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1.
Signal Transduct Target Ther ; 6(1): 128, 2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33776057

RESUMO

Currently, pyroptosis has received more and more attention because of its association with innate immunity and disease. The research scope of pyroptosis has expanded with the discovery of the gasdermin family. A great deal of evidence shows that pyroptosis can affect the development of tumors. The relationship between pyroptosis and tumors is diverse in different tissues and genetic backgrounds. In this review, we provide basic knowledge of pyroptosis, explain the relationship between pyroptosis and tumors, and focus on the significance of pyroptosis in tumor treatment. In addition, we further summarize the possibility of pyroptosis as a potential tumor treatment strategy and describe the side effects of radiotherapy and chemotherapy caused by pyroptosis. In brief, pyroptosis is a double-edged sword for tumors. The rational use of this dual effect will help us further explore the formation and development of tumors, and provide ideas for patients to develop new drugs based on pyroptosis.

2.
Mol Ther ; 2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33744468

RESUMO

Tumor cells increase glutamate release through the cystine/glutamate transporter cystine-glutamate exchange (xCT) to balance oxidative homeostasis in tumor cells and promote tumor progression. Although clinical studies have shown the potential of targeting programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) signaling in melanoma, response rates are low. However, it remains unclear how glutamate metabolism affects anti-PD-1/PD-L1 treatment efficacy in melanoma. Here, we demonstrated that although inhibition of xCT either by pharmacological inhibitor (sulfasalazine [SAS]), approved by US Food and Drug Administration (FDA) for inflammatory diseases, or genetic knockdown induced reactive oxygen species (ROS)-related death in melanoma cells, inhibition of xCT significantly reduced the efficacy of anti-PD-1/PD-L1 immune checkpoint blockade through upregulating PD-L1 expression via the transcription factors IRF4/EGR1, as a consequence, exosomes carrying relatively large amounts of PD-L1 secreted from melanoma cells resulted in M2 macrophage polarization and reduced the efficacy of anti-PD-1/PD-L1 therapy in melanoma. Taken together, our results reveal that inhibition of xCT by SAS is a promising therapeutic strategy for melanoma; on the other hand, SAS treatment blunted the efficacy of anti-PD-1/PD-L1 via exosomal PD-L1-induced macrophage M2 polarization and eventually induced anti-PD-1/PD-L1 therapy resistance.

3.
J Dermatol Sci ; 2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33676788

RESUMO

BACKGROUND: Mast cells play an important role in allergic responses and persistently exposure to environmental fine particulate matter (PM2.5) exacerbates allergic diseases,but the details remained elucidative. OBJECTIVES: To investigate the effect of PM2.5 on IgE-mediated mast cell responses through an IgE-mediated mouse model and mast cell activation. METHODS: The ß-hexosaminidase release and a BALB/c model of passive cutaneous anaphylaxis (PCA) was used to test IgE-mediated mast cells activation in vitro and in vivo. RNA-Seq technique was conducted to study the gene expression profile. Reactive oxygen species (ROS) production was measured by flow-cytometry. RT-PCR,WB and ELISA were performed to examine targeting molecules expression. RESULTS: PM2.5 facilitated IgE-mediated degranulation and increased cytokines expression in mast cells. Meanwhile, the Evan's blue extravasation as well as serum cytokines in mice was increased after treatment with PM2.5. Furthermore, PM2.5 treatment dramatically increased the expression of Gadd45b which is an oxidative stress molecule that directly activates down-stream pathway, such as MEKK4/JNK. PM2.5 treatment activated MEKK4, JNK1/2 but not ERK1/2 and p38. Meanwhile, Knockdown of Gadd45b significantly attenuated PM2.5-mediated JNK1/2 activation and expression of cytokines. In addition, a JNK1/2-specific inhibitor SP600125 blocked IgE-mediated mast cell activation and cytokine release in PCA model mice. Moreover, PM2.5 treatment increased the ROS level and ROS inhibitor dramatically blocked the PM2.5-induced ROS production and reversed the PM2.5-mediated gene expression in the mitochondrial respiratory chain. CONCLUSIONS: PM2.5 regulates ROS production through Gadd45b/MEKK4/JNK pathway, facilitating IgE-mediated mast cell activation.

4.
Exp Dermatol ; 2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33751677

RESUMO

Symptomatic dermographism (SD) is a recurrent inflammatory skin disease related to immunity; however, the details remain elusive. In view of the important role of gut microbiota in immune regulation, the purpose of this study is to investigate the alterations of gut microbiota in SD and explore the potential bacterial biomarkers for diagnosis. A case-control study including SD patients and normal controls (NCs) was carried out. Gut microbiota of the participants was analysed by the 16S rDNA sequencing of faecal samples. The linear discriminant analysis effect size and the receiver operating characteristic curve (ROC) analysis were used to identify the bacterial biomarkers. Forty-four participants were included in this study. The alpha-diversity and beta-diversity of gut microbiota differed significantly between SD patients and NCs. The abundance of Verrucomicrobia, Ruminococcaceae and their subordinate taxa were reduced in SD patients, while Enterobacteriales and its subordinate taxon exhibited higher relative abundance compared with NCs. Subdoligranulum and Ruminococcus bromii showed a potential diagnostic value for SD, and Prevotella stercorea was negatively relevant to duration of SD. Furthermore, the pyruvate, butyric acid and histamine metabolism pathway were likely to be involved in the pathogenesis of SD. Our results revealed that the gut microbiota of SD patients experienced obvious changes, and Verrucomicrobia, Ruminococcaceae and Enterobacteriales were microbiota signatures for SD.

5.
IEEE Trans Haptics ; PP2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33523817

RESUMO

The neurophysiological characteristics of sustained attention states are unclear in discrete multi-finger force control tasks. In this study, we developed an immersive visuo-haptic task for conducting stimulus-response measurements. Visual cues were randomly provided to signify the required amplitude and tolerance of fingertip force. Participants were required to respond to the visual cues by pressing force transducers using their fingertips. Response time variation was taken as a behavioral measure of sustained attention states during the task. 50% low-variability trials were classified as the optimal state and the other high-variability trials were classified as the suboptimal state using z-scoring over time. A 64-channel electroencephalogram (EEG) acquisition system was used to collect brain activities during the tasks. The haptics-elicited potential amplitude at 20 ~ 40 ms in latency and over the frontal-central region significantly decreased in the optimal state. Furthermore, the alpha-band power in the spectra of 8 ~ 13 Hz was significantly suppressed in the frontal-central, right temporal, and parietal regions in the optimal state. Taken together, we have identified neuroelectrophysiological features that were associated with sustained attention during multi-finger force control tasks, which would be potentially used in the development of closed-loop attention detection and training systems exploiting haptic interaction.

7.
Cell Prolif ; 54(3): e12991, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33522656

RESUMO

OBJECTIVE: Premature senescence is related to progerin and involves in endothelial dysfunction and liver diseases. Activating sirtuin 1 (SIRT1) ameliorates liver fibrosis. However, the mechanisms of premature senescence in defenestration of hepatic sinusoidal endothelial cells (HSECs) and how SIRT1 affects HSECs fenestrae remain elusive. METHODS: We employed the CCl4 -induced liver fibrogenesis rat models and cultured primary HSECs in vitro, administered with the SIRT1-adenovirus vector, the activator of SIRT1 and knockdown NOX2. We measured the activity of senescence-associated ß-galactosidase (SA-ß-gal) in HSECs. Meanwhile, the protein expression of SIRT1, NOX2, progerin, Lamin A/C, Ac p53 K381 and total p53 was detected by Western blot, co-immunoprecipitation and immunofluorescence. RESULTS: In vivo, premature senescence was triggered by oxidative stress during CCl4 -induced HSECs defenestration and liver fibrogenesis, whereas overexpressing SIRT1 with adenovirus vector lessened premature senescence to relieve CCl4 -induced HSECs defenestration and liver fibrosis. In vitro, HSECs fenestrae disappeared, with emerging progerin-associated premature senescence; these effects were aggravated by H2 O2 . Nevertheless, knockdown of NOX2, activation of SIRT1 with resveratrol and SIRT1-adenovirus vector inhibited progerin-associated premature senescence to maintain fenestrae through deacetylating p53. Furthermore, more Ac p53 K381 and progerin co-localized with the abnormal accumulation of actin filament (F-actin) in the nuclear envelope of H2 O2 -treated HSECs; in contrast, these effects were rescued by overexpressing SIRT1. CONCLUSION: SIRT1-mediated deacetylation maintains HSECs fenestrae and attenuates liver fibrogenesis through inhibiting oxidative stress-induced premature senescence.


Assuntos
Células Endoteliais/metabolismo , Cirrose Hepática/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Sirtuína 1/farmacologia , Envelhecimento , Animais , Senescência Celular/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Cirrose Hepática/patologia , Ratos Sprague-Dawley , Resveratrol/farmacologia , Sirtuína 1/metabolismo
8.
Int J Biol Sci ; 17(1): 285-297, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33390850

RESUMO

Melanoma is an aggressive form of skin cancer characterized by rapid invasion and metastasis. CD147 is known to be functioning in cell invasion. In this study, we showed that CD147 was translocated from the cell membrane to the mitochondria in advanced melanoma. Melanoma patients with CD147 localized to the mitochondria confer a worse prognosis. The mitochondrial CD147 levels are correlated with the invasion potential of various melanoma cell lines as well as mitochondrial energy metabolism. Depletion of CD147 decreased the activity of mitochondrial complex V. STRING analysis for protein-protein interaction networks (PPIN) in CD147-depleted melanoma cells showed that mitochondrial proteins HSP60 and ATP5B, a subunit of mitochondrial complex V, were node proteins. HSP60 upregulation was correlated with a worse prognosis of melanoma patients. Co-immunoprecipitation (Co-IP) assay indicates that CD147 interacts with HSP60. These data suggested that mitochondrial CD147 may prompt HSP60 to activate ATP5B, thereby promoting the mitochondrial aerobic oxidation and the invasive abilities of melanoma cells. Correlation analysis of the data acquired from patients was helpful to draw a 5-year survival curve for patients who screened positive and negative for mitochondrial CD147. This study unravels the function of CD147 in tumor invasion and highlights it as a potential tumor therapeutic target.

10.
Theranostics ; 11(2): 754-767, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33391503

RESUMO

High-throughput metabolite profiling provides the opportunity to reveal metabolic mechanisms and identify biomarkers. Psoriasis is an immune-mediated chronic inflammatory disease. However, the role of metabolism in psoriasis pathogenesis remains unclear. Methods: Plasma samples of individuals (45 psoriasis and 45 sex-, age-, and BMI-matched healthy controls) were collected. Non-targeted metabolomics and amino acid- or carnitine-targeted metabolomics were conducted, then, plasma samples of mice induced by imiquimod (IMQ) were subjected to the amino acid- and carnitine-targeted metabolomic profiling. Flow cytometry was used to study the effect of L-carnitine (LC(C0)) on IMQ-induced psoriatic inflammation. Results: Through the non-targeted metabolomics approach, we detected significantly altered amino acids and carnitines in psoriasis patients. Amino acid-targeted metabolomic profiling identified 37 amino acids altered in psoriasis, of these 23 were markedly upregulated, including essential amino acids (EAAs), and branched-chain amino acids (BCAAs), whereas glutamine, cysteine, and asparagine were significantly down-regulated. Carnitine-targeted metabolomic profiling identified 40 significantly altered carnitines, 14 of which included palmitoylcarnitine (C16) and were markedly downregulated in psoriasis, whereas hexanoylcarnitine (C6) and 3-OH-octadecenoylcarnitine (C18:1-OH) were significantly upregulated. Interestingly, glutamine, asparagine, and C16 levels were negatively correlated with the PASI score. Moreover, a higher abundance of LC(C0) was associated with markedly reduced IMQ-induced epidermal thickening and infiltration of Th17 cells in skin lesions, indicating LC(C0) supplementation as a potential therapy for psoriasis treatment. Conclusion: Our results suggested the metabolism of amino acids and carnitines are significantly altered in psoriasis, especially the metabolism of EAAs, BCAAs, and LC(C0), which may play key roles in the pathogenesis of psoriasis.

11.
Sci Total Environ ; 760: 144311, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33341622

RESUMO

Recovering nitrogen and phosphorus from waste water in the form of struvite is an effective way to recycle resources. The insufficient purity of the resulting struvite and the large loss of nitrogen and phosphorus are the challenges at present. Therefore, it is urgent to develop innovative method in struvite crystallization process for efficient nitrogen and phosphorus recovery. This study proposed a crystallization method to reduce the loss of nitrogen and phosphorus by a struvite fluidized bed reactor (FBR) with optimized structure and operation conditions. The properties of struvite obtained under various conditions in the reactor were studied, and the internal operating conditions of the reactor were simulated with COMSOL Multiphysics to verify the effectiveness of the reactor optimization. This reactor achieved stable operation under the conditions of N/P = 1:1 and pH = 9.0. The purity of struvite obtained reached 98.5%, the conversion rate of ammonia nitrogen reached 97.2%, and struvite crystals could grow to 84 µm within 24 h. The simulation results showed that the Venturi tubes installed at multiple locations increased the turbulent energy to 4 × 10-4 m2/s2, which greatly improved the mass transfer efficiency. The trajectory of the crystal particles was consistent with the fluid flow field, which promoted the purification and growth of the crystal. In general, the new FBR with enhanced external recirculation would be a very feasible way to improve crystal growth and crystal purification of struvite, and it could enhance the recovery efficiency of nitrogen and phosphorus with reduced cost.

13.
J Cell Physiol ; 2020 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-33222224

RESUMO

Long noncoding RNAs (lncRNAs) have been found to play essential roles in the occurrence and development of multiple human cancers. Accumulating evidence has shown that LINC00473, an oncogenic lncRNA, is upregulated in various human malignancies and related to poor clinical outcomes. Besides, LINC00473 overexpression can promote cell proliferation, migration, and invasion through multiple potential mechanisms, indicating that it may serve as a novel prognostic biomarker and therapeutic target for human cancers. Here, we reviewed the biological functions, molecular mechanisms, and clinical implications of LINC00473 in human cancers.

14.
Front Oncol ; 10: 579625, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33194704

RESUMO

Tre2-Bub2-Cdc16 (TBC) proteins are conserved in eukaryotic organisms and function as negative feedback dominating the GAPs for Rab GTPases, while the function of TBC proteins in melanoma remains unclear. In this study, we observed the differential expression of 33 TBC genes in TCGA datasets classified by clinical features. Seven prognostic-associated TBC genes were identified by LASSO Cox regression analysis. Mutation analysis revealed distinctive frequency alteration in the seven prognostic-associated TBCs between cases with high and low scores. High-risk score and cluster 1 based on LASSO Cox regression and consensus clustering analysis were relevant to clinical features and unfavorable prognosis. GSVA analysis showed that prognostic-associated TBCs were related to metabolism and protein transport signaling pathway. Correlation analysis indicated the relationship between the prognostic-associated TBCs with RAB family members, invasion-related genes and immune cells. The prognostic nomogram model was well established to predict survival in melanoma. What's more, interference of one of the seven TBC proteins TBC1D7 was confirmed to inhibit the proliferation, migration and invasion of melanoma cells in vitro. In summary, we preliminarily investigated the impact of TBCs on melanoma through multiple bioinformatics analysis and experimental validation, which is helpful for clarifying the mechanism of melanoma and the development of anti-tumor drugs.

15.
Bioorg Chem ; 105: 104453, 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33197849

RESUMO

CD147 is a transmembrane glycoprotein and a member of immunoglobulin superfamily, is strongly expressed in melanoma cells. CD147 has a pivotal role in tumor development. Therefore, it is a potential drug target for melanoma. In this article, we report the discovery of the first CD147 protein proteolysis targeting chimeras (PROTACs) derived from the natural product pseudolaric acid B (PAB). The representative compound 6a effectively induced degradation of CD147 and inhibited melanoma cells in vitro and in vivo. 6a could be used as the novel type of anticancer agent or as a part of the molecular biology research toolkit used in the gain-of-function study of the dynamic roles of CD147 in cancer networks.

16.
Cancer Lett ; 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33246091

RESUMO

Pyruvate kinase M2 (PKM2), a key rate-limiting enzyme of glycolysis, is a critical regulator in tumor metabolism. PKM2 has been demonstrated to overexpressed in various cancers and promoted proliferation and metastasis of tumor cells. The errant expression of PKM2 has inspired people to investigate the function of PKM2 and the therapeutic potential in cancer. In addition, some studies have shown that the upregulation of PKM2 in tumor tissues is associated with the altered expression of lncRNAs and the poor survival. Therefore, researchers have begun to unravel the specific molecular mechanisms of lncRNA-mediated PKM2 expression in cancer metabolism. As the tumor microenvironment (TME) is essential in tumor development, it is necessary to identify the role of PKM2 in TME. In this review, we will introduce the role of PKM2 in different cancers as well as TME, and summarize the molecular mechanism of PKM2-related lncRNAs in cancer metabolism. We expect that this work will lead to a better understanding of the molecular mechanisms of PKM2 that may help in developing therapeutic strategies in clinic for researchers.

17.
Sci Total Environ ; : 143223, 2020 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-33160668

RESUMO

The pollution of karst aquifers by acid mine drainage (AMD) waters is increasing. Major and minor ions (Ca2+, Mg2+, HCO3-, SO42-, F-, and Fe), stable sulfur and oxygen isotopes of dissolved sulfates (δ34SSO4 and δ18OSO4) and oxygen isotope of water (δ18OH2O), were analyzed in rainwater, surface water, groundwater, and AMD water sampled from the Babu subterranean stream watershed, in Southwest China. The principal aim of this study was to explore the impact of AMD waters on the evolution of karst aquifers. Based on hydrogeochemistry and stable isotopes (δ18OH2O, δ18OSO4 and δ34SSO4): (1) the chemistry of AMD waters was primarily controlled by pyrite oxidation, karst conduit water by AMD waters and mixing with calcite and dolomite dissolution, and spring water by atmospheric precipitation and carbonate dissolution; (2) contamination of the karst conduit water was mainly attributed to the input of AMD waters, resulting in a shift of δ34SSO4 towards more negative values (from 3.4‰ to -13.2‰); (3) the quality of karst conduit water changed from suitable to unsuitable for irrigation and drinking, particularly due to the increase in total Fe, SO42-, and F- concentrations, reflecting the cumulative effect of AMD waters derived from tailings dumps; this influence was enhanced during rainstorm/drought and anthropogenic activities; and (4) the flow of contaminated groundwater through the conduit promoted the dissolution of carbonates, especially during the dry season due to the greater proportion of AMD in the groundwater. This released more CO2 to the atmosphere. We believe that analysis of stable isotopes (δ18OH2O, δ18OSO4, and δ34SSO4), combined with hydrogeochemistry, is effective for exploring the impact of AMD on karst aquifers. Therefore, reasonable treatment methods should be taken to reduce the negative impacts of tailings dumps on karst aquifers.

18.
Front Oncol ; 10: 1710, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33014847

RESUMO

Metabolic reprogramming is closely related to melanoma. However, the prognostic role of metabolism-related genes (MRGs) remains to be elucidated. We aimed to establish a nomogram by combining MRGs signature and clinicopathological factors to predict melanoma prognosis. Eighteen prognostic MRGs between melanoma and normal samples were identified using The Cancer Genome Atlas (TCGA) and GSE15605. WARS (HR = 0.881, 95% CI = 0.788-0.984, P = 0.025) and MGST1 (HR = 1.124, 95% CI = 1.007-1.255, P = 0.037) were ultimately identified as independent prognostic MRGs with LASSO regression and multivariate Cox regression. The MRGs signature was established according to these two genes and externally validated in the Gene Expression Omnibus (GEO) dataset. Kaplan-Meier survival analysis indicated that patients in the high-risk group had significantly poorer overall survival (OS) than those in the low-risk group. Furthermore, the MRGs signature was identified as an independent prognostic factor for melanoma survival. An MRGs nomogram based on the MRGs signature and clinicopathological factors was developed in TCGA cohort and validated in the GEO dataset. Calibration plots showed good consistency between the prediction of nomogram and actual observation. The receiver operating characteristic curve and decision curve analysis indicated that MRGs nomogram had better OS prediction and clinical net benefit than the stage system. To our knowledge, we are the first to develop a prognostic nomogram based on MRGs signature with better predictive power than the current staging system, which could assist individualized prognosis prediction and improve treatment.

19.
Cancer Cell Int ; 20: 429, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32905356

RESUMO

Tumor necrosis factor receptor (TNFR)-related factors (TRAFs) are important linker molecules in the tumor necrosis factor superfamily (TNFSF) and the Toll-like/interleukin-1 receptor (TLR/ILR) superfamily. There are seven members: TRAF1-TRAF7, among those members, tumor necrosis factor receptor-associated factor 6 (TRAF6) is upregulated in various tumors, which has been related to tumorigenesis and development. With the in-depth study of the relationship between TRAF6 and different types of tumors, TRAF6 has oncogenic characteristics involved in tumorigenesis, tumor development, invasion, and metastasis through various signaling pathways, therefore, targeting TRAF6 has provided a novel strategy for tumor treatment. This review summarizes and analyzes the role of TRAF6 in tumorigenesis and tumor development in combination with the current research on TRAF6 and tumors.

20.
J Cell Mol Med ; 24(20): 11646-11655, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32916775

RESUMO

The skin is the main barrier between the human body and the outside world, which not only plays the role of a physical barrier but also functions as the first line of defence of immunology. Langerhans cells (LCs), as dendritic cells (DC) that play an important role in the immune system, are mainly distributed in the epidermis. This review focuses on the role of these epidermal LCs in regulating skin threats (such as microorganisms, ultraviolet radiation and allergens), especially psoriasis. Since human and mouse skin DC subsets share common ontogenetic characteristics, we can further explore the role of LCs in psoriatic inflammation.

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