lignans and Reperfusion-Injury

Topics: Animals; Antioxidants; Brain Ischemia; Heme Oxygenase-1; Lignans; Mice; NF-E2-Related Factor 2; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Superoxide Dismutase; Syringa

Magnolol is a component of the bark of Magnolia officinalis, which is a traditional herbal remedy used in China. In this study, we investigated whether magnolol can reduce myocardial injury induced by renal ischemia and reperfusion (I/R).. Renal I/R was elicited by a 60-minute occlusion of the bilateral renal arteries and a 24-hour reperfusion in Sprague-Dawley rats. Magnolol was administered intravenously 10 minutes before renal I/R to evaluate its effects on myocardial injury induced by renal I/R.. Renal I/R significantly increased the serum levels of creatine phosphokinase (CPK), lactate dehydrogenase (LDH), and cardiac troponin I and caused myocardial damage. The terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive nuclei and caspase-3 activation was significantly increased in the myocardium, indicating increase of apoptosis. Echocardiography revealed left ventricular dysfunction, as evidenced by reduction of left ventricular ejection fraction and left ventricular fractional shortening. Furthermore, serum levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 were significantly elevated, while the IL-10 level was suppressed. However, intravenously, pretreatment with magnolol at doses of 0.003 and 0.006 mg/kg 10 minutes before renal I/R significantly prevented the increases of CPK, LDH, and cardiac troponin I levels, as well as the histological damage and the apoptosis in the myocardium. Echocardiography showed significant improvement of left ventricular function. Furthermore, the increases in TNF-α, IL-1β, and IL-6 and the decrease in IL-10 were significantly limited, while Bcl-2 was increased and Bax was decreased in the myocardium. Phosphorylation of Akt and extracellular signal-regulated kinases 1 and 2 was increased, while phosphorylation of p38 and c-Jun N-terminal kinase was reduced.. Magnolol reduces myocardial injury induced by renal I/R. The underlying mechanisms for this effect might be related to modulation of the production of pro- and anti-inflammatory cytokines and the limiting of apoptosis.

Topics: Animals; Apoptosis; Biphenyl Compounds; Interleukin-10; Interleukin-6; Ischemia; Lignans; Myocardial Reperfusion Injury; Myocardium; Rats; Rats, Sprague-Dawley; Reperfusion; Reperfusion Injury; Stroke Volume; Troponin I; Tumor Necrosis Factor-alpha; Ventricular Function, Left

Stroke is the central disorder underlined by ischemia-reperfusion (I/R) injury. Eleutheroside E (EE) is administered as the shield in some ischemia tissues with anti-inflammatory action. However, whether EE defends I/R-induced damage in the brain remains unknown. Here, we demonstrated that EE significantly alleviated the cerebral I/R injury and reduced the apoptosis of hippocampal neuron cells in rats. During the anti-apoptosis process, EE significantly upregulated the expression of 5-hydroxytryptamine receptor 2C (Htr2c) gene. Silencing Htr2c expression dramatically weakened the protective effect of EE on I/R-induced apoptosis of rat hippocampal neuron. EE-regulated Htr2c also remarkably inhibited the expression of caspase-3, -6 and -7, thereby suggesting a plausible anti-apoptosis mechanism associated with Htr2c/caspase axis. These findings elicit the potentially clinical strategy that targets Htr2c to improve outcome of ischemia brain.

Topics: Animals; Glucosides; Lignans; Rats; Rats, Sprague-Dawley; Reperfusion Injury

Brain ischemia/reperfusion (I/R) injury is a common pathological process after ischemic stroke. Pinoresinol diglucoside (PDG) has antioxidation and anti-inflammation activities. However, whether PDG ameliorates brain I/R injury is still unclear. In this study, middle cerebral artery occlusion (MCAO) model was established with male C57BL/6 mice, and the mice were treated with 5 and 10 mg/kg PDG via intravenous injection, respectively. The neurological deficit, infarct volume, and brain water content were then evaluated. HE staining and Nissl staining were used to analyze neuron injury. Besides, enzyme-linked immunosorbent assay and colorimetry assay were used to examine the level of inflammatory markers and oxidative stress markers, and Western blot was used to detect the expressions of p-p65, Nrf2, and HO-1. It was revealed that PDG could significantly alleviate the MCAO-induced neurological dysfunction of the mice and reduce the infarct volume, brain water content, and neuron injury. PDG treatment decreased the levels of TNF-α, IL-1β, IL-6, NO, ROS, and MDA, and significantly increased the activities of SOD, GSH, and GSH-Px in the brain tissue of the mice. Additionally, PDG could repress the activation of p65 and promote Nrf2 and HO-1 expressions. In conclusion, PDG exerts anti-inflammatory and antioxidation effects via regulating the NF-κB pathway and Nrf2/HO-1 pathway, thereby reducing the I/R-induced brain injury of mice.

Topics: Animals; Brain; Brain Ischemia; Cytokines; Disease Models, Animal; Heme Oxygenase-1; Lignans; Male; Membrane Proteins; Mice, Inbred C57BL; Middle Cerebral Artery; Neuroinflammatory Diseases; Neurons; NF-E2-Related Factor 2; Oxidative Stress; Reperfusion Injury

Epidemic modeling has been a key tool for understanding the impact of global viral outbreaks for over two decades. Recent developments of the COVID-19 pandemic have accelerated research using compartmental models, like SI, SIR, SEIR, with their appropriate modifications. However, there is a large body of recent research consolidated on homogeneous population mixing models, which are known to offer reduced tractability, and render conclusions hard to quantify. As such, based on our recent work, introducing the heterogeneous geo-spatial mobility population model (GPM), we adapt a modified SIR-V (susceptible-infected-recovered-vaccinated) epidemic model which embodies the idea of patient relapse from R back to S, vaccination of R and S patients (reducing their infectiousness), thus altering the infectiousness of V patients (from

Topics: Acute Lung Injury; Adherens Junctions; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antigens, CD; Antineoplastic Agents, Phytogenic; Antioxidants; Apoptosis; beta Catenin; Brain Ischemia; Cadherins; Carcinogenesis; Catalysis; Cell Line; Cells, Cultured; Curcuma; Curcumin; Dioxoles; Disease Models, Animal; Endothelial Cells; Epithelial Cells; Heme Oxygenase (Decyclizing); Humans; Inflammasomes; Intestinal Diseases; Intestinal Mucosa; Ischemic Stroke; Kidney Neoplasms; Lignans; Lung; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; NAD(P)H Dehydrogenase (Quinone); Nanostructures; NF-E2-Related Factor 2; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative Stress; Phosphatidylinositol 3-Kinases; Phytotherapy; Plant Extracts; Pneumonia; PPAR gamma; Proto-Oncogene Proteins c-akt; Pyroptosis; Rats; Rats, Sprague-Dawley; Rats, Wistar; Reperfusion Injury; Respiratory Distress Syndrome; Sepsis; Sesamum; Signal Transduction; Silybin; Silybum marianum; Silymarin; Sirtuin 3; Titanium; Transfection; Treatment Outcome; White Matter

Cerebral ischemia-reperfusion (CIR) is a common feature of ischemic stroke and is a major cause of disability and death among stroke patients worldwide. Phyllanthin, a lignin polyphenol, is known for its varied biological properties, although its protective effects against CIR have not been reported. We evaluated the neuroprotective property of phyllanthin against CIR as well as the involvement of the AMP-activated protein kinase/nuclear factor erythroid 2-related factor 2 (AMPK/Nrf2) and nuclear factor kappa B (NF-κB) signaling pathways. Experimental animals were divided into five groups: controls (sham-operated), CIR-induced by middle cerebral artery occlusion (MCAO), and CIR-induced and administered phyllanthin at 2.5, 5, and 10 mg/kg, respectively. We investigated neurological functions, various signaling genes, and inflammatory clues. The results of in vitro assays demonstrated that phyllanthin assertively improved cellular functions through abrogation of the Nrf2 pathway. In vivo, CIR rats demonstrated neurological function deficits, while ischemic severity was evidenced by the activation of neuroinflammatory cytokines and tissue oxidative stress. Moreover, the expression of apoptosis markers such as Bax, B-cell lymphoma (Bcl-2), caspase-3, COX-2, PGE2, and LOX-1 abruptly increased. Phyllanthin prevented brain dysfunction and cerebral edema, and protected brain integrity. Conversely, it improved antioxidative enzyme activity, abrogated inflammatory cytokines, and increased IL-10 in chemokines. Also, phyllanthin significantly reduced Nrf2 and AMPK levels, with reduced expression of NF-κB indicating that cross-talk between the NF-kB and Nrf2 pathways is activated in CIR. Phyllanthin rescues the ischemic brain by regulating cellular signaling, which supports its use for complications like CIR and associated injury.

Topics: Animals; Antioxidants; Cell Line, Tumor; Lignans; Neuroblastoma; Neuroprotective Agents; Rats; Rats, Wistar; Reperfusion Injury

Ischemia-reperfusion injury (IRI) refers to tissue damage that occurs when blood supply returns to tissue after a period of ischemia, anoxia or hypoxia. It occurs frequently during shock, organ transplantation and heart failure. It can cause impairment or even renal failure. Macelignan is a lignin isolated from the seeds of Myristica fragrans. It has been reported to inhibit neuroinflammation and oxidative toxicity. The preventive or therapeutic effects of macelignan on renal IRI has not been reported. The present study investigated the effects of macelignan on renal IRI in rats, and the underlying mechanism(s). Healthy adult male Sprague Dawley rats (n = 50) aged 7 - 9 weeks (mean weight = 220 ± 20 g) were used in this study. The rats were randomly assigned to five groups of 10 rats each: sham   treated group, IRI group and 40 mg macelignan/kg body weight (bwt) group, 80 mg macelignan/kg bwt group, and 160 mg macelignan/kg bwt group. Ischemia-reperfusion injury was induced in the rats using standard procedure. The results showed that serum levels of creatinine, blood urea nitrogen (BUN), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α) and gamma interferon (IFN-γ) were significantly higher in IRI group than in sham treated group, but were significantly and dose-dependently reduced after treatment with macelignan (p < 0.05). The activities of catalase and superoxide dismutase (SOD), and reduced glutathione (GSH) level were significantly reduced in IRI group, when compared with sham treated group, but were significantly and dose-dependently increased after treatment with macelignan (p < 0.05). However, the level of malondialdehyde (MDA) was significantly higher in IRI group than in sham treated group, but treatment with macelignan reduced it significantly and dose-dependently (p < 0.05). Macelignan also significantly and dose-dependently inhibited IRI-induced apoptosis in epithelial cells of renal tubules (p < 0.05). The results of Western blotting showed that IRI significantly upregulated the expressions of bax and caspase-3, and down-regulated the expression of bcl-2 in epithelial cells of renal tubules (p < 0.05). However, treatment with macelignan significantly and dose-dependently down-regulated the expressions of bax and caspase-3 in these cells, but significantly and dose-dependently upregulated the expression of bcl-2. These results show that macelignan confers protection on renal IRI via mechanisms involving inhibition of infla

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Biomarkers; Blood Urea Nitrogen; Caspase 3; Catalase; Creatinine; Epithelial Cells; Glutathione; Inflammation; Interferon-gamma; Interleukin-6; Kidney; Lignans; Male; Malondialdehyde; Rats, Sprague-Dawley; Reperfusion Injury; Superoxide Dismutase; Tumor Necrosis Factor-alpha

The endoplasmic reticulum stress (ERS) and ERS-related neuronal apoptosis contribute to the cerebral ischemia/reperfusion (I/R) injury. (-)-Clausenamide has been reported to be nootropic and improve learning and memory in amnesia animal models. However, whether (-)-Clau could protect neurons from ischemic injury and the possible mechanism needed further study. The present study aimed to explore the effects of (-)-Clau on primary cortical neurons treated with oxygen-glucose deprivation/reoxygenation (OGD/R).. Rat primary cortical neurons were used to set up an injury model of OGD/R which imitated the clinical I/R injury. Cell viability and apoptosis were measured by CCK-8 assay, LDH detection and TUNEL staining, respectively. The activation of GRP78/eIF2α-ATF4-CHOP signaling pathway, one of the three branches of ERS, and cleaved caspase-3, the apoptotic marker, were assessed by western blotting.. OGD/R induced activation of GRP78/eIF2α-ATF4-CHOP signaling pathway. (-)-Clau significantly attenuated OGD/R-induced decrease in the cellular viability and the activation of GRP78, eIF2α, ATF4 and CHOP. To further confirm the effect of (-)-Clau on OGD/R-induced ERS activation, the ERS inducer Tunicamycin (TM) was applied. TM significantly abolished (-)-Clau's protective effect against ERS and neuronal apoptosis, indicating that the protective effect of (-)-Clau was dependent on inhibiting ERS.. The present work demonstrated for the first time that (-)-Clau could reverse the activation of GRP78/eIF2α-ATF4-CHOP branch, thus inhibited ERS and the subsequent apoptosis induced by OGD/R and promoted cell viability in vitro. (-)-Clau could serve as a promising therapeutic agent in the treatment for ischemic stroke in the future.. ATF4: activating transcription factor-4; ATF6: activating transcription factor-6; CHOP: transcriptional induction of CCAAT/enhancer binding protein homologous protein; (-)-Clau: 3-hydroxy-4-phenyl-5a-hydroxybenzylN-methyl-g-lactam; eIF2α: eukaryotic initiation factor 2α; ER: endoplasmic reticulum; ERS: endoplasmic reticulum stress; GRP78: 78-kDa glucose regulated protein; I/R: ischemia/reperfusion; IRE1: inositol requiring enzyme-1; JNK: c-Jun N-terminal kinase; OGD/R: oxygen-glucose deprivation/reoxygenation; PERK: double-stranded RNA-dependent protein kinase-like ER kinase; TM: Tunicamycin; UPR: unfolded protein response.

Topics: Animals; Apoptosis; Brain Ischemia; Cell Survival; Endoplasmic Reticulum Stress; Female; Lactams; Lignans; Male; Neurons; Neuroprotective Agents; Primary Cell Culture; Rats, Wistar; Reperfusion Injury; Signal Transduction

I/R: schemia/reperfusion; IL: interleukin; MCAO/R: middle cerebral artery occlusion and reperfusion; NF-κB: nuclear; TLR4: Toll-like receptor 4; TNF-α: tumor necrosis factor-α.

Topics: Animals; Anti-Inflammatory Agents; Brain Ischemia; Cyclooctanes; Lignans; Male; NF-kappa B; Polycyclic Compounds; Rats, Sprague-Dawley; Reperfusion Injury; Signal Transduction; Toll-Like Receptor 4

The neuroprotective role of schizandrin (SA) in cerebral ischemia-reperfusion (I/R) was recently highlighted. However, whether SA plays a regulatory role on autophagy in cerebral I/R injury is still unclear. This study aimed to explore whether the neuroprotective mechanisms of SA were linked to its regulation of AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/autophagy pathway in vivo and in vitro. The present study confirmed that SA significantly improved oxygen-glucose deprivation/re-oxygenation (OGD/R)-induced PC12 cells injury. The results of immunoblotting and confocal microscope showed that SA decreased autophagy in OGD/R-injured PC12 cells, which was reflected by the decreased Beclin-1 and LC3-II expression, autophagy flux level, and LC3 puncta formation. In addition, the autophagy inducer rapamycin partially prevented the effects of SA on cell viability and autophagy after OGD/R, whereas the autophagy inhibitor 3-methyladenine (3-MA) exerted the opposite effect. The results of Western blotting showed that SA markedly decreased the phosphorylation of AMPK (p-AMPK), whereas the phosphor-mTOR (p-mTOR) levels increased in the presence of OGD/R insult. Furthermore, pretreatment with the AMPK inducer AICAR partially reversed the protective effects and autophagy inhibition of SA. However, AMPK inhibitor Compound C pretreatment further promoted the inhibition of SA on autophagy induction and cell damage induced by OGD/R. Taken together, these findings demonstrate that SA protects against OGD/R insult by inhibiting autophagy through the regulation of the AMPK-mTOR pathway and that SA may have therapeutic value for protecting neurons from cerebral ischemia.

Topics: AMP-Activated Protein Kinases; Animals; Autophagy; Cyclooctanes; Disease Models, Animal; Glucose; Lignans; Mice; Models, Biological; Molecular Structure; Neurons; Neuroprotective Agents; Oxidation-Reduction; Oxygen; Polycyclic Compounds; Rats; Reperfusion Injury; Signal Transduction; Stroke; TOR Serine-Threonine Kinases

In the present study, the neuroprotective potential of magnolol against ischemia-reperfusion brain injury was examined via in vivo and in vitro experiments. Magnolol exhibited strong radical scavenging and antioxidant activity, and significantly inhibited the production of interleukin‑6, tumor necrosis factor‑a and nitrite/nitrate (NOX) in lipopolysaccharide-stimulated BV2 and RAW 264.7 cells when applied at concentrations of 10 and 50 µM, respectively. Magnolol (100 µM) also significantly attenuated oxygen‑glucose deprivation‑induced damage in neonatal rat hippocampal slice cultures, when administered up to 4 h following the insult. In a rat model of stable ischemia, compared with a vehicle‑treated ischemic control, pretreatment with magnolol (0.01‑1 mg/kg, intravenously) significantly reduced brain infarction following ischemic stroke, and post‑treatment with magnolol (1 mg/kg) remained effective and significantly reduced infarction when administered 2 h following the onset of ischemia. Additionally, magnolol (0.3 and 1 mg/kg) significantly reduced the accumulation of superoxide anions at the border zones of infarction and reduced oxidative damage in the ischemic brain. This was assessed by measuring the levels of NOX, malondialdehyde and myeloperoxidase, the ratio of glutathione/oxidized glutathione and the immunoreactions of 8‑hydroxy‑2'‑deoxyguanosine and 4‑hydroxynonenal. Thus, magnolol was revealed to protect against ischemia‑reperfusion brain damage. This may be partly attributed to its antioxidant, radical scavenging and anti‑inflammatory effects.

Topics: Animals; Antioxidants; Biphenyl Compounds; Brain; Brain Ischemia; Cell Line; Glucose; Lignans; Male; Mice; Neuroprotective Agents; Oxidative Stress; Oxygen; Rats, Sprague-Dawley; RAW 264.7 Cells; Reperfusion Injury

Topics: Acute Kidney Injury; Animals; Anti-Inflammatory Agents; Apoptosis; Disease Models, Animal; Dose-Response Relationship, Drug; Furans; Inflammation; Kidney; Lignans; Male; Mice, Inbred C57BL; Oxidative Stress; Reperfusion Injury

Arctigenin (ATG) has been shown to possess anti-inflammatory, immunemodulatory, anti-viral, anti-microbial, anti-carcinogenic, vasodilatory and anti-platelet aggregation properties. However, the protective role of ATG in prevention of arrhythmias induced by myocardial ischemia/reperfusion is unknown. The aim of this study was to investigate the anti-arrhythmia effect of ATG in an ischemia/reperfusion injured rat heart model and explore the related mechanisms.. Rats were randomly exposed to sham operation, myocardial ischemia/ reperfusion (MI/R) alone, ATG+ MI/R, pretreated with ATG in low (12.5 mg/kg/day), medium (50 mg/kg/day) and high dose (200 mg/kg/day), respectively. Ventricular arrhythmias were assessed. The activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and the level of malondialdehyde (MDA) in myocardial tissue were determined by chemical analysis.. Compared to MI/R, rats pretreated with ATG in doses of 50 mg/kg/day and 200 mg/kg/day showed significantly reduced incidence and duration of ventricular fibrillation, ventricular tachycardia and ventricular ectopic beat (VEB), and decreased the arrhythmia score during the 30-min ischemia. Incidence and duration of ventricular tachycardia, infarction size and arrhythmia scores in these groups were significantly decreased during the 120-min reperfusion. No ventricular fibrillation occurred during the period of reperfusion. Rats pretreated with ATG in doses of 50 mg/kg/day and 200 mg/kg/ day markedly enhanced the activities of antioxidant enzymes SOD and GSH-Px, reduced the level of MDA. No differences were observed between the group pretreated with a low dose of ATG and the sham group. Administration of ATG significantly increased the expression of antioxidant stress protein Nrf2, Trx1 and Nox1.. Our data suggested that ATG plays anti-arrhythmia role in ischemia/reperfusion injury, which is probably associated with attenuating oxidative stress by Nrf2 signaling pathway.

Topics: Animals; Arrhythmias, Cardiac; Disease Models, Animal; Furans; Glutathione Peroxidase; Lignans; Male; Malondialdehyde; Myocardial Infarction; Myocardium; NADPH Oxidase 1; NF-E2-Related Factor 2; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Superoxide Dismutase; Thioredoxins

Schisantherin A (SchA) is a dibenzocyclooctadiene lignan isolated from the fruit of Schisandra sphenanthera. The role of SchA in liver injury induced by ischemia and reperfusion (I/R) has not yet been elucidated. The present study hypothesized the protective effects of SchA in hepatic I/R model. Either sham laparotomy or hepatic I/R was induced in C57BL/6 male mice after SchA or vehicle administration. Liver function, histological damage, oxidative/nitrosative stress, inflammatory infiltration, cytokine production, cell apoptosis, cell autophagy, and I/R-associated intracellular signaling pathway were assessed to evaluate the impact of SchA pretreatment on I/R-induced liver injury. After liver I/R injury, the mice pretreated with appropriate SchA displayed significantly preserved liver function, less histological damage, ameliorated oxidative/nitrosative stress, attenuated inflammatory state, and reduced cell apoptosis. However, no differences in the autophagic response were detected after SchA pretreatment. The underlying protective mechanism putatively involves the inhibition of mitogen-activated protein kinase (MAPK) signaling pathway. Based on the beneficial effects, SchA pretreatment may serve as a potential prophylactic measure to prevent liver I/R injury related to various clinical conditions.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Cyclooctanes; Dioxoles; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Humans; Lignans; Liver; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Reperfusion Injury; Schisandraceae; Signal Transduction

Magnolol, a neolignan compound isolated from traditional Chinese medicine Magnolia officinalis, has a potentially therapeutic influence on ischemic stroke. Previous studies have demonstrated that cerebral ischemia-reperfusion (I-R) and blood-brain barrier (BBB) are involved in the pathogeneses of stroke. Therefore, in vivo and in vitro studies were designed to investigate the effects of magnolol on I-R-induced neural injury and BBB dysfunction. In cerebral I-R model of mice, cerebral infarct volumes, brain water content, and the exudation of Evans blue were significantly reduced by intravenous injection with magnolol at the doses of 1.4, 7.0, and 35.0 μg/kg. When primary cultured microglial cells were treated with 1 μg/ml lipopolysaccharide (LPS) plus increasing concentrations of magnolol, ranging from 0.01 to 10 μmol/L, magnolol could statistically inhibit LPS-induced NO release, TNF-α secretion, and expression of p65 subunit of NF-κB in the nucleus of microglial cells. In the media of brain microvascular endothelial cells (BMECs), oxygen and glucose deprivation-reperfusion (OGD-R) could remarkably lead to the elevation of TNF-α and IL-1β levels, while magnolol evidently reversed these effects. In BBB model in vitro, magnolol dose- and time-dependently declined BBB hyperpermeability induced by oxygen and glucose deprivation (OGD), OGD-R, and ephrin-A1 treatment. More importantly, magnolol could obviously inhibit phosphorylation of EphA2 (p-EphA2) not only in ephrin-A1-treated BMECs but also in cerebral I-R model of mice. In contrast to p-EphA2, magnolol significantly increased ZO-1 and occludin levels in BMECs subjected to OGD. Taken together, magnolol can protect neural damage from cerebral ischemia- and OGD-reperfusion, which may be associated with suppressing cerebral inflammation and improving BBB function.

Topics: Animals; Biphenyl Compounds; Blood-Brain Barrier; Brain Ischemia; Dose-Response Relationship, Drug; Interleukin-1beta; Lignans; Mice; Microglia; Nitric Oxide; Phosphorylation; Rats; Rats, Sprague-Dawley; Receptor, EphA2; Reperfusion Injury; Tumor Necrosis Factor-alpha

Toll-like receptor 4 (TLR4) and C5aR1 (CD88) have been recognized as potential therapeutic targets for the reduction of inflammation and secondary damage and improvement of outcome after ischemia and reperfusion (I/R). The inflammatory responses which induce cell apoptosis and necrosis after I/R brain injury lead to a limited process of neural repair. To further comprehend how these targets function in I/R state, we investigated the pathological changes and TLR4 and C5aR1 signaling pathways in vitro and in vivo models of I/R brain injury in this study. Meanwhile, we explored the roles of schisantherin A on I/R brain injury, and whether it exerted neuroprotective effects by regulating the TLR4 and C5aR1 signaling pathways or not. The results showed that schisantherin A significantly reduced the neuronal apoptosis induced by oxygen and glucose deprivation and reperfusion (OGD/R) injury in primary culture of rat cortical neurons. Also, schisantherin A alleviated neurological deficits, reduced infarct volume, attenuated oxidation stress, inflammation and apoptosis in ischemic parietal cortex of rats after middle cerebral artery occlusion and reperfusion (MCAO/R) injury. Moreover, the activated TLR4 and C5aR1 signaling pathways were inhibited by schisantherin A treatment. In conclusion, TLR4 and C5aR1 played a vital role during I/R brain injury in rats, and schisantherin A exhibited neuroprotective effects by TLR4 and C5aR1 signaling pathways. These findings also provided new insights that would aid in elucidating the effect of schisantherin A against cerebral I/R and support the development of schisantherin A as a potential treatment for ischemic stroke.

Topics: Animals; Apoptosis; Brain Ischemia; Cell Survival; Cerebral Cortex; Cyclooctanes; Dioxoles; Inflammation; Lignans; Necrosis; Neurons; Neuroprotective Agents; Oxidative Stress; Parietal Lobe; Primary Cell Culture; Rats, Sprague-Dawley; Receptor, Anaphylatoxin C5a; Reperfusion Injury; Signal Transduction; Toll-Like Receptor 4

Magnolol, a constituent of the bark of Magnolia officinalis, has been reported to decrease myocardial stunning and infarct size. In this study, we investigated whether magnolol can reduce renal ischemia and reperfusion (I/R) injury. Renal I/R, induced by a 60-min occlusion of bilateral renal arteries and a 24-h reperfusion, significantly increased blood urea nitrogen (BUN) and creatinine levels, and caused histological damage to the kidneys of rats. Apoptosis, as evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining and caspase-3 activation, was significantly increased in the kidneys. Furthermore, serum levels of tumor necrosis factor-[Formula: see text] (TNF-[Formula: see text]), interleukin-1β (IL-1β), and interleukin-6 (IL-6) were significantly elevated, while the interleukin-10 (IL-10) level was suppressed. However, intravenous pretreatment with magnolol at doses of 0.003[Formula: see text]mg/kg and 0.006[Formula: see text]mg/kg 10[Formula: see text]min before renal I/R significantly limited the increases of BUN, creatinine, the histological damage, and apoptosis in the kidneys. The increases in TNF-[Formula: see text], IL-1β, and IL-6, and the decrease in IL-10 were also significantly inhibited. Additionally, magnolol increased Bcl-2 and decreased Bax in the kidneys. Phosphorylation of the prosurvival kinases, including Akt and extracellular signal-regulated kinases 1 and 2 (ERK1/2), was elevated, while phosphorylation of the pro-apoptotic mitogen-activated protein kinases, including p38 and c-Jun N-terminal kinase (JNK), was suppressed. In conclusion, magnolol reduces renal I/R injury. The underlying mechanisms for this effect might be related to the prevention of apoptosis, possibly via the inhibition of both extrinsic and intrinsic apoptotic pathways, including the reduction of TNF-[Formula: see text] production and the modulation of pro- and anti-apoptotic signaling elements.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Biphenyl Compounds; Blood Urea Nitrogen; Creatinine; Dose-Response Relationship, Drug; Infusions, Intravenous; Interleukin-10; Interleukin-1beta; Interleukin-6; Ischemia; JNK Mitogen-Activated Protein Kinases; Kidney; Lignans; Male; Mitogen-Activated Protein Kinase 3; Phosphorylation; Phytotherapy; Proto-Oncogene Proteins c-bcl-2; Rats, Sprague-Dawley; Reperfusion Injury; Signal Transduction; Tumor Necrosis Factor-alpha

Honokiol is the predominant active ingredient in the commonly used traditional Chinese medicine, Magnolia, which has been confirmed in previous studies to exhibit anti-oxidation, antimicrobial, antitumor and other pharmacological effects. However, its effects on renal ischemia/reperfusion injury (IRI) remain to be elucidated. The present study aimed to examine the effects of honokiol on renal IRI, and to investigate its potential protective mechanisms in the heart. Male adult Wistar albino rats were induced into a renal IRI model. Subsequently, the levels of serum creatinine, blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP), and the levels of serum nitrite and the kidney nitrite were examined in the IRI group. The levels of oxidative stress, inducible nitric oxide synthase (iNOS), inflammatory factors and caspase-3 were evaluated using a series of commercially available kits. The levels of phosphorylated signal transducer and activator of transcription 3 (p-STAT3) and the protein expression levels of STAT3 were determined using western blotting. Pretreatment with honokiol significantly reduced the levels of serum creatinine, BUN, ALT, AST and ALP, and the level of nitrite in the kidney of the IRI group, compared with the control group. The levels of malondialdehyde, the activity of myeloperoxidase, and the gene expression and activity of iNOS were reduced in the IRI rats, compared with the sham-operated rats, whereas the levels of superoxide dismutase and catalase were increased following treatment with honokiol in the IRI rats. In addition, the expression levels of tumor necrosis factor-α and interleukin-6 in the IRI rats were increased by honokiol. Treatment with honokiol suppressed the protein expression levels of p-STAT3 and caspase-3 in the IRI rats. These findings indicated that honokiol protects against renal IRI via the suppression of oxidative stress, iNOS, inflammation and STAT3 in the rat.

Topics: Animals; Biphenyl Compounds; Gene Expression Regulation; Humans; Inflammation; Kidney; Lignans; Nitric Oxide Synthase Type II; Oxidative Stress; Rats; Reperfusion Injury; STAT3 Transcription Factor

The purpose of this study was to investigate the protective effect of honokiol on experimental ischemia/reperfusion injury of rat ovary.. A total of 40 female Wistar albino rats were used in this study. The rats were divided into five groups as follows: sham (Group I), torsion (Group II), torsion + detorsion (Group III), torsion + detorsion + saline (Group IV), and torsion + detorsion + honokiol (Group V). Bilateral adnexa in all the rats except for those in the sham group were exposed to torsion for 3 hours. The rats in Group IV were administered saline, whereas the rats in Group V were administered honokiol by intraperitoneal route 30 minutes before detorsion. Tissue and plasma concentrations of malondialdehyde and nitric oxide were determined. Ovarian tissue was histologically evaluated. Data analyses were performed by means of Kruskal-Wallis test and Mann-Whitney U-test (Bonferroni correction) in SPSS 15.0 (Statistical Package for Social Sciences; SPSS Inc., Chicago, IL, USA).. The torsion and detorsion groups had higher scores in vascular congestion, hemorrhage, and inflammatory cell infiltration compared with the sham group (P<0.005). In addition, total histopathological scores were significantly higher in the torsion and detorsion groups compared with the sham group (P<0.005). A significant reduction was observed in hemorrhage, inflammatory cell infiltration, and cellular degeneration scores, of all histopathological scores, in the honokiol group (P<0.005). Ovarian tissue concentrations of malondialdehyde were significantly higher in the torsion and detorsion groups compared with the sham and honokiol groups (P<0.005). Ovarian tissue concentrations of nitric oxide, on the other hand, were significantly higher in the torsion group compared with the sham, saline, and honokiol groups (P<0.005).. Honokiol has a beneficial effect on ovarian torsion-related ischemia/reperfusion injury.

Topics: Animals; Biphenyl Compounds; Female; Lignans; Ovarian Diseases; Protective Factors; Rats; Rats, Wistar; Reperfusion Injury

The present study was aimed to assess the in vivo acute effects of oleuropein or/and pinoresinol, polyphenols widely diffused in natural sources, on rat pial microvascular responses during transient BCCAO and reperfusion.. Rat pial microcirculation was visualized by fluorescence microscopy through a closed cranial window. Pial arterioles were classified into five orders of branching. Capillaries were assigned order 0, the smallest arterioles order 1 and the largest ones order 5.. Rats subjected to BCCAO and reperfusion showed: arteriolar diameter decrease, microvascular leakage, leukocyte adhesion in venules, and reduction in capillary perfusion. Pretreatment with oleuropein or pinoresinol, a higher dose before BCCAO determined dilation in all arteriolar orders RE. Microvascular leakage was reduced as well as leukocyte adhesion and ROS formation, while capillary perfusion was protected. Inhibition of endothelium nitric oxide synthase prior to oleuropein or pinoresinol reduced the effect of these polyphenols on pial arteriolar diameter and leakage. These substances, administered together, prevented microvascular damage to a larger extent.. Oleuropein and pinoresinol were both able to protect pial microcirculation from I-reperfusion injury, to increase nitric oxide release and to reduce oxidative stress preserving pial blood flow distribution.

Topics: Animals; Arterioles; Brain Injuries; Cerebrovascular Circulation; Furans; Iridoid Glucosides; Iridoids; Lignans; Male; Microcirculation; Rats; Rats, Wistar; Reperfusion Injury; Vasodilator Agents

Hypoxia-inducible factor 1 (HIF-1) is a master regulator of hypoxic response and has been a prime therapeutic target for ischemia/reperfusion (I/R)-derived myocardial dysfunction and tissue damage. There is also increasing evidence that HIF-1 plays a central role in regulating aging, both through interactions with key longevity factors including Sirtuins and mTOR, as well as by directly promoting longevity in Caenorhabditis elegans.We investigated a novel function and the underlying mechanism of syringaresinol, a lignan compound, in modulation of HIF-1 and protection against cellular damage and death in a cardiomyocyte model of I/R injury. Syringaresinol caused destabilization of HIF-1α following H/R and then protected against hypoxia/reoxygenation (H/R)-induced cellular damage, apoptosis, and mitochondrial dysfunction in a dose-dependent manner. Knock-down of FOXO3 by specific siRNAs completely abolished the ability of syringaresinol to inhibit HIF-1 stabilization and apoptosis caused by H/R. Syringaresinol stimulated the nuclear localization and activity of FOXO3 leading to increased expression of antioxidant genes and decreased levels of reactive oxygen species (ROS) following H/R. Our results provide a new mechanistic insight into a functional role of syringaresinol against H/R-induced cardiomyocyte injury and death. The degradation of HIF-1α through activation of FOXO3 is a potential therapeutic strategy for ischemia-related diseases.

Topics: Animals; Antioxidants; Apoptosis; Caspase 3; Cell Death; Cell Hypoxia; Cell Line; Cell Survival; Flow Cytometry; Forkhead Box Protein O3; Forkhead Transcription Factors; Furans; Hypoxia-Inducible Factor 1, alpha Subunit; Lignans; Microscopy, Fluorescence; Mitochondria; Myocardium; Myocytes, Cardiac; Oxygen; Rats; Reactive Oxygen Species; Reperfusion Injury; RNA, Small Interfering; Up-Regulation

Neuroprotective agents can rescue ischemic penumbra in cerebral ischemia. However, the clinically effective neuroprotective agents for cerebral ischemic injury remain deficient in clinic so far. This study was undertaken to investigate the brain protective effect of 002C-3 and its potential mechanisms in rats, and its preliminary toxicity in mice. A transient middle cerebral artery occlusion (tMCAO) model in rats was used to evaluate its effect and mechanism, a dose limited experiment was used to evaluate its preliminary toxicity. 10-50μg/kg of 002C-3 (single iv bolus after reperfusion) significantly reduced neurological scores, infarct volumes and brain water contents, and the effect was more potent than that of magnolol under the same mole dose; 50μg/kg of 002C-3 significantly decreased the number of TUNEL-positive cells, reduced the activity of caspase-3, and lowered the autophagy-related proteins LC3-II and Beclin-1 level in I-R cerebral tissue. At 1000 times' dose of high effective dose (ip) 002C-3 failed to show evident toxicity in mice, and the mean body weight of mice treated with 002C-3 was almost the same as that of the vehicle control, but magnolol caused evident toxicity and death. In conclusion, 002C-3 has significant protective effect against cerebral ischemia-reperfusion injury; the effect is more potent than magnolol; this effect is maybe associated with its inhibition of both apoptosis and autophagy; its toxicity is greatly reduced compared to magnolol. These results provided data for its further research and development.

Topics: Animals; Apoptosis; Autophagy; Biphenyl Compounds; Brain; Brain Infarction; Caspase 3; Infarction, Middle Cerebral Artery; Lignans; Male; Mice; Neuroprotective Agents; Rats, Sprague-Dawley; Reperfusion Injury

Fargesin displayed similar chromatographic retention peak to metoprolol in the cardiac muscle/cell membrane chromatography (CM/CMC) and β1 adrenergic receptor/cell membrane chromatography (β1AR/CMC) models. To provide more biological information about fargesin, we investigated the effects of fargesin on isoproterenol-(ISO-) induced cells injury in the high expression β1 adrenergic receptor/Chinese hamster ovary-S (β1AR/CHO-S) cells and occluding the left coronary artery- (LAD-) induced myocardial ischemia/reperfusion (MI/R) injury in rats. The results in vitro showed that ISO-induced canonical cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) levels were decreased by fargesin in β1AR/CHO-S cells. Fargesin attenuated the serum creatine kinase (CK), lactate dehydrogenase (LDH), and improved histopathological changes of ischemic myocardium compared with the I/R rats. Similar results were obtained with Evans Blue/TTC staining, in which fargesin notably reduced infarct size. Moreover, compared with the I/R group, fargesin increased COX release and the activities of some endogenous antioxidative enzymes including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), but suppressed malondialdehyde (MDA), and intracellular ROS release. Additionally, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay demonstrated fargesin suppressed myocardial apoptosis, which may be related to inhibition of caspase-3 activity. Taken together, these results provided substantial evidences that fargesin as a potential β1AR antagonist through cAMP/PKA pathway could protect against myocardial ischemia/reperfusion injury in rats. The underlining mechanism may be related to inhibiting oxidative stress and myocardial apoptosis.

Topics: Adrenergic beta-1 Receptor Antagonists; Animals; Apoptosis; Benzodioxoles; Cardiotonic Agents; Catalase; CHO Cells; Creatine Kinase; Cricetulus; Disease Models, Animal; Glutathione Peroxidase; Heart; L-Lactate Dehydrogenase; Lignans; Malondialdehyde; Molecular Structure; Myocardium; Oxidative Stress; Rats; Rats, Wistar; Reactive Oxygen Species; Reperfusion Injury; Superoxide Dismutase

This study was designed to investigate the effect of w007B, a newly synthesized derivative of honokiol, on MCAO reperfusion, and its therapeutic time window and related mechanisms in rats. Neurological deficit scores, infarct size and brain water content were measured after 24 h reperfusion following 2 h ischemia. The results showed that w007B (10 and 50 μg/kg, IV immediately after reperfusion) markedly decreased neurological deficit scores, reduced infarct size and alleviated brain water content, and then 50 μg/kg w007B given within 3 h after reperfusion (5 h after ischemia) significantly attenuated ischemia-induced brain injury. Additionally, no sign of toxicity was observed when a single dose of 50mg/kg w007B (1000 times of the highest effective dose, IP) was administered. To explore the underlying mechanisms, the expression level of apoptosis, inflammation and autophagy-related markers in brain tissue were detected with kits or by western blot. It was observed that w007B rapidly and significantly reduced caspase-3 activity and NO production in the injured semi-brain, and also lowered the level of the p65 subunit of NF-κB in the nucleus. Besides, it also reduced the expression of Beclin-1 and LC3B-II, and increased the level of p62, the autophagy-related proteins in I/R-injured hemisphere. In conclusion, w007B exerts neuroprotective effect on cerebral ischemia-reperfusion injury with wider therapeutic time window and better safety; its mechanisms may be associated with its anti-inflammation, anti-apoptosis and anti-autophagy action. These results suggest that w007B shows strong potential as a clinical neuroprotective candidate for the treatment of ischemic stroke.

Topics: Animals; Apoptosis; Autophagy; Biphenyl Compounds; Body Weight; Cerebrovascular Circulation; Disease Models, Animal; Female; Inflammation; Lignans; Male; Mice; Mice, Inbred ICR; Neuroprotective Agents; NF-kappa B; Nitric Oxide; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sex Factors; Time Factors

SMXZF is a combination of Rb1, Rg1, schizandrin, and DT-13 (6:9:5:4) derived from Sheng-mai San, a widely used Chinese traditional medicine for the treatment of cardiovascular and cerebral diseases. The present study explores the inhibitory effects and signaling pathways of SMXZF on autophagy induced by cerebral ischemia-reperfusion injury. Male C57BL/6 mice were subjected to ischemia-reperfusion insult by right middle cerebral artery occlusion (MCAO) for 1 hr with subsequent 24 hr reperfusion. Three doses of SMXZF (4.5, 9, and 18 mg/kg) were administered intraperitoneally (i.p.) after ischemia for 1 hr. An autophagic inhibitor, 3-methyladenine (3-MA; 300 μg/kg), was administered i.p. 20 min before ischemia as a positive drug. We found that SMXZF significantly increased cerebral blood flow and reduced the infarct volume, brain water content, and the neurological deficits in a dose-dependent manner. Similar to the positive control, SMXZF at 18 mg/kg also significantly inhibited autophagosome formation. Immunofluorescence staining and Western blotting demonstrated that SMXZF could significantly decrease the expression levels of beclin1 and microtubule-associated protein 1 light chain 3. SMXZF also remarkably inhibited the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) as well as the expression of c-Jun N-terminal kinase (JNK) and its phosphorylation induced by 24 hr reperfusion. Finally, we demonstrated that the optimal administration time of SMXZF was at the early period of reperfusion. This study reveals that SMXZF displays neuroprotective effect against focal ischemia-reperfusion injury, possibly associated with autophagy inactivation through AMPK/mTOR and JNK pathways.

Topics: Adenine; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Autophagy; Brain; Brain Infarction; Cyclooctanes; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Combinations; Drugs, Chinese Herbal; Ginsenosides; Infarction, Middle Cerebral Artery; Lignans; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Polycyclic Compounds; Renal Circulation; Reperfusion Injury; Saponins; Time Factors; TOR Serine-Threonine Kinases

Brain ischemia appears to be associated with innate immunity. Recent reports showed that C3a and C5a, as potent targets, might protect against ischemia induced cell death. In traditional Chinese medicine, the fruit of Schizandra chinesis Baill (Fructus schizandrae) has been widely used as a tonic. In the present study, we sought to evaluate the neuroprotective effects of schizandrin A, a composition of S. chinesis Baill, against oxygen and glucose deprivation followed by reperfusion (OGD/R)-induced cell death in primary culture of rat cortical neurons, and to test whether C3a and C5a affected cortical neuron recovery from ischemic injury after schizandrin A treatment. The results showed that schizandrin A significantly reduced cell apoptosis and necrosis, increased cell survival, and decreased intracellular calcium concentration ([Ca(2+)]i) and lactate dehydrogenase (LDH) release in primary culture of rat cortical neurons after OGD/R. Mechanism studies suggested that the modulation of extracellular-regulated kinase (ERK), c-Jun NH2-terminal kinases (JNK), and p38, as well as caspase-3 activity played an important role on the progress of neuronal apoptosis. C5aR participated in the neuroprotective effect of schizandrin A in primary culture of rat cortical neurons after OGD/R. Our findings suggested that schizandrin A might act as a candidate therapeutic target drug used for brain ischemia and related diseases.

Topics: Animals; Apoptosis; Brain Ischemia; Calcium; Caspase 3; Cell Death; Cell Hypoxia; Cell Survival; Cells, Cultured; Cyclooctanes; Glucose; L-Lactate Dehydrogenase; Lignans; MAP Kinase Signaling System; Medicine, Chinese Traditional; Neurons; Neuroprotective Agents; Phytotherapy; Polycyclic Compounds; Rats; Receptor, Anaphylatoxin C5a; Receptors, G-Protein-Coupled; Reperfusion Injury; Schisandra; Signal Transduction

In the present study, the potential antioxidant and anti-inflammatory effects of Acanthopanax divaricatus vat. albeofructus (AE) and acanthoside-D (AD) isolated from AE against hepatic ischemia-reperfusion (I/R) injury were investigated in a rat model. Male Sprague-Dawley rats (200-220 g) were randomized into seven groups: normal controls; sham-operated controls; I/R injury model; I/R injury model with AE pretreatment at 150, 300, and 600 mg/kg body weight; and I/R injury model with AD pretreatment at 600 μg/kg body weight (equivalent to high dose of AE). The AE and AD pretreatments were administered orally for 2 weeks prior to I/R injury surgery. All rats recovered for 1 week with AE and AD treatment after surgery. Compared to the normal control groups, the I/R injury model group without supplemental treatment showed a significantly lower level of serum superoxide dismutase (SOD) and significantly higher levels of tumor necrosis factor-alpha (TNF-α, interleukin (IL)-6, serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP), as well as lactate dehydrogenase (LDH) activity. The I/R-induced decrease in SOD and increases in TNF-α and IL-6 were resolved, at least partially, by AE and AD treatments, as evidenced by significantly higher antioxidant activities and significantly lower inflammatory cytokine levels in the treatment groups as compared to the I/R injury model group. The AE and AD treatment groups also showed significantly higher levels of serum IL-10 than I/R injury model group. Histological examination revealed that the AE and AD treated groups had less extensive liver necrosis than I/R injury model group. Concomitantly, AE lowered the I/R-induced increases in AST, ALT, ALP levels and LDH activity. In conclusion, AE and AD are capable of alleviating I/R-induced hepatic injury by inhibiting inflammatory cell infiltration, thereby mitigating the release of inflammatory cytokines and balancing the oxidant-antioxidant status mediated by p38 MAPK and JNK/SAPK signaling.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Eleutherococcus; Furans; Glucosides; Ischemia; L-Lactate Dehydrogenase; Lignans; Liver; Male; MAP Kinase Kinase 4; p38 Mitogen-Activated Protein Kinases; Plant Extracts; Rats; Rats, Sprague-Dawley; Reperfusion Injury

Honokiol, a major bioactive constituent of the bark of Magnolia officinalis has been confirmed to have the neuroprotective effect on ischemic stroke in rats. This study was designed to observe the therapeutic time window of honokiol microemulsion on cerebral ischemia-reperfusion injury to support its potential for future clinical trials and further explore the underlying mechanisms. Honokiol microemulsion (50μg/kg, i.v. at 0, 1 or 3h after reperfusion) significantly reduced neurological deficit, infarct volume and brain water content in rats subjected to cerebral ischemia-reperfusion, and honokiol (0.1-10μM) significantly attenuated oxygen-glucose deprivation- or glutamate-induced injury of fetal rat cortical neurons. In co-immunoprecipitation and western blot test, honokiol decreased the intensity of nNOS related to PSD95 but failed to affect that of PSD95 related to NR2B in NR2B-PSD95-nNOS complex, and it also inhibited the translocation of nNOS from cytosol to membrane without affecting total nNOS expression, and then markedly decreased NO production in cortical neurons. Besides, the results of whole-cell patch-clamp recordings showed that honokiol reversibly inhibited the NMDA current by about 64%. In conclusion, honokiol has a therapeutic window of at least 5h after the onset of cerebral ischemia or 3h after reperfusion in rats, which may be in part ascribed to the disruption of the PSD95-nNOS interaction leading to the inhibition of neurotoxic NO production.

Topics: Animals; Biphenyl Compounds; Bisbenzimidazole; Blotting, Western; Cell Hypoxia; Cells, Cultured; Central Nervous System Depressants; Cerebral Cortex; Coloring Agents; Cytosol; Disks Large Homolog 4 Protein; Glucose; Glutamic Acid; Immunoprecipitation; In Vitro Techniques; Infarction, Middle Cerebral Artery; Intracellular Signaling Peptides and Proteins; L-Lactate Dehydrogenase; Lignans; Male; Membrane Proteins; Nitric Oxide; Nitric Oxide Synthase Type I; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Reperfusion Injury; Translocation, Genetic

This study was designed to investigate the effects of honokiol, a neuroprotective agent, on cerebral edema in cerebral ischemia reperfusion (IR) mice and its mechanism of anti-inflammation. Honokiol (0.7-70μg/kg) significantly reduced brain water contents and decreased the exudation of Evans blue dye from brain capillaries in cerebral IR mice. Honokiol (0.1-10μM) significantly reduced the p65 subunit level of NF-κB in the nucleus of primary culture-microglia. It (0.01-10μM) evidently reduced nitric oxide (NO) level in the microglia culture medium and in the microglia and astrocytes coculture medium. Honokiol (0.01-10μM) significantly decreased the level of TNF-α in the microglia medium or coculture cell medium. Honokiol (10μM) decreased the level of Regulated upon Activation Normal T-cell Expressed and Secreted (RANTES/CCL5) protein in medium of microglia or astrocytes. In conclusion, Honokiol has a potent anti-inflammatory effect in cerebral ischemia-reperfusion mice and this effect might be attributed to its inhibition ability on the NF-κB activation, consequently blocking the production of inflammatory factors including: NO, tumor necrosis factor-α (TNF-α) and RANTES/CCL5 in glial cells. These results provide evidence for the anti-inflammatory effect of honokiol for the potential treatment of ischemic stroke.

Topics: Animals; Anti-Inflammatory Agents; Astrocytes; Biphenyl Compounds; Brain Edema; Brain Ischemia; Capillary Permeability; Chemokine CCL5; Coculture Techniques; Cytokines; Drugs, Chinese Herbal; Female; Inflammation; Lignans; Male; Mice; Microglia; Neuroglia; NF-kappa B; Nitric Oxide; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Tumor Necrosis Factor-alpha

Hypertonic saline (HTS) administration can decrease the inflammation following ischemia reperfusion. Magnolol is a potent antioxidant. The present study investigated whether combined treatment of magnolol and HTS could provide further protection in mesenteric ischemia reperfusion injury.. Male C3H/HeOuJ mice were randomly segregated into the following groups: sham-operated (sham), vehicle treatment and mesenteric ischemia reperfusion (MSIR) (vehicle-treated), magnolol treatment and MSIR (magnolol-treated), HTS treatment and MSIR (HTS-treated), as well as co-administration of magnolol plus HTS and MSIR (combined-treated). In MSIR, mice were subjected to mesenteric ischemia for 60 min followed by reperfusion for 30 min. Lung injury was evaluated by lung edema (water ratio) and myeloperoxide (MPO) activity; RNA expression of inducible nitric oxide synthetase (iNOS), TNF-α, and IL-6 were assayed by real time RT-PCR. The formation of peroxynitrite in plasma was assayed by the peroxynitrite-dependent oxidation of dihydrorhodamine 123 (DHR 123) to rhodamine.. Compared with those in the sham-treated group, lung edema and MPO activity, expressions of iNOS, TNF-α and IL-6, and plasma peroxynitrite were significantly increased in the vehicle-treated group. Significant attenuations of these parameters were found in the magnolol-treated or HTS-treated animals. Combined treatment of magnolol and HTS further suppressed the lung edema, iNOS, and TNF-α expressions, and plasma peroxynitrite, compared with the results of a single treatment of magnolol or HTS.. Compared with single-agent use, co-administration of magnolol and HTS further decreases iNOS expression and plasma peroxynitrite as well as the degree of lung injury from MISR. These results may provide another treatment measure for post-injury immunomodulation.

Topics: Animals; Antioxidants; Biphenyl Compounds; Interleukin-6; Lignans; Lung; Male; Mesentery; Mice; Mice, Inbred C3H; Models, Animal; Nitric Oxide Synthase Type II; Peroxides; Peroxynitrous Acid; Pulmonary Edema; Regional Blood Flow; Reperfusion Injury; Saline Solution, Hypertonic; Tumor Necrosis Factor-alpha

To investigate the protective effect of honokiol, a phytochemical used in traditional medicine, on testicular injury after torsion/detorsion (T/D) in a rat model. Testicular torsion is a medical emergency that can cause impairment of semen quality and permanent testicular atrophy or loss.. Male Wistar rats were randomized to each time point of each group (n = 6/time point/group). After 2 hours of torsion, the testes were counter-rotated to the natural position. The rats in each group underwent a sham operation, T/D, or T/D with honokiol treatment (5 mg/kg and 10 mg/kg intraperitoneally, immediately before detorsion). Bilateral orchiectomy was performed at 6 and 24 hours and 3 months after detorsion. The testes were examined histologically. Apoptosis and endoplasmic reticulum stress were detected by Western blot.. Histologic examination revealed that testicular T/D induced acute injury after 6 and 24 hours, and spermatogenesis was decreased at 3 months of follow-up. At 24 hours after T/D, increases were found in the activation of apoptosis-related molecules [poly (ADP-ribose) polymerase and caspases 3 and 7], and the expression levels of endoplasmic reticulum stress-associated molecules (phosphorylated-eukaryotic translation initiation factor 2 subunit α and CCAAT/enhancer-binding protein homologous protein). These increases were significantly reversed with honokiol treatment. Furthermore, honokiol effectively reversed the inhibition of spermatogenesis in testes treated with T/D for 3 months.. The results of our study have shown that the endoplasmic reticulum stress-related apoptotic pathway is involved in testicular injury after testicular T/D. It remains to be determined whether alterations in this pathway would have a protective affect against reperfusion damage.

Topics: Animals; Apoptosis; Biphenyl Compounds; Drugs, Chinese Herbal; Endoplasmic Reticulum; Lignans; Male; Rats; Rats, Wistar; Reperfusion Injury; Spermatic Cord Torsion; Spermatogenesis

Although magnolol is cytoprotective against warm ischemia/reperfusion injury, its effect on cold preservation has not been fully investigated. This study aimed at examining whether magnolol maintains the liver graft integrity after cold preservation and elucidating the underlying mechanisms in terms of apoptotic signaling under both normothermic and hypothermic conditions. After being preserved in Ringer's lactate (RL) at 4 degrees C for 6h ex vivo, the magnolol-treated grafts demonstrated significantly higher AST, ALT, and LDH levels in perfusates than those from negative controls. TUNEL staining showed no difference in the number of apoptotic nuclei in both groups, whereas a more intense apoptotic signal in magnolol-treated grafts was shown as compared with the controls. In vitro data showed no significant difference in viability of RL-preserved clone-9 hepatocytes between the magnolol-treated and control groups, while magnolol pretreatment at 30min before cold preservation prominently induced hepatocyte cell death. RT-PCR and Western blotting analyses revealed a suppression in Bcl-2, but an up-regulation in Bax expression in clone-9 cells after magnolol treatment. Magnolol suppressed the ratios of NF-kappaB to I-kappaBalpha protein contents and I-kappaBalpha phosphorylation induced by TNF-alpha, and potentiated mitochondrial cytochrome c release and subsequent caspase-3 cleavage. Conversely, caspase-3 inhibitor attenuated magnolol-induced hepatotoxicity. We concluded that magnolol could not protect liver grafts from cold ischemia/reperfusion injury. High concentration of magnolol under serum-reduced conditions attenuates NF-kappaB-mediated signaling and induces intrinsic apoptotic pathway, thereby inducing in vitro hepatotoxicity.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Biphenyl Compounds; Blotting, Western; Caspase 3; Chemical and Drug Induced Liver Injury; Cold Temperature; Cryopreservation; Cytochromes c; I-kappa B Proteins; In Situ Nick-End Labeling; Lignans; Liver; Liver Transplantation; Magnolia; Male; Mitochondria; NF-kappa B; Plant Bark; Plant Extracts; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Reverse Transcriptase Polymerase Chain Reaction; Serum; Signal Transduction; Tumor Necrosis Factor-alpha

Cinnamophilin (CINN, (8R, 8'S)-4, 4'-dihydroxy-3, 3'-dimethoxy-7-oxo-8, 8'-neolignan) protects against ischemic stroke in mice. While some anti-oxidative effects of CINN have been characterized, its therapeutic window and molecular basis for neuroprotection remain unclear. We evaluated antioxidant and anti-inflammatory properties and therapeutic window of CINN against brain ischemia using a panel of in vitro and in vivo assays. Data from lipid peroxidation and radical scavenging assays showed that CINN was a robust antioxidant and radical scavenger. CINN effectively inhibited the production of tumor necrosis factor alpha (TNF-alpha), nitrite/nitrate, interleukin-6 (IL-6) in lipopolysaccharide (LPS)-stimulated RAW 264.7 and BV2 cells (P<0.05, respectively). Relative to controls, CINN, administrated at 80 mg/kg, 2, 4, or 6 h postinsult, but not 12 h, significantly reduced brain infarction by 34-43% (P<0.05) and improved neurobehavioral outcome (P<0.05) following transient focal cerebral ischemia in rats. CINN (10-30 microM) also significantly reduced oxygen-glucose deprivation-induced neuronal damage (P<0.05) in rat organotypic hippocampal slices, even when it was administrated 2, 4, or 6 h postinsult. Together, CINN protects against ischemic brain damage with a therapeutic window up to 6 h in vivo and in vitro, which may, at least in part, be attributed by its direct antioxidant and anti-inflammatory effects.

Topics: Analysis of Variance; Animals; Animals, Newborn; Antioxidants; Benzothiazoles; Body Weight; Cell Line, Transformed; Disease Models, Animal; Dose-Response Relationship, Drug; Glucose; Guaiacol; Hippocampus; Hypoxia; Interleukin-6; Ischemic Attack, Transient; Lignans; Lipid Peroxidation; Microglia; Nitrates; Nitrites; Organ Culture Techniques; Peroxidase; Phenethylamines; Polysaccharides; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sulfonic Acids; Time Factors; Tumor Necrosis Factor-alpha

We investigated the protective effects of magnolol, an active antioxidant and free radical scavenger extracted from Magnolia officinalis, in a hind limb ischemic-reperfusion animal model. Adult male Sprague-Dawley rats were subjected to hind limb ischemic insult for 2 hours and were intravenously treated with magnolol at 0.01 mg/kg (n=8), 0.3 mg/kg (n=8) mg/kg or 1 mg/kg (n=8) mg/kg, or vehicle (n=8). At 24 h post-insult, the levels of nitrite/nitrate (NOX), malondialdehyde (MDA) and myeloperoxidase (MPO), as well as the degree of muscle damage, were assessed. Relative to controls, animals treated with magnolol (0.3 and 1 mg/kg) had attenuated muscular inflammation, edema and damage. Magnolol (0.3-1 mg/kg) also effectively reduced postischemic rises in the MDA, NOx and MPO levels (p<0.05, respectively). Magnolol administrated at 0.01 mg/kg, however, failed to protect against the ischemic-perfusion limb injury. In addition, magnolol (0.01-1 mg/kg) did not affect local muscular blood reperfusion or other physiological parameters, including hematocrit, glucose, arterial blood gases and mean arterial blood pressure. Thus, intravenous administration with magnolol at 0.3-1 mg/kg protects against ischemic limb damage in rats. This cytoprotection may be attributed to its antioxidant, anti-nitrosative and anti-inflammatory actions.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Body Temperature; Drug Evaluation, Preclinical; Hindlimb; Lignans; Magnolia; Male; Malondialdehyde; Nitric Oxide; Peroxidase; Phytotherapy; Plant Extracts; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Reperfusion Injury

Schisandrin B (Sch B), a dibenzocyclooctadiene derivative isolated from the fruit of Schisandra chinensis, has been shown to enhance mitochondrial antioxidant status in liver, heart and brain tissues in rodents. Whether or not long-term Sch B treatment can protect against oxidative stress-induced cerebral damage remains unclear. In the present study, the effect of long-term Sch B treatment (1-30 mg/kg/dx15) on cerebral ischemia/reperfusion (I/R) injury was examined in rats. Sch B treatment protected against I/R-induced cerebral damage, as evidenced by the significant increase in the percentage of 2,3,5-triphenyl tetrazolium chloride (TTC)-stained tissues in representative brain slices, when compared with the Sch B-untreated and I/R control. The cerebroprotection was associated with an enhancement in cerebral mitochondrial antioxidant status, as assessed by the level/activity of reduced glutathione, alpha-tocopherol and Mn-superoxide dismutase, as well as the improvement/preservation of mitochondrial structural integrity, as assessed by the extents of malondialdehyde production, Ca(2+) loading and cytochrome c release, as well as the sensitivity to Ca(2+)-induced permeability transition, in control and I/R-challenged rats. In conclusion, long-term Sch B treatment could enhance cerebral mitochondrial antioxidant status as well as improve mitochondrial structural integrity, thereby protecting against I/R injury.

Topics: alpha-Tocopherol; Animals; Antioxidants; Area Under Curve; Brain Ischemia; Cyclooctanes; Female; Fruit; Glutathione; Lignans; Malondialdehyde; Mitochondria; Polycyclic Compounds; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Schisandra; Superoxide Dismutase

Dietary flaxseed (FS) is a nutritional whole grain with high contents of omega-3 fatty acids and lignans with anti-inflammatory and antioxidant properties. We evaluated FS in a murine model of pulmonary ischemia-reperfusion injury (IRI) by dietary supplementation of 0% (control) or 10% (treatment) FS before IRI. Mice fed 0% FS undergoing IRI had a significant decrease in arterial oxygenation (Pa(O(2))) and a significant increase in bronchoalveolar lavage (BAL) protein compared with sham-operated mice. However, mice fed 10% FS undergoing IRI had a significant improvement in both Pa(O(2)) and BAL protein compared with mice fed 0% FS undergoing IRI. In addition, oxidative lung damage was decreased in 10% FS-supplemented mice undergoing IRI, as assessed by malondialdehyde levels. Immunohistochemical staining of lungs for iPF(2alpha)-III F(2) isoprostane, a measure of lipid oxidation, was diminished. FS-supplemented mice had less reactive oxygen species (ROS) release from the vascular endothelium in lungs in an ex vivo model of IRI, and alveolar macrophages isolated from FS-fed mice had significantly reduced ROS generation in response to oxidative burst. Pulmonary microvascular endothelial cells produced less ROS in a flow cessation model of ischemia when preincubated with purified FS lignan metabolites. Pharmacological inhibition of heme oxygenase-1 (HO-1) resulted in only a partial reduction of FS protection in the same model. We conclude that dietary FS is protective against IRI in an experimental murine model and that FS affects ROS generation and ROS detoxification via pathways not limited to upregulation of antioxidant enzymes such as HO-1.

Topics: Animals; Antioxidants; Cell Death; Cells, Cultured; Dietary Supplements; Disease Models, Animal; Endothelial Cells; Female; Flax; Free Radical Scavengers; Hydrogen Peroxide; In Vitro Techniques; Lignans; Lung; Macrophages, Alveolar; Mice; Oxidative Stress; Oxygen; Perfusion; Phytotherapy; Plant Extracts; Reactive Oxygen Species; Reperfusion Injury; Respiratory Burst

To observe the effect and mechanism of clausenamide on the expression of Bcl-2 and apoptosis after focal cerebral ischemia/reperfusion in renovascular hypertensive rats.. Seventy-five renovascular hypertensive rats were randomly divided into three groups (25 in each group): clausenamide intervention group, single ischemia/reperfusion model group and sham-operated group. Focal cerebral ischemia was reproduced by ligature for 2 hours and loosening of the ligature in the rats. No arterial ligature was applied in sham-operated group. Computerized pathological image analyzer was used to determine the number of cells positive for Bcl-2 by immunohistochemical staining, and also the counts of apoptotic cells after TdT-mediated dUTP nick end labeling (TUNEL) staining respectively in coronal sections of brain after reperfusion (6, 12, 24, 48 and 72 hours).. (1) The expression of Bcl-2 protein was detected 6 hours after reperfusion, peaking at 24 hours, then declined gradually. The Bcl-2 protein positive cell counts at every time point in clausenamide intervention group were significantly higher than simple ischemia/reperfusion model group (all P<0.01). (2) The number of apoptotic cells was increased with reperfusion, reaching its peak at 72 hours. The apoptosis counts in clausenamide intervention group were significantly lower than single ischemia/reperfusion model group (all P<0.01). At all time points, except at 48 hours after reperfusion, as there was no significant difference (all P>0.05). No Bcl-2 positive cells and only 0-2 apoptotic cells could be discernible in brain sections from sham-operated animals or in the contralateral side of ischemia in animals of the other groups.. Expression of Bcl-2 protein is enhanced and apoptosis appears after focal cerebral ischemia/reperfusion in rat brain. Clausenamide can enhance the expression of Bcl-2 protein and inhibit apoptosis remarkably. Clausenamide may coordinate with Bcl-2 in inhibiting apoptosis. This may be the mechanism of protection of brain cells from ischemic damage of clausenamide treatment.

Topics: Animals; Apoptosis; Brain Ischemia; Disease Models, Animal; Hypertension; Lactams; Lignans; Male; Proto-Oncogene Proteins c-bcl-2; Random Allocation; Rats; Rats, Wistar; Reperfusion Injury

Acute neuroprotective effects of cinnamophilin (CINN; (8R, 8'S)-4, 4'-dihydroxy-3, 3'-dimethoxy-7-oxo-8, 8'-neolignan), a novel antioxidant and free radical scavenger, were studied in a mouse model of transient middle cerebral artery (MCA) occlusion. CINN was administered intraperitoneally either 15 min before (pretreatment) or 2 h after the onset of MCA occlusion (postischemic treatment). Relative to vehicle-treated controls, animals pretreated with CINN, at 20-80 mg/kg, had significant reductions in brain infarction by 33-46% and improvements in neurobehavioral outcome. Postischemic administration with CINN (80 mg/kg) also significantly reduced brain infarction by 43% and ameliorated neurobehavioral deficits. Additionally, CINN administration significantly attenuated in situ accumulation of superoxide anions (O2-) in the boundary zones of infarct at 4 h after reperfusion. Consequently, CINN-treated animals exhibited significantly decreased levels of oxidative damage, as assessed by immunopositive reactions for 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 4-hydroxynonenal (4-HNE), and the resultant inflammatory reactions at 24 h post-insult. It is concluded that CINN effectively reduced brain infarction and improved neurobehavioral outcome following a short-term recovery period after severe transient focal cerebral ischemia in mice. The finding of a decreased extent of reactive oxygen species and oxidative damage observed with CINN treatment highlights that its antioxidant and radical scavenging ability is contributory.

Topics: Animals; Antioxidants; Brain Ischemia; Cerebral Cortex; Cerebrovascular Circulation; Free Radical Scavengers; Guaiacol; Infarction, Middle Cerebral Artery; Lignans; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Reperfusion Injury; Time Factors

Cell apoptosis following warm ischemia-reperfusion injury is a major concern in clinical issues such as organ transplantation, trauma, and cardiogenic shock. The purpose of this study was to evaluate the possible role of magnolol, a Chinese herb drug, in apoptotic injury and the kinetic expression of apoptotic-related genes in rat livers subjected to warm ischemia-reperfusion (WI/R).. Three weeks prior to the experiment 10 rats underwent a portosystemic shunt operation according to Bengmerk's method. The rats were divided into three groups. Group 1 (GI) was the control group, Group 2 (GII) and Group 3 (GIII) the magnolol-treated groups. GI and GII were subjected to 2 h and GIII to 3 h of WI/R by clamping the portal vein and hepatic artery under ether anesthesia.. Results show that all the control rats died after 2 h WI/R. Apoptotic cells were detected under microscopy as well as by DNA assay. Magnolol-treated groups tolerated warm ischemia-reperfusion for 2 h and significantly less apoptotic cells were observed (198 +/- 22 vs 42.6 +/- 28). But magnolol-treated rats could not tolerate 3 h warm ischemia-reperfusion. RT-PCR of liver tissue shows that there is an upregulated expression of the anti-apoptotic Bcl-xL gene and suppression of the Bcl-xS gene in GII.. Magnolol has an anti-apoptotic effect and protects the liver against WI/R for 2 h but not for 3 h through upregulation of the anti-apoptotic Bcl-XL gene and suppression of the Bcl-xS gene.

Topics: Animals; Apoptosis; bcl-X Protein; Biphenyl Compounds; Drugs, Chinese Herbal; Enzyme Inhibitors; Gene Expression Regulation; Lignans; Liver; Models, Animal; Nitric Oxide Synthase; Proto-Oncogene Proteins c-bcl-2; Rats; Reperfusion Injury

We have previously shown that honokiol, an active component of Magnolia officinalis, displayed protective effect against focal cerebral ischemia-reperfusion (FCI/R) injury in rats. Production of reactive oxygen species (ROS) and infiltration of neutrophils to injured tissue play deleterious roles during cerebral ischemia. To study the mechanism(s) in mediating neuroprotective effect of honokiol, FCI/R-induced neutrophil infiltration and lipid peroxidation in brain tissue, and activation of neutrophils in-vitro were examined. Intravenous administration of honokiol (0.01-1.0 microg/kg) 15 min before (pretreatment) or 60 min after (post-treatment) middle cerebral artery occlusion reduced the total infarcted volume by 20-70% in dose-dependent manner. Pretreatment or post-treatment of honokiol at concentration of 0.1 and 1.0 microg/kg significantly decreased the neutrophil infiltration in the infarcted brain. Time course of neutrophil infiltration was performed in parallel with the lipid peroxidation in infracted brain tissue during FCI/R injury. The results indicate that honokiol can protect brain tissue against lipid peroxidation and neutrophil infiltration during FCI/R injury and cerebral infarction induced by FCI/R is accompanied with a prominent neutrophil infiltration to the infarcted area during FCI/R course. In-vitro, honokiol (0.1-10 microM) significantly diminished fMLP (N-formyl-methionyl-leucyl-phenylalanine)- or PMA (phorbol-12-myristate-13-acetate)-induced neutrophil firm adhesion, a prerequisite step behind neutrophil infiltration, and ROS production in neutrophils. Intracellular calcium overloading activates calcium-stimulated enzymes and further exaggerates FCI/R injury. Honokiol (0.1-10 microM) impeded the calcium influx induced by fMLP (a receptor agonist), AlF(4)(-) (a G-protein activator) or thapsigargin (an intracellular calcium pool releaser). Therefore, we conclude that the amelioration of FCI/R injury by honokiol can be attributed to its anti-oxidative and anti-inflammatory actions through, at least in part, limiting lipid peroxidation and reducing neutrophil activation/infiltration by interfering firm adhesion, ROS production, and calcium overloading that may be primed/activated during FCI/R injury.

Topics: Animals; Biphenyl Compounds; Brain Ischemia; Calcium; Calcium Signaling; Cell Adhesion; Cerebral Infarction; Chemotaxis, Leukocyte; Dose-Response Relationship, Drug; Infarction, Middle Cerebral Artery; Lignans; Lipid Peroxidation; Male; N-Formylmethionine Leucyl-Phenylalanine; Neuroprotective Agents; Neutrophils; Rats; Rats, Long-Evans; Reactive Oxygen Species; Reperfusion Injury; Tetradecanoylphorbol Acetate

In the present study, we examined the time-dependent changes in the mitochondrial glutathione status and ATP generation capacity in the myocardium as well as the susceptibility of the myocardium to ischemia-reperfusion (IR) injury in female Sprague Dawley rats treated with a single pharmacological dose (1.2 mmol/kg) of schisandrin B (Sch B). Sch B treatment produced a time-dependent enhancement in myocardial mitochondrial glutathione status, as evidenced by increases in myocardial mitochondrial reduced glutathione (GSH) level and activities of glutathione reductase, Se-glutathione peroxidase (GPX) and glutathione S-transferases, with the response reaching maximum at 48 h post-dosing and then declining gradually to the control level at 96 h post-dosing. The enhancement of mitochondrial glutathione status was associated with an increase in myocardial ATP generation capacity, with the value peaking at 72 h post-dosing. These beneficial effects of Sch B on the myocardium was paralleled by a time-dependent decrease in the susceptibility to IR injury, with the maximum protection demonstrable at 48 h post-dosing. The cardioprotection was associated with increases in myocardial GSH level and activities of glutathione antioxidant enzymes (except for GPX whose activity was suppressed) as well as tissue ATP level/ATP generation capacity. The results suggest that Sch B treatment can precondition the myocardium by enhancing the mitochondrial glutathione status and ATP generation capacity, thereby protecting against IR injury.

Topics: Adenosine Triphosphate; Animals; Antioxidants; Cyclooctanes; Female; Glutathione; Heart; Lignans; Mitochondria, Heart; Myocardium; Polycyclic Compounds; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Time Factors

The effects of (-)clausenamide (clau) on spatial cognitive functions and hippocampal long-term potentiation (LTP) after transient focal cerebral ischemia in rats were investigated. Four weeks after middle cerebral artery occlusion, Morris water maze tasks demonstrated that 2 h of transient forebrain ischemia resulted in a significant decrease in spatial discrimination performance. The escape latency at 4 and 5 days of acquisition trial was lower in the ischemic rats than in sham-operated rats (33.8+/-6.7 sec and 26.8+/-5 sec versus 12.2+/-4.0 sec and 10.4+/-3.6 sec), chronic treatment with clau (10 mg kg(-1) p.o. once daily) significantly improved the impairment (12.4+/-4.1 sec and 15.2+/-3.1 sec). After Morris water maze, the changes in population spike (PS) amplitude were recorded as an index of LTP in the perforant path-dentate gyrus synapses. There was no difference in PS amplitude between the sham-operated and vehicle-treated animals, whereas the fractional increase of PS 20-50 min after tetanus was significantly larger in clau-treated group. Histopathological analysis revealed that clau could protect against neuron loss in the regions of cortex and striatum. In conclusion, these data indicate a beneficial effect of clau for synaptic plasticity and cognitive function impaired by transient focal cerebral ischemia.

Topics: Action Potentials; Animals; Brain; Brain Ischemia; Cognition Disorders; Drugs, Chinese Herbal; Infarction, Middle Cerebral Artery; Ischemic Attack, Transient; Lactams; Lignans; Male; Maze Learning; Nerve Degeneration; Neurons; Rats; Rats, Wistar; Recovery of Function; Reperfusion Injury; Treatment Outcome

Topics: Animals; Anti-Arrhythmia Agents; Biphenyl Compounds; Intestinal Mucosa; Intestine, Small; Lignans; Microcirculation; Rats; Reperfusion Injury

Isolated Langendorff-perfused rat hearts were subjected to a fixed period of ischemia followed by increasing periods of reperfusion for investigating the changes in the extent of ischemia-reperfusion (IR) injury and tissue levels of non-enzymatic antioxidants. Effects of schisandrin B (Sch B) and (+/-) alpha-lipoic acid (LA) pretreatment were also examined. A 40-min of ischemia (40-I) followed by 20- or 40-min of reperfusion (20-R or 40-R) caused sustainable tissue damage in isolated hearts, as indicated by the increased extent of lactate dehydrogenase (LDH) leakage and impaired contractile force. The myocardial IR injury was associated with a marked decrease in tissue ascorbic acid (V(C)) level. However, myocardial reduced glutathione (GSH) and alpha-tocopherol (V(E)) levels remained relatively unchanged except under a more severe IR condition (40-I, 40-R). Pretreating rats with Sch B or LA at a daily dose of 1.2 mmol/kg for 3 days protected against IR injury in isolated hearts to varying degrees. While only Sch B pretreatment could improve the recovery of contractile force, LA pretreatment produced a better inhibitory effect on LDH leakage. The protection against IR injury was associated with significant increases in myocardial V(E) and V(C) levels in both Sch B and LA pretreated hearts. The ensemble of results suggests that the cardioprotection afforded by Sch B or LA pretreatment may at least in part be attributed to the modulation on the interplay among non-enzymatic antioxidants under oxidative stress induced by IR.

Topics: Animals; Antioxidants; Ascorbic Acid; Cyclooctanes; Female; Heart; L-Lactate Dehydrogenase; Lignans; Male; Models, Chemical; Myocardium; Oxidative Stress; Perfusion; Polycyclic Compounds; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Thioctic Acid; Time Factors

A mechanism suggested to cause injury to preserved organs is the generation of oxygen free radicals. Lipid peroxidation is one of the biological damages caused by oxygen free radicals. It is our aim to investigate whether magnolol, a strong antioxidant, suppresses the generation of oxygen free radicals and improves the viability of cold-preserved warm-reperfused rat livers.. In vitro lipid peroxidation was induced in rat hepatic mitochondria with ADP and FeSO4. The inhibitory effect of magnolol on lipid peroxidation was measured with oxygen consumption and malondialdehyde (MDA) formation. Subsequently, we preserved and reperfused rat livers in preservation solutions that contained magnolol. The hepatic enzymes and liver MDA were measured to assess the protective effect of magnolol on isolated rat livers.. In rat hepatic mitochondria, magnolol was 470 times more potent than alpha-tocopherol in inhibiting oxygen consumption and 340 times more potent than alpha-tocopherol in inhibiting MDA formation. Addition of magnolol to Ringer's lactate solution had a protective effect, in terms of MDA formation and leakage of hepatic enzymes, on warm-reperfused but not cold-stored liver tissue. Addition of magnolol to University of Wisconsin (UW) solution, a widely used preservation solution, did not modify the effect of this solution on isolated liver tissues.. We conclude that magnolol is an effective antioxidant and suppresses lipid peroxidation in rat liver mitochondria and can be used as a rinsing solution in protecting transplanted organs from lipid peroxidation during reperfusion, especially for those organs not preserved with UW solution.

Topics: Animals; Antioxidants; Biphenyl Compounds; Cold Temperature; In Vitro Techniques; Lignans; Lipid Peroxidation; Liver; Male; Malondialdehyde; Mitochondria, Liver; Organ Preservation; Oxygen Consumption; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Vitamin E

Honokiol, a compound extracted from the Chinese medicinal herb Magnolia officinalis, has a strong antioxidant effect on the inhibition of lipid peroxidation in rat heart mitochondria. To investigate the protective effect of honokiol on hepatocytes from peroxidative injury, oxygen consumption and malondialdehyde formation for in vitro iron-induced lipid peroxidation were assayed, and the mitochondrial respiratory function for in vivo ischemia-reperfusion injury were evaluated in rat liver, respectively. The inhibitory effect of honokiol on oxygen consumption and malondialdehyde formation during iron-induced lipid peroxidation in liver mitochondria showed obvious dose-dependent responses with a concentration of 50% inhibition being 2.3 x 10(-7) M and 4.96 x 10(-7) M, respectively, that is, 550 times and 680 times more potent than alpha-tocopherol, respectively. When rat livers were introduced with ischemia 60 min followed by reperfusion for 60 min, and then pretreated with honokiol (10 micrograms/kg BW), the mitochondrial respiratory control ratio (the quotient of the respiration rate of State 3 to that of State 4) and ADP/O ratio from the honokiol-treated livers were significantly higher than those of non-treated livers during reperfusion. The dose-dependent protective effect of honokiol on ischemia-reperfusion injury was 10 microgram-100 micrograms/Kg body weight. We conclude that honokiol is a strong antioxidant and shed insight into clinical implications for protection of hepatocytes from ischemia-reperfusion injury.

Topics: Animals; Biphenyl Compounds; Gastrointestinal Agents; Lignans; Lipid Peroxidation; Liver; Liver Diseases; Male; Malondialdehyde; Mitochondria, Liver; Oxidation-Reduction; Phosphorylation; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Vitamin E

We used cinnamophilin, a novel dual inhibitor of thromboxane synthase and thromboxane A2 (TXA2) receptor, and superoxide dismutase (SOD) with catalase to examine their protective effect against reperfusion injury in rat skeletal muscle. In 5 groups of 6 wistar rats three hours of ischaemia were induced in one hind limb by application of a tourniquet to the proximal thigh; the contralateral limb served as an internal, nonischaemic control. The first group did not receive any drug nor was it reperfused. In the other four groups, normal saline (reperfusion control), dimethylsulphoxide (DMSO), cinnamophilin, or SOD with catalase was given before removal of the tourniquet and one hour of reperfusion followed. Skeletal muscle injury was measured by a quantitative spectrophotometric assay of triphenyltetrazolium chloride (TTC) reduction and by muscle weight gain. One hour of reperfusion significantly (p<0.05) lowered TTC reduction in ischaemic limbs in the reperfusion control group in comparison with the rats in 3h ischaemia alone. Among the four reperfusion groups, only the cinnamophilin group had significantly lower decrease of TTC reduction and significantly lower muscle weight gain. These results demonstrate the protective effect of cinnamophilin against reperfusion injury of the ischaemic skeletal muscle in rats.

Topics: Animals; Catalase; Female; Guaiacol; Hindlimb; Ischemia; Lignans; Muscle, Skeletal; Random Allocation; Rats; Rats, Wistar; Receptors, Thromboxane; Reperfusion Injury; Superoxide Dismutase; Thromboxane-A Synthase; Tissue Survival