RESUMO
Emerging evidence suggests that ferroptosis is involved in the pathogenesis of ulcerative colitis (UC). However, the key regulator of this process remains uncertain. In this study, we aimed to explore the roles of solute carrier (SLC) family 6 member 14 (SLC6A14) in regulating ferroptosis in UC. The expression of SLC6A14 was significantly increased and positively associated with that of prostaglandin-endoperoxide synthase 2 (PTGS2) in tissue samples from patients with UC. Moreover, a series of in vitro and in vivo experiments showed that SLC6A14 knockdown markedly suppressed ferroptosis. RNA sequencing revealed that SLC6A14 inhibited the expression of P21 (RAC1)-activated kinase 6 (PAK6) and that PAK6 knockdown abolished the effects of SLC6A14 on RAS-selective lethal 3 (RSL3)-induced ferroptosis in Caco-2 cells. Furthermore, chromatin immunoprecipitation (ChIP) and Western blot analysis demonstrated that SLC6A14 negatively regulated PAK6 expression in a CCAAT enhancer binding protein beta (C/EBPß)-dependent manner. Collectively, these findings indicate that SLC6A14 facilitates ferroptosis in UC by promoting C/EBPß expression and binding activity to inhibit PAK6 expression, suggesting that targeting SLC6A14-C/EBPß-PAK6 axis-mediated ferroptosis may be a promising therapeutic alternative for UC.
Assuntos
Colite Ulcerativa , Ferroptose , Humanos , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Colite Ulcerativa/genética , Ciclo-Oxigenase 2 , Células CACO-2 , Ferroptose/genética , Células Epiteliais/metabolismo , Quinases Ativadas por p21/genética , Quinases Ativadas por p21/metabolismo , Sistemas de Transporte de AminoácidosRESUMO
Fusarium head blight (FHB) is a destructive wheat disease worldwide and significantly affects grain yield and quality in wheat. To understand the genetic basis underlying type II FHB resistance in two elite wheat cultivars-Yangmai 4 (YM4) and Yangmai 5 (YM5)-quantitative trait loci (QTL) mapping was conducted in two recombinant inbred line (RIL) populations derived from the crosses of YM4 and YM5 with susceptible cultivar Yanzhan 1 (YZ1), respectively. A survey with markers linked to Fhb1, Fhb2, Fhb4, and Fhb5 in landrace Wangshuibai indicated the nonexistence of these known FHB resistance genes or QTL in YM4, YM5, and YZ1. One overlapped resistance QTL was identified in both RIL populations (namely, QFhb.Y4.2D/QFhb.Y5.2D) with a large effect on FHB resistance. One novel resistance QTL (QFhb.Y4.5A) mapped on chromosome 5A was detected only in the YM4/YZ1 population. The resistance alleles of both QFhb.Y4.2D/QFhb.Y5.2D and QFhb.Y4.5A did not increase the plant height and did not significantly affect the heading date and flowering date. Kompetitive allele-specific PCR markers for QFhb.Y4.2D/QFhb.Y5.2D and QFhb.Y4.5A had been developed to verify in an additional set of 244 geographically diverse cultivars or lines. Pyramiding of the two resistance alleles decreased the percentage of symptomatic spikelets by 51.77% relative to the cultivars or lines without these two resistance alleles. QFhb.Y4.2D/QFhb.Y5.2D and QFhb.Y4.5A were shown to be useful alternatives in FHB resistance breeding programs. The results will facilitate marker-assisted selection for introgression of the favorable alleles for improving FHB resistance in breeding programs.
Assuntos
Fusarium , Locos de Características Quantitativas , Locos de Características Quantitativas/genética , Mapeamento Cromossômico , Triticum/genética , Fusarium/genética , Doenças das Plantas/genética , Melhoramento VegetalRESUMO
INTRODUCTION: B7-H4 is overexpressed in colorectal cancer (CRC) and plays an important role in tumor growth and immunosuppression. However, the exact mechanism that regulates B7-H4 expression remains largely unknown. Here, we investigated whether protein kinase C δ (PKCδ) regulates the expression of B7-H4 in CRC. METHODS: By using immunohistochemical (IHC) and immunofluorescence (IF) staining, we analyzed the expression of B7-H4 and phospho-PKCδ (p-PKCδ) in 225 colorectal tumor samples and determined the clinical significance of the expression patterns. In vitro experiments were performed with the CRC cell lines HCT116 and SW620 to detect the effect of PKCδ activation on B7-H4 expression, and xenograft-bearing mice were treated with rottlerin to monitor the expression of B7-H4 and tumor metastasis. RESULTS: The B7-H4 expression level was significantly correlated with the p-PKCδ level (r = 0.378, P < 0.001) in tumor tissues. Coexpression of p-PKCδ and B7-H4 was significantly associated with moderate/poor differentiation (P = 0.024), lymph node metastasis (P = 0.001) and advanced Dukes' stage (P = 0.002). Western blot analysis showed that Phorbol-12-Myristate-13-Acetate (TPA) increased B7-H4 expression in a concentration-dependent manner and that rottlerin abrogated the TPA-induced increase in B7-H4 expression. The protein levels of B7-H4 and p-STAT3 were significantly reduced by a PKCδ-specific siRNA. Moreover, the STAT3 inhibitor cryptotanshinone significantly decreased the B7-H4 protein level in CRC cells. Knockdown of B7-H4 or PKCδ suppressed cell migration and motility. Rottlerin also inhibited B7-H4 expression and tumor metastasis in vivo. CONCLUSION: The B7-H4 expression level is significantly correlated with the p-PKCδ level and tumor metastasis in CRC samples. B7-H4 expression is upregulated by STAT3 activation via PKCδ and plays roles in PKCδ-induced cancer cell motility and metastasis, suggesting that the PKCδ/STAT3/B7-H4 axis may be a potential therapeutic target for CRC.
RESUMO
Long noncoding RNAs (lncRNAs) have been investigated in multiple human cancers including gastric cancer (GC). Our research aims to explore the role of H19 in aerobic glycolysis, proliferation, and immune escape of GC cells. The expression of H19 in GC samples was analyzed using Gene Expression Profiling Interactive Analysis, Gene Expression Omnibus data, and real-time quantitative PCR analysis. Relative quantification of glucose consumption and lactate production from cell supernatant were applied to assess the aerobic glycolysis of GC cells. Subcellular fractionation, luciferase reporter, and western blot assays certified the binding between genes. Cell Counting Kit-8 and colony formation assays were used to determine GC cell proliferation. Flow cytometry, ELISA, and real-time quantitative PCR assays were applied to analyze the immunosuppressive effect of H19. H19 was highly expressed in samples of patients with GC, and associated with tumor growth in vivo. H19 knockdown suppressed glucose consumption, lactate production, and proliferation of GC cells by regulating the microRNA (miR)-519d-3p/lactate dehydrogenase A (LDHA) axis. Both miR-519d-3p depletion and LDHA overexpression could reverse the H19 knockdown-induced decrease in aerobic glycolysis and proliferation. Moreover, conditioned medium from stable knockdown H19 GC cells modulated the activity of immune cells including γδT cells, Jurkat cells, and tumor-associated macrophages in a miR-519d-3p/LDHA/lactate axis-dependent manner. The H19/miR-519d-3p/LDHA axis mainly contributed to aerobic glycolysis, proliferation, and immune escape of GC cells.
Assuntos
Proliferação de Células , L-Lactato Desidrogenase/metabolismo , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Neoplasias Gástricas/patologia , Evasão Tumoral , Efeito Warburg em Oncologia , Animais , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , L-Lactato Desidrogenase/genética , Camundongos , MicroRNAs/genética , RNA Longo não Codificante/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/metabolismoRESUMO
Immunotherapy based on γδT cells has limited efficiency in solid tumors, including colon cancer (CC). The immune evasion of tumor cells may be the main cause of the difficulties of γδT cell-based treatment. In the present study, we explored whether and how B7-H3 regulates the resistance of CC cells to the cytotoxicity of Vγ9Vδ2 (Vδ2) T cells. We observed that B7-H3 overexpression promoted, while B7-H3 knockdown inhibited, CC cell resistance to the killing effect of Vδ2 T cells in vitro and in vivo. Mechanistically, we showed that B7-H3-mediated CC cell resistance to the cytotoxicity of Vδ2 T cells involved a molecular pathway comprising STAT3 activation and decreased ULBP2 expression. ULBP2 blockade or knockdown abolished the B7-H3 silencing-induced increase in the cytotoxicity of Vδ2 T cells to CC cells. Furthermore, cryptotanshinone, a STAT3 phosphorylation inhibitor, reversed the B7-H3 overexpression-induced decrease in ULBP2 expression and attenuated the killing effect of Vδ2 T cells on CC cells. Moreover, there was a negative correlation between the expression of B7-H3 and ULBP2 in the tumor tissues of CC patients. Our results suggest that the B7-H3-mediated STAT3/ULBP2 axis may be a potential candidate target for improving the efficiency of γδT cell-based immunotherapy in CC.
Assuntos
Antígenos B7/metabolismo , Vacinas Anticâncer/imunologia , Neoplasias do Colo/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Fator de Transcrição STAT3/metabolismo , Linfócitos T/metabolismo , Animais , Antígenos B7/genética , Neoplasias do Colo/terapia , Citotoxicidade Imunológica , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Técnicas de Silenciamento de Genes , Células HCT116 , Xenoenxertos , Humanos , Imunoterapia Adotiva , Peptídeos e Proteínas de Sinalização Intercelular/genética , Camundongos , Camundongos SCID , Receptores de Antígenos de Linfócitos T gama-delta/genética , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Transdução de Sinais , Linfócitos T/imunologia , Linfócitos T/transplante , Evasão TumoralRESUMO
Overwork is a common phenomenon worldwide. Although previous studies have found that long working hours can cause physical and mental health problems in employees, the nature of the relationship between working hours and job satisfaction remains little understood. We have theorised that there is a curvilinear association between working hours and job satisfaction, and tested this hypothesis. A total of 771 adult Chinese employees submitted self-reported measures of working hours, job satisfaction, and job autonomy. The results show that working hours have an inverted U-shaped association with job satisfaction. Work scheduling autonomy and decision-making autonomy moderate this relationship. Here we present our data and discuss their theoretical and practical implications. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12144-021-02463-3.
RESUMO
BACKGROUND: Fusarium head blight (FHB), primarily caused by Fusarium graminearum, is a major threat to wheat production and food security worldwide. Breeding stably and durably resistant cultivars is the most effective approach for managing and controlling the disease. The success of FHB resistance breeding relies on identification of an effective resistant germplasm. We conducted a genome-wide association study (GWAS) using the high-density wheat 90 K single nucleotide polymorphism (SNP) assays to better understand the genetic basis of FHB resistance in natural population and identify associated molecular markers. RESULTS: The resistance to FHB fungal spread along the rachis (Type II resistance) was evaluated on 171 wheat cultivars in the 2016-2017 (abbr. as 2017) and 2017-2018 (abbr. as 2018) growing seasons. Using Illumina Infinum iSelect 90 K SNP genotyping data, a genome-wide association study (GWAS) identified 26 loci (88 marker-trait associations), which explained 6.65-14.18% of the phenotypic variances. The associated loci distributed across all chromosomes except 2D, 6A, 6D and 7D, with those on chromosomes 1B, 4A, 5D and 7A being detected in both years. New loci for Type II resistance were found on syntenic genomic regions of chromsome 4AL (QFhb-4AL, 621.85-622.24 Mb) and chromosome 5DL (QFhb-5DL, 546.09-547.27 Mb) which showed high collinearity in gene content and order. SNP markers wsnp_JD_c4438_5568170 and wsnp_CAP11_c209_198467 of 5D, reported previously linked to a soil-borne wheat mosaic virus (SBWMV) resistance gene, were also associated with FHB resistance in this study. CONCLUSION: The syntenic FHB resistant loci and associated SNP markers identified in this study are valuable for FHB resistance breeding via marker-assisted selection.
Assuntos
Mapeamento Cromossômico , Cromossomos de Plantas/genética , Resistência à Doença , Fusarium/fisiologia , Doenças das Plantas/genética , Triticum/genética , Estudo de Associação Genômica Ampla , Doenças das Plantas/microbiologia , Sintenia , Triticum/microbiologiaRESUMO
Wheat yellow mosaic virus (WYMV) has spread rapidly and causes serious yield losses in the major wheat-growing areas in China. Because it is vectored by the fungus-like organism Polymyxa graminis that survives for long periods in soil, it is difficult to eliminate by conventional crop management or fungicides. There is also only limited resistance in commercial cultivars. In this research, fourteen independent transgenic events were obtained by co-transformation with the antisense NIb8 gene (the NIb replicase of WYMV) and a selectable gene bar. Four original transgenic lines (N12, N13, N14 and N15) and an offspring line (N12-1) showed high and durable resistance to WYMV in the field. Four resistant lines were shown to have segregated and only contain NIb8 (without bar) by PCR and herbicide resistance testing in the later generations. Line N12-1 showed broad-spectrum resistance to WYMV isolates from different sites in China. After growing in the infested soil, WYMV could not be detected by tissue printing and Western blot assays of transgenic wheat. The grain yield of transgenic wheat was about 10% greater than the wild-type susceptible control. Northern blot and small RNA deep sequencing analyses showed that there was no accumulation of small interfering RNAs targeting the NIb8 gene in transgenic wheat plants, suggesting that transgene RNA silencing, a common mechanism of virus-derived disease resistance, is not involved in the process of WYMV resistance. This durable and broad-spectrum resistance to WYMV in transgenic wheat will be useful for alleviating the damage caused by WYMV.
Assuntos
Agricultura , RNA Polimerases Dirigidas por DNA/genética , Resistência à Doença/genética , Doenças das Plantas/imunologia , Potyviridae/genética , RNA Antissenso/genética , Triticum/virologia , Segregação de Cromossomos , Cruzamentos Genéticos , Genes Virais , Resistência a Herbicidas/genética , Doenças das Plantas/virologia , Plantas Geneticamente Modificadas , Reação em Cadeia da Polimerase , RNA Interferente Pequeno/metabolismo , Transgenes , Triticum/genética , Triticum/imunologiaRESUMO
The rotational and vibrational dynamics of molecules in copper sulfate pentahydrate crystal are investigated with terahertz dielectric spectra. It is shown that the relaxation-like dielectric dispersion in the low frequency region is related to the reorientation of water molecules under the driving of terahertz electric field, whereas the resonant dispersion can be ascribed to lattice vibration. It is also found that, due to the hydrogen-bond effect, the vibrational mode at about 1.83 THz along [-111] direction softens with decreasing temperature, that is, the crystal expands in this direction when cooled. On the contrary, the mode hardens in the direction perpendicular to [-111] during the cooling process. This contributes to the further understanding of the molecular structure and bonding features of hydrate crystals.
RESUMO
BACKGROUND: Genetic background plays an important role in the occurrence and development of gastric cancer (GC). With the application of genome-wide association study (GWAS), an increasing number of tumor susceptibility genes in gastric cancer have been discovered. While little of them can be further applicated in clinical diagnosis and treatment due to the lack of in-depth analysis. METHODS: A GWAS of peripheral blood leukocytes from GC patients was performed to identify and obtain genetic background data. In combination with a clinical investigation, key SNP mutations and mutated genes were screened. Via in vitro and in vivo experiments, the function of the mutated gene was verified in GC. Via a combination of molecular function studies and amino acid network analysis, co-mutations were discovered and further identified as potential therapeutic targets. RESULTS: At the genetic level, the G allele of rs104886038 in DHCR7 was a protective factor identified by the GWAS. Clinical investigation showed that patients with the rs104886038 A/G genotype, age ≥ 60, smoking ≥ 10 cigarettes/day, heavy drinking and H. pylori infection were independent risk factors for GC, with odds ratios of 12.33 (95% CI, 2.10 ~ 72.54), 20.42 (95% CI, 2.46 ~ 169.83), and 11.39 (95% CI, 1.82 ~ 71.21), respectively. Then molecular function studies indicated that DHCR7 regulated cell proliferation, migration, and invasion as well as apoptosis resistance via cellular cholesterol biosynthesis pathway. Further amino acid network analysis based on the predicted structure of DHCR7 and experimental verification indicated that rs104886035 and rs104886038 co-mutation reduced the stability of DHCR7 and induced its degradation. DHCR7 mutation suppressed the malignant behaviour of GC cells and induced apoptosis via inhibition on cell cholesterol biosynthesis. CONCLUSION: In this work, we provided a comprehensive multi-dimensional analysis strategy which can be applied to in-depth exploration of GWAS data. DHCR7 and its mutation sites identified by this strategy are potential theratic targets of GC via inhibition of cholesterol biosynthesis.
Assuntos
Oxirredutases atuantes sobre Doadores de Grupo CH-CH , Neoplasias Gástricas , Humanos , Aminoácidos/genética , Colesterol/metabolismo , Estudo de Associação Genômica Ampla , Mutação , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Neoplasias Gástricas/genéticaRESUMO
Research evidence shows that effective nutritional intervention could prevent or reduce intestinal inflammatory injury in newborn infants. Iron free lactoferrin (apo-LF), one of the main types of lactoferrin (LF), is a bioactive protein in milk that plays a vital role in maintaining intestinal health. The potential mechanism by which apo-LF modulates intestinal inflammation is, however, still unclear. In the study we first explored key genes and pathways in vitro by transcriptome date analysis and then validated them in vivo to reveal the underlying molecular mechanism. The results showed that apo-LF pretreatment effectively inhibited lipopolysaccharide (LPS)-induced primary intestinal epithelial cells (IECs) inflammation in the co-culture system (primary IECs and immune cells), which was specifically manifested as the reduction of the concentration of TNF-α, IL-6 and IL-1ß and increased the concentration of IFN-γ. In addition, transcriptome data analysis revealed that the key pathway for apo-LF to exert anti-inflammatory effects was the NF-κB/PPAR signaling pathway. Further validation was performed using western blotting in colonic tissues of young mice and it was found that the major proteins of NF-κB signaling pathway (NF-κB, TNF-α and IL-1ß) were inhibited by apo-LF and the target proteins of PPAR signaling pathway (PPAR-γ and PFKFB3) were activated by apo-LF. Taken together, this suggests that apo-LF has a protective effect against LPS-induced intestinal inflammatory injury via modulating the NF-κB/PPAR signaling pathway, which provides new insights for further anti-inflammatory study of apo-LF.
RESUMO
The effect of the curing temperature (T c) on the properties of PBO aerogel was investigated in this paper. The compressive strength of PBO aerogel prepared was much higher than that of PBO aerogel of the same density in other kinds of literature. With the robust F-type polybenzoxazine (PBO) aerogels with ultra-high Young's modulus (733.7 MPa at 0.48 g/cm3 and 1070 MPa at 0.57 g/cm3), excellent properties were obtained through a facile and scalable room-temperature HCl-catalyzed sol-gel method, followed by the ambient pressure drying technique. It is found that T c plays a vital role in the polymerization process and the evolution of the microstructure of the 3D porous PBO network, where the necks between the nanoparticles become thick and strong when T c is up to 150 °C, resulting in a pearl necklace-to-worm transformation in the micro-structure and significant growth in mechanical properties, but if T c is higher than 180 °C, the pore volume and specific surface area will decrease sharply. Moreover, all synthetic PBO aerogels here possessed inherent flame retardancy and a high residual char rate in the volume density (0.32-0.57 g/cm3). These properties make the F-type PBO aerogels a candidate material in aerospace applications or other fields.
RESUMO
The purpose of this study is to address the effect and mechanism of stromal cellderived factor1 (SDF1)α/chemokine (CXC motif) receptor 4 (CXCR4) signaling on capillary tube formation of human retinal vascular endothelial cells (HRECs). The expression of CXCR4 in HRECs was quantified by reverse transcription (RTPCR) and western blotting. The effects of SDF1α/CXCR4 signaling in capillary tube formation and migration of HRECs was examined using threedimensional Matrigel assay and wound scratching assay respectively in vitro. Cell proliferation of HRECs was examined using cell counting kit (CCK)8 assay in the presence of different concentrations of SDF1α protein. The effect of SDF1α/CXCR4 signaling in HREC expression of VEGF, basic fibroblast growth factor (bFGF), IL8 and intercellular cell adhesion molecule (ICAM)1 was examined using RTPCR and western blotting. RTPCR and western blot analysis revealed CXCR4 was expressed in HRECs. The number of intact capillary tubes formed by HRECs in the presence of SDF1α was markedly more compared with a PBS treated control group. However, it was reduced with treatment with an CXCR4 antagonist. Wound scratching assay showed a significant increase in the number of migrated HRECs under SDF1α stimulation and the number was reduced with treatment with an CXCR4 antagonist. RTPCR and western blotting showed that SDF1α significantly promoted VEGF, bFGF, IL8 and ICAM1 expression in HRECs. The proliferation of HRECs in the presence of SDF1α was promoted in a dosagedependent manner. SDF1α/CXCR4 signaling can increase HREC capillary tube formation through promoting HREC migration, proliferation and expression of VEGF, bFGF, IL8 and ICAM1.
Assuntos
Quimiocina CXCL12 , Células Endoteliais , Movimento Celular , Proliferação de Células , Células Cultivadas , Quimiocina CXCL12/metabolismo , Células Endoteliais/metabolismo , Humanos , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-8/metabolismo , Sistema de Sinalização das MAP Quinases , Fosfatidilinositol 3-Quinases/metabolismo , Receptores CXCR4/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Weak-gluten wheat is the main raw material for crisp and soft foods such as cookies, cakes, and steamed breads in China. However, it remains challenging to find an appropriate fertilization regime to balance the yield and quality of wheat for special uses (such as cookie making). Here, four nitrogen (N) fertilizer treatments were compared in terms of effects on the yield-, grain-, flour-, and dough-related traits and cookie quality of nine weak-gluten wheat varieties. Compared with other treatments, the treatment M (which had 180 kg ha-1 N fertilizers with basal fertilizer:tillering fertilizer:jointing fertilizer = 5:1:4) was a superior fertilization strategy as it could ensure a higher yield (4.46 kg block-1) and proper traits related to cookie quality. Moreover, environmental conditions and wheat genotypes exhibited significant effects on many quality-related traits. The quality of Chinese crisp biscuits showed a significant association with unit weight, redness, and solvent retention capacity in lactic acid solution, while that of American cookies was influenced by thousand-grain weight, hardness, rate of yield flour, and formation time as indicated by the Mantel test. Additional Pearson correlation analysis demonstrated that thousand-grain weight, hardness, and rate of yield flour can affect the quality of American cookies. Our findings demonstrate that it is necessary to comprehensively consider local conditions, variety selection, and optimal fertilization to achieve high-quality weak-gluten wheat for cookie making.
RESUMO
Patients with metastatic cancer refractory to standard systemic therapies have a poor prognosis and few therapeutic options. Radiotherapy can shape the tumor microenvironment (TME) by inducing immunogenic cell death and promoting tumor recognition by natural killer cells and T lymphocytes. Granulocyte macrophage-colony stimulating factor (GM-CSF) was known to promote dendric cell maturation and function, and might also induce the macrophage polarization with anti-tumor capabilities. A phase II trial (ChiCTR1900026175) was conducted to assess the clinical efficacy and safety of radiotherapy, PD-1 inhibitor and GM-CSF (PRaG regimen). This trial was registered at http://www.chictr.org.cn/index.aspx. A PRaG cycle consisted of 3 fractions of 5 or 8 Gy delivered for one metastatic lesion from day 1, followed by 200 µg subcutaneous injection of GM-CSF once daily for 2 weeks, and intravenous infusion of PD-1 inhibitor once within one week after completion of radiotherapy. The PRaG regimen was repeated every 21 days for at least two cycles. Once the PRaG therapy was completed, the patient continued PD-1 inhibitor monotherapy until confirmed disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). A total of 54 patients were enrolled with a median follow-up time of 16.4 months. The ORR was 16.7%, and the disease control rate was 46.3% in intent-to-treat patients. Median progression-free survival was 4.0 months (95% confidence interval [CI], 3.3 to 4.8), and median overall survival was 10.5 months (95% CI, 8.7 to 12.2). Grade 3 treatment-related adverse events occurred in five patients (10.0%) and grade 4 in one patient (2.0%). Therefore, the PRaG regimen was well tolerated with acceptable toxicity and may represent a promising salvage treatment for patients with chemotherapy-refractory solid tumors. It is likely that PRaG acts via heating upthe TME with radiotherapy and GM-CSF, which was further boosted by PD-1 inhibitors.
Assuntos
Quimiorradioterapia , Segunda Neoplasia Primária , Quimiorradioterapia/efeitos adversos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Segunda Neoplasia Primária/terapia , Terapia de Salvação , Resultado do Tratamento , Microambiente TumoralRESUMO
A retrospective cohort study including 112 patients suffering from esophageal squamous cell carcinoma (ESCC) was performed to investigate the expression of B7-H4 in ESCC and determine its association with patient's clinicopathological parameters and survival. Expression levels of B7-H4 on tumor cells and densities of tumor infiltrating lymphocytes (TILs) in the surgical specimens of ESCC tissues were characterized using immunohistochemical assays. Uni- and multivariate analyses were performed to evaluate the prognostic value of B7-H4 expression levels and densities of TILs in tumor sections. Positive B7-H4 immunostaining was observed in 107 of 112 (95.5%) of ESCC tissue sections. We further divided all patients into two major subgroups, a lower B7-H4 expression group with 46 patients and a higher B7-H4 expression group with 66 patients. We found that expression levels of B7-H4 on tumor cells were significantly correlated with patient's gender (P = 0.0288), distant metastasis (P = 0.0500), and TNM stage (P = 0.0258). Moreover, tumor cell B7-H4 expression was inversely correlated with densities of CD3(+) T cells in tumor nest (P = 0.0424) and CD8(+) T cells in tumor stroma (P = 0.0229). The overall survival rate of the patients with higher B7-H4 expression was significantly worse than that of the patients with lower B7-H4 expression (P = 0.0105, Hazard Ratio: 1.854, 95%CI:1.152-2.902). Markers of cell-mediated immune responses such as CD3, CD8, and T-bet were associated with better patient survival. The present study demonstrated that B7-H4 expression in human ESCC is associated with cancer progression, reduced tumor immunosurveillance and worse patient outcomes. B7-H4 can serve as a novel prognostic predictor for human ESCC and a potential target for the immune therapy against this malignancy.
Assuntos
Antígeno B7-1/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidade , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/mortalidade , Linfócitos do Interstício Tumoral/patologia , Animais , Progressão da Doença , Feminino , Humanos , Técnicas Imunoenzimáticas , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Microambiente Tumoral , Inibidor 1 da Ativação de Células T com Domínio V-SetRESUMO
Aflatoxin M1 (AFM1) is the only mycotoxin with maximum residue limit in milk, which may result in serious human diseases. On the contrary, lactoferrin (Lf) is an active protein with multiple functions. Studies have confirmed that Lf has a powerful potential to protect the intestines, but the influence of Lf on mycotoxins is not clear. This study aims to explore whether Lf can protect the cytotoxicity induced by AFM1, and determine the underlying mechanisms in human normal colonic epithelial NCM460 cells. The results indicated that AFM1 decreased the cell viability, and increased the levels of apoptosis and autophagy of NCM460 cells. Lf can alleviate the cytotoxicity induced by AFM1 through enhancing cell viability, significantly down-regulated the expression of apoptotic genes and proteins (BAX, caspase3, caspase9, caspase3, and caspase9), and regulated the gene and protein expression of autophagy factors (Atg5, Atg7, Atg12, Beclin1, ULK1, ULK2, LC3, and p62). Furthermore, interference of the key gene Atg5 of autophagy can reduce AFM1-induced apoptosis, which is consistent with the role of Lf, implying that Lf may protect AFM1-induced intestinal injury by inhibiting excessive autophagy-mediated apoptosis. Taken together, our data indicated that Lf has a mitigating effect on apoptosis induced by AFM1 through the autophagy pathway.
RESUMO
The aim of the present study was to investigate the role of plateletderived growth factor (PDGF)BB/PDGF receptor (R)ß signaling in an experimental murine corneal neovascularization (CrNV) model. Experimental CrNV was induced by alkali injury. The intracorneal expression of PDGFBB was examined using immunohistochemistry. The effect of PDGFBB on CrNV was evaluated using immunofluorescence staining. The expression levels of PDGFRß in human retinal endothelial cells (HRECs) under normal conditions or following cobalt chloride treatment, which induced hypoxic conditions, was assessed using reverse transcriptionquantitative PCR. The effect of exogenous treatment of PDGFBB on the proliferation, migration and tube formation of HRECs under normoxic or hypoxic conditions was evaluated in vitro using Cell Counting Kit8, wound healing and 3D Matrigel capillary tube formation assays, respectively. The results indicated that the intracorneal expression levels of the proteins of PDGFBB and PDGFRß were detectable on days 2 and 7 following alkali injury. The treatment with neutralizing antiPDGFBB antibody resulted in significant inhibition of CrNV. The intracorneal expression levels of vascular endothelial growth factor A, matrix metallopeptidase (MMP)2 and MMP9 proteins were downregulated, while the expression levels of thrombospondin (TSP)1, TSP2, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)1 and ADAMTS2 were upregulated significantly in mice treated with antiPDGFBB antibody. The expression levels of PDGFRß were upregulated in HRECs under hypoxic conditions compared with those noted under normoxic conditions. Recombinant human PDGFBB promoted the proliferation, migration and tube formation of HRECs under hypoxic conditions. The data indicated that PDGFBB/PDGFRß signaling was involved in CrNV and that it promoted endothelial cell proliferation, migration and tube formation. The proangiogenic effects of this pathway may be mediated via the induction of proangiogenic cytokine secretion and the suppression of antiangiogenic cytokine secretion.
Assuntos
Álcalis/toxicidade , Becaplermina/metabolismo , Lesões da Córnea/induzido quimicamente , Neovascularização da Córnea/metabolismo , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Animais , Linhagem Celular , Lesões da Córnea/metabolismo , Lesões da Córnea/patologia , Neovascularização da Córnea/induzido quimicamente , Neovascularização da Córnea/patologia , Humanos , Camundongos , Transdução de Sinais/efeitos dos fármacosRESUMO
Ulcerative colitis (UC) is a relapsing and remitting inflammatory bowel disease (IBD), but current conventional drugs lack efficacy. Astragalus polysaccharide (APS) is an active ingredient of Astragalus membranaceus and has been shown to ameliorate experimental colitis. In the present study, we aimed to investigate how APS affects the ferroptosis of intestinal epithelial cells in dextran sulfate sodium (DSS)-induced experimental colitis in mice. Our data showed that APS administration attenuated total weight loss, colon length shortening, disease activity index (DAI) scores, histological damage, and the expression of inflammatory cytokines in the colon of DSS-challenged mice. Moreover, we observed that treatment with APS obviously inhibited ferroptosis in both DSS-challenged mice and RSL3-stimulated Caco-2 cells, as indicated by the decrease in the expression of ferroptosis-associated genes (PTGS2, FTH, and FTL) and the levels of surrogate ferroptosis markers (MDA, GSH, and iron load). Mechanistically, the inhibitory effects of APS on ferroptosis in DSS-challenged mice and RSL3-stimulated Caco-2 cells were associated with the NRF2/HO-1 pathway. Collectively, our findings identify a new role of APS in preventing ferroptosis in a murine model of experimental colitis and human Caco-2 cells via inhibiting NRF2/HO-1 pathway.
Assuntos
Fator 2 Relacionado a NF-E2RESUMO
Emerging evidence suggests that cellular senescence induced by chemotherapy has been recognized as a new weapon for cancer therapy. This study aimed to research novel functions of B7-H3 in cellular senescence induced by a low dose of doxorubicin (DOX) in colorectal cancer (CRC). Here, our results demonstrated that B7-H3 knockdown promoted, while B7-H3 overexpression inhibited, DOX-induced cellular senescence. B7-H3 knockdown dramatically enhanced the growth arrest of CRC cells after low-dose DOX treatment, but B7-H3 overexpression had the opposite effect. By RNA-seq analysis and western blot, we showed that B7-H3 prevented cellular senescence and growth arrest through the AKT/TM4SF1/SIRT1 pathway. Blocking the AKT/TM4SF1/SIRT1 pathway dramatically reversed B7-H3-induced resistance to cellular senescence. More importantly, B7-H3 inhibited DOX-induced cellular senescence of CRC cells in vivo. Therefore, targeting B7-H3 or the B7-H3/AKT/TM4SF1/SIRT1 pathway might be a new strategy for promoting cellular senescence-like growth arrest during drug treatment in CRC.