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INTRODUCTION: Cardiopulmonary bypass (CPB) leads to severe inflammation and lung injury. Our previous study showed that Ac2-26 (an active n-terminal peptide of Annexin A1) can reduce acute lung injury. The aim of this study was to evaluate the effect of Ac2-26 on lung injury in CPB rats. METHODS: Forty rats were randomly divided into the sham, CPB, Ac, Ac/serine/threonine kinase 1 (AKT1), and Ac/ glycogen synthase kinase (GSK)-3ß groups. The rats in the sham group only received anesthesia, intubation, and cannulation. The rats in the other 4 groups received the standard CPB procedure. The rats in the CPB, Ac, Ac/AKT1, and Ac/GSK3ß groups were immediately injected with saline, Ac2-26 (1 mg/kg), Ac2-26 combined with short hairpin RNA (AKT1), or Ac2-26 combined with a GSK3ß inhibitor after CPB. At 12 h after the end of CPB, the PaO2/ fraction of inspired oxygen ratio, wet/dry weight ratio and protein content in the bronchoalveolar lavage fluid (BALF) were recorded. The numbers of macrophages and neutrophils in the BALF and blood were determined. Cytokine levels in the blood and BALF were investigated. Lung tissue histology and apoptosis were estimated. The expression of nuclear factor kappa- B, AKT1, GSK3ß, endothelial nitric oxide synthase and apoptosis-related proteins was analyzed. The survival of all the rats was recorded. RESULTS: Compared with the rats in the sham group, all the parameters examined worsened in the rats that received CPB. Compared with those in the CPB group, Ac2-26 significantly improved pulmonary capillary permeability, reduced cytokine levels, and decreased histological scores and apoptosis. The protective effect of Ac2-26 on lung injury was significantly reversed by AKT1 short hairpin RNA or a GSK3ß inhibitor. CONCLUSIONS: Ac2-26 significantly reduced lung injury and inflammation after CPB. The protective effect of Ac2-26 mainly depended on the AKT1/GSK3ß/endothelial nitric oxide synthase pathway.
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BACKGROUND: Eighty percent of stroke patients develop upper limb dysfunction, especially hand dysfunction, which has a very slow recovery, resulting in economic burden to families and society. AIM: To investigate the impact of task-oriented training based on acupuncture therapy on upper extremity function in patients with early stroke. METHODS: Patients with early stroke hemiplegia who visited our hospital between January 2021 and October 2022 were divided into a control group and an observation group, each with 50 cases. The control group underwent head acupuncture plus routine upper limb rehabilitation training (acupuncture therapy). In addition to acupuncture and rehabilitation, the observation group underwent upper limb task-oriented training (30 min). Each group underwent treatment 5 d/wk for 4 wk. Upper extremity function was assessed in both groups using the Fugl-Meyer Assessment-Upper Extremity (FMA-UE), Wolf Motor Function Rating Scale (WMFT), modified Barthel Index (MBI), and Canadian Occupational Performance Measure (COPM). Quality of life was evaluated using the Short-Form 36-Item Health Survey (SF-36). Clinical efficacy of the interventions was also evaluated. RESULTS: Before intervention, no significant differences were observed in the FMA-UE, MBI, and WMFT scores between the two groups (P > 0.05). After intervention, the FMA-UE, WMFT, MBI, COPM-Functional Mobility and Satisfaction, and SF-36 scores increased in both groups (P < 0.05), with even higher scores in the observation group (P < 0.05). The observation group also obtained a higher total effective rate than the control group (P < 0.05). CONCLUSION: Task-oriented training based on acupuncture rehabilitation significantly enhanced upper extremity mobility, quality of life, and clinical efficacy in patients with early stroke.
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OBJECTIVE: To analyse and discuss the association of gender differences with the risk and incidence of poststroke aphasia (PSA) and its types, and to provide evidence-based guidance for the prevention and treatment of poststroke aphasia in clinical practice. DATA SOURCES: Embase, PubMed, Cochrane Library and Web of Science were searched from January 1, 2002, to December 1, 2023. STUDY SELECTION: Including the total number of strokes, aphasia, the number of different sexes or the number of PSA corresponding to different sex. DATA EXTRACTION: Studies with missing data, aphasia caused by nonstroke and noncompliance with the requirements of literature types were excluded. DATA SYNTHESIS: 36 papers were included, from 19 countries. The analysis of 168,259 patients with stroke and 31,058 patients with PSA showed that the risk of PSA was 1.23 times higher in female than in male (OR = 1.23, 95% CI = 1.19-1.29, P < 0.001), with a prevalence of PSA of 31% in men and 36% in women, and an overall prevalence of 34% (P < 0.001). Analysis of the risk of the different types of aphasia in 1,048 patients with PSA showed a high risk in females for global, broca and Wenicke aphasia, and a high risk in males for anomic, conductive and transcortical aphasia, which was not statistically significant by meta-analysis. The incidence of global aphasia (males vs. females, 29% vs. 32%) and broca aphasia (17% vs 19%) were higher in females, and anomic aphasia (19% vs 14%) was higher in males, which was statistically significant (P < 0.05). CONCLUSIONS: There are gender differences in the incidence and types of PSA. The risk of PSA in female is higher than that in male.
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Afasia , Accidente Cerebrovascular , Femenino , Humanos , Masculino , Incidencia , Afasia/diagnóstico , Afasia/epidemiología , Afasia/etiología , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/epidemiología , Cooperación del PacienteRESUMEN
Background: Breathing exercises improve oxidative stress in healthy young adults and patients with diabetes, hypertension, and chronic obstructive pulmonary disease. Furthermore, the mechanism of respiratory intervention is controversial. Therefore, in this meta-analysis, we aimed to systematically evaluate the effects of breathing exercises on oxidative stress biomarkers in humans and provide evidence for the clinical application of breathing exercises. Methods: The Embase, PubMed, Cochrane Library, Web of Science, CNKI, and WANFANG databases were searched for studies about the effects of breathing exercises on human oxidative stress levels, with no restraints regarding time, race, or language. The experimental group included various breathing exercises, and the outcome index included malondialdehyde, superoxide dismutase, and glutathione, nitric oxide, vitamin C, or total antioxidant capacity levels from a randomized controlled trial. Data were extracted by more than two authors and reviewed by one author. Results: Ten studies were included from five countries. Data from patients with no disease, chronic obstructive pulmonary disease, hypertension, or diabetes were included. Participants who performed breathing exercises had greater changes in the included biomarkers than those who did not, suggesting that these biomarkers can be used to evaluate oxidative stress after respiratory interventions. Conclusion: Breathing exercises increased SOD and GSH activities and decreased MDA content. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022337119, identifier CRD42022337119.
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The Eating Assessment Tool-10 (EAT-10) is used worldwide to screen people quickly and easily at high risk for swallowing disorders. However, the best EAT-10 cutoff value is still controversial. In this systematic review and meta-analysis, we estimated and compared the diagnostic accuracy of EAT-10 cutoff values of 2 and 3 for screening dysphagia. We searched the PubMed, Web of Science, EMBASE, Cochrane Library, CNKI, WANFANG, and VIP databases from May 2008 to March 2022. The meta-analysis included 7 studies involving 1064 subjects from 7 different countries. Two studies were classified as high quality and five studies as medium quality. With an EAT-10 cutoff value of 2, using flexible endoscopic evaluation of swallowing or video fluoroscopic swallowing study as the gold standard, the pooled sensitivity, specificity, positive and negative likelihood ratios, and diagnostic odds ratio were 0.89 (95% confidence interval [CI] 0.82-0.93), 0.59 (95% CI 0.39-0.77), 2.17 (95% CI 1.38-3.42), 0.19 (95% CI 0.13-0.29), and 11.49 (95% CI 5.86-22.53), respectively. When a cutoff of 3 was used, these values were 0.85 (95% CI 0.68-0.94), 0.82 (95% CI 0.65-0.92), 4.84 (95% CI 1.72-13.50), 0.18 (95% CI 0.07-0.46), and 26.24 (95% CI 5.06-135.95), respectively. Using EAT-10 cutoff values of 2 and 3, the areas under the curve were 0.873 (95% CI 0.82-0.93) and 0.903 (95% CI 0.88-0.93), respectively, showing good diagnostic performance. EAT-10 can be used as a preliminary screening tool for dysphagia. However, a cutoff of 3 is recommended for EAT-10 due to better diagnostic accuracy.
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Trastornos de Deglución , Humanos , Trastornos de Deglución/diagnóstico , Deglución , Fluoroscopía , Oportunidad Relativa , Sensibilidad y EspecificidadRESUMEN
AIM: ZCJ14, a gefitinib analog, exhibited prominent anti-cancer effect both in vitro and in vivo. The present study aims to investigate the inhibitory effects of ZCJ14 on human cancer cells, and explored its possible mechanism of action. MAIN METHODS: The inhibitory effect of ZCJ14 on human-derived tumor cells in vitro was mainly measured by MTT and colony formation assays. The nude mouse xenograft models were established to figure out the inhibitory effect of ZCJ14 on solid tumors in vivo. Western blotting assays were used to detect the phosphorylation level of EGFR down-streaming proteins and the proteomic technique was used to study the proteome alterations of cancer cells triggered by ZCJ14. KEY FINDINGS: ZCJ14 inhibited the proliferation of A549 (lung cancer), HCT116 (colorectal cancer) and MCF-7 (breast cancer) cells in vitro with 48 h IC50 values of 0.83, 0.85 and 0.92 µM, respectively. It suppressed the growth of A549, NCI-H1975, NCI-H1299 and MCF-7, HCT116 tumors in mouse xenograft models, and had almost no toxicity. At the same dose, the inhibitory effect of ZCJ14 on solid tumors was better than the corresponding positive drugs. ZCJ14 does not exert anti-tumor effects through inhibition of EGFR pathway, but by enhancing steroid biosynthesis and inhibiting ubiquitin-mediated proteolysis. SIGNIFICANCE: Based on the excellent anti-tumor effect of ZCJ14 on human tumor cell lines, it can be used as an effective anti-tumor drug candidate. In addition, the results of proteomic study in this paper can provide clues for further study of the anti-tumor mechanism of ZCJ14.
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Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Proliferación Celular , Resistencia a Antineoplásicos , Receptores ErbB/metabolismo , Gefitinib/farmacología , Humanos , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Proteoma , Proteómica , Esteroides/farmacología , Ubiquitinas/farmacología , Ubiquitinas/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The aim of this study was to evaluate the performance of passive muscle stiffness in diagnosing and assessing disease progression in Duchenne muscular dystrophy (DMD). Boys with DMD and age-matched controls were recruited. Shear wave elastography (SWE) videos were collected by performing dynamic stretching of the gastrocnemius medius (GM). At ankle angles from plantar flexion (PF) 30° to dorsiflexion (DF) 20°, the shear modulus of the GM was measured for each 10° of ankle movement. Shear modulus at each ankle angle was compared between the DMD and control group. Correlation between passive muscle stiffness and motor function grading was also analyzed. A total of 26 patients with DMD and 20 healthy boys were enrolled. At multiple stretch levels, passive muscle stiffness of the GM was significantly higher in patients with DMD than in those in the control group (all p values <0.05). The shear modulus of GM at an ankle angle of DF 10° had the largest area under the receiver operating characteristic curve in differentiating DMD patients from normal subjects (AUCâ¯=â¯0.902, 95% confidence interval: 0.814-0.990). Motor function grading was a significant determinant of passive muscle stiffness at an ankle angle of DF 10° (Bâ¯=â¯21.409, tâ¯=â¯3.372, pâ¯=â¯0.003). Passive muscle stiffness may potentially serve as a useful non-invasive tool to monitor disease progression in DMD patients.
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Diagnóstico por Imagen de Elasticidad , Distrofia Muscular de Duchenne , Articulación del Tobillo/diagnóstico por imagen , Progresión de la Enfermedad , Humanos , Masculino , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/fisiología , Distrofia Muscular de Duchenne/diagnóstico por imagenRESUMEN
AIM: To compare the clinical outcomes of wavefront guided femtosecond LASIK (WFG LASIK) and conventional femtosecond LASIK (NWFG LASIK) in eyes with myopia and myopia astigmatism. METHODS: This was a retrospective, nonrandomized, comparative investigation enrolling 236 eyes of 122 patients (18-50y) with low & moderate and high myopia. The WFG group including 97 eyes (50 patients) undergone WFG LASIK and the NWFG group including 139 eyes (72 patients) undergone conventional LASIK. Mean efficacy index, high order aberrations (HOAs), pupil size and the quality of visual questionnaire were evaluated 6mo postoperatively. RESULTS: There is no difference between WFG group (-0.054±0.049 in logMAR) and NWFG group (-0.040±0.056) in uncorrected distance visual acuity (UDVA) postoperatively. The myopia astigmatism is higher in WFG group than that in NWFG group (P<0.05). However, the mean efficacy index (MEI) in the WFG group (1.09±0.106) is better than that in the NWFG group (1.036±0.124; P<0.001). Increased HOAs were observed in NWFG group (0.30±0.196) than that in WFG group (0.146±0.188; P<0.001). The pupil size is larger in WFG group (5.15±0.76 mm) than that in NWFG group (4.32±0.52 mm). The patients are satisfied with the clinical surgery, yet WFG group showed better visual quality using the questionnaire survey. Meanwhile, high myopia would result in worse MEI, HOAs and visual quality than low & moderate myopia. CONCLUSION: WFG and NWFG FS-LASIK are both effective and safe procedures to correct low & moderate and high myopia, but WFG FS-LASIK gives a better postoperative MEI, aberrometric control and predictable outcome. Meanwhile, WFG FS-LASIK is better than NWFG FS-LASIK in correction of myopia astigmatism. Low & moderate myopia allow better clinical outcomes than high myopia using any surgical method.
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In this research, the anti-cancer activity of the Populus euphratica extract was evaluated with Cell Counting Kit-8 (CCK-8) assay. The inhibitory activity of the Populus euphratica extract on the activation levels of VEGF signaling pathway in the cancer cells was measured with real time RT-PCR. Next, the high-throughput Illumina pair-end sequencing was performed to detect the chloroplast (cp) genome of Populus euphratica for genome evolution assessment. The CCK-8 results indicated that the extract of Populus euphratica exhibited the significantly suppression effect on the viability of the cancer cells, and the data of the real time RT-PCR showed the activation levels of VEGF signaling pathway in the cancer cells was also reduced obviously by the Populus euphratica extract. The circular cp genome of the Populus euphratica is 157,806 bp, encoding 131 genes, containing 8 Ribosomal RNA genes (rRNAs), 37 Transfer RNA genes (tRNAs) and 86 Protein coding genes (PCGs). And the results of the phylogenetic analysis indicated that the Populus euphratica. Furthermore, phylogenetic analysis revealed that Populus euphratica has the closest relationship with Populus pruinosa. In addition to Populus pruinosa, Populus ilicifolia also has closely relationship with Populus euphratica. These three species could be clustered on the same clade.
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Antineoplásicos/farmacología , Cloroplastos/genética , Neoplasias de la Boca/tratamiento farmacológico , Extractos Vegetales/farmacología , Populus/química , Populus/genética , Mapeo Cromosómico , Genoma del Cloroplasto , Genoma de Planta , Filogenia , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: p50-associated cyclooxygenase-2 extragenic RNA (PACER) is a recently identified antisense long non-coding RNA (lncRNA) located on the upstream of the promoter region of cyclooxygenase-2 (COX-2). Preliminary studies have suggested that PACER is involved in the regulation of COX-2 expression in macrophagocyte and osteosarcoma cells. However, the role of this lncRNA in colorectal cancer (CRC) remains elusive. Here, we investigated the expression of PACER and its effect on cell proliferation and invasion to explore the role of PACER in CRC. METHODS: Real-time quantitative PCR (RT-qPCR) analysis was used to evaluate the expression of PACER in CRC tissues and cells. Methyl thiazolyl tetrazolium (MTT) analysis was then used to investigate the inhibition effect of PACER knock-down in cell proliferation. The promoting role of this lncRNA on invasion by CRC cells was analysed by wound-healing assays, colony-formation assay, and transwell assays. We then used fluorescence in situ hybridization (FISH) to establish the subcellular localization of PACER. COX-2 protein levels were quantified by Western blot analysis and grayscale scanning analysis following the knock-down of PACER. Luciferase assay was carried out to monitor the modulation of the COX-2 promoter region by PACER. Tumor xenografts models were used to investigate the impact of PACER on the tumorigenesis of CRC cells in vivo. Enzyme-linked immunosorbent assay (ELISA) was then used to quantify prostaglandin E2 (PGE2) production upon knock-down of PACER. RESULTS: RT-qPCR analysis revealed that PACER was highly expressed in CRC tissues and cells, and a high PACER-expression level was associated with poor prognosis. MTT assay, wound-healing assay, colony-formation assay, and transwell assay revealed that PACER enhanced CRC-cell proliferation, invasion, and metastasis in vitro. Analysis of lncRNA localization by FISH showed that it mainly resided in the nucleus. RT-qPCR showed that PACER increased mRNA levels of COX-2. Western blot analysis demonstrated, under normal circumstances, that knock-down of PACER decreased the COX-2 protein level. In the case of p50 absence, COX-2 protein increased rapidly and remained highly expressed after knocking down PACER. Luciferase assay revealed that PACER modulated the COX-2 promoter region. Mouse xenograft models of CRC revealed that PACER promoted colorectal tumorigenesis in vivo. ELISA revealed that PACER knock-down inhibited PGE2 production. CONCLUSIONS: PACER modulates COX-2 expression through the nuclear factor kappa B (NF-κB) pathway in CRC. An increased level of PACER enhances proliferation, migration, and invasion of tumor cells by increasing COX-2 and PGE2 synthesis.
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BACKGROUND: Some recent studies on insulin receptor tyrosine kinase substrate (IRTKS) have focused more on its functions in diseases. However, there is a lack of research on the role of IRTKS in carcinomas and its mechanism remains ambiguous. In this study, we aimed to clarify the role and mechanism of IRTKS in the carcinogenesis of colorectal cancer (CRC). METHODS: We analysed the expression of IRTKS in CRC tissues and normal tissues by researching public databases. Cancer tissues and adjacent tissues of 67 CRC patients who had undergone radical resection were collected from our center. Quantitative real-time polymerase chain reaction and immunohistochemistry were performed in 52 and 15 pairs of samples, respectively. In vitro and in vivo experiments were conducted to observe the effect of IRTKS on CRC cells. Gene Set Enrichment Analysis and Metascape platforms were used for functional annotation and enrichment analysis. We detected the protein kinase B (AKT) phosphorylation and cell viability of SW480 transfected with small interfering RNAs (siRNAs) with or without basic fibroblast growth factor (bFGF) through immunoblotting and proliferation assays. RESULTS: The expression of IRTKS in CRC tissues was higher than that in adjacent tissues and normal tissues (all P < 0.05). Disease-free survival of patients with high expression was shorter. Overexpression of IRTKS significantly increased the proliferation rate of CRC cells in vitro and the number of tumor xenografts in vivo. The phosphorylation level of AKT in CRC cells transfected with pLVX-IRTKS was higher than that in the control group. Furthermore, siRNA-IRTKS significantly decreased the proliferation rate of tumor cells and the phosphorylation level of AKT induced by bFGF. CONCLUSION: IRTKS mediated the bFGF-induced cell proliferation through the phosphorylation of AKT in CRC cells, which may contribute to tumorigenicity in vivo.
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The epidermal growth factor receptor (EGFR) signaling is frequently activated in lung cancer. In our previous study, a new class of compounds containing pyrido[3,4-d]pyrimidine scaffold with an acrylamide moiety was designed as irreversible EGFR-tyrosine kinase inhibitors to overcome acquired EGFR-T790M resistance. In this study, we selected the most promising compound Z25h to further investigate its effects and the underlying mechanism against non-small cell lung adenocarcinoma cells in vitro. Four different non-small cell lung adenocarcinoma cell lines were selected to test the antiviability profile of Z25h, and Hcc827 was the most sensitive to the drug treatment. Z25h caused cell cycle arrest at G0-G1 phase, and triggered strong early apoptosis in Hcc827 cells at 0.1 µM and late apoptosis in A549, H1975 and H1299 cells at 10 µM by 48 h treatment. Z25h inhibited the activation of EGFR and its downstream PI3K/AKT/mTOR pathway in the four tested cell lines, leading to the inhibition of cellular biosynthetic and metabolic processes and the promotion of apoptotic process. However, the effect of Z25h on mitogen-activated protein kinase pathway varies from cell lines. In addition, Z25h sensitized H1975 cells to X-ray radiation, and it also enhanced the radiation effect on A549 cells, while no obvious effect of Z25h was observed on the cell viability inhibition of H1299 cells induced by radiation. Hereby, Z25h might be considered as a potential therapeutic drug candidate for non-small cell lung adenocarcinoma treatment.
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Adenocarcinoma del Pulmón/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Pirimidinas/farmacología , Células A549 , Adenocarcinoma del Pulmón/enzimología , Adenocarcinoma del Pulmón/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Receptores ErbB/antagonistas & inhibidores , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patologíaRESUMEN
The development of local anesthetic (LA) system is the application of commercial drug for the pain management that indorses the reversible obstructive mechanism of neural transmission through preventing the innervation process in human peripheral nerves. Ropivacaine (RV) is one of the greatest frequently used LA s with the actions of long-lasting and low-toxicity for the post-operative pain management. In this work, we have approached novel design and development of glycosylated chitosan (GCS) encapsulated mesoporous silica nanoparticles (GCS-MONPs)-based nano-scaffold for sustainable distributions and controlled/supported arrival of stacked RV for targeting sites, which can be activated by either outer ultrasound activating to discharge the payload, foundation on-request and dependable analgesia. The structural and morphology analyses result established that prepared nano-formulations have successful molecular interactions and RV loaded spherical morphological structures. The drug release profile of developed nanostructure with ultrasound-activation has been achieved 50% of drug release in 2 h and 90% of drug release was achieved in 12 h, which displays more controlled release when compared to free RV solution. The in vitro cell compatibility analysis exhibited GCS-MONPs with RV has improved neuron cell survival rates when compared to other samples due to its porous surface and suitable biopolymer proportions. The analysis of ex vitro and in vivo pain relief analysis demonstrated treated animal models have high compatibility with GCS-MONPs@RV, which was confirmed by histomorphology. This developed MONPs based formulations with ultrasound-irradiation gives a prospective technique to clinical agony the board through on-request and dependable help with discomfort.
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Anestésicos Locales/administración & dosificación , Quitosano/química , Portadores de Fármacos/química , Nanopartículas/química , Ropivacaína/administración & dosificación , Dióxido de Silicio/química , Animales , Química Farmacéutica/métodos , Portadores de Fármacos/efectos de la radiación , Liberación de Fármacos , Estabilidad de Medicamentos , Fibroblastos/efectos de los fármacos , Masculino , Nanopartículas/efectos de la radiación , Neuronas/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Ondas UltrasónicasRESUMEN
BACKGROUND: Claudin 7 is often abnormally expressed in cancers and promotes the progression of some malignancies. However, the role of claudin 7 in stage II colorectal cancer (CRC) has not been studied. AIM: To assess the expression and prognostic value of claudin 7 in stage II CRC. METHODS: We retrospectively studied 231 stage II CRC patients who underwent radical surgery at our hospital from 2013 to 2014. The protein expression level of claudin 7 was assessed and its relationship with clinicopathological features and prognosis was statistically analyzed. The independent prognostic factors were identified by Cox proportional hazards models. A prognostic grading system was constructed to stratify the survival of CRC patients. RESULTS: The expression of claudin 7 was significantly reduced in cancer tissues compared with normal tissues (P < 0.001), and its low expression was closely related to recurrence of the disease (P = 0.017). Multivariate analysis confirmed that claudin 7 low expression (claudin 7-low) (P = 0.028) and perineural invasion positivity (PNI+) (P = 0.026) were independent predictors of poor disease-free survival (DFS). A prognostic grading system based on the status of claudin 7 and PNI classified the patients into three prognostic grades: grade A (claudin 7-high and PNI-), grade B (claudin 7-low and PNI-, claudin 7-high and PNI+), and grade C (claudin 7-low and PNI+). The DFS was significantly different among the three grades (grade B vs grade A, P = 0.032; grade C vs grade A, P < 0.001; grade C vs grade B, P = 0.040). CONCLUSION: Claudin 7 can be used as a new prognostic marker to predict the DFS of patients with stage II CRC. The prognostic grading system with the addition of claudin 7 can further improve prognosis stratification of patients.
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Type 2 diabetes (T2D) and Alzheimer's disease (AD) share several common pathophysiological features. Huperzine A (Hup A), a Lycopodium alkaloid extracted from the Chinese herb moss Huperzia serrata, is a specific and reversible inhibitor of acetylcholinesterase, which is clinically used for the treatment of AD. In this study, we investigated whether Hup A improved the metabolic and cognitive functions in the high fat-induced (HFD) obese mice and genetic ob/ob mice. HFD and ob/ob mice were treated with Hup A (0.1, 0.3 mg · kg-1 · d-1, ig) for 3 months. Body weight was monitored and glucose tolerance tests were performed. Novel object recognition test and Morris water maze assay were conducted to evaluate the cognitive functions. We found that the Hup A treatment had no significant effect on peripheral metabolism of obese mice, whereas Hup A (0.1, mg · kg-1 · d-1) improved both the abilities of object recognition and spatial memory in HFD-fed mice, but not in ob/ob mice. Furthermore, Hup A treatment significantly upregulated the insulin and phosphorylated Akt levels in the cortex of HFD-fed mice, but not ob/ob mice. In addition, Hup A (0.3, mg · kg-1 · d-1) significantly decreased cortical ß-secretase (BACE1) expression. In conclusion, these results demonstrate that treatment with Hup A (0.1, mg · kg-1 · d-1) can effectively improve the cognitive functions, at least in diet-induced obese mice.
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Alcaloides/farmacología , Disfunción Cognitiva/tratamiento farmacológico , Insulina/metabolismo , Obesidad/complicaciones , Sesquiterpenos/farmacología , Alcaloides/administración & dosificación , Animales , Inhibidores de la Colinesterasa/administración & dosificación , Inhibidores de la Colinesterasa/farmacología , Cognición/efectos de los fármacos , Disfunción Cognitiva/etiología , Dieta Alta en Grasa/efectos adversos , Relación Dosis-Respuesta a Droga , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Obesidad/tratamiento farmacológico , Reconocimiento en Psicología/efectos de los fármacos , Sesquiterpenos/administración & dosificación , Transducción de Señal/efectos de los fármacos , Memoria Espacial/efectos de los fármacosRESUMEN
The PI3K pathway is aberrantly activated in many cancers and plays a critical role in tumour cell proliferation and survival, making it a rational therapeutic target. In the present study, the effects and the underlying mechanism of a new PI3K inhibitor, W941, were investigated in non-small-cell lung cancer (NSCLC). The results of this study showed that W941 inhibited the growth of A549 and Hcc827 cells with IC50 values of 0.12 and 0.23 µM, respectively, and that W941 markedly inhibited the growth of A549 xenograft tumours in a nude mouse model without decreasing body weight. Western blotting assays showed that W941 inhibited the phosphorylation of downstream proteins in the PI3K pathway (AKT, mTOR, p70S6K and 4EBP1) in both A549 and Hcc827 cells. In addition, after W941 treatment, a dose-dependent increase in the ratio of the LC3-II/I ratio was observed. When cells were pre-treated with chloroquine or bafilomycin A1, W941 increased the LC3-II/I ratio, suggesting that W941 acted as an autophagy inducer. Moreover, autophagy blockers enhanced apoptosis after W941 treatment, indicating that W941-induced autophagy actually protected the cells against its cytotoxicity. Our findings suggest that the combination of a PI3K inhibitor with an autophagy inhibitor might be a novel option for NSCLC treatment.
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Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de las Quinasa Fosfoinosítidos-3/uso terapéutico , Animales , Antineoplásicos/farmacología , Autofagia/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Neoplasias Pulmonares/patología , Ratones Endogámicos BALB C , Ratones Desnudos , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Transducción de Señal/efectos de los fármacos , Carga Tumoral/efectos de los fármacosRESUMEN
BACKGROUND: Imbalance of intestinal microbiota was closely related to colitis. Under these circumstances, regulation of enteric flora may be beneficial to the repair of inflammation. We aimed to investigate the effects of probiotics (Bifidobacterium and Lactobacillus), prebiotics and their combination on inflammation, and microflora in mice of acute colitis. METHODS: C57BL/6J mice were divided into six groups randomly (blank control group, model control group, probiotics group, synbiotics group, lactitol group and probioticsâ+âlactitol group). Each group was given 2.5% dextran sulfate sodium drinking water for 5 days other than the blank control group. Except for the model control group, the other four groups were intervened with probiotics, synbiotics (probiotics and inulin), lactitol, and probiotics + lactitol. Mice were sacrificed after 1 week of gavage, and pathologic scores were calculated. The feces of different periods and intestinal mucosa samples were collected to analyze the differences of intestinal microbiota by 16S rRNA sequencing. Differences of two groups or multiple groups were statistically examined through unpaired Student t test and analysis of variance (ANOVA), respectively. ANOVA, Tukey, Anosim, and metastats analysis were used to compare differences of microbiota among different groups. RESULTS: After gavage for 1 week, the pathologic scores of groups with the intervention were significantly lower than those in the model control group, and the difference was statistically significant (Pâ<â0.05). The model control group was higher in the genus of Bacteroides (relative abundance: 0.3679 vs. 0.0099, Pâ=â0.0016) and lower in Lactobacillus (relative abundance: 0.0020 vs. 0.0122, Pâ=â0.0188), Roseburia (relative abundance: 0.0004 vs. 0.0109, Pâ=â0.0157), compared with the blank control group. However, the same phenomenon was not found in groups gavaged with probiotics and lactitol. Compared with model control group, mice with intervention were increased with Bifidobacterium (relative abundance: 0.0172 vs. 0.0039, Pâ=â0.0139), Lachnospiraceae_NK4A136_group (relative abundance: 0.1139 vs. 0.0320, Pâ=â0.0344), Lachnospiraceae_UCG-006 (relative abundance: 0.0432 vs. 0.0054, Pâ=â0.0454), and decreased with Alistipes (relative abundance: 0.0036 vs. 0.0105, Pâ=â0.0207) in varying degrees. The mucosal flora was more abundant than the fecal flora, and genus of Mucispirillum (relative abundance: 0.0207 vs. 0.0001, Pâ=â0.0034) was more common in the mucosa. Lactitol group showed higher level of Akkermansia than model control group (relative abundance: 0.0138 vs. 0.0055, Pâ=â0.0415), probiotics group (relative abundance: 0.0138 vs. 0.0022, Pâ=â0.0041), and synbiotics group (relative abundance: 0.0138 vs. 0.0011, Pâ=â0.0034), while probiotics + lactitol group had more abundant Akkermansia than synbiotics group (relative abundance: 0.0215 vs. 0.0013, Pâ=â0.0315). CONCLUSIONS: Probiotics and prebiotics reduce the degree of inflammation in acute colitis mice obviously. Mice with acute colitis show reduced beneficial genera and increased harmful genera. Supplementation of probiotics and prebiotics display the advantage of increasing the proportion of helpful bacteria and regulating the balance of intestinal microbiota. Lactitol might promote the proliferation of Akkermansia.
Asunto(s)
Colitis/tratamiento farmacológico , Microbioma Gastrointestinal/efectos de los fármacos , Prebióticos , Probióticos/farmacología , Probióticos/uso terapéutico , Análisis de Varianza , Animales , Colitis/microbiología , Sulfato de Dextran/toxicidad , Microbioma Gastrointestinal/genética , Ratones , Ratones Endogámicos C57BL , ARN Ribosómico 16S/genética , Distribución Aleatoria , Alcoholes del Azúcar/farmacología , Alcoholes del Azúcar/uso terapéuticoRESUMEN
BACKGROUND & AIMS: Paneth cells secrete antimicrobial proteins including lysozyme via secretory autophagy as part of the mucosal protective response. The ELAV like RNA-binding protein 1 (ELAVL1, also called HuR) regulates stability and translation of messenger RNAs (mRNAs) and many aspects of mucosal physiology. We studied the posttranscriptional mechanisms by which HuR regulates Paneth cell function. METHODS: Intestinal mucosal tissues were collected from mice with intestinal epithelium (IE)-specific disruption of HuR (IE-HuR-/-), HuRfl/fl-Cre- mice (controls), and patients with inflammatory bowel diseases and analyzed by histology and immunohistochemistry. Paneth cell functions were determined by lysozyme-immunostaining assays. We isolated primary enterocytes from IE-HuR-/- and control mice and derived intestinal organoids. HuR and the chaperone CNPY3 were overexpressed from transgenes in intestinal epithelial cells (IECs) or knocked down with small interfering RNAs. We performed RNA pulldown assays to investigate interactions between HuR and its target mRNAs. RESULTS: Intestinal tissues from IE-HuR-/- mice had reduced numbers of Paneth cells, and Paneth cells had fewer lysozyme granules per cell, compared with tissues from control mice, but there were no effects on Goblet cells or enterocytes. Intestinal mucosa from patients with inflammatory bowel diseases had reduced levels of HuR and fewer Paneth cells. IE-HuR-/- mice did not have the apical distribution of TLR2 in the intestinal mucosa as observed in control mice. IECs from IE-HuR-/- mice expressed lower levels of CNPY3. Intestinal organoids from IE-HuR-/- mice were smaller and contained fewer buds compared with those generated from controls, and had fewer lysozyme-positive cells. In IECs, knockdown of HuR decreased levels of the autophagy proteins LC3-I and LC3-II, compared with control cells, and prevented rapamycin-induced autophagy. We found HuR to interact directly with the Cnpy3 mRNA coding region and increase levels of CNPY3 by increasing the stability and translation of Cnpy3 mRNA. CNPY3 bound TLR2, and cells with knockdown of CNPY3 or HuR lost membrane localization of TLR2, but increased cytoplasmic levels of TLR2. CONCLUSIONS: In studies of mice, IECs, and human tissues, we found HuR to increase expression of CNPY3 at the posttranscriptional level. CNPY3 is required for membrane localization of TLR2 and Paneth cell function.
Asunto(s)
Membrana Celular/metabolismo , Proteína 1 Similar a ELAV/metabolismo , Intestino Delgado/metabolismo , Chaperonas Moleculares/metabolismo , Células de Paneth/metabolismo , Procesamiento Postranscripcional del ARN , Receptor Toll-Like 2/metabolismo , Animales , Estudios de Casos y Controles , Células Cultivadas , Proteína 1 Similar a ELAV/deficiencia , Proteína 1 Similar a ELAV/genética , Humanos , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patología , Intestino Delgado/patología , Ratones Endogámicos C57BL , Ratones Noqueados , Chaperonas Moleculares/genética , Células de Paneth/patología , Transporte de Proteínas , Transducción de Señal , Regulación hacia ArribaRESUMEN
Objective To explore whether aging increases severity of colitis in mice and its mechanism.Methods Young (6-8 weeks)and aged (56 weeks) C57Bl/6 mice were divided into the control and experimental group (n=5,each). Dextran sodium sulfate(DSS) was used to induce acute colitis mouse model in the experimental group.The mRNA expressions of tumor necrosis factor-α(TNF-α)and interleukin-6(IL-6)in colon were measured by RT-PCR. Tight junctions (TJs) of intestinal epithelial cells was examined by transmission electron microscopy (TEM). Protein expressions of E-cadherin and occludin were detected by Western blotting and immunohistochemistry in colon.Results Compared with the young DSS-induced mice,the aged DSS-induced mice had more weight loss(t=3.679,P=0.006),higher disease indexes (t=2.496,P=0.037),higher histologic scores(U=0.000,P=0.008) and higher colonic IL-6 level (U=4.000,P=0.191). The TJs of intestinal epithelial cells were discontinuous in old healthy rats,and the TJs were destroyed significantly in both young and aged DSS-induced mice. Compared with the young DSS-induced mice,the aged DSS-induced mice had decreased protein expressions of E-cadherin (t=0.184,P=0.863)and occludin (t=0.399,P=0.710).Conclusions Aging leads to more severe disease following DSS challenge. Age-related deterioration in the functions of the gastrointestinal barrier and integrity may be one of the possible mechanisms.