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1.
Sci Total Environ ; 711: 134589, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32000315

RESUMO

Antimony (Sb) is a toxic element for both human and plants, but the toxic responses of plants to different forms of antimony and the associated mechanisms are unknown. This study was carried out to investigate the effects of different forms of Sb [Sb(III) and Sb(V)] on the root exudates, root endogenous hormones, root cell wall components and antioxidant systems in rice plant via three hydroponic experiments. The results showed that Sb(III) displayed a higher toxicity than Sb(V) to the plant which accumulated much more Sb in its tissues under Sb(III) exposure than that under Sb(V) exposure. Under Sb(III) exposure, most of absorbed Sb was found to be Sb(III) in the shoots and roots; however when plants were exposed to Sb(V), most of absorbed Sb in this rice plant was Sb(V). Only two kinds of endogenous hormones were detected as abscisic acid (ABA) and salicylic acid (SA). The addition of Sb(III) significantly increased the content of ABA but Sb(V) did not, probably suggesting the higher toxicity of Sb(III) than Sb(V) might be due to the stimulation of ABA content. The addition of Sb(III) significantly increased the concentration of oxalic acid but decreased the concentrations of formic, acetic and maleic acids. Sb(V) also enhanced the oxalic acid concentration at 20 mg L-1 Sb(V) treatment level but reduced the concentrations of formic and acetic acids. Different forms of Sb dose-dependently increased the content of pectin, but significantly enhanced the content of lignin in cell wall. Different forms of Sb induced oxidative stress, but rice plant triggered the activities of superoxide dismutase (SOD) and ascorbate peroxidase (APX) to counteract the oxidative stress.

2.
Transplant Proc ; 52(1): 20-25, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32000939

RESUMO

BACKGROUND: Organ transplantation is an important method to save the lives of patients suffering from organ failure. However, the low rate of organ donation is a common problem worldwide. Many potential organ donors in the intensive care unit (ICU) are not properly identified, which is one reason for the low donation rate. ICU nurses play a key role in organ donation but may be uncertain regarding some issues. In this study, an analysis of the reasons why ICU nurses in western China are reluctant to encourage patients and their families to donate organs is performed, providing a reference for promoting ICU nurse participation in organ donation work. METHODS: From August to November of 2017, using a purposive sampling method, we conducted semi-structured, in-depth interviews using a phenomenological research method with 18 ICU nurses who were working in 4 large hospitals with organ transplant accreditation in Chongqing City, China, and analyzed the data with phenomenology. RESULTS: Reasons for the reluctance of ICU nurses in encouraging patients to donate organs were categorized into the following 4 themes: limitation of the nurses' professional role, influence of the family's negative emotions, lack of training regarding organ donation in medical institutions, and impact of a conservative social attitude. CONCLUSION: Chinese medical and health institutions need to attach importance to the duties and roles of ICU nurses in organ donation work, the creation of a good death culture, the implementation of training for organ donation specialist nurses, and the strengthening of advocacy efforts for organ donation so that ICU nurses' reluctance in engaging in organ donation coordination in China can be mitigated and the nurses can better participate in promoting organ donation to potential donors.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32026316

RESUMO

Proteasome inhibitor bortezomib is one of the most effective drugs currently available for the treatment of multiple myeloma (MM). However, the intrinsic and acquired resistance to bortezomib can limit its effectiveness. The activation of heat shock response has been characterized as a potential resistance mechanism protecting MM cells from bortezomib-induced cell death. In this study, in response to bortezomib therapy, we discovered that HSP70 is one of the most substantially upregulated heat shock proteins. In order to further explore approaches to sensitizing bortezomib-based treatment for MM, we investigated whether targeting HSP70 using a specific inhibitor VER-155008 combined with bortezomib could overcome the acquired resistance in MM. We found that HSP70 inhibitor VER-155008 alone significantly decreased MM cell viability. Moreover, the combination of VER-155008 and bortezomib synergistically induced MM cell apoptosis markedly in vitro. Notably, the combined treatment was found to increase the cleavage of PARP, an early marker of chemotherapy-induced apoptosis. Importantly, the reduction of anti-apoptotic Bcl-2 family member Bcl-2, Bcl-xL, and Mcl-1 and the induction of pro-apoptotic Bcl-2 family member BH3-only protein NOXA and Bim were confirmed to be tightly associated with the synergism. Finally, the ER stress marker CHOP (CCAAT-enhancer binding protein homologous protein), which can cause transcriptional activation of genes involved in cell apoptosis, was markedly induced by both VER-155008 and bortezomib. Taken together, our finding of a strong synergistic interaction between VER-155008 and bortezomib may support for combination therapy in MM patients in the future.

4.
J Am Chem Soc ; 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32003979

RESUMO

TDP-43 is a primary pathological hallmark protein of amyotrophic lateral sclerosis and frontotemporal lobar degeneration, which may exist in the form of amyloid inclusions in the cells of patients. In addition to serving as a biomarker for these diseases, TDP-43 can also directly trigger neurodegeneration. We previously determined the amyloidogenic core region of TDP-43 (residues 311-360) and showed by solution NMR that this region includes two α-helices [(321-330) and (335-343)] in solution. We suggested that the helix-to-sheet structural transformation initiates TDP-43 aggregation. In the present study, X-ray diffraction shows that TDP-43 (311-360) aggregates adopt a cross-ß structure. Thioredoxin (Trx)-fused TDP-43 (311-360) can undergo liquid-liquid phase separation (LLPS) before fibrillation, suggesting that phase separation is an intermediate step before amyloid formation. Solid-state NMR (SSNMR), carried out to elucidate the structural changes of TDP-43 (311-360) at the atomic level, indicates five ß-strands of the amyloids formed, with the major two ß-strands contributed by the first helical region in the solution structure. The NMR evidence is also in support of the fibril having a parallel in-register conformation, implying a mechanism in which the helix-helix interactions in LLPS are converted into ß-strand parallel lateral association upon fibrillation. Our studies have assigned many key interresidue interactions that contribute to the stability of the fibril, including F316 with I318 and Q327 and W334 with A325, A326, A329, and S332. SSNMR with 1H detection reveals a unique close interaction between the indole Nε1-Hε1 of W334 and the side-chain carbonyl of Q343. This interaction could be a very important factor in initiating TDP-43 (311-360) folding/misfolding in LLPS.

5.
Artigo em Inglês | MEDLINE | ID: mdl-32057363

RESUMO

Insulin biosynthesis and secretion by pancreatic ß cells are critical for the maintenance of blood glucose homeostasis. Here, we show that the expression of glutathione S-transferase omega-1 (GSTO1) is upregulated in the primary islet cells of diabetic Goto-Kakizaki (GK) rats. Knocking out GSTO1 upregulated insulin transcripts and increased the insulin content in both INS-1 cells and primary islet cells. In contrast, overexpression of GSTO1 reduced the insulin content. Furthermore, knocking out GSTO1 increased the expression of pancreatic duodenal homeobox-1 (PDX1) at both the transcription and protein levels. These results indicate that GSTO1 may be involved in the regulation of insulin biosynthesis by modulating the transcriptional expression of PDX1.

6.
Artigo em Inglês | MEDLINE | ID: mdl-32057701

RESUMO

Immune checkpoint inhibitors (ICIs) and immunotherapy have proven to be a transformative therapy for many forms of cancer treatment. While many antibodies targeting the PD-1, PD-L1, and CTLA-4 pathways have been approved for clinical use by the FDA, it is clear that a single ICI is not sufficient to eradicate disease. ICI combination strategies are being extensively investigated to advance cancer treatment to next curative stage. Among the immune checkpoint inhibitors being actively investigated, the potential of VISTA (V-domain Ig suppressor of T cell activation), a unique B7 family member that functions as both ligand and receptor, is being actively pursued. This article summarizes the expression and immunomodulatory effects of VISTA in autoimmune diseases and cancer, and assesses its potential as an additional component of immune checkpoint cancer therapy.

8.
Oncol Rep ; 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32020224

RESUMO

DEK has been revealed to be overexpressed in many cancers and associated with cancer progression. The aim of the present study was to elucidate the role of DEK with a specific focus on its underlying mechanism in lung cancers. DEK expression in lung cancers and normal lung tissues and the correlations between DEK expression and clinicopathological parameters of lung cancers were investigated using the data from The Cancer Genome Atlas (TCGA). DEK expression was upregulated by DEK transfection or downregulated by DEK shRNA interference in A549 and H1299 cells. The effects of DEK on the Wnt signaling pathway and epithelial­mesenchymal transition (EMT) were examined using western blotting. Proliferative and invasive abilities were observed in A549 and H1299 cells treated with DEK using an MTT assay, colony formation assay, and Transwell migration and invasion assays. The expression of DEK was higher in lung cancer tissues than that in normal lung tissues. DEK expression was positively correlated with the expression of epidermal growth factor receptor (EGFR) and KRAS in lung adenocarcinomas. High expression of DEK indicated poor prognosis in lung adenocarcinomas (P=0.018). Enhanced expression of DEK upregulated the levels of active­ß­catenin and Wnt target genes, such as cyclin D1, c­Myc and MMP7 and increased the proliferative and invasive abilities of lung cancer cells. Enhanced expression of DEK in A549 and H1299 cells also increased the levels of EGFR, KRAS, vimentin, Snail, and N­cadherin, and decreased the level of E­cadherin. The opposite results were obtained with knockdown of DEK expression. DEK was highly expressed in lung cancers and indicated poor prognosis in lung adenocarcinomas. DEK expression activated the Wnt signaling pathway and EMT process and promoted the proliferation and invasion of lung cancers.

9.
Chem Commun (Camb) ; 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32016279

RESUMO

A ruthenium-catalyzed allylic C(sp3)-H activation strategy has been employed to develop an intermolecular coupling of alkenyl sulfonamides with alkynes. This protocol features the diastereoselective construction of [3.3.0] and [4.3.0] bicyclic sultams in one step.

10.
J Exp Bot ; 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32016356

RESUMO

Auxin-induced cell elongation relies in part on the acidification of the cell wall, a process known as acid growth that presumably triggers expansin-mediated wall loosening via altered interactions between cellulose microfibrils. Cellulose microfibrils are a major determinant for anisotropic growth and they provide the scaffold for cell wall assembly. Little is known about how acid growth depends on cell wall architecture. To explore the relationship between acid growth-mediated cell elongation and plant cell wall architecture, two mutants (jia1-1 and csi1-3) that are defective in cellulose biosynthesis and cellulose microfibril organization were analyzed. The study revealed that cell elongation is dependent on CSI1-mediated cell wall architecture but not on the overall crystalline cellulose content. We observed a correlation between loss of crossed-polylamellate walls and loss of auxin- and fusicoccin-induced cell growth in csi1-3. Furthermore, induced loss of crossed-polylamellate walls via disruption of cortical microtubules mimics the effect of csi1 in acid growth. We hypothesize that CSI1- and microtubule-dependent crossed-polylamellate walls are required for acid growth in Arabidopsis hypocotyls.

11.
Gen Physiol Biophys ; 39(1): 49-58, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32039824

RESUMO

As a naturally occurring flavone, luteolin has received much attention due to its antioxidant, anti-inflammatory and anticancer functions. In the present study, we investigated the effect of luteolin on colonic motility and its mechanism using isometric muscle recording and the whole-cell patch-clamp technique in mice. Luteolin dose-dependently inhibited colonic smooth muscles motility and CMMC significantly. BayK8644, an L-type Ca2+ channel agonist, significantly attenuated the luteolin-induced inhibition. Moreover, the calcium currents recorded in colonic smooth muscle cells were dramatically inhibited by luteolin. However, no significant changes were found in the luteolin-induced inhibitory effect in the presence of TEA, a nonselective K+ channel blocker, glibenclamide, an ATP-dependent K+ channel blocker, and apamin, a small-conductance Ca2+-activated K+ channel blocker. Additionally, luteolin did not affect potassium currents. Furthermore, TTX, a Na+ channel blocker, L-NAME, an inhibitor of nitric oxide (NO) synthase, ODQ, an inhibitor of NO-sensitive guanylyl cyclase, and Ani9, a specific ANO1 channels blocker, had no effect on the luteolin-induced suppression. These results suggest that luteolin inhibited colonic smooth muscle motility by inhibiting L-type calcium channels in mice but not through potassium channels, the enteric nervous system (ENS), NO signaling pathways or ANO1 channels of interstitial cells of Cajal (ICCs).

12.
Mol Reprod Dev ; 2020 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-32064722

RESUMO

Uniparental embryos have uniparental genomes and are very useful models for studying the specific gene expression of parents or for exploring the biological significance of genomic imprinting in mammals. However, the early developmental efficiency of androgenetic embryos is significantly lower than that of parthenogenetic embryos. In addition, oocytes are able to reprogram sperm nuclei after fertilization to guarantee embryonic development by maternally derived reprogramming factors, which accumulate during oogenesis. However, the importance of maternal material in the efficiency of reprogramming the pronucleus of androgenetic embryos is not known. In this study, androgenetic embryos were constructed artificially by pronucleus transfer (PT) or double sperm injection (DS). Compared with DS embryos, PT embryos that were derived from two zygotes contained more maternal material, like 10-11 translocation methylcytosine deoxygenase 3 (Tet3) and histone variant 3.3 (H3.3). Our experiments confirmed the better developmental potential of PT embryos, which had higher blastocyst rates, a stronger expression of pluripotent genes, a lower expression of apoptotic genes, and superior blastocyst quality. Our findings indicate that the aggregation of more maternal materials in the paternal pronucleus facilitate the reprogramming of the paternal genome, improving embryonic development in PT androgenesis.

13.
Nat Plants ; 6(1): 4, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31949310
14.
Am J Clin Pathol ; 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31977029

RESUMO

OBJECTIVES: Interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) and interferon-induced transmembrane protein 3 (IFITM3) are commonly induced by type I interferon. The study aims to investigate the expression and clinical significance of IFIT1 and IFITM3 in head and neck squamous cell carcinoma (HNSCC). METHODS: Immunohistochemistry was applied on tissue microarray to reveal IFIT1 and IFITM3 expression in 275 HNSCC, 69 dysplasia, and 42 normal mucosa samples. The clinicopathologic features associated with IFIT1 and IFITM3 expression in HNSCC patients were analyzed. RESULTS: IFIT1 and IFITM3 were highly expressed in HNSCC tissues. High expression of IFIT1 and IFITM3 predicts a negative prognosis for patients (P < .01). IFIT1 and IFITM3 expression was associated with programmed cell death ligand 1, B7-H4, V-domain Ig suppressor of T-cell activation, indoleamine 2,3-dioxygenase, and macrophage marker immunoreactivity. CONCLUSIONS: IFIT1 and IFITM3 were overexpressed in HNSCC and indicated poor prognoses for patients with HNSCC. IFIT1 and IFITM3 expression was correlated with several immune checkpoint molecules and tumor-associated macrophage markers.

15.
J Ethnopharmacol ; 251: 112540, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31917278

RESUMO

BACKGROUND: In recent years, the morbidity of Alzheimer's disease in the world has become more and more serious. Therefore, it is an important means to find new drugs for treating AD from traditional medicines. It was found that Corydalis edulis Maxim. has a significant effect in the treatment of Alzheimer's disease (AD) in traditional application. In this work, we evaluated the efficacy of Corydalis edulis Maxim. total alkaloids (CETA) in AD model rats. METHODS: In this work, CETA was prepared by alkali extraction and acid precipitation, 11 alkaloids were identified by UPLC-MS/MS from CETA. AD model rats induced with D-galactose (D-gal) for 7 weeks. In modeling, the different doses of CETA (5, 20 mg/kg/Day) were continuously administered. Firstly, the change of the cognitive function, behavior, brain tissue pathology, and the activity of ROS, MDA, SOD, IL-1ß, TNF-α and CAT in rat hippocampal homogenate was measurement. Finally, the protein expression of Aß, microtubule-associated protein 2 (MAP2) and nuclear factor (κBp65) in rat brain was measurement. RESULT: CETA was found to have the activity in regulating AD. Compared with the normal control group, the levels of SOD and CAT in the hippocampus of the AD model group were decreased, and the level of ROS, MDA, IL-1ß and TNF-α was increased. The protein expression of Aß, and NF-κB were increased, and MAP2 were decreased. After treatment by CETA, the levels of SOD and CAT in hippocampus of AD model rats was significantly increased, ROS, MDA, IL-1ß and TNF-α were significantly decreased. The protein expression of Aß, and NF-κB were decreased, and MAP2 were increased. CONCLUSION: CETA can improve the learning and memory ability in AD model. The mechanism may be achieved by regulating the oxidative stress and inflammatory of AD rats, inhibiting the protein expression levels of Aß, and NF-κB, and promote the protein expression the levels of MAP2. Among them, 5 mg/kg is more effective than 20 mg/kg of CETA. Therefore, the therapeutic potential of CETA has been confirmed by our research, which may be a valuable drug for the treatment of AD.

16.
Artigo em Inglês | MEDLINE | ID: mdl-31981517

RESUMO

BACKGROUND: Colonoscopy with computer-aided detection (CADe) has been shown in non-blinded trials to improve detection of colon polyps and adenomas by providing visual alarms during the procedure. We aimed to assess the effectiveness of a CADe system that avoids potential operational bias. METHODS: We did a double-blind randomised trial at the endoscopy centre in Caotang branch hospital of Sichuan Provincial People's Hospital in China. We enrolled consecutive patients (aged 18-75 years) presenting for diagnostic and screening colonoscopy. We excluded patients with a history of inflammatory bowel disease, colorectal cancer, or colorectal surgery or who had a contraindication for biopsy; we also excluded patients who had previously had an unsuccessful colonoscopy and who had a high suspicion for polyposis syndromes, inflammatory bowel disease, and colorectal cancer. We allocated patients (1:1) to colonoscopy with either the CADe system or a sham system. Randomisation was by computer-generated random number allocation. Patients and the endoscopist were unaware of the random assignment. To achieve masking, the output of the system was shown on a second monitor that was only visible to an observer who was responsible for reporting the alerts. The primary outcome was the adenoma detection rate (ADR), which is the proportion of individuals having a complete colonoscopy, from caecum to rectum, who had one or more adenomas detected. The primary analysis was per protocol. We also analysed characteristics of polyps and adenomas missed initially by endoscopists but detected by the CADe system. This trial is complete and is registered with http://www.chictr.org.cn, ChiCTR1800017675. FINDINGS: Between Sept 3, 2018, and Jan 11, 2019, 1046 patients were enrolled to the study, of whom 36 were excluded before randomisation, 508 were allocated colonoscopy with polyp detection using the CADe system, and 502 were allocated colonoscopy with the sham system. After further excluding patients who met exclusion criteria, 484 patients in the CADe group and 478 in the sham group were included in analyses. The ADR was significantly greater in the CADe group than in the sham group, with 165 (34%) of 484 patients allocated to the CADe system having one or more adenomas detected versus 132 (28%) of 478 allocated to the sham system (odds ratio 1·36, 95% CI 1·03-1·79; p=0·030). No complications were reported among all colonoscopy procedures. Polyps initially missed by the endoscopist but identified by the CADe system were generally small in size, isochromatic, flat in shape, had an unclear boundary, were partly behind colon folds, and were on the edge of the visual field. INTERPRETATION: Polyps initially missed by the endoscopist had characteristics that are sometimes difficult for skilled endoscopists to recognise. Such polyps could be detected using a high-performance CADe system during colonoscopy. The effect of CADe during colonoscopy on the incidence of interval colorectal cancer should be investigated. FUNDING: None.

17.
Acupunct Med ; : acupmed2016011263, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31996011

RESUMO

OBJECTIVE: The aim of this study was to investigate the effect of electroacupuncture (EA) on recovery from acute sciatic nerve crush injury and the expression of pS6 in rats. METHODS: A total of 108 adult male Sprague-Dawley rats were randomly divided into control, model, EA and EA+rapamycin (EA+Rapa) groups. 28 rats were allocated to undergo measurement of sciatic functional index (SFI); one rat in the EA+Rapa group was unsuccessfully modelled and excluded because of an anaesthetic problem. The remaining 80 rats were allocated to undergo Western blot detection of S6 ribosomal protein (pS6, ser240/244). The model was created by mechanical clamping of the sciatic nerve stem. EA stimulation at GB30 and ST36 for 15 min separately was applied once daily for rats in the EA and EA+Rapa groups. For rats in the EA+Rapa group, rapamycin, a mammalian target of rapamycin (mTor) pathway inhibitor, was injected intramuscularly (1 mg/kg/day) near the site of crush injury in the sciatic nerve and an equivalent amount of dimethyl sulfoxide was injected in the other three groups every other day. After treatment for 7, 14, 28 and 42 days post-operation, the SFI of 27 rats was obtained to evaluate recovery of motor function and five rats from each group per stage were used for Western blot detection of pS6. RESULTS: The SFI values showed that EA could significantly promote recovery of the injured sciatic nerve but rapamycin hindered the therapeutic effect of EA. Moreover, immunoblotting indicated that EA improved the expression of pS6 in the area of the sciatic nerve crush injury and local injection of rapamycin near the injured sciatic nerve decreased its expression. The pS6 level correlated with the extent of recovery of the injury. CONCLUSIONS: This study indicated that EA may activate the mTOR signalling pathway to enhance expression of pS6 and facilitate recovery following sciatic nerve crush injury.

18.
Neurosci Lett ; 718: 134750, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31926175

RESUMO

Depression is a highly prevalent mental disease and increasingly become a global public health problem. Recent studies have shown that the dysfunction of liver was associated with depression. However, the previous studies have not been fully explained the relationship between depression and liver injury. The present study was aimed to investigate whether chronic liver injury could induce depressive-like behavior. Chronic liver injury was induced by intraperitoneal injection of carbon (CCl4), D-galactosamine (D-GalN) and thioacetamide (TAA), respectively. And the results showed that the serum activities of ALT in CCl4, D-GalN and TAA groups were significantly increased in both male and female mice compared with the control group, while the activities of AST increased only in CCl4 group. Meanwhile, H&E staining showed that CCl4, D-GalN and TAA induced hepatocytes injury in both male and female mice. Moreover, the sucrose preference was significantly decreased and the immobility time in forced swimming test and tail suspension test were significantly prolonged in CCl4 and D-GalN group compared with control group. Our findings demonstrated that chronic liver injury induced by CCl4 and D-GalN could induce depressive-like behaviors in mice.

19.
Ying Yong Sheng Tai Xue Bao ; 31(1): 333-339, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-31957412

RESUMO

A large amount of azo dye wastewater is discharged into the environment, with serious risks to ecosystems and human health. Therefore, the development of treatment technology of azo dye wastewater was of practical significance. Photocatalytic methods showed promising application prospects due to easy to implement and effective. In this study, layered black phosphorus nanosheet (LBP) was used as a catalyst through liquid phase exfoliation method. Methyl orange (MO) was employed as a model azo dye to investigate the catalytic mechanism of LBP. The dominant transient species involved in the photocatalytic reaction was probed by quenching and fluorescence probe experiments. Degradation pathways of MO were proposed according to degradation products identified by the liquid chromatography-mass spectrometry. The results showed that degradation rate (kobs) of MO at acidic condition (pH=3.0) or alkaline condition (pH=11.0) was higher than that at neutral condition (pH=7.0). Degradation pathways of MO included that the azo bond was attacked by hydroxyl radicals (·OH) photogenerated by the LBP, and the intermediate products were further oxidized by ·OH to produce N, N-dimethyl-4-(2-p-phenylmethylhydrazine) aniline, 2-(dimethylamino)-5-((4(dimethylamino) phenyl) diazenyl) phenol and N, N-dimethyl-4-nitroaniline.


Assuntos
Ecossistema , Fósforo , Compostos Azo , Águas Residuárias
20.
Nanoscale ; 12(5): 3359-3369, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-31984408

RESUMO

The tumor microenvironment (TME) acts as an ecosystem that includes not only tumor cells, but also stromal cells such as cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs). In addition, the abnormal extracellular environment (ECM), of which the mechanical forces are regulated by fibronectin (Fn) and collagen I, orchestrates tumorigenesis and progression by directly promoting invasion and cellular transformation of the ecosystem. Herein, we develop a novel peptide-modified liposome incorporated into doxorubicin (FnBPA5-AAN-Dox) as an ecological therapy system, which targets not only the cellular compartment but also non-cellular components of breast cancer. FnBPA5 is a Fn-binding peptide showing high affinity with relaxed Fn and collagen I in the ECM as well as α-SMA-expressing CAFs. However, the fast clearance by Fn-excreting organs such as the liver and spleen limits the accumulation of FnBPA5-Dox in the TME. The AAN peptide, which targets legumain overexpressed in the TAMs, could extend the circulation time and improve the therapeutic response as well as modulate the tumor immune microenvironment (TMIE). Given twice at an equivalent dose of 5 mg kg-1 intravenously, the multi-in-one 'ecological therapy' applied AAN-FnBPA5-Dox showed excellent antitumor efficacy in 4T1 breast cancer mice, and the tumor growth inhibition (TGI) is up to 98.20% compared with saline. Immunofluorescence, flow cytometry and reverse transcription polymerase chain reaction (RT-PCR) results revealed that the dramatic improvement in antitumor efficacy can be attributed to the multifunctional targets of the drug delivery system.

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