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Eur J Pharmacol [journal]
- Baicalein protects against polymicrobial sepsis-induced liver injury via inhibition of inflammation and apoptosis in mice. [JOURNAL ARTICLE]
- Eur J Pharmacol 2014 Dec 20.
Liver dysfunction has been known to occur frequently in cases of sepsis. Baicalein, the main active ingredient of the Scutellaria root, exerts anti-inflammatory and anti-apoptotic properties in endotoxic shock. However, the role of baicalein in polymicrobial sepsis-induced liver injury and its regulatory mechanisms remain unclear. In this study, we aimed to investigate the protective effects of baicalein on polymicrobial sepsis-induced liver injury and to explore the possible mechanisms. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) in C57BL/6 mice. Mice were treated with baicalein (100mg/kg, i.p) at 1h, 6h and 12h following CLP. Baicalein significantly improved the survival of septic mice. Treatment with baicalein ameliorated the CLP-induced liver injury, as indicated by the lower serum aminotransferase levels and the fewer histopathologic abnormalities. Baicalein reduced the neutrophil infiltration and the hepatic inflammatory cytokine expression and release. It also decreased the hepatic and the serum high-mobility group box 1 and macrophage migration inhibitory factor levels in septic mice. Moreover, baicalein significantly inhibited the mitogen-activated protein kinases (MAPKs) activation and suppressed the transcriptional activity of nuclear factor-kappa B (NF-κB). In conclusion, these results suggest that baicalein treatment could protect against the sepsis-induced liver injury, and improve the survival of mice with polymicrobial sepsis. The mechanism of the protective action of baicalein seems to involve its ability to reduce inflammatory response, inhibit hepatic apoptosis, and to suppress MAPKs and NF-κB activation.
- Assessment of anti-arrhythmic activity of antipsychotic drugs in an animal model: Influence of non-cardiac α1-adrenergic receptors. [JOURNAL ARTICLE]
- Eur J Pharmacol 2014 Dec 18.
Torsades de Pointes (TdP) is a potentially lethal cardiac arrhythmia and a known adverse effect of many drugs secondary to block of the rapidly activating delayed rectifier potassium current (IKr). In animal models antipsychotic drugs have shown reduced pro-arrhythmic potential compared to drugs with comparable IKr-blocking characteristics. The reduced pro-arrhythmic properties of antipsychotic drugs has been attributed to a variety of different causes e.g., effects on α1-adrenergic receptors, β-adrenergic receptors, muscarinic receptors or cardiac ion channels like Ca(2+)- and Na(+)-channels. Since only limited experimental information exists about the effects of α1-adrenergic receptor activity of antipsychotic drugs in pro-arrhythmic models, we have decided to investigate this. In this study we show that four antipsychotic drugs all have high affinity for α1-adrenergic receptor (sertindole>risperidone>haloperidol>olanzapine) and all block IKr (sertindole>haloperidol>risperidone>olanzapine). In canine Purkinje fibres, α1-adrenergic stimulation prolonged action potential duration; however, the stimulation does not cause afterdepolarizations, even in the presence of dofetilide-induced delayed repolarization. We showed for the first time in an in vivo pro-arrhythmic rabbit model that several antipsychotic drugs in accordance with their known α1-adrenergic receptor blocking properties reduced the incidence of drug-induced TdP and that the overall ability of the antipsychotic drugs to prevent TdP was associated with prevention of methoxamine induced increase in blood pressure. Further investigations are required to clarify the relative importance of α1-adrenergic receptor antagonism in conjunction with the additional effects of antipsychotic drugs on various receptors and ion channels.
- Epicatechin breaks preformed glycated serum albumin and reverses the retinal accumulation of advanced glycation end products. [JOURNAL ARTICLE]
- Eur J Pharmacol 2014 Dec 19.
The accumulation of advanced glycation end products (AGEs) is associated with many of the complications of diabetes mellitus, including diabetic retinopathy. AGE-breakers, such as N-phenacylthiazolium and alagebrium, have been proposed as therapeutic agents for reversing the increase in protein crosslinking in diabetes. (-)-Epicatechin is a major dietary flavonoid with a wide range of health-promoting biological activities. The aim of this study was to determine the potential effect of (-)-epicatechin in reducing the burden of AGEs in vitro and in vivo and to evaluate whether the reduced AGE burden could translate into improvement in retinal vascular function in exogenously AGE-injected rats. Glycated human serum albumin was purified from patients with diabetes. The breakdown of the already formed AGEs was studied by treating glycated human serum albumin with (-)-epicatechin. To study the effect of (-)-epicatechin on retinal vascular function, exogenously AGE-injected rats were treated with (-)-epicatechin (50 and 100mg/kg i.p.) for two weeks. Apoptosis of retinal vascular cells was quantified using TUNEL staining. The AGE load in the retinas was determined via immunohistochemical staining and western blot analysis. (-)-Epicatechin was able to break preformed glycated human serum albumin in vitro as well as reduce AGE accumulation in retinas in vivo in a dose dependent manner. In exogenously AGE-injected rats, treatment with (-)-epicatechin was evidenced by an improved retinal vascular apoptosis. AGE burden in retinas was also reduced upon treatment. This study suggests that (-)-epicatechin could represent a valuable drug for the treatment of diabetic retinopathy by reducing the AGE burden.
- Deoxysappanone B, a homoisoflavone from the Chinese medicinal plant Caesalpinia sappan L., protects neurons from microglia-mediated inflammatory injuries via inhibition of IκB kinase (IKK)-NF-κB and p38/ERK MAPK pathways. [JOURNAL ARTICLE]
- Eur J Pharmacol 2014 Dec 18.
Caesalpinia sappan L. (Lignum Sappan) is a Chinese medicinal plant for treating ischemic cerebral apoplexy. Deoxysappanone B (DSB), a homoisoflavone compound isolated from C. sappan L. (Lignum Sappan), was studied for anti-neuroinflammatory and neuroprotective properties using lipopolysaccharide (LPS)-induced BV-2 microglia neuroinflammation model and LPS-induced microglia-neuron co-culture system. Our findings showed that DSB effectively inhibited BV-2 microglia-mediated neuroinflammatory mediators׳ release including NO, PGE2, TNF-α, IL-6 and reactive oxygen species. Moreover, DSB markedly protected neurons against inflammatory microglia-mediated neurotoxicity in a microglia-neuron co-culture system. Mechanism study revealed that DSB blocked two major neuroinflammation-related signaling pathways including IKK-IκB-nuclear factor kappaB (NF-κB) and p38/ERK mitogen-activated protein kinase (MAPK) cascades, further leading to the inhibition of neuroinflammatory mediators׳ production. The present study provides evidence that the anti-neuroinflammatory and neuroprotective effect of DSB are due to the suppression of neuroinflammatory mediators׳ production as well as inflammation-induced neurotoxicity through regulation of multi-targets. Therefore, DSB may serve as a neuroprotective agent for the treatment of neuroinflammatory disorders and inflammation-related neuronal injury.
- Differential tolerance to morphine antinociception in assays of pain-stimulated vs. pain-depressed behavior in rats. [JOURNAL ARTICLE]
- Eur J Pharmacol 2014 Dec 18.
In preclinical research on pain and analgesia, noxious stimuli can stimulate expression of some behaviors (e.g. withdrawal reflexes) and depress others (e.g. feeding, locomotion, and positively reinforced operant responding). Tolerance to morphine antinociception is a robust and reliable phenomenon in preclinical assays of pain-stimulated behavior, but development of morphine tolerance in assays of pain-depressed behavior has not been studied. This study compared morphine antinociceptive tolerance in parallel assays of pain-stimulated and pain-depressed behavior in male Sprague-Dawley rats. Intraperitoneal injection of dilute lactic acid served as a noxious stimulus to stimulate a stretching response in one group of rats and to depress operant responding for electrical brain stimulation (intracranial self-stimulation; ICSS) in another group of rats. Antinociception produced by morphine (1.0mg/kg) was determined after a regimen of chronic treatment with either saline or morphine in separate subgroups of rats in each procedure. In rats receiving chronic saline, acid alone stimulated a stretching response and depressed ICSS, and both acid effects were blocked by 1.0mg/kg morphine. Rats receiving chronic morphine displayed hyperalgesic responses to the acid noxious stimulus in both procedures. Complete tolerance developed to morphine antinociception in the assay of acid-stimulated stretching, but morphine retained full antinociceptive effectiveness in the assay of acid-depressed ICSS. These results suggest that morphine antinociception in an assay of pain-depressed behavior is relatively resistant to tolerance. More broadly, these results suggest that antinociceptive tolerance can develop at different rates or to different degrees for different measures of antinociception.
- Anti-inflammatory effects of a triple-bond resveratrol analog: Structure and function relationship. [JOURNAL ARTICLE]
- Eur J Pharmacol 2014 Dec 18.
Resveratrol is a polyphenol found in grapes and red wine, showing well-characterized anti-inflammatory and antiproliferative activities. In order to exceed resveratrol׳s biological effects and to reveal the structural determinants of the molecule׳s activity, numerous derivatives were synthesized recently. Most of these resveratrol analogs vary from the original molecule in the number, position or identity of the phenolic functional groups. Investigation of the analogs provided important data regarding structure-activity relationship of the molecule. With the exception of cis- and trans-resveratrol and the reduced form dihydroresveratrol, little is known about the molecular effects of the stilbene backbone. In the present study we investigated the anti-inflammatory properties of a new, triple-bond resveratrol analog, 3,4',5-trihydroxy-diphenylacetylene (TDPA) on lipopolysaccharide-stimulated RAW macrophages. We found that the analog had weaker antioxidant activity and stronger inhibitory effect on nuclear factor-kappaB activation, and on cyclooxygenase-2, tumor necrosis factor α and interleukin-6 production. It also prevented lipopolysaccharide-induced depolarization of the mitochondrial membrane. In contrast to resveratrol, TDPA increased the phosphorylation of c-Jun N-terminal and p38 mitogen activated protein kinases. In summary, we identified a novel compound with better anti-inflammatory properties than resveratrol. Our results contributed to a better understanding of the structural determinants of resveratrol׳s biological activities.
- Effects of bleomycin, etoposide and cisplatin treatment on Leydig cell structure and transcription of steroidogenic enzymes in rat testis. [JOURNAL ARTICLE]
- Eur J Pharmacol 2014 Dec 15.
Cytotoxic anticancer chemotherapy affects pituitary-testicular hormonal axis in humans and in animals. This study investigated the effects on Leydig cells of three cycles of bleomycin, etoposide and cisplatin (0.75, 7.5, and 1.5mg/kg, respectively; BEP) chemotherapy in rat testis. The chemotherapy has induced hyperplasia of and degenerative changes in Leydig cells at the end of BEP exposure, which remained so even after a recovery time of 63 days. The increased testicular oxidative stress at the end of the chemotherapy returned to normal level after the recovery time. The chemotherapy has stimulated the transcription of scavenger receptor class type-B1 (SCARB1), steroidogenic acute-regulatory protein (StAR), cytochrome P450 cholesterol side-chain cleavage (CYP11A1), CYP17A1, and inhibited that of 17β-hydroxysteroid dehydrogenase (HSD17B6) and CYP19A1 in association with increased cholesterol and decreased testosterone levels. Even after the recovery time, the chemotherapy still had inhibitory effects on the transcription of all of the above genes in addition to luteinizing hormone receptor and HSD3B1, but not on the StAR gene. The cholesterol and testosterone levels also did not show any significant differences with the control group. The decreased testosterone level at the end of chemotherapy was probably due to inhibition of HSD3B1 and HSD17B6 genes. In conclusion, clinically relevant dose-levels and treatment protocols of BEP chemotherapy adversely affect Leydig cell function. The BEP chemotherapy inhibits the transcription of steroidogenic enzymes and that these effects sustain over an extended period of time without returning to normal levels.
- Ang-(1-7) exerts protective role in blood-brain barrier damage by the balance of TIMP-1/MMP-9. [JOURNAL ARTICLE]
- Eur J Pharmacol 2014 Dec 15.
Cerebrovascular disease (CVD) ranks as the top three health risks, specially cerebral ischemia characterized with the damage of blood-brain barrier (BBB). The angiotensin Ang-(1-7) was proven to have a protective effect on cerebrovascular diseases. However, its role on blood-brain barrier and the underlying molecular mechanism remains unclear. In this study, Ang-(1-7) significantly relieved damage of ischemia reperfusion injury on blood-brain barrier in cerebral ischemia reperfusion injury (IRI) rats. Furthermore, its treatment attenuated BBB permeability and brain edema. Similarly, Ang-(1-7) also decreased the barrier permeability of brain endothelial cell line RBE4. Further analysis showed that Ang-(1-7) could effectively restore tight junction protein (claudin-5 and zonula occludens ZO-1) expression levels both in IRI-rats and hypoxia-induced RBE4 cells. Furthermore, Ang-(1-7) stimulation down-regulated hypoxia-induced matrix metalloproteinase-9 (MMP-9) levels, whose silencing with (matrix metalloproteinase-9 hemopexin domain) MMP9-PEX inhibitor significantly increased the expression of claudin-5 and ZO-1. Further mechanism analysis demonstrated that Ang-(1-7) might junction protein levels by tissue inhibitor of metalloproteinase 1 (TIMP1)-MMP9 pathway, because Ang-(1-7) enhanced TIMP1 expression, whose silencing obviously attenuated the inhibitor effect of Ang-(1-7) on MMP-9 levels and decreased Ang-(1-7)-triggered increase in claudin-5 and ZO-1. Together, this study demonstrated a protective role of Ang-(1-7) in IRI-induced blood-brain barrier damage by TIMP1-MMP9-regulated tight junction protein expression. Accordingly, Ang-(1-7) may become a promising therapeutic agent against IRI and its complications.
- Neuroprotective effect of 3-morpholinosydnonimine against Zn(2+)-induced PC12 cell death. [JOURNAL ARTICLE]
- Eur J Pharmacol 2014 Dec 15.
Excessive intracellular accumulation of zinc (Zn(2+)) is neurotoxic and contributes to a number of neuropathological conditions. Here, we investigated the protective effect of 3-morpholinosydnonimine (SIN-1) against Zn(2+)-induced neuronal cell death in differentiated PC12 cells. We found that Zn(2+)-induced PC12 cell death was reduced in a concentration-dependent manner by pretreatment with SIN-1. The intracellular accumulation of Zn(2+) was not affected by pretreatment with SIN-1, indicating that SIN-1-induced neuroprotection was not attributable to reduced influx of Zn(2+) into cells. SIN-1C, the stable decomposition product of SIN-1, failed to prevent Zn(2+)-induced cell death. Furthermore, the protective effect of SIN-1 against Zn(2+)-induced PC12 cell death was almost completely abolished by uric acid, a free radical scavenger, suggesting that reactive oxygen and nitrogen species generated by SIN-1 may contribute to the protective effect. SIN-1 prevented the inactivation of glutathione reductase (GR) and the increase in the ratio of oxidized glutathione/total glutathione (GSSG/total GSH) induced by Zn(2+). Addition of membrane permeable GSH ethyl ester (GSH-EE) to PC12 cells prior to Zn(2+) treatment significantly increased cell viability. We therefore conclude that SIN-1 may exert neuroprotective effect against Zn(2+)-induced cell death in differentiated PC12 cells by preventing inhibition of GR and increase in GSSG/total GSH ratio.
- Nicotine facilitates reinnervation of phenol-injured perivascular adrenergic nerves in the rat mesenteric resistance artery. [JOURNAL ARTICLE]
- Eur J Pharmacol 2014 Dec 13.
Nicotine has been shown to have neuroprotective and neurotrophic actions in the central nervous system. To elucidate the peripheral neurotrophic effects of nicotine, we determined whether nicotine affected the reinnervation of mesenteric perivascular nerves following a topical phenol treatment. A topical phenol treatment was applied to the superior mesenteric artery proximal to the abdominal aorta in Wistar rats. We examined the immunohistochemistry of the distal small arteries 7 days after the treatment. The topical phenol treatment markedly reduced the density of tyrosine hydroxylase (TH)-LI and calcitonin gene-related peptide (CGRP)-LI fibers in these arteries. The administration of nicotine at a dose of 3mg/kg/day (1.5mg/kg/injection, twice a day), but not once a day or its continuous infusion using a mini-pump significantly increased the density of TH-LI nerves without affecting CGRP-LI nerves. A pretreatment with nicotinic acetylcholine receptor antagonists hexamethonium, mecamylamine, and methyllycaconitine, but not dextrometorphan, canceled the TH-LI nerve reinnervation induced by nicotine. Nicotine significantly increased NGF levels in the superior cervical ganglia (SCG) and mesenteric arteries, but not in the dorsal root ganglia, and also up-regulated the expression of NGF receptors (TrkA) in the SCG, which were canceled by hexamethonium. These results suggested that nicotine exhibited neurotrophic effects that facilitated the reinnervation of adrenergic TH-LI nerves by activating α7 nicotinic acetylcholine receptor and NGF in the SCG.