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Psoriasis is a chronic, proliferative, and inflammatory skin disease closely associated with inflammatory cytokine production. Cyclophilin A (CypA) is an important proinflammatory factor; however, its role in psoriasis remains unclear. The present data indicate that CypA levels are increased in the lesion skin and serum of patients with psoriasis, which is positively correlated with the psoriasis area severity index. Furthermore, extracellular CypA (eCypA) triggered psoriasis-like inflammatory responses in keratinocytes. Moreover, anti-CypA mAb significantly reduced pathological injury, keratinocyte proliferation, cytokine expression in imiquimod-induced mice. Notably, the therapeutic effect of anti-CypA mAb was better than that of the clinically used anti-IL-17A mAb and methotrexate. Mechanistically, eCypA binds to ACE2 and CD147 and is blocked by anti-CypA mAb. eCypA not only induces the dimerization and phosphorylation of ACE2 to trigger the JAK1/STAT3 signaling pathway for cytokine expression but also interacts with CD147 to promote PI3K/AKT/mTOR signaling-mediated keratinocyte proliferation. These findings demonstrate that the binding of eCypA to ACE2 and CD147 cooperatively triggers psoriasis-like inflammation and anti-CypA mAb is a promising candidate for the treatment of psoriasis.
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Senecavirus A (SVA) is an emerging virus that poses a threat to swine herds worldwide. To date, the role of tripartite motif 5 (TRIM5) in the replication of viruses has not been evaluated. Here, TRIM5 was reported to inhibit SVA replication by promoting the type I interferon (IFN) antiviral response mediated by retinoic acid-inducible gene I (RIG-I). TRIM5 expression was significantly upregulated in SVA-infected cells, and TRIM5 overexpression inhibited viral replication and promoted IFN-α, IFN-ß, interleukin-1beta (IL-1ß), IL-6, and IL-18 expression. Conversely, interfering with the expression of TRIM5 had the opposite effect. Viral adsorption and entry assays showed that TRIM5 did not affect the adsorption of SVA but inhibited its entry. In addition, TRIM5 promoted the expression of RIG-I and RIG-I-mediated IFNs and proinflammatory cytokines, and this effect was also proven by inhibiting the expression of TRIM5. These findings expand the scope of knowledge on host factors inhibiting the replication of SVA and indicate that targeting TRIM5 may aid in the development of new agents against SVA.
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Interferón Tipo I , Picornaviridae , Replicación Viral , Animales , Interferón Tipo I/metabolismo , Porcinos , Picornaviridae/fisiología , Picornaviridae/inmunología , Proteínas de Motivos Tripartitos/metabolismo , Proteínas de Motivos Tripartitos/genética , Enfermedades de los Porcinos/virología , Enfermedades de los Porcinos/inmunologíaRESUMEN
We systematically reviewed the application of artificial intelligence (AI) in predicting lymph node metastasis (LNM) in T1 colorectal cancer (CRC). Thirteen studies with 8417 patients were included. AI demonstrated high potential in predicting LNM with sensitivity, specificity, and AUC ranging from 0.561 to 1.0, 0.45 to 1.0, and 0.717 to 1.0, respectively, reducing unnecessary surgeries by approximately 70%.
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The present study aimed to explore the potential neural correlates during feedback evaluation during decision-making under risk and ambiguity in MCI. Nineteen individuals with MCI and twenty age-matched HCs were enrolled. Decision-making performance under risk and ambiguity was examined with the modified game of dice task (GDT) and an Iowa gambling task (IGT). Using task-related EEG data, reward positivity (RewP) and feedback P3 (fb-P3) were used to characterize participants' motivation and allocation of cognitive resources. Also, response time and event-related oscillation (ERO) were used to evaluate information processing speed, and the potent of post-feedback information integration and behavioral modulation. MCI patients had lower RewP (p = 0.022) and fb-P3 (p = 0.045) amplitudes in the GDT than HCs. Moreover, the amount and valence of feedback modulated the RewP (p = 0.008; p = 0.017) and fb-P3 (p < 0.001; p < 0.001). In the IGT, in addition to the significantly reduced fb-P3 observed in MCI patients (p = 0.010), the amount and valence of feedback modulated the RewP (p = 0.002; p = 0.020). Furthermore, MCI patients took longer to make decisions (t = 2.15, p = 0.041). The ERO analysis revealed that delta power was reduced in MCI (GDT: p = 0.045; p = 0.011). The findings suggest that, during feedback evaluation when making risky and ambiguous decisions, motivation, allocation of cognitive resources, information processing and neuronal excitability were attenuated in MCI. It implies that neural activity related to decision making was compromised in MCI.
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Accumulating evidence indicated that HHEX participated in the initiation and development of several cancers, but the potential roles and mechanisms of HHEX in hepatocellular carcinoma (HCC) were largely unclear. Cancer stem cells (CSCs) are responsible for cancer progression owing to their stemness characteristics. We reported that HHEX was a novel CSCs target for HCC. We found that HHEX was overexpressed in HCC tissues and high expression of HHEX was associated with poor survival. Subsequently, we found that HHEX promoted HCC cell proliferation, migration, and invasion. Moreover, bioinformatics analysis and experiments verified that HHEX promoted stem cell-like properties in HCC. Mechanistically, ABI2 serving as a co-activator of transcriptional factor HHEX upregulated SLC17A9 to promote HCC cancer stem cell-like properties and tumorigenesis. Collectively, the HHEX-mediated ABI2/SLC17A9 axis contributes to HCC growth and metastasis by maintaining the CSC population, suggesting that HHEX serves as a promising therapeutic target for HCC treatment.
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Carcinogénesis , Carcinoma Hepatocelular , Proliferación Celular , Neoplasias Hepáticas , Células Madre Neoplásicas , Humanos , Células Madre Neoplásicas/patología , Células Madre Neoplásicas/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Carcinogénesis/patología , Animales , Línea Celular Tumoral , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Regulación Neoplásica de la Expresión Génica , Movimiento Celular , Masculino , Invasividad Neoplásica , Transducción de Señal , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Ratones Desnudos , Femenino , Metástasis de la NeoplasiaRESUMEN
BACKGROUND: Senecavirus A (SVA) caused porcine idiopathic vesicular disease (PIVD) showing worldwide spread with economic losses in swine industry. Although some progress has been made on host factors regulating the replication of SVA, the role of Z-DNA binding protein 1 (ZBP1) remains unclear. METHODS: The expression of ZBP1 in SVA-infected 3D/421 cells was analyzed by quantitative real-time PCR (qRT-PCR) and western blot. Western blot and qRT-PCR were used to detect the effects of over and interference expression of ZBP1 on SVA VP2 gene and protein. Viral growth curves were prepared to measure the viral proliferation. The effect on type I interferons (IFNs), interferon-stimulated genes (ISGs), and pro-inflammatory cytokines in SVA infection was analyzed by qRT-PCR. Western blot was used to analysis the effect of ZBP1 on NF-κB signaling pathway and inhibitor are used to confirm. RESULTS: ZBP1 is shown to inhibit the replication of SVA by enhancing NF-κB signaling pathway mediated antiviral response. SVA infection significantly up-regulated the expression of ZBP1 in 3D4/21 cells. Infection of cells with overexpression of ZBP1 showed that the replication of SVA was inhibited with the enhanced expression of IFNs (IFN-α, IFN-ß), ISGs (ISG15, PKR, and IFIT1) and pro-inflammatory cytokines (IL-6, IL-8, and TNF-α), while, infected-cells with interference expression of ZBP1 showed opposite effects. Further results showed that antiviral effect of ZBP1 is achieved by activation the NF-κB signaling pathway and specific inhibitor of NF-κB also confirmed this. CONCLUSIONS: ZBP1 is an important host antiviral factor in SVA infection and indicates that ZBP1 may be a novel target against SVA.
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Macrófagos Alveolares , FN-kappa B , Picornaviridae , Transducción de Señal , Replicación Viral , Animales , Porcinos , FN-kappa B/metabolismo , Macrófagos Alveolares/virología , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/inmunología , Picornaviridae/fisiología , Línea Celular , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Citocinas/metabolismo , Citocinas/genéticaRESUMEN
The role of host factors in the replication of emerging senecavirus A (SVA) which induced porcine idiopathic vesicular disease (PIVD) distributed worldwide remains obscure. Here, interferon-induced transmembrane (IFITM) protein 1 and 2 inhibit SVA replication by positive feedback with RIG-I signaling pathway was reported. The expression levels of IFITM1 and IFITM2 increased significantly in SVA infected 3D4/21 cells. Infection experiments of cells with over and interference expression of IFITM1 and IFITM2 showed that these two proteins inhibit SVA replication by regulating the expression of interferon beta (IFN-ß), IFN-stimulated gene 15 (ISG-15), interleukin 6 (IL-6), IL-8, tumor necrosis factor alpha (TNF-α), IFN regulatory factor-3 (IRF3), and IRF7. Further results showed that antiviral responses of IFITM1 and IFITM2 were achieved by activating retinoic acid-inducible gene I (RIG-I) signaling pathway which in turn enhanced the expression of IFITM1 and IFITM2. It is noteworthy that conserved domains of these two proteins also paly the similar role. These findings provide new data on the role of host factors in infection and replication of SVA and help to develop new agents against the virus.
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Antígenos de Diferenciación , Interferón beta , Proteínas de la Membrana , Picornaviridae , Transducción de Señal , Animales , Retroalimentación , Interferón beta/genética , Porcinos , Replicación Viral/genética , Antígenos de Diferenciación/metabolismo , Proteínas de la Membrana/metabolismoRESUMEN
The acute respiratory virus infection can induce uncontrolled inflammatory responses, such as cytokine storm and viral pneumonia, which are the major causes of death in clinical cases. Cyclophilin A (CypA) is mainly distributed in the cytoplasm of resting cells and released into the extracellular space in response to inflammatory stimuli. Extracellular CypA (eCypA) is upregulated and promotes inflammatory response in severe COVID-19 patients. However, how eCypA promotes virus-induced inflammatory response remains elusive. Here, we observe that eCypA is induced by influenza A and B viruses and SARS-CoV-2 in cells, mice, or patients. Anti-CypA mAb reduces pro-inflammatory cytokines production, leukocytes infiltration, and lung injury in virus-infected mice. Mechanistically, eCypA binding to integrin ß2 triggers integrin activation, thereby facilitating leukocyte trafficking and cytokines production via the focal adhesion kinase (FAK)/GTPase and FAK/ERK/P65 pathways, respectively. These functions are suppressed by the anti-CypA mAb that specifically blocks eCypA-integrin ß2 interaction. Overall, our findings reveal that eCypA-integrin ß2 signaling mediates virus-induced inflammatory response, indicating that eCypA is a potential target for antibody therapy against viral pneumonia.
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COVID-19 , Ciclofilina A , Ciclofilina A/metabolismo , Animales , Humanos , Ratones , COVID-19/metabolismo , COVID-19/virología , COVID-19/inmunología , Antígenos CD18/metabolismo , SARS-CoV-2 , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/virología , Neumonía Viral/metabolismo , Neumonía Viral/inmunología , Citocinas/metabolismo , Anticuerpos Monoclonales/farmacología , Transducción de Señal , Virus de la Influenza A , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: Colorectal cancer (CRC) is the leading cause of cancer deaths, and treatment, especially in the metastatic stage, is challenging. Immune checkpoint inhibitors (ICIs) have revolutionized CRC treatment, but response varies, emphasizing the need for effective biomarkers. This study explores SPEN mutations as potential biomarkers. METHODS: Using data from the Memorial Sloan Kettering Cancer Center (MSKCC) and The Cancer Genome Atlas (TCGA)-Colorectal Cancer, this research applied bioinformatics tools and statistical analysis to SPEN (Split Ends) mutant and wild-type CRC patients treated with ICIs. Focus areas included mutation rates, immune cell infiltration, and DNA damage response pathways. RESULTS: The SPEN mutation rate was found to be 13.8% (15/109 patients) in the MSKCC cohort and 6.65% (35/526 patients) in the TCGA cohort. Our findings indicate that CRC patients with SPEN mutations had a longer median overall survival (OS) than the wild-type group. These patients also had higher tumor mutational burden (TMB), microsatellite instability (MSI) scores, and programmed death-ligand 1 (PD-L1) expression. SPEN mutants also exhibited increased DNA damage response (DDR) pathway mutations and a greater presence of activated immune cells, like M1 macrophages and CD8+ T cells, while wild-type patients had more resting/suppressive immune cells. Furthermore, distinct mutation patterns, notably with TP53, indicated a unique molecular subtype in SPEN-mutated CRC. CONCLUSIONS: We conclude that SPEN mutations might improve ICI efficacy in CRC due to increased immunogenicity and an inflammatory tumor microenvironment. SPEN mutations could be predictive biomarkers for ICI responsiveness, underscoring their value in personalized therapy and highlighting the importance of genomic data in clinical decisions. This research lays the groundwork for future precision oncology studies.
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BACKGROUND: Accumulating evidence demonstrated that Hippo signaling pathway is implicated in tumor initiation and progression. However, there have been limited studies on establishing signatures utilizing genes related to the Hippo pathway to evaluate prognosis and clinical efficacy in colorectal cancer (CRC) patients. METHODS: Hippo pathway-associated genes with prognostic significance were identified in the TCGA database. Subsequently, a prognostic signature associated with the Hippo pathway was constructed using Cox and LASSO regression analyses. Survival analysis, ROC analysis, and stratified analyses were conducted to appraise the performance effect of our prognostic model. We also explored the relationship between the risk score and tumor immune microenvironment. Furthermore, GO analyses and GSEA were performed for SERPINE1. Additional experiments were conducted to illuminate the underlying function and possible mechanism of SERPINE1 in CRC cell proliferation and migration. RESULTS: We identified 58 differentially expressed genes associated with Hippo pathway that have prognostic significance in CRC. Among them, five genes (PPP2CB, SERPINE1, WNT5A, TCF7L1, and LEF1) were selected to establish a prognostic signature for CRC. Multivariate analysis demonstrated that this signature exhibited excellent diagnostic and prognostic performance, providing maximum benefits for CRC patients. In accordance with the prognostic signatures, the cases were divided into low-risk and high-risk groups. Remarkably, the high-risk group displayed lower immune scores, reduced immune cell infiltration, and decreased expression of immune checkpoints. Low-risk group could more possibly benefit from conventional chemotherapeutic and targeted therapies. CRC exhibited significantly elevated expression of SERPINE1, which was linked to worst overall survival. Moreover, inhibition of SERPINE1 suppressed proliferation, invasion, and migration of CRC cells via Notch pathway. CONCLUSIONS: To sum up, we established a novel immunological prognostic signature utilizing genes associated with the Hippo pathway. This signature offers accurate prognostic prediction and can guide individualized therapy for patients with CRC.
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Transformación Celular Neoplásica , Neoplasias Colorrectales , Humanos , Pronóstico , Proliferación Celular , Transducción de Señal , Neoplasias Colorrectales/genética , Microambiente Tumoral , Inhibidor 1 de Activador Plasminogénico/genéticaRESUMEN
N6 methyladenosine (m6A), methylation at the sixth N atom of adenosine, is the most common and abundant modification in mammalian mRNAs and non-coding RNAs. Increasing evidence shows that the alteration of m6A modification level could regulate tumour proliferation, metastasis, self-renewal, and immune infiltration by regulating the related expression of tumour genes. However, the role of m6A modification in colorectal cancer (CRC) drug resistance is unclear. Here, MeRIP-seq and RNA-seq techniques were utilized to obtain mRNA, lncRNA expression, and their methylation profiles in 5-Fluorouracil (5-FU)-resistant colon cancer HCT-15 cells and control cells. In addition, we performed detailed bioinformatics analysis as well as in vitro experiments of lncRNA to explore the function of lncRNA with differential m6A in CRC progression and drug resistance. In this study, we obtained the m6A methylomic landscape of CRC cells and resistance group cells by MeRIP-seq and RNA-seq. We identified 3698 differential m6A peaks, of which 2224 were hypermethylated, and 1474 were hypomethylated. Among the lncRNAs, 60 were hypermethylated, and 38 were hypomethylated. GO and KEGG analysis annotations showed significant enrichment of endocytosis and MAPK signalling pathways. Moreover, knockdown of lncRNA ADIRF-AS1 and AL139035.1 promoted CRC proliferation and invasive metastasis in vitro. lncRNA- mRNA network showed that ADIRF-AS1 and AL139035.1 May play a key role in regulating drug resistance formation. We provide the first m6A methylation profile in 5-FU resistance CRC cells and analyse the functions of differential m6A-modified mRNAs and lncRNAs. Our results indicated that differential m6A RNAs were significantly associated with MAPK signalling and endocytosis after induction of 5-FU resistance. Knockdown of LncRNA ADIRF-AS1 and AL139035.1 promotes CRC progression and might be critical in regulating drug resistance formation.
We outline the first m6A methylation profile of mRNA and lncRNA in CRC cells involved in 5-FU resistance.This study sought to identify the critical genes that produced 5-FU resistance by analysing the functions of differentially m6A-modified mRNAs and lncRNAs.
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Neoplasias del Colon , ARN Largo no Codificante , Animales , ARN Largo no Codificante/genética , ARN Mensajero/genética , Metilación de ADN , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/genética , Fluorouracilo/farmacología , Adenosina/farmacología , MamíferosRESUMEN
Swine flu caused by swine influenza A virus (swIAV) is an acute respiratory viral disease that is spreading in swine herds worldwide. Although the effect of some host factors on replication of swIAV has been identified, the role of CD46 in this process is unclear. Here, we report that CD46 inhibits the replication of swIAV by promoting the production of type I interferons (IFNs) in porcine kidney (PK-15) cells. CD46 knockout (CD46-KO) and stably expressing (CD46-overexpression) PK-15 cells were prepared using lentivirus-mediated CRISPR/Cas9 gene editing and seamless cloning technology. The results of virus infection in CD46-overexpression PK-15 cells showed that the replication of H1N1 and H3N2 swIAVs were inhibited, and the production of type I IFNs (IFN-α, IFN-ß), interferon regulatory factor (IRF) 3, and mitochondrial antiviral-signaling protein (MAVS) was enhanced. Virus infection in CD46-KO PK-15 cells showed the opposite results. Further results showed that CD46-KO PK-15 cells have a favorable ability to proliferate influenza viruses compared to Madin-Darby canine kidney (MDCK) and PK-15 cells. These findings indicate that CD46 acts as promising target regulating the replication of swIAV, and help to develop new agents against infection and replication of the virus.
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Subtipo H1N1 del Virus de la Influenza A , Virus de la Influenza A , Interferón Tipo I , Enfermedades de los Porcinos , Virosis , Animales , Perros , Subtipo H1N1 del Virus de la Influenza A/fisiología , Subtipo H3N2 del Virus de la Influenza A , Interferón Tipo I/genética , Porcinos , Virosis/veterinaria , Replicación Viral/genéticaRESUMEN
BACKGROUND: Dementia has become a major public health concern due to its heavy disease burden. Mild cognitive impairment (MCI) is a transitional stage between healthy aging and dementia. Early identification of MCI is an essential step in dementia prevention. OBJECTIVE: Based on machine learning (ML) methods, this study aimed to develop and validate a stable and scalable panel of cognitive tests for the early detection of MCI and dementia based on the Chinese Neuropsychological Consensus Battery (CNCB) in the Chinese Neuropsychological Normative Project (CN-NORM) cohort. METHODS: CN-NORM was a nationwide, multicenter study conducted in China with 871 participants, including an MCI group (n=327, 37.5%), a dementia group (n=186, 21.4%), and a cognitively normal (CN) group (n=358, 41.1%). We used the following 4 algorithms to select candidate variables: the F-score according to the SelectKBest method, the area under the curve (AUC) from logistic regression (LR), P values from the logit method, and backward stepwise elimination. Different models were constructed after considering the administration duration and complexity of combinations of various tests. Receiver operating characteristic curve and AUC metrics were used to evaluate the discriminative ability of the models via stratified sampling cross-validation and LR and support vector classification (SVC) algorithms. This model was further validated in the Alzheimer's Disease Neuroimaging Initiative phase 3 (ADNI-3) cohort (N=743), which included 416 (56%) CN subjects, 237 (31.9%) patients with MCI, and 90 (12.1%) patients with dementia. RESULTS: Except for social cognition, all other domains in the CNCB differed between the MCI and CN groups (P<.008). In feature selection results regarding discrimination between the MCI and CN groups, the Hopkins Verbal Learning Test-5 minutes Recall had the best performance, with the highest mean AUC of up to 0.80 (SD 0.02) and an F-score of up to 258.70. The scalability of model 5 (Hopkins Verbal Learning Test-5 minutes Recall and Trail Making Test-B) was the lowest. Model 5 achieved a higher level of discrimination than the Hong Kong Brief Cognitive test score in distinguishing between the MCI and CN groups (P<.05). Model 5 also provided the highest sensitivity of up to 0.82 (range 0.72-0.92) and 0.83 (range 0.75-0.91) according to LR and SVC, respectively. This model yielded a similar robust discriminative performance in the ADNI-3 cohort regarding differentiation between the MCI and CN groups, with a mean AUC of up to 0.81 (SD 0) according to both LR and SVC algorithms. CONCLUSIONS: We developed a stable and scalable composite neurocognitive test based on ML that could differentiate not only between patients with MCI and controls but also between patients with different stages of cognitive impairment. This composite neurocognitive test is a feasible and practical digital biomarker that can potentially be used in large-scale cognitive screening and intervention studies.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/diagnóstico , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/psicología , Pruebas de Estado Mental y Demencia , Pruebas Neuropsicológicas , Aprendizaje AutomáticoRESUMEN
Influenza B circulates annually and causes substantial disease burden in humans. However, little is known about the infection mechanisms of influenza B virus (IBV). Here, we find that the host factor cyclophilin A (CypA) facilitates IBV replication by targeting IBV non-structural protein 1 (BNS1) and nucleoprotein (BNP). CypA promotes OTUD4-mediated K48-linked BNS1 deubiquitination to stabilize BNS1 by upregulating OTUD4 expression. Meanwhile, CypA and the E3 ligase MIB1 competitively interact with BNP to inhibit its proteasomal degradation. Moreover, cyclosporine A treatment or CypA R55A mutation results in an impaired function of CypA in IBV replication. Notably, BNP hijacks CypA into the nucleus to enhance the activity of viral ribonucleoprotein complexes by enhancing the interaction between BNP and IBV polymerase basic protein 1. Taken together, this study unveils the critical role of CypA in facilitating IBV replication, suggesting that CypA is a promising target for anti-IBV drug.
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A flexible free-standing cathode is innovatively constructed with NaCrO2 as the electrochemical active substance via an electrospinning technique. The as constructed NaCrO2@C flexible free-standing cathode exhibits exceptional rate performance (106 mA h g-1 at 10C) and cyclability (retention rate of 87.5% after 300 cycles at 0.2C). This work provides a brand-new perspective to the development of flexible free-standing cathodes.
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Zeolitic imidazolate frameworks (ZIFs) are an important subclass of metal-organic frameworks (MOFs). Recently, we reported a new kind of MOF, namely tetrahedral imidazolate frameworks with auxiliary ligands (TIF-Ax), by adding linear ligands (Hint) into the zinc-imidazolate system. Introducing linear ligands into the M2+-imidazolate system overcomes the limitation of imidazole derivatives. Thanks to the synergistic effect of two different types of ligands, a series of new TIF-Ax with interesting topologies and a special pore environment has been reported, and they have attracted extensive attention in gas adsorption, separation, catalysis, heavy metal ion capture, and so on. In this review, we give a comprehensive overview of TIF-Ax, including their synthesis methods, structural diversity, and multi-field applications. Finally, we also discuss the challenges and perspectives of the rational design and syntheses of new TIF-Ax from the aspects of their composition, solvent, and template. This review provides deep insight into TIF-Ax and a reference for scholars with backgrounds of porous materials, gas separation, and catalysis.
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Cytokine storms caused by viruses are associated with elevated cytokine levels and uncontrolled inflammatory responses that can lead to acute respiratory distress syndrome. Current antiviral therapies are not sufficient to prevent or treat these complications. Cyclophilin A (CypA) is a key factor that regulates the production of multiple cytokines and could be a potential therapeutic target for cytokine storms. Here, three proteolysis targeting chimeras (PROTACs) targeting CypA were designed. These PROTACs bind to CypA, enhance its ubiquitination, and promote its degradation in both cell lines and mouse organs. During influenza B virus (IBV) infection, PROTAC-mediated CypA depletion reduces P65 phosphorylation and NF-κB-mediated proinflammatory cytokine production in A549 cells. Moreover, Comp-K targeting CypA suppresses excessive secretion of proinflammatory cytokines in bronchoalveolar lavage fluid, reduces lung injury, and enhances survival rates of IBV-infected mice. Collectively, we provide PROTACs targeting CypA, which are potential candidates for the control of cytokine storms.
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Long non-coding RNAs have recently attracted considerable attention due to their aberrant expression in human diseases. LncMIR31HG is a novel lncRNA that is abnormally expressed in multiple diseases and implicated in various stages of disease progression. A large proportion of recent studies have indicated that MIR31HG has biological functions by triggering various signalling pathways in the pathogenesis of human diseases, especially cancers. More importantly, the abnormal expression of MIR31HG makes it a potential biomarker in diagnosis and prognosis, as well as a promising target for treatments. This review aims to systematically summarize the gene polymorphism, expression profiles, biological roles, underlying mechanisms, and clinical applications of MIR31HG in human diseases.
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Circular RNAs (circRNAs) are involved in various biological roles, including viral infection and antiviral immune responses. To identify influenza A virus (IAV) infection-related circRNAs, we compared the circRNA profiles of A549 cells upon IAV infection. We found that circVAMP3 is substantially upregulated after IAV infection or interferon (IFN) stimulation. Furthermore, IAV and IFN-ß induced the expression of QKI-5, which promoted the biogenesis of circVAMP3. Overexpression of circVAMP3 inhibited IAV replication, while circVAMP3 knockdown promoted viral replication, suggesting that circVAMP3 restricts IAV replication. We verified the effect of circVAMP3 on viral infection in mice and found that circVAMP3 restricted IAV replication and pathogenesis in vivo. We also found that circVAMP3 functions as a decoy to the viral proteins nucleoprotein (NP) and nonstructural protein 1 (NS1). Mechanistically, circVAMP3 interfered with viral ribonucleoprotein complex activity by reducing the interaction of NP with polymerase basic 1, polymerase basic 2, or vRNA and restored the activation of IFN-ß by alleviating the inhibitory effect of NS1 to RIG-I or TRIM25. Our study provides new insights into the roles of circRNAs, both in directly inhibiting virus replication and in restoring innate immunity against IAV infection.
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Gripe Humana , ARN Circular , Proteína 3 de Membrana Asociada a Vesículas , Animales , Humanos , Ratones , Gripe Humana/genética , Interferones , Nucleoproteínas , Nucleotidiltransferasas , ARN Circular/genética , Proteína 3 de Membrana Asociada a Vesículas/genéticaRESUMEN
BACKGROUND: Whether encoding or retrieval failure contributes to memory binding deficit in amnestic mild cognitive impairment (aMCI) has not been elucidated. Also, the potential brain structural substrates of memory binding remained undiscovered. OBJECTIVE: To investigate the characteristics and brain atrophy pattern of encoding and retrieval performance during memory binding in aMCI. METHODS: Forty-three individuals with aMCI and 37 cognitively normal controls were recruited. The Memory Binding Test (MBT) was used to measure memory binding performance. The immediate and delayed memory binding indices were computed by using the free and cued paired recall scores. Partial correlation analysis was performed to map the relationship between regional gray matter volume and memory binding performance. RESULTS: The memory binding performance in the learning and retrieval phases was worse in the aMCI group than in the control group (Fâ=â22.33 to 52.16, all pâ<â0.001). The immediate and delayed memory binding index in the aMCI group was lower than that in the control group (pâ<â0.05). The gray matter volume of the left inferior temporal gyrus was positively correlated with memory binding test scores (râ=â0.49 to 0.61, pâ<â0.05) as well as the immediate (râ=â0.39, pâ<â0.05) and delayed memory binding index (râ=â0.42, pâ<â0.05) in the aMCI group. CONCLUSION: aMCI may be primarily characterized by a deficit in encoding phase during the controlled learning process. Volumetric losses in the left inferior temporal gyrus may contribute to encoding failure.