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Chemotherapy is an important adjuvant treatment of glioma, while the efficacy is far from satisfactory, due not only to the biological barriers of blood‒brain barrier (BBB) and blood‒tumor barrier (BTB) but also to the intrinsic resistance of glioma cells via multiple survival mechanisms such as up-regulation of P-glycoprotein (P-gp). To address these limitations, we report a bacteria-based drug delivery strategy for BBB/BTB transportation, glioma targeting, and chemo-sensitization. Bacteria selectively colonized into hypoxic tumor region and modulated tumor microenvironment, including macrophages repolarization and neutrophils infiltration. Specifically, tumor migration of neutrophils was employed as hitchhiking delivery of doxorubicin (DOX)-loaded bacterial outer membrane vesicles (OMVs/DOX). By virtue of the surface pathogen-associated molecular patterns derived from native bacteria, OMVs/DOX could be selectively recognized by neutrophils, thus facilitating glioma targeted delivery of drug with significantly enhanced tumor accumulation by 18-fold as compared to the classical passive targeting effect. Moreover, the P-gp expression on tumor cells was silenced by bacteria type III secretion effector to sensitize the efficacy of DOX, resulting in complete tumor eradication with 100% survival of all treated mice. In addition, the colonized bacteria were finally cleared by anti-bacterial activity of DOX to minimize the potential infection risk, and cardiotoxicity of DOX was also avoided, achieving excellent compatibility. This work provides an efficient trans-BBB/BTB drug delivery strategy via cell hitchhiking for enhanced glioma therapy.
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Environmental endocrine disrupting chemicals are a kind of exogenous chemicals that generally exist in the environment, and can disturb the endocrine homeostasis and adversely affect reproductive, immune, neurological, and other functions after entering the body, among which the damage to the reproductive system is the most significant one. Studies have confirmed that the long-term exposure to environmental endocrine disrupting chemicals have irreversible and harmful effects on primordial germ cell growth, reproductive organ development, and reproductive endocrine regulation, and also have obvious correlations with the occurrence and development of various reproductive system tumors. This paper reviewed various reproductive toxicities induced by common environmental endocrine disrupting chemicals in the developmental and reproductive stages, and associated mechanisms involved in the occurrence and development of reproductive system tumors.
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Objective@#To discuss the characteristics of symptoms improvement based on the follow-up evaluation of Eustachian tube balloon dilation medium to long-term efficacy in patients with symptomatic Eustachian tube dysfunction (SETD).@*Methods@#Patients from 2015 to 2017 were followed up after Eustachian tube balloon dilation (with the sense of aural fullness, or tinnitus and hearing ambiguity). All participants had been done ETDQ-7 before surgery and were re-evaluated with ETDQ-7 in follow-up. The improvement of overall and individual symptoms scores in ETDQ-7, the effects of gender and the difference of scores at different stages (12-18 months, 18-24 months and 24-30 months) after the operation were analyzed.@*Results@#There were 29 patients, including 16 males and 13 females, whose age ranged from 20 to 62 years old. The medium to long-term score of ETDQ-7 significantly declined after surgery (27.0±7.9 vs. 14.1±7.5, P<0.05). Among all symptoms, symptoms like "blockage feeling in ear or being like under the water, constriction feeling" , "sound of blisters or explosions in the ear" decreased obviously (P<0.05). Comparing different stages after surgery, the scores of ETDQ-7 existed no difference (P>0.05). And the difference of gender showed no significant influence on surgery effects.@*Conclusion@#The subjective symptoms of patients with Eustachian tube dysfunction diagnosed with SETD can be significantly improved in the medium to long-term follow-up after Eustachian tube balloon dilation, and the degree of improvement is not linearly related to the postoperative time.
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OBJECTIVE Aim to explore the value and the selection of observation target of P1 component in children with cochlear implant(CI). METHODS 13 children(4.37±0.73 years old) with right side CI and one year of regular post-CI rehabilitation were recruited as CI group. 15 gender and age (4.25±0.84)years matched children with left side external and middle ear malformation were selected as control group. We collected their AEP which showed their reaction to 1000 Hz pure tone and analyzed the P1 component. RESULTS The cut off value between CI group and control groupwas 10.4mV for P1 Amplitude(P1A) and 110.5 mV for P1 Latency(P1L). More precisely, the values of CI group were above the cut off value while the values of control group were below it. Whether choosing P1A or P1L as dividing standard, the AUC were between 0.5 and 0.9(AUC: P1A0.733, P1L0.800), which showed medium distinguishing significance. P1L component showed greater You-den index(0.590>0.471) and sensitivity(0.923> 0.538) while P1A showed greater specificity(0.933>0.667). CONCLUSION P1L shows greater ability in distinguishing the difference between CI group and control group while P1A has advantage in determining their common feature. Generally, P1L shows higher value in studying CI children. We need to make choice between P1A and P1L in different situation and use P1A and P1L standard in series or parallel.
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Objective To investigate the effect of PDLIM4 (PDZ and LIM domain 4) gene on the prognosis and radiosensitivity of glioma. Methods The differentially expressed genes were analyzed by bioinformatics technique using GSE53733 gene chip. The expression of PDLIM4 protein was detected by Western blot. The effects of PDLIM4 gene on glioma prognosis and glioma cell radiosensitivity were studied by using real-time fluorescence quantitative PCR, siRNA, MTT and cell flow cytometry assays. Results PDLIM4 gene had the most significant differential expression in the chip (logFC=1. 055897, P<0. 05). The PCR assay of 40 glioma cases in our hospital confirmed that expression of PDLIM4 showed obvious difference between high- and low-grade gliomas (t =4. 44, P <0. 05), which was correlated with the survival of patients (χ2 =5. 52, P<0. 05). Moreover, PDLIM4 gene was involved in radioresistance of glioma cells (t = 35.99, P < 0.05). Conclusions PDLIM4 gene expression level correlates with malignant degree and prognosis of glioma and also contributes to cell radioresistance.
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Objective To investigate the effect of PDLIM4 (PDZ and LIM domain 4) gene on the prognosis and radiosensitivity of glioma. Methods The differentially expressed genes were analyzed by bioinformatics technique using GSE53733 gene chip. The expression of PDLIM4 protein was detected by Western blot. The effects of PDLIM4 gene on glioma prognosis and glioma cell radiosensitivity were studied by using real-time fluorescence quantitative PCR, siRNA, MTT and cell flow cytometry assays. Results PDLIM4 gene had the most significant differential expression in the chip (logFC=1. 055897, P<0. 05). The PCR assay of 40 glioma cases in our hospital confirmed that expression of PDLIM4 showed obvious difference between high- and low-grade gliomas (t =4. 44, P <0. 05), which was correlated with the survival of patients (χ2 =5. 52, P<0. 05). Moreover, PDLIM4 gene was involved in radioresistance of glioma cells (t = 35.99, P < 0.05). Conclusions PDLIM4 gene expression level correlates with malignant degree and prognosis of glioma and also contributes to cell radioresistance.
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<p><b>OBJECTIVE</b>The cochlear nucleus (CN) neurons show 3 principal response patterns to short tone bursts, namely the primary-like, chopper and onset response patterns. We previously established an excitatory model to simulate the response patterns of CN neurons to stimuli. In this study, we aimed to investigate the effects of excitatory intensity on the CN neuron response patterns and explore the role of inhibitory inputs under normal physiological conditions.</p><p><b>METHODS</b>Based on the platform of Matlab and the excitatory model derived from the integrate-and-fire model, we altered the intensity of excitatory inputs in dB range and obtained the histograms to analyze the changes in the response patterns of the neurons using OriginPro 7.5 data analysis software.</p><p><b>RESULTS</b>The original primary-like response pattern of the neurons did not vary significantly while the chopper and onset response patterns changed into primary-like responses with the increase of the excitatory input intensity. But this response pattern alteration as a result of excitatory input intensity changes was rarely observed under normal physiological conditions.</p><p><b>CONCLUSIONS</b>The CN neurons receive balanced excitatory and inhibitory inputs, which stabilize the neuronal membrane potential within a limited range. The balanced inhibitory inputs decide the response pattern of a given neuron.</p>
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Acoustic Stimulation , Cochlear Nucleus , Physiology , Evoked Potentials, Auditory , Models, Neurological , Neurons , PhysiologyABSTRACT
AIM: To investigate the molecular mechanisms of apoptosis and to elucidate the apoptosis signaling pathway triggered by etoposide in Jurkat human leukemia cells. METHODS: Apoptosis was detected using annexin V - FITC and propidium iodide (PI) staining, respectively, and annexin V - FITC positive cells and hypodiploid cells were analyzed by flow cytometry. Mitochondrial membrane potential (△Ψm) was detected using 3,3' - dihexyloxycarbocyanine iodide [ DiOC6 (3)] staining and △Ψm low cells were analyzed by flow cytometry. Preparation of cytosolic extracts and isolation of mitochondria were completed by centrifugation. Western blotting analysis was used to evaluate the level of cytochrome c, caspase - 3, and poly ( ADP - ribose) polymerase (PARP) expression. RESULTS: Etoposide induced apoptosis showing phosphatidylserine externalization and DNA fragmentation in a time - dependent manner and the apoptosis could be inhibited by a broad caspase inhibitor benzyloxycarbonyl - Val - Ala - Asp - fluoromethylketone ( zVAD. fmk). Collapse of △Ψm induced by etoposide preceded DNA fragmentation and phosphatidylserine externalization. In contrast, it was not blocked by zVAD. fmk. Etoposide caused cytochrome c release from mitochondria into cytosol, subsequent activation of caspase-3 (32 kD) presented with an intermediate (20 kD) and its active product (17kD), and cleavage of full- length PARP (116 kD) into the so- called apoptotic 85 kD fragment. CONCLUSION:Etoposide - induced Jurkat cell apoptosis is initiated through mitochondria signaling pathway with cytochrome c release into cytoplasm and caspase is the ultimate executioner of cell apoptosis.
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Free amino acids were analysed in 90 human milk samples during the first 6 weeks of lactation in Nanjin city. Glutatnic acid was the most and taurine was the second abundant component of the free amino acids in human milk. The free essential amino acids were highest in colostral milk and declined with advancing lactation. The possible roles of free amino acids in human milk for feeding infant in the first stage was discussed. The results of this study support that breast milk is beneficial for infants and suggest that the formulas should be supplemented with taurine.