Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 482
Filtrar
1.
Technol Health Care ; 2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33843708

RESUMO

OBJECTIVE: This is a case study on the application of a piggy-back lens in the correction of severe keratoconus. METHODS: From the results of general eye examination, refractive state examination, and corneal morphology examination on the patient, it was determined that corneal protrusion and deformation of the right eye were obvious. The right eye was corrected using a piggy-back lens and the left eye with a rigid gas-permeable contact lens (RGPCL) alone. RESULTS: The right-eye lens fit well and the lens coverage was good. Both the static and dynamic fit results for the left-eye lens were good. After wearing the glasses for one month, the patient attended a review and stated that the lenses were comfortable to wear. The patient's vision was good after wearing the lenses. No obvious congestion was found in the conjunctiva under a slit lamp. The effects on both eyes of wearing RGPCLs were favorable. The corneal curvature reduced and the corneal thickness only changed to a small degree. CONCLUSION: For keratoconus patients, application of a piggy-back lens can improve corrected visual acuity, comfort levels, and safety, prolong the wearing time, and enhance the effect of orthokeratology.

2.
Cancer Lett ; 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33836250

RESUMO

Bladder cancer is a clinically heterogeneous disease with a poor prognosis. In the current study, anti-proliferation assay of a Euphorbiaceae diterpenoid library led to the identification of an anti-bladder cancer agent Jolkinolide B (JB). JB showed significant cytotoxicity against a panel of bladder cancer cell lines and suppressed the growth of cisplatin (CDDP)-resistant bladder cancer xenografts in single or combination treatments. Mechanistic study revealed that, besides inducing mitogen-activated protein kinase (MAPK)-related apoptosis, JB could trigger the paraptosis via activation of reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress and extracellular signal-regulated kinase (ERK) pathway. The excessive production of ROS could be induced by JB via inhibition of thioredoxin reductase 1 (TrxR1) and depletion of glutathione (GSH). Collectively, JB that targets thioredoxin and GSH systems to induce two distinct cell death modes may serve as a promising candidate in future anti-bladder cancer drug development.

3.
Redox Biol ; 41: 101929, 2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33714738

RESUMO

BACKGROUND: Mesenchymal stem cell therapy improves ischemic heart failure via incompletely understood mechanisms. C1q-TNFα related protein-9 (CTRP9) is a novel anti-oxidative cardiokine capable of improving the local microenvironment and cell survival by its c-terminal active globular domain (gCTRP9). The current study attempted to: 1) identify active gCTRP9 c-terminal polypeptides with stem cell protective function; 2) determine whether a lead polypeptide may enable/enhance cortical bone-derived mesenchymal stem cell (CBSC) cardioprotection against post-myocardial infarction (post-MI) remodeling; and 3) define the responsible underlying cellular/molecular mechanisms. METHODS AND RESULTS: Utilizing I-TASSER structure prediction and 3-D active site modeling, we cloned and purified 3 gCTRP9 fragments (CTRP9-237, CTRP9-277, and CTRP9-281). Their activation of cell salvage kinase was compared against gCTRP9. Among the three fragments, CTRP9-281 (a 45 residue-containing polypeptide) exerted comparable or greater ERK1/2 activation compared to gCTRP9. Treatment with CTRP9-281 or gCTRP9 significantly increased CBSC proliferation and migration, and attenuated oxidative stress-induced CBSC apoptosis. CTRP9-281 and gCTRP9 comparably upregulated SOD2 and SOD3 expression. However, CTRP9-281, not gCTRP9, upregulated FGF2 and VEGFA expression/secretion in an ERK1/2 dependent manner. Administration of gCTRP9 or CTRP9-281 alone attenuated post-MI cardiac dysfunction and improved CBSC retention in the infarcted heart in similar fashion. However, CTRP9-281 exerted greater synergistic effect with CBSC than gCTRP9 related to pro-angiogenic, anti-fibrotic, and anti-remodeling effects. Mechanistically, CTRP9-281 significantly increased SOD2-rich and VEGFA-rich exosome production by CBSC. Exosomes from CTRP9-281 treated CBSC significantly attenuated oxidative stress-induced cardiomyocyte apoptosis in vitro. An exosome generation inhibitor attenuated CTRP9-281 enhancement of CBSC cardioprotection in vivo. CONCLUSION: We identified a CTRP9 polypeptide that upregulates SOD2/SOD3 expression and improves CBSC survival/retention, similar to gCTRP9. Moreover, CTRP9-281 stimulates VEGFA-rich exosome production by CBSC, exerting superior pro-angiogenic, anti-fibrotic, and cardioprotective actions.

4.
Anal Chim Acta ; 1156: 338362, 2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33781461

RESUMO

Reactive oxygen species (ROS) and reactive sulfur species (RSS) participate in many physiological activities and help maintaining the redox homeostasis in biological system. The complicated intrinsic connection between specific ROS/RSS needs to be further explored. Herein, a novel fluorescent probe (MB-NAP-N3) with longer emission wavelength has been rationally designed and synthesized based on the conjugation of the methylene blue moiety and the naphthalimide moiety for the detection of hypochlorous acid (HClO) and hydrogen sulfide (H2S). The dual-signal probe exhibits rapid turn-on fluorescence responses for individual and successive detection of H2S and HClO in green and red channels, respectively. Owning to its advantages such as fast response, good selectivity and high sensitivity, the probe was successfully applied to detect endogenous and exogenous HClO/H2S in living cells. Furthermore, the outstanding luminescence performance makes it suitable for the visualization of the in vivo interaction between the two analytes in zebrafish.

5.
ACS Sens ; 6(3): 1384-1391, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33721991

RESUMO

Cellular redox homeostasis is predominantly controlled by the ratio of thiols and disulfides, and reversible thiol-disulfide exchange reactions are fundamental of the biological redox regulation. However, due to the dynamic exchanges of thiols and disulfides, the detection, especially the in situ detection, of protein disulfides (PDS) is challenging. We employ the strategy, i.e., the increase of emission upon an environment-sensitive dye binding to proteins, to design PDS probes and discover a two-photon probe PDSTP590 (S6) that selectively recognizes PDS in live organisms. With the aid of the probe, we further disclose the elevation of PDS in brains of the mouse stroke model.

6.
Mol Plant ; 14(4): 541-543, 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33647479
7.
Oncoimmunology ; 10(1): 1865670, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33537171

RESUMO

Somatic mutations of STK11 or KEAP1 are associated with poor clinical outcomes for advanced non-small-cell lung cancer (aNSCLC) patients receiving immune checkpoint inhibitors (ICIs), chemotherapy, or targeted therapy. Which treatment regimens work better for STK11 or KEAP1 mutated (SKmut) aNSCLC patients is unknown. In this study, the efficacy of atezolizumab versus docetaxel in SKmut aNSCLC was compared. A total of 157 SKmut aNSCLC patients were identified from POPLAR and OAK trials, who were tested by blood-based FoundationOne next-generation sequencing assay. Detailed clinical data and genetic alterations were collected. Two independent cohorts were used for biomarker validation (n = 30 and 20, respectively). Median overall survival was 7.3 months (95% confidence interval [CI], 4.8 to 9.9) in the atezolizumab group versus 5.8 months (95% CI, 4.4 to 7.2) in the docetaxel group (adjusted hazard ratio [HR] for death, 0.70; 95% CI, 0.49 to 0.99; P = .042). Among atezolizumab-treated patients, objective response rate, disease control rate, and durable clinical benefit were higher when blood tumor mutation burden (bTMB) and PD-L1 being higher (biomarker 1, n = 61) or with FAT3 mutation-positive tumors (biomarker 2, n = 83) than otherwise. The interactions for survival between these two biomarkers and treatments were significant, which were further validated in two independent cohorts. In SKmut patients with aNSCLC, atezolizumab was associated with significantly longer overall survival in comparison to docetaxel. Having FAT3 mutation or high TMB and PD-L1 expression potentially predict favorable response in SKmut patients receiving atezolizumab.

9.
J Hazard Mater ; 413: 125305, 2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33611041

RESUMO

In this study, novel Fe3C-porous carbon composites (Fe3C-C) were prepared via the pyrolysis of Fe2O3 loaded MOF-74(Zn), which could integrate both strong adsorption properties and excellent peroxymonosulfate (PMS) activating performance for the removal of bisphenol A (BPA) in water. Results indicated that the composite obtained at 1000 °C (Fe3C-C1000) exhibited optimal catalytic capability. Specifically, 0.1 mM BPA could be completely removed by 0.1 g/L Fe3C-C1000 within 10 min after the adsorption enrichment. Afterwards, the mechanism of Fe3C-C/PMS system was unveiled based on quenching tests, electron spin resonance analysis, electrochemical analysis, PMS consumption detection and solvent exchange (H2O to D2O) test. The BPA degradation pathways were also analyzed through identifying its decomposition intermediates. Results showed that the Fe3C and porous carbon constituents could activate PMS via radical and non-radical mechanisms respectively, and BPA was readily degraded through both pathways. Additionally, it was found that the Fe3C-C1000/PMS system could maintain conspicuous catalytic performance in a variety of complicated water matrices with wide pH application range and long-time use stability. This study suggests a new insight for the design and development of novel catalyst which can be used for the removal of refractory organic contaminants with high concentrations in water media.

10.
Mol Genet Genomic Med ; : e1577, 2021 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-33620149

RESUMO

PURPOSE: Objective to summarize the clinical features and laboratory findings of 28 Chinese children with hereditary spherocytosis (HS), and analyze these mutations. METHOD: Collected and analyzed the clinical data of all children and their parents, and completed the relevant laboratory examinations of all children. Analyzed the sequence of related genes by second-generation sequencing technology, and verified the suspected mutations by Sanger sequencing method. Analyzed all biological information using the Single Nucleotide Polymorphism database, the 1000 Human Genome Project, and the Exosome Aggregation Consortium. RESULT: New mutations were detected in the HS coding region of 28 children. Among them, there were 13 cases (46.4%) with ANK1 mutation, 10 cases (35.7%) with SPTB mutation, three cases (10.7%) with SLC4A1 mutation, and two cases (7.2%) with SPTA1 mutation. All mutations cause amino acid changes in the coding gene, as well as subsequent changes in protein structure or loss of function. CONCLUSION: All the newly discovered gene coding region mutation sites detected are the suspected pathogenic causes of the 28 Chinese children. At the same time, the second-generation gene sequencing technology is an effective means to diagnose HS. Different mutation types and different mutation regions have no significant correlation with the severity of anemia. The novel gene mutation sites in 28 children studied in this paper have not yet been included in the human genome database, dbSNP (v138), or ExAC database. The new gene mutations found in HS children can provide a theoretical basis for further exploring the genetic causes of HS in Chinese children.

11.
Eye (Lond) ; 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33637966

RESUMO

OBJECTIVES: To evaluate the changes of retinal nerve fibre layer (RNFL) and ganglion cell layer/inner plexiform layer (GCL/IPL) with the severity of thyroid eye disease (TED). METHODS: One hundred and forty-five eyes of 75 patients with TED and 70 eyes of 35 healthy controls were included. The eyes with TED were divided into mild group (35 eyes), moderate-to-severe group (42 eyes) and DON group (68 eyes). The thickness of RNFL and GCL/IPL were measured by optic coherence tomography (OCT). Clinical activity score (CAS), best corrected visual acuity (BCVA), intraocular pressure (IOP), proptosis and mean deviation (MD) by Humphrey perimetry were assessed. RESULTS: The CAS had significant difference between the three groups (p < 0.001). The proptosis and IOP were significantly higher in DON group and moderate-to-severe group than mild group (p < 0.05). The MD and BCVA were significantly worse in DON group compared with mild group and moderate-to-severe group (p < 0.001). The mean GCL/IPL thickness was thinnest in DON group (p < 0.001). The mean RNFL thickness had significant difference between moderate-to-severe group and DON group (p = 0.036). The mean GCL/IPL thickness had a significant correlation with MD (r = 0.449, p < 0.001) and VA (r = -0.388, p < 0.001), whereas the mean RNFL thickness had no significant correlation with MD (p = 0.082) or VA (p = 0.226). CONCLUSIONS: Subclinical optic neuropathy might progress in the patients with moderate-to-severe TED. OCT measurements of GCL/IPL and RNFL are useful to detect the early changes of optic nerve. The thinning of GCL/IPL might be a strong suggestion for closer vision follow-up and earlier decompression surgery.

12.
Eye (Lond) ; 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33608640

RESUMO

BACKGROUND: Growing evidence supports an individualised approach rather than radical surgery for conjunctival melanoma (CM). This study aimed to compare the long-term outcome between individualised and conventional exenteration techniques. METHODS: Our study retrospectively recruited advanced CM (clinical T3 stage) patients treated with individualised (13 cases) or conventional (18 cases) exenteration from June 2014 to April 2019. The individualised approach preserved at least three quadrants of the orbit, and the conventional procedures removed at least one third of the orbital tissues. The medical records were collected and analyzed during April 2020, including demographics, tumour characteristics, surgical details, postoperative rehabilitation and tumour-related prognosis. RESULTS: The tumour basal diameter was statistically (P = 0.011) larger in the conventional group (23.3 ± 7.6 mm) than in the individualised group (15.4 ± 6.3 mm). More tissues were preserved in the individualised group, resulting in a shorter duration of wound healing (2.1 ± 0.6 vs. 3.6 ± 2.0 weeks, P = 0.018) and less incidence of hollow appearance (15% vs. 72%, P = 0.003) than the conventional group. After follow-up for 39.3 ± 17.3 months, a comparison of survival curves showed no significant differences (P = 0.638) between the two groups. The 1- and 2-year overall survival rates were estimated as 100% and 80.0% in the individualised group, and 93.8% and 72.5% in the conventional group, respectively. Low or mixed pigmentation was identified as the risk factor for tumour-related mortality based on multivariate regression analysis. CONCLUSIONS: The individualised approach to exenteration offers improved aesthetic results while still maximises the curable chance for advanced CM.

13.
J Orthop Surg Res ; 16(1): 150, 2021 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33610167

RESUMO

OBJECTIVE: We aimed to investigate the therapeutic effects of Moringa oleifera leaf extracts on osteogenic induction of rat bone marrow mesenchymal stem cells (BMSCs) following peroxidative damage and to explore the underlying mechanisms. METHODS: Conditioned medium was used to induce osteogenic differentiation of BMSCs, which were treated with H2O2, Moringa oleifera leaf extracts-containing serum, or the phosphatidyl inositol-3 kinase (PI3K) inhibitor wortmannin, alone or in combination. Cell viability was measured using the MTT assay. Cell cycle was assayed using flow cytometry. Expression levels of Akt, phosphorylated (p)Akt, Foxo1, and cleaved caspase-3 were analyzed using western blot analysis. The mRNA levels of osteogenesis-associated genes, including alkaline phosphatase (ALP), collagen І, osteopontin (OPN), and Runx2, were detected using qRT-PCR. Reactive oxygen species (ROS) and malondialdehyde (MDA) levels, as well as superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), and ALP activity were detected using commercially available kits. Osteogenic differentiation capability was determined using alizarin red staining. RESULTS: During osteogenic induction of rat BMSCs, H2O2 reduced cell viability and proliferation, inhibited osteogenesis, increased ROS and MDA levels, and decreased SOD and GSH-PX activity. H2O2 significantly reduced pAkt and Foxo1 expression, and increased cleaved caspase-3 levels in BMSCs. Additional treatments with Moringa oleifera leaf extracts partially reversed the H2O2-induced changes. Wortmannin partially attenuated the effects of Moringa oleifera leaf extracts on protein expression of Foxo1, pAkt, and cleaved caspase-3, as well as mRNA levels of osteogenesis-associated genes. CONCLUSION: Moringa oleifera leaf extracts ameliorate peroxidative damage and enhance osteogenic induction of rat BMSCs by activating the PI3K/Akt/Foxo1 pathway.

14.
Future Oncol ; 17(7): 795-805, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33541123

RESUMO

Background: A series of studies have demonstrated that NPAS2 plays a critical role in the development and progression of several cancers. However, the association between genetic variants in the NPAS2 gene and the clinical outcome of patients with non-small-cell lung cancer (NSCLC) has not been investigated. Methods: Six functional SNPs in NPAS2 were selected and genotyped using the Sequenom iPLEX genotyping system in a cohort of 484 Chinese NSCLC patients undergoing surgery. Multivariate Cox proportional hazards model were used for the prognosis analysis. Results: We found that SNP rs2305158 exhibited a significant association with overall survival of NSCLC patients in the dominant model (hazard ratio [HR]: 0.68; 95% CI: 0.49-0.95; p = 0.02). Lymph node metastasis was significantly associated with increased death risk (HR: 1.73; 95% CI: 1.24-2.40; p = 0.001) in patients with the homozygous wildtype (WW) genotype of rs2305158. However, no significant association was observed between them in patients carrying a heterozygous variant (WV) or homozygous variant (VV) genotype of rs2305158. Finally, in the joint and interaction analysis, the patients carrying homozygous wildtype (WW) genotype and lymph node metastasis from N1 to N3 conferred a significant increased effect on death (HR: 2.29; 95% CI: 1.40-3.76; p = 0.001). Conclusions: Our results suggest that NPAS2 polymorphisms may serve as an independent prognostic marker for NSCLC patients.

15.
Exp Eye Res ; 205: 108501, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33600811

RESUMO

The angiotensin-converting enzyme 2 (ACE2) receptor has been proved for SARS-CoV-2 cell entry after auxiliary cellular protease priming by transmembrane protease serine 2 (TMPRSS2), but the co-effect of this molecular mechanism was unknown. Here, single-cell sequencing was performed with human conjunctiva and the results have shown that ACE2 and TMPRSS2 were highly co-expressed in the goblet cells with genes involved in immunity process. This identification of conjunctival cell types which are permissive to virus entry would help to understand the process by which SARS-CoV-2 infection was established. These finding might be suggestive for COVID-19 control and protection.

16.
Nat Commun ; 12(1): 440, 2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33469052

RESUMO

The main challenges for programmed cell death 1(PD-1)/PD-1 ligand (PD-L1) checkpoint blockade lie in a lack of sufficient T cell infiltration, tumor immunosuppressive microenvironment, and the inadequate tumor accumulation and penetration of anti-PD-1/PD-L1 antibody. Resetting tumor-associated macrophages (TAMs) is a promising strategy to enhance T-cell antitumor immunity and ameliorate tumor immunosuppression. Here, mannose-modified macrophage-derived microparticles (Man-MPs) loading metformin (Met@Man-MPs) are developed to efficiently target to M2-like TAMs to repolarize into M1-like phenotype. Met@Man-MPs-reset TAMs remodel the tumor immune microenvironment by increasing the recruitment of CD8+ T cells into tumor tissues and decreasing immunosuppressive infiltration of myeloid-derived suppressor cells and regulatory T cells. More importantly, the collagen-degrading capacity of Man-MPs contributes to the infiltration of CD8+ T cells into tumor interiors and enhances tumor accumulation and penetration of anti-PD-1 antibody. These unique features of Met@Man-MPs contribute to boost anti-PD-1 antibody therapy, improving anticancer efficacy and long-term memory immunity after combination treatment. Our results support Met@Man-MPs as a potential drug to improve tumor resistance to anti-PD-1 therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Micropartículas Derivadas de Células/imunologia , Portadores de Fármacos/farmacologia , Neoplasias/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , Sinergismo Farmacológico , Feminino , Humanos , /uso terapêutico , Memória Imunológica , Masculino , Metformina/farmacologia , Metformina/uso terapêutico , Camundongos , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Células RAW 264.7 , Evasão Tumoral/efeitos dos fármacos , Evasão Tumoral/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , /imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Int J Mol Sci ; 22(2)2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33467535

RESUMO

Cell can integrate the caspase family and mammalian target of rapamycin (mTOR) signaling in response to cellular stress triggered by environment. It is necessary here to elucidate the direct response and interaction mechanism between the two signaling pathways in regulating cell survival and determining cell fate under cellular stress. Members of the caspase family are crucial regulators of inflammation, endoplasmic reticulum stress response and apoptosis. mTOR signaling is known to mediate cell growth, nutrition and metabolism. For instance, over-nutrition can cause the hyperactivation of mTOR signaling, which is associated with diabetes. Nutrition deprivation can inhibit mTOR signaling via SH3 domain-binding protein 4. It is striking that Ras GTPase-activating protein 1 is found to mediate cell survival in a caspase-dependent manner against increasing cellular stress, which describes a new model of apoptosis. The components of mTOR signaling-raptor can be cleaved by caspases to control cell growth. In addition, mTOR is identified to coordinate the defense process of the immune system by suppressing the vitality of caspase-1 or regulating other interferon regulatory factors. The present review discusses the roles of the caspase family or mTOR pathway against cellular stress and generalizes their interplay mechanism in cell fate determination.

18.
Invest New Drugs ; 2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33507454

RESUMO

Background The CXCR4 chemokine receptor promotes tumor survival through mechanisms that include suppressing antitumor immune responses. Mavorixafor (X4P-001) is an oral, selective, allosteric CXCR4 inhibitor that decreases the recruitment of immunosuppressive cells into the tumor microenvironment and increases activated cytotoxic Tcell infiltration. Methods Patients with metastatic clear cell renal cell carcinoma (ccRCC) unresponsive to nivolumab monotherapy received oral mavorixafor 400 mg daily plus 240 mg intravenous nivolumab every 2 weeks. Results Nine patients were enrolled, median age 65 years. At baseline 4 had progressive disease (PD) and 5 had stable disease (SD). One of 5 patients with SD at study entry on prior nivolumab monotherapy had a partial response (PR) on combination treatment; all 4 patients with PD at study entry had a best response of SD with the combination treatment (median duration: 6.7 months; range: 3.7-14.7). Four patients discontinued therapy due to treatment-related adverse events (AEs). Grade ≥ 3 drug-related AEs were elevated alanine and aspartate aminotransferase (2 patients each); and autoimmune hepatitis, chronic kidney disease, increased lipase, maculopapular rash, and mucosal inflammation (1 patient each). A robust increase in levels of chemokine (C-X-C motif) ligand 9 CXCL9 on mavorixafor appeared to correlate with clinical benefit. Conclusions The CXCR4 inhibition mediated by mavorixafor, in combination with PD-1 blockade to enhance antitumor immune responses in patients unresponsive to checkpoint inhibitor monotherapy, is worthy of further study. Mavorixafor and nivolumab combination therapy in patients with advanced ccRCC demonstrated potential antitumor activity and a manageable safety profile.Trial registration: ClinicalTrials.gov identifier: NCT02923531. Date of registration: October 04, 2016.

19.
Theranostics ; 11(4): 1937-1952, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33408790

RESUMO

Development of efficient therapeutic strategy to incorporate ultrasound (US)-triggered sonodynamic therapy (SDT) and ferroptosis is highly promising in cancer therapy. However, the SDT efficacy is severely limited by the hypoxia and high glutathione (GSH) in the tumor microenvironment, and ferroptosis is highly associated with reactive oxygen species (ROS) and GSH depletion. Methods: A manganese porphyrin-based metal-organic framework (Mn-MOF) was constructed as a nanosensitizer to self-supply oxygen (O2) and decrease GSH for enhanced SDT and ferroptosis. In vitro and in vivo analysis, including characterization, O2 generation, GSH depletion, ROS generation, lipid peroxidation, antitumor efficacy and tumor immune microenvironment were systematically evaluated. Results: Mn-MOF exhibited catalase-like and GSH decreasing activity in vitro. After efficient internalization into cancer cells, Mn-MOF persistently catalyzed tumor-overexpressed H2O2 to in-situ produce O2 to relieve tumor hypoxia and decrease GSH and GPX4, which facilitated the formation of ROS and ferroptosis to kill cancer cells upon US irradiation in hypoxic tumors. Thus, strong anticancer and anti-metastatic activity was found in H22 and 4T1 tumor-bearing mice after a single administration of Mn-MOF upon a single US irradiation. In addition, Mn-MOF showed strong antitumor immunity and improved immunosuppressive microenvironment upon US irradiation by increasing the numbers of activated CD8+ T cells and matured dendritic cells and decreaing the numbers of myeloid-derived suppressor cells in tumor tissues. Conclusions: Mn-MOF holds great potential for hypoxic cancer therapy.

20.
Biosci Rep ; 41(1)2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33350453

RESUMO

BACKGROUND: Bladder cancer is considered a malignant tumour characterised by great heterogeneity. Engrailed-2 may be a gene implicated in bladder cancer. Bioinformatics analysis found base pair complementation between microRNA-27b and engrailed-2. The present study aimed to investigate the reciprocal association between microRNA-27b and engrailed-2 in bladder cancer. METHODS: The microRNA-27b and the protein of engrailed-2 in the tissues and cells of the bladder were detected. The processes of apoptosis, proliferation, invasion, and migration of tumour cells were evaluated. The co-action between microRNA-27b and engrailed-2 was detected by a luciferase reporter system. Finally, the interaction between microRNA-27b and engrailed-2 was further verified in vivo. RESULTS: The study found that the expression level of microRNA-27b is lower in bladder cancer tissues and cells than that in neighbouring ordinary tissues, whereas the opposite outcome was observed regarding the expression level of engrailed-2. Furthermore, microRNA-27b expression level is not significantly linked to the age of patients with bladder cancer; however, it is significantly associated with the clinicopathological grade of bladder cancer. Notably, engrailed-2 is negatively regulated by microRNA-27b. Transfection with microRNA-27b was associated with a significant reduction in the activity of bladder cancer cells and promoted apoptosis, while engrailed-2 restoration effectively reversed the above effects of microRNA-27b on bladder cancer in vitro and in vivo. CONCLUSIONS: In conclusion, engrailed-2 is engaged in the development and process of bladder cancer through the negative mediation of microRNA-27b; additionally, microRNA-27b/engrailed-2 could form a signalling pathway with a significant effect on the process of bladder cancer.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...