Abstract T P239: Therapeutic Efficacy and Pharmacological Mechanisms of SP-8203 for Treatment of Cerebral Ischemia

In cerebral ischemia, neurons and glia are deteriorated by various mechanisms including excitotoxicity, oxidative stress and inflammatory responses. Thus, pharmacological blockade of multiple cytotoxic pathways would be a therapeutic strategy for the treatment of ischemic injury. We recently identified a novel multi-potent neuroprotectant SP-8203. Pharmacological efficacy and action mechanism of SP-8203 were evaluated in rat transient middle cerebral artery occlusion (MCAO). Post-ischemic treatment (i.v.) of SP-8203 reduced cerebral ischemic injury in a dose-dependent manner (0.03 ~ 10 mg/kg) and at clinically relevant therapeutic time window (up to 12 h after ischemia onset). Similar efficacy was also obtained in beagle dogs subjected to permanent MCAO. Although it did not ameliorate the excitotoxicity, SP-8203 markedly reduced ischemia-evoked oxidative stress via up-regulation of anti-oxidant enzymes, specifically Mn-SOD and Cu/Zn-SOD, but not catalase and glutathione reductase. SP-8203 also reduced the infiltration of ED-1-immunopositive monocytes and MPO-positive neutrophils into ischemic brain lesions of rats. Moreover, SP-8203 significantly reduced the release of pro-inflammatory cytokines/chemokines (e.g. IL-1beta, TNF-alpha, MCP-1) and also the expression of iNOS and resultant formation of nitrotyrosine. Early (3 h) thrombolysis with tPA restored perfusion and reduced infarction in embolic rat models. However, late 6-h tPA did not decrease infarction, but instead increased intracerebral hemorrhage and mortality. Interestingly, SP-8203 treatment at 1.5 h before late (6 h) tPA infusion markedly reduced tPA-evoked cerebral hemorrhage and mortality. Blood levels of MMPs were significantly correlated with the changes of hemorrhage and mortality. Taken together, SP-8203 has multiple neuroprotective activities in cerebral ischemia: up-regulation of anti-oxidant enzymes, reduction of inflammatory cells recruitment, and suppression of anti-inflammatory cytokines/chemokines and MMP expression. Thanks to the multiple neuroprotective mechanisms, SP-8203 could be a promising drug candidate for stroke treatment, especially in combination of tPA by extending therapeutic time window.

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Fucoxanthin Ameliorates Oxidative Stress and Airway Inflammation in Tracheal Epithelial Cells and Asthmatic Mice

Cells ◽

10.3390/cells10061311 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1311

Author(s):

Shu-Ju Wu ◽

Chian-Jiun Liou ◽

Ya-Ling Chen ◽

Shu-Chen Cheng ◽

Wen-Chung Huang

Keyword(s):

Oxidative Stress ◽

Epithelial Cells ◽

Airway Inflammation ◽

Inflammatory Cytokines ◽

Inflammatory Responses ◽

Therapeutic Potential ◽

Eosinophil Infiltration ◽

Tracheal Epithelial Cells ◽

Tracheal Epithelial ◽

And Oxidative Stress

Fucoxanthin is isolated from brown algae and was previously reported to have multiple pharmacological effects, including anti-tumor and anti-obesity effects in mice. Fucoxanthin also decreases the levels of inflammatory cytokines in the bronchoalveolar lavage fluid (BALF) of asthmatic mice. The purpose of the present study was to investigate the effects of fucoxanthin on the oxidative and inflammatory responses in inflammatory human tracheal epithelial BEAS-2B cells and attenuated airway hyperresponsiveness (AHR), airway inflammation, and oxidative stress in asthmatic mice. Fucoxanthin significantly decreased monocyte cell adherence to BEAS-2B cells. In addition, fucoxanthin inhibited the production of pro-inflammatory cytokines, eotaxin, and reactive oxygen species in BEAS-2B cells. Ovalbumin (OVA)-sensitized mice were treated by intraperitoneal injections of fucoxanthin (10 mg/kg or 30 mg/kg), which significantly alleviated AHR, goblet cell hyperplasia and eosinophil infiltration in the lungs, and decreased Th2 cytokine production in the BALF. Furthermore, fucoxanthin significantly increased glutathione and superoxide dismutase levels and reduced malondialdehyde (MDA) levels in the lungs of asthmatic mice. These data demonstrate that fucoxanthin attenuates inflammation and oxidative stress in inflammatory tracheal epithelial cells and improves the pathological changes related to asthma in mice. Thus, fucoxanthin has therapeutic potential for improving asthma.

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Cystine reduces tight junction permeability and intestinal inflammation induced by oxidative stress in Caco-2 cells

Amino Acids ◽

10.1007/s00726-021-03001-y ◽

2021 ◽

Author(s):

Tatsuya Hasegawa ◽

Ami Mizugaki ◽

Yoshiko Inoue ◽

Hiroyuki Kato ◽

Hitoshi Murakami

Keyword(s):

Oxidative Stress ◽

Tight Junction ◽

Mrna Expression ◽

Inflammatory Cytokines ◽

Inflammatory Responses ◽

Intestinal Barrier ◽

Barrier Dysfunction ◽

Whole Cells ◽

Intestinal Barrier Dysfunction ◽

Pro Inflammatory Cytokines

AbstractIntestinal oxidative stress produces pro-inflammatory cytokines, which increase tight junction (TJ) permeability, leading to intestinal and systemic inflammation. Cystine (Cys2) is a substrate of glutathione (GSH) and inhibits inflammation, however, it is unclear whether Cys2 locally improves intestinal barrier dysfunction. Thus, we investigated the local effects of Cys2 on oxidative stress-induced TJ permeability and intestinal inflammatory responses. Caco-2 cells were cultured in a Cys2-supplemented medium for 24 h and then treated with H2O2 for 2 h. We assessed TJ permeability by measuring transepithelial electrical resistance and the paracellular flux of fluorescein isothiocyanate–dextran 4 kDa. We measured the concentration of Cys2 and GSH after Cys2 pretreatment. The mRNA expression of pro-inflammatory cytokines was assessed. In addition, the levels of TJ proteins were assessed by measuring the expression of TJ proteins in the whole cells and the ratio of TJ proteins in the detergent-insoluble fractions to soluble fractions (IS/S ratio). Cys2 treatment reduced H2O2-induced TJ permeability. Cys2 did not change the expression of TJ proteins in the whole cells, however, suppressed the IS/S ratio of claudin-4. Intercellular levels of Cys2 and GSH significantly increased in cells treated with Cys2. Cys2 treatment suppressed the mRNA expression of pro-inflammatory cytokines, and the mRNA levels were significantly correlated with TJ permeability. In conclusion, Cys2 treatment locally reduced oxidative stress-induced intestinal barrier dysfunction possively due to the mitigation of claudin-4 dislocalization. Furthermore, the effect of Cys2 on the improvement of intestinal barrier function is related to the local suppression of oxidative stress-induced pro-inflammatory responses.

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Geongangbuja-Tang Decoction and Its Active Ingredient, Aconiti Lateralis Radix Preparata, Exerts Inhibitory Effects on Heat Stress-Induced Inflammation in Mice

Applied Sciences ◽

10.3390/app11156902 ◽

2021 ◽

Vol 11 (15) ◽

pp. 6902

Author(s):

Eugene Huh ◽

Wonil Lee ◽

Yujin Choi ◽

Tae Hee Lee ◽

Myung Sook Oh

Keyword(s):

Heat Stress ◽

Energy Metabolism ◽

Inflammatory Cytokines ◽

Hpa Axis ◽

Inflammatory Responses ◽

Heat Exposure ◽

Mouse Serum ◽

Dependent Manner ◽

Active Constituent ◽

Pro Inflammatory Cytokines

Heat stress induces the hypothalamic-pituitary-adrenal (HPA) axis activation, influences biological responses, and reduces energy metabolism. Geongangbuja-tang (GBT) and its components, Zingiberis Rhizoma (ZOR) and Aconiti Lateralis Radix Preparata (ALRP) have been used to induce energy metabolism; however, the effects of GBT and its ingredients on heat-induced inflammatory responses have not yet been investigated. In this study, we performed an open-field test to evaluate locomotor activity in mice. To assess the effects of GBT and its ingredients on inflammation, the protein levels of c-fos, pro-inflammatory cytokines, and cortisol were measured in the mouse hypothalamus and serum. The results showed that GBT alleviated locomotive activity and reduced c-fos levels in a dose-dependent manner under the heat exposure. After investigating the active constituent of GBT, we found that compared to GBT and ZOR, ALRP significantly suppressed c-fos expression under heat stress. Subsequently, ALRP decreased the expression of pro-inflammatory cytokines, such as interleukin-9 and -13 and prostaglandin, under the heat stress in the mouse hypothalamus. Moreover, treatment with ALRP inhibited cortisol secretion in the mouse serum following heat exposure. These results indicate that GBT and its active component, ALRP, could be the thermoregulatory agents that regulate the HPA axis.

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Curcumin and Endometriosis

International Journal of Molecular Sciences ◽

10.3390/ijms21072440 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2440 ◽

Cited By ~ 1

Author(s):

Alexandre Vallée ◽

Yves Lecarpentier

Keyword(s):

Oxidative Stress ◽

Inflammatory Responses ◽

Uterine Cavity ◽

Main Role ◽

Oxygen Species ◽

Inflammatory Agent ◽

Gynecological Disorders ◽

Anti Oxidant ◽

Anti Inflammatory

Endometriosis is one of the main common gynecological disorders, which is characterized by the presence of glands and stroma outside the uterine cavity. Some findings have highlighted the main role of inflammation in endometriosis by acting on proliferation, apoptosis and angiogenesis. Oxidative stress, an imbalance between reactive oxygen species and antioxidants, could have a key role in the initiation and progression of endometriosis by resulting in inflammatory responses in the peritoneal cavity. Nevertheless, the mechanisms underlying this disease are still unclear and therapies are not currently efficient. Curcumin is a major anti-inflammatory agent. Several findings have highlighted the anti-oxidant, anti-inflammatory and anti-angiogenic properties of curcumin. The purpose of this review is to summarize the potential action of curcumin in endometriosis by acting on inflammation, oxidative stress, invasion and adhesion, apoptosis and angiogenesis.

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Safflower Yellow B Protects Brain against Cerebral Ischemia Reperfusion Injury through AMPK/NF-kB Pathway

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/7219740 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 6

Author(s):

Shibin Du ◽

Youliang Deng ◽

Hongjie Yuan ◽

Yanyan Sun

Keyword(s):

Brain Injury ◽

Cerebral Ischemia ◽

Pc12 Cells ◽

Inflammatory Cytokines ◽

Nuclear Translocation ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Dependent Manner ◽

Secondary Damage

Inflammation had showed its important role in the pathogenesis of cerebral ischemia and secondary damage. Safflower yellow B (SYB) had neuroprotective effects against oxidative stress-induced brain injuries, but the mechanisms were still largely unknown to us. In this study, we tried to investigate the anti-inflammation effects of SYB and the possible roles of AMPK/NF-κB signaling pathway on these protective effects. In vivo, brain ischemia/reperfusion (I/R) was induced by transient middle cerebral artery occlusion for 2 h and reperfusion for 20 h. Neurofunctional evaluation, infarction area, and brain water contents were measured. Brain injury markers and inflammatory cytokines levels were measured by ELISA kits. In vitro, cell viability, apoptosis, and LDH leakage were measured after I/R in PC12 cells. The expression and phosphorylation levels of AMPK, NF-κB p65, and P-IκB-α in cytoplasm and nuclear were measured by Western blotting. SiRNA experiment was performed to certify the role of AMPK. The results showed SYB reduced infarct size, improved neurological outcomes, and inhibited brain injury after I/R. In vitro test, SYB treatment alleviated PC12 cells injury and apoptosis and inhibited the inflammatory cytokines (IL-1, IL-6, TNF-α, and COX-2) in a dose-dependent manner. SYB treatment induced AMPK phosphorylation and inhibited NF-κB p65 nuclear translocation both in brain and in PC12 cells. Further studies also showed that the inhibition of NF-κB activity of SYB was through AMPK. In conclusion, SYB protected brain I/R injury through reducing expression of inflammatory cytokines and this effect might be partly due to the inhibition of NF-κB mediated by AMPK.

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Honokiol ameliorates radiation-induced brain injury via the activation of SIRT3

Journal of International Medical Research ◽

10.1177/0300060520963993 ◽

2020 ◽

Vol 48 (10) ◽

pp. 030006052096399

Author(s):

Guixiang Liao ◽

Zhihong Zhao ◽

Hongli Yang ◽

Xiaming Li

Keyword(s):

Oxidative Stress ◽

Brain Injury ◽

Inflammatory Responses ◽

Tissue Injury ◽

Interleukin 1 ◽

Dependent Manner ◽

Ht22 Cells ◽

Tnf Α ◽

Radiation Induced ◽

Cox 2

Objective Sirtuin 3 (SIRT3) plays a vital role in regulating oxidative stress in tissue injury. The aim of this study was to evaluate the radioprotective effects of honokiol (HKL) in a zebrafish model of radiation-induced brain injury and in HT22 cells. Methods The levels of reactive oxygen species (ROS), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β) were evaluated in the zebrafish brain and HT22 cells. The expression levels of SIRT3 and cyclooxygenase-2 (COX-2) were measured using western blot assays and real-time polymerase chain reaction (RT-PCR). Results HKL treatment attenuated the levels of ROS, TNF-α, and IL-1β in both the in vivo and in vitro models of irradiation injury. Furthermore, HKL treatment increased the expression of SIRT3 and decreased the expression of COX-2. The radioprotective effects of HKL were achieved via SIRT3 activation. Conclusions HKL attenuated oxidative stress and pro-inflammatory responses in a SIRT3-dependent manner in radiation-induced brain injury.

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Vinpocetine protects liver against ischemia–reperfusion injury

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2013-0097 ◽

2013 ◽

Vol 91 (12) ◽

pp. 1064-1070 ◽

Cited By ~ 24

Author(s):

Hala Fahmy Zaki ◽

Rania Mohsen Abdelsalam

Keyword(s):

Oxidative Stress ◽

Inflammatory Cytokines ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Liver Lipid ◽

Cerebrovascular Disorders ◽

Cellular Damage ◽

Dependent Manner ◽

Oxidative Stress Biomarkers ◽

Serum Transaminases

Hepatic ischemia–reperfusion (IR) injury is a clinical problem that leads to cellular damage and organ dysfunction mediated mainly via production of reactive oxygen species and inflammatory cytokines. Vinpocetine has long been used in cerebrovascular disorders. This study aimed to explore the protective effect of vinpocetine in IR injury to the liver. Ischemia was induced in rats by clamping the common hepatic artery and portal vein for 30 min followed by 30 min of reperfusion. Serum transaminases and liver lactate dehydrogenase (LDH) activities, liver inflammatory cytokines, oxidative stress biomarkers, and liver histopathology were assessed. IR resulted in marked histopathology changes in liver tissues coupled with elevations in serum transaminases and liver LDH activities. IR also increased the production of liver lipid peroxides, nitric oxide, and inflammatory cytokines interleukin-1β and interleukin-6, in parallel with a reduction in reduced glutathione and interleukin-10 in the liver. Pretreatment with vinpocetine protected against liver IR-induced injury, in a dose-dependent manner, as evidenced by the attenuation of oxidative stress as well as inflammatory and liver injury biomarkers. The effects of vinpocetine were comparable with that of curcumin, a natural antioxidant, and could be attributed to its antioxidant and anti-inflammatory properties.

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