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1.
Front Cell Neurosci ; 16: 892197, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35783103

RESUMO

Death-associated protein kinase 1 (DAPK1), a Ca2+/calmodulin-dependent serine/threonine-protein kinase, promotes neurons apoptosis in ischemic stroke and Alzheimer's disease (AD). We hypothesized that knockdown DAPK1 may play a protective role in traumatic brain injury (TBI) and explore underlying molecular mechanisms. ELISA, Western blotting, immunofluorescence, dual-luciferase assay, and Reverse Transcription and quantitative Polymerase Chain Reaction (RT-qPCR) were used to determine the mechanism for the role of DAPK1 in TBI. Open field and novel objective recognition tests examined motor and memory functions. The morphology and number of synapses were observed by transmission electron microscopy and Golgi staining. DAPK1 was mainly found in neurons and significantly increased in TBI patients and TBI mice. The dual-luciferase assay showed that DAPK1 was upregulated by miR-124 loss. The number of TUNEL+ cells, expression levels of cleaved caspase3 and p-NR2B/NR2B were significantly reduced after knocking-down DAPK1 or overexpressing miR-124 in TBI mice; and motor and memory dysfunction was recovered. After Tat-NR2B were injected in TBI mice, pathological and behavioral changes were mitigated while the morphology while the number of synapses were not affected. Overall, DAPK1 is a downstream target gene of miR-124 that regulates neuronal apoptosis in TBI mice via NR2B. What's more, DAPK1 restores motor and memory dysfunctions without affecting the number and morphology of synapses.

2.
Redox Biol ; 54: 102390, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35793583

RESUMO

Mitochondrial dysfunction and oxidative injury, which contribute to worsening of neurological deficits and poor clinical outcomes, are hallmarks of secondary brain injury after TBI. Adiponectin (APN), beyond its well-established regulatory effects on metabolism, is also essential for maintaining normal brain functions by binding APN receptors that are ubiquitously expressed in the brain. Currently, the significance of the APN/APN receptor (AdipoR) signaling pathway in secondary injury after TBI and the specific mechanisms have not been conclusively determined. In this study, we found that APN knockout aggravated brain functional deficits, increased brain edema and lesion volume, and exacerbated oxidative stress as well as apoptosis after TBI. These effects were significantly alleviated after APN receptor agonist (AdipoRon) treatment. Moreover, we found that AdipoR1, rather than AdipoR2, mediated the protective effects of APN/AdipoR signaling against oxidative stress and brain injury after TBI. In neuron-specific AdipoR1 knockout mice, mitochondrial damage was more severe after TBI, indicating a potential association between APN/AdipoR1 signaling inactivation and mitochondrial damage. Mechanistically, neuron-specific knockout of SIRT3, the most important deacetylase in the mitochondria, reversed the neuroprotective effects of AdipoRon after TBI. Then, PRDX3, a critical antioxidant enzyme in the mitochondria, was identified as a vital downstream target of the APN/SIRT3 axis to alleviate oxidative injury after TBI. Finally, we revealed that APN/AdipoR1 signaling promotes SIRT3 transcription by activating the AMPK-PGC pathway. In conclusion, APN/AdipoR1 signaling plays a protective role in post-TBI oxidative damage by restoring the SIRT3-mediated mitochondrial homeostasis and antioxidant system.


Assuntos
Lesões Encefálicas Traumáticas , Mitocôndrias , Estresse Oxidativo , Receptores de Adiponectina , Sirtuína 3 , Adiponectina/genética , Adiponectina/metabolismo , Animais , Antioxidantes/metabolismo , Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/metabolismo , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Receptores de Adiponectina/agonistas , Receptores de Adiponectina/genética , Receptores de Adiponectina/metabolismo , Transdução de Sinais , Sirtuína 3/genética , Sirtuína 3/metabolismo
3.
Gynecol Oncol ; 166(1): 138-147, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35595569

RESUMO

OBJECTIVE: The role of kallikrein-related peptidase 5 (KLK5) has been studied in several diseases, including skin and ovarian cancers. However, its role in cervical cancer remains unclear, particularly in regulating the radiation resistance and growth of cervical cancer cells. Radiation resistance of cervical cancer is associated with local recurrence, distant metastasis, and reduced survival. METHODS: We first analyzed radiotherapy-naive samples and relevant clinical data from patients with cervical cancer who received radiotherapy without surgery or other antitumor treatment from 2014 to 2016. Subsequently, biopsied tissues, in vitro cells, and transplanted tumors in nude mice were investigated. RESULTS: Gene sequencing and clinical data analysis showed that KLK5 overexpression was associated with a poor prognosis post-radiotherapy. In in vitro cell and tumor transplantation experiments, KLK5 overexpression significantly increased radiation resistance. However, downregulating KLK5 expression increased radiosensitivity. CONCLUSION: Our results confirm that KLK5 is vital to the radioresistance of cervical cancer, and provide a new target and marker for the treatment of radioresistance in cervical cancer.


Assuntos
Calicreínas , Neoplasias do Colo do Útero , Agressão , Animais , Biomarcadores Tumorais/genética , Feminino , Humanos , Calicreínas/genética , Camundongos , Camundongos Nus , Tolerância a Radiação/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/radioterapia
4.
Front Immunol ; 13: 823910, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35493457

RESUMO

Glioma is the most common primary malignant brain tumor in adults with very poor prognosis. The limited new therapeutic strategies for glioma patients can be partially attributed to the complex tumor microenvironment. However, knowledge about the glioma immune microenvironment and the associated regulatory mechanisms is still lacking. In this study, we found that, different immune subtypes have a significant impact on patient survival. Glioma patients with a high immune response subtype had a shorter survival compared with patients with a low immune response subtype. Moreover, the number of B cell, T cell, NK cell, and in particular, the macrophage in the immune microenvironment of patients with a high immune response subtype were significantly enhanced. In addition, 132 genes were found to be related to glioma immunity. The functional analysis and verification of seven core genes showed that their expression levels were significantly correlated with the prognosis of glioma patients, and the results were consistent at tissue levels. These findings indicated that the glioma immune microenvironment was significantly correlated with the prognosis of glioma patients and multiple genes were involved in regulating the progression of glioma. The identified genes could be used to stratify glioma patients based on immune subgroup analysis, which may guide their clinical treatment regimen.


Assuntos
Neoplasias Encefálicas , Glioma , Adulto , Neoplasias Encefálicas/patologia , Glioma/patologia , Humanos , Imunofenotipagem , Prognóstico , Microambiente Tumoral/genética
5.
Med Sci Monit ; 28: e935307, 2022 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-35459760

RESUMO

BACKGROUND We aimed to develop a combined model of quantitative parameters derived from 3 different magnetic resonance imaging (MRI) diffusion models and laboratory data related to prostate-specific antigen (PSA) for differentiating between prostate cancer (PCa) and benign lesions. MATERIAL AND METHODS Eighty-four patients pathologically confirmed as having PCa or benign disease were enrolled. All patients underwent multiparametric MRI before biopsy, added intravoxel incoherent motion (IVIM) imaging, and diffusion kurtosis imaging (DKI). The following data were collected: quantitative parameters of diffusion-weighted imaging (DWI), IVIM, and DKI, preoperative total PSA, free/total PSA ratio, and PSA density (PSAD) values. A combined logistic regression model was established by above MRI quantitative parameters and PSA data to diagnose PCa. The Prostate Imaging Reporting and Data System version 2 (PI-RADS v2) was used to assess the lesions for comparison. RESULTS Thirty-two patients had PCa and 52 patients had benign lesions. In multivariate logistic regression analysis, only apparent diffusion coefficient (ADC) and PSAD were significant variables (P<0.05) and were thus retained in the model. The area under curve value of the combined model (0.911) was higher than that of ADC, PSAD, and PI-RADS v2 (0.887, 0.861, and 0.859, respectively) in univariate analysis, but without any statistically significant differences. The combined model generated greater clinical benefit than the independent application of ADC, PSAD, and PI-RADS v2. CONCLUSIONS ADC and PSAD were the 2 most important metrics for distinguishing PCa from benign lesions. The combined model of ADC and PSAD demonstrated satisfactory discrimination and improved clinical net benefit.


Assuntos
Antígeno Prostático Específico , Neoplasias da Próstata , Imagem de Difusão por Ressonância Magnética/métodos , Humanos , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética , Masculino , Próstata/diagnóstico por imagem , Próstata/patologia , Antígeno Prostático Específico/análise , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Estudos Retrospectivos
6.
Front Cell Neurosci ; 16: 850866, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35321205

RESUMO

Astrocytes are essential in maintaining normal brain functions such as blood brain barrier (BBB) homeostasis and synapse formation as the most abundant cell type in the central nervous system (CNS). After the stroke, astrocytes are known as reactive astrocytes (RAs) because they are stimulated by various damage-associated molecular patterns (DAMPs) and cytokines, resulting in significant changes in their reactivity, gene expression, and functional characteristics. RAs perform multiple functions after stroke. The inflammatory response of RAs may aggravate neuro-inflammation and release toxic factors to exert neurological damage. However, RAs also reduce excitotoxicity and release neurotrophies to promote neuroprotection. Furthermore, RAs contribute to angiogenesis and axonal remodeling to promote neurological recovery. Therefore, RAs' biphasic roles and mechanisms make them an effective target for functional recovery after the stroke. In this review, we summarized the dynamic functional changes and internal molecular mechanisms of RAs, as well as their therapeutic potential and strategies, in order to comprehensively understand the role of RAs in the outcome of stroke disease and provide a new direction for the clinical treatment of stroke.

8.
Appl Opt ; 61(3): 812-817, 2022 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-35200788

RESUMO

Spectral filtering is essential in daytime quantum key distribution (QKD), which can suppress the strong background noise caused by scattered solar irradiation. An integrated Fabry-Perot filter is implemented based on a scheme that combines a Fabry-Perot etalon and a dense-wavelength-division-multiplex filter for narrow linewidth filtering and broad-spectrum noise suppression, respectively. This filter is integrated into a butterfly package with single-mode fibers for optical input and output, thereby enhancing high robustness and ease of use. The measurement results show that the filter has a linewidth of 25.6 pm, a noise suppression of over 44.7 dB ranging between 1380-1760 nm, an optical efficiency of 74.5% with variation less than 0.9% in 120 min, and a polarization fidelity after compensation exceeding 99.9%. The ability of fine-tuning the central wavelength with 9.5 pm/°C makes it very suitable for satellite-based applications under the Doppler effect. Further analysis is also given to demonstrate the prospects of applying this filter in future satellite-based daytime QKD applications.

9.
Adv Sci (Weinh) ; 9(7): e2104112, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35038242

RESUMO

Traumatic brain injury (TBI) is a risk factor for posttraumatic stress disorder (PTSD). Augmented fear is a defining characteristic of PTSD, and the amygdala is considered the main brain region to process fear. The mechanism by which the amygdala is involved in fear conditioning after TBI is still unclear. Using single-nucleus RNA sequencing (snRNA-seq), transcriptional changes in cells in the amygdala after TBI are investigated. In total, 72 328 nuclei are obtained from the sham and TBI groups. 7 cell types, and analysis of differentially expressed genes (DEGs) reveals widespread transcriptional changes in each cell type after TBI are identified. In in vivo experiments, it is demonstrated that Decorin (Dcn) expression in the excitatory neurons of the amygdala significantly increased after TBI, and Dcn knockout in the amygdala mitigates TBI-associated fear conditioning. Of note, this effect is caused by a Dcn-mediated decrease in the expression of perineuronal nets (PNNs), which affect the glutamate-γ-aminobutyric acid balance in the amygdala. Finally, the results suggest that Dcn functions by interacting with collagen VI α3 (Col6a3). Consequently, the findings reveal transcriptional changes in different cell types of the amygdala after TBI and provide direct evidence that Dcn relieves fear conditioning by regulating PNNs.


Assuntos
Tonsila do Cerebelo , Lesões Encefálicas Traumáticas , Tonsila do Cerebelo/fisiologia , Animais , Lesões Encefálicas Traumáticas/genética , Decorina/genética , Medo/fisiologia , Camundongos , Análise de Sequência de RNA
10.
Acad Radiol ; 29 Suppl 3: S44-S51, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-33504445

RESUMO

RATIONALE AND OBJECTIVES: The purpose of this study was to explore conventional MRI features that can accurately differentiate central nervous system embryonal tumor, not otherwise specified (CNS ETNOS) from glioblastoma (GBM) in adults. MATERIALS AND METHODS: Preoperative conventional MRI images of 30 CNS ETNOS and 98 GBMs were analyzed by neuroradiologists retrospectively to identify valuable MRI features. Five blinded neuroradiologists independently reviewed all these MRI images, and scored MRI features on a five-point scale. Kendall's coefficient of concordance was used to measure inter-rater agreement. Diagnostic value was assessed by the area under the curve (AUC) of receiver operating curve, and sensitivity and specificity were also calculated. RESULTS: Seven MRI features, including isointensity on T1WI, T2WI, and FLAIR, ill-defined margin, severe peritumoral edema, ring enhancement, and broad-based attachment sign, were helpful for the differential diagnosis of these two entities. Among these features, ring enhancement showed the highest inter-rater concordance (0.80). Ring enhancement showed the highest AUC value (0.79), followed by severe peritumoral edema (0.67). The combination of seven features showed the highest AUC value (0.86), followed by that of three features (ill-defined margin, severe peritumoral edema, and ring enhancement) (0.83). CONCLUSION: Enhancement pattern, peritumoral edema, and margin are valuable for the discrimination between CNS ETNOS and GBM in adults.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Adulto , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Sistema Nervoso Central/patologia , Glioblastoma/diagnóstico por imagem , Glioblastoma/patologia , Humanos , Imageamento por Ressonância Magnética/métodos , Margens de Excisão , Estudos Retrospectivos
11.
Int J Biol Sci ; 17(12): 3013-3023, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34421346

RESUMO

Background: Drug resistance is one of the biggest challenges in cancer therapy. temozolomide (TMZ) represents the most important chemotherapeutic option for glioma treatment. However, the therapeutic efficacy of TMZ remains very limited due to its frequent resistance in glioma, and the underlying mechanisms were not fully addressed. Herein, we demonstrate that the elevated expression of CD147 contributes to TMZ resistance in glioma cells, potentially through the post-translational regulation of Nrf2 expression. Methods: Cell-based assays of CD147 triggered drug resistance were performed through Edu-incorporation assay, CCK8 assay, TUNEL staining assay and flow cytometric assay. Luciferase reporter assay, protein stability related assays, co-immunoprecipitation assay were used to determine CD147 induction of Nrf2 expression through ß-TrCP dependent ubiquitin system. Finally, the effect of the CD147/Nrf2 signaling on glioma progression and TMZ resistance were evaluated by functional experiments and clinical samples. Results: Based on the analysis of clinical glioma tissues, CD147 is highly expressed in glioma tissues and positively associated with tumor malignancy. Suppression of CD147 expression increased the inhibitory effect of TMZ on cell survival in both U251 and T98G cells, whereas the gain of CD147 function blocked TMZ-induced ROS production and cell death. Mechanistic study indicates that CD147 inhibited GSK3ß/ß-TrCP-dependent Nrf2 degradation by promoting Akt activation, and subsequently increased Nrf2-mediated anti-oxidant gene expressions. Supporting the biological significance, the reciprocal relationship between CD147 and Nrf2 was observed in glioma tissues, and associated with patient outcome. Conclusions: Our data provide the first evidence that glioma resistance to TMZ is potentially due to the activation of CD147/Nrf2 axis. CD147 promotes Nrf2 stability through the suppression of GSK3ß/ß-TrCP dependent Nrf2 protein degradation, which results in the ablation of TMZ induced ROS production. As such, we point out that targeting CD147/Nrf2 axis may provide a new strategy for the treatment of TMZ resistant gliomas.


Assuntos
Basigina/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Temozolomida/farmacologia , Animais , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/metabolismo , Humanos , Masculino , Camundongos , Camundongos Nus , Fator 2 Relacionado a NF-E2/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas Contendo Repetições de beta-Transducina/metabolismo
13.
JCI Insight ; 6(15)2021 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-34228647

RESUMO

Passage of systemically delivered pharmacological agents into the brain is largely blocked by the blood-brain-barrier (BBB), an organotypic specialization of brain endothelial cells (ECs). Tumor vessels in glioblastoma (GBM), the most common malignant brain tumor in humans, are abnormally permeable, but this phenotype is heterogeneous and may differ between the tumor's center and invasive front. Here, through single-cell RNA sequencing (scRNA-seq) of freshly isolated ECs from human glioblastoma and paired tumor peripheral tissues, we have constructed a molecular atlas of human brain ECs providing unprecedented molecular insight into the heterogeneity of the human BBB and its molecular alteration in glioblastoma. We identified 5 distinct EC phenotypes representing different states of EC activation and BBB impairment, and associated with different anatomical locations within and around the tumor. This unique data resource provides key information for designing rational therapeutic regimens and optimizing drug delivery.


Assuntos
Transporte Biológico/genética , Barreira Hematoencefálica , Neoplasias Encefálicas , Proteínas de Transporte/genética , Permeabilidade da Membrana Celular/genética , Células Endoteliais , Glioblastoma , Variação Biológica da População , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/fisiopatologia , Encéfalo/patologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Sistemas de Liberação de Medicamentos/métodos , Descoberta de Drogas , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos
14.
Nanomicro Lett ; 13(1): 76, 2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-34138330

RESUMO

Currently, electromagnetic radiation and interference have a significant effect on the operation of electronic devices and human health systems. Thus, developing excellent microwave absorbers have a huge significance in the material research field. Herein, a kind of ultrafine zinc oxide (ZnO) nanoparticles (NPs) supported on three-dimensional (3D) ordered mesoporous carbon spheres (ZnO/OMCS) is prepared from silica inverse opal by using phenolic resol precursor as carbon source. The prepared lightweight ZnO/OMCS nanocomposites exhibit 3D ordered carbon sphere array and highly dispersed ultrafine ZnO NPs on the mesoporous cell walls of carbon spheres. ZnO/OMCS-30 shows microwave absorbing ability with a strong absorption (- 39.3 dB at 10.4 GHz with a small thickness of 2 mm) and a broad effective absorption bandwidth (9.1 GHz). The outstanding microwave absorbing ability benefits to the well-dispersed ultrafine ZnO NPs and the 3D ordered mesoporous carbon spheres structure. This work opened up a unique way for developing lightweight and high-efficient carbon-based microwave absorbing materials.

15.
Front Mol Biosci ; 8: 648752, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33937330

RESUMO

Background: Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is a type I transmembrane protein that functions as an endoplasmic reticulum (ER) stress sensor to regulate global protein synthesis. Recent research studies suggest that PERK, as an important receptor protein of unfolded protein response, is involved in the pathogenesis of many cancers. This study aimed to investigate PERK expression and its relationship with prognosis in pan-cancer and attempted to explore the relevant mechanism of PERK involved in the regulation of cancer pathogenesis. Methods: The Oncomine and TIMER databases were used to analyze the expression of PERK between pan-cancer samples and normal samples. Survival analysis was performed using the PrognoScan, Kaplan-Meier (K-M) plotter, and UALCAN databases. Gene set enrichment analysis (GSEA) was used to perform the functional enrichment analysis of the PERK gene in breast invasive carcinoma (BRCA), head and neck squamous cell carcinoma (HNSC), and thyroid carcinoma (THCA). The TIMER database was used to investigate the correlation between PERK expression and tumor-infiltrating immune cells and analyze the relationship of PERK with marker genes of immune cells which were downloaded from the CellMarker database in BRCA, HNSC, and THCA. Results: PERK was differentially expressed in various cancers, such as breast cancer, liver cancer, lung cancer, gastric carcinoma, lymphoma, thyroid cancer, leukemia, and head and neck squamous cell carcinomas. The high expression of PERK was associated with a poor prognosis in KIRP, LGG, BRCA, and THCA and with a favorable prognosis in HNSC. The results of GSEA indicated that PERK was mainly enriched in immune-related signaling pathways in BRCA, HNSC, and THCA. Moreover, PERK expression was significant positively correlated with infiltrating levels of macrophages and dendritic cells and was strongly associated with a variety of immune markers, especially macrophage mannose receptor 1 (MRC1, also called CD206) and T-helper cells (Th). Conclusion: The high expression of PERK could promote the infiltration of multiple immune cells in the tumor microenvironment and could deteriorate the outcomes of patients with breast and thyroid cancers, suggesting that PERK as well as tumor-infiltrating immune cells could be taken as potential biomarkers of prognosis.

16.
J Community Hosp Intern Med Perspect ; 11(2): 220-223, 2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33889324

RESUMO

Tuberculosis and sarcoidosis are both granulomatous diseases centered on the lung but capable of myriad extrapulmonary manifestations. Because of substantial similarity in their presentations, these two entities can be notoriously challenging to differentiate. This can be particularly true of countries in which tuberculosis is rarely encountered because of a reflexive tendency to ascribe granulomatous inflammation in the lung to sarcoidosis, especially if the granulomas are non-necrotizing. However, as our case from a non-endemic country reminds, sarcoidosis can be comfortably diagnosed only after convincing exclusion of infectious causes of granulomas. Distinguishing these two diseases is of utmost importance as, despite their overlapping presentations, they have completely non-overlapping treatments which can lead to harm if erroneously applied. At the end of our discussion, we summarize the clinical features favoring one diagnosis over the other.

18.
Nano Lett ; 21(6): 2412-2421, 2021 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-33705152

RESUMO

JQ1, a specific inhibitor of bromodomain-containing protein 4 (BRD4), could have great potential in the treatment of cervical cancer. However, its clinical application is limited by its short plasma half-life and limited antitumor efficacy. In this work, cisplatin (CDDP) was first utilized as the stabilizer and cooperator in the nanosystem (mPEG113-b-P(Glu10-co-Phe10)-CDDP/JQ1, called PGP-CDDP/JQ1) to break through the efficiency limitation of JQ1. The PGP-CDDP/JQ1 had a combination index (CI) of 0.21, exerting a strong cytotoxic synergistic effect. In vivo experiments revealed that PGP-CDDP/JQ1 had a significantly higher tumor inhibition effect (tumor inhibition rate: 85% vs 14%) and plasma stability of JQ1 (area under the curve (AUC0-∞): 335.97 vs 16.88 µg × h/mL) than free JQ1. The mechanism underling the synergism of JQ1 with CDDP in PGP-CDDP/JQ1 was uncovered to be inhibiting Plk1-mutant Trp53 axis. Thus, this study provides an optional method for improving the clinical application of JQ1 in cervical cancer.


Assuntos
Antineoplásicos , Neoplasias do Colo do Útero , Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Cisplatino/farmacologia , Feminino , Humanos , Proteínas Nucleares/genética , Fatores de Transcrição , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/genética
19.
Clin Sci (Lond) ; 135(4): 597-611, 2021 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-33564880

RESUMO

BACKGROUND: Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD) that is associated with immune dysfunction. Recent studies have indicated that the neurosecretory hormone oxytocin (OXT) has been proven to alleviate experimental colitis. METHODS: We investigated the role of OXT/OXT receptor (OXTR) signalling in dendritic cells (DCs) using mice with specific OXTR deletion in CD11c+ cells (OXTRflox/flox×CD11c-cre mice) and a dextran sulfate sodium (DSS)-induced colitis model. RESULTS: The level of OXT was abnormal in the serum or colon tissue of DSS-induced colitis mice or the plasma of UC patients. Both bone marrow-derived DCs (BMDCs) and lamina propria DCs (LPDCs) express OXTR. Knocking out OXTR in DCs exacerbated DSS-induced acute and chronic colitis in mice. In contrast, the injection of OXT-pretreated DCs significantly ameliorated colitis. Mechanistically, OXT prevented DC maturation through the phosphatidylinositol 4,5-bisphosphate 3-kinase (Pi3K)/AKT pathway and promoted phagocytosis, adhesion and cytokine modulation in DCs. Furthermore, OXT pre-treated DCs prevent CD4+ T cells differentiation to T helper 1 (Th1) and Th17. CONCLUSIONS: Our results suggest that OXT-induced tolerogenic DCs efficiently protect against experimental colitis via Pi3K/AKT pathway. Our work provides evidence that the nervous system participates in the immune regulation of colitis by modulating DCs. Our findings suggest that generating ex vivo DCs pretreated with OXT opens new therapeutic perspectives for the treatment of UC in humans.


Assuntos
Colite Ulcerativa/imunologia , Células Dendríticas/imunologia , Ocitocina/metabolismo , Ocitocina/farmacologia , Receptores de Ocitocina/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Colite/induzido quimicamente , Células Dendríticas/metabolismo , Sulfato de Dextrana/administração & dosagem , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Ocitocina/sangue , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Ocitocina/genética , Transdução de Sinais
20.
Respir Med Case Rep ; 30: 101106, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32551220

RESUMO

The term "endemic mycoses" refers to a group of fungi that maintains a baseline rate of infection only in certain geographical regions due to the hospitable enviormental conditions these regions offer. In the United States, Histoplasma capsulatum, Coccidioides spp, and Blastomyces dermatitidis are the three most prevalent endemic human fungal infections. The traditional endemic regions for these pathogens are defined based on data acquired many decades ago, and case detection is subject to diagnostic delays even in classically endemic areas, a problem that is likely to be magnified in areas less familiar with these fungal infections. The present series includes an example of each of these infections diagnosed in a medical center situated in the suburbs of New York City, a location not considered endemic for any of them. Likely routes of acquisition for the three patients are considered, and the history of encounters with these pathogens in New York State is briefly recounted. Altogether, this report is intended to serve as a reminder to clinicians that traditional distribution maps for the endemic mycoses are bound to be outdated in the face of modern trends in globalization, population dynamics, and ecological change.

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