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1.
Chemosphere ; 288(Pt 1): 132509, 2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34627811

RESUMO

Herein, polypyrrole/titanium oxide/reduced graphene oxide (PTi/r-GO) electrodes were prepared and successfully applied for the photoelectrocatalytic (PEC) degradation of methyl orange (MO) under visible light. Polypyrrole-TiO2 composites rich in p-n heterojunctions were first prepared, then modified with r-GO to improve the electrical conductivity and facilitate charge separation under visible light irradiation. The obtained PTi/r-GO composites were then deposited onto a titanium mesh, which served as the working electrode in PEC experiments. A MO removal efficiency of 93% was achieved in 50 min using PTi/r-GO electrode under PEC conditions (Xe lamp, λ > 420 nm, bias of 0.6 V, 0.1 M Na2SO4 electrolyte), which was far higher than MO removal efficiencies under electrocatalytic oxidation (22%) or photocatalytic oxidation (47%) conditions. This confirmed that excellent activity of the PTi/r-GO electrode under PEC conditions was due to a combination of electrochemical and photocatalytic oxidation processes (involving •OH and •O2- generation). Further, PTi/r-GO was very stable under the applied PEC conditions, with the MO removal efficiency remaining >90% after five cycles. PEC degradation pathways for MO on PTi/r-GO were explored, with a number of key intermediates in the MO mineralization process identified. Results demonstrate that PEC electrodes combining p-type polypyrrole, n-type TiO2 and rGO are very effective in the treatment of hazardous organic compounds in wastewater.

2.
Sci Rep ; 11(1): 20077, 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34635713

RESUMO

Cardiac remodeling is a physiological adaptation to aerobic exercise and which is characterized by increases in ventricular volume and the number of cardiomyocytes. The mitochondrial derived peptide MOTS-c functions as an important regulator in physical capacity and performance. Exercise elevates levels of endogenous MOTS-c in circulation and in myocardium, while MOTS-c can significantly enhance exercise capacity. However, the effects of aerobic exercise combined with MOTS-c on cardiac structure and function are unclear. We used pressure-volume conductance catheter technique to examine cardiac function in exercised rats with and without treatment with MOTS-c. Surprisingly, MOTS-c improved myocardial mechanical efficiency, enhanced cardiac systolic function, and had a tendency to improve the diastolic function. The findings suggest that using exercise supplements could be used to modulate the cardiovascular benefits of athletic training.

3.
Biochem Biophys Res Commun ; 581: 12-19, 2021 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-34653673

RESUMO

CD8+ T cells play a critical role during adaptive immune response, which often change locations and expand or contract in numbers under different states. In the past, many attempts to develop CD8+T cells that express luciferase in vivo have involved the use of viral transduction, which has drawbacks of hardly tracked via detection of luciferase signal in untouched natural states. Here, we generate a transgenic mouse model via CRISPR-mediated genome editing, C57BL/6-CD8aem(IRES-AkaLuci-2A-EGFP) knock-in mice(CD8a-Aka mice), as a novel tool for non-invasive imaging of CD8+ T cells, which expressed a highly sensitive luciferase-Akaluciferase. Our study offers a convenient and robust tool for understanding fundamental CD8+ T cell biology in experimental applications and preclinical translational studies.

4.
Front Mol Neurosci ; 14: 730604, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34630036

RESUMO

As mitochondrial dysfunction has increasingly been implicated in neurological diseases, much of the investigation focuses on the response of the mitochondria. It appears that mitochondria can respond to external stimuli speedy fast, in seconds. Understanding how mitochondria sense the signal and communicate with cytosolic pathways are keys to understand mitochondrial regulation in diseases or in response to trauma. It was not until recently that a novel mitochondrial protein, phosphoglycerate mutase family member 5 (PGAM5) has emerged to be a new regulator of mitochondrial homeostasis. Although controversial results reveal beneficial as well as detrimental roles of PGAM5 in cancers, these findings also suggest PGAM5 may have diverse regulation on cellular physiology. Roles of PGAM5 in neuronal tissues remain to be uncovered. This review discusses current knowledge of PGAM5 in neurological diseases and provides future perspectives.

5.
Front Genet ; 12: 739520, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34630529

RESUMO

Background: Lung adenocarcinoma is one of the most common malignant tumors of the respiratory system, ranking first in morbidity and mortality among all cancers. This study aims to establish a ferroptosis-related gene-based prognostic model to investigate the potential prognosis of lung adenocarcinoma. Methods: We obtained gene expression data with matching clinical data of lung adenocarcinoma from the The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The ferroptosis-related genes (FRGs) were downloaded from three subgroups in the ferroptosis database. Using gene expression differential analysis, univariate Cox regression, and LASSO regression analysis, seven FRGs with prognostic significance were identified. The result of multivariate Cox analysis was utilized to calculate regression coefficients and establish a risk-score formula that divided patients with lung adenocarcinoma into high-risk and low-risk groups. The TCGA results were validated using GEO data sets. Then we observed that patients divided in the low-risk group lived longer than the overall survival (OS) of the other. Then we developed a novel nomogram including age, gender, clinical stage, TNM stage, and risk score. Results: The areas under the curves (AUCs) for 3- and 5-years OS predicted by the model were 0.823 and 0.852, respectively. Calibration plots and decision curve analysis also confirmed the excellent predictive performance of the model. Subsequently, gene function enrichment analysis revealed that the identified FRGs are important in DNA replication, cell cycle regulation, cell adhesion, chromosomal mutation, oxidative phosphorylation, P53 signaling pathway, and proteasome processes. Conclusions: Our results verified the prognostic significance of FRGs in patients with lung adenocarcinoma, which may regulate tumor progression in a variety of pathways.

6.
Hypertens Res ; 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34645988

RESUMO

We aimed to evaluate the relationship of the albumin-to-creatinine ratio (ACR) with the risk of first stroke and examine possible effect modifiers in hypertensive patients. A total of 11,632 hypertensive participants with urinary ACR measurements and without a history of stroke from the China Stroke Primary Prevention Trial (CSPPT) were included in this analysis. The primary outcome was first stroke. Over a median follow-up of 4.4 years, 728 first strokes were identified, of which 633 were ischemic, 89 were hemorrhagic, and 6 were uncertain types. Overall, there was a significant positive association between natural log-transformed ACR and the risk of first stroke (HR, 1.11; 95% CI: 1.03-1.20) and first ischemic stroke (HR, 1.12; 95% CI: 1.03-1.22). Consistently, participants with ACR ≥ 10 mg/g had a significantly higher risk of first stroke (HR, 1.26; 95% CI: 1.06-1.50) and first ischemic stroke (HR, 1.33; 95% CI: 1.10-1.59) than those with ACR < 10 mg/g. Moreover, the association of ACR with first stroke was significantly stronger in participants with higher total homocysteine (tHcy) levels (<10 versus ≥ 10 µmol/L; P for interaction = 0.044). However, there was no significant association between ACR and first hemorrhagic stroke (per natural log [ACR] increment: HR, 1.02; 95% CI: 0.82-1.27). In summary, hypertensive patients with ACR ≥ 10 mg/g had a significantly increased risk of first stroke or first ischemic stroke. This positive association was more pronounced among participants with higher tHcy levels.

7.
Psychosom Med ; 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34654026

RESUMO

OBJECTIVE: We aimed to investigate the prospective association between self-perceived psychological stress and first stroke, and examine possible effect modifiers among adults with hypertension. METHODS: A total of 20,688 hypertensive adults with information on self-perceived psychological stress at baseline were included from the China Stroke Primary Prevention Trial (CSPPT). Participants were randomly assigned to a double-blind treatment of receiving a single tablet daily with either 10 mg enalapril and 0.8 mg folic acid or 10 mg enalapril alone. Follow up visits occurred every 3 months after randomization. Psychological stress was measured with a one-item 3-point rating scale. The primary outcome was first stroke (fatal or nonfatal). RESULTS: The median treatment period was 4.5 years. Compared with participants with low levels of psychological stress, those with high psychological stress had a significantly higher risk of first stroke (adjusted HR, 1.40; 95%CI: 1.01, 1.94) or first ischemic stroke (adjusted HR, 1.45; 95%CI: 1.01, 2.09). Moreover, a stronger positive relationship between psychological stress and first stroke was found in participants with time-averaged mean arterial pressure (MAP) <101 mmHg (median) (P-interaction = 0.004) during the treatment period. However, our study did not find a significant association between psychological stress and first hemorrhagic stroke. CONCLUSIONS: Higher psychological stress was associated with an increased risk of first stroke among treated hypertensive patients, especially in those with lower MAP during the treatment period.

8.
Bioengineered ; 12(1): 6343-6353, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34506231

RESUMO

Resveratrol (Res) has been shown to exhibit anti-cancer properties in gastric cancer. However, its clinical application is limited by its poor pharmacokinetics, stability, and low solubility. Hence, this study aimed to explore and verify a better delivery system for gastric cancer therapy. Using transmission electron microscopy, Fourier transform infrared (FTIR) spectroscopy, and ultraviolet (UV) spectrometry, we observed the shape and encapsulation of resveratrol-modified mesoporous silica nanoparticles (MSN-Res) that were synthesized by chemical methods. To explore the anti-cancer effects of these MSN-Res in vivo and in vitro, we established AGS and HGC-27 tumor-bearing mouse models. Meanwhile, the proliferation of gastric cancer cells in vitro and in vivo was assessed by Cell Counting Kit-8, EdU, and Ki-67 immunohistochemical staining methods, while cellular apoptosis, and invasion and migration were detected by TdT-mediated dUTP nick end labeling (TUNEL) and Transwell assays, respectively. FTIR and UV results showed that we successfully synthesized and loaded drugs. Safety evaluation experiments showed that neither MSN-SH nor MSN-Res had toxic effects on the normal tissues of animals. Moreover, in vitro experiments revealed that MSN-Res significantly inhibited the proliferation, invasion, and migration of gastric cancer cells. Furthermore, TUNEL assay showed that MSN-Res promoted apoptosis in gastric cancer. These results were confirmed by the nude mouse tumorigenesis experiment. In conclusion, we demonstrated that MSN-Res showed better inhibitory effect on the development of gastric cancer than Res alone, indicating that MSN-Res could be a promising drug delivery system for gastric cancer treatment.

9.
Chem Commun (Camb) ; 57(76): 9728-9731, 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34474461

RESUMO

Fluorescently labeled calix[4]arene glycoconjugates demonstrate multifunctional potential in both Warburg effect mediated tumor imaging and GLUT1 targeted drug delivery. Nitrobenzoxadiazole and mannose conjugated NBD-Man-CA was found to be selectively recognized by GLUT1 and act as a "molecular carrier" for selective tumor targeting.

10.
Kidney Int Rep ; 6(9): 2525, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34490410

RESUMO

[This corrects the article DOI: 10.1016/j.ekir.2020.07.010.][This corrects the article DOI: 10.1016/j.ekir.2021.07.022.].

11.
Front Pharmacol ; 12: 708034, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34483916

RESUMO

Dysregulation of microRNA (miRNA) biogenesis is involved in drug addiction. Argonaute2 (Ago2), a specific splicing protein involved in the generation of miRNA, was found to be dysregulated in the nucleus accumbens (NAc) of methamphetamine (METH)-sensitized mice in our previous study. Here, we determined whether Ago2 in the NAc regulates METH sensitization in mice and identified Ago2-dependent miRNAs involved in this process. We found a gradual reduction in Ago2 expression in the NAc following repeated METH use. METH-induced hyperlocomotor activity in mice was strengthened by knocking down NAc neuronal levels of Ago2 but reduced by overexpressing Ago2 in NAc neurons. Surprisingly, miR-3068-5p was upregulated following overexpression of Ago2 and downregulated by silencing Ago2 in the NAc. Knocking down miR-3068-5p, serving as an Ago2-dependent miRNA, strengthened the METH sensitization responses in mice. These findings demonstrated that dysregulated Ago2 in neurons in the NAc is capable of regulating METH sensitization and suggested a potential role of Ago2-dependent miR-3068-5p in METH sensitization.

12.
Kidney Int Rep ; 6(9): 2526-2531, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34490411

RESUMO

[This corrects the article DOI: 10.1016/j.ekir.2021.07.021.][This corrects the article DOI: 10.1016/j.ekir.2020.07.010.].

13.
Front Cell Dev Biol ; 9: 694675, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34336841

RESUMO

Giardia duodenalis, also known as Giardia lamblia or Giardia intestinalis, is an important opportunistic, pathogenic, zoonotic, protozoan parasite that infects the small intestines of humans and animals, causing giardiasis. Several studies have demonstrated that innate immunity-associated Toll-like receptors (TLRs) are critical for the elimination of G. duodenalis; however, whether TLR9 has a role in innate immune responses against Giardia infection remains unknown. In the present study, various methods, including reverse transcriptase-quantitative polymerase chain reaction, Western blot, enzyme-linked immunosorbent assay, immunofluorescence, inhibitor assays, and small-interfering RNA interference, were utilized to probe the role of TLR9 in mouse macrophage-mediated defenses against G. lamblia virus (GLV)-free or GLV-containing Giardia trophozoites. The results revealed that in G. duodenalis-stimulated mouse macrophages, the secretion of proinflammatory cytokines, including interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and IL-12 p40, was enhanced, concomitant with the significant activation of TLR9, whereas silencing TLR9 attenuated the host inflammatory response. Notably, the presence of GLV exacerbated the secretion of host proinflammatory cytokines. Moreover, G. duodenalis stimulation activated multiple signaling pathways, including the nuclear factor κB p65 (NF-κB p65), p38, ERK, and AKT pathways, the latter three in a TLR9-dependent manner. Additionally, inhibiting the p38 or ERK pathway downregulated the G. duodenalis-induced inflammatory response, whereas AKT inhibition aggravated this process. Taken together, these results indicated that G. duodenalis may induce the secretion of proinflammatory cytokines by activating the p38 and ERK signaling pathways in a TLR9-dependent manner in mouse macrophages. Our in vitro findings on the mechanism underlying the TLR9-mediated host inflammatory response may help establish the foundation for an in-depth investigation of the role of TLR9 in the pathogenicity of G. duodenalis.

14.
Drug Des Devel Ther ; 15: 3443-3450, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34413631

RESUMO

Objective: To investigate the hearing protection outcomes of different drug-eluting analog electrode arrays implanted into guinea pig cochleae. Methods: Sixty guinea pigs were randomly divided into a negative control group and five experimental groups implanted separately with blank (drug carrier), dexamethasone (DXM), aracytine (Ara-C), Ara-C+DXM, and nicotinamide adenine dinucleotide (NAD+) eluting analog electrode arrays. Micro CT was used to supervise the surgical procedure. Auditory brainstem response (ABR) thresholds of the guinea pigs were measured and analyzed. Results and Conclusions: Compared with the negative control, all other groups showed a significant increase in ABR threshold (p<0.001) after surgery. Among them, there was no obvious difference between the blank (0 vs 90 days: 59.70±10.57 vs 64.60±9.47 dB SPL) and the NAD+ group (0 vs 90 days: 59.90±9.87 vs 64.70±8.65 dB SPL). On the other hand, the ABR thresholds in the DXM (0 days: 58.10±10.73 dB SPL; 90 days: 51.70±9.07 dB SPL) and the Ara-C group (0 days: 59.00±10.05 dB SPL; 90 days: 51.60±8.48 dB SPL) decreased significantly compared with the former two groups (p<0.001). However, the Ara-C+DXM group showed no further benefit (p>0.05). In addition, a significantly higher survival rate of spiral ganglion neurons in cochleae was observed in the Ara-C and/or DXM groups.

15.
Neuro Endocrinol Lett ; 42(4): 236-244, 2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34436844

RESUMO

OBJECTIVES: Osteoblasts play an important role in the process of osteogenesis and prevention of osteonecrosis. Dexamethasone, a type of glucocorticoids (GCs), induce apoptosis of osteoblasts and lead to the occurrence of non-traumatic osteonecrosis. This study aimed to explore the effects of different doses and duration of Dexamethasone on osteoblast apoptosis of rats in vitro. METHODS: Proliferation and apoptosis of osteoblasts after Dexamethasone treatment were detected using cell counting kit-8 (CCK-8) assay and FITC-Annexin V/PI staining. The expressions of caspase-3 and -9 in osteoblasts after Dexamethasone treatment were analyzed using western blotting and qRT-PCR. Dexamethasone remarkably inhibited proliferation and induced apoptosis of osteoblasts in a dose-and duration-dependent manner. RESULTS: As the intervention time extended, the expression of caspase-3 mRNA and caspase-9 mRNA in different Dexamethasone groups gradually increased in a duration-dependent manner. With the same time of intervention (12h, 24h, 48h), the expression of caspase-3 and -9 mRNA gradually increased in a dose-dependent manner. After treated with 5 * 10-8M, 5 * 10-7M, 5 * 10-6M and 5 * 10-5M Dexamethasone for 24 hours, the expression of cleaved caspase-3 and -9 protein increased in a dose-dependent manner. CONCLUSION: Dexamethasone can induce osteoblast apoptosis in a duration- and dose-dependent manner.

16.
Oncogene ; 40(37): 5639-5650, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34321604

RESUMO

Long noncoding RNAs (lncRNAs) have been reported to exert important roles in tumors, including clear cell renal cell carcinoma (ccRCC). PVT1 is an important oncogenic lncRNA which has critical effects on onset and development of various cancers, however, the underlying mechanism of PVT1 functioning in ccRCC remains largely unknown. VHL deficiency-induced HIF2α accumulation is one of the major factors for ccRCC. Here, we identified the potential molecular mechanism of PVT1 in promoting ccRCC development by stabilizing HIF2α. PVT1 was significantly upregulated in ccRCC tissues and high PVT1 expression was associated with poor prognosis of ccRCC patients. Both gain-of-function and loss-of function experiments revealed that PVT1 enhanced ccRCC cells proliferation, migration, and invasion and induced tumor angiogenesis in vitro and in vivo. Mechanistically, PVT1 interacted with HIF2α protein and enhanced its stability by protecting it from ubiquitination-dependent degradation, thereby exerting its biological significance. Meanwhile, HIF2α bound to the enhancer of PVT1 to transactivate its expression. Furthermore, HIF2α specific inhibitor could repress PVT1 expression and its oncogenic functions. Therefore, our study demonstrates that the PVT1/ HIF2α positive feedback loop involves in tumorigenesis and progression of ccRCC, which may be exploited for anticancer therapy.

17.
Artigo em Inglês | MEDLINE | ID: mdl-34313802

RESUMO

RATIONALE: MicroRNAs (miRNAs) regulate neuroplasticity-related proteins and are implicated in methamphetamine (METH) addiction. RhoA is a small Rho GTPase that regulates synaptic plasticity and addictive behaviors. Nevertheless, the functional relationship between RhoA and upstream miRNAs of METH addiction remains unclear. OBJECTIVE: To explore the molecular biology and epigenetic mechanisms of the miR-31-3p/RhoA pathway in METH addiction. METHODS: RhoA protein and its potential upstream regulator, miR-31-3p, were detected. A dual luciferase reporter was employed to determine whether RhoA constituted a specific target of miR-31-3p. Following adeno-associated virus (AAV)-mediated knockdown or overexpression of miR-31-3p or RhoA in the dorsal hippocampus (dHIP), mice were subjected to conditioned place preference (CPP) to investigate the effects of miR-31-3p and RhoA on METH-induced addictive behaviors. RESULTS: RhoA protein was significantly decreased in the dHIP of CPP mice with a concomitant increase in miR-31-3p. RhoA was identified as a direct target of miR-31-3p. Knockdown of miR-31-3p in the dHIP was associated with increased RhoA protein and attenuation of METH-induced CPP. Conversely, overexpression of miR-31-3p was associated with decreased RhoA protein and enhancement of METH effects. Similarly, knockdown of RhoA in the dHIP enhanced METH-induced CPP, whereas RhoA overexpression attenuated the effects of METH. Parallel experiments using sucrose preference revealed that the effects of miR-31-3p/RhoA pathway modulation were specific to METH. CONCLUSIONS: Our findings indicate that the miR-31-3p/RhoA pathway in the dHIP modulates METH-induced CPP in mice. Our results highlight the potential role of epigenetics represented by non-coding RNAs in the treatment of METH addiction.

18.
PeerJ ; 9: e11697, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34268011

RESUMO

Background: PIMREG is upregulated in multiple cancer types. However, the potential role of PIMREG in lung adenocarcinoma (LUAD) remains unclear. The present study aimed to explore its clinical significance in LUAD. Methods: Using the Cancer Genome Atlas (TCGA) databases, we obtained 513 samples of LUAD and 59 normal samples from the Cancer Genome Atlas (TCGA) databases to analyze the relationship between PIMREG and LUAD. We used t and Chi-square tests to evaluate the level of expression of PIMREG and its clinical implication in LUAD. The prognostic value of PIMREG in LUAD was identified through the Kaplan-Meier method, Cox regression analysis, and nomogram. Gene set enrichment analysis (GSEA) and single-sample gene set enrichment analysis (ssGSEA) were performed to screen biological pathways and analyze the correlation of the immune infiltrating level with the expression of PIMREG in LUAD. Results: PIMREG was highly expressed in patients with LUAD. Specifically, the level of PIMREG gradually increased from pathological stage I to IV. Further, we validated the higher expression of PIMREG expressed in LUAD cell lines. Moreover, PIMREG had a high diagnostic value, with an -AUC of 0.955. Kaplan-Meier survival and Cox regression analyses revealed that the high expression of PIMREG was independently associated with poor clinical outcomes. In our prognostic nomogram, the expression of PIMREG implied a significant prognostic value. Gene set enrichment analysis (GSEA) identified that the high expression PIMREG phenotype was involved in the mitotic cell cycle, mRNA splicing, DNA repair, Rho GTPase signaling, TP53 transcriptional regulation, and translation pathways. Next, we also explored the correlation of PIMREG and tumor-immune interactions and found a negative correlation between PIMREG and the immune infiltrating level of T cells, macrophages, B cells, dendritic cells (DCs) , and CD8+ T cells in LUAD. Conclusions: High levels of PIMREG correlated with poor prognosis and immune infiltrates in LUAD.

19.
Brief Bioinform ; 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-34237133

RESUMO

Increasing evidences show the clinical significance of the interaction between hypoxia and immune in clear cell renal cell carcinoma (ccRCC) microenvironment. However, reliable prognostic signatures based on a combination of hypoxia and immune have not been well established. Moreover, many studies have only used RNA-seq profiles to screen the prognosis feature of ccRCC. Presently, there is no comprehensive analysis of multiomics data to mine a better one. Thus, we try and get it. First, t-SNE and ssGSEA analysis were used to establish tumor subtypes related to hypoxia-immune, and we investigated the hypoxia-immune-related differences in three types of genetic or epigenetic characteristics (gene expression profiles, somatic mutation, and DNA methylation) by analyzing the multiomics data from The Cancer Genome Atlas (TCGA) portal. Additionally, a four-step strategy based on lasso regression and Cox regression was used to construct a satisfying prognostic model, with average 1-year, 3-year and 5-year areas under the curve (AUCs) equal to 0.806, 0.776 and 0.837. Comparing it with other nine known prognostic biomarkers and clinical prognostic scoring algorithms, the multiomics-based signature performs better. Then, we verified the gene expression differences in two external databases (ICGC and SYSU cohorts). Next, eight hub genes were singled out and seven hub genes were validated as prognostic genes in SYSU cohort. Furthermore, it was indicated high-risk patients have a better response for immunotherapy in immunophenoscore (IPS) analysis and TIDE algorithm. Meanwhile, estimated by GDSC and cMAP database, the high-risk patients showed sensitive responses to six chemotherapy drugs and six candidate small-molecule drugs. In summary, the signature can accurately predict the prognosis of ccRCC and may shed light on the development of novel hypoxia-immune biomarkers and target therapy of ccRCC.

20.
Parasit Vectors ; 14(1): 358, 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34238339

RESUMO

BACKGROUND: Giardia duodenalis is an extracellular protozoan parasite that causes giardiasis in mammals. The presentation of giardiasis ranges from asymptomatic to severe diarrhea, and the World Health Organization lists it in the Neglected Diseases Initiative. Extracellular vesicles (EVs) are a key mediator of intracellular communication. Although previous studies have shown that G. intestinalis can regulate a host's innate immune response, the role of G. intestinalis EVs (GEVs) in triggering a G. intestinalis-induced innate immune response remains to be further explored. METHODS: In this study, GEVs, G. intestinalis and GEVs + G. intestinalis were inoculated into macrophages, respectively. The transcription and secretion levels of proinflammatory cytokines, including interleukin (IL)-1ß, IL-6 and tumor necrosis factor alpha (TNF-α), were measured using real-time quantitative PCR (qPCR) and enzyme-linked immunosorbent assays (ELISAs). The phosphorylation levels of the MAPK, AKT and NF-κB signaling pathways in GEV-stimulated mouse macrophages were examined using western blotting and immunofluorescence methods. The roles of activated pathways in the GEV-triggered inflammatory response were determined using inhibition assays, western blotting and ELISAs. RESULTS: The results showed that pretreatment with GEVs enhanced with G. intestinalis (GEVs + G. intestinalis) induced IL-1ß, IL-6 and TNF-α transcription and secretion from mouse macrophages compared to stimulation with either GEVs or G. intestinalis alone. Inoculation of mouse macrophages with GEVs upregulated the phosphorylation levels of the p38 MAPK, p44/42 MAPK (Erk1/2), AKT and NF-κB signaling pathways and led to the nuclear translocation of NF-κB p65. Blocking the activated p38, Erk and NF-κB signaling pathways significantly downregulated the secretion of proinflammatory cytokines, and blocking the activated AKT signaling pathway demonstrated reverse effects. CONCLUSIONS: The results of this study reveal that GEVs can enhance G. intestinalis-induced inflammatory response levels in mouse macrophages through activation of the p38, ERK and NF-κB signaling pathways. The role of GEVs in regulating host cell immune responses may provide insights into exploring the underlying mechanisms in G. intestinalis-host interactions.

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