scholarly journals Deubiquitinating enzyme USP48 mediates pyroptosis and meliorates immune evasion in tumors by stabilizing GSDME expression

2021 ◽  
Author(s):  
wang yunshan ◽  
Yidan Ren ◽  
Maoxiao Feng ◽  
Xiaoyan Liu ◽  
Xiaodong Hao ◽  
...  
Keyword(s):  
Gene Knockout ◽  
Tumor Formation ◽  
Deubiquitinating Enzyme ◽  
Biological Processes ◽  
Regulatory Effect ◽  
Related Factors ◽  
Single Cell Sequencing ◽  
Formation Experiment ◽  
Effect Of Pd ◽  
Related Proteins

Abstract Pyroptosis is a kind of programmed cell death, which is characterized by the activation of inflammatory caspase and the cleavage of gasdermin proteins. It is widely involved in the occurrence and development of tumors. Studies have shown that ubiquitin related proteins play a key regulatory role in many biological processes. However, the role and molecular mechanism of ubiquitin-related proteins in pyroptosis have not been well identified. Here, using CRISPR-Cas9 screening, we identified a deubiquitinating enzyme (USP48) that has the most significant regulatory effect on cell pyroptosis. USP48 stabilizes GsderminE (GSDME) expression by causing deubiquitination of it, thereby achieving its regulatory effect on pyroptosis. USP48 prevents the degradation of GSDME by inhibiting K63-linked ubiquitination at positions K120 and K189 of GSDME. Clinical tissue testing confirmed that the expression of USP48 has a significant positive correlation with GSDME and pyroptosis-related factors. GSDME plays a crucial role in the regulation of cell pyroptosis by USP48. The single-cell sequencing results showed that the functions of T cells and tumor-associated macrophages in the tumor microenvironment are inhibited to varying degrees after USP48 gene knockout. Finally, the tumor formation experiment in mice confirmed that overexpression of USP48 could effectively improve the therapeutic effect of PD-1 inhibitors. These findings define a pyroptosis regulation pathway and indicate that activation of the pharmacological activity of USP48 may provide an effective strategy to sensitize cancer cells to pyroptosis-related immunotherapeutic resistance.

scholarly journals A Study on Mesoporous Silica Loaded With Novel Photosensitizers HCE6 and Oxaliplatin for the Treatment of Cholangiocarcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Pei-Jian Zhang ◽  
Meng-Dong Liu ◽  
Fang-Yong Fan ◽  
Ke-Xia Liu
Keyword(s):  
Mesoporous Silica ◽  
High Performance ◽  
Mesoporous Silica Nanoparticles ◽  
Tumor Formation ◽  
Tunel Staining ◽  
Mouse Tumor ◽  
Related Factors ◽  
Killing Effect ◽  
Transmission Electron ◽  
Apoptotic Factors

PurposeCholangiocarcinoma (CCA) is a malignant tumor with a high incidence. The therapeutic effect of conventional chemotherapy and radiotherapy is not obvious. Photodynamic therapy (PDT) is an ideal modality to fight cancer, and the nature of photosensitizer limits its application in clinical therapy. The aim of this study was to explore a novel mode of drug delivery for the intervention of bile duct cancer.MethodsOxaliplatin and photosensitizer HCE6 were loaded with mesoporous silica nanoparticles (MSNs) to synthesize Oxaliplatin/HCE6-MSNs (OH-MSNs); the structure of OH-MSNs was characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS), the drug release rate was detected by high performance liquid chromatography; the cellular activity, apoptosis level, and the expression levels of intracellular apoptosis and autophagy-related factors of OH-MSNs on cholangiocarcinoma cells were observed by CCK-8, flow cytometry, colony formation assay, and Western blot; the effects of OH-MSNs on cholangioma growth were observed by mouse tumor formation, immunohistochemistry, and tissue Tunel staining.ResultsThe release of OH-MSNs to Oxaliplatin was enhanced under acidic conditions; compared with Oxaliplatin or O-MSNs, OH-MSNs showed more potent killing effects against cholangiocarcinoma cells (P<0.05), and exerted notably inhibitory effects on the activity of cholangiocarcinoma cells (P<0.05), promoted their apoptosis (P<0.05), and greatly facilitated the expression of pro-apoptotic factors and autophagic factors in cholangiocarcinoma cells (P<0.05), and markedly inhibited the expression of anti-apoptotic factors and autophagic inhibitory factors (P<0.05); moreover, OH-MSNs could significantly suppress the growth of mouse cholangiocarcinoma (P<0.05) and induce apoptosis of tumor cells compared with Oxaliplatin or O-MSNs (P<0.05).ConclusionMSNs loading greatly increases the killing effect of Oxaliplatin on cholangiocarcinoma cells and upgrades the autophagic level of cholangiocarcinoma cells, while OH-MSNs synthesized by further loading HCE6 have a more apparent killing effect on cholangiocarcinoma cells.

scholarly journals PPInfer: a Bioconductor package for inferring functionally related proteins using protein interaction networks

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 1969
Author(s):  
Dongmin Jung ◽  
Xijin Ge
Keyword(s):  
Protein Interaction ◽  
Protein Interaction Networks ◽  
Interaction Networks ◽  
Biological Processes ◽  
Bioconductor Package ◽  
Biological Functions ◽  
Ppi Network ◽  
Protein Protein Interaction ◽  
Ppi Networks ◽  
Related Proteins

Interactions between proteins occur in many, if not most, biological processes. This fact has motivated the development of a variety of experimental methods for the identification of protein-protein interaction (PPI) networks. Leveraging PPI data available STRING database, we use network-based statistical learning methods to infer the putative functions of proteins from the known functions of neighboring proteins on a PPI network. This package identifies such proteins often involved in the same or similar biological functions. The package is freely available at the Bioconductor web site (http://bioconductor.org/packages/PPInfer/).

scholarly journals PPInfer: a Bioconductor package for inferring functionally related proteins using protein interaction networks

F1000Research ◽  
2018 ◽  
Vol 6 ◽  
pp. 1969 ◽  
Author(s):  
Dongmin Jung ◽  
Xijin Ge
Keyword(s):  
Protein Interaction ◽  
Protein Interaction Networks ◽  
Interaction Networks ◽  
Biological Processes ◽  
Bioconductor Package ◽  
Biological Functions ◽  
Ppi Network ◽  
Protein Protein Interaction ◽  
Ppi Networks ◽  
Related Proteins

Interactions between proteins occur in many, if not most, biological processes. This fact has motivated the development of a variety of experimental methods for the identification of protein-protein interaction (PPI) networks. Leveraging PPI data available in the STRING database, we use a network-based statistical learning methods to infer the putative functions of proteins from the known functions of neighboring proteins on a PPI network. This package identifies such proteins often involved in the same or similar biological functions. The package is freely available at the Bioconductor web site (http://bioconductor.org/packages/PPInfer/).

scholarly journals m6A Modification: A Double-Edged Sword in Tumor Development

2021 ◽  
Vol 11 ◽  
Author(s):  
Runnan Gao ◽  
Mujie Ye ◽  
Baihui Liu ◽  
Meng Wei ◽  
Duan Ma ◽  
...  
Keyword(s):  
Dynamic Properties ◽  
Tumor Development ◽  
Tumor Formation ◽  
Cancer Development ◽  
Research Progress ◽  
Biological Processes ◽  
Rna Methylation ◽  
Anti Cancer ◽  
Elevated Expression

Modification of m6A, as the most abundant mRNA modification, plays diverse roles in various biological processes in eukaryotes. Emerging evidence has revealed that m6A modification is closely associated with the activation and inhibition of tumor pathways, and it is significantly linked to the prognosis of cancer patients. Aberrant reduction or elevated expression of m6A regulators and of m6A itself have been identified in numerous tumors. In this review, we give a description of the dynamic properties of m6A modification regulators, such as methyltransferases, demethylases, and m6A binding proteins, and indicate the value of the balance between these proteins in regulating the expression of diverse genes and the underlying effects on cancer development. Furthermore, we summarize the “dual-edged weapon” role of RNA methylation in tumor progression and discuss that RNA methylation can not only result in tumorigenesis but also lead to suppression of tumor formation. In addition, we summarize the latest research progress on small-molecule targeting of m6A regulators to inhibit or activate m6A. These studies indicate that restoring the balance of m6A modification via targeting specific imbalanced regulators may be a novel anti-cancer strategy.

scholarly journals The proteasomal deubiquitinating enzyme PSMD14 regulates macroautophagy by controlling Golgi-to-ER retrograde transport

2020 ◽  
Author(s):  
HA Bustamante ◽  
K Cereceda ◽  
AE González ◽  
GE Valenzuela ◽  
Y Cheuquemilla ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Golgi Apparatus ◽  
Membrane Trafficking ◽  
Retrograde Transport ◽  
Deubiquitinating Enzyme ◽  
20S Proteasome ◽  
Biological Processes ◽  
Pharmacological Inhibition ◽  
Protein Membrane ◽  
A Subunit

ABSTRACTUbiquitination regulates several biological processes. Here, we search for ubiquitin-related genes implicated in protein membrane trafficking performing a High-Content siRNA Screening including 1,187 genes of the human “ubiquitinome” using Amyloid Precursor Protein (APP) as a reporter. We identified the deubiquitinating enzyme PSMD14, a subunit of the 19S regulatory particle of the proteasome, specific for K63-Ub chains in cells, as a novel key regulator of Golgi-to-endoplasmic reticulum (ER) retrograde transport. Silencing or pharmacological inhibition of PSMD14 caused a robust and rapid inhibition of Golgi-to-ER retrograde transport which leads to a potent blockage of macroautophagy by a mechanism associated with the retention of Atg9A and Rab1A at the Golgi apparatus. Because pharmacological inhibition of the proteolytic core of the 20S proteasome did not recapitulate these effects, we concluded that PSMD14, and their K-63-Ub chains, act as a crucial regulator factor for macroautophagy by controlling Golgi-to-ER retrograde transport.

Galectin-3 immunolabelling correlates with BCL2 expression in canine cutaneous mast cell tumours

2021 ◽  
Author(s):  
Thiago Henrique M. Vargas ◽  
Camila N. Barra ◽  
Lidia H. Pulz ◽  
Greice C. Huete ◽  
Karine G. Cadrobbi ◽  
...  
Keyword(s):  
Mast Cell ◽  
Prognostic Marker ◽  
Clinical Presentation ◽  
Prognostic Indicator ◽  
Biological Processes ◽  
Ki67 Index ◽  
Galectin 3 ◽  
Cutaneous Mast Cell ◽  
Related Proteins ◽  
Bcl2 Expression

AbstractMast cell tumour (MCT) is the most frequent skin neoplasm in dogs. These tumours are characterised by variable behaviour and clinical presentation that make prognosis an important and challenging task in the veterinary practice. Galectin-3 (Gal-3) is known to influence several biological processes that are important in the cancer context and has been described as a prognostic marker for several human cancers. The aim of the present work was to characterise Gal-3 immunolabelling in canine cutaneous MCTs and to investigate its value as a prognostic marker for the disease. Thirty-four random cases of canine cutaneous MCT that were surgically treated with wide margins were included in this study. Gal-3 expression was evaluated using immunohistochemistry and the results were compared with the expression of apoptosis-related proteins, Ki67 index, histopathological grades, mortality due to the disease and post-surgical survival. The majority of the MCTs (65.8%) were positive for Gal-3. Gal-3 immunolabelling was variable among the samples (2.7%–86.8% of the neoplastic cells). The protein was located in the cytoplasm or in the cytoplasm and the nucleus. Gal-3 positivity was correlated with BCL2 expression (P < 0.001; r = 0.604), but not with Ki67 and BAX. No significant differences were detected between histological grades or in the survival analysis. Gal-3 expression correlates with BCL2 expression in MCTs. Although an efficient marker for several human neoplasms, the results presented herein suggest that Gal-3 immunolabelling is not an independent prognostic indicator for this disease.

Quantitative Proteomics Reveals SOS2-related Proteins in Arabidopsis under Salt Stress

2021 ◽  
Vol 18 ◽  
Author(s):  
Xiang Yu ◽  
Xiaoyun Zhao ◽  
Yongqing Yang ◽  
Zhen Li
Keyword(s):  
Salt Stress ◽  
Quantitative Proteomics ◽  
Ion Homeostasis ◽  
Protein A ◽  
Salt Resistance ◽  
Biological Processes ◽  
Land Utilization ◽  
Data Independent Acquisition ◽  
Using Data ◽  
Related Proteins

Background: Soil salinity is a major issue that seriously affects plant growth and cultivated land utilization. Salt tolerance is one of the most fundamental biological processes that ensures plants survival. SOS2 is one of the most important components of the Salt Overly Sensitive (SOS) signaling pathway, which maintains plant ion homeostasis under salt stress. The SOS2-related signaling pathways remain incompletely exploited especially at the proteomics level. Objective: In this paper, proteins potentially interacting with and regulated by SOS2 in Arabidopsis were identified. Methods: The proteomes of Arabidopsis Wild Type (WT) and SOS2-deficient mutant (sos2-2) exposed to 100 mM NaCl for 6 h were compared, proteins were identified using data-independent acquisition-based quantitative proteomics strategy. Results: A total of 7470 proteins were identified and quantified, 372 Differentially Expressed Proteins (DEP) were detected between WT and sos2-2 mutant under normal condition and 179 DEPs were identified under salt treatment. Functional analysis showed that the DEPs were mainly involved in protein binding and catalytic activity. Among the DEPs under salt stress, the protein expressions of AVP1, Photosystem II reaction center protein A, B, C, and stress-responsive protein (KIN2) were significantly up-regulated. LHCA1, LHCA2, LHCA4, ATPD and ATPE were significantly down-regulated. These proteins were involved in biological processes including: stress response, photosynthesis, transport and heat shock. Conclusion: These results revealed complexity of the functions of SOS2 in maintaining intracellular homeostasis, in addition to its function in sodium homeostasis. Plant salt resistance is not independent but closely related to metabolic processes including photosystem, ATP synthase, transport and other stress resistances.

Rosmarinic Acid Induces Proliferation Suppression of Hepatoma Cells Associated with NF-κB Signaling Pathway

2020 ◽  
Author(s):  
Yanjun An ◽  
Jiandong Zhao ◽  
Yourui Zhang ◽  
Wen Wu ◽  
Jiangtao Hu ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Hepg2 Cell ◽  
Rosmarinic Acid ◽  
Caspase 3 ◽  
Migration And Invasion ◽  
Drug Candidate ◽  
Tunel Staining ◽  
Phosphatidylinositol 3 Kinase ◽  
Related Factors ◽  
Related Proteins

Abstract Background: Rosmarinic acid (RA) is a natural phenolic compound that acts as a Fyn inhibitor by 53 homology modeling of the human Fyn structure. Therefore, the apoptosis mechanism related to NF-κB signaling pathway induced by RA in HepG2 was investigated. Methods: The cell growth, apoptosis, and proliferation of HepG2 regulated by various concentrations of RA were studied. The proteins expression of MMP-2, MMP-9, PI3K, AKT, NF-κB, and apoptosis-related proteins Bax, Bcl-2, cleaved caspase-3 were detected. Results: RA significantly reduced proliferation rates, inhibited migration and invasion, and decreased the expressions of invasion-related factors, such as matrix metalloproteinase (MMP)-2 and MMP-9. TUNEL staining revealed that RA resulted in a dose-dependent increase of HepG2 cell apoptosis. In line with this finding, the expression of apoptosis suppressor protein Bcl-2 was downregulated and that of the pro-apoptotic proteins Bax and cleaved caspase-3 was increased. In addition, we found that the phosphatidylinositol 3-kinase (PI3K)/Akt/nuclear factor kappa B (NF-κB) signaling pathway was involved in RA-mediated inhibition of HepG2 cell metastasis. Conclusion: Our study identified that RA as a drug candidate for the treatment of HCC.

scholarly journals The Arabidopsis JMJ29 Protein Controls Circadian Oscillation through Diurnal Histone Demethylation at the CCA1 and PRR9 Loci

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 529
Author(s):  
Hong Gil Lee ◽  
Pil Joon Seo
Keyword(s):  
Clock Gene ◽  
Chromatin Modification ◽  
Histone Demethylase ◽  
Diurnal Fluctuation ◽  
Circadian Oscillation ◽  
Biological Processes ◽  
Histone Demethylation ◽  
Clock Gene Expression ◽  
Related Proteins ◽  
Core Clock Gene

The circadian clock matches various biological processes to diurnal environmental cycles, such as light and temperature. Accumulating evidence shows that chromatin modification is crucial for robust circadian oscillation in plants, although chromatin modifiers involved in regulating core clock gene expression have been limitedly investigated. Here, we report that the Jumonji C domain-containing histone demethylase JMJ29, which belongs to the JHDM2/KDM3 group, shapes rhythmic changes in H3K4me3 histone marks at core clock loci in Arabidopsis. The evening-expressed JMJ29 protein interacts with the Evening Complex (EC) component EARLY FLOWERING 3 (ELF3). The EC recruits JMJ29 to the CCA1 and PRR9 promoters to catalyze the H3K4me3 demethylation at the cognate loci, maintaining a low-level expression during the evening time. Together, our findings demonstrate that interaction of circadian components with chromatin-related proteins underlies diurnal fluctuation of chromatin structures to maintain circadian waveforms in plants.

scholarly journals Ferritinophagic Flux Was a Driving Force in Determination of Status of EMT, Ferroptosis, and NDRG1 Activation in Action of Mechanism of 2-Pyridylhydrazone Dithiocarbamate S-Acetic Acid

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Hao Li ◽  
Wei Zhou ◽  
Huiping Wei ◽  
Longlong Li ◽  
Xu Wang ◽  
...  
Keyword(s):  
Acetic Acid ◽  
Driving Force ◽  
Epithelial Mesenchymal Transition ◽  
Ros Production ◽  
Regulatory Effect ◽  
Mesenchymal Transition ◽  
Cellular Events ◽  
The Status ◽  
Related Proteins

Ferritinophagy is a process of ferritin degradation in lysosomes; however, how its effect on other cellular events, such as epithelial-mesenchymal transition (EMT) and ferroptosis remains elusive. In this study, we determined how ferritinophagic flux influence the status of EMT and ferroptosis in HepG2 cell. Our data revealed that 2-pyridylhydrazone dithiocarbamate s-acetic acid (PdtaA) induced EMT inhibition involved ferritinophagy-mediated ROS production, but addition of ferrostatin-1 could attenuate the effect of PdtaA on the regulation of EMT-related proteins, suggesting that ferroptosis might involve in the EMT regulation. Next, downregulation of Gpx4 and xCT as well as enhanced lipid peroxidation further supported that PdtaA was able to induce ferroptosis. Knockdown of NCOA4 significantly attenuated the regulatory effect of PdtaA on related proteins which highlighted that the strength of ferritinophagic flux (NCOA4/ferritin) was a driving force in determination of the status of EMT and ferroptosis. Furthermore, NDRG1 activation was also observed, and knockdown of NDRG1 similarly influenced the expressions of ferroptosis-related proteins, suggesting that NDRG1 also involved ferroptosis induction, which was first reported. Taken together, PdtaA-induced EMT inhibition, ferroptosis, and NDRG1 activation all depended on the strength of ferritinophagic flux.

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