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Intelligent responsive drug delivery system opens up new avenues for realizing safer and more effective combination immunotherapy. Herein, a kind of tumor cascade-targeted responsive liposome (NLG919@Lip-pep1) is developed by conjugating polypeptide inhibitor of PD-1 signal pathway (AUNP-12), which is also a targeted peptide that conjugated with liposome carrier through matrix metalloproteinase-2 (MMP-2) cleavable peptide (GPLGVRGD). This targeted liposome is prepared through a mature preparation process, and indoleamine-2,3-dioxygenase (IDO) inhibitor NLG919 was encapsulated into it. Moreover, mediated by the enhanced permeability and retention effect (EPR effect) and AUNP-12, NLG919@Lip-pep1 first targets the cells that highly express PD-L1 in tumor tissues. At the same time, the over-expressed MMP-2 in the tumor site triggers the dissociation of AUNP-12, thus realizing the precise block of PD-1 signal pathway, and restoring the activity of T cells. The exposure of secondary targeting module II VRGDC-NLG919@Lip mediated tumor cells targeting, and further relieved the immunosuppressive microenvironment. Overall, this study offers a potentially appealing paradigm of a high efficiency, low toxicity, and simple intelligent responsive drug delivery system for targeted drug delivery in breast cancer, which can effectively rescue and activate the body's anti-tumor immune response and furthermore achieve effective treatment of metastatic breast cancer.
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[This corrects the article DOI: 10.1016/j.apsb.2021.04.022.].
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Considering that photodynamic therapy (PDT)-induced oxygen consumption and microvascular damage could exacerbate hypoxia to drive more glycolysis and angiogenesis, a novel approach to potentiate PDT and overcome the resistances of hypoxia is avidly needed. Herein, morpholine-modified PEGylated bilirubin was proposed to co-deliver chlorin e6, a photosensitizer, and diclofenac (Dc). In acidic milieu, the presence of morpholine could enable the nanocarriers to selectively accumulate in tumor cells, while PDT-generated reactive oxidative species (ROS) resulted in the collapse of bilirubin nanoparticles and rapid release of Dc. Combining with Dc showed a higher rate of apoptosis over PDT alone and simultaneously triggered a domino effect, including blocking the activity and expression of lactate dehydrogenase A (LDHA), interfering with lactate secretion, suppressing the activation of various angiogenic factors and thus obviating hypoxia-induced resistance-glycolysis and angiogenesis. In addition, inhibition of hypoxia-inducible factor-1α (HIF-1α) by Dc alleviated hypoxia-induced resistance. This study offered a sequentially responsive platform to achieve sufficient tumor enrichment, on-demand drug release and superior anti-tumor outcomes in vitro and in vivo.
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Solid tumors always exhibit local hypoxia, resulting in the high metastasis and inertness to chemotherapy. Reconstruction of hypoxic tumor microenvironment (TME) is considered a potential therapy compared to directly killing tumor cells. However, the insufficient oxygen delivery to deep tumor and the confronting "Warburg effect" compromise the efficacy of hypoxia alleviation. Herein, we construct a cascade enzyme-powered nanomotor (NM-si), which can simultaneously provide sufficient oxygen in deep tumor and inhibit the aerobic glycolysis to potentiate anti-metastasis in chemotherapy. Catalase (Cat) and glucose oxidase (GOx) are co-adsorbed on our previously reported CAuNCs@HA to form self-propelled nanomotor (NM), with hexokinase-2 (HK-2) siRNA further condensed (NM-si). The persistent production of oxygen bubbles from the cascade enzymatic reaction propels NM-si to move forward autonomously and in a controllable direction along H
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Insurmountable blood‒brain barrier (BBB) and complex pathological features are the key factors affecting the treatment of Alzheimer's disease (AD). Poor accumulation of drugs in lesion sites and undesired effectiveness of simply reducing A
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Tourette′s syndrome (TS) is a common neurodevelopmental disorder that affects the learning and life of children. So far, its pathogenesis remains unclear and its treatment effect is limited. As an important means of non-pharmacological treatment, neuromodulation technology has some curative effects on TS. This article describes the progress in neuromodulation therapy of TS, so as to facilitate the development of new technologies for the treatment of such patients.
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Tourette's syndrome (TS) is a common neurodevelopmental disorder that affects the learning and life of children.So far,its pathogenesis remains unclear and its treatment effect is limited.As an important means of non-pharmacological treatment,neuromodulation technology has some curative effects on TS.This article describes the progress in neuromodulation therapy of TS,so as to facilitate the development of new technologies for the treatment of such patients.
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In order to better evaluate the transport effect of nanoparticles through the nasal mucosa, an nasal cavity-mimic model was designed based on M cells. The differentiation of M cells was induced by co-culture of Calu-3 and Raji cells in invert model. The ZO-1 protein staining and the transport of fluorescein sodium and dexamethasone showed that the inverted co-culture model formed a dense monolayer and possessed the transport ability. The differentiation of M cells was observed by up-regulated expression of Sialyl Lewis A antigen (SLAA) and integrin 1, and down-regulated activity of alkaline phosphatase. After targeting M cells with iRGD peptide (cRGDKGPDC), the transport of nanoparticles increased. , the co-administration of iRGD could result in the increase of nanoparticles transported to the brain through the nasal cavity after intranasal administration. In the evaluation of immune effect , the nasal administration of OVA-PLGA/iRGD led to more release of IgG, IFN-, IL-2 and secretory IgA (sIgA) compared with OVA@PLGA group. Collectively, the study constructed M cell model, and proved the enhanced effect of targeting towards M cell with iRGD on improving nasal immunity.
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The mitogen-activated protein kinases (MAPK) pathway, often known as the RAS-RAF-MEK-ERK signal cascade, functions to transmit upstream signals to its downstream effectors to regulate physiological process such as cell proliferation, differentiation, survival and death. As the most frequently mutated signaling pathway in human cancer, targeting the MAPK pathway has long been considered a promising strategy for cancer therapy. Substantial efforts in the past decades have led to the clinical success of BRAF and MEK inhibitors. However, the clinical benefits of these inhibitors are compromised by the frequently occurring acquired resistance due to cancer heterogeneity and genomic instability. This review briefly introduces the key protein kinases involved in this pathway as well as their activation mechanisms. We also generalize the correlations between mutations of MAPK members and human cancers, followed by a summarization of progress made on the development of small molecule MAPK kinases inhibitors. In particular, this review highlights the potential advantages of ERK inhibitors in overcoming resistance to upstream targets and proposes that targeting ERK kinase may hold a promising prospect for cancer therapy.
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Objective To study the prescription and preparation technology of breviscapine microemulsion for parenteral injection,and to evaluate its quality.Methods The prescription was selected and optimized through single-factor test and the pseudo-ternary phase diagram method.The preparation technology was investigated,and the particle diameter,drug content,encapsulation efficiency and haemolyticus were evaluated.Results The prescription composition of breviscapine microemulsion was soybean oil:phospholipid:HS15:PEG400:water=1:0.1:0.55:0.55:6.64 (m/m),with the drug content of 4.01 mg·mL-1,the acquired breviscapine microemulsion exhibited light yellow,uniform and transparent,with average particle diameter of 92.1 nm and encapsulation efficiency of 96.8%.The compatibility test showed no drug precipitation and the preparation was no hemolytic crisis.Conclusion The preparation of breviscapine microemulsion injection is correspond to the main index of parenteral injection.
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Objective@#To explore the clinical efficacy in patients who underwent endoscopic nasopharyngectomy for primary advanced nasopharyngeal carcinoma (NPC).@*Methods@#Forty-five patients who underwent endoscopic nasopharyngectomy for primary advanced NPC encountered between Aug. 2007 and Sep. 2015 were retrospectively reviewed. Twenty-seven patients were male (60.0%), and 18 patients were female (40.0%), the ratio of male to female was 3∶2. The median age was 53 years old (ranged from 13 to 75 years old). The median onset time was 5 months (ranged from 1 to 72 months). TNM stage: 16 cases were at stage Ⅲ (35.6%), 29 at stage Ⅳ (64.4%); T3 16 cases (35.6%), T4 29 cases (64.4%); N0 38 cases (84.4%), N2 7 cases (15.6%). No patients were found to have distance metastasis. All patients underwent endoscopic resection of lesions. Postoperatively all the patients were treated with radiotherapy or chemoradiotherapy. Using SPSS 19.0 software, Kaplan-Meier and Log-rank test were done for the assessmen of survival rate; Cox proportional hazards model was used for the univariate analysis of prognostic factors.@*Results@#The median follow-up was 36 months (ranged from 6 to 97 months), with 36 cases surviving (80.0%), 9 cases died (20.0%); 15 cases relapsed (33.3%). The overall 1 year survival rates (SR), 3 year SR, 5 year SR was 90.6%, 81.0%, 76.0%, respectively. The survival univariate analysis indicated the recurrence and metastasis were correlated with the survival (χ2 value was 16.644, 6.451, respectively, all P<0.05).@*Conclusion@#The patients who undergo endoscopic nasopharyngectomy for primary advanced NPC have better survival rate with lower recurrent rate and metastatic rate.
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Objective To investigate the nutritional management level of Department of Clinical Nutrition in elderly inpatients through analyzing the actual hospital dietary intakes in elderly inpatients in Peking Union Medical College Hospital from 2013-2015.Methods Using continuous sampling, the nutrients contents and the eating rates of hospital meals ordered by the elderly inpatients on the 1st, 15th, 29th of every month from May 2013 to October 2015 were selected.The intake levels of energy, protein, calcium, vitamin A, vitamin B1 , and vitamin C were calculated and compared with the Chinese dietary reference intakes (DRIs).The nutritional in-take differences between diabetes diet and the basic hospital diet were also compared.Results A total of 90 days of hospital dietary data from 8 402 elderly inpatients were included in the study.The average eating rate was (50.1 ±4.2)%, which was lower than the general eating rate of the hospital [ (59.0 ±4.0)%, P<0.001]. Only protein intake from hospital diet reached the requirement target [male (103.1 ±47.3)%, femal (98.3 ± 33.8)%].Individual compliance rates were 63.2%and 59.8%, respectively, while the other kinds of nutrients were lower.The compliance rates of energy [ (73.3 ±26.3)%vs.(62.1 ±38.2)%, P<0.001] and ma-jor nutrient intake [ protein: ( 119.1 ±41.2 )% vs.( 93.3 ±65.1 )%, P <0.001; calcium: ( 55.5 ± 26.7)% vs.(34.3 ±34.2)%, P <0.001; vitamin A: (75.2 ±48.3)% vs.(57.4 ±97.1)%, P<0.001;vitamin B1:(76.4 ±38.2)%vs.(52.1 ±46.6)%, P<0.001;vitamin C:(92.2 ±51.4)%vs. (49.3 ±55.0)%, P<0.001) in diabetes diet group were significantly higher than those in the basic hospi-tal diet group.Conclusions The nutritional intakes from hospital diets may not meet the nutritional require-ments based on DRIs in elderly inpatients.Medical diet designed by physicians and dietitians should be ex-panded to improve the nutritional management level for these patients.
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Objective To investigate the protective effects and mechanism of Faecalibacterium prausnitzii (Fp) and its products in 2,4,6-trinitrobenzene sulfonic acid (TNBS) induced colitis rats.Methods A total of 40 Sprague-Dawley rats were divided into healthy control group,colitis model group,Fp supernatant group,Fp bacteria group and Bifidobacterium longum (B.longum) group.The rats of the later four groups were enemaed with TNBS to establish the model.At five days before and one day after modeling,the rats were gavaged with phosphate buffer saline (PBS),the supernatant of Fp,live Fp bacteria and live B.longum respectively.Rats were executed at 48 hour after modeling.The colon tissues were taken for pathology examination.The content of short-chain fatty acids (SCFA) in fecal was tested by gas chromatography.The plasma level of interleukin-10 (IL- 10),interleukin-12 ( IL-12),interleukin-17 (IL-17) and interleukin-23 (IL-23) were detected by enzyme-linked immunosorbnent assay (ELISA) and the expression of IL-17 in intestinal mucosal tissues was measured by immunohistochemistry.The data were analyzed by one way ANOVA.Results Compared with the healthy control group,the rats of colitis group suffered serious weight loss and their intestinal pathology score increased [(193.57±14) g vs (170.25±19.18) g,(1.00±0.99) vs (3.34±0.38),t=2.83 and 7.55,all P value＜0.05].The Fp supernatant group showed protective effects in terms of weight and intestinal pathology score [(187.00± 14.67) g,(2.50±0.44),t=2.1 and 2.9,all P＜0.05].Compared with healthy control group,the plasma and colon tissue IL-17 concentration of colitis model group increased (16.61 pg/ml±2.45 pg/ml vs 20.47 pg/ml± 1.45 pg/ml,0.83±0.98 vs 5.14±0.90) (all P＜0.05).Compared with the colitis model group,the plasma and colon tissue IL-17 concentration of Fp supernatant group decreased ( 17.54 pg/ml± 1.51 pg/ml and 2.86±0.69).Conclusion Fp can regulate immune response and suppress rat colonic inflammation,which may be related with the expression of IL-17.
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Objective To explore the therapeutic effects and the mechanisms of Faecalibacterium prausnitzii (Fp) on trinitro-benzene-sulfonic acid-induced colitis.Methods Sixty Sprague-Dawley rats were divided into healthy control group, colitis model control group, Fp pretreated group,Fp supernatant pretreated group,Fp treated group and Fp supernatant treated group.Disease activity index (DAI),histological injury of colonic tissue,the content of butyrate in feces,forkhead box protein 3 (Foxp3) regulatory T cells (Treg) in peripheral blood and spleen and the level of interlenkin (IL)-17 and IL-6 in serum were evaluated.All the data were statistical analyzed by single factor analysis of variance. Results Compared with colitis model control group, DAI significantly lowered and histological injury obviously improved in Fp pretreated group, Fp supernatant pretreated group,Fp treated group and Fp supernatant treated group.The effects of Fp pretreated group were better than those of Fp treated group and Fp supernatant pretreated group were better than Fp supernatant treated group.The concentration of butyrate in Fp pretreated group,Fp supernatant pretreated group,Fp treated group and Fp supernatant treated group was (3091.08 ±485.50) × 106 mol/L,(1714.64 ± 351.25) × 10(-8) mol/L,(2064.75 ± 295.04) × 10-6 mol/L and (1089.13±321.23) × 10-6 mol/L respectively,there was significant difference between Fp pretreated group and other groups (F=49.796,P＜0.01).The peripheral blood level of Foxp3+ Treg in Fp supernatant pretreated group was highest.The spleen level of Foxp3+ Treg in Fp pretreated group and Fp supernatant pretreated group were significantly higher than that of other groups.The serum level of IL-17 and IL-6 in Fp pretreated group,Fp supernatant pretreated group,Fp treated group and Fp supernatant treated group was significantly lower than that of colitis model group.Conclustons Fp plays a role in promoting the repair of intestinal inflammatory reaction in colitis model rats.The mechanism may be related with butyrate producing,the peripheral blood and spleen level of Foxp3+ Treg up-regulating,suppressing the secretion of proinflammatory cytokine IL-17 and IL-6.Rebuilding the balance of Treg/Th17 to reduce local intestinal inflammation.
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Objective Hirsutella sinensis (HS) is the anmorph of Ophiocordyceps sinensis (Cordyceps sinensis). O.sinensis and Panax notoginseng are two popular Chinese herbs, commonly used in traditional Chinese prescriptions for the treatment of various diseases. A combination of HS extract with P. notoginseng saponin (PNS) extract demonstrated more prominent lung-protective activity than the two herbs individually used in our preliminary studies. This study further investigated the action of their combination (HSPNS) on anti pulmonary fibrosis using a Bleomycin (BLM)induced mouse model. Methods BLM-treated Kunming mice was given HSPNS daily for 7, 14 or 28 d via ig administration. After treatment, following parameters were monitored using proper methods, respectively. Lung index, serum and lung malondialdehyde (MDA) and hydroxyproline (HYP) contents, lung superoxide dismutase (SOD) activity, transforming growth factor β1 (TGF-β1), and expression levels of collagen Ⅰ (Col- Ⅰ) and collagen Ⅲ (Col-Ⅲ). The lung biopsies were also dissected for semiquantitative histological analysis. Results The results indicated that HSPNS significantly reduced lung index, MDA and HYP contents, and expression levels of TGF-β1,Col- Ⅰ, and Col-Ⅲ. The combination also remarkably enhanced SOD activity compared with BLM-induced group.Moreover, the severe pulmonary fibrosis histopathological changes induced by BLM could be attenuated by HSPNS treatment. Conclusion These results suggest that HSPNS could significantly inhibit the progression of pulmonary fibrosis induced by BLM and its inhibitory effect might associate with its ability to scavenge free radicals, decrease TGF-β1 level, and inhibit collagen synthesis.
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Objective To study the value of MR three-dimensional volumetric interpolated breath-hold examination(3D-VIBE)and conventional MR imaging (including MRCP) in diagnosing cholangiocarcinoma early and evaluating the respectability of cholangiocarcinoma. Methods 20 patients with malignant obstruction of bile duct were scaned by conventional MR imaging(including MRCP) and dynamic-enhanced 3D-VIBE triple-phase acquisitions. MR imaging features of the tumors were analysed and the re-spectability of cholangiocarcinoma was also evaluated. The differences between conventional MR imaging and 3D-VIBE in displaying the tumors and the infiltration extent of the tumors were compared. Results The sensitivity ratio in showing the tumors were 85 and 95% with conventional MR imaging and 3D-VIBE, respectively, and there was statistically significant difference between two sequences in displaying infiltration of adjacent organs by the tumors(P<0.05). Conclusion 3D-VIBE is superior to conventional MR imaging in the early diagnosis,preoperative assessment of the infiltration extent and the tumor respectability of cholangiocarcino-ma.