scholarly journals N-acetyl cysteine induces quiescent-like pancreatic stellate cells from an active state and attenuates cancer-stroma interactions

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Haimin Feng ◽  
Taiki Moriyama ◽  
Kenoki Ohuchida ◽  
Nan Sheng ◽  
Chika Iwamoto ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pancreatic Cancer ◽  
Stress Level ◽  
Lipid Droplets ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Oxidative Stress Level ◽  
Acetyl Cysteine ◽  
And Migration

Abstract Background Pancreatic stellate cells (PSCs) occupy the majority of the pancreatic cancer microenvironment, contributing to aggressive behavior of pancreatic cancer cells (PCCs). Recently, anti-fibrotic agents have proven to be an effective strategy against cancer, but clinical trials have shown little efficacy, and the driving mechanism remains unknown. N-acetyl-cysteine (NAC) is often used for pulmonary cystic fibrosis. Pioglitazone, an agonist of peroxisome proliferator-activated receptor gamma, was habitually used for type II diabetes, but recently reported to inhibit metastasis of PCCs. However, few studies have focused on the effects of these two agents on cancer-stromal interactions. Method We evaluated the expression of α-smooth muscle actin (α-SMA) and the number of lipid droplets in PSCs cultured with or without NAC. We also evaluated changes in invasiveness, viability, and oxidative level in PSCs and PCCs after NAC treatment. Using an indirect co-culture system, we investigated changes in viability, invasiveness, and migration of PSCs and PCCs. Combined treatment effects of NAC and Pioglitazone were evaluated in PSCs and PCCs. In vivo, we co-transplanted KPC-derived organoids and PSCs to evaluate the effects of NAC and Pioglitazone’s combination therapy on subcutaneous tumor formation and splenic xenografted mouse models. Results In vitro, NAC inhibited the viability, invasiveness, and migration of PSCs at a low concentration, but not those of PCCs. NAC treatment significantly reduced oxidative stress level and expression of α-SMA, collagen type I in PSCs, which apparently present a quiescent-like state with a high number of lipid droplets. Co-cultured PSCs and PCCs mutually promoted the viability, invasiveness, and migration of each other. However, these promotion effects were attenuated by NAC treatment. Pioglitazone maintained the NAC-induced quiescent-like state of PSCs, which were reactivated by PCC-supernatant, and enhanced chemosensitivity of PCCs. In vivo, NAC and Pioglitazone’s combination suppressed tumor growth and liver metastasis with fewer stromal components and oxidative stress level. Conclusion NAC suppressed activated PSCs and attenuated cancer-stromal interactions. NAC induces quiescent-like PSCs that were maintained in this state by pioglitazone treatment.

scholarly journals N-acetyl Cysteine Induces Quiescent-like Pancreatic Stellate Cells From an Active State and Attenuates Cancer-stroma Interactions

2020 ◽  
Author(s):  
Haimin Feng ◽  
Taiki Moriyama ◽  
Kenoki Ohuchida ◽  
Nan Sheng ◽  
Chika Iwamoto ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Mouse Model ◽  
Tumor Growth ◽  
Lipid Droplets ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Type I ◽  
Acetyl Cysteine ◽  
And Migration

Abstract Background: Pancreatic stellate cells (PSCs) occupy the majority of the pancreatic cancer microenvironment, contributing to an aggressive behavior of pancreatic cancer cells (PCCs). Recently, anti-fibrotic agents have proven to be an effective strategy against cancer, but clinical trials have shown little efficacy and the driving mechanism remains unknown. N-acetyl-cysteine (NAC) is often used for cystic fibrosis. Pioglitazone, an agonist of peroxisome proliferator-activated receptor gamma, was often used for type II diabetes, but recently reported to inhibit metastasis of PCCs. However, few studies have focused on the effects of these two agents on cancer-stromal interactions. Method: We evaluated the expression of α-smooth muscle actin (α-SMA) and the number of lipid droplets in PSCs cultured with or without NAC. We also evaluated changes in invasiveness and proliferation in PSCs and PCCs after NAC treatment. Using an indirect coculture system, we investigated changes in proliferation, invasiveness, and migration of PSCs and PCCs. Combined treatment effects of NAC and pioglitazone were evaluated in PSCs and PCCs. In vivo, PCCs and PSCs were subcutaneously injected into mice to evaluate tumor growth. We co-transplanted KPC-derived organoids and PSCs using a splenic xenografted mouse model and evaluated the effect of combination of NAC and pioglitazone.Results: In vitro, NAC inhibited the proliferation, invasiveness, and migration of PSCs at a low concentration, but not those of PCCs. NAC treatment significantly reduced expression of α-SMA, collagen type I and fibronectin in PSCs. NAC-treated PSCs apparently present quiescent-like state with a high number of lipid droplets. Co-cultured PSCs and PCCs mutually promoted the proliferation, invasiveness, and migration of each other. However, these promotion effects were attenuated by NAC treatment. Pioglitazone maintained the NAC-induced quiescent-like state of PSCs, which were reactivated by PCC-supernatant, and enhanced chemosensitivity of PCCs. In vivo, administration of NAC to mice with subcutaneously implanted PCCs and PSCs significantly reduced tumor growth with less stromal components. The combination of NAC and pioglitazone suppressed liver metastasis in the 3D-organoid xenografted mouse model Conclusion: NAC suppressed activated PSCs and attenuates cancer-stromal interactions. NAC induces quiescent-like PSCs that were maintained in this state by pioglitazone treatment.

scholarly journals ZBTB20 Positively Regulates Oxidative Stress, Mitochondrial Fission, and Inflammatory Responses of ox-LDL-Induced Macrophages in Atherosclerosis

2021 ◽  
Vol 2021 ◽  
pp. 1-18
Author(s):  
Jun Tao ◽  
Junxiong Qiu ◽  
Liuyi Lu ◽  
Lisui Zhang ◽  
Yuan Fu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stress Level ◽  
Inflammatory Responses ◽  
Oxidized Ldl ◽  
Mitochondrial Fission ◽  
Atherosclerotic Lesion ◽  
Density Lipoprotein ◽  
In Vivo Studies ◽  
Oxidative Stress Level

Atherosclerosis (AS) is one of the most serious and common cardiovascular diseases affecting human health. AS is featured by the accumulation of plaques in vessel walls. The pathophysiology of AS is relevant in the low-density lipoprotein (LDL) uptake by macrophages, as well as the conversion of macrophages to foam cells. However, the mechanisms about how macrophages regulate AS have not been fully elucidated. In this study, we aimed to illuminate the roles of ZBTB20 and to excavate the underlying regulative mechanisms of ZBTB20 in AS. The microarray analysis revealed that ZBTB20 was a hub gene in the oxidative stress and inflammatory responses induced by oxidized LDL (ox-LDL) in AS. Correspondingly, our validation studies showed that ZBTB20 increased in either the human atherosclerotic lesion or the ox-LDL-stimulated macrophages. Moreover, the knockdown of ZBTB20 decreased M1 polarization, suppressed the proinflammatory factors, inhibited mitochondrial fission, and reduced the oxidative stress level of macrophages induced by ox-LDL. The mechanistic studies revealed that the ZBTB20 knockdown suppressed NF-κB/MAPK activation and attenuated the mitochondrial fission possibly via regulating the nucleus translocation of NRF2, a pivotal transcription factor on redox homeostasis. Our in vivo studies showed that the sh-ZBTB20 adenovirus injection could reduce the progression of AS in apolipoprotein E-deficient (ApoE-/-) mice. All in all, these results suggested that ZBTB20 positively regulated the oxidative stress level, mitochondrial fission, and inflammatory responses of macrophages induced by ox-LDL, and the knockdown of ZBTB20 could attenuate the development of AS in ApoE-/- mice.

scholarly journals O-P03 A composite polymeric nanoparticle as a sensitiser for sonodynamic therapy (SDT)-based treatment of pancreatic cancer

2021 ◽  
Vol 108 (Supplement_9) ◽  
Author(s):  
Sian Farrell ◽  
Heather Nesbitt ◽  
Laura Mairs ◽  
Nikolitsa Nomikou ◽  
Bridgeen Callan ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Power Density ◽  
Stellate Cells ◽  
Composite Nanoparticles ◽  
Pancreatic Stellate Cells ◽  
Residual Tumour ◽  
Tumour Stroma ◽  
The Impact

Abstract Background Pancreatic cancer remains one of the most recalcitrant forms of cancer with poor prognosis and limited treatment options. SDT is a novel, targeted approach to the treatment of solid tumours. Based on the generation of cytotoxic reactive oxygen species (ROS) following the exposure of a sonosensitiser to ultrasound, the approach is designed to extracorporeally target less accessible lesions. Here we describe the production of a poly(lactic-co-glycolic acid) (PLGA), polyethyleneimine (PEI), Rose Bengal (RB) and indocyanine green (ICG) containing composite nanoparticles and describe their use in SDT-mediated treatment of pancreatic cancer using both in vitro and in vivo target models. Methods Nanoparticles were prepared using an oil in water emulsion and solvent diffusion-based approach. These were designated RB-ICGNP. In vitro SDT treatment consisted of exposing BxPC3 (human PDAC cells), T110029 (murine PDAC cells) or hPSC (immortalised human pancreatic stellate cells) to RB-ICGNP and subsequently treating with ultrasound for 30 s at a frequency of 1 MHz, a power density of 3.0 W/cm2 (SATP) using a duty cycle of 50% at a pulse repetition frequency of 100 Hz. For in vivo studies, BxPC3 (xenograft) and T110029 (syngeneic) tumours were treated with a power density of 3.5 W/cm2 ultrasound for 3.5 min. Results Conclusions Using in vitro and in vivo (human xenograft and murine syngeneic) models of pancreatic cancer, RB-ICGNP composite nanoparticles may be employed as a sensitiser for SDT-based treatment of pancreatic cancer. Since pancreatic stellate cells were more sensitive to SDT, the latter may have an impact on tumour stroma. Staining of residual tumour tissues from SDT-treated animals for connective tissue (stroma) confirmed the latter. Since tumour stroma presents a significant challenge to treatment of pancreatic cancer and represents a negative prognostic marker, the impact delivered by SDT may be exploited to potentiate alternative therapeutic approaches.

Regulation of Influenza Virus-Caused Oxidative Stress by Kegan Liyan Oral Prescription, as Monitored by Ascorbyl Radical ESR Signals

2009 ◽  
Vol 37 (06) ◽  
pp. 1167-1177 ◽  
Author(s):  
Shaojin Duan ◽  
Lizhen Gu ◽  
Yanyun Wang ◽  
Rongbo Zheng ◽  
Jingfen Lu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Ascorbic Acid ◽  
Influenza Virus ◽  
Stress Level ◽  
Down Regulation ◽  
Oxidative Stress Level ◽  
Virus Pneumonia ◽  
Healthy Control

To study the oxidative stress level of the influenza virus A FM1 subset-infected mouse in intranasal inhalation as a model, we employ an ascorbyl radical's ESR (electron spin resonance) spectrum as an oxidative stress biomarker. These infected mice were pretreated with Ribavirin, ascorbic acid, superoxide dismutase (SOD) or Kegan Liyan oral prescription (KGLY, proprietary Chinese medicine for influenza and common cold) in the stomach tube for 3 days, and then followed by the virus-infecting for 4 days. On the 4th day, samples were collected. It is recognized the strength of ascorbyl radical's ESR signal ( A -.) (a H4 = 0.177 Gauss, g = 2.00517) denotes oxidative stress level in vivo and in vitro. The magnitude of ESR spectrum (28.65 ± 10.71 AU) in mice infected with influenza virus was significantly higher than those of healthy control mice (19.10 ± 3.61 AU). Serum A -. in mice treated with Ribavirin, ascorbic acid, SOD and KGLY declined to 19.70 ± 6.05, 18.50 ± 2.93 and 16.25 ± 3.59, 18.40 ± 2.14 AU respectively. It is close to A -. signal height in healthy controls via down-regulation of the influenza virus-caused oxidative stress level getting decline in the lung index of pneumonia as compare to those of untreated healthy and the influenza virus infected mice pneumonia. It is well known that SOD can prevent the influenza virus pneumonia enhancing mouse survival rate; Ribavirin can treat viral diseases. Data from this study suggested that KGLY may indirectly relieve influenza virus-infected pneumonia via down- regulation of virus caused oxidative stress coupled with a redox reaction cascade as ribavirin, ascorbic acid and SOD.

scholarly journals HGF/MET Axis Induces Tumor Secretion of Tenascin-C and Promotes Stromal Rewiring in Pancreatic Cancer

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3519
Author(s):  
Chiara Modica ◽  
Martina Olivero ◽  
Francesca Zuppini ◽  
Melissa Milan ◽  
Cristina Basilico ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Stromal Compartment ◽  
Tenascin C ◽  
Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma is an aggressive tumor characterized by the presence of an abundant stromal compartment contributing significantly to the malignant phenotype. Pancreatic stellate cells are peculiar fibroblasts present in the stroma and represent the predominant source of extracellular matrix proteins, pro-inflammatory cytokines, and growth factors, including hepatocyte growth factor (HGF). Exploiting a co-culture system of human pancreatic stellate cells and cancer cells, we demonstrated that fibroblast activation was reduced upon HGF/MET axis inhibition. To unveil the signaling pathways sustaining stroma modulation orchestrated by MET activation in the tumor, we analyzed the gene expression profile in pancreatic cancer cells stimulated with HGF and treated with HGF/MET inhibitors. Transcriptome analysis showed that, among all the genes modulated by HGF, a subset of 125 genes was restored to the basal level following treatment with the inhibitors. By examining these genes via ingenuity pathway analysis, tenascin C emerged as a promising candidate linking MET signaling and tumor microenvironment. MET-dependent tenascin C modulation in pancreatic cancer cells was validated at RNA and protein levels both in vitro and in vivo. In conclusion, this work identifies tenascin C as a gene modulated by MET activation, suggesting a role in MET-mediated tumor-stroma interplay occurring during pancreatic tumor progression.

Development of the Express Method for Determining the Oxidative Stress Level of the Population

Food Industry ◽  
2018 ◽  
Vol 3 (4) ◽  
Author(s):  
Ekaterina V. Pastushkova ◽  
Olga V. Chugunova ◽  
Leonid S. Volkanin
Keyword(s):  
Oxidative Stress ◽  
Stress Level ◽  
Express Method ◽  
Oxidative Stress Level
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