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1.
Immunol Lett ; : 106902, 2024 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-39181335

RESUMEN

Urushiol-induced allergic contact dermatitis (ACD) is a chronic inflammatory skin disease in which skin barrier dysfunction leads to pruritus and eczematous lesions. ACD is triggered by immune imbalance. Aloe emodin is an anthraquinone derivative extracted from rhubarb, aloe and other traditional Chinese medicines. It has a wide range of pharmacological effects, including anti-inflammatory, anti-tumor, and anti-allergic effects. The purpose of our study was to demonstrate the effectiveness of aloe-emodin on urushiol-induced acute pruritus and allergic contact dermatitis. The results showed that urushiol could stimulate keratinocytes to release chemokines CXCL1, CXCL2, CCL2, TSLP, and TNF-α, which recruit or activate mast cells. Aloe-emodin treatment inhibited inflammatory-response-induced mast cell degranulation in skin lesions and suppressed the expression of inflammatory cytokines, such as interleukin-4, and interleukin-6. Therefore, the results indicate that aloe-emodin can improve urushiol-induced acute pruritus and allergic contact dermatitis in mice by inhibiting mast cell degranulation.

2.
mSystems ; : e0079424, 2024 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-39166878

RESUMEN

Budd-Chiari syndrome (B-CS) is a rare and lethal condition characterized by hepatic venous outflow tract blockage. Gut microbiota has been linked to numerous hepatic disorders, but its significance in B-CS pathogenesis is uncertain. First, we performed a case-control study (Ncase = 140, Ncontrol = 63) to compare the fecal microbiota of B-CS and healthy individuals by metagenomics sequencing. B-CS patients' gut microbial composition and activity changed significantly, with a different metagenomic makeup, increased potentially pathogenic bacteria, including Prevotella, and disease-linked microbial function. Imbalanced cytokines in patients were demonstrated to be associated with gut dysbiosis, which led us to suspect that B-CS is associated with gut microbiota and immune dysregulation. Next, 16S ribosomal DNA sequencing on fecal microbiota transplantation (FMT) mice models examined the link between gut dysbiosis and B-CS. FMT models showed damaged liver tissues, posterior inferior vena cava, and increased Prevotella in the disturbed gut microbiota of FMT mice. Notably, B-CS-FMT impaired the morphological structure of colonic tissues and increased intestinal permeability. Furthermore, a significant increase of the same cytokines (IL-5, IL-6, IL-9, IL-10, IL-17A, IL-17F, and IL-13) and endotoxin levels in B-CS-FMT mice were observed. Our study suggested that gut microbial dysbiosis may cause B-CS through immunological dysregulation. IMPORTANCE: This study revealed that gut microbial dysbiosis may cause Budd-Chiari syndrome (B-CS). Gut dysbiosis enhanced intestinal permeability, and toxic metabolites and imbalanced cytokines activated the immune system. Consequently, the escalation of causative factors led to their concentration in the portal vein, thereby compromising both the liver parenchyma and outflow tract. Therefore, we proposed that gut microbial dysbiosis induced immune imbalance by chronic systemic inflammation, which contributed to the B-CS development. Furthermore, Prevotella may mediate inflammation development and immune imbalance, showing potential in B-CS pathogenesis.

3.
Cell Mol Life Sci ; 81(1): 355, 2024 Aug 19.
Artículo en Inglés | MEDLINE | ID: mdl-39158695

RESUMEN

Caspase-8, an aspartate-specific cysteine protease that primarily functions as an initiator caspase to induce apoptosis, can downregulate innate immunity in part by cleaving RIPK1 and IRF3. However, patients with caspase-8 mutations or deficiency develop immunodeficiency and are prone to viral infections. The molecular mechanism underlying this controversy remains unknown. Whether caspase-8 enhances or suppresses antiviral responses against influenza A virus (IAV) infection remains to be determined. Here, we report that caspase-8 is readily activated in A549 and NL20 cells infected with the H5N1, H5N6, and H1N1 subtypes of IAV. Surprisingly, caspase-8 deficiency and two caspase-8 inhibitors, Z-VAD and Z-IETD, do not enhance but rather downregulate antiviral innate immunity, as evidenced by decreased TBK1, IRF3, IκBα, and p65 phosphorylation, decreased IL-6, IFN-ß, MX1, and ISG15 gene expression; and decreased IFN-ß production but increased virus replication. Mechanistically, caspase-8 cleaves and inactivates CYLD, a tumor suppressor that functions as a deubiquitinase. Caspase-8 inhibition suppresses CYLD cleavage, RIG-I and TAK1 ubiquitination, and innate immune signaling. In contrast, CYLD deficiency enhances IAV-induced RIG-I and TAK1 ubiquitination and innate antiviral immunity. Neither caspase-3 deficiency nor treatment with its inhibitor Z-DEVD affects CYLD cleavage or antiviral innate immunity. Our study provides evidence that caspase-8 activation in two human airway epithelial cell lines does not silence but rather enhances innate immunity by inactivating CYLD.


Asunto(s)
Caspasa 8 , Proteína 58 DEAD Box , Enzima Desubiquitinante CYLD , Inmunidad Innata , Virus de la Influenza A , Gripe Humana , Quinasas Quinasa Quinasa PAM , Ubiquitinación , Humanos , Enzima Desubiquitinante CYLD/metabolismo , Enzima Desubiquitinante CYLD/genética , Caspasa 8/metabolismo , Caspasa 8/genética , Quinasas Quinasa Quinasa PAM/metabolismo , Quinasas Quinasa Quinasa PAM/genética , Quinasas Quinasa Quinasa PAM/inmunología , Virus de la Influenza A/inmunología , Proteína 58 DEAD Box/metabolismo , Proteína 58 DEAD Box/genética , Proteína 58 DEAD Box/inmunología , Gripe Humana/inmunología , Gripe Humana/virología , Células A549 , Animales , Transducción de Señal/inmunología , Receptores Inmunológicos
4.
Sci Rep ; 14(1): 17403, 2024 07 29.
Artículo en Inglés | MEDLINE | ID: mdl-39075134

RESUMEN

Traumatic cervical spinal cord injury (TCSCI) often causes varying degrees of motor dysfunction, common assessed by the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI), in association with the American Spinal Injury Association (ASIA) Impairment Scale. Accurate prediction of motor function recovery is extremely important for formulating effective diagnosis, therapeutic and rehabilitation programs. The aim of this study is to investigate the validity of a novel nested ensemble algorithm that uses the very early ASIA motor score (AMS) of ISNCSCI examination to predict motor function recovery 6 months after injury in TCSCI patients. This retrospective study included complete data of 315 TCSCI patients. The dataset consisting of the first AMS at ≤ 24 h post-injury and follow-up AMS at 6 months post-injury was divided into a training set (80%) and a test set (20%). The nested ensemble algorithm was established in a two-stage manner. Support Vector Classification (SVC), Adaboost, Weak-learner and Dummy were used in the first stage, and Adaboost was selected as second-stage model. The prediction results of the first stage models were uploaded into second-stage model to obtain the final prediction results. The model performance was evaluated using precision, recall, accuracy, F1 score, and confusion matrix. The nested ensemble algorithm was applied to predict motor function recovery of TCSCI, achieving an accuracy of 80.6%, a F1 score of 80.6%, and balancing sensitivity and specificity. The confusion matrix showed few false-negative rate, which has crucial practical implications for prognostic prediction of TCSCI. This novel nested ensemble algorithm, simply based on very early AMS, provides a useful tool for predicting motor function recovery 6 months after TCSCI, which is graded in gradients that progressively improve the accuracy and reliability of the prediction, demonstrating a strong potential of ensemble learning to personalize and optimize the rehabilitation and care of TCSCI patients.


Asunto(s)
Algoritmos , Recuperación de la Función , Traumatismos de la Médula Espinal , Humanos , Traumatismos de la Médula Espinal/rehabilitación , Traumatismos de la Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/diagnóstico , Masculino , Femenino , Adulto , Persona de Mediana Edad , Estudios Retrospectivos , Médula Cervical/lesiones , Médula Cervical/fisiopatología , Anciano , Adulto Joven , Pronóstico , Vértebras Cervicales/lesiones , Vértebras Cervicales/fisiopatología
5.
J Immunol Res ; 2024: 3145695, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38983273

RESUMEN

Background: This work focused on investigating the role of programmed death ligand 2 (PD-L2) in the progression of breast cancer by utilizing breast cancer specimens and cells. Materials and Methods: The serum levels of soluble PD-L2 (sPD-L2) in breast cancer patients and healthy individuals were analyzed by means of the enzyme-linked immunosorbent assay, and the PD-L2 levels within 416 resected breast cancer specimens were assessed through immunohistochemistry. Concurrently, in vitro cell experiments and in vivo animal experiments were carried out to analyze the relationship between PD-L2 and the invasion and migration of breast cancer. Results: The concentration of sPD-L2 in breast cancer patients significantly increased compared to that in the control groups. Additionally, breast cancer patients with high concentrations of sPD-L2 had higher Ki67 values (≥30%) and tumor grades. PD-L2 was expressed in 79.09% of the cancer samples, which exhibited a positive correlation with the progesterone receptor (PR) and the human epidermal growth factor receptor 2 (HER2). Furthermore, we discovered that knockdown of PD-L2 inhibited the migratory and invasive abilities of both MCF-7 and MDA-MB231 cells. Conclusion: Our findings demonstrated that knockdown of PD-L2 suppressed tumor growth, providing novel insights into important biological functions.


Asunto(s)
Neoplasias de la Mama , Movimiento Celular , Progresión de la Enfermedad , Proteína 2 Ligando de Muerte Celular Programada 1 , Humanos , Femenino , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/genética , Animales , Proteína 2 Ligando de Muerte Celular Programada 1/metabolismo , Proteína 2 Ligando de Muerte Celular Programada 1/genética , Ratones , Línea Celular Tumoral , Persona de Mediana Edad , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Adulto , Proliferación Celular , Células MCF-7 , Regulación Neoplásica de la Expresión Génica , Invasividad Neoplásica , Anciano , Inmunohistoquímica , Clasificación del Tumor , Biomarcadores de Tumor/metabolismo , Modelos Animales de Enfermedad , Receptores de Progesterona/metabolismo , Técnicas de Silenciamiento del Gen
6.
Cell Commun Signal ; 22(1): 372, 2024 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-39044278

RESUMEN

Many DNA viruses develop various strategies to inhibit cell death to facilitate their replication. However, whether influenza A virus (IAV), a fast-replicating RNA virus, attenuates cell death remains unknown. Here, we report that IAV infection induces TAK1 phosphorylation in a murine alveolar epithelial cell line (LET1) and a murine fibroblastoma cell line (L929). The TAK1-specific inhibitor 5Z-7-Oxzeneonal (5Z) and TAK1 knockout significantly enhance IAV-induced apoptosis, as evidenced by increased PARP, caspase-8, and caspase-3 cleavage. TAK1 inhibition also increases necroptosis as evidenced by increased RIPK1S166, RIPK3T231/S232, and MLKLS345 phosphorylation. Mechanistically, TAK1 activates IKK, which phosphorylates RIPK1S25 and inhibits its activation. TAK1 also activates p38 and its downstream kinase MK2, which phosphorylates RIPK1S321 but does not affect RIPK1 activation. Further investigation revealed that the RIPK1 inhibitor Nec-1 and RIPK1 knockout abrogate IAV-induced apoptosis and necroptosis; re-expression of wild-type but not kinase-dead (KD)-RIPK1 restores IAV-induced cell death. ZBP1 knockout abrogates IAV-induced cell death, whereas RIPK3 knockout inhibits IAV-induced necroptosis but not apoptosis. 5Z treatment enhances IAV-induced cell death and slightly reduces the inflammatory response in the lungs of H1N1 virus-infected mice and prolongs the survival of IAV-infected mice. Our study provides evidence that IAV activates TAK1 to suppress RIPK1-dependent apoptosis and necroptosis, and that RIPK3 is required for IAV-induced necroptosis but not apoptosis in epithelial cells.


Asunto(s)
Apoptosis , Quinasas Quinasa Quinasa PAM , Necroptosis , Proteína Serina-Treonina Quinasas de Interacción con Receptores , Animales , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Quinasas Quinasa Quinasa PAM/metabolismo , Quinasas Quinasa Quinasa PAM/genética , Ratones , Fosforilación , Infecciones por Orthomyxoviridae/virología , Infecciones por Orthomyxoviridae/patología , Línea Celular , Virus de la Influenza A/fisiología , Ratones Endogámicos C57BL , Humanos
7.
Int J Gen Med ; 17: 725-738, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38481615

RESUMEN

Background and Aim: Cervical hyperextension injury is very frequent with anterior longitudinal ligament (ALL) injury, and the ligament damage has a remarkable effect on whether and what type of operation should be performed. This study aims to establish a new scoring system for the accurate diagnosis of ALL damage. Methods: The imaging data of the consecutive patients was measured and scored by four radiologists. Intraoperative exploration was performed by three surgeons. The crude and adjusted odds ratios (cOR and aOR) and receiver operating characteristic curve (ROC) were constructed to assess the diagnostic accuracy of the scoring system. Results: A total of 255 patients with cervical spine trauma were included in this study. There was no statistical difference in the relationship between demographics and ALL injuries (P > 0.05). Thickness of prevertebral soft tissue (aOR = 11.922, P = 0.004), intervertebral disk angle (aOR = 13.21, P = 0.002), avulsion fracture of the anterior edge of the vertebral body (aOR = 13.844, P = 0.029), ALL disrupted in T1-weighted sequence (aOR = 18.349, P < 0.001), and high signal area in T2-weighted sequence (aOR = 20.898, P = 0.002) had significantly higher diagnostic accuracy. The scoring system's sensitivity and specificity were 94.0% and 88.1%, respectively, and the accuracy was 90.8%. Conclusion: The study established a new scoring system for ALL injuries based on the analysis of a series of clinical data and statistics. A total of five scoring items, a total score of 7 points, and an ALL injury may be diagnosed when the score is not less than 3 points. This scoring system enables an efficient and accurate diagnosis of all injuries.

8.
RSC Adv ; 14(6): 3808-3819, 2024 Jan 23.
Artículo en Inglés | MEDLINE | ID: mdl-38274165

RESUMEN

Glutathione (GSH) is a major antioxidant in organisms. An alteration in GSH concentration has been implicated in a number of pathological conditions. Therefore, GSH sensing has become a critical issue. In this study, a disposable strip used for tyrosinase-modified electrochemical testing was fabricated for the detection of GSH levels in vivo. The system is based on tyrosinase as a biorecognition element and a screen-printed carbon electrode (SPCE) as an amperometric transducer. On the tyrosinase-SPCE strips, the oxidation reaction from catechol to o-quinone was catalyzed by tyrosinase. The tyrosinase-SPCE strips were modified with gold nanoparticles (AuNPs). In the presence of AuNPs of 25 nm diameter, the cathodic peak current of cyclic voltammetry (CV) was significantly enhanced by 5.2 fold. Under optimized conditions (250 µM catechol, 50 mM phosphate buffer, and pH 6.5), the linear response of the tyrosinase-SPCE strips ranged from 31.25 to 500 µM GSH, with a detection limit of approximately 35 µM (S/N > 3). The tyrosinase-SPCE strips have been used to detect real samples of plasma and tissue homogenates in a mouse experiment. The mice were orally administrated with N-acetylcysteine (NAC) 100 mg kg-1 once a day for 7 days; the plasma GSH significantly enhanced 2.8 fold as compared with saline-treated mice (1123 vs. 480 µM µg-1 protein). NAC administration also could alleviate the adverse effect of GSH reduction in the mice treated with doxorubicin.

9.
Hepatobiliary Pancreat Dis Int ; 23(3): 293-299, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-36690523

RESUMEN

BACKGROUND: Acute suppurative terminal cholangitis (ASTC) is rarer than acute obstructive cholangitis and is not well studied. To explore this subtype of acute cholangitis, we described our clinical experience with ASTC. METHODS: We performed a retrospective review of patients with ASTC admitted to our center from September 2014 to August 2020. We analyzed their clinical characteristics, including etiology, clinical manifestations, imaging features, treatment and prognosis. RESULTS: A total of 32 ASTC patients were included in the analysis. The majority of the patients had a history of biliary operations, and clinical manifestations were occult and atypical. The positive rate of bacterial culture was 46.9%. All the patients had typical imaging features on computed tomography and magnetic resonance imaging. Treatment with effective antibiotics was provided as soon as diagnosis was established. After treatment, most patients had a good outcome. Elevated levels of total bilirubin, aspartate aminotransferase, procalcitonin and gamma-glutamyltransferase were the characteristics of critically ill patients and were associated with relatively poor prognosis. CONCLUSIONS: Our results demonstrated that ASTC should be recognized as a new subtype of acute cholangitis, and that earlier diagnosis and more personalized treatments are needed.


Asunto(s)
Colangitis , Humanos , Supuración/complicaciones , Pronóstico , Colangitis/diagnóstico , Colangitis/terapia , Hospitalización , Tomografía Computarizada por Rayos X , Enfermedad Aguda , Estudios Retrospectivos
10.
Mol Immunol ; 165: 19-27, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38134517

RESUMEN

OBJECTIVE: The primary pathological changes of rheumatoid arthritis (RA) include chronic synovial inflammation, bone destruction, and aggressive pannus formation on cartilage, in which angiogenesis plays a critical role. B7-H3, an important immune checkpoint molecule, represents a novel target in tumor therapy and plays a significant role in the pathogenesis of autoimmune diseases. However, its biological mechanism in RA remains unclear. METHODS: Hematoxylin-eosin (HE) staining and immunohistochemistry were used to explore the histological characteristics and expression of B7-H3, CD34, and vascular endothelial growth factor (VEGF) in patients with RA and collagen-induced arthritis (CIA) mice. ELISA was used to detect VEGF, soluble B7-H3, and disease markers in the peripheral blood of patients. A monoclonal anti-B7-H3 antibody was used to treat CIA mice by blocking B7-H3-mediated signaling. RESULTS: The ELISA and HE staining results showed a positive correlation between the expression of B7-H3 and the degree of joint cavity destruction and pannus formation. B7-H3 expression also correlated with increased expression of the vessel biomarkers CD34 and VEGF. Anti-B7-H3 effectively reduced pannus formation in CIA mice. CONCLUSION: B7-H3 modulates angiogenic activity in the joint synovium, demonstrating its therapeutic value in the context of RA.


Asunto(s)
Artritis Experimental , Artritis Reumatoide , Animales , Humanos , Ratones , Angiogénesis , Anticuerpos Monoclonales/uso terapéutico , Artritis Experimental/metabolismo , Artritis Reumatoide/patología , Inflamación/patología , Neovascularización Patológica/metabolismo , Membrana Sinovial/patología , Factores de Transcripción , Factor A de Crecimiento Endotelial Vascular/metabolismo
11.
J Am Chem Soc ; 145(46): 25471-25477, 2023 Nov 22.
Artículo en Inglés | MEDLINE | ID: mdl-37939354

RESUMEN

Nanohydrogelation of covalent organic frameworks (COFs) will undoubtedly open up new applications for them in water, such as aqueous catalysis and biomedicine. It is currently a great challenge to achieve water dispersion of COFs through either bottom-up construction strategies or top-down exfoliating technologies. Herein, poly(N-isopropylacrylamide) (PNIPAM)-postmodified COF nanohydrogels (COF-NHGs) are successfully designed and synthesized via in situ atom-transfer radical polymerization (ATRP) on a scaffold of COFs. During the polymer growth process, the bulk COFs are exfoliated into nanosheets with a lateral size of ∼500 nm and a thickness of ∼6.5 nm. Moreover, their size can be precisely controlled by the degree of polymerization of PNIPAMs. In aqueous solution, the obtained COF-NHGs are assembled into nanohydrogels retaining intra-plane crystallinity and exhibit a temperature-sensitive sol-gel phase transition. With excellent solubility in organic solvents, the COF-NHGs' intrinsic physical properties in the solution state can be characterized through their solution nuclear magnetic resonance and ultraviolet absorption spectra. These results put forward new opportunities for regulating the solution processability of COFs and building an intelligent, stimuli-response platform of COF-polymer composite nanohydrogels for device applications.

12.
mBio ; 14(5): e0139523, 2023 Oct 31.
Artículo en Inglés | MEDLINE | ID: mdl-37830811

RESUMEN

IMPORTANCE: It is well established that exopolysaccharide (EPS) is an integral structural component of bacterial biofilms necessary for assembly and maintenance of the three-dimensional architecture of the biofilm. However, the process and role of EPS turnover within a developing biofilm is not fully understood. Here, we demonstrated that Xylella fastidiosa uses a self-produced endoglucanase to enzymatically process its own EPS to modulate EPS polymer length. This enzymatic processing of EPS dictates the early stages of X. fastidiosa's biofilm development, which, in turn, affects its behavior in planta. A deletion mutant that cannot produce the endoglucanase was hypervirulent, thereby linking enzymatic processing of EPS to attenuation of virulence in symptomatic hosts, which may be a vestige of X. fastidiosa's commensal behavior in many of its other non-symptomatic hosts.


Asunto(s)
Celulasa , Xylella , Celulasa/genética , Polímeros , Biopelículas , Xylella/genética
13.
J Phys Chem Lett ; 14(36): 8145-8150, 2023 Sep 14.
Artículo en Inglés | MEDLINE | ID: mdl-37669464

RESUMEN

The cryopreservation of cells, tissue, and organs is essential in both fundamental research and practical applications, such as modern regenerative medicine and technological applications. However, the formation of ice crystals during ice recrystallization can have harmful or even fatal effects on biological systems. To address this challenge, we explore the ice recrystallization inhibition (IRI) activity of two natural silk proteins of Bombyx mori, fibroin and sericin. We found that silk fibroin (SF) had higher ice recrystallization inhibition activity than silk sericin (SS). Moreover, SF aqueous solutions perform better in inhibiting ice recrystallization than SF phosphate-buffered saline solutions. Sum-frequency generation spectroscopy shows that stronger electrostatic interactions are responsible for the higher IRI ability of SF. This work is significant for broadening the applications of silk proteins in biomedical fields.


Asunto(s)
Bombyx , Fibroínas , Sericinas , Animales , Seda , Hielo
14.
Med Oncol ; 40(8): 242, 2023 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-37452976

RESUMEN

Prostate cancer (PCa) refers to epithelial malignancies occurring in prostate and is the most commonly diagnosed cancer among men. Flap structure-specific endonuclease 1 (FEN1) is one of the major base excise repair enzymes and is abnormally expressed in a variety of cancers, which contributes to cancer progression. Targeting FEN1 serves as a potent strategy for cancer therapy. However, how FEN1 acts on PCa cell proliferation and its role in chemotherapeutic response remain largely unknown. In this study, we show that knockdown of FEN1 by CRISPR/Cas9 system impedes the proliferation and migration of PCa cells. FEN1 Inhibitor SC13 induced DNA damage accumulation and further resulted in apoptosis of PCa cells. Furthermore, genetic knockdown of FEN1 or inhibition of FEN1 by SC13 promoted DNA damage and enhanced docetaxel (DTX)-induced chemotherapeutic response in PCa cells. Collectively, these findings demonstrate the importance of FEN1 in PCa cell proliferation and implicate FEN1 as a promising target for monotherapy or combination therapeutic strategy in PCa treatment.


Asunto(s)
Antineoplásicos , Neoplasias de la Próstata , Masculino , Humanos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Próstata , Línea Celular Tumoral , Daño del ADN , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Endonucleasas de ADN Solapado/genética
15.
Immunogenetics ; 75(5): 425-431, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37405419

RESUMEN

The programmed death-1 (PD-1) pathway has been shown to deliver an inhibitory signal, and aberrant expression of the PD-1 molecule and/or its ligand programmed death ligand 1 (PD-L1) has been demonstrated in human diseases, while its other ligand, programmed death ligand 2 (PD-L2), has rarely been studied. Here, we investigated the expression of PD-L2 in synovial tissue and blood from patients with rheumatoid arthritis (RA). Soluble PD-L2 and inflammatory cytokine levels in serum among healthy controls and patients with RA were compared via enzyme-linked immunosorbent assay (ELISA). Membrane PD-L2 on monocytes in blood was analyzed through flow cytometry (FCM). The different expression levels of PD-L2 between the RA and non-RA synovium were semi-quantified by immunohistochemical (IHC) staining. The soluble PD-L2 levels in serum from patients with RA were significantly lower than those in healthy subjects, correlating with active parameters (rheumatoid factor) and inflammatory cytokine secretion. The FCM results showed that patients with RA had significantly increased percentages of PD-L2-expressing CD14+ monocytes and correlated with inflammatory cytokines. PD-L2 expression on macrophages in the synovium from patients with RA was recorded by IHC staining with a higher score, and its correlation with pathological scores and clinical features was determined. Together, our results revealed aberrant expression of PD-L2 in RA, which may be a promising biomarker and therapeutic target associated with the pathogenesis of RA.


Asunto(s)
Artritis Reumatoide , Receptor de Muerte Celular Programada 1 , Humanos , Ligandos , Artritis Reumatoide/metabolismo , Inflamación , Citocinas
16.
Cancer Lett ; 558: 216106, 2023 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-36841418

RESUMEN

Hepatocellular carcinoma (HCC) is a common digestive tract malignancy that seriously threatens human life and health. Early HCC may be treated by intervention, surgery, and internal radiotherapy, while the choice for late HCC is primarily chemotherapy to prolong patient survival. Lenvatinib (LT) is a Food and Drug Administration (FDA)-approved frontline drug for the treatment of advanced liver cancer and has achieved excellent clinical efficacy. However, its poor solubility and severe side effects cannot be ignored. In this study, a bionic nanodrug delivery platform was successfully constructed. The platform consists of a core of Lenvatinib wrapped with a pH-sensitive polymer, namely, poly(ß-amino ester)-polyethylene glycol-amine (PAE-PEG-NH2), and a shell formed by a cancer cell membrane (CCM). The prepared nanodrugs have high drug loading capacity, long-term stability, good biocompatibility, and a long retention time. In addition, the targeting effect of tumor cell membranes and the pH-responsive characteristics of the polymer materials enable them to precisely target tumor cells and achieve responsive release in the tumor microenvironment, which makes them suitable for effective drug delivery. In vivo experiments revealed that the nanodrug showed superior tumor accumulation and therapeutic effects in subcutaneous tumor mice model and could effectively eliminate tumors within 21 days. As a result, it opens up a new way to reduce side effects and improve the specific therapeutic effect of first-line clinical medications to treat tumors.


Asunto(s)
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanopartículas , Animales , Ratones , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/patología , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Polímeros/uso terapéutico , Polietilenglicoles , Nanopartículas/uso terapéutico , Membrana Celular , Antineoplásicos/uso terapéutico , Microambiente Tumoral
17.
Chem Commun (Camb) ; 59(3): 302-305, 2023 Jan 03.
Artículo en Inglés | MEDLINE | ID: mdl-36507910

RESUMEN

A pair of chiral, emissive and porous tubular multi-functional organic molecular cages were synthesized easily by imine chemistry of 4,4',4'',4'''-(ethene-1,1,2,2-tetrayl)-tetrabenzaldehyde (ETTBA) with (R,R)- or (S,S)-diaminocyclohexane (CHDA). It was found that the chirality of CHDA was transferred and amplified to tetraphenylethylene (TPE) in the process of formation of cages, which further endowed the cages with circularly polarized luminescence (CPL) characteristics. As a result of the synergy of the chirality and porous structure in the solid state, both cages exhibited a good chiral adsorption enantioselectivity to a series of aromatic racemates.

18.
Acta Pharmacol Sin ; 44(2): 321-331, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-35655094

RESUMEN

Metabolic cardiomyopathy (MC) is characterized by intracellular lipid accumulation and utilizing fatty acids as a foremost energy source, thereby leading to excess oxidative stress and mitochondrial dysfunction. There is no effective therapy available yet. In this study we investigated whether defective mitophagy contributed to MC and whether urolithin A (UA), a naturally occurring microflora-derived metabolite, could protect against MC in experimental obese mice. Mice were fed high fat diet for 20 weeks to establish a diet-induced obese model. We showed that mitochondrial autophagy or mitophagy was significantly downregulated in the heart of experimental obese mice. UA (50 mg·kg-1·d-1, for 4 weeks) markedly activated mitophagy and ameliorated MC in obese mice by gavage. In PA-challenged H9C2 cardiomyocytes, UA (5 µM) significantly increased autophagosomes and decreased autolysosomes. Furthermore, UA administration rescued PINK1/Parkin-dependent mitophagy and relieved mitochondrial defects in the heart of obese mice, which led to improving cardiac diastolic function and ameliorating cardiac remodelling. In PA-challenged primarily isolated cardiomyocytes, both application of mitophagy inhibitor Mdivi-1 (15 µM) and silencing of mitophagy gene Parkin blunted the myocardial protective effect of UA. In summary, our data suggest that restoration of mitophagy with UA ameliorates symptoms of MC, which highlights a therapeutic potential of UA in the treatment of MC.


Asunto(s)
Cardiomiopatías , Mitofagia , Ratones , Animales , Ratones Obesos , Proteínas Quinasas/metabolismo , Cardiomiopatías/metabolismo , Miocitos Cardíacos/metabolismo , Obesidad/complicaciones , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo
19.
ACS Appl Mater Interfaces ; 14(48): 53567-53574, 2022 Dec 07.
Artículo en Inglés | MEDLINE | ID: mdl-36413752

RESUMEN

It remains a great challenge to design and synthesize organic luminescent molecules with strong emission in both dilute solution and aggregate state. Herein, an organic cage with dodecadansyl groups (D-RCC1) from an easy sulfonation reaction displays strong emissive behavior in dilute organic solution with a quantum yield of 42%. Moreover, D-RCC1 exhibits an ultrahigh quantum yield of 92% in the solid state, which is more than 3 times that of 27% for the model compound D-DEA. The results of the experiment and theoretical calculation show that the three-dimensional symmetrical skeleton of the organic cage anchored evenly by multiple dye molecules effectively satisfies both high local density and a symmetrical distribution of chromophores, which prevents the interaction of dye molecules and ensures that dye molecules have strong emission in both single-molecule and aggregate states.

20.
Elife ; 112022 10 25.
Artículo en Inglés | MEDLINE | ID: mdl-36282174

RESUMEN

As the most aggressive tumor, the outcome of pancreatic cancer (PACA) has not improved observably over the last decade. Anatomy-based TNM staging does not exactly identify treatment-sensitive patients, and an ideal biomarker is urgently needed for precision medicine. Based on expression files of 1280 patients from 10 multicenter cohorts, we screened 32 consensus prognostic genes. Ten machine-learning algorithms were transformed into 76 combinations, of which we selected the optimal algorithm to construct an artificial intelligence-derived prognostic signature (AIDPS) according to the average C-index in the nine testing cohorts. The results of the training cohort, nine testing cohorts, Meta-Cohort, and three external validation cohorts (290 patients) consistently indicated that AIDPS could accurately predict the prognosis of PACA. After incorporating several vital clinicopathological features and 86 published signatures, AIDPS exhibited robust and dramatically superior predictive capability. Moreover, in other prevalent digestive system tumors, the nine-gene AIDPS could still accurately stratify the prognosis. Of note, our AIDPS had important clinical implications for PACA, and patients with low AIDPS owned a dismal prognosis, higher genomic alterations, and denser immune cell infiltrates as well as were more sensitive to immunotherapy. Meanwhile, the high AIDPS group possessed observably prolonged survival, and panobinostat may be a potential agent for patients with high AIDPS. Overall, our study provides an attractive tool to further guide the clinical management and individualized treatment of PACA.


Asunto(s)
Perfilación de la Expresión Génica , Neoplasias Pancreáticas , Humanos , Perfilación de la Expresión Génica/métodos , Consenso , Inteligencia Artificial , Panobinostat , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Aprendizaje Automático , Biomarcadores , Neoplasias Pancreáticas
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