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During chronic wound healing, the inflammatory phase can endure for extended periods, heavily impeding or halting the process. Regular inspections and dressing changes are crucial. Modern dressings like hydrogels, hydrocolloids, and foam provide protection and an optimal healing environment. However, they have limitations in offering real-time wound bed status and healing rate. Evaluation relies heavily on direct observation, and passive dressings fail to identify subtle healing differences, preventing adaptive adjustments in biological factors and drug concentrations. In recent years, the clinical field recognizes the value of integrating intelligent diagnostic tools into wound dressings. By monitoring biomarkers linked to chronic wounds' inflammatory state, real-time data can be captured, reducing medical interventions and enabling more effective treatment plans. This fosters innovation in chronic wound care. Researchers have developed smart dressings with sensing, active drug delivery, and self-adjustment capabilities. These dressings detect inflammatory markers like temperature, pH, and oxygen content, enhancing drug bioavailability on the wound surface. As wound healing technology evolves, these smart dressings hold immense potential in chronic wound care and treatment. This comprehensive review updates our understanding on the role and mechanism of action of the smart dressings in chronic refractory wounds by summarizing and discussing the latest research progresses, including the intelligent monitoring of wound oxygen content, temperature, humidity, pH, infection, and enzyme kinetics; intelligent drug delivery triggered by temperature, pH, near-infrared, and electricity; as well as the intelligent self-adjustment of pressure and shape. The review also delves into the constraints and future perspectives of smart dressings in clinical settings, thereby advancing the development of smart wound dressings for chronic wound healing and their practical application in clinical practice.
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Enhancers are a class of noncoding DNA, serving as crucial regulatory elements in governing gene expression by binding to transcription factors. The identification of enhancers holds paramount importance in the field of biology. However, traditional experimental methods for enhancer identification demand substantial human and material resources. Consequently, there is a growing interest in employing computational methods for enhancer prediction. In this study, we propose a two-stage framework based on deep learning, termed CapsEnhancer, for the identification of enhancers and their strengths. CapsEnhancer utilizes chaos game representation to encode DNA sequences into unique images and employs a capsule network to extract local and global features from sequence "images". Experimental results demonstrate that CapsEnhancer achieves state-of-the-art performance in both stages. In the first and second stages, the accuracy surpasses the previous best methods by 8 and 3.5%, reaching accuracies of 94.5 and 95%, respectively. Notably, this study represents the pioneering application of computer vision methods to enhancer identification tasks. Our work not only contributes novel insights to enhancer identification but also provides a fresh perspective for other biological sequence analysis tasks.
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Biología Computacional , Elementos de Facilitación Genéticos , Biología Computacional/métodos , Humanos , Dinámicas no Lineales , Aprendizaje ProfundoRESUMEN
BACKGROUND: Exosomes are nanometer-sized, lipid bilayer membrane vesicles that are secreted by various cell types. Mesenchymal stem cells (MSCs) have been shown to exert therapeutic effects through the secretion of exosomes via a paracrine pathway. Functions: Recent studies have demonstrated that MSC-derived exosomes (MSC-Exos) can effectively transport various bioactive substances, including proteins, mRNAs, microRNAs, long non-coding RNAs, circular RNAs, and lipids, into target cells. This process regulates multiple aspects during wound repair, such as the inflammatory response, cell proliferation, migration, differentiation, angiogenesis, and matrix remodeling. POTENTIAL APPLICATIONS: By promoting wound healing and inhibiting scar formation, MSC-Exos have shown great promise for clinical applications in wound repair. This review highlights the recent advances in our understanding of the role and mechanism of MSC-Exos during wound repair, providing insights into their potential use in future therapeutic strategies.
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Antiviral peptides (AVPs) have shown potential in inhibiting viral attachment, preventing viral fusion with host cells and disrupting viral replication due to their unique action mechanisms. They have now become a broad-spectrum, promising antiviral therapy. However, identifying effective AVPs is traditionally slow and costly. This study proposed a new two-stage computational framework for AVP identification. The first stage identifies AVPs from a wide range of peptides, and the second stage recognizes AVPs targeting specific families or viruses. This method integrates contrastive learning and multi-feature fusion strategy, focusing on sequence information and peptide characteristics, significantly enhancing predictive ability and interpretability. The evaluation results of the model show excellent performance, with accuracy of 0.9240 and Matthews correlation coefficient (MCC) score of 0.8482 on the non-AVP independent dataset, and accuracy of 0.9934 and MCC score of 0.9869 on the non-AMP independent dataset. Furthermore, our model can predict antiviral activities of AVPs against six key viral families (Coronaviridae, Retroviridae, Herpesviridae, Paramyxoviridae, Orthomyxoviridae, Flaviviridae) and eight viruses (FIV, HCV, HIV, HPIV3, HSV1, INFVA, RSV, SARS-CoV). Finally, to facilitate user accessibility, we built a user-friendly web interface deployed at https://awi.cuhk.edu.cn/â¼dbAMP/AVP/.
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Antivirales , Biología Computacional , Péptidos , Antivirales/farmacología , Péptidos/química , Biología Computacional/métodos , Humanos , Virus , Aprendizaje Automático , AlgoritmosRESUMEN
The emergence and spread of antibiotic-resistant bacteria pose a significant public health threat, necessitating the exploration of alternative antibacterial strategies. Antibacterial peptide (ABP) is a kind of antimicrobial peptide (AMP) that has the potential ability to fight against bacteria infection, offering a promising avenue for developing novel therapeutic interventions. This study introduces AMPActiPred, a three-stage computational framework designed to identify ABPs, characterize their activity against diverse bacterial species, and predict their activity levels. AMPActiPred employed multiple effective peptide descriptors to effectively capture the compositional features and physicochemical properties of peptides. AMPActiPred utilized deep forest architecture, a cascading architecture similar to deep neural networks, capable of effectively processing and exploring original features to enhance predictive performance. In the first stage, AMPActiPred focuses on ABP identification, achieving an Accuracy of 87.6% and an MCC of 0.742 on an elaborate dataset, demonstrating state-of-the-art performance. In the second stage, AMPActiPred achieved an average GMean at 82.8% in identifying ABPs targeting 10 bacterial species, indicating AMPActiPred can achieve balanced predictions regarding the functional activity of ABP across this set of species. In the third stage, AMPActiPred demonstrates robust predictive capabilities for ABP activity levels with an average PCC of 0.722. Furthermore, AMPActiPred exhibits excellent interpretability, elucidating crucial features associated with antibacterial activity. AMPActiPred is the first computational framework capable of predicting targets and activity levels of ABPs. Finally, to facilitate the utilization of AMPActiPred, we have established a user-friendly web interface deployed at https://awi.cuhk.edu.cn/â¼AMPActiPred/.
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Antibacterianos , Antibacterianos/farmacología , Antibacterianos/química , Péptidos Antimicrobianos/química , Péptidos Antimicrobianos/farmacología , Bacterias/efectos de los fármacos , Biología Computacional/métodos , Redes Neurales de la Computación , Pruebas de Sensibilidad MicrobianaRESUMEN
Inflammation is a biological response to harmful stimuli, aiding in the maintenance of tissue homeostasis. However, excessive or persistent inflammation can precipitate a myriad of pathological conditions. Although current treatments such as NSAIDs, corticosteroids, and immunosuppressants are effective, they can have side effects and resistance issues. In this backdrop, anti-inflammatory peptides (AIPs) have emerged as a promising therapeutic approach against inflammation. Leveraging machine learning methods, we have the opportunity to accelerate the discovery and investigation of these AIPs more effectively. In this study, we proposed an advanced framework by ensemble machine learning and deep learning for AIP prediction. Initially, we constructed three individual models with extremely randomized trees (ET), gated recurrent unit (GRU), and convolutional neural networks (CNNs) with attention mechanism and then used stacking architecture to build the final predictor. By utilizing various sequence encodings and combining the strengths of different algorithms, our predictor demonstrated exemplary performance. On our independent test set, our model achieved an accuracy, MCC, and F1-score of 0.757, 0.500, and 0.707, respectively, clearly outperforming other contemporary AIP prediction methods. Additionally, our model offers profound insights into the feature interpretation of AIPs, establishing a valuable knowledge foundation for the design and development of future anti-inflammatory strategies.
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Aprendizaje Profundo , Humanos , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Péptidos/farmacología , Inflamación/tratamiento farmacológico , Algoritmos , Aprendizaje AutomáticoRESUMEN
OBJECTIVE: Abdominal aortic aneurysm (AAA) is characterized by vascular smooth muscle cell (VSMC) injury. Circ_0000285 has been declared to drive cancer development, but its role in AAA remains unclear. We thus intended to disclose circ_0000285's role and molecular mechanism in AAA. METHODS: VSMCs were exposed to hydrogen peroxide (H2O2) to induce cell injury. Circ_0000285, miR-599, and regulator of G protein signaling 17 (RGS17) mRNA expressions were ascertained by conducting RT-qPCR assay while the levels of RGS17 protein was ascertained via western blotting. MiR-599's predicted binding with circ_0000285 and RGS17 were validated by means of the dual-luciferase reporter experiment. Cell proliferation was evaluated through the CCK-8 and EdU assays. Cell apoptosis was assessed via the caspase-3 activity assay. RESULTS: The AAA samples and H2O2-treated VSMCs manifested high expressions of circ_0000285 and RGS17 as well as a poor miR-599 expression. H2O2 treatment impaired the proliferation of VSMCs while stimulating their apoptosis. Circ_0000285 overexpression further repressed cell proliferation and enhanced apoptosis in H2O2-treated VSMCs while miR-599 enrichment partly reversed these effects. Circ_0000285 directly bound to miR-599, and miR-599 interacted with RGS17 3'UTR. RGS17 overexpression also suppressed cell proliferation and stimulated apoptosis in H2O2-treated VSMCs. Nevertheless, these effects were offset by miR-599 enrichment. CONCLUSION: Circ_0000285 governed the miR-599/RGS17 network to regulate H2O2-induced VSMC injuries, thereby promoting the development of AAA.
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Aneurisma de la Aorta Abdominal , MicroARNs , Proteínas RGS , Humanos , MicroARNs/genética , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Peróxido de Hidrógeno/farmacología , Transducción de Señal , Aneurisma de la Aorta Abdominal/genética , Aneurisma de la Aorta Abdominal/metabolismo , Aneurisma de la Aorta Abdominal/patología , Proliferación Celular/genética , Apoptosis , Proteínas RGS/metabolismo , Proteínas RGS/farmacologíaRESUMEN
Background: Chemoresistance is problematic and its mechanisms are unclear in breast cancer. More predictive markers are urgently required. Methods: GSE32646, GSE34138, and GSE20271 were downloaded from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs) between chemosensitive and chemoresistant tumors. LinkedOmics was used to analyze ADAM-like Decysin-1 (ADAMDEC1) expression among patients with different clinical characteristics and detect co-expression genes for functional analysis. Tumor Immune Estimation Resource (TIMER) and an integrated repository portal for tumor-immune system interactions (TISIDB) were used to investigate the association between the target gene and the immune response. Gene Set Cancer Analysis (GSCA) was utilized to explore the related pathways of ADAMDEC1 and evaluate the correlation between the expression of ADAMDEC1 and drug sensitivity. RNA22, miRWalk, and miRmap were used to predict the upstream micro ribonucleic acids (miRNAs) regulating ADAMDEC1 expression, while DIANA-LncBase v2 was applied to predict the upstream long non-coding ribonucleic acids (lncRNAs). Kaplan-Meier curve analysis was applied to determine the survival time. Results: We identified that ADAMDEC1 was upregulated among chemosensitive triple-negative breast cancer (TNBC) tissues in GSE32646, GSE34138, and GSE20271. Higher expression of ADAMDEC1 indicated longer survival in breast cancer. Next, we found that ADAMDEC1 was significantly related to the immune response in breast cancer through functional enrichment analysis and further meta-data validation. Moreover, we recognized that hsa-miR-4534 was the potential upstream miRNA regulating ADAMDEC1 expression and Taurine Up-Regulated 1 (TUG1) was the most likely upstream lncRNA of ADAMDEC1 and hsa-miR-4534. Finally, the correlation between ADAMDEC1 and chemosensitivity was confirmed through drug database analysis. Conclusions: Elevated ADAMDEC1 expression is associated with increased chemosensitivity and better prognosis in breast cancer patients.
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The rapid growth of the distributed generators (DGs) integration into the distribution systems (DSs) creates new technical issues; conventional relay settings need to be updated depending on the network topology and operational mode as fault protection a major challenge. This emphasizes the need for new fault protection methods to ensure secure protection and prevent undesirable tripping. Total harmonic distortion (THD) is an important indicator for assessing the quality of the grid. Here, a new protection system based on the THD of the grid voltages is proposed to address fault events in the electrical distribution network. The proposed protection system combines the THD with the estimates of the amplitude voltages and the zero-sequence component for defining an algorithm based on a finite state machine (FSM) for the detection, identification, and isolation of faults in the grid. The algorithm employs communication lines between all the protective devices (PDs) of the system to transmit tripping signals, allowing PDs to be coordinated. A second order generalized integrator (SOGI) and multiple SOGI (MSOGI) are used to obtain the THDs, estimated amplitude voltages, and zero-sequence component, which allows for fast detection with a low computational burden. The protection algorithm performance is evaluated through simulations in MATLAB/Simulink and a comparative study is developed between the proposed protection method and a differential relay (DR) protection system. The proposed method shows its capability to detect and isolate faults during different fault types with different fault resistances in different locations in the proposed network. In all the tested scenarios, the detection time of the faults has been between 7-10 ms. Moreover, this method gave the best solution as it has a higher accuracy and faster response than the conventional DR protection system.
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Algoritmos , Comunicación , Fenómenos Físicos , Sistemas de Computación , ElectricidadRESUMEN
Background and Aims: Monocyte/macrophage-associated CD163 is an indicator of the severity of liver inflammation and cirrhosis, but the difference of soluble CD163 (sCD163) levels in chronic hepatitis B (CHB) patients and hepatitis B surface antigen (HBsAg)-loss patients is unclear. Herein, we aimed to compare the sCD163 levels in CHB patients and HBsAg-loss patients with or without antiviral treatment. Methods: sCD163 and CD163 expression on monocytes were compared among four groups, healthy subjects, treatment-naïve CHB patients, spontaneous HBsAg-loss patients, and treatment-related HBsAg-loss patients. The correlation between sCD163 levels and clinical parameters in CHB patients was analyzed. A group of 80 patients with hepatitis B virus (HBV) infection and liver biopsy were recruited. Results: sCD163 levels were higher in the CHB group than in the other three groups. sCD163 levels were higher in treatment-related HBsAg-loss patients than in spontaneous HBsAg-loss patients. sCD163 levels were negatively correlated with hepatitis B e-antigen (HBeAg) and HBsAg levels in HBeAg-positive patients. Liver biopsy results further demonstrated that sCD163 levels were elevated in CHB patients with substantial inflammation (A≥2) or fibrosis (F≥2). The sCD163 model was more sensitive in predicting inflammation than other noninvasive models. Its levels were higher in patients with normal alanine aminotransferase levels and significant inflammation (A≥2) than in patients with no or mild inflammation. Conclusions: sCD163 and CD163 expression on monocytes were associated with CHB inflammation and HBsAg loss, and may be used as markers to predict HBV-specific immune activation.
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BACKGROUND: By determining the hepatitis B virus (HBV) surface antigen (HBsAg) positive rate postexposure and HBV-specific antigen/antibody (Ag/Ab) level in patients with rheumatic diseases, we aimed at exploring the rheumatic link to HBV control. METHODS: Patients who underwent HBV screening in the Ruijin Hospital from 2020 to 2021 were enrolled for the exposure rate estimation. Among antibody to HBV core antigen (HBcAb)-positive patients, we adopted propensity score matching (PSM) to study the impact of rheumatism on HBsAg seroprevalence after exposure. A second PSM evaluated the Ag/Ab differences. We also had HBsAg prevalence in human leukocyte antigen B2 (HLA-B27) tested patients studied. RESULTS: With 33,989 screened patients, exposure rates remained comparable between rheumatic and non-rheumatic patients: 48.94 vs. 49.86%. PSM first yielded 2,618 balanced pairs. We observed significantly fewer patients with rheumatic diseases in HBsAg positive cases than negative ones (p < 0.001). In the second round, PSM matched 279 pairs, HBsAg (p < 0.001) and HBeAg (p < 0.05) positivity rates were significantly lower in the rheumatic patients, whereas HBsAb positivity rate (p < 0.001) and level (p < 0.01) were significantly higher. Though the value of HBcAb was overall significantly lower (p < 0.001) within the realm of rheumatic diseases, patients with ankylosing spondylitis (AS) demonstrated a significantly higher value than other rheumatic diseases. We saw significantly fewer HBV infections in HLA-B27 positive subjects than in the negative ones (p < 0.001). CONCLUSION: In this propensity score-matched study, rheumatic patients had an advantage in HBV control. In rheumatic patients, HBcAb levels, together with the beneficial role of HLA-B27, were highlighted.
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Hepatitis B virus (HBV) middle surface antigen (MHBs) mutation or deletion occurs in patients with chronic HBV infection. However, the functional role of MHBs in HBV infection is still an enigma. Here, we reported that 7.33% (11/150) isolates of CHB patients had MHBs start codon mutations compared with 0.00% (0/146) in acute hepatitis B (AHB) patients. Interestingly, MHBs loss accounted for 11.88% (126/1061) isolates from NCBI GenBank, compared with 0.09% (1/1061) and 0.00% (0/1061) for HBV large surface antigen (LHBs) loss and HBV small surface antigen (SHBs) loss, respectively. One persistent HBV clone of genotype B (B56, MHBs loss) from a CHB patient was hydrodynamically injected into BALB/c mice. B56 persisted for >70 weeks in BALB/c mice, whereas B56 with restored MHBs (B56M+) was quickly cleared within 28 days. Serum cytokine assays demonstrated that CXCL1, CXCL2, IL-6 and IL-33 were significantly increased during rapid HBV clearance in B56M+ mice. Furthermore, the enhancers and promoters of B56 were proved to be required for B56 persistence in mice. Ablating MHBs expression improved the persistence of a new clone (HBV1.3, genotype B) which was recreated by using enhancers and promoters of B56. These data demonstrated that MHBs deletion can promote the persistence of specific HBV variants in a hydrodynamic mouse model. MHBs re-expression restored a rapid clearance of HBV, which was accompanied by cytokine responses including the elevation of CXCL1, CXCL2, IL-6 and IL-33.
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Virus de la Hepatitis B , Interleucina-33 , Animales , Antígenos de Superficie , Modelos Animales de Enfermedad , Antígenos de Superficie de la Hepatitis B/genética , Virus de la Hepatitis B/genética , Humanos , Interleucina-6/genética , Ratones , Ratones Endogámicos BALB CRESUMEN
Pulmonary microvascular endothelial cells (PMVECs) uniquely express an α1G-subtype of voltage-gated T-type Ca2+ channel. We have previously revealed that the α1G channel functions as a background Ca2+ entry pathway that is critical for the cell proliferation, migration, and angiogenic potential of PMVECs, a novel function attributed to the coupling between α1G-mediated Ca2+ entry and constitutive Akt phosphorylation and activation. Despite this significance, mechanism(s) that link the α1G-mediated Ca2+ entry to Akt phosphorylation remain incompletely understood. In this study, we demonstrate that Ca2+/calmodulin-dependent protein kinase (CaMK) 4 serves as a downstream effector of the α1G-mediated Ca2+ entry to promote the angiogenic potential of PMVECs. Notably, CaMK2 and CaMK4 are both expressed in PMVECs. Pharmacological blockade or genetic knockdown of the α1G channel led to a significant reduction in the phosphorylation level of CaMK4 but not the phosphorylation level of CaMK2. Pharmacological inhibition as well as genetic knockdown of CaMK4 significantly decreased cell proliferation, migration, and network formation capacity in PMVECs. However, CaMK4 inhibition or knockdown did not alter Akt phosphorylation status in PMVECs, indicating that α1G/Ca2+/CaMK4 is independent of the α1G/Ca2+/Akt pathway in sustaining the cells' angiogenic potential. Altogether, these findings suggest a novel α1G-CaMK4 signaling complex that regulates the Ca2+-dominated angiogenic potential in PMVECs.
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Canales de Calcio Tipo T/metabolismo , Señalización del Calcio , Proteína Quinasa Tipo 4 Dependiente de Calcio Calmodulina/metabolismo , Calcio/metabolismo , Células Endoteliales/enzimología , Pulmón/irrigación sanguínea , Microvasos/enzimología , Neovascularización Fisiológica , Inhibidores de la Angiogénesis/farmacología , Animales , Señalización del Calcio/efectos de los fármacos , Proteína Quinasa Tipo 4 Dependiente de Calcio Calmodulina/antagonistas & inhibidores , Proteína Quinasa Tipo 4 Dependiente de Calcio Calmodulina/genética , Movimiento Celular , Proliferación Celular , Células Cultivadas , Células Endoteliales/efectos de los fármacos , Masculino , Microvasos/efectos de los fármacos , Neovascularización Fisiológica/efectos de los fármacos , Fosforilación , Inhibidores de Proteínas Quinasas/farmacología , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Hypertrophic scars (HS) are common pathologic processes emerged during wound-healing process. The receptor-interacting protein kinase (RIP) might participate in keloid formation. AIMS: This study aimed to investigate Necrostatin-1 (Nec-1), a RIP1/RIP3 inhibitor, in the formation of hypertrophic scar. METHODS: Human hypertrophic scar fibroblasts (HSF) were extracted from patients with hypertrophic scar. Transforming growth factor-ß1 (TGF-ß1) was performed to induce wound-healing process including cell proliferation (CCK-8, Flow cytometry, and Western blot), migration (Transwell assay, Western blot), collagen production (Western blot), and extracellular matrix dysfunction (Western blotting and immunofluorescence). RESULTS: Our results reported that Nec-1 inhibited TGF-ß1-induced cell proliferation and promoted G0/G1 phase arrest in HSF. In addition, Nec-1 attenuated TGF-ß1-induced cell migration and inhibited the expression of MMP2 and MMP9 in TGF-ß1-induced HSF. Besides, Nec-1 also reduced TGF-ß1-induced collagen production and α-smooth muscle actin expression in HSF. CONCLUSIONS: The present data in this study showed the potential role of Nec-1 as a novel treatment for HS.
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Cicatriz Hipertrófica , Células Cultivadas , Cicatriz Hipertrófica/tratamiento farmacológico , Cicatriz Hipertrófica/patología , Fibroblastos/patología , Humanos , Imidazoles/farmacología , Indoles , Factor de Crecimiento Transformador beta , Factor de Crecimiento Transformador beta1RESUMEN
BACKGROUND AND AIM: It has been reported that serum quantification of anti-HBc (qAnti-HBc) could predict antiviral response in chronic hepatitis B (CHB) patients, while its role in hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) remains unclear. Its implication in HBV-ACLF was evaluated in this study. METHODS: Baseline serum qAnti-HBc levels were retrospectively detected in HBV-ACLF and CHB patients using recently developed double-sandwich immunoassay. The association of qAnti-HBc level with clinical outcomes was evaluated by multiple logistic regression. Nomogram was adopted to formulate an algorithm incorporating qAnti-HBc for the prediction of survival in HBV-ACLF. The post-hospitalization of HBV-ACLF patients were followed-up for 1 year. RESULTS: Eighty-eight HBV-ACLF as training set, 80 HBV-ACLF as validation set and 216 CHB cases were included. Serum qAnti-HBc level was significantly higher in HBV-ACLF (4.95 ± 0.54 log10 IU/mL) than CHB patients (4.47 ± 0.84 log10 IU/mL) (P < 0.01). Among HBV-ACLF cases, both in training and validation set, patients with poor outcomes had lower qAnti-HBc level. Area under receiver operating characteristic curve of the novel qAnti-HBc inclusive model was 0.82, superior to 0.73 from model for end-stage liver disease scores (P = 0.018), which was confirmed in validation set. During follow-up, the qAnti-HBc level declined at month 3 and month 6, then plateaued at 3.84 log10 IU/mL. CONCLUSIONS: Serum qAnti-HBc level was associated with disease severity and might be served as a novel biomarker in the prediction of HBV-ACLF clinical outcomes. The underlying immunological mechanism warrants further investigation.
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Insuficiencia Hepática Crónica Agudizada/diagnóstico , Insuficiencia Hepática Crónica Agudizada/etiología , Anticuerpos contra la Hepatitis B/sangre , Antígenos del Núcleo de la Hepatitis B/inmunología , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/diagnóstico , Adulto , Biomarcadores/sangre , Femenino , Estudios de Seguimiento , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Cancer will become the leading cause of death worldwide in the 21st century, meanwhile, immunotherapy is the most popular cancer treatment method in recent years. COPI Coat Complex Subunit Beta 1 (COPB1) relates to human innate immunity. However, the role of COPB1 in pan-cancer remains unclear. OBJECTIVE: The purpose of this study was to explore the relationship between COPB1 mRNA expression and tumor infiltrating lymphocytes and immune examination sites in pan-cancer. METHODS: Data from multiple online databases were collected. The BioGPS, UALCAN Database, COSMIC, cBioPortal, Cancer Regulome tools, Kaplan-Meier Plotter and TIMER website were utilized to perform the analysis. RESULTS: Upregulation of COPB1 has been widely observed in tumor tissues compared with normal tissues. Although COPB1 has poor prognosis in pan-cancer, COPB1 high expression was beneficial to the survival of ESCA patients. Unlike ESCA, COPB1 expression in STAD was positively correlated with tumor infiltrating lymphocytes, including B cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells. Finally, we also found that the expression of COPB1 in STAD was positively correlated with PD-L1 and CTLA4. CONCLUSIONS: COPB1 may be a prognostic biomarker for pan-carcinoma, and also provide an immune anti-tumor strategy for STAD based on the expression of COPB1.
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Proteína Coatómero/inmunología , Minería de Datos/métodos , Neoplasias/inmunología , Proteína Coatómero/biosíntesis , Proteína Coatómero/genética , Femenino , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Masculino , Neoplasias/genética , Pronóstico , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Regulación hacia ArribaRESUMEN
The role of inflammation response has been well documented in the development of acute lung injury (ALI). However, little is known about the functions of miRNAs in the regulation of inflammation in ALI. The aim of this study was to explore the effects of miRNAs in the regulation of inflammation in ALI and to elucidate the biomolecular mechanisms responsible for these effects. The expression profiles of miRNAs in lung tissues from lipopolysaccharide (LPS)-induced ALI mice model were analyzed using a microarray. It was observed that microRNA-221-3p (miR-221) was significantly increased in lung tissues in ALI mice. The inhibition of miR-221 attenuated lung injury including decreased lung W/D weight ratio and lung permeability and survival rates of ALI mice, as well as apoptosis, whereas its agomir-mediated upregulation exacerbated the lung injury. Concomitantly, miR-221 inhibition significantly reduced LPS-induced pulmonary inflammation, while LPS-induced pulmonary inflammation was aggravated by miR-221 upregulation. Of note, suppressor of cytokine signaling-1 (SOCS1), an effective suppressor of the NF-κB signaling pathway, was found to be a direct target of miR-221 in RAW264.7 cells. Overexpression of SOCS1 by pcDNA-SOCS1 plasmids markedly reversed the miR-221 inhibition-mediated inhibitory effects on inflammation and apoptosis in LPS-treated RAW264.7 cells. Finally, it was found that miR-221 inhibition suppressed LPS induced the activation of the NF-κB signaling pathway, as demonstrated by downregulation of phosphorylated-IκBα, p-p65 and upregulation of IκBα, whilst miR-221 overexpression had an opposite result in ALI mice. Our findings demonstrate that inhibition of miR-221 can alleviate LPS-induced inflammation via inactivation of SOCS1/NF-κB signaling pathway in ALI mice.
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Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/metabolismo , Lipopolisacáridos/farmacología , MicroARNs/antagonistas & inhibidores , MicroARNs/metabolismo , FN-kappa B/metabolismo , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Animales , Antagomirs/farmacología , Apoptosis/genética , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Modelos Animales de Enfermedad , Inflamación/metabolismo , Masculino , Ratones , MicroARNs/genética , Células RAW 264.7 , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Proteína 1 Supresora de la Señalización de Citocinas/genética , TransfecciónRESUMEN
The present study sought to determine the pharmacological effects of penehyclidine, an anticholinergic agent, on the angiogenic capacity of pulmonary microvascular endothelial cells (PMVECs). In vitro Matrigel network formation assay, cell proliferation assay, cell-matrix adhesion assay, and wound-healing assay were performed in PMVECs with or without exposure to penehyclidine or, in some cases, glycopyrrolate or acetylcholine, over a concentration range. In addition, the phosphorylation state of Akt and ERK, as well as the endogenous level of mTOR and RICTOR were examined in PMVECs by Western blot following the cells exposure to penehyclidine or, for some proteins, glycopyrrolate or acetylcholine. Finally, Western blot for Akt phosphorylation and in vitro Matrigel network formation assay were performed in PMVECs following their exposure to penehyclidine with or without phosphoinositide 3-kinase (PI3K) inhibitor LY294002 or mTOR inhibitor torin-1. We found that, in PMVECs, penehyclidine affected the network formation and cell migration, but not proliferation or cell-matrix adhesion, in a concentration-specific manner, i.e., penehyclidine increased the network formation and cell migration at lower concentrations but increased these processes at higher concentrations. Coincidentally, we observed that penehyclidine concentration-specifically affected the phosphorylation state of Akt in PMVECs, i.e., increased Akt phosphorylation at lower concentrations and decreased it at higher concentrations. In contrast, glycopyrrolate was found straightly to decrease network formation and Akt phosphorylation in a concentration-dependent manner. Further, we demonstrated that PI3K or mTOR blockade abolished both the enhanced network formation and the increased Akt phosphorylation by penehyclidine. Hence, penehyclidine may differentially alter the angiogenic capacity of PMVECs through affecting the Akt signaling pathway downstream of PI3K and mTOR. Findings from this study suggest a unique pharmacological feature of penehyclidine, which may imply its clinical and therapeutic value in modulating angiogenesis.
Asunto(s)
Antagonistas Colinérgicos/farmacología , Células Endoteliales/efectos de los fármacos , Neovascularización Fisiológica/efectos de los fármacos , Quinuclidinas/farmacología , Animales , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Cromonas/farmacología , Células Endoteliales/citología , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Pulmón/irrigación sanguínea , Pulmón/citología , Pulmón/efectos de los fármacos , Morfolinas/farmacología , Fosfatidilinositol 3-Quinasa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Pulmonary microvascular endothelial cells (PMVECs) display a rapid angioproliferative phenotype, essential for maintaining homeostasis in steady-state and promoting vascular repair after injury. Although it has long been established that endothelial cytosolic Ca2+ ([Ca2+]i) transients are required for proliferation and angiogenesis, mechanisms underlying such regulation and the transmembrane channels mediating the relevant [Ca2+]i transients remain incompletely understood. In the present study, the functional role of the microvascular endothelial site-specific α1G T-type Ca2+ channel in angiogenesis was examined. PMVECs intrinsically possess an in vitro angiogenic "network formation" capacity. Depleting extracellular Ca2+ abolishes network formation, whereas blockade of vascular endothelial growth factor receptor or nitric oxide synthase has little or no effect, suggesting that the network formation is a [Ca2+]i-dependent process. Blockade of the T-type Ca2+ channel or silencing of α1G, the only voltage-gated Ca2+ channel subtype expressed in PMVECs, disrupts network formation. In contrast, blockade of canonical transient receptor potential (TRP) isoform 4 or TRP vanilloid 4, two other Ca2+ permeable channels expressed in PMVECs, has no effect on network formation. T-type Ca2+ channel blockade also reduces proliferation, cell-matrix adhesion, and migration, three major components of angiogenesis in PMVECs. An in vivo study demonstrated that the mice lacking α1G exhibited a profoundly impaired postinjury cell proliferation in the lungs following lipopolysaccharide challenge. Mechanistically, T-type Ca2+ channel blockade reduces Akt phosphorylation in a dose-dependent manner. Blockade of Akt or its upstream activator, phosphatidylinositol-3-kinase (PI3K), also impairs network formation. Altogether, these findings suggest a novel functional role for the α1G T-type Ca2+ channel to promote the cell's angiogenic potential via a PI3K-Akt signaling pathway.