEN

Fetal adenocarcinoma of the lung (FLAC) is a rare form of lung adenocarcinoma and was divided into high-grade (H-FLAC) and low-grade (L-FLAC) subtypes. Despite the existence of some small case series studies, a comprehensive multi-omics study of FLAC has yet to be undertaken. In this study, we depicted the multi-omics landscapes of this rare lung cancer type by performing multi-regional sampling on 20 FLAC cases. A comparison of multi-omics profiles revealed significant differences between H-FLAC and L-FLAC in a multi-omic landscape. Two subtypes also showed distinct relationships between multi-layer intratumor heterogeneity (ITH). We discovered that a lower genetic ITH was significantly associated with worse recurrence-free survival and overall survival in FLAC patients, whereas higher methylation ITH in H-FLAC patients suggested a short survival. Our findings highlight the complex interplay between genetic and transcriptional heterogeneity in FLAC and suggest that different types of ITH may have distinct implications for patient prognosis.

3.
Genome Med ; 16(1): 79, 2024 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-38849905

RESUMEN

BACKGROUND: Gastric cancer is the fifth most common cancer type. Most patients are diagnosed at advanced stages with poor prognosis. A non-invasive assay for the detection of early-stage gastric cancer is highly desirable for reducing associated mortality. METHODS: We collected a prospective study cohort of 110 stage I-II gastric cancer patients and 139 non-cancer individuals. We performed whole-genome sequencing with plasma samples and profiled four types of cell-free DNA (cfDNA) characteristics, fragment size pattern, copy number variation, nucleosome coverage pattern, and single nucleotide substitution. With these differential profiles, we developed an ensemble model to detect gastric cancer signals. Further, we validated the assay in an in-house first validation cohort of 73 gastric cancer patients and 94 non-cancer individuals and an independent second validation cohort of 47 gastric cancer patients and 49 non-cancer individuals. Additionally, we evaluated the assay in a hypothetical 100,000 screening population by Monte Carlo simulation. RESULTS: Our cfDNA-based assay could distinguish early-stage gastric cancer from non-cancer at an AUROC of 0.962 (95% CI: 0.942-0.982) in the study cohort, 0.972 (95% CI: 0.953-0.992) in the first validation cohort and 0.937 (95% CI: 0.890-0.983) in the second validation cohort. The model reached a specificity of 92.1% (128/139) and a sensitivity of 88.2% (97/110) in the study cohort. In the first validation cohort, 91.5% (86/94) of non-cancer individuals and 91.8% (67/73) of gastric cancer patients were correctly identified. In the second validation cohort, 89.8% (44/49) of non-cancer individuals and 87.2% (41/47) of gastric cancer patients were accurately classified. CONCLUSIONS: We introduced a liquid biopsy assay using multiple dimensions of cfDNA characteristics that could accurately identify early-stage gastric cancer from non-cancerous conditions. As a cost-effective non-invasive approach, it may provide population-wide benefits for the early detection of gastric cancer. TRIAL REGISTRATION: This study was registered on ClinicalTrials.gov under the identifier NCT05269056 on March 7, 2022.


Asunto(s)
Biomarcadores de Tumor , Ácidos Nucleicos Libres de Células , Detección Precoz del Cáncer , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/sangre , Biopsia Líquida/métodos , Detección Precoz del Cáncer/métodos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Estudios Prospectivos , Variaciones en el Número de Copia de ADN , Adulto , ADN Tumoral Circulante/sangre , ADN Tumoral Circulante/genética
4.
Artículo en Inglés | MEDLINE | ID: mdl-38862405

RESUMEN

Controlling the crystal facets of semiconductor nanocrystals (NCs) has been proven as an effective approach to tune their physicochemical properties. However, the study on facet-engineering of metastable zinc blende CdS (zb-CdS) and its heterostructures is still not fully explored. In this study, the zb-CdS and Au@zb-CdS core-shell NCs with tunable terminating facets are controllably synthesized, and their photocatalytic performance for water splitting are evaluated. It is found that the {111} facets of the zb-CdS NCs display higher intrinsic activity than the {100} counterparts, which originates from these surfaces being much more efficient, facilitating electron transition to enhance the adsorption ability and the dissociation of the adsorbed water, as revealed by theoretical calculations. Moreover, the Au@zb-CdS core-shell NCs exhibit better photocatalytic performance than the zb-CdS NCs terminated with the same facets under visible light irradiation (≥400 nm), which is mainly ascribed to the accelerated electron separation at the interface, as demonstrated by femtosecond transient absorption (fs-TA) spectroscopy. Importantly, the quantum yield of plasmon-induced hot electron transfer quantified by fs-TA in the Au@zb-CdS core-shell octahedrons can be reached as high as 1.2% under 615 nm excitation, which is higher than that of the Au@zb-CdS core-shell cubes. This work unravels the face-dependent photocatalytic performance of the metastable semiconductor NCs via a combination of experiments and theoretical calculations, providing the understanding of the underlying mechanism of these photocatalysts.

5.
Apoptosis ; 2024 Jun 09.
Artículo en Inglés | MEDLINE | ID: mdl-38853204

RESUMEN

TRAF2 and NCK interacting kinase (TNIK), a critical interacting protein kinase, is currently receiving wide attention. TNIK is found in various human body organs and tissues and participates in cell motility, proliferation, and differentiation. On the one hand, its aberrant expression is related to the onset and progression of numerous malignant tumors. On the other hand, TNIK is important in neuronal growth, proliferation, differentiation, and synaptic formation. Thus, the novel therapeutic strategies for targeting TNIK offer a promising direction for cancer, neurological or psychotic disorders. Here, we briefly summarized the biological information of TNIK, reviewed the role and regulatory mechanism in cancer and neuropsychiatric diseases, and introduced the research progress of inhibitors targeting TNIK. Taken together, this review hopes to contribute to the in-depth understanding of the function and regulatory mechanism of TNIK, which is of great significance for revealing the role of TNIK in the occurrence and treatment of diseases.

6.
Theranostics ; 14(8): 3358-3384, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38855176

RESUMEN

With the increase in the aging population, the occurrence of neurological disorders is rising. Recently, stem cell therapy has garnered attention due to its convenient sourcing, minimal invasiveness, and capacity for directed differentiation. However, there are some disadvantages, such as poor quality control, safety assessments, and ethical and logistical issues. Consequently, scientists have started to shift their attention from stem cells to extracellular vesicles due to their similar structures and properties. Beyond these parallels, extracellular vesicles can enhance biocompatibility, facilitate easy traversal of barriers, and minimize side effects. Furthermore, stem cell-derived extracellular vesicles can be engineered to load drugs and modify surfaces to enhance treatment outcomes. In this review, we summarize the functions of native stem cell-derived extracellular vesicles, subsequently review the strategies for the engineering of stem cell-derived extracellular vesicles and their applications in Alzheimer's disease, Parkinson's disease, and stroke, and discuss the challenges and solutions associated with the clinical translation of stem cell-derived extracellular vesicles.


Asunto(s)
Enfermedad de Alzheimer , Vesículas Extracelulares , Enfermedad de Parkinson , Células Madre , Accidente Cerebrovascular , Humanos , Vesículas Extracelulares/trasplante , Vesículas Extracelulares/metabolismo , Enfermedad de Parkinson/terapia , Enfermedad de Parkinson/metabolismo , Enfermedad de Alzheimer/terapia , Enfermedad de Alzheimer/metabolismo , Animales , Accidente Cerebrovascular/terapia , Trasplante de Células Madre/métodos
7.
Clin Lab ; 70(6)2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38868888

RESUMEN

BACKGROUND: The aim of this study was to evaluate the therapeutic regimen of a patient with myelodysplastic syndrome (MDS) who developed invasive fungal infections caused by drug-resistant Candida tropicalis after chemotherapy and to investigate the effect of drug treatment. METHODS: We referred to the Diagnostic Criteria and Treatment Principles of invasive fungal diseases in patients with hematological diseases and malignant tumors (2013, fourth revised edition) and the Expert Consensus on Clinical Application of Posaconazole (2022 Edition). In addition, the drug treatment regimens of drug-resistant Candida tropicalis were reviewed. The doctors in charge were involved in the drug treatment process, and the ra-tional drug use was selected according to evidence-based medicine. RESULTS: After 4 months of use, the nodules around the body disappeared, and there was no further fever during follow-up. After 6 months of use, posaconazole was discontinued, and the patient continued to follow-up for 1 month without further fever or nodules. CONCLUSIONS: The combination of posaconazole, amphotericin B liposome, and micafungin is effective in the treatment of fluconazole-resistant Candida tropicalis infection.


Asunto(s)
Anfotericina B , Antifúngicos , Farmacorresistencia Fúngica , Síndromes Mielodisplásicos , Triazoles , Humanos , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/complicaciones , Antifúngicos/uso terapéutico , Triazoles/uso terapéutico , Triazoles/administración & dosificación , Anfotericina B/uso terapéutico , Candida tropicalis/efectos de los fármacos , Masculino , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Infecciones Fúngicas Invasoras/diagnóstico , Infecciones Fúngicas Invasoras/microbiología , Micafungina/uso terapéutico , Micafungina/administración & dosificación , Anciano , Persona de Mediana Edad , Resultado del Tratamiento
9.
Biomed Pharmacother ; 175: 116739, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38759288

RESUMEN

BACKGROUND: Ketamine, as a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptors, was originally used in general anesthesia. Epidemiological data show that ketamine has become one of the most commonly abused drugs in China. Ketamine administration might cause cognitive impairment; however, its molecular mechanism remains unclear. The glymphatic system is a lymphoid system that plays a key role in metabolic waste removal and cognitive regulation in the central nervous system. METHODS: Focusing on the glymphatic system, this study evaluated the behavioral performance and circulatory function of the glymphatic system by building a short-term ketamine administration model in mice, and detected the expression levels of the 5-HT2c receptor, ΔFosb, Pten, Akt, and Aqp4 in the hippocampus. Primary astrocytes were cultured to verify the regulatory relationships among related indexes using a 5-HT2c receptor antagonist, a 5-HT2c receptor short interfering RNA (siRNA), and a ΔFosb siRNA. RESULTS: Ketamine administration induced ΔFosb accumulation by increasing 5-HT2c receptor expression in mouse hippocampal astrocytes and primary astrocytes. ΔFosb acted as a transcription factor to recognize the AATGATTAAT bases in the 5' regulatory region of the Aqp4 gene (-1096 bp to -1087 bp), which inhibited Aqp4 expression, thus causing the circulatory dysfunction of the glymphatic system, leading to cognitive impairment. CONCLUSIONS: Although this regulatory mechanism does not involve the Pten/Akt pathway, this study revealed a new mechanism of ketamine-induced cognitive impairment in non-neuronal systems, and provided a theoretical basis for the safety of clinical treatment and the effectiveness of withdrawal.


Asunto(s)
Astrocitos , Disfunción Cognitiva , Sistema Glinfático , Hipocampo , Ketamina , Animales , Ketamina/farmacología , Ketamina/toxicidad , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/metabolismo , Ratones , Masculino , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Sistema Glinfático/efectos de los fármacos , Sistema Glinfático/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Acuaporina 4/metabolismo , Acuaporina 4/genética , Receptor de Serotonina 5-HT2C/metabolismo , Receptor de Serotonina 5-HT2C/genética , Ratones Endogámicos C57BL , Células Cultivadas , Proteínas Proto-Oncogénicas c-fos/metabolismo , Proteínas Proto-Oncogénicas c-fos/genética , Fosfohidrolasa PTEN/metabolismo , Fosfohidrolasa PTEN/genética
10.
Biosens Bioelectron ; 259: 116385, 2024 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-38759310

RESUMEN

Cell-substrate interaction plays a critical role in determining the mechanical status of living cell membrane. Changes of substrate surface properties can significantly alter the cell mechanical microenvironment, leading to mechanical changes of cell membrane. However, it is still difficult to accurately quantify the influence of the substrate surface properties on the mechanical status of living cell membrane without damage. This study addresses the challenge by using an electrochemical sensor made from an ultrasmall quartz nanopipette. With the tip diameter less than 100 nm, the nanopipette-based sensor achieves highly sensitive, noninvasive and label-free monitoring of the mechanical status of single living cells by collecting stable cyclic membrane oscillatory signals from continuous current versus time traces. The electrochemical signals collected from PC12 cells cultured on three different substrates (bare ITO (indium tin oxides) glass, hydroxyl modified ITO glass, amino modified ITO glass) indicate that the microenvironment more favorable for cell adhesion can increase the membrane stiffness. This work provides a label-free electrochemical approach to accurately quantify the mechanical status of single living cells in real-time, which may help to better understand the relationship between the cell membrane and the extra cellular matrix.


Asunto(s)
Técnicas Biosensibles , Membrana Celular , Técnicas Electroquímicas , Compuestos de Estaño , Técnicas Biosensibles/instrumentación , Técnicas Biosensibles/métodos , Animales , Ratas , Células PC12 , Compuestos de Estaño/química , Técnicas Electroquímicas/métodos , Membrana Celular/química , Adhesión Celular , Vibración , Propiedades de Superficie , Diseño de Equipo
11.
PLoS One ; 19(5): e0303531, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38820298

RESUMEN

For a multi-dimensional measure of positive youth development (PYD), its factor structure should be invariant across groups and over time. This study examined the factorial validity of the 44-item short form of the "Chinese Positive Youth Development Scale" (CPYDS-SF) that assesses 15 dimensions of PYD attributes. Using two waves of longitudinal data with a one-year interval in between, this study examined the factor structure of the scale and whether the structure is invariant between gender groups and across time. The data were collected from 3,328 adolescents at Wave 1 and 3,638 adolescents at Wave 2, with a matched sample of 2,905 adolescents (mean age = 12.57 ± 0.72 at Wave 1; 49.54% girls). Confirmatory factor analysis revealed that the 15-factor structure fitted the data well. The findings of invariance tests further supported this structure's invariance across gender and time, indicating a stable factor structure of CPYDS-SF among Chinese adolescents. These findings suggest that CPYDS-SF can be used to examine gender differences and the longitudinal development of PYD qualities among Chinese adolescents.


Asunto(s)
Desarrollo del Adolescente , Humanos , Adolescente , Masculino , Femenino , Análisis Factorial , Niño , Estudios Longitudinales , China , Encuestas y Cuestionarios , Psicometría/métodos , Pueblo Asiatico , Pueblos del Este de Asia
12.
Comput Biol Med ; 177: 108666, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38820773

RESUMEN

BACKGROUND: α-1,3-mannosyltransferase (ALG3) holds significance as a key member within the mannosyltransferase family. Nevertheless, the exact function of ALG3 in cancer remains ambiguous. Consequently, the current research aimed to examine the function and potential mechanisms of ALG3 in various types of cancer. METHODS: Deep pan-cancer analyses were conducted to investigate the expression patterns, prognostic value, genetic variations, single-cell omics, immunology, and drug responses associated with ALG3. Subsequently, in vitro experiments were executed to ascertain the biological role of ALG3 in breast cancer. Moreover, the link between ALG3 and CD8+ T cells was verified using immunofluorescence. Lastly, the association between ALG3 and chemokines was assessed using qRT-PCR and ELISA. RESULTS: Deep pan-cancer analysis demonstrated a heightened expression of ALG3 in the majority of tumors based on multi-omics evidence. ALG3 emerges as a diagnostic and prognostic biomarker across diverse cancer types. In addition, ALG3 participates in regulating the tumor immune microenvironment. Elevated levels of ALG3 were closely linked to the infiltration of bone marrow-derived suppressor cells (MDSC) and CD8+ T cells. According to in vitro experiments, ALG3 promotes proliferation and migration of breast cancer cells. Moreover, ALG3 inhibited CD8+ T cell infiltration by suppressing chemokine secretion. Finally, the inhibition of ALG3 enhanced the responsiveness of breast cancer cells to 5-fluorouracil treatment. CONCLUSION: ALG3 shows potential as both a prognostic indicator and immune infiltration biomarker across various types of cancer. Inhibition of ALG3 may represent a promising therapeutic strategy for tumor treatment.


Asunto(s)
Linfocitos T CD8-positivos , Fluorouracilo , Humanos , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/metabolismo , Fluorouracilo/farmacología , Quimiocinas/metabolismo , Quimiocinas/genética , Femenino , Línea Celular Tumoral , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Neoplasias/genética , Neoplasias/metabolismo , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Multiómica
13.
J Asian Nat Prod Res ; 26(7): 803-811, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38721701

RESUMEN

Two new triterpenes mayteneri A (1), mayteneri B (2), and seven known compounds (3-9) were isolated from stems of Maytenus hookeri Loes. The chemical structures of compounds 1 and 2 were established by 1D, 2D NMR, HRESIMS analysis, and calculating electronic circular dichroism (ECD). The structures of known compounds 3-9 were determined by comparison of their spectral with those reported. Compounds 4-7 showed significant inhibitory activity for NLRP3 inflammasome, with the IC50 values of 2.36-3.44 µM.


Asunto(s)
Maytenus , Ácido Oleanólico , Estructura Molecular , Ácido Oleanólico/química , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/aislamiento & purificación , Ácido Oleanólico/farmacología , Maytenus/química , Triterpenos/química , Triterpenos/farmacología , Triterpenos/aislamiento & purificación , Tallos de la Planta/química , Animales , Ratones , Inflamasomas/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores
14.
J Hazard Mater ; 473: 134627, 2024 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-38776818

RESUMEN

Chemical stabilization is frequently used to stabilize lead (Pb) or arsenate (As), but faces challenges in Pb-As co-contaminated soils because of the antagonistic reactions between chemical stabilizers and contaminants. In this work, we innovated an effective and cost-efficient stepwise steam flash heating (SSFH) strategy to simultaneously immobilize Pb and As, and unraveled the underlying mechanisms. The combination of 1.5% Ca(H2PO4)2 and 2% Fe2(SO4)3 only decreased 1.99% Pb by toxicity characteristic leaching procedure (TCLP-Pb) but increased 17.8% of TCLP-As due to the antagonistic effects. SSFH with Ca(H2PO4)2 in the first step and Fe2(SO4)3 in the second step achieved the minimal TCLP-Pb and TCLP-As of 0.778 and 0.327 mg/L, respectively. It also reduced 69.8% of leachable As in 100-year acid rain simulation, indicating a favorable long-term stabilization performance. Additionally, SSFH approach reduced 43.2% stabilizer dosage and 14.9% cost. X-ray absorption near edge structure (XANES) documented that the stepwise SFH promoted the transformation of Pb(NO3)2 and NaAsO2/NaAsO3/As2O3/As2O5 into stable Pb3(PO4)2 and FeAsO4, preventing the formation of AsO43- and FePO4. Our findings proved the state-of-the-art SSFH approach and unraveled its mechanisms to stabilize Pb and As co-contamination in soils, offering a green and sustainable remediation alternative for the management of heavy metal contaminated sites. ENVIRONMENTAL IMPLICATION: A novel stepwise SFH approach can be applied to overcome the stabilizer antagonist effects by separately immobilizing Pb and As in two sequential steps. It also decreased 43.2% of stabilizer dosage and 14.9% of cost comparing to conventional chemical stabilization. This approach can be used for other metal co-contaminated soils facing similar antagonistic challenges, and our work raises a state-of-the-art solution for cost-effective, green and sustainable remediation practices.

15.
Eur J Pharm Sci ; 199: 106794, 2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-38788908

RESUMEN

Myocardial fibrosis can induce cardiac dysfunction and remodeling. Great attention has been paid to traditional chinese medicine (TCM) 's effectiveness in treating MF. Radix Angelica sinensis (Oliv.) Diels and Radix Astragalus mongholicus Bunge ultrafiltration extract (RAS-RA), which is a key TCM compound preparation, have high efficacy in regulating inflammation. However, studies on its therapeutic effect on radiation-induced myocardial fibrosis (RIMF) are rare. In this study, RAS-RA had therapeutic efficacy in RIMF and elucidated its mechanism of action. First, we formulated the prediction network that described the relation of RAS-RA with RIMF according to data obtained in different databases. Then, we conducted functional enrichment to investigate the functions and pathways associated with potential RIMF targets for RAS-RA. In vivo experiments were also performed to verify these functions and pathways. Second, small animal ultrasound examinations, H&E staining, Masson staining, transmission electron microscopy, Enzyme-linked immunosorbent assay (ELISA), Western-blotting, Immunohistochemical method and biochemical assays were conducted to investigate the possible key anti-RIMF pathway in RAS-RA. In total, 440 targets were detected in those 21 effective components of RAS-RA; meanwhile, 1,646 RIMF-related disease targets were also discovered. After that, PPI network analysis was conducted to identify 20 key targets based on 215 overlap gene targets. As indicated by the gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) analysis results, inflammation and PI3K/AKT/mTOR pathways might have important effects on the therapeutic effects on RIMF. Molecular docking analysis revealed high binding of effective components to targets (affinity < -6 kcal/mol). Based on experimental verification results, RAS-RA greatly mitigated myocardial fibrosis while recovering the cardiac activity of rats caused by X-rays. According to relevant protein expression profiles, the PI3K/AKT/mTOR pathway was important for anti-fibrosis effect of RAS-RA. Experimental studies showed that RAS-RA improved cardiac function, decreased pathological damage and collagen fiber deposition in cardiac tissues, and improved the mitochondrial structure of the heart of rats. RAS-RA also downregulated TNF-α, IL-6, and IL-1ß levels. Additionally, RAS-RA improved the liver and kidney functions and pathological injury of rat kidney and liver tissues, enhanced liver and kidney functions, and protected the liver and kidneys. RAS-RA also increased PI3K, AKT and mTOR protein levels within cardiac tissues and downregulated α-SMA, Collagen I, and Collagen III. The findings of this study suggested that RAS-RA decreased RIMF by suppressing collagen deposition and inflammatory response by inhibiting the PI3K/AKT/mTOR pathway. Thus, RAS-RA was the potential therapeutic agent used to alleviate RIMF.


Asunto(s)
Angelica sinensis , Medicamentos Herbarios Chinos , Fibrosis , Farmacología en Red , Ratas Sprague-Dawley , Animales , Angelica sinensis/química , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Masculino , Ratas , Planta del Astrágalo/química , Miocardio/patología , Miocardio/metabolismo , Ultrafiltración/métodos , Transducción de Señal/efectos de los fármacos , Cardiomiopatías/tratamiento farmacológico , Cardiomiopatías/etiología , Cardiomiopatías/metabolismo , Serina-Treonina Quinasas TOR/metabolismo
16.
Free Radic Biol Med ; 221: 203-214, 2024 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-38788982

RESUMEN

Sepsis-associated encephalopathy (SAE) is a severe complication that affects the central nervous system and is a leading cause of increased morbidity and mortality in intensive care units. Psoralidin (PSO), a coumarin compound isolated from the traditional Chinese medicine Psoralea corylifolia L., can penetrate the blood-brain barrier and has various pharmacological activities, including anti-inflammation, anti-oxidation and anti-depression. This study aims to explore whether PSO alleviates SAE and delve into the underlying mechanisms. We found that PSO treatment significantly reduced sepsis scores, aspartate transaminase (AST) and aspartate transaminase (LDH), while increased anal temperature and neurological scores in CLP-injured mice. Moreover, PSO treatment ameliorated sepsis-associated cognitive impairment, mood, anxiety disorders, inhibited inflammatory responses, as well as attenuated endoplasmic reticulum stress (ERS). These results were also validated in vitro experiments, PSO treatment reduced ROS, inflammation response, and attenuated ERS in LPS-injured N2a cells. Importantly, tunicamycin (TUN), as ERS agonist, significantly reversed the protective effect of PSO on LPS-injured N2a cells, as evidenced by increased expression levels of IL-6, NLRP3, CHOP, and ATF6. Likewise, ATF6 overexpression also reversed the protective effect of PSO. In conclusion, these results confirmed that PSO has a protective effect on SAE, which was largely attributed to neuroinflammation and ERS. These findings provide new insights into the neuroprotective role of PSO and suggest that PSO is a new therapeutic intervention of SAE.


Asunto(s)
Benzofuranos , Cumarinas , Estrés del Retículo Endoplásmico , Encefalopatía Asociada a la Sepsis , Animales , Estrés del Retículo Endoplásmico/efectos de los fármacos , Ratones , Cumarinas/farmacología , Encefalopatía Asociada a la Sepsis/tratamiento farmacológico , Encefalopatía Asociada a la Sepsis/metabolismo , Encefalopatía Asociada a la Sepsis/patología , Benzofuranos/farmacología , Masculino , Lipopolisacáridos/toxicidad , Sepsis/tratamiento farmacológico , Sepsis/complicaciones , Sepsis/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Modelos Animales de Enfermedad , Especies Reactivas de Oxígeno/metabolismo , Tunicamicina/farmacología , Ratones Endogámicos C57BL
17.
Lupus Sci Med ; 11(1)2024 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-38806217

RESUMEN

OBJECTIVES: To investigate the effectiveness of belimumab on active lupus nephritis (LN) and explore the predictors, including serological biomarkers, of renal response to belimumab in a real-world setting. METHODS: This multicentre, real-world observational study enrolled patients with active LN receiving intravenous belimumab as an add-on therapy with 24-hour urine protein≥1 g and estimated glomerular filtration rate≥30 mL/min/1.73 m2 at baseline. Complete renal response (CRR), partial renal response (PRR), no renal response (NRR) and primary efficacy renal response (PERR) were evaluated. Multivariable logistic regression was used to identify risk factors for NRR to belimumab at 6 months. RESULTS: Among the 122 patients enrolled, the proportions of patients achieving CRR, PRR, NRR and PERR were 35.9%, 17.1%, 47.0% and 44.4% at 6 months (n=117) and 55.6%, 19.4%, 26.4% and 58.3% at 12 months (n=72), respectively. Proteinuria, daily prednisone dosage and Systemic Lupus Erythematosus Disease Activity Index 2000 scores significantly decreased at 6 and 12 months (p<0.0001). NRR at 6 months (NRR6) was the strongest negative predictor of CRR at 12 months. Baseline anti-dsDNA positivity inversely predicted NRR6 (OR=0.32,95% CI=0.10 to 0.98, p=0.049), while anti-SSA/Ro60 positively predicted NRR6 (OR=3.16, 95% CI=1.14 to 8.74, p=0.027). The combination of anti-SSA/Ro60 and anti-dsDNA serotype quantitatively predicted belimumab renal response. CONCLUSION: The effectiveness of belimumab was reproducible in Chinese patients with active LN. The simple yet interesting serotype predictive model needs further validation and its possible underlying mechanistic relevance deserves further exploration.


Asunto(s)
Anticuerpos Antinucleares , Anticuerpos Monoclonales Humanizados , Tasa de Filtración Glomerular , Inmunosupresores , Nefritis Lúpica , Humanos , Nefritis Lúpica/tratamiento farmacológico , Nefritis Lúpica/inmunología , Femenino , Masculino , Anticuerpos Monoclonales Humanizados/uso terapéutico , Adulto , Anticuerpos Antinucleares/sangre , Inmunosupresores/uso terapéutico , Persona de Mediana Edad , Tasa de Filtración Glomerular/efectos de los fármacos , Resultado del Tratamiento , Riñón/fisiopatología , Riñón/efectos de los fármacos , Riñón/inmunología , Biomarcadores/sangre , Adulto Joven , Proteinuria/tratamiento farmacológico , ADN
19.
Nat Commun ; 15(1): 3961, 2024 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-38729932

RESUMEN

Mechanically interlocked molecules (MIMs) including famous catenanes show switchable physical properties and attract continuous research interest due to their potential application in molecular devices. The advantages of using spin crossover (SCO) materials here are enormous, allowing for control through diverse stimuli and highly specific functions, and enabling the transfer of the internal dynamics of MIMs from solution to solid state, leading to macroscopic applications. Herein, we report the efficient self-assembly of catenated metal-organic frameworks (termed catena-MOFs) induced by stacking interactions, through the combination of rationally selected flexible and conjugated naphthalene diimide-based bis-pyridyl ligand (BPND), [MI(CN)2]- (M = Ag or Au) and Fe2+ in a one-step strategy. The obtained bimetallic Hofmann-type SCO-MOFs [FeII(BPND){Ag(CN)2}2]·3CHCl3 (1Ag) and [FeII(BPND{Au(CN)2}2]·2CHCl3·2H2O (1Au) possess a unique three-dimensional (3D) catena-MOF constructed from the polycatenation of two-dimensional (2D) layers with hxl topology. Both complexes undergo thermal- and light-induced SCO. Significantly, abnormal increases in the maximum emission intensity and dielectric constant can be detected simultaneously with the switching of spin states. This research opens up SCO-actuated bistable MIMs that afford dual functionality of coupled fluorescence emission and dielectricity.

20.
Clin Lab ; 70(5)2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38747919

RESUMEN

BACKGROUND: For many years it has been postulated that the immune system controls the progress of multiple myeloma (MM). However, the phenotypes of T cells in MM remain to be elucidated. In this study, we compared the phenotypes of T cells, which were obtained from the peripheral blood, in MM patients with those in healthy donors (HD). The expression of CCR7, CD57, CD28, HLA-DR, CD38, CD45RA, and CD45RO were assessed on T cells from MM patients and HDs using multicolor flow cytometry (MFC). METHODS: For this study, 17 newly diagnosed MM patients were selected, and 20 healthy people were selected as a control group. MFC was used to detect the markers on T cells. RESULTS: We detected significant increases in the expression levels of HLA-DR, CD38, and CD57on CD8+ T cells, significant decreases in the expression levels of CD28 and CD45RA on CD8+ T cells, and a decrease of CD4+ effec-tor T cells in MM patients, compared to the HD group. CONCLUSIONS: Our study shows that the accumulation of peripheral CD8+CD57+T cells, CD8+CD38high T cells, and CD8+HLA-DR+CD38high T cells is reflective of an ongoing antitumor T cell response and a progressive immune dysfunction in MM. During chemotherapy, the recovery of immune function can be monitored by detecting the proportion of activated molecules of T lymphocytes.


Asunto(s)
ADP-Ribosil Ciclasa 1 , Antígenos CD28 , Citometría de Flujo , Antígenos HLA-DR , Antígenos Comunes de Leucocito , Mieloma Múltiple , Humanos , Mieloma Múltiple/inmunología , Antígenos CD28/inmunología , Antígenos CD28/metabolismo , ADP-Ribosil Ciclasa 1/metabolismo , Antígenos HLA-DR/inmunología , Antígenos HLA-DR/metabolismo , Antígenos HLA-DR/sangre , Antígenos Comunes de Leucocito/metabolismo , Masculino , Persona de Mediana Edad , Femenino , Anciano , Antígenos CD57/metabolismo , Estudios de Casos y Controles , Inmunofenotipificación/métodos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Adulto , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Glicoproteínas de Membrana/inmunología
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