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BACKGROUND: The successful treatment and improvement of acute kidney injury (AKI) depend on early-stage diagnosis. However, no study has differentiated between the three stages of AKI and non-AKI patients following heart surgery. This study will fill this gap in the literature and help to improve kidney disease management in the future. METHODS: In this study, we applied Raman spectroscopy (RS) to uncover unique urine biomarkers distinguishing heart surgery patients with and without AKI. Given the amplified risk of renal complications post-cardiac surgery, this approach is of paramount importance. Further, we employed the partial least squares-support vector machine (PLS-SVM) model to distinguish between all three stages of AKI and non-AKI patients. RESULTS: We noted significant metabolic disparities among the groups. Each AKI stage presented a distinct metabolic profile: stage 1 had elevated uric acid and reduced creatinine levels; stage 2 demonstrated increased tryptophan and nitrogenous compounds with diminished uric acid; stage 3 displayed the highest neopterin and the lowest creatinine levels. We utilized the PLS-SVM model for discriminant analysis, achieving over 90% identification rate in distinguishing AKI patients, encompassing all stages, from non-AKI subjects. CONCLUSIONS: This study characterizes the incidence and risk factors for AKI after cardiac surgery. The unique spectral information garnered from this study can also pave the way for developing an in vivo RS method to detect and monitor AKI effectively.
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Lesión Renal Aguda , Biomarcadores , Procedimientos Quirúrgicos Cardíacos , Espectrometría Raman , Urinálisis , Humanos , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/orina , Lesión Renal Aguda/etiología , Espectrometría Raman/métodos , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Biomarcadores/orina , Urinálisis/métodos , Creatinina/orina , Máquina de Vectores de Soporte , Ácido Úrico/orina , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/orina , Complicaciones Posoperatorias/etiología , Factores de Riesgo , Análisis de los Mínimos CuadradosRESUMEN
Lung adenocarcinoma (LUAD) is highly lethal tumor; understanding immune response is crucial for current effective treatment. Research investigated immunogenic cell death (ICD) impact on LUAD through 75 ICD-related genes which encompass cell damage, endoplasmic reticulum stress, microenvironment, and immunity. Transcriptome data and clinical info were analyzed, revealing two ICD-related clusters: B, an immune osmotic subgroup, had better prognosis, stronger immune signaling, and higher infiltration, while A represented an immune-deficient subgroup. Univariate Cox analysis identified six prognostic genes (AGER, CD69, CD83, CLEC9A, CTLA4, and NT5E), forming a validated risk score model. It was validated across datasets, showing predictive performance. High-risk group had unfavorable prognosis, lower immune infiltration, and higher chemotherapy sensitivity. Conversely, low-risk group had better prognosis, higher immune infiltration, and favorable immunotherapy response. The key gene NT5E was examined via immunohistochemistry, with higher expression linked to poorer prognosis. NT5E was predominantly expressed in B cells, fibroblasts, and endothelial cells, correlated with immune checkpoints. These outcomes suggest that NT5E can serve as a LUAD therapeutic target. The study highlights gene predictive value, offers an efficient tumor assessment tool, guides clinical treatment strategies, and identifies NT5E as therapeutic target for LUAD.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Humanos , Células Endoteliales , Muerte Celular Inmunogénica , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Inmunoterapia , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Microambiente TumoralRESUMEN
Inhibition of acid phosphatase, which significantly contributes to inosine 5'-monophosphate (IMP) degradation, is crucial for preventing flavor deterioration of aquatic products during storage. In this study, the inhibitory effect of epicatechin gallate (ECG) on the activity of acid phosphatase isozymes (ACPI and ACPII) was analyzed using inhibition kinetics, fluorescence spectroscopy, isothermal titration calorimetry, and molecular simulation. ACPI and ACPII with molecular weights of 59.5 and 37.3 kDa, respectively, were purified from rainbow trout liver. ECG reversibly inhibited ACPI and ACPII activities via mixed-type inhibition, with half maximal inhibitory concentration (IC50) of 0.24 ± 0.01 mmol/L and 0.27 ± 0.03 mmol/L, respectively. Fluorescence spectra indicated that ECG statically quenched the intrinsic fluorescence of ACPI and ACPII. ECG could spontaneously bind to ACPI and ACPII through hydrogen bonding and van der Waals forces and exhibited a higher affinity for ACPI than for ACPII. In addition, molecular dynamic simulation revealed that ECG-ACPI and ECG-ACPII complexes were relatively stable during the entire simulation process. Our findings provide a theoretical basis for the use of ECG as an inhibitor of ACP to improve the flavor of aquatic products.
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Catequina/análogos & derivados , Oncorhynchus mykiss , Animales , Oncorhynchus mykiss/metabolismo , Simulación del Acoplamiento Molecular , Hígado , Fosfatasa Ácida/metabolismoRESUMEN
The juice exudation of aquatic products oozes out during storage can influence storage quality. Herein, a novel basil essential oil liposome unidirectional water-conducting sustained-release preservation pads (BEOL/UCSP) were prepared with nylon mesh as water-conducting layer, basil essential oil liposome (BEOL) as sustained-release preservation layer, and diatomite and absorbent-cotton as water-absorbing layer. EL/UCSP, ß-CL/UCSP, and BEO/UCSP were prepared after BEOL was replaced by eugenol liposome, ß-caryophyllene liposome, and BEO. BEOL are microspheres with bilayer structure, had good storage stability, centrifugal stability, thermal stability, embedding capacity, sustained-release, and oxidation resistance, and the main components of preservatives had a synergistic effect on antibacterial properties. The pads without preservative can initially slow down quality deterioration. BEOL/UCSP can directionally absorb exudate and realize long-term sustained-release of preservative, has excellent antibacterial and antioxidant effect, and extended shelf life of Lateolabrax japonicus fillets from 6.0 days to 12.8 days. The BEOL/UCSP can provide technical theoretical support for preservation materials.
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Ocimum basilicum , Aceites Volátiles , Animales , Aceites Volátiles/farmacología , Aceites Volátiles/química , Conservación de Alimentos , Ocimum basilicum/química , Liposomas , Preparaciones de Acción Retardada , Peces , AntibacterianosRESUMEN
E3 ubiquitin ligases (E3s) play a pivotal role in regulating the specificity of protein ubiquitination, and their significant functions as regulators of immune responses against tumors are attracting considerable interest. RBCK1-an RBR E3 ligase-is involved in immune regulation and tumor development. However, the potential effect of RBCK1 on glioma remains enigmatic. In the present study, we performed comprehensive analyses of multilevel data, which disclosed distribution characteristics of RBCK1 in pan-cancer, especially in glioma. Functional roles of RBCK1 were further confirmed using immunohistochemistry, cell biological assays, and xenograft experiments. Aberrant ascending of RBCK1 in multiple types of cancer was found to remodel the immunosuppressive microenvironment of glioma by regulating immunomodulators, cancer immunity cycles, and immune cell infiltration. Notably, the MES-like/RBCK1High cell population, a unique subset of cells in the microenvironment, suppressed T cell-mediated cell killing in glioma. Elevated expression levels of RBCK1 suggested a glioma subtype characterized by immunosuppression and hypo-responsiveness to immunotherapy but manifesting surprisingly increased responses to anti-angiogenic therapy. In conclusion, anti-RBCK1 target therapy might be beneficial for glioma treatment. Moreover, RBCK1 assisted in predicting molecular subtypes of glioma and response rates of patients to different clinical treatments, which could guide personalized therapy.
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Accurate identification of tissue types in surgical margins is essential for ensuring the complete removal of cancerous cells and minimizing the risk of recurrence. The objective of this study was to explore the clinical utility of Raman spectroscopy for the detection of oral squamous cell carcinoma (OSCC) in both tumor and healthy tissues obtained from surgical resection specimens during surgery. This study enrolled a total of 64 patients diagnosed with OSCC. Among the participants, approximately 50% of the cases were classified as the most advanced stage, referred to as T4. Raman experiments were conducted on cryopreserved tissue samples collected from patients diagnosed with OSCC. Prominent spectral regions containing key oral biomarkers were analyzed using the partial least squares-support vector machine (PLS-SVM) method, which is a powerful multivariate analysis technique for discriminant analysis. This approach effectively differentiated OSCC tissue from non-OSCC tissue, achieving a sensitivity of 95.7% and a specificity of 93.3% with 94.7% accuracy. In the current study, Raman analysis of fresh tissue samples showed that OSCC tissues contained significantly higher levels of nucleic acids, proteins, and several amino acids compared to the adjacent healthy tissues. In addition to differentiating between OSCC and non-OSCC tissues, we have also explored the potential of Raman spectroscopy in classifying different stages of OSCC. Specifically, we have investigated the classification of T1, T2, T3, and T4 stages based on their Raman spectra. These findings emphasize the importance of considering both stage and subsite factors in the application of Raman spectroscopy for OSCC analysis. Future work will focus on expanding our tissue sample collection to better comprehend how different subsites influence the Raman spectra of OSCC at various stages, aiming to improve diagnostic accuracy and aid in identifying tumor-free margins during surgical interventions.
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In this study, the coaxial nanofiber films were prepared by coaxial electrospinning technique with cinnamaldehyde (CMA) and tea polyphenol (TP) as core material and polylactic acid (PLA) as shell material, and to obtain food packaging materials with great physicochemical and antibacterial properties, zinc oxide (ZnO) sol were added into PLA, and ZnO/CMA/TP-PLA coaxial nanofiber films were prepared. Meanwhile, the microstructure and physicochemical properties were determined, and the antibacterial properties and mechanism were investigated with Shewanella putrefaciens (S. putrefaciens) as target. The results show that the ZnO sol makes the physicochemical properties and antibacterial properties of the coaxial nanofiber films improve. Among them, the 1.0 % ZnO/CMA/TP-PLA coaxial nanofibers have smooth and continuous uniform surfaces, and their encapsulation effect on CMA/TP and antibacterial properties are the optimal. The synergistic action of CMA/TP and ZnO sol cause severe depression and folding of the cell membrane of S. putrefaciens, makes cell membrane permeability increase and of intracellular materials spillage, interference the bacteriophage protein expression, and makes macromolecular protein degraded. In this study, the introduction of oxide sols into polymeric shell materials by in-situ synthesis technique can provide theoretical support and methodological guidance for the application of electrospinning technology in the field of food packaging.
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Nanofibras , Shewanella putrefaciens , Óxido de Zinc , Nanofibras/química , Óxido de Zinc/química , Polifenoles , Poliésteres/química , Antibacterianos/química , TéRESUMEN
Acid phosphatase (ACP) is a key enzyme that hydrolyzes inosinic acid. The mechanisms underlying the interaction between rosmarinic acid (RA) and ACP and the inhibition of the enzyme were investigated using inhibition kinetics, UV-visible and fluorescence spectroscopy, circular dichroism, and molecular docking. The results showed that RA was a reversible inhibitor of ACP and that the inhibition mechanism was uncompetitive. The ACP fluorescence was quenched by RA, and the quenching mode was static. The interaction of ACP with RA was driven by H bonds and van der Waals forces. The addition of RA increased the α-helix content and decreased the ß-sheet, ß-turn, and random coil contents in ACP, thereby altering the secondary structure of the enzyme. This study enriched our understanding of inhibitory and interaction mechanisms involving ACP and RA.
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Fosfatasa Ácida , Cinamatos , Simulación del Acoplamiento Molecular , Fosfatasa Ácida/química , Cinamatos/química , Cinamatos/farmacología , Hígado , Ácido RosmarínicoRESUMEN
Drug-induced liver injury (DILI) still poses a major clinical challenge and is a leading cause of acute liver failure. Inhibitor of nuclear factor kappa B kinase subunit epsilon (IKBKE) is essential for inflammation and metabolic disorders. However, it is unclear how IKBKE regulates cellular damage in acetaminophen (APAP)-induced acute liver injury. Here, we found that the deficiency of IKBKE markedly aggravated APAP-induced acute liver injury by targeting RIPK1. We showed that APAP-treated IKBKE-deficient mice exhibited severer liver injury, worse mitochondrial integrity, and enhanced glutathione depletion than wild-type mice. IKBKE deficiency may directly upregulate the expression of total RIPK1 and the cleaved RIPK1, resulting in sustained JNK activation and increased translocation of RIPK1/JNK to mitochondria. Moreover, deficiency of IKBKE enhanced the expression of pro-inflammatory factors and inflammatory cell infiltration in the liver, especially neutrophils and monocytes. Inhibition of RIPK1 activity by necrostatin-1 significantly reduced APAP-induced liver damage. Thus, we have revealed a negative regulatory function of IKBKE, which acts as an RIPK1/JNK regulator to mediate APAP-induced hepatotoxicity. Targeting IKBKE/RIPK1 may serve as a potential therapeutic strategy for acute or chronic liver injury.
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Acetaminofén , Enfermedad Hepática Inducida por Sustancias y Drogas , Animales , Ratones , Acetaminofén/toxicidad , Hígado , Glutatión/metabolismo , Mitocondrias/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Ratones Endogámicos C57BL , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Hepatocitos/metabolismo , Quinasa de Factor Nuclear kappa BRESUMEN
The abnormal activation of the nuclear factor-kappa B (NF-κB) signaling pathway is an important precipitating factor for the inception and development of colorectal cancer (CRC), one of the most common tumors worldwide. As a pro-apoptotic transcription factor, monocyte chemotactic protein-induced protein 1 (MCPIP1) has been closely associated with many tumor types. In the present study, the expression of MCPIP1 was firstly discovered reduced in CRC tissues and correlated with poor patient prognosis. The decreased expression was caused by promoter hypermethylation. Overexpressed MCPIP1 was found to inhibit the proliferative and migratory abilities of CRC cells, whereas knockdown of MCPIP1 produced the opposite result. The subsequent investigation demonstrated that MCPIP1 exerted its "anti-cancer" effect by suppression of the NF-κB signaling pathway through negative regulation of K63-linked ubiquitylation of TNF receptor associated factor 6 (TRAF6). Therefore, our results indicate a prognostic marker for CRC and a theoretical basis for MCPIP1 as a treatment.
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Neoplasias Colorrectales , FN-kappa B , Humanos , FN-kappa B/metabolismo , Factor 6 Asociado a Receptor de TNF/genética , Factor 6 Asociado a Receptor de TNF/metabolismo , Factor 6 Asociado a Receptor de TNF/farmacología , Transducción de Señal , Ubiquitinación , Neoplasias Colorrectales/genéticaRESUMEN
Background: Chitinase-3-like protein 1 (CHI3L1) is overexpressed in various types of tumors, especially in glioma, and contributes to tumor progression. However, the definite role of CHI3L1 and involved pathway in glioma progression are not completely understood. Methods: CHI3L1 expression in human gliomas and its association with patient survival was determined using enzyme-linked immunosorbent assay, western blot, immunohistochemistry, and public databases. Single-cell RNA-seq was used to characterize the landscape of tumor and myeloid cells. Human proteome microarray assay was applied to identify the binding partners of CHI3L1. Protein-protein interactions were analyzed by co-immunoprecipitation and cellular co-localization. The roles of CHI3L1 in glioma proliferation and invasion were investigated in tumor cell lines by gain- and loss- of function, as well as in vivo animal experiments. Results: CHI3L1 was up-regulated in all disease stages of glioma, which was closely related with tumor survival, growth, and invasion. CHI3L1 was primarily expressed in glioma cells, followed by neutrophils. Moreover, glioma cells with high expression of CHI3L1 were significantly enriched in NF-κB pathway. Pseudo-time trajectory analysis revealed a gradual transition from CHI3L1low to CHI3L1high glioma cells, along with the NF-κB pathway gradually reversed from inhibition to activation. Intriguingly, CHI3L1 binds to actinin alpha 4 (ACTN4) and NFKB1, and enhances the NF-κB signaling pathway by promoting the NF-κB subunit nuclear translocation in glioma cells. Further, CHI3L1 were released into the tumor microenvironment (TME) and interacted with CD44 expressed on tumor-associated macrophages to activate AKT pathway, thereby contributing to M2 macrophage polarization. In addition, CHI3L1 positively correlated to the expression of immune checkpoints, such as CD274 (PD-L1) and HAVCR2 (LAG3), which then remodeled the TME to an immunosuppressive phenotype. Conclusion: Our research revealed that CHI3L1 facilitated NF-κB pathway activation within glioma cells and reprogramed the TME, thereby serving as a promising therapeutic target for glioma.
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Proteína 1 Similar a Quitinasa-3 , Glioma , Transducción de Señal , Microambiente Tumoral , Animales , Humanos , Actinina/metabolismo , Antígeno B7-H1 , Proteína 1 Similar a Quitinasa-3/genética , Proteína 1 Similar a Quitinasa-3/metabolismo , Glioma/patología , FN-kappa B/metabolismo , Proteoma , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
Trimethylamine-N-oxide demethylase (TMAOase) is a key enzyme for the decomposition of trimethylamine oxide into formaldehyde. The study investigated the inhibitory effects of (+)-catechin on TMAOase and involved mechanism to minimize the formaldehyde (FA) content of seafood during storage. TMAOase was purified by DEAE-52 cellulose and Sephacryl S-300 chromatography and the inhibitory mechanism of TMAOase was studied by Lineweaver-Burk plots, fluorescence spectroscopy, and circular dichroism. Specific activity of 37 ± 0.7 U/mg was obtained with 205 -fold purification and 15% yield, and molecular mass was 25 kDa. (+)-Catechin was a reversible inhibitor of TMAOase and its induced mechanism was the non-competitive inhibition type. (+)-Catechin binding to TMAOase formed a complex with the binding constant (Ksv) of 0.72 × 103 at 298 K. The formation of complex induced the static fluorescence quenching and changes in the conformation of TMAOase, leading to a reduction in the rate of catalysis.
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Catequina , Aldehído-Liasas , Metilaminas , ÓxidosRESUMEN
Impressive clinical benefit is seen in clinic with PD-1 inhibitors on portion of cancer patients. Yet, there remains an urgent need to develop effective synergizers to expand their clinical application. Tumor-associated macrophage (TAM), a type of M2-polarized macrophage, eliminates or suppresses T-cell-mediated anti-tumor responses. Transforming TAMs into M1 macrophages is an attractive strategy of anti-tumor therapy. Here, we conducted a high-throughput screening and found that Carfilzomib potently drove M2 macrophages to express M1 cytokines, phagocytose tumor cells, and present antigens to T cells. Mechanistically, Carfilzomib elicited unfolded protein response (UPR), activated IRE1α to recruit TRAF2, and activated NF-κB to transcribe genes encoding M1 markers in M2 macrophages. In vivo, Carfilzomib effectively rewired tumor microenvironment through reprogramming TAMs into M1-like macrophages and shrank autochthonous lung cancers in transgenic mouse model. More importantly, Carfilzomib synergized with PD-1 antibody to almost completely regress autochthonous lung cancers. Given the safety profiles of Carfilzomib in clinic, our work suggested a potentially immediate application of combinational treatment with Carfilzomib and PD-1 inhibitors for patients with solid tumors.
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Inhibidores de Puntos de Control Inmunológico/farmacología , Neoplasias Pulmonares , Oligopéptidos/farmacología , Microambiente Tumoral , Macrófagos Asociados a Tumores/inmunología , Animales , Reprogramación Celular , Endorribonucleasas , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Ratones , Ratones Transgénicos , Proteínas Serina-Treonina QuinasasRESUMEN
CD5 molecule like (CD5L), a member of the scavenger receptor cysteine-rich domain superfamily, plays a critical role in immune homeostasis and inflammatory disease. Acetaminophen (APAP) is a safe and effective antipyretic analgesic. However, overdose may cause liver damage or even liver failure. APAP hepatotoxicity is characterized by extensive necrotic cell death and a sterile inflammatory response, in which the role of CD5L remains to be investigated. In this study, we found that the expression of CD5L was increased in the livers of mice after APAP overdose. Furthermore, CD5L deficiency reduced the increase of alanine transaminase (ALT) level, histopathologic lesion area, c-Jun N-terminal kinase (JNK)/extracellular signal-regulated kinase (ERK) phosphorylation level, Transferase-Mediated dUTP Nick End-Labeling positive (TUNEL+) cells proportion, vascular endothelial cell permeability and release of inflammatory cytokines induced by excess APAP. Therefore, our findings reveal that CD5L may be a potential therapeutic target for prevention and treatment of APAP-induced liver injury.
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N6-methyladenosine (m6A) RNA modification is a reversible mechanism that regulates eukaryotic gene expression. Growing evidence has demonstrated an association between m6A modification and tumorigenesis and response to immunotherapy. However, the overall influence of m6A regulators on the tumor microenvironment and their effect on the response to immunotherapy in lung adenocarcinoma remains to be explored. Here, we comprehensively analyzed the m6A modification patterns of 936 lung adenocarcinoma samples based on 24 m6A regulators. First, we described the features of genetic variation in these m6A regulators. Many m6A regulators were aberrantly expressed in tumors and negatively correlated with most tumor-infiltrating immune cell types. Furthermore, we identified three m6A modification patterns using a consensus clustering method. m6A cluster B was preferentially associated with a favorable prognosis and enriched in metabolism-associated pathways. In contrast, m6A cluster A was associated with the worst prognosis and was enriched in the process of DNA repair. m6A cluster C was characterized by activation of the immune system and a higher stromal cell score. Surprisingly, patients who received radiotherapy had a better prognosis than patients without radiotherapy only in the m6A cluster C group. Subsequently, we constructed an m6A score model that qualified the m6A modification level of individual samples by using principal component analysis algorithms. Patients with high m6A score were characterized by enhanced immune cell infiltration and prolonged survival time and were associated with lower tumor mutation burden and PD-1/CTLA4 expression. The combination of the m6A score and tumor mutation burden could accurately predict the prognosis of patients with lung adenocarcinoma. Furthermore, patients with high m6A score exhibited greater prognostic benefits from radiotherapy and immunotherapy. This study demonstrates that m6A modification is significantly associated with tumor microenvironment diversity and prognosis. A comprehensive evaluation of m6A modification patterns in single tumors will expand our understanding of the tumor immune landscape. In addition, our m6A score model demonstrated that the level of immune cell infiltration plays a significant role in cancer immunotherapy and provides a basis to increase the efficiency of current immune therapies and promote the clinical success of immunotherapy.
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Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/mortalidad , Adenosina/análogos & derivados , Biomarcadores de Tumor , ARN Mensajero/genética , Adenocarcinoma del Pulmón/diagnóstico , Adenocarcinoma del Pulmón/terapia , Biología Computacional/métodos , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunomodulación , Inmunoterapia , Estimación de Kaplan-Meier , Metilación , Modelos Biológicos , Mutación , Clasificación del Tumor , Estadificación de Neoplasias , Pronóstico , ARN Mensajero/metabolismo , Resultado del TratamientoRESUMEN
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic worldwide. Currently, however, no effective drug or vaccine is available to treat or prevent the resulting coronavirus disease 2019 (COVID-19). Here, we report our discovery of a promising anti-COVID-19 drug candidate, the lipoglycopeptide antibiotic dalbavancin, based on virtual screening of the FDA-approved peptide drug library combined with in vitro and in vivo functional antiviral assays. Our results showed that dalbavancin directly binds to human angiotensin-converting enzyme 2 (ACE2) with high affinity, thereby blocking its interaction with the SARS-CoV-2 spike protein. Furthermore, dalbavancin effectively prevents SARS-CoV-2 replication in Vero E6 cells with an EC50 of ~12 nM. In both mouse and rhesus macaque models, viral replication and histopathological injuries caused by SARS-CoV-2 infection are significantly inhibited by dalbavancin administration. Given its high safety and long plasma half-life (8-10 days) shown in previous clinical trials, our data indicate that dalbavancin is a promising anti-COVID-19 drug candidate.
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Enzima Convertidora de Angiotensina 2/metabolismo , Antivirales , SARS-CoV-2/metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismo , Teicoplanina/análogos & derivados , Animales , Antivirales/farmacocinética , Antivirales/farmacología , Células CACO-2 , Chlorocebus aethiops , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Transgénicos , Unión Proteica/efectos de los fármacos , Teicoplanina/farmacocinética , Teicoplanina/farmacología , Células VeroRESUMEN
A surface acoustic wave (SAW) sensor was investigated for its application in C-reactive protein (CRP) detection. Piezoelectric lithium niobate (LiNbO3) substrates were used to study their frequency response characteristics in a SAW sensor with a CRP sensing area. After the fabrication of the SAW sensor, the immobilization process was performed for CRP/anti-CRP interaction. The CRP/anti-CRP interaction can be detected as mass variations in the sensing area. These mass variations may produce changes in the amplitude of sensor response. It was clearly observed that a CRP concentration of 0.1 µg/mL can be detected in the proposed SAW sensor. A good fitting linear relationship between the detected insertion loss (amplitude) and the concentrations of CRP from 0.1 µg/mL to 1 mg/mL was obtained. The detected shifts in the amplitude of insertion loss in SAW sensors for different CRP concentrations may be useful in the diagnosis of risk of cardiovascular diseases.
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Proteína C-Reactiva , Enfermedades Cardiovasculares , Sonido , Proteína C-Reactiva/análisis , Enfermedades Cardiovasculares/diagnósticoRESUMEN
Non-enzymatic chitinase-3 like-protein-1 (CHI3L1) belongs to glycoside hydrolase family 18. It binds to chitin, heparin, and hyaluronic acid, and is regulated by extracellular matrix changes, cytokines, growth factors, drugs, and stress. CHI3L1 is synthesized and secreted by a multitude of cells including macrophages, neutrophils, synoviocytes, chondrocytes, fibroblast-like cells, smooth muscle cells, and tumor cells. It plays a major role in tissue injury, inflammation, tissue repair, and remodeling responses. CHI3L1 has been strongly associated with diseases including asthma, arthritis, sepsis, diabetes, liver fibrosis, and coronary artery disease. Moreover, following its initial identification in the culture supernatant of the MG63 osteosarcoma cell line, CHI3L1 has been shown to be overexpressed in a wealth of both human cancers and animal tumor models. To date, interleukin-13 receptor subunit alpha-2, transmembrane protein 219, galectin-3, chemo-attractant receptor-homologous 2, and CD44 have been identified as CHI3L1 receptors. CHI3L1 signaling plays a critical role in cancer cell growth, proliferation, invasion, metastasis, angiogenesis, activation of tumor-associated macrophages, and Th2 polarization of CD4+ T cells. Interestingly, CHI3L1-based targeted therapy has been increasingly applied to the treatment of tumors including glioma and colon cancer as well as rheumatoid arthritis. This review summarizes the potential roles and mechanisms of CHI3L1 in oncogenesis and disease pathogenesis, then posits investigational strategies for targeted therapies.
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Neoplasias Óseas , Proteína 1 Similar a Quitinasa-3 , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Proteínas de Neoplasias , Osteosarcoma , Animales , Neoplasias Óseas/enzimología , Neoplasias Óseas/genética , Proteína 1 Similar a Quitinasa-3/biosíntesis , Proteína 1 Similar a Quitinasa-3/genética , Humanos , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Especificidad de Órganos , Osteosarcoma/enzimología , Osteosarcoma/genéticaRESUMEN
BACKGROUND: Lysine succinylation is an emerging posttranslational modification that has garnered increased attention recently, but its role in gastric cancer (GC) remains underexplored. METHODS: Proteomic quantification of lysine succinylation was performed in human GC tissues and adjacent normal tissues by mass spectrometry. The mRNA and protein levels of lactate dehydrogenase A (LDHA) in GC and adjacent normal tissues were analyzed by qRT-PCR and western blot, respectively. The expression of K222-succinylated LDHA was measured in GC tissue microarray by the K222 succinylation-specific antibody. The interaction between LDHA and sequestosome 1 (SQSTM1) was measured by co-immunoprecipitation (co-IP) and proximity ligation assay (PLA). The binding of carnitine palmitoyltransferase 1A (CPT1A) to LDHA was determined by co-IP. The effect of K222-succinylated LDHA on tumor growth and metastasis was evaluated by in vitro and in vivo experiments. RESULTS: Altogether, 503 lysine succinylation sites in 303 proteins were identified. Lactate dehydrogenase A (LDHA), the key enzyme in Warburg effect, was found highly succinylated at K222 in GC. Intriguingly, this modification did not affect LDHA ubiquitination, but reduced the binding of ubiquitinated LDHA to SQSTM1, thereby decreasing its lysosomal degradation. We demonstrated that CPT1A functions as a lysine succinyltransferase that interacts with and succinylates LDHA. Moreover, high K222-succinylation of LDHA was associated with poor prognosis in patients with GC. Finally, overexpression of a succinylation-mimic mutant of LDHA promoted cell proliferation, invasion, and migration. CONCLUSIONS: Our data revealed a novel lysosomal pathway of LDHA degradation, which is mediated by the binding of K63-ubiquitinated LDHA to SQSTM1. Strikingly, CPT1A succinylates LDHA on K222, which thereby reduces the binding and inhibits the degradation of LDHA, as well as promotes GC invasion and proliferation. This study thus uncovers a new role of lysine succinylation and the mechanism underlying LDHA upregulation in GC.