Expression of TXNIP is associated with angiogenesis and postoperative relapse of conventional renal cell carcinoma

AbstractOne of the common mediator of tumour progression is the oxidative stress induced by inflammatory tumour microenvironment (TME). Activated fibroblasts, local and immune cells produce reactive oxygen species (ROS) supporting tumour cell proliferation and pave the way for metastatic tumour growth. TXNIP regulates ROS generation by inhibiting the antioxidative function of thioredoxin (TXN). The shift of TXNIP/TXN balance towards overexpression of TXNIP is associated with proliferation of endothelial cells during tumor angiogenesis. The oxidative stress activates the hypoxia inducible factor-1 (HIF-1), which plays an important role in the biology of conventional RCC (cRCC). Under oxydative stress TXNIP interacts with NLRP3 inflammasome leading to maturation and secretion of inflammatory cytokine IL1β. To establish the role of TXNIP and downstream genes HIF1α and IL1β in the biology of cRCC, we have applied immunohistochemistry to multi-tissue arrays containing tumours of 691 patients without detectable metastases at the time of operation. We found that cRCC displaying a fine organised capillary network with nuclear translocation of TXNIP and expressing IL1β have a good prognosis. In contrary, we showed a significant correlation between cytoplasmic TXNIP expression, inefficient vascularisation by unorganized and tortuous vessels causing tumour cell necrosis and postoperative tumour relapse of cRCC.

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Ox-LDL induced endothelial progenitor cells oxidative stress via p38/Keap1/Nrf2 pathway

10.21203/rs.3.rs-348365/v1 ◽

2021 ◽

Author(s):

Qijun Jiang ◽

Chengpeng Li ◽

Zhigang Gong ◽

Zhigang Li ◽

Shifang Ding

Keyword(s):

Oxidative Stress ◽

Membrane Potential ◽

Progenitor Cells ◽

Endothelial Progenitor Cells ◽

Nuclear Translocation ◽

Tube Formation ◽

Ros Generation ◽

Endothelial Progenitor ◽

Migration Ability ◽

Nrf2 Pathway

Abstract Background In many studies, endothelial progenitor cells (EPCs) highly expressing antioxidant protein were induced oxidative stress and apoptosis by Oxidized-low density lipoprotein (ox-LDL). Nrf2 which was resently reported to regulate the antioxidant genes and cellular redox regulators was highly expressed in EPCs. However, its role in ox-LDL induced EPCs oxidative stress and apoptosis has not been fully illustrated. Methods EPCs isolated from human peripheral blood mononuclear cells were treated with different concentration of ox-LDL, Keap1 siRNA and a specific p38 MAPK inhibitor SB203580, then used to assay the whole cellular Nrf2 (total Nrf2, t-Nrf2), cytoplasmic Nrf2 (c-Nrf2), nuclear Nrf2 (n- Nrf2), NAD(P) H:quinone oxidoreductase 1 (NQO1) protein levels and Bax /Bcl-2 with western blot, NQO1 mRNA levels with RT-PCR, ROS level with H2DCF-DA, the loss/disruption of mitochondrial membrane potential (MMP) with JC-1, apoptosis with Annexin-V and PI,migration ability with transwell chambers and tube formation. Results The ox-LDL treatment decreased the n-Nrf2/Histone H3 to c-Nrf2/GAPDH ratio, NQO1 mRNA and protein expression levels. Treatment of ox-LDL enhanced the ROS production, induced loss of membrane potential, increase in cell shrinkage, pyknotic nuclei and apoptosis of EPCs. The Keap1 knockdown with Keap1 siRNA increased the nuclear translocation of Nrf2, the NQO1 mRNA and protein transcription levels, and prevented ox-LDL induced ROS generation and formation of JC-1 monomers. Treatment of ox-LDL increased the activation of p38. Pretreatment with SB203580 significantly eliminated ox-LDL induced the inhibition of Nrf2 nuclear translocation, the depression of the mRNA transcription levels of NQO-1, the ROS generation and the formation of JC-1 monomers in EPCs. The pretreatment of Keap1 siRNA decreased the Bax/Bcl-2 ratio which was increased by the treatment of ox-LDL in EPCs. The ox-LDL treatment decreased EPCs migration activity and tube formation. Whereas the pre-treatment with Keap1 siRNA preserved the migration ability and tube formation of EPCs Conclusion Ox-LDL induced EPCs oxidative stress and apoptosis via p38/Keap1/Nrf2 pathway.

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Curcumin Suppresses the Lipid Accumulation and Oxidative Stress Induced by Benzo[a]pyrene Toxicity in HepG2 Cells

Antioxidants ◽

10.3390/antiox10081314 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1314

Author(s):

Seung-Cheol Lee ◽

Seung-Cheol Jee ◽

Min Kim ◽

Soee Kim ◽

Min Kyoung Shin ◽

...

Keyword(s):

Oxidative Stress ◽

Cytochrome P450 ◽

Cell Viability ◽

Lipid Accumulation ◽

Hepg2 Cells ◽

Nuclear Translocation ◽

The Body ◽

Ros Generation ◽

Related Factor ◽

And Oxidative Stress

Benzo[a]pyrene (B[a]P) is a potentially hepatotoxic group-1 carcinogen taken up by the body through ingestion of daily foods. B[a]P is widely known to cause DNA and protein damages, which are closely related to cell transformation. Accordingly, studies on natural bioactive compounds that attenuate such chemical-induced toxicities have significant impacts on public health. This study aimed to uncover the mechanism of curcumin, the major curcuminoid in turmeric (Curcuma longa), in modulating the lipid accumulation and oxidative stress mediated by B[a]P cytotoxicity in HepG2 cells. Curcumin treatment reduced the B[a]P-induced lipid accumulation and reactive oxygen spicies (ROS) upregulation and recovered the cell viability. Cytochrome P450 family 1 subfamily A polypeptide 1 (CYP1A1) and Cytochrome P450 subfamily B polypeptide 1 (CYP1B1) downregulation resulting from decreased aryl hydrocarbon receptor (AhR) translocation into nuclei attenuated the effects of B[a]P-induced lipid accumulation and repressed cell viability, respectively. Moreover, the curcumin-induced reduction in ROS generation decreased the nuclear translocation of Nuclear factor erythroid-2-related factor 2 (Nrf2) and the expression of phase-II detoxifying enzymes. These results indicate that curcumin suppresses B[a]P-induced lipid accumulation and ROS generation which can potentially induce nonalcoholic fatty liver disease (NAFLD) and can shed a light on the detoxifying effect of curcumin.

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Lysyl oxidase drives tumour progression by trapping EGF receptors at the cell surface

Nature Communications ◽

10.1038/ncomms14909 ◽

2017 ◽

Vol 8 (1) ◽

Cited By ~ 31

Author(s):

HaoRan Tang ◽

Leo Leung ◽

Grazia Saturno ◽

Amaya Viros ◽

Duncan Smith ◽

...

Keyword(s):

Cell Surface ◽

Therapeutic Potential ◽

Lysyl Oxidase ◽

Tumour Progression ◽

Growth Factor Receptor ◽

Tumour Microenvironment ◽

Metastatic Tumour ◽

Egf Receptors ◽

Molecule Inhibitor

Abstract Lysyl oxidase (LOX) remodels the tumour microenvironment by cross-linking the extracellular matrix. LOX overexpression is associated with poor cancer outcomes. Here, we find that LOX regulates the epidermal growth factor receptor (EGFR) to drive tumour progression. We show that LOX regulates EGFR by suppressing TGFβ1 signalling through the secreted protease HTRA1. This increases the expression of Matrilin2 (MATN2), an EGF-like domain-containing protein that traps EGFR at the cell surface to facilitate its activation by EGF. We describe a pharmacological inhibitor of LOX, CCT365623, which disrupts EGFR cell surface retention and delays the growth of primary and metastatic tumour cells in vivo. Thus, we show that LOX regulates EGFR cell surface retention to drive tumour progression, and we validate the therapeutic potential of inhibiting this pathway with the small molecule inhibitor CCT365623.

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Antioxidative Effects of Carrot-Derived Nanovesicles in Cardiomyoblast and Neuroblastoma Cells

Pharmaceutics ◽

10.3390/pharmaceutics13081203 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1203

Author(s):

Do Kyung Kim ◽

Won Jong Rhee

Keyword(s):

Oxidative Stress ◽

Myocardial Infarction ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neuroblastoma Cells ◽

Size Exclusion ◽

Drug Candidate ◽

Ros Generation ◽

High Concentration ◽

Antioxidative Function

Oxidative stress is implicated in many diseases, including cardiovascular and neurodegenerative diseases. Because an increased level of oxidative stress causes apoptosis, it is necessary to inhibit cellular responses to oxidative stress. In this study, Carex, a nanovesicle from carrot, was isolated and investigated as a novel biomaterial with antioxidative function in cardiomyoblasts and neuroblastoma cells. A high concentration of nanovesicles was purified from carrots, using size-exclusion chromatography in combination with ultrafiltration. The characterization of Carex demonstrated that it had properties similar to those of extracellular vesicles. Carex showed low cytotoxicity in both H9C2 cardiomyoblasts and SH-SY5Y neuroblastoma cells, when a high level of Carex was delivered to the cells. Carex was further investigated for its antioxidative and apoptotic effects, and it significantly inhibited ROS generation and apoptosis in vitro in myocardial infarction and Parkinson’s disease models. Carex inhibited the reduction of antioxidative molecule expression, including Nrf-2, HO-1, and NQO-1, in both models. Considering its antioxidative function and high production yield, Carex is a potential drug candidate for the treatment of myocardial infarction as well as Parkinson’s disease. Thus, the results demonstrated in this study will contribute to an exploration of a novel drug, using nanovesicles from plants, including carrots.

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Anti-neoplastic action of aspirin against a T-cell lymphoma involves an alteration in the tumour microenvironment and regulation of tumour cell survival

Bioscience Reports ◽

10.1042/bsr20110027 ◽

2011 ◽

Vol 32 (1) ◽

pp. 91-104 ◽

Cited By ~ 20

Author(s):

Anjani Kumar ◽

Naveen Kumar Vishvakarma ◽

Abhishek Tyagi ◽

Alok Chandra Bharti ◽

Sukh Mahendra Singh

Keyword(s):

T Cell ◽

Growth Factor ◽

Cell Survival ◽

Tumour Cell ◽

Tumour Growth ◽

Cell Lymphoma ◽

Tumour Progression ◽

Tumour Microenvironment ◽

T Cell Lymphoma ◽

Tumour Bearing

The present study explores the potential of the anti-neoplastic action of aspirin in a transplantable murine tumour model of a spontaneously originated T-cell lymphoma designated as Dalton's lymphoma. The antitumour action of aspirin administered to tumour-bearing mice through oral and/or intraperitoneal (intratumoral) routes was measured via estimation of survival of tumour-bearing mice, tumour cell viability, tumour progression and changes in the tumour microenvironment. Intratumour administration of aspirin examined to assess its therapeutic potential resulted in retardation of tumour progression in tumour-bearing mice. Oral administration of aspirin to mice as a prophylactic measure prior to tumour transplantation further primed the anti-neoplastic action of aspirin administered at the tumour site. The anti-neoplastic action of aspirin was associated with a decline in tumour cell survival, augmented induction of apoptosis and nuclear shrinkage. Tumour cells of aspirin-treated mice were found arrested in G0/G1 phase of the cell cycle and showed nuclear localization of cyclin B1. Intratumoral administration of aspirin was accompanied by alterations in the biophysical, biochemical and immunological composition of the tumour microenvironment with respect to pH, level of dissolved O2, glucose, lactate, nitric oxide, IFNγ (interferon γ), IL-4 (interleukin-4), IL-6 and IL-10, whereas the TGF-β (tumour growth factor-β) level was unaltered. Tumour cells obtained from aspirin-treated tumour-bearing mice demonstrated an altered expression of pH regulators monocarboxylate transporter-1 and V-ATPase along with alteration in the level of cell survival regulatory molecules such as survivin, vascular endothelial growth factor, heat-shock protein 70, glucose transporter-1, SOCS-5 (suppressor of cytokine signalling-5), HIF-1α (hypoxia-inducible factor-1α) and PUMA (p53 up-regulated modulator of apoptosis). The study demonstrates a possible indirect involvement of the tumour microenvironment in addition to a direct but limited anti-neoplastic action of aspirin in the retardation of tumour growth.

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Identification of PIEZO1 as a potential prognostic marker in gliomas

Scientific Reports ◽

10.1038/s41598-020-72886-8 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Wenjianlong Zhou ◽

Xiangxiang Liu ◽

Jan Willem Maurits van Wijnbergen ◽

Linhao Yuan ◽

Yuan Liu ◽

...

Keyword(s):

Mechanical Properties ◽

Cell Proliferation ◽

Tumour Cell ◽

Tumour Progression ◽

Malignant Gliomas ◽

Tumour Microenvironment ◽

Solid Tumours ◽

The Cancer Genome Atlas ◽

Tumour Cell Proliferation ◽

Genome Atlas

Abstract In multiple solid tumours, including gliomas, the mechanical properties change as the disease progresses. If and how mechanical cues regulate tumour cell proliferation is currently not fully studied. PIEZO1 has recently been identified as a crucial mechanosensitive cation channel in multiple solid tumours. However, we didn’t find any clinical data describing the association between PIEZO1 expression and glioma. To investigate the role of PIEZO1 in gliomas, we analysed PIEZO1 gene expression at the transcriptome level, genomic profiles and the association of PIEZO1 with clinical practice. In total, 1633 glioma samples with transcriptome data, including data from the Chinese Glioma Genome Atlas RNAseq, the Cancer Genome Atlas RNAseq and GSE16011 databases, were included in this study. Clinical information and genomic profiles including somatic mutations were also obtained. We found that PIEZO1 expression was highly correlated with malignant clinical and molecular subtypes of glioma. Gene ontology analysis showed that expression of PIEZO1 was correlated with tumour microenvironment-related genes that encode proteins involved in extracellular matrix (ECM) organization, angiogenesis and cell migration. Additionally, PIEZO1 was shown to be involved in tumour progression by serving as the central checkpoint of multiple ECM remodelling-related signalling pathways to modulate tumour cell proliferation and the tumour microenvironment in turn. Finally, high PIEZO1 expression was correlated with reduced survival time and acted as a robust biomarker for poor prognosis in gliomas. Taken together, the results indicated that high PIEZO1 expression is closely associated with highly malignant gliomas. Importantly, PIEZO1 serves as a key factor involved in sensing mechanical properties in the tumour and can regulate both tumour cells and their microenvironment to promote glioma progression, and it is also a potential therapeutic target for the treatment of gliomas.

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Phorbol 12-Myristate 13-Acetate Induced Toxicity Study and the Role of Tangeretin in Abrogating HIF-1α-NF-κB Crosstalk In Vitro and In Vivo

International Journal of Molecular Sciences ◽

10.3390/ijms21239261 ◽

2020 ◽

Vol 21 (23) ◽

pp. 9261

Author(s):

Sukkum Ngullie Chang ◽

Debasish Kumar Dey ◽

Seong Taek Oh ◽

Won Ho Kong ◽

Kiu Hyung Cho ◽

...

Keyword(s):

Inflammatory Response ◽

Nuclear Translocation ◽

Hypoxia Inducible Factor ◽

Tumor Promoter ◽

Root Tip ◽

Ros Generation ◽

Dependent Manner ◽

Human Keratinocyte

Phorbol 12-myristate 13-acetate (PMA) is a potent tumor promoter and highly inflammatory in nature. Here, we investigated the toxic effects of PMA on different model system. PMA (10 μg) caused chromosomal aberrations on the Allium cepa root tip and induced mitotic dysfunction. Similarly, PMA caused embryonic and larval deformities and a plummeted survivability rate on zebrafish embryo in a dose-dependent manner. Persistently, PMA treatment on immortalized human keratinocyte human keratinocyte (HaCaT) cells caused massive inflammatory rush at 4 h and a drop in cell survivability at 24 h. Concomitantly, we replicated a cutaneous inflammation similar to human psoriasis induced by PMA. Herein, we used tangeretin (TAN), as an antagonist to counteract the inflammatory response. Results from an in vivo experiment indicated that TAN (10 and 30 mg/kg) significantly inhibited PMA stimulated epidermal hyperplasia and intra-epidermal neutrophilic abscesses. In addition, its treatment effectively neutralized PMA induced elevated reactive oxygen species (ROS) generation on in vitro and in vivo systems, promoting antioxidant response. The association of hypoxia-inducible factor 1-alpha (HIF-1α)-nuclear factor kappa-light-chain-enhancer of activated b cells (NF-κB) crosstalk triggered by PMA enhanced PKCα-ERK1/2-NF-κB pathway; its activation was also significantly counteracted after TAN treatment. Conclusively, we demonstrated TAN inhibited the nuclear translocation of HIF-1α and NF-κB p65. Collectively, TAN treatment ameliorated PMA incited malignant inflammatory response by remodeling the cutaneous microenvironment.

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CD38 Deficiency Protects the Heart from Ischemia/Reperfusion Injury through Activating SIRT1/FOXOs-Mediated Antioxidative Stress Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/7410257 ◽

2016 ◽

Vol 2016 ◽

pp. 1-14 ◽

Cited By ~ 25

Author(s):

Xiao-Hui Guan ◽

Xiao-Hong Liu ◽

Xuan Hong ◽

Ning Zhao ◽

Yun-Fei Xiao ◽

...

Keyword(s):

Oxidative Stress ◽

Reperfusion Injury ◽

Nuclear Translocation ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Stable Cell Line ◽

Ros Generation ◽

H9c2 Cells ◽

Antioxidative Stress ◽

Stress Pathway

Ischemia/reperfusion (I/R) injury induces irreversible oxidative stress damage to the cardiac muscle. We previously observed that CD38 deficiency remarkably protects mouse embryonic fibroblasts (MEFs) from oxidative stress-induced injury. However, whether CD38 deficiency protects from I/R injury in the heart is not explored. Here, we showed that the hearts of CD38 deficient mice or wild type mice supplied with exogenous NAD were significantly protected from ischemia/reperfusion injury, seen as reduction of the myocardial infarct sizes when the mice were subjected to 30 min ischemia followed by 24 hours of reperfusion. Consistently, the protection of CD38 deficiency on hypoxia/reoxygenation (H/R) injury was confirmed with a CD38 knockdown H9c2 stable cell line. Furthermore, we observed that knockdown of CD38 remarkably inhibited ROS generation and intracellular Ca2+overloading induced by H/R in H9c2 cells. The FOXO1 and FOXO3 expressions were significantly elevated by H/R injury in CD38 knockdown cells compared with normal H9c2 cells. The cell immunofluorescence assay showed that FOXO1 nuclear translocation was significantly increased in CD38 knockdown H9c2 cells. In addition, we demonstrated that the increase of FOXO1 nuclear translocation was associated with the increased expressions of antioxidant catalase and SOD2 and the attenuated expression of the ROS generation enzyme NOX4. In conclusion, our results provide new evidence that CD38 deficiency protects the heart from I/R injury through activating SIRT1/FOXOs-mediated antioxidative stress pathway.

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Aralia taibaiensis Protects Cardiac Myocytes against High Glucose-Induced Oxidative Stress and Apoptosis

The American Journal of Chinese Medicine ◽

10.1142/s0192415x15500664 ◽

2015 ◽

Vol 43 (06) ◽

pp. 1159-1175 ◽

Cited By ~ 19

Author(s):

Jialin Duan ◽

Guo Wei ◽

Chao Guo ◽

Jia Cui ◽

Jiajia Yan ◽

...

Keyword(s):

Oxidative Stress ◽

Diabetic Cardiomyopathy ◽

High Glucose ◽

Nuclear Translocation ◽

Disease Risk ◽

Cardiovascular Disease Risk ◽

Liver Microsomes ◽

Ros Generation ◽

Rat Liver Microsomes ◽

H9c2 Cells

Patients with type 2 diabetes have increased cardiovascular disease risk compared with those without diabetes. Hyperglycemia can induce reactive oxygen species (ROS) generation, which contributes to the development of diabetic cardiomyopathy. Our previous study has demonstrated that the total saponins of Aralia taibaiensis (sAT), a frequently-used antidiabetic medicine in traditional Chinese medicine (TCM), can scavenge free radicals in vitro and have good anti-oxidant ability on lipid peroxidation of rat liver microsomes. This work was designed to investigate whether sAT could protect the heart while it was used in the treatment of diabetes. Oxidative stress was induced in H9c2 cells by high glucose (33 mM) and glucose oxidase (15 mU, G/GO) and the protective effects of sAT were evaluated. Treatment of H9c2 cells with G/GO resulted in an increase in cell death, intracellular ROS level and cell oxidative injury, which were markedly reduced by sAT treatment. Further study revealed that sAT induced the nuclear translocation of Nrf2 and expression of its downstream targets. Moreover, Nrf2 siRNA markedly abolished the cytoprotective effects of sAT. sAT exerted cytoprotective effects against oxidative stress induced by hyperglycemia and the cardioprotective effects of sAT might be through the Nrf2/ARE pathway. Thus, sAT might be a promising candidate for the treatment of diabetic cardiomyopathy.

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Protective Role of 4-Octyl Itaconate in Murine LPS/D-GalN-Induced Acute Liver Failure via Inhibiting Inflammation, Oxidative Stress, and Apoptosis

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/9932099 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Ruidong Li ◽

Wenchang Yang ◽

Yuping Yin ◽

Peng Zhang ◽

Yaxin Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Liver Failure ◽

Acute Liver Failure ◽

Murine Model ◽

Nuclear Translocation ◽

Thiobarbituric Acid ◽

Underlying Mechanism ◽

Protective Role ◽

Ros Generation ◽

Related Factor

Oxidative stress, inflammation, and apoptosis are crucial in the pathogenesis of acute liver failure (ALF). 4-Octyl itaconate (OI) showed antioxidative and anti-inflammatory properties in many disease models. However, its role in lipopolysaccharide- (LPS-)/D-galactosamine- (D-GalN-) induced ALF is still not investigated. Here, we established an ALF murine model induced by LPS/D-GalN administration. And we found that OI improved survival rate in the murine ALF model. Our results also showed that OI alleviated LPS/D-GalN-induced hepatic histopathological injury and reduced the serum activities of alanine transaminase and aspartate transaminase. Moreover, OI reduced serum levels of proinflammatory cytokines such as monocyte chemotactic protein-1, tumor necrosis factors-α, and interlukin-6. Additionally, OI mitigated oxidative stress and alleviated lipid peroxidation in a murine model of ALF. This was evaluated by a reduction of thiobarbituric acid reactive substances (TBARS) in liver tissues. In addition, OI increased the ratio of reduced glutathione/oxidized glutathione and the activities of antioxidant enzymes including catalase and superoxide dismutase. Moreover, the apoptosis of hepatocytes in the liver was inhibited by OI. Furthermore, we found that OI inhibited LPS-induced nuclear translocation and activation of factor-kappa B (NF-κB) p65 in macrophages which could be inhibited by OI-induced activation of nuclear factor erythroid-2-related factor (Nrf2) signaling. Additionally, D-GalN-induced reactive oxygen species (ROS) generation and apoptosis in hepatocytes were inhibited by OI-induced activation of Nrf2 signaling. Therefore, the underlying mechanism for OI’s protective effect in LPS/D-GalN-induced ALF may be associated with deactivation of NF-κB signaling in macrophages to reduce inflammation and inhibition of ROS-related hepatocyte apoptosis by activating Nrf2. In conclusion, OI showed a protective role in LPS/D-GalN-induced ALF by reducing inflammation, enhancing antioxidant capacity, and inhibiting cell apoptosis.

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