scholarly journals Amylin deposition activates HIF1α and 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3) signaling in failing hearts of non-human primates

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Miao Liu ◽  
Nan Li ◽  
Chun Qu ◽  
Yilin Gao ◽  
Lijie Wu ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Hypoxia Inducible Factor ◽  
Oxygen Species ◽  
Promising Target ◽  
Fructose 2 ◽  
Intracellular Ca ◽  
Underlying Mechanisms ◽  
Lactate Levels

AbstractHyperamylinemia induces amylin aggregation and toxicity in the pancreas and contributes to the development of type-2 diabetes (T2D). Cardiac amylin deposition in patients with obesity and T2D was found to accelerate heart dysfunction. Non-human primates (NHPs) have similar genetic, metabolic, and cardiovascular processes as humans. However, the underlying mechanisms of cardiac amylin in NHPs, particularly related to the hypoxia inducible factor (HIF)1α and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) signaling pathways, are unknown. Here, we demonstrate that in NHPs, amylin deposition in heart failure (HF) contributes to cardiac dysfunction via activation of HIF1α and PFKFB3 signaling. This was confirmed in two in vitro cardiomyocyte models. Furthermore, alterations of intracellular Ca2+, reactive oxygen species, mitochondrial function, and lactate levels were observed in amylin-treated cells. Our study demonstrates a pathological role for amylin in the activation of HIF1α and PFKFB3 signaling in NHPs with HF, establishing amylin as a promising target for heart disease patients.

scholarly journals Molecular and Cellular Mechanisms of Metformin in Cervical Cancer

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2545
Author(s):  
Ya-Hui Chen ◽  
Po-Hui Wang ◽  
Pei-Ni Chen ◽  
Shun-Fa Yang ◽  
Yi-Hsuan Hsiao
Keyword(s):  
Cervical Cancer ◽  
Potential Role ◽  
Treatment Options ◽  
Cellular Mechanisms ◽  
Anticancer Effects ◽  
Clinical Benefits ◽  
Underlying Mechanisms

Cervical cancer is one of the major gynecologic malignancies worldwide. Treatment options include chemotherapy, surgical resection, radiotherapy, or a combination of these treatments; however, relapse and recurrence may occur, and the outcome may not be favorable. Metformin is an established, safe, well-tolerated drug used in the treatment of type 2 diabetes; it can be safely combined with other antidiabetic agents. Diabetes, possibly associated with an increased site-specific cancer risk, may relate to the progression or initiation of specific types of cancer. The potential effects of metformin in terms of cancer prevention and therapy have been widely studied, and a number of studies have indicated its potential role in cancer treatment. The most frequently proposed mechanism underlying the diabetes–cancer association is insulin resistance, which leads to secondary hyperinsulinemia; furthermore, insulin may exert mitogenic effects through the insulin-like growth factor 1 (IGF-1) receptor, and hyperglycemia may worsen carcinogenesis through the induction of oxidative stress. Evidence has suggested clinical benefits of metformin in the treatment of gynecologic cancers. Combining current anticancer drugs with metformin may increase their efficacy and diminish adverse drug reactions. Accumulating evidence is indicating that metformin exerts anticancer effects alone or in combination with other agents in cervical cancer in vitro and in vivo. Metformin might thus serve as an adjunct therapeutic agent for cervical cancer. Here, we reviewed the potential anticancer effects of metformin against cervical cancer and discussed possible underlying mechanisms.

scholarly journals KCNQ1OT1 accelerates gastric cancer progression via miR-4319/DRAM2 axis

2020 ◽  
Vol 34 ◽  
pp. 205873842095459
Author(s):  
Jijun Wang ◽  
Fan Wu ◽  
Yaoyao Li ◽  
Lei Pang ◽  
Xiaohong Wang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Growth ◽  
Cancer Progression ◽  
Promising Target ◽  
Tumor Tissues ◽  
Rna Immunoprecipitation ◽  
Opposite Strand ◽  
Underlying Mechanisms

Introduction: This work was to explore the connection of KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1) and microRNA-4319 (miR-4319), and to investigate the associated underlying mechanisms in gastric cancer (GC) progression. Methods: Quantitative real-time PCR was performed to measure KCNQ1OT1, miR-4319 and DNA-damage regulated autophagy modulator 2 (DRAM2) expression levels in GC cells. Moreover, expression level of KCNQ1OT1 and DRAM2 in GC tissues was analyzed at ENCORI website ( http://starbase.sysu.edu.cn/index.php ). Cell proliferation, colony formation assay and flow cytometry assays were performed to analyze effects of KCNQ1OT1, miR-4319 and DRAM2 on cell growth and death. Dual-luciferase activity reporter assay and RNA immunoprecipitation assay was conducted to verify the interactions of KCNQ1OT1 or DRAM2 and miR-4319. Results and Conclusion: We found KCNQ1OT1 level was increased in tumor tissues and cells. Force the expression of KCNQ1OT1 promotes, while knockdown KCNQ1OT1 inhibits GC cell growth. Further studies indicated miR-4319 functioned as a bridge between KCNQ1OT1 and DRAM2. Finally, we showed KCNQ1OT1/miR-4319/DRAM2 axis regulates GC cell growth in vitro and in vivo. lncRNA KCNQ1OT1 promotes GC progression by sponging miR-4319 to upregulate DRAM2, indicating KCNQ1OT1 might be a promising target for GC treatment.

scholarly journals Loss of the SdhB, but Not the SdhA, Subunit of Complex II Triggers Reactive Oxygen Species-Dependent Hypoxia-Inducible Factor Activation and Tumorigenesis

2007 ◽  
Vol 28 (2) ◽  
pp. 718-731 ◽  
Author(s):  
Robert D. Guzy ◽  
Bhumika Sharma ◽  
Eric Bell ◽  
Navdeep S. Chandel ◽  
Paul T. Schumacker
Keyword(s):  
Reactive Oxygen Species ◽  
Rna Interference ◽  
Growth Rates ◽  
Hypoxia Inducible Factor ◽  
Tumor Formation ◽  
Ros Production ◽  
Oxygen Species ◽  
Complex Ii

ABSTRACT Mitochondrial complex II is a tumor suppressor comprised of four subunits (SdhA, SdhB, SdhC, and SdhD). Mutations in any of these should disrupt complex II enzymatic activity, yet defects in SdhA produce bioenergetic deficiency while defects in SdhB, SdhC, or SdhD induce tumor formation. The mechanisms underlying these differences are not known. We show that the inhibition of distal subunits of complex II, either pharmacologically or via RNA interference of SdhB, increases normoxic reactive oxygen species (ROS) production, increases hypoxia-inducible factor alpha (HIF-α) stabilization in an ROS-dependent manner, and increases growth rates in vitro and in vivo without affecting hypoxia-mediated activation of HIF-α. Proximal pharmacologic inhibition or RNA interference of complex II at SdhA, however, does not increase normoxic ROS production or HIF-α stabilization and results in decreased growth rates in vitro and in vivo. Furthermore, the enhanced growth rates resulting from SdhB suppression are inhibited by the suppression of HIF-1α and/or HIF-2α, indicating that the mechanism of SdhB-induced tumor formation relies upon ROS production and subsequent HIF-α activation. Therefore, differences in ROS production, HIF proliferation, and cell proliferation contribute to the differences in tumor phenotype in cells lacking SdhB as opposed to those lacking SdhA.

Abstract 343: Upregulated S1P Lyase Exerts Cardioprotective Effects through Inhibiting S1P/HIF-1a-Mediated Oxidative/Nitrative Stress during Myocardial Ischemia/Reperfusion

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Ling Tao ◽  
Wenjun Yan ◽  
Fen Zhou ◽  
Fuyang Zhang ◽  
Lu Sun ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Ischemia Reperfusion ◽  
Hypoxia Inducible Factor ◽  
Group Versus ◽  
Coronary Artery Occlusion ◽  
Saline Group ◽  
Neonatal Rat ◽  
Nitrative Stress ◽  
Underlying Mechanisms ◽  
S1p Lyase

Sphingosine-1-phosphate (S1P) signaling directs a diverse array of biological processes, such as anti-apoptosis, promoting in[[Unable to Display Character: &#64258;]]ammatory, and inducing fibrosis. Therefore, S1P levels need to be tightly controlled through the delicate interplay of its generating enzymes and its degrading enzymes. S1P lyase (SPL1) is a stress-activated enzyme responsible for irreversible S1P catabolism. This study was designed to determine the role of SPL1 in ischemia/reperfusion (I/R) induced cardiac dysfunction and the underlying mechanisms. Mice were subjected to 40 minutes left coronary artery occlusion followed by reperfusion for 24 hours, 1 week, or 4 weeks. First, we observed that SPL1 expression in cardiac tissue was upregulated by about 4-fold in response to I/R (n=6, P <0.01 versus sham). Further, oral administration of THI (an SPL1 inhibitor, 25 mg/L, daily) increased plasma S1P level and deteriorated I/R-induced apoptosis and fibrosis determined 1 week after I/R (all P <0.05 versus I/R + saline group), and cardiac dysfunction (ejection fraction: 39.1 ± 3.1% in I/R + THI group versus 50.7 ± 2.8% in I/R + saline group determined 4 weeks after I/R, P <0.05). After 1 week of I/R, hearts from THI-fed mice exhibited increased hypoxia-inducible factor-1α (HIF-1α) expression, along with significant oxidative/nitrative damage as evidenced by gp91 phox , inducible nitric oxide synthase (iNOS), and 3-nitrotyrosine abundance (all P <0.05 versus vehicle). To define the underlying mechanisms of SPL1 in I/R-induced heart injury, neonatal rat ventricular myocytes were cultured and submitted to hypoxia/reoxygenation (H/R, 9 hours/3 hours) with or without THI treatment. Importantly, THI significantly increased gp91 phox , iNOS, and 3-nitrotyrosine level, as well as apoptosis (n=8, all P <0.05 versus H/R), all of which were inhibited by pretreatment with HIF-1α siRNA (all P <0.05 versus scramble RNA). The present study demonstrated for the first time that SPL1 is remarkably upregulated during I/R and protects heart from I/R-induced S1P/HIF-1α-mediated oxidative/nitrative stress, suggesting SPL1 as a potential targets of therapy for ischemic heart disease.

scholarly journals Ultraviolet light A irradiation induces immunosuppression associated with the generation of reactive oxygen species in human neutrophils

2016 ◽  
Vol 09 (01) ◽  
pp. 1650001 ◽  
Author(s):  
Cunbo Li ◽  
Xuechen Shi ◽  
Mincai Chen ◽  
Guangxue Xu ◽  
Xinglei Su ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Ultraviolet Light ◽  
Inflammatory Responses ◽  
Reactive Oxygen ◽  
Human Neutrophils ◽  
Oxygen Species ◽  
Immune Functions ◽  
Uva Irradiation ◽  
Underlying Mechanisms

Ultraviolet blood irradiation has been used as a physical therapy to treat many nonspecific diseases in clinics; however, the underlying mechanisms remain largely unclear. Neutrophils, the first line of host defense, play a crucial role in a variety of inflammatory responses. In the present work, we investigated the effects of ultraviolet light A (UVA) on the immune functions of human neutrophils at the single-cell level by using an inverted fluorescence microscope. N-Formyl-methionyl-leucyl-phenylalanine (FMLP), a classic physiological chemotactic peptide, was used to induce a series of immune responses in neutrophils in vitro. FMLP-induced calcium mobilization, migration, and phagocytosis in human neutrophils was significantly blocked after treatment with 365[Formula: see text]nm UVA irradiation, demonstrating the immunosuppressive effects of UVA irradiation on neutrophils. Similar responses were also observed when the cells were pretreated with H2O2, a type of reactive oxygen species (ROS). Furthermore, UVA irradiation resulted in an increase in NAD(P)H, a member of host oxidative stress in cells. Taken together, our data indicate that UVA irradiation results in immunosuppression associated with the production of ROS in human neutrophils.

scholarly journals Pterostilbene Alleviates Cholestasis by Promoting SIRT1 Activity in Hepatocytes and Macrophages

2021 ◽  
Vol 12 ◽  
Author(s):  
Chuanrui Ma ◽  
Jiaqing Xiang ◽  
Guixiao Huang ◽  
Yaxi Zhao ◽  
Xinyu Wang ◽  
...  
Keyword(s):  
Liver Injury ◽  
Signaling Pathway ◽  
Cholestatic Liver Disease ◽  
P53 Signaling ◽  
Promising Target ◽  
Underlying Mechanisms ◽  
Cholestatic Liver Injury ◽  
P53 Signaling Pathway

Background and purpose: FXR is a promising target for the treatment of human cholestatic liver disease (CLD). SIRT1 is a deacetylase which promotes FXR activity through deacetylating FXR. Pterostilbene (PTE) is an activator of SIRT1. However, the role of PTE in cholestasis has so far not been investigated. We examined whether PTE treatment alleviate liver injury in DDC or ANIT-induced experimental cholestasis, and explored the underlying mechanisms.Experimental approach: Mice with DDC- or ANIT-induced cholestasis were treated with different dose of PTE. Primary hepatocytes and bone marrow derived macrophages were used in vitro to assess the molecular mechanism by which PTE may improve CLD. Identical doses of UDCA or PTE were administered to DDC- or ANIT-induced cholestasis mice.Key results: PTE intervention attenuated DDC or ANIT-induced cholestasis. PTE inhibited macrophage infiltration and activation in mouse liver through the SIRT1-p53 signaling pathway, and it improved hepatic bile metabolism through the SIRT1-FXR signaling pathway. Compare with UDCA, the same doses of PTE was more effective in improving cholestatic liver injury caused by DDC or ANIT.Conclusion and implications: SIRT1 activation in macrophages may be an effective CLD treatment avenue. Using CLD models, we thus identified PTE as a novel clinical candidate compound for the treatment of CLD.

scholarly journals Apatinib Promotes Apoptosis of Pancreatic Cancer Cells through Downregulation of Hypoxia-Inducible Factor-1α and Increased Levels of Reactive Oxygen Species

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Ke He ◽  
Lu Wu ◽  
Qianshan Ding ◽  
Farhan Haider ◽  
Honggang Yu ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Cycle ◽  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Biological Function ◽  
Hypoxia Inducible Factor ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Pancreatic Cancer Cells

At present, apatinib is considered a new generation agent for the treatment of patients with gastric cancer. However, the effects of apatinib on pancreatic cancer have not been clarified. This study investigated the impact of apatinib on the biological function of pancreatic cancer cells and the potential mechanism involved in this process. Using the Cell Counting Kit-8 method, we confirmed that apatinib treatment inhibited cell proliferation in vitro. Moreover, the migration rate of pancreatic cells was inhibited. The effects of apatinib on apoptosis and cell cycle distribution of pancreatic carcinoma cells were detected by flow cytometry. The number of apoptotic cells was significantly increased, and the cell cycle was altered. Furthermore, we demonstrated that apatinib inhibited the expression of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor, and markers of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR signaling pathway, which increased the levels of reactive oxygen species in vitro. Apatinib significantly inhibited the biological function of pancreatic cancer cells. It promoted apoptosis, downregulated the expression of HIF-1α, and increased the levels of reactive oxygen species.

Hyperlipidemia Impairs Osseointegration via the ROS/Wnt/β-Catenin Pathway

2021 ◽  
pp. 002203452098324
Author(s):  
Y.N. Wang ◽  
T.T. Jia ◽  
Y. Feng ◽  
S.Y. Liu ◽  
W.J. Zhang ◽  
...  
Keyword(s):  
Titanium Surface ◽  
Titanium Implant ◽  
Titanium Implants ◽  
Oxygen Species ◽  
High Fat ◽  
Promising Therapeutic Target ◽  
Novel Drugs ◽  
Underlying Mechanisms

The influence of hyperlipidemia on titanium implant osseointegration and the underlying mechanisms is not well understood. This study investigates the changes in osseointegration and explores the potential mechanisms in hyperlipidemia conditions. In vivo, specialized titanium implants were implanted in the femurs of diet-induced or genetic hyperlipidemia mice. In vitro, primary murine osteoblasts were cultured on the titanium surface in high-fat medium. Results showed that hyperlipidemia led to poor osseointegration in both types of mice in vivo, and high-fat medium impaired the osteogenic differentiation of primary osteoblasts on the titanium surface in vitro. In addition, high-fat medium caused significant overproduction of reactive oxygen species (ROS) and inhibition of the Wnt/β-catenin pathway in osteoblasts. Both N-acetyl-L-cysteine (NAC, an ROS antagonist) and Wnt3a (an activator of the Wnt/β-catenin pathway) attenuated the poor osteogenic ability of osteoblasts. In addition, NAC reactivated the Wnt/β-catenin pathway in osteoblasts under high-fat stimulation. These results demonstrate that hyperlipidemia impairs osseointegration via the ROS/Wnt/β-catenin pathway and provide support for the ROS or Wnt/β-catenin pathway as a promising therapeutic target for the development of novel drugs or implant materials to improve the osseointegration of implants in hyperlipidemic patients.

scholarly journals Harmine Alleviated Sepsis-Induced Cardiac Dysfunction by Modulating Macrophage Polarization via the STAT/MAPK/NF-κB Pathway

2022 ◽  
Vol 9 ◽  
Author(s):  
Weibin Ruan ◽  
Xinyun Ji ◽  
Yating Qin ◽  
Xinxin Zhang ◽  
Xiaoning Wan ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Macrophage Polarization ◽  
Raw 264.7 Cells ◽  
Drug Induced ◽  
M1 Polarization ◽  
M1 Phenotype ◽  
Phenotype Markers ◽  
Cox 2 ◽  
Underlying Mechanisms

Sepsis is a dysregulated systemic inflammatory response that often leads to cardiac dysfunction, which is termed sepsis-induced cardiomyopathy (SIC). Harmine, a natural β-carboline alkaloid compound, has been shown to exert pharmacological effects on several diseases. Here, we investigated whether harmine protected against SIC development and the underlying mechanisms. In vitro, the expression of the M1 phenotype markers iNOS and COX-2 was increased in RAW 264.7 cells stimulated with lipopolysaccharide (LPS), but this effect was reversed by the harmine intervention. Furthermore, LPS-induced increases in the levels of inflammatory cytokines, including IL-1β, IL-6, TNF-α, iNOS, COX-2, PGE2 and TXB2, generated by macrophages were suppressed when the cells were pretreated with harmine. Meanwhile, our findings showed that harmine administration effectively attenuated inflammation and apoptosis in H9c2 cells in the proinflammatory environment produced by macrophages, as evidenced by reductions in NLRP3 and cleaved caspase 3 levels and the p-NF-κB/NF-κB ratio. The western blot results indicated that the mechanisms underlying harmine-mediated inhibition of M1 polarization might be associated with suppression of STAT1/3, NF-κB and MAPK activation. Furthermore, an LPS injection induced cardiac dysfunction and decreased the survival rate of mice, which were alleviated by harmine treatment, and the relevant mechanism was possibly attributed to a drug-induced attenuation of the inflammatory and apoptotic processes in cardiomyocytes. Collectively, these results implied that harmine treatment protected against SIC by suppressing M1 phenotypic polarization and inflammation in macrophages.

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