RESUMO
Studies have shown that the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome is detrimental to the functional recovery of the sciatic nerve, but the regulatory mechanisms of the NLRP3 inflammasome in peripheral nerves are unclear. C-X-C motif chemokine 12 (CXCL12) can bind to C-X-C chemokine receptor type 4 (CXCR4) and participate in a wide range of nerve inflammation by regulating the NLRP3 inflammasome. Based on these, we explore whether CXCL12-CXCR4 axis regulates the NLRP3 inflammasome in the peripheral nerve. We found that CXCR4/CXCL12, NLRP3 inflammasome-related components, pyroptosis-related proteins and inflammatory factors in the sciatic nerve injured rats were markedly increased compared with the sham-operated group. AMD3100, a CXCR4 antagonist, reverses the activation of NLRP3 inflammasome, Schwann cell pyroptosis and sciatic nerve demyelination. We further treated rat Schwann cells with LPS (lipopolysaccharide) and adenosine triphosphate (ATP) to mimic the cellular inflammation model of sciatic nerve injury, and the results were consistent with those in vivo. In addition, both in vivo and in vitro experiments demonstrated that AMD3100 treatment reduced the phosphorylation of nuclear factor κB (NF-κB) and the expression of thioredoxin interacting protein (TXNIP), which contributes to activating NLRP3 inflammasome. Therefore, our findings suggest that, after sciatic nerve injury, CXCL12-CXCR4 axis may promote Schwann cell pyroptosis and sciatic nerve demyelination through activating NLRP3 inflammasome and slow the recovery process of the sciatic nerve.
Assuntos
Doenças Desmielinizantes , Inflamassomos , Ratos , Animais , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose , Proteínas NLR/metabolismo , Nervo Isquiático , Células de Schwann/metabolismo , Inflamação/metabolismo , Doenças Desmielinizantes/metabolismo , Proteínas de Ciclo Celular/metabolismo , Quimiocina CXCL12/metabolismoRESUMO
Elderly people over the age of 65 are those most likely to experience Alzheimer's disease (AD), and aging and AD are associated with apparent metabolic alterations. Currently, there is no curative medication against AD and only several drugs have been approved by the FDA, but these drugs can only improve the symptoms of AD. Many preclinical and clinical trials have explored the impact of adjusting the whole-body and intracellular metabolism on the pathogenesis of AD. The most recent evidence suggests that mitochondria initiate an integrated stress response to environmental stress, which is beneficial for healthy aging and neuroprotection. There is also an increasing awareness of the differential risk and potential targeting strategies related to the metabolic level and microbiome. As the main participants in intracellular metabolism, mitochondrial bioenergetics, mitochondrial quality-control mechanisms, and mitochondria-linked inflammatory responses have been regarded as potential therapeutic targets for AD. This review summarizes and highlights these advances.
Assuntos
Doença de Alzheimer , Humanos , Idoso , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Envelhecimento/metabolismo , Estresse Oxidativo/fisiologia , Metabolismo Energético , Mitocôndrias/metabolismoRESUMO
This study aimed to further investigate the effect of PLD1 on the biological characteristics of human cervical cancer (CC) cell line, CASKI and the potential related molecular mechanism. CRISPR/Cas9 genome editing technology was used to knock out the PLD1 gene in CASKI cells. Cell function assays were performed to evaluate the effect of PLD1 on the biological function of CASKI cells in vivo and in vitro. A PLD1-overexpression rescue experiment in these knockout cells was performed to further confirm its function. Two PLD1-knockout CASKI cell lines (named PC-11 and PC-40, which carried the ins1/del4 mutation and del1/del2/ins1 mutation, respectively), were constructed by CRISPR/Cas9. PLD1 was overexpressed in these knockout cells (named PC11-PLD1 and PC40-PLD1 cells), which rescued the expression of PLD1 by approximately 71.33% and 74.54%, respectively. In vivo, the cell function assay results revealed that compared with wild-type (WT)-CASKI cells, the ability of PC-11 and PC-40 cells to proliferate, invade and migrate was significantly inhibited. The expression of H-Ras and phosphorylation of Erk1/2 (p-Erk1/2) was decreased in PC-11 and PC-40 cells compared with WT-CASKI cells. PC-11 and PC-40 cells could sensitize CASKI cells to cisplatin. More importantly, the proliferation, migration and invasion of PC11-PLD1 and PC40-PLD1 cells with PLD1 overexpression were significantly improved compared with those of the two types of PLD1 knockout cells. The sensitivity to cisplatin was decreased in PC11-PLD1 and PC40-PLD1 cells compared with PC-11 and PC-40 cells. In vivo, in the PC-11 and PC-40 tumour groups, tumour growth was significantly inhibited and tumour weight (0.95 ± 0.27 g and 0.66 ± 0.43 g vs. 1.59 ± 0.67 g, p = 0.0313 and 0.0108) and volume (1069.41 ± 393.84 and 1077.72 mm3 ± 815.07 vs. 2142.94 ± 577.37 mm3 , p = 0.0153 and 0.0128) were significantly reduced compared to those in the WT-CASKI group. Tumour differentiation of the PC-11 and PC40 cells was significantly better than that of the WT-CASKI cells. The immunohistochemistry results confirmed that the expression of H-Ras and p-Erk1/2 was decreased in PC-11 and PC-40 tumour tissues compared with WT-CASKI tumour tissues. PLD1 promotes CC progression by activating the RAS pathway. Inhibition of PLD1 may serve as an attractive therapeutic modality for CC.
Assuntos
Fosfolipase D , Neoplasias do Colo do Útero , Linhagem Celular Tumoral , Proliferação de Células , Cisplatino/farmacologia , Feminino , Humanos , Imuno-Histoquímica , Fosfolipase D/genética , Fosfolipase D/metabolismo , Fosfolipase D/farmacologia , Neoplasias do Colo do Útero/patologiaRESUMO
To determine the differentially expressed proteins (DEPs) between paired samples of cervical cancer (CC) and paracancerous tissue by quantitative proteomics and to examine the effects of DUSP7 expression on the tumorigenesis and progression of CC. Proteomic profiles of three paired samples of CC and paracancerous tissue were quantitatively analysed to identify DEPs. The relationship between DEP expression and patient clinicopathological characteristics and prognosis was evaluated. The effects of the selected DEPs on CC progression were examined in SIHA cells. A total of 129 DEPs were found. Western blot and immunohistochemistry (IHC) staining analyses confirmed the results from quantitative proteomic analysis showing that the selected DEP, HRAS, P-ERK1/2, and PLD1 levels were increased, whereas the DUSP7 level was decreased in CC tissue compared with the paired normal paracancerous tissues. The IHC results from the CC TMA analysis showed that the decreased expression of DUSP7 (p = 0.045 and 0.044) was significantly associated with a tumour size >2 cm and parametrial infiltration. In addition, the decreased expression of DUSP7 and increased expression of p-ERK1/2 were adversely related to patient relapse (p = 0.003 and 0.001) and survival (p = 0.034 and 0.006). The expression of HRAS and p-ERK1/2 was decreased in DUSP7-SIHA cells compared with NC-SIHA cells (p = 0.0003 and 0.0026). Biological functions in vitro, including invasion, migration and proliferation and tumour formation in vivo were decreased in DUSP7-SIHA cells (all p < 0.05) but increased in shDUSP7-SIHA cells (all p < 0.05). DUSP7 inhibits cervical cancer progression by inactivating the RAS pathway.
Assuntos
Fosfatases de Especificidade Dupla/metabolismo , Transdução de Sinais , Neoplasias do Colo do Útero/metabolismo , Proteínas ras/metabolismo , Adulto , Idoso , Animais , Biomarcadores , Carcinogênese/genética , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Fosfatases de Especificidade Dupla/genética , Feminino , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Imuno-Histoquímica , Camundongos , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Proteoma , Proteômica/métodos , Neoplasias do Colo do Útero/etiologia , Neoplasias do Colo do Útero/patologiaRESUMO
The sensitive chitosan (CTS) detection methods based on the resonance Rayleigh scattering (RRS) quenching method and fluorescence quenching of Eosin Y were put forward. In the HAC-NaAC buffer solution, Eosin Y interacted with Triton X-100 to generate the binary complex which served as the RRS spectral probe. When CTS was interacted with the binary complex, the RRS intensity decreased with the increase of CTS. At the same time, the fluorescence intensity of Eosin Y decreased in the presence of Triton X-100, and the fluorescence intensity of "Eosin Y+Triton X-100" system further decreased when CTS was added. So it was further proved that there was a forming complex in "Eosin Y+Triton X100+CTS" system. The interaction was characterized by zeta potential, RRS, fluorescence spectrum, and UV-Vis spectroscopy. Under optimal conditions, there was a good linear relationship between the RRS decreased intensity (ΔI) and the concentration of CTS in the range of 0.05-1.30 µg/mL, with a regression equation of ΔI = 1325c + 73.66 and correlation coefficient (R2) of 0.9907. The detection limit was 0.0777 µg/mL. Likewise, the linear range of the fluorescence quenching was 0.03-1.30 µg/mL; the regression equation was ΔF = 1926c + 294.0 with R2 = 0.9800 under fluorescence quenching. The detection limit was 0.0601 µg/mL. Therefore, the dual-channel sensor for the determination of CTS was applied to the health products, and the results were satisfactory. The t test result showed that there was no statistical difference between the two methods.
Assuntos
Quitosana/análise , Amarelo de Eosina-(YS)/química , Corantes Fluorescentes/química , Cápsulas , Limite de Detecção , Espectrometria de Fluorescência/métodosRESUMO
Dysregulation of Wnt signaling has been implicated in tumorigenesis. The role of Transducin ß-like proteins TBL1-TBLR1 in the promotion of Wnt/ß-catenin-mediated oncogenesis has recently been emphasized; however, the molecular basis of activation of Wnt signaling by the corepressor TBL1-TBLR1 is incompletely understood. Here, we show that both TBL1 and TBLR1 are SUMOylated in a Wnt signaling-dependent manner, and that this modification is selectively reversed by SUMO-specific protease I (SENP1). SUMOylation dismissed TBL1-TBLR1 from the nuclear hormone receptor corepressor (NCoR) complex, increased recruitment of the TBL1-TBLR1-ß-catenin complex to the promoter of Wnt target genes, and consequently led to activation of Wnt signaling. Conversely, SENP1 decreased formation of the TBL1-TBLR1-ß-catenin complex, leading to inhibition of ß-catenin-mediated transcription. Importantly, inhibition of SUMOylation significantly decreased the tumorigenicity of SW480 colon cancer cells. Thus, our data reveal a mechanism for activation of Wnt signaling via the SUMOylation-dependent disassembly of the corepressor complex.
Assuntos
Proteínas Nucleares/metabolismo , Transdução de Sinais , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Células 3T3 , Animais , Humanos , Camundongos , Proteínas Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteínas Repressoras/metabolismo , Sumoilação , Transducina/genética , Transducina/metabolismo , Transfecção , Células Tumorais Cultivadas , Proteínas Wnt/genética , beta Catenina/genéticaRESUMO
We conducted this study to identify clinico-pathologic and prognostic factors that are associated with fatty acid binding protein-4 (FABP4) and to discuss its therapeutic potentials in patients with breast cancer (BC). In a total of 75 patients with an established diagnosis of invasive ductal carcinoma of the breast, we performed a retrospective analysis of the medical records and analyzed their immunohistochemical findings. Following evaluation of baseline and clinico-pathological characteristics such as the age, immunohistochemical expressions of FABP4, TNM stage, tumor grade, lymphatic and perineural invasion, estrogen receptor (ER) and progesterone receptor (PR), disease-free survival (DFS), overall survival (OS), recurrence and death, we analyzed correlations of the expression of FABP4 with clinico-pathologic and prognostic factors. Our results showed that tumor grade and recurrence had a significant correlation with the expression of FABP4 (P = 0.002 and 0.049, respectively). Moreover, we also found that the DFS had a significant correlation with the expression of FABP4 (P = 0.049). It can therefore be concluded that the expression of FABP4 might have a prognostic value in patients with BC. But further studies are warranted to establish its potentials as a prognostic indicator.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Proteínas de Ligação a Ácido Graxo/biossíntese , Adulto , Idoso , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Prognóstico , Estudos RetrospectivosRESUMO
BACKGROUND: In an integrated curriculum, multiple instructors take part in a course in the form of team teaching. Accordingly, medical schools strive to manage each course run by numerous instructors. As part of the curriculum management, course evaluation is conducted, but a single, retrospective course evaluation does not comprehensively capture student perception of classes by different instructors. This study aimed to demonstrate the need for individual class evaluation, and further to identify teaching characteristics that instructors need to keep in mind when preparing classes. METHODS: From 2014 to 2015, students at one medical school left comments on evaluation forms after each class. Courses were also assessed after each course. Their comments were categorized by connotation (positive or negative) and by subject. Within each subject category, test scores were compared between positively and negatively mentioned classes. The Mann-Whitney U test was performed to test group differences in scores. The same method was applied to the course evaluation data. RESULTS: Test results for course evaluation showed group difference only in the practice/participation category. However, test results for individual class evaluation showed group differences in six categories: difficulty, main points, attitude, media/contents, interest, and materials. That is, the test scores of classes positively mentioned in six domains were significantly higher than those of negatively mentioned classes. CONCLUSIONS: It was proved that individual class evaluation is needed to manage multi-instructor courses in integrated curricula of medical schools. Based on the students' extensive feedback, we identified teaching characteristics statistically related to academic achievement. School authorities can utilize these findings to encourage instructors to develop effective teaching characteristics in class preparation.
Assuntos
Educação de Graduação em Medicina/normas , Estudantes de Medicina , Ensino/normas , Currículo , Educação de Graduação em Medicina/métodos , Avaliação Educacional , Estudos de Avaliação como Assunto , Retroalimentação , Feminino , Humanos , Masculino , Modelos Educacionais , República da Coreia , Estudos Retrospectivos , Estudantes de Medicina/psicologia , Adulto JovemRESUMO
To discover serological colorectal cancer (CRC) markers, we analyzed cell line secretome to gather proteins of higher potential to be secreted from tissues into circulation. A total of 898 human proteins were identified, of which 62.2% were predicted to be released or shed from cells. The identified proteins were compared with tissue proteomes to find candidate proteins whose expressions were elevated in tumor tissues compared with normal tissues as revealed by (i) quantitative proteomic analysis based on cICAT and mTRAQ or (ii) data mining of immunohistochemical images piled in Human Protein Atlas database. By applying various stringent criteria, 11 candidate proteins were selected. Among these, we validated an significant increase (p = 0.0018) of melanotransferrin (TRFM) at the plasma level of CRC patients through Western blotting, using 130 plasma samples containing 30 healthy controls, 80 CRC patients, and 20 patients of other diseases. Finally, we measured the expression level of TRFM in 325 plasma samples containing 77 healthy controls and 228 CRC patients (34.6 ± 4.2 ng/mL and 67.0 ± 6.4 ng/mL, p < 0.0001) through ELISA and demonstrated the area under the receiver operating characteristic curve of 0.723 (p < 0.0001) with a 92.5% specificity, 48.2% sensitivity, and 95.7% positive predictive value. Furthermore, unlike CEA and PAI-1, up-regulation of TRFM in pathological stages I & II groups compared with stages III & IV groups lead us to expect the use TRFM for early-stage diagnosis of CRC. In this study, we suggest TRFM as a potential serological marker for CRC and expect our discovery strategy to help identify highly cancer-specific and body-fluid-accessible biomarkers.
Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Colorretais/diagnóstico , Regulação Neoplásica da Expressão Gênica/fisiologia , Glicoproteínas de Membrana/sangue , Proteômica/métodos , Área Sob a Curva , Western Blotting , Cromatografia Líquida , Neoplasias Colorretais/sangue , Biologia Computacional , Mineração de Dados , Ensaio de Imunoadsorção Enzimática , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Imuno-Histoquímica , Glicoproteínas de Membrana/genética , Espectrometria de Massas em TandemRESUMO
BACKGROUND: AT-rich interactive domain 3A (ARID3A) is a member of the ARID family of DNA-binding proteins. Previous reports have shown that ARID3A controls cell growth in a p53-dependent manner. Recently, it has been reported that expression of the ARID3A protein was markedly increased in colon cancer tissue compared with matched normal colonic mucosa. However, little is currently known about the role of ARID3A in colorectal cancer (CRC). The aim of this study was to investigate the clinical significance of ARID3A expression in CRC. METHODS: We examined ARID3A expression in 690 CRC patients using tissue microarray and immunohistochemistry. Kaplan-Meier analysis and Cox proportional hazard models were used to estimate the impact of ARID3A expression on overall survival. RESULTS: Of the 690 cases, 195 tumors were strongly positive for ARID3A, 187 were weakly positive, and 308 were negative. ARID3A expression in CRC was significantly correlated with age, degree of differentiation, depth of invasion, lymph node metastasis, distant metastasis, tumor-node-metastasis stage, status of microsatellite instability, and carcinoembryonic antigen levels. The overall survival of CRC patients with strong ARID3A expression was significantly longer than that of patients with weak or negative ARID3A expression. We also performed an additional survival analysis on 388 colon cancer patients and 302 rectal cancer patients. In doing so, a favorable prognostic effect of ARID3A expression was revealed only in the colon cancer group (p = 0.002), not in rectal cancer. Moreover, we showed that the effect of ARID3A on the survival was correlated with p53 status. Using multivariate analysis, we found that strong expression of ARID3A was an independent predictor for better prognosis in CRC. CONCLUSIONS: Our data suggested that strong expression of ARID3A may predict a good prognosis in patients with CRC.
Assuntos
Adenoma/química , Biomarcadores Tumorais/análise , Carcinoma/química , Neoplasias do Colo/química , Neoplasias do Colo/patologia , Proteínas de Ligação a DNA/análise , Neoplasias Retais/química , Neoplasias Retais/patologia , Fatores de Transcrição/análise , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antígeno Carcinoembrionário/sangue , Carcinoma/secundário , Criança , Colo/química , Neoplasias do Colo/genética , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Mucosa Intestinal/química , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Neoplasias Retais/genética , Taxa de Sobrevida , Fatores de Transcrição/genética , Proteína Supressora de Tumor p53/análise , Adulto JovemRESUMO
Oxidative stress is one of the earlier events causing neuronal dysfunction in Alzheimer's disease (AD). Gomisin N (GN), a lignin isolated from Schisandra chinensis, has anti-oxidative stress effects. There are currently no studies on the neuroprotective potential of GN in AD. In this study, two AD models were treated with GN for 8 weeks. The cognitive functions, amyloid deposition, and neuronal death were assessed. Additionally, the expressions of critical proteins in the GSK3ß/Nrf2 signaling pathway were determined in vivo and in vitro. We showed that GN significantly upregulated the expressions of Nrf2, p-GSK3ßSer9/GSK3ß, NQO1 and HO-1 proteins in SHSY-5Y/APPswe cells after H2O2 injury, whereas the PI3K inhibitor LY294002 reversed the increase in the expressions of Nrf2, p-GSK3ßSer9/GSK3ß, NQO1 and HO-1 proteins induced by GN administration. In a further study, GN could significantly improve the learning and memory dysfunctions of the rat and mouse AD models, reduce the area of Aß plaques in the hippocampus and cortex, and increase the number and function of neurons. Here, we first demonstrate the neuroprotective effects of GN on AD in vivo and in vitro. A possible mechanism by which GN prevents AD is proposed: GN significantly increased the expressions of Nrf2, p-GSK3Ser9/GSK3ß and NQO1 proteins in the brain of AD animal models and promoted Nrf2 nuclear translocation, then activated Nrf2 downstream genes to combat oxidative stress in AD pathogenesis. GN might be a promising therapeutic agent for AD.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Glicogênio Sintase Quinase 3 beta , Lignanas , Fator 2 Relacionado a NF-E2 , Fármacos Neuroprotetores , Estresse Oxidativo , Transdução de Sinais , Fator 2 Relacionado a NF-E2/metabolismo , Doença de Alzheimer/tratamento farmacológico , Animais , Glicogênio Sintase Quinase 3 beta/metabolismo , Transdução de Sinais/efeitos dos fármacos , Lignanas/farmacologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Humanos , Camundongos , Ratos Sprague-Dawley , Ratos , Modelos Animais de Doenças , Schisandra/química , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ciclo-Octanos/farmacologia , Linhagem Celular Tumoral , Cromonas/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismoRESUMO
Macrophages play a crucial role in the inflammatory response following sciatic nerve injury. Studies have demonstrated that C-X-C motif chemokine (CXCL) 1 recruit macrophages by binding to C-X-C chemokine receptor (CXCR) 2 and participates in the inflammatory response of various diseases. Based on these findings, we aimed to explore the role of the CXCL1-CXCR2 axis in the repair process after peripheral nerve injury. Initially, we simulated sciatic nerve injury and observed an increased expression of CXCL1 and CXCR2 in the nerves of the injury group. Both in vivo and in vitro experiments confirmed that the heightened CXCL1 expression occurs in Schwann cells and is secreted, while the elevated CXCR2 is expressed by recruited macrophages. In addition, in vitro experiments demonstrated that the binding of CXCL1 to CXCR2 can activate the NLRP3 inflammasome and promote the production of interleukin-1 beta (IL-1ß) in macrophages. However, after mice were subjected to sciatic nerve injury, the number of macrophages and the expression of inflammatory factors in the sciatic nerve were reduced following treatment with the CXCR2 inhibitor SB225002. Simultaneously, we evaluated the sciatic nerve function index, the expression of p75 neurotrophic factor receptor (p75NTR), and myelin proteins, and all of these results were improved with the use of SB225002. Thus, our results suggest that after sciatic nerve injury, the CXCL1-CXCR2 axis mediates the inflammatory response by promoting the recruitment and activation of macrophages, which is detrimental to the repair of the injured nerves. In contrast, treatment with SB225002 promotes the repair of injured sciatic nerves.
Assuntos
Quimiocina CXCL1 , Traumatismos dos Nervos Periféricos , Receptores de Interleucina-8B , Animais , Camundongos , Quimiocina CXCL1/metabolismo , Macrófagos/metabolismo , Compostos de Fenilureia/farmacologia , Nervo IsquiáticoRESUMO
Peripheral nerve injury seriously endangers human life and health, but there is no clinical drug for the treatment of peripheral nerve injury, so it is imperative to develop drugs to promote the repair of peripheral nerve injury. Erythropoietin (EPO) not only has the traditional role of promoting erythropoiesis, but also has a tissue-protective effect. Over the past few decades, researchers have confirmed that EPO has neuroprotective effects. However, side effects caused by long-term use of EPO limited its clinical application. Therefore, EPO derivatives with low side effects have been explored. Among them, ARA290 has shown significant protective effects on the nervous system, but the biggest disadvantage of ARA290, its short half-life, limits its application. To address the short half-life issue, the researchers modified ARA290 with thioether cyclization to generate a thioether cyclized helical B peptide (CHBP). ARA290 and CHBP have promising applications as peptide drugs. The neuroprotective effects they exhibit have attracted continuous exploration of their mechanisms of action. This article will review the research on the role of EPO, ARA290 and CHBP in the nervous system around this developmental process, and provide a certain reference for the subsequent research.
Assuntos
Eritropoetina , Fármacos Neuroprotetores , Traumatismos dos Nervos Periféricos , Eritropoetina/uso terapêutico , Humanos , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Animais , Fármacos Neuroprotetores/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Peptídeos/uso terapêutico , Peptídeos/farmacologia , OligopeptídeosRESUMO
Understanding the mechanisms of resistance of hepatocellular carcinoma (HCC) to targeted therapies and immune checkpoint blockade is critical for the development of new combination therapies and improving patient survival. Here, we found that in HCC, anti-programmed cell death 1 ligand 1 (PD-L1) therapy reduces liver cancer growth, but the tumors eventually become resistant to continued therapy. Experimental analyses shows that the infiltration of pathogenic T helper 17 (pTh17) cells increases in drug-resistant HCC, and pTh17 cells secrete interleukin-17A (IL-17A), which promotes the expression of PD-L1 on the surface of HCC cells and produces resistance to anti-PD-L1 therapy. Anti-IL-17A combined with PD-L1 blockade significantly increased the infiltration of cytotoxic CD8+ T cells expressing high levels of interferon-γ and reduced treatment resistance in HCC. These results support the combination of anti-PD-L1 and anti-IL-17A as a novel strategy to induce effective T cell-mediated anti-tumor immune responses.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Linfócitos T CD8-Positivos , Antígeno B7-H1/metabolismo , Células Th17/metabolismo , Imunoterapia/métodos , Anticorpos Monoclonais/metabolismo , Microambiente TumoralRESUMO
AIM: In order to understand the different processes and mechanisms of cognitive function and resveratrol (RES) as an active participant in pathophysiological events that affect cognitive function. METHODS: First, the Web of Science (core collection) was selected as the data source. To ensure the comprehensiveness and accuracy of the search data, the index was selected as "SCI-EXPANDED", and the search formula was TS = resveratrol AND TS = ("cognitive" OR "memory" OR "cognition" OR "mood"). Next, details of authors, keywords, journals, countries, institutions, references, and more were analyzed by CiteSpace and VOSviewer software. Finally, we explored the mechanism by which RES could improve cognitive impairment, that involves healthy young adults, healthy elderly, post-menopausal women, and diseases involving Alzheimer's disease (AD), diabetes-related cognitive impairment, mental illness, post-stroke cognitive impairment, and neonatal hypoxic-ischemic injury. RESULTS: 287 valid papers were obtained. The scientometric results demonstrated 287 papers used in this study came from 1601 authors from 443 organizations in 38 countries, published in 169 journals, and cited 13,680 literatures from 2431 journals. Depression, AD, cerebral ischemia, diabetic cognitive impairment, and cognitive function in the elderly are all keywords of the co-occurrence network. CONCLUSION: This study supports the hypothesis that chronic RES intake may positively affect brain function. But it has become challenging to determine the optimal dose, time and duration of RES and improve the bioavailability of RES, which many researchers need to overcome.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Idoso , Recém-Nascido , Adulto Jovem , Humanos , Feminino , Resveratrol/uso terapêutico , Cognição , AfetoRESUMO
Accumulating evidence suggested that both gut microbiome and sex play a critical role in the efficacy of immune checkpoint blockade therapy. Considering the reciprocal relationship between sex hormones and gut microbiome, the sex hormone-gut microbiome axis may participate in the regulation of the response to immune checkpoint inhibitors (ICIs). In this review, it was attempted to summarize the current knowledge about the influences of both sex and gut microbiome on the antitumor efficacy of ICIs and describe the interaction between sex hormones and gut microbiome. Accordingly, this review discussed the potential of enhancing the antitumor efficacy of ICIs through regulating the levels of sex hormones through manipulation of gut microbiome. Collectively, this review provided reliable evidence concerning the role of the sex hormone-gut microbiome axis in tumor immunotherapy.
Assuntos
Microbioma Gastrointestinal , Neoplasias , Humanos , Imunoterapia , Hormônios Esteroides Gonadais , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias/terapiaRESUMO
The prevalence of depression in diabetes mellitus (DM) patients is very high, and it severely impacts the prognosis and quality of life of these patients. Sodium-glucose co-transporter 2 (SGLT2) inhibitors, a new type of oral hypoglycemic drugs, have been shown to alleviate depressive symptoms in DM patients; however, the mechanism underlying this effect is not well understood. The lateral habenula (LHb) plays an important role in the pathogenesis of depression expresses SGLT2, suggesting that the LHb may mediate antidepressant effects of SGLT2 inhibitors. The current study aimed to investigate the involvement of the LHb in the antidepressant effects of the SGLT2 inhibitor dapagliflozin. Chemogenetic methods were used to manipulate the activity of LHb neurons. Behavioral tests, Western blotting, immunohistochemistry, and neurotransmitter assays were used to determine the effects of dapagliflozin on the behavior of DM rats, AMP-activated protein kinase (AMPK) pathway and c-Fos expression in the LHb and 5-hydroxyindoleacetic acid (5-HIAA)/5-hydroxytryptamine (5-HT) ratio in the dorsal raphe nucleus (DRN). We found that DM rats demonstrated depressive-like behavior, increased c-Fos expression, and decreased AMPK pathway activity in the LHb. Inhibition of LHb neurons alleviated the depressive-like behavior of DM rats. Both systemic and local LHb administration of dapagliflozin alleviated the depressive-like behavior and reversed the changes of the AMPK pathway and c-Fos expression in the LHb of DM rats. Dapagliflozin, when microinjected into the LHb, also increased 5-HIAA /5-HT in the DRN. These results suggest that dapagliflozin directly acts on the LHb to alleviate DM-induced depressive-like behavior and that the underlying mechanism involves activating the AMPK signaling pathway, leading to the inhibition of LHb neuronal activity, which in turn increases serotonergic activity in the DRN. These results will help develop new strategies for the treatment of DM-induced depression.
Assuntos
Diabetes Mellitus , Habenula , Ratos , Animais , Depressão/tratamento farmacológico , Depressão/etiologia , Depressão/metabolismo , Serotonina/metabolismo , Habenula/metabolismo , Ácido Hidroxi-Indolacético/metabolismo , Ácido Hidroxi-Indolacético/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Qualidade de Vida , Transportador 2 de Glucose-Sódio/metabolismo , Transportador 2 de Glucose-Sódio/farmacologia , Antidepressivos/farmacologia , Antidepressivos/uso terapêuticoRESUMO
Interleukin 17A (IL-17A) is a major member of the IL-17 cytokine family and is produced mainly by T helper 17 (Th17) cells. Other cells such as CD8+ T cells, γδ T cells, natural killer T cells and innate lymphoid-like cells can also produce IL-17A. In healthy individuals, IL-17A has a host-protective capacity, but excessive elevation of IL-17A is associated with the development of autoimmune diseases and cancer. Monoclonal antibodies (mAbs) targeting IL-17A (e.g., ixekizumab and secukinumab) or IL-17A receptor (IL-17RA) (e.g., brodalumab) would be investigated as potential treatments for these diseases. Currently, the application of IL-17A-targeted drugs in autoimmune diseases will provide new ideas for the treatment of tumors, and its combined application with immune checkpoint inhibitors has become a research hotspot. This article reviews the mechanism of action of IL-17A and the application of anti-IL-17A antibodies, focusing on the research progress on the mechanism of action and therapeutic blockade of IL-17A in various tumors such as colorectal cancer (CRC), lung cancer, gastric cancer and breast cancer. Moreover, we also include the results of therapeutic blockade in the field of cancer as well as recent advances in the regulation of IL-17A signaling.
Assuntos
Doenças Autoimunes , Neoplasias , Humanos , Linfócitos T CD8-Positivos , Imunidade Inata , Interleucina-17 , Neoplasias/tratamento farmacológico , Células Th17RESUMO
The C-X-C chemokine ligand (CXCL) 1 and its receptor C-X-C chemokine receptor (CXCR) 2 are widely expressed in the peripheral nervous systems (PNS) and central nervous systems (CNS) and are involved in the development of inflammation and pain after various nerve injuries. Once a nerve is damaged, it affects not only the neuron itself but also lesions elsewhere in its dominant site. After the CXCL1/CXCR2 axis is activated, multiple downstream pathways can be activated, such as c-Raf/MAPK/AP-1, p-PKC-µ/p-ILK/NLRP3, JAK2/STAT3, TAK1/NF-κB, etc. These pathways in turn mediate cellular motility state or cell migration. CXCR2 is expressed on the surface of neutrophils and monocytes/macrophages. These cells can be recruited to the lesion through the CXCL1/CXCR2 axis to participate in the inflammatory response. The expression of CXCR2 in neurons can activate some pathways in neurons through the CXCL1/CXCR2 axis, thereby causing damage to neurons. CXCR2 is also expressed in astrocytes, and when CXCR2 activated, it increases the number of astrocytes but impairs their function. Since inflammation can occur at almost any site of injury, elucidating the mechanism of CXCL1/CXCR2 axis' influence on inflammation may provide a favorable target for clinical treatment. Therefore, this article reviews the research progress of the CXCL1/CXCR2 axis in neurological diseases, aiming to provide a more meaningful theoretical basis for the treatment of neurological diseases.