scholarly journals Non-Lethal Sonodynamic Therapy Inhibits Atherosclerotic Plaque Progression in ApoE-/- Mice and Attenuates ox-LDL-mediated Macrophage Impairment by Inducing Heme Oxygenase-1

2017 ◽  
Vol 41 (6) ◽  
pp. 2432-2446 ◽  
Author(s):  
Yu Wang ◽  
Wei Wang ◽  
Haobo Xu ◽  
Yan Sun ◽  
Jing Sun ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Western Blotting ◽  
Heme Oxygenase ◽  
Atherosclerotic Plaque ◽  
Heme Oxygenase 1 ◽  
Atherosclerotic Plaques ◽  
Protective Effects ◽  
Plaque Progression ◽  
Sonodynamic Therapy ◽  
Low Intensity

Background: Previous studies from our group showed that low-intensity sonodynamic therapy (SDT) has protective effects on atherosclerosis (AS). However, because the intensity of ultrasound passing through tissue is attenuated, the consequences of very low-intensity SDT, referred to as non-lethal SDT (NL-SDT), on atherosclerotic plaques are unclear. The aim of this study was to determine whether NL-SDT affects atherosclerotic plaques and to elucidate the possible underlying mechanisms. Methods: An AS model was established using ApoE-/- mice fed a western diet. En face Oil Red O staining was used to measure atherosclerotic plaque size. Hematoxylin and eosin staining and immunohistochemical staining were used to observe plaque morphology and assess the location of macrophages and heme oxygenase 1 (HO-1). HO-1 mRNA and protein levels in AS plaques were evaluated by real-time PCR and western blotting. Human THP-1 cells and mouse peritoneal macrophages were used in this study. Western blotting was used to investigate the expression of cellular proteins after NL-SDT. Macrophage apoptosis was evaluated by TUNEL assays and flow cytometry with Annexin V/PI double staining. Intracellular reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were measured with 2′-7′-dichlorofluorescein diacetate (DCFH-DA) and 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethyl benzimidazolyl carbocyanine iodide (JC-1) staining, respectively. Results: NL-SDT significantly inhibited AS progression and reduced the necrotic core area. NL-SDT induced HO-1 expression in lesional macrophages and in cultured macrophages. NL-SDT activated the protein kinase B (AKT) and extracellular signal-related protein kinase (ERK) pathways and the transcription factor NF-E2-related factor 2 (Nrf2).NL-SDT significantly reduced oxidized LDL (ox-LDL)-induced macrophage MMP collapse, ROS production and cell apoptosis. Zinc protoporphyrin (ZnPP), a HO-1-specific inhibitor, reversed the protective effects of NL-SDT. Conclusion: NL-SDT inhibits atherosclerotic plaque progression and increases plaque stability. In vitro, NL-SDT has a protective effect on ox-LDL-induced macrophage impairment via HO-1.

Rapid inhibition of atherosclerotic plaque progression by sonodynamic therapy

2018 ◽  
Vol 115 (1) ◽  
pp. 190-203 ◽  
Author(s):  
Xin Sun ◽  
Shuyuan Guo ◽  
Jianting Yao ◽  
Huan Wang ◽  
Chenghai Peng ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Standard Of Care ◽  
Atherosclerotic Plaques ◽  
Plaque Progression ◽  
Peripheral Artery ◽  
Sonodynamic Therapy ◽  
Non Invasive ◽  
Atherosclerotic Burden ◽  
Artery Disease ◽  
Apoe Deficient Mouse

Abstract Aims Currently, efficient regimens to reverse atherosclerotic plaques are not available in the clinic. Herein, we present sonodynamic therapy (SDT) as a novel methodology to rapidly inhibit progression of atherosclerotic plaques. Methods and results In atherosclerotic rabbit and apoE-deficient mouse models, SDT efficiently decreased the atherosclerotic burden within 1 week, revealing a decrease in the size of the atherosclerotic plaque and enlarged lumen. The shrunken atherosclerotic plaques displayed compositional alterations, with a reduction in lesional macrophages and lipids. The rapid efficacy of SDT may be due to its induction of macrophage apoptosis, enhancement of efferocytosis, and amelioration of inflammation in the atherosclerotic plaque. Compared with atorvastatin, the standard of care for atherosclerosis, SDT showed more significant plaque shrinkage and lumen enlargement during 1 week treatment. Furthermore, SDT displayed good safety without obvious side effects. In a pilot clinical trial recruiting the patients suffering atherosclerotic peripheral artery disease, combination therapy of SDT with atorvastatin efficiently reduced progression of atherosclerotic plaque within 4 weeks, and its efficacy was able to last for at least 40 weeks. Conclusion SDT is a non-invasive and efficacious regimen to inhibit atherosclerotic plaque progression.

scholarly journals Upregulation of Heme Oxygenase-1 by Hemin Alleviates Sepsis-Induced Muscle Wasting in Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Xiongwei Yu ◽  
Wenjun Han ◽  
Changli Wang ◽  
Daming Sui ◽  
Jinjun Bian ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Heme Oxygenase ◽  
Muscle Atrophy ◽  
Muscle Wasting ◽  
Cecal Ligation ◽  
Skeletal Muscle Atrophy ◽  
Enzyme Linked Immunosorbent Assay ◽  
Heme Oxygenase 1 ◽  
Protective Effects ◽  
Sod Activity

Hemin, an inducer of heme oxygenase-1 (HO-1), can enhance the activation of HO-1. HO-1 exhibits a variety of activities, such as anti-inflammatory, antioxidative, and antiapoptotic functions. The objective of this study was to investigate the effects of hemin on sepsis-induced skeletal muscle wasting and to explore the mechanisms by which hemin exerts its effects. Cecal ligation and perforation (CLP) was performed to create a sepsis mouse model. Mice were randomly divided into four groups: control, CLP, CLP plus group, and CLP-hemin-ZnPP (a HO-1 inhibitor). The weight of the solei from the mice was measured, and histopathology was examined. Cytokines were measured by enzyme-linked immunosorbent assay (ELISA). Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting were used to assess the expression levels of HO-1 and atrogin-1. Furthermore, we investigated the antioxidative effects of HO-1 by detecting malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity. CLP led to dramatic skeletal muscle weakness and atrophy, but pretreatment with hemin protected mice against CLP-mediated muscle atrophy. Hemin also induced high HO-1 expression, which resulted in suppressed proinflammatory cytokine and reactive oxygen species (ROS) production. The expression of MuRF1 and atrogin-1, two ubiquitin ligases of the ubiquitin-proteasome system- (UPS-) mediated proteolysis, was also inhibited by increased HO-1 levels. Hemin-mediated increases in HO-1 expression exert protective effects on sepsis-induced skeletal muscle atrophy at least partly by inhibiting the expression of proinflammatory cytokines, UPS-mediated proteolysis, and ROS activation. Therefore, hemin might be a new treatment target against sepsis-induced skeletal muscle atrophy.

Mechanism of Hepatic Heme Oxygenase-1 Induction by Isoflurane

2006 ◽  
Vol 104 (1) ◽  
pp. 101-109 ◽  
Author(s):  
Alexander Hoetzel ◽  
Daniel Leitz ◽  
Rene Schmidt ◽  
Eva Tritschler ◽  
Inge Bauer ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Phospholipase A2 ◽  
Heme Oxygenase ◽  
Kupffer Cell ◽  
Cell Function ◽  
Heme Oxygenase 1 ◽  
Gadolinium Chloride ◽  
Kinase C

Background The heme oxygenase pathway represents a major cell and organ protective system in the liver. The authors recently showed that isoflurane and sevoflurane up-regulate the inducible isoform heme oxygenase 1 (HO-1). Because the activating cascade remained unclear, it was the aim of this study to identify the underlying mechanism of this effect. Methods Rats were anesthetized with pentobarbital intravenously or with isoflurane per inhalation (2.3 vol%). Kupffer cell function was inhibited by dexamethasone or gadolinium chloride. Nitric oxide synthases were inhibited by either N(omega)-nitro-L-arginine methyl ester or S-methyl thiourea. N-acetyl-cysteine served as an antioxidant, and diethyldithiocarbamate served as an inhibitor of cytochrome P450 2E1. Protein kinase C and phospholipase A2 were inhibited by chelerythrine or quinacrine, respectively. HO-1 was analyzed in liver tissue by Northern blot, Western blot, immunostaining, and enzymatic activity assay. Results In contrast to pentobarbital, isoflurane induced HO-1 after 4-6 h in hepatocytes in the pericentral region of the liver. The induction was prevented in the presence of dexamethasone (P < 0.05) and gadolinium chloride (P < 0.05). Inhibition of nitric oxide synthases or reactive oxygen intermediates did not affect isoflurane-mediated HO-1 up-regulation. In contrast, chelerythrine (P < 0.05) and quinacrine (P < 0.05) resulted in a blockade of HO-1 induction. Conclusion The up-regulation of HO-1 by isoflurane in the liver is restricted to parenchymal cells and depends on Kupffer cell function. The induction is independent of nitric oxide or reactive oxygen species but does involve protein kinase C and phospholipase A2.

scholarly journals Hydromorphone Protects against CO2 Pneumoperitoneum-Induced Lung Injury via Heme Oxygenase-1-Regulated Mitochondrial Dynamics

2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Jia Shi ◽  
Shi-Han Du ◽  
Jian-Bo Yu ◽  
Yan-Fang Zhang ◽  
Si-Meng He ◽  
...  
Keyword(s):  
Lung Injury ◽  
Heme Oxygenase ◽  
Mitochondrial Dynamics ◽  
Stress Index ◽  
Heme Oxygenase 1 ◽  
Mitochondrial Morphology ◽  
Gynecological Surgery ◽  
Protective Effects ◽  
Co2 Pneumoperitoneum ◽  
Blood Samples

Various pharmacological agents and protective methods have been shown to reverse pneumoperitoneum-related lung injury, but identifying the best strategy is challenging. Herein, we employed lung tissues and blood samples from C57BL/6 mice with pneumoperitoneum-induced lung injury and blood samples from patients who received laparoscopic gynecological surgery to investigate the therapeutic role of hydromorphone in pneumoperitoneum-induced lung injury along with the underlying mechanism. We found that pretreatment with hydromorphone alleviated lung injury in mice that underwent CO2 insufflation, decreased the levels of myeloperoxidase (MPO), total oxidant status (TOS), and oxidative stress index (OSI), and increased total antioxidant status (TAS). In addition, after pretreatment with hydromorphone, upregulated HO-1 protein expression, reduced mitochondrial DNA content, and improved mitochondrial morphology and dynamics were observed in mice subjected to pneumoperitoneum. Immunohistochemical staining also verified that hydromorphone could increase the expression of HO-1 in lung tissues in mice subjected to CO2 pneumoperitoneum. Notably, in mice treated with HO-1-siRNA, the protective effects of hydromorphone against pneumoperitoneum-induced lung injury were abolished, and hydromorphone did not have additional protective effects on mitochondria. Additionally, in clinical patients who received laparoscopic gynecological surgery, pretreatment with hydromorphone resulted in lower serum levels of club cell secretory protein-16 (CC-16) and intercellular adhesion molecule-1 (ICAM-1), a lower prooxidant-antioxidant balance (PAB), and higher heme oxygenase-1 (HO-1) activity than morphine pretreatment. Collectively, our results suggest that hydromorphone protects against CO2 pneumoperitoneum-induced lung injury via HO-1-regulated mitochondrial dynamics and may be a promising strategy to treat CO2 pneumoperitoneum-induced lung injury.

scholarly journals Hydrogen Gas Attenuates Hypoxic-Ischemic Brain Injury via Regulation of the MAPK/HO-1/PGC-1a Pathway in Neonatal Rats

2020 ◽  
Vol 2020 ◽  
pp. 1-16 ◽  
Author(s):  
Peipei Wang ◽  
Mingyi Zhao ◽  
Zhiheng Chen ◽  
Guojiao Wu ◽  
Masayuki Fujino ◽  
...  
Keyword(s):  
Brain Injury ◽  
Protein Kinase ◽  
Pc12 Cells ◽  
Heme Oxygenase 1 ◽  
Ischemic Brain Injury ◽  
Protective Effects ◽  
Neonatal Rats ◽  
Ischemic Brain ◽  
Differentiated Pc12 Cells ◽  
Hypoxic Ischemic Brain Injury

Neonatal hypoxic-ischemic encephalopathy (HIE) is a leading cause of death in neonates with no effective treatments. Recent advancements in hydrogen (H2) gas offer a promising therapeutic approach for ischemia reperfusion injury; however, the impact of this approach for HIE remains a subject of debate. We assessed the therapeutic effects of H2 gas on HIE and the underlying molecular mechanisms in a rat model of neonatal hypoxic-ischemic brain injury (HIBI). H2 inhalation significantly attenuated neuronal injury and effectively improved early neurological outcomes in neonatal HIBI rats as well as learning and memory in adults. This protective effect was associated with initiation time and duration of sustained H2 inhalation. Furthermore, H2 inhalation reduced the expression of Bcl-2-associated X protein (BAX) and caspase-3 while promoting the expression of Bcl-2, nuclear factor erythroid-2-related factor 2, and heme oxygenase-1 (HO-1). H2 activated extracellular signal-regulated kinase and c-Jun N-terminal protein kinase and dephosphorylated p38 mitogen-activated protein kinase (MAPK) in oxygen-glucose deprivation/reperfusion (OGD/R) nerve growth factor-differentiated PC12 cells. Inhibitors of MAPKs blocked H2-induced HO-1 expression. HO-1 small interfering RNA decreased the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and sirtuin 1 (SIRT1) and reversed the protectivity of H2 against OGD/R-induced cell death. These findings suggest that H2 augments cellular antioxidant defense capacity through activation of MAPK signaling pathways, leading to HO-1 expression and subsequent upregulation of PGC-1α and SIRT-1 expression. Thus, upregulation protects NGF-differentiated PC12 cells from OGD/R-induced oxidative cytotoxicity. In conclusion, H2 inhalation exerted protective effects on neonatal rats with HIBI. Early initiation and prolonged H2 inhalation had better protective effects on HIBI. These effects of H2 may be related to antioxidant, antiapoptotic, and anti-inflammatory responses. HO-1 plays an important role in H2-mediated protection through the MAPK/HO-1/PGC-1α pathway. Our results support further assessment of H2 as a potential therapeutic for neurological conditions in which oxidative stress and apoptosis are implicated.

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