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Purpose/Aim: Pulmonary fibrosis (PF) is characterized by the progressive and ultimately fatal accumulation of fibroblasts and extracellular matrix in the lung that distorts its architecture and compromises its function.Objective: The present study investigated the potential protective effects of schisandrin B (Sch B) on the Wingless/Integrase-1 (Wnt) signaling pathway in attenuating inflammation and oxidative stress in ICR mice.Methods: Sixty healthy ICR mice were randomly divided into the following groups: control group, bleomycin (BLM) group, Sch B low dose (Sch B-L) group, Sch B medium dose (Sch B-M) group, Sch B high dose (Sch B-H) group, and dexamethasone (DXM) group. The expression of transforming growth factor (TGF)-β1 was examined by ELISA. In addition, the levels of superoxide dismutase (SOD), hydroxyproline (HYP), and the total antioxidant capacity (T-AOC) were determined. The protein and mRNA levels of matrix metalloproteinase 7 (MMP7) and β-catenin in mice were analyzed by western blot and quantitative real -quantitative time PCR (qRT-PCR), respectively.Results: Lung tissues from the BLM group exhibited significantly more inflammatory changes and a significantly greater number of collagen fibers than lung tissues from the control group. In addition, the lung tissues from these BLM-treated mice exhibited slightly increased MMP7 and β-catenin protein expression. Lung tissues from the Sch B-H group exhibited fewer inflammatory changes and fewer collagen fibers than lung tissues from the BLM group. Furthermore, the lung tissues from the Sch B-H mice exhibited decreased HYP and TGF-β1 levels, but increased SOD and T-AOC levels.Conclusions: The present study provided evidence that Sch B may be a potential therapeutic agent for the treatment of PF.

Anwulignan (AN) is a monomer lignan fromiSchisandra sphenanthera/iRehd. et Wits (iSchisandra sphenanthera/ifructus,iSchisandra sphenanthera/i). The protective effect of AN against the indomethacin (IND)-induced gastric injury to mice and the related mechanism of action was investigated in this study. The effect of AN was mainly assessed by observing the gastric tissue morphology, gastric ulcer index (GUI), ulcer inhibition rate (UIR), gastric juice volume (GJV) and pH value. Chemical colorimetry, immunofluorescence, ELISA, and Western blot were used to detect related factors in the gastric tissue. The results showed that AN reduced the GUI, increased the UIR, inhibited the GJV, and increased the gastric pH value. AN significantly increased cyclooxygenase-1, cyclooxygenase-2, and prostaglandin E2 expression levels in the gastric tissue, activated nuclear factor (erythroid-derived 2)-like 2 (Nrf2), increased heme oxygenase-1 expression, enhanced the activity of superoxide dismutase and glutathione peroxidase, and decreased the malondialdehyde content. AN reduced the phosphorylation of nuclear factor-κ gene binding (NF-κB) p65 and its nuclear translocation, the key protein of NF-κB signaling pathway in the gastric tissue, and the content of the pathway downstream signaling molecules, including interleukin-6, interleukin-1iβ/i, and tumor necrosis factor-iα/i, to play an anti-inflammatory role. AN inhibited the downstream signals B-cell lymphoma 2-associated x protein and cleaved caspase-3 in gastric tissue, and activated B-cell lymphoma 2, to play an antiapoptotic role, which were further verified by Hoechst staining. Therefore, AN has a significant protection against the gastric injury induced by IND in mice, and the mechanism may be concerned in its activation of Nrf2, inhibition of NF-κB signaling pathway, and anti-apoptotic effect. SIGNIFICANCE STATEMENT: Anwulignan (AN) significantly reduced the indomethacin-induced gastric injury in mice, and its antioxidation, anti-inflammation, and antiapoptosis were considered to be involve in the effect, suggesting that AN should be a potential drug or food supplement for gastric injury induced by indomethacin.

Schisandra chinensis (S. chinensis) is one of the core drugs used for relieving cough and asthma in traditional Chinese medicine. However, there are few basic studies on the treatment of respiratory diseases with S. chinensis in modern pharmacology, and the material basis and mechanism of its antiasthmatic effect are still unclear. Lignans are the main active components of S. chinensis. The aim of this study was to observe the relaxation effect of S. chinensis lignans (SCL) on the tracheal smooth muscle of rats by in vitro tracheal perfusion experiments, and to explore the mechanism by preincubation with L-type calcium channel blocker verapamil, four potassium channel blockers glibenclamide, tetraethylamine, 4-aminopyridine and barium chloride (BaCl(2)), β-adrenoceptor blocker propranolol, nitric oxide synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME), and the cyclooxygenase inhibitor indomethacin, respectively. The results showed that SCL (0.25–1.75 mg/mL) reduced the contraction of isolated tracheal smooth muscle induced by acetylcholine, the preincubation with verapamil and glibenclamide could attenuate the relaxation effect, whereas propranolol, 4-aminopyridine, BaCl(2), tetraethylamine, L-NAME, and indomethacin had no such effect. These results suggest that SCL has a significant relaxation effect on the isolated tracheal smooth muscle of rats, and the mechanism may be related to the inhibition of extracellular calcium influx and intracellular calcium release from the sarcoplasmic reticulum, as well as the activation of ATP-sensitive potassium channels. These findings may provide a pharmacological basis for the traditional use of S. chinensis to treat asthma.

Schisandra chinensis is a hepatoprotective herb that has been used for centuries in China. Polysaccharide is one of the major active components in S. chinensis, which has been reported to improve liver injuries induced by carbon tetrachloride, alcohol, or high-fat diet. In this study, we observed the effects and corresponding mechanisms of the secondary component of Schisandra polysaccharide (acidic polysaccharide, SCAP) on a murine model of severe acute liver injury induced by acetaminophen (APAP). SCAP significantly decreased the serum alanine aminotransferase (ALT), aspartate aminotransferas (AST), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) levels, and was found to alleviate hepatic pathological alterations in the mouse model. Meanwhile, SCAP revealed a protective effects on the liver injury-related enzymes and factors, such as significantly diminished malondialdehyde (MDA) levels and glutathione (GSH) depletion, reduced ratio of B-cell lymphoma-2 (Bcl-2)-associated X protein (Bax)/Bcl-2, prohibited cleaved caspase-3 expression, and elevated the expression of p-AMPK, p-Akt, p-glycogen synthase kinase 3β (GSK 3β), nuclear factor erythroid 2–derived-like 2 (Nrf 2) and heme oxygenase-1 (HO-1) proteins in the liver tissues of the mouse model. In conclusion, we speculated that the protective activities of SCAP on the APAP-induced mouse model of acute liver injury might be related to its antioxidation, anti-inflammation and anti-apoptosis properties. Keywords: Schisandra chinensis, Polysaccharide, Hepatoprotection, Antioxidation

1. Schizandrol A is an active component in schisandra, also the representative component for the identification of schisandra. 2. A rapid resolution liquid chromatography coupled with quadruple-time-of-flight mass spectrometry (RRLC-QTOF/MS) was developed to investigate the pharmacokinetics of schizandrol A after its intragastric administration (50 mg/kg) in rats. 3. Schizandrol A was rapidly absorbed (T

Anwulignan is one of the monomer compounds in the lignans from Schisandra sphenanthera. In this study, we observed the effect of anwulignan on intestinal ischemia/reperfusion (II/R) injury in male Sprague-Dawley rats and explored the underlying mechanisms. The results showed that pretreatment with oral anwulignan could significantly increase the mesenteric blood microcirculatory flow velocity; relieve the congestion and pathologic injury of jejunum; enhance the autonomic tension of jejunum smooth muscle and its reactivity to acetylcholine; increase the activities of superoxide dismutase, catalase, glutathione S-transferase, and choline acetyltransferase; increase the contents of acetylcholine and glutathione in the serum or jejunal tissue; decrease the activities of myeloperoxidase, protein kinase C, and nicotinamide adenine dinucleotide phosphate oxidase; reduce the contents of malondialdehyde, 8-hydroxy-2-deoxyguanosine, nicotinamide adenine, reactive oxygen species, tumor necrosis factor-α, interleukin (IL)-6, and IL-1β; increase the expression levels of muscarinic receptor 3, PI3K, phosphorylation protein kinase B, p-GSK3β Ser9, Nrf2, p-Nrf2, heme oxygenase (decycling) 1, and b-cell lymphoma 2 in the jejunal tissue; and decrease the expression levels of p-GSK3β Tyr216, kelch-like ECH-associated protein 1, Bax, and cleaved caspase-3, suggesting that anwulignan can ameliorate II/R-induced jejunal tissue injury in rats and that the mechanism may be related to its activating the PI3K/protein kinase B pathway and then regulating the Nrf2/Anti-oxidative Response Element signaling pathway and the expression of apoptosis-related proteins to play antioxidant and antiapoptotic roles. SIGNIFICANCE STATEMENT Anwulignan can significantly reduce jejunal tissue injury and the production of inflammatory factors in rats with intestinal ischemia-reperfusion injury, improve the antioxidant capacity, and reduce the apoptosis of jejunal tissue, and it has the effect of significantly improving intestinal ischemia-reperfusion injury in rats, suggesting that anwulignan may be used as a potential drug for the prevention and treatment of intestinal ischemia-reperfusion injury or a resource for the development of health food.

The aim of this paper was to investigate the active components of Schisandra chinensis in the treatment of asthma and the related mechanisms by a network pharmacology approach. The active components of Schisandra chinensis and the corresponding targets were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Eight active components in Schisandra chinensis and 56 related targets were screened out according to two indicators, oral bioavailability (OB) and drug-likeness (DL). A total of 132 targets related to asthma were screened out through Therapeutic Target Database (TTD) data. The String database and Cytoscape software were used to build the "drug-active compound-target" network and protein-protein interaction (PPI) network. The key targets were further predicted by the analysis of related biological processes and the pathway-enrichment. A total of 10 intersection targets between Schisandra chinensis and asthma were obtained by building Venn diagrams, and lignans in Schisandra chinensis were found to be associated with asthma. The key targets Ptgs2 and Nos2 were further screened out, and schisandrol B (SCB) was predicted as the most related key component to asthma. A mouse asthma model was established with ovalbumin and aluminum hydroxide for verifying the effect of SCB and related mechanisms. The results showed that SCB could inhibit the gene expression of proinflammatory factors to play a therapeutic role in asthma by reducing the expression of Nos2 and Ptgs2 and regulating the NF-κB signaling pathway to intervene in the process of cell metabolism in mice. These results suggest that SCB can alleviate the severity of asthma through the mechanisms predicted by network pharmacology, and provide a basis for further understanding of the application of Schisandra chinensis in the treatment of asthma.

Aims Schisandra is a good choice in Traditional Chinese Medicine for the therapy of cardiovascular diseases, but whether it contains a or some specific component (s) responsible these effects are still unclear. In the present study, we explored whether Schisantherin A (SCA) causes vasorelaxation in isolated rat thoracic aorta. Main methods We selected SCA, one of the main monomers of lignans from Schisandra, to examine its vasorelaxant effect on the isolated rat thoracic aorta and also exploited several tool inhibitors to probe its underlying mechanisms. Key findings SCA produced relaxation concentration-dependently on the endothelium-intact (43.56 ± 2.17%) and endothelium-denuded thoracic aorta strips (18.76 ± 3.95%) pre-contracted by phenylephrine (PE). However, after treated with indomethacin or L-NAME, SCA showed only partial vasorelaxant effects. Whereas, this vasorelaxation by SCA was not changed with specific K+-channel inhibitors, i.e. barium chloride (BaCl2), 4-aminopyridine (4-AP), tetraethylamine (TEA), and glibenclamide. SCA had no effect on the aorta strips pre-contracted by PE in neither Ca2+-free nor CaCl2 conditions. But, in the Ca2+ free and high K+ environment, SCA partly abolished the vasocontraction induced by CaCl2. Significance It was the first report to demonstrate that SCA had endothelium-dependent and -independent vasorelaxant effects on the isolated rat thoracic aorta, and the underlying mechanisms might be involved into its promoting the production of nitric oxide (NO) and prostacyclin (PGI2), and inhibiting the voltage-dependent calcium channels (VDCCs) opening. This study may partially explain the use of Schisandra in cardiovascular diseases and facilitate further drug development as well.

Objective: To examine the anti-fatigue function of anwulignan from Schisandra and its underlying mechanism. Methods: After an excessive fatigue mouse model was created, anwulignan was administered to the mice, and its effect on exercise tolerance was studied by the weight-bearing swimming test, rotarod test, grip strength test, and tail suspension test. The biochemical indicators closely related to fatigue, including blood urea nitrogen (BUN), lactic acid (LD), lactate dehydrogenase (LDH), and creatine kinase (CK) in the serum; liver glycogen (LG) in the liver tissue; muscle glycogen (MG); inorganic phosphate (Pi) and Annexin V in the gastrocnemius; superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities; malondialdehyde (MDA), catalase (CAT), and thiobarbituric acid reactive substances (TBARS); and the 8-hydroxy-2-deoxyguanosine (8-OHdG) and reactive oxygen species (ROS) content in both serum and the gastrocnemius were detected. Morphological changes were also observed. The anti-fatigue-related proteins of the NRF2/ARE, Bcl2, and PGC-1α pathways in the gastrocnemius of the mice were detected by western blot. Results: Anwulignan significantly increased the exercise tolerance by decreasing BUN, LD, LDH, CK, Pi, MDA, TBARS, 8-OHdG, ROS, and Annexin V levels and increasing LG, MG, SOD, CAT, and GSH-Px levels, significantly upregulated the expression of NRF2 and Bcl2 proteins, which are anti-oxidation and anti-apoptosis regulators, and also activated the p38MAPK-PGC-1α pathway. Conclusion: Anwulignan can increase exercise tolerance and relieve fatigue in an excessive fatigue mouse model. The underlying mechanism may be through its regulatory effect on the NRF2 and PGC-1α signaling pathway. This study will provide scientific data for anwulignan to be developed as a novel and efficient component in anti-oxidant or anti-fatigue health food.

Background Aging is a spontaneous and inevitable phenomenon of biology, which can lead to the gradual deterioration of tissues and organs. One of the age-related deterioration processes is immunosenescence, which leads to changes in the function of immune systems, including immune cells and associated cytokines. A proper modulation of immune responses can improve the age-related immunosenescence process and then reach healthy aging. Schisandra sphenanthera, a traditional Chinese medicine, has been used as both a medicine and a nutritional supplement for thousands of years. Anwulignan, a monomer compound of Schisandra sphenanthera lignans, has been reported to possess an immunomodulatory effect. Therefore, this study was designed to further explore whether Anwulignan could also modulate the immune functions in aging model mice and the underlying mechanism. Methods D-galactose (D-gal) is often used as an inducer of immunosenescence in animals. In this study, a mice model was created by subcutaneous D-gal (220 mg kg−1) for successive 42 days. Then, the blood and spleen tissue samples were taken for the analysis and observation of cytokine levels, immunoglobulin levels, leukocyte numbers, and the phagocytic activity of macrophages, as well as the histological changes, the proliferation ability of lymphocytes, and the biochemical parameters in the spleen tissue. Results Anwulignan significantly increased the serum levels of IL-2, IL-4, IFN-γ, lgG, lgM, and lgA, decreased the content of TNF-α and IL-6 in the aging mice, and increased the blood leukocyte number, the phagocytic activity, the lymphocyte proliferation, and the spleen index in vitro. Anwulignan also significantly increased the activities of SOD and GSH-Px, decreased the contents of MDA and 8-OHdG in the spleen tissue, up-regulated the expressions of Nrf2, HO-1, and Bcl2, down-regulated the expressions of Keap1, Caspase-3, and Bax in the spleen cells, and reduced the apoptosis of spleen lymphocytes. Conclusion Anwulignan can restore the immune function that is declined in D-gal-induced aging mice partly related to its antioxidant capacity by activating the Nrf2/ARE pathway and downstream enzymes, as well as its anti-apoptotic effect by regulating Caspase-3 and the ratio of Bcl2 to Bax in the spleen.

Aim Schisandra chinensis is a well-known traditional Chinese medicine used mainly as a recipe for hepatoprotection. Modern researches have revealed that the hepatoprotection is related to its lignans and crude polysaccharide. In this study, we examined the effect and mechanism of Schisandra chinensis acidic polysaccharide (SCAP) on the liver injury induced by ethanol. Main methods SCAP was extracted with water extraction and ethanol precipitation. Liver injury models of both mice and HepG2 cells were produced by ethanol. The liver index, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in serum of the mice and cell culture supernatant were examined; HE staining was performed for observing pathological changes of liver. The malondialdehyde (MDA) level and superoxide dismutase (SOD) activities in serum, liver tissue and HepG2 cells, and triglyceride (TG) content in liver tissue were tested. Western blot was conducted to determine cytochrome P450 2E1 (CYP2E1) expression in liver tissue of mice and HepG2 cells. Key findings SCAP significantly reduced serial AST and ALT levels in the injuried liver and HepG2 cells induced by ethanol and also decreased TG level in the liver tissue. SCAP also obviously improved the hepatopathological changes and decreased MDA level as well as increased SOD activities in the serum, liver tissue and HepG2 cells induced by ethanol. Furthermore, Western blot analysis indicated that SCAP significantly inhibited the upregulation of CYP2E1 protein. Significance SCAP has a protective effect on ethanol-induced liver injury in mice and cells, and the mechanism underlying may be via inhibiting the expression of CYP2E1 protein and then alleviating oxidative stress injury induced by ethanol.

Our previous study showed that pravastatin prevents ischemia and reperfusion-induced lethal ventricular fibrillation in rats. This study explored whether pravastatin decreases myocardial infarct size and this effect is associated with endothelial nitric oxide synthase (eNOS) expression in myocardium. Rats were treated with ischemia (30 minutes) and reperfusion (60 minutes) after chronic oral administration of pravastatin, fluvastatin, or vehicle once daily for 22 days. Electrocardiograms and blood pressure were continuously recorded, myocardial infarct size was measured by TTC-staining, and eNOS expression was measured by western blot. The results showed that pravastatin and fluvastatin significantly reduced myocardial infarct size. No statistical differences were found in the areas at risk among all groups. However, a significant reduction in infarct size was observed in three pravastatin groups and one fluvastatin group compared to control. Both pravastatin and fluvastatin significantly increased eNOS protein expression in ischemic and non-ischemic tissues compared to control. Our results suggest that pravastatin decreases cardiovascular mortality beyond its cholesterol-lowering effect. Pravastatin is more potent than fluvastatin in reducing infarct size. These effects may be associated with elevation of eNOS expression.

The aim of this study was to analyze the active components of Schisandra chinensis on liver injury and its mechanism in mice by network pharmacology. The active components of S. chinensis were found through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and their corresponding targets were predicted. The targets of liver injury were searched through Therapeutic Targets Database (TTD), DisGeNET and drugbank databases, and the Venn diagram was constructed to obtain the action targets. The "drug-active component-target" network and protein-protein interaction network (PPI) were constructed by using STRING database and Cytoscape software, and the key targets were further screened by the enrichment analysis of relevant KEGG pathways. Finally, a CCl4-induced mouse liver injury model was established to verify the efficacy and related targets of S. chinensis and clarify its mechanism. Eight active components and 56 related targets of S. chinensis were screened out based on their oral bioavailability (OB) and drug likeness (DL). Five targets of S. chinensis related to liver injury were found by using the Venn diagram. The key targets, namely Ptgs2 and Nos2 genes, were further screened out by constructing a PPI network, and Schisandrol B (SCB) was considered the key component most closely related to the liver injury in S. chinensis. The results indicate that SCB may play a role in the treatment of the CCl4-induced liver injury by down-regulating the expression of iNOS and COX-2, and regulating the expression of NF-κB and IL-17 signaling pathway to inhibit the expression of proinflammatory factors.

Backgroud Schisandra chinensis, a traditional Chinese medicine for liver protection, can significantly improve liver fibrosis. However, it is still unclear which active components in Schisandra chinensis play an anti-fibrosis role. Purpose The purpose of present study was to observe the anti-fibrosis effect of schisantherin A (SCA) on liver fibrosis and explore its underlying mechanism. Methods The liver fibrosis model of mice was constructed by the progressive intraperitoneal injection of thioacetamide (TAA), and SCA (1, 2, and 4 mg/kg) was administered by gavage for 5 weeks. The biochemical indicators and inflammatory cytokines were measured, changes in the pathology of the mice liver were observed by hematoxylin & eosin (H&E) and Masson stainings for studying the anti-fibrosis effect of SCA. A hepatic stellate cell (HSCs) activation model induced by transforming growth factor-β1 (TGF-β1) was established, and the effect of SCA on the HSCs proliferation was observed by MTT assay. The expressions of target proteins related to transforming growth factor-β-activated kinase 1 (TAK1)/mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathways were evaluated by western blotting, immunohistochemistry or immunofluorescence analysis, to explore the potential mechanism of SCA. Results SCA could significantly ameliorate the pathological changes of liver tissue induced by TAA, and reduce the serum transaminase level, the hydroxyproline level and the expression of α-smooth muscle actin (α-SMA) and collagen 1A1 (COL1A1) proteins in the liver tissue. SCA could significantly lower the levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) in the serum and liver tissue, and down-regulate the expression of target proteins related to TAK1/MAPK and NF-κB pathways in the liver tissue. The in vitro studies demonstrated that SCA significantly inhibited the proliferation and activation of HCS-T6 cells induced by TGF-β1, decreased TNF-α and IL-6 levels, and inhibited the TAK1 activation induced by TGF-β1 and then the expression of MAPK and NF-κB signaling pathway-related proteins. Conclusion Together, SCA can ameliorate the liver fibrosis induced by TAA and the HSC-T6 cell activation induced by TGF-β1 in mice, and its mechanism may be to inhibit the HSCs activation and inflammatory response by inhibiting TGF-β1 mediated TAK1/MAPK and signal pathways.

The aim of this study was to explore the chemical composition and the effect of essential oil of Angelicae dahuricae radix on a nitroglycerin (NTG)-induced rat model of migraine. The CO2 supercritical fluid extraction method was optimized for the extraction of essential oil of A. dahuricae radix (EOAD) and its chemical composition was determined. The migraine model was established by subcutaneous injection of NTG (10 mg/kg) 1 h after the last administration of EOAD. The therapeutic effect of EOAD and its underlying mechanism were assessed by monitoring behavioral changes, levels of nitric oxide (NO) in serum and brain tissues, plasma levels of calcitonin gene-related peptide (CGRP) and endothelin (ET), and ET/NO ratio. The optimal conditions for CO2 supercritical fluid extraction of EOAD, as determined by orthogonal test [L9(34)], were as follows: 2 h extraction time, 20 MPa pressure, 40°C temperature, and 30 mesh. The yield of EOAD was 1.8%. On gas chromatography–mass spectrometry, 45 peaks were...

Schisandra chinensis lignans are the main active components of the traditional Chinese medicine Schisandra chinensis in East Asia. At present, there are more and more medicines and health foods in which the total S. chinensis lignans extracts are considered as the main active components, but little research has been done on the active components of S. chinensis lignans in the blood and main target organs. In this study, the components of S. chinensis lignans in the blood, liver and brain tissues of rats at different time points after the intragastrical administration of S. chinensis lignans were determined by a metabolomic method based on high-performance liquid chromatography with quadrupole time-of-flight tandem mass spectrometry spectrometry. Twelve Schisandra chinensis lignans and 15 metabolites in the blood, liver, and brain of rats were identified. The results showed that the main metabolic ways of S. chinensis lignans in rats were hydroxylation, demethylation, and demethylation-hydroxylation, and some of them might undergo demethylation, dehydrogenation, epoxidation, and elimination reaction. The time-dose characteristics of S. chinensis lignans and their metabolites in the blood and target organs were analyzed, which may be helpful to elucidate the active substances that really exert the pharmacodynamic effects of S. chinensis lignans in organisms.

We have previously demonstrated the hepatoprotective effect of

SIRT2 is a protein deacetylase with tumor suppressor activity in breast and liver tumors where it is mutated; however, the critical substrates mediating its antitumor activity are not fully defined. Here we demonstrate that SIRT2 binds, deacetylates, and inhibits the peroxidase activity of the antioxidant protein peroxiredoxin (Prdx-1) in breast cancer cells. Ectopic overexpression of SIRT2, but not its catalytically dead mutant, increased intracellular levels of reactive oxygen species (ROS) induced by hydrogen peroxide, which led to increased levels of an overoxidized and multimeric form of Prdx-1 with activity as a molecular chaperone. Elevated levels of SIRT2 sensitized breast cancer cells to intracellular DNA damage and cell death induced by oxidative stress, as associated with increased levels of nuclear FOXO3A and the proapoptotic BIM protein. In addition, elevated levels of SIRT2 sensitized breast cancer cells to arsenic trioxide, an approved therapeutic agent, along with other intracellular ROS-inducing agents. Conversely, antisense RNA-mediated attenuation of SIRT2 reversed ROS-induced toxicity as demonstrated in a zebrafish embryo model system. Collectively, our findings suggest that the tumor suppressor activity of SIRT2 requires its ability to restrict the antioxidant activity of Prdx-1, thereby sensitizing breast cancer cells to ROS-induced DNA damage and cell cytotoxicity. Cancer Res; 76(18); 5467–78. ©2016 AACR.

Jiaqi Gao,1,* Zepeng Yu,1,* Shu Jing,2 Weihai Jiang,2 Cong Liu,1 Chunyan Yu,1 Jinghui Sun,1 Chunmei Wang,1 Jianguang Chen,1 He Li1 1Department of Pharmacology, College of Pharmacy, Beihua University, Jilin City, People’s Republic of China; 2Affiliated Hospital of Beihua University, Jilin City, People’s Republic of China *These authors contributed equally to this work Background: Liver aging is a significant risk factor for chronic liver diseases. Oxidative stress has been considered as a conjoint pathological mechanism for the initiation and progression of liver aging. It has been reported that D-galactose (D-gal)-induced hepatic injury is an experimental model well established closely similar to morphological and functional features of liver aging. Schisandra sphenanthera Rehd. et Wils (S. sphenanthera, Schisandraceae), as a famous tradi-tional Chinese medicine, has been used for thousands of years in China to treat various disorders, including liver dysfunctions. This study was aimed to understand whether Anwulignan, one of the monomeric compounds in the lignans from S. sphenanthera, could improve the hepatic injury induced by D-gal in mice and to examine the possible mechanisms. Methods: ICR mice were used to produce hepatic injury by 220 mg kg-1 D-gal subcutaneously once daily for 42 days. The effects of oral Anwulignan on liver index; serial AST and ALT levels; histological changes; SOD, GSH-Px, MDA, and 8-OHdG in the liver and peripheral blood; expression of p38 mitogen-activated protein kinase (MAPK), Nrf2, and HO-1 in the liver; and HepG2 cell viability, and decrease caspase-3 contents in liver were examined. Results: Anwulignan could significantly increase the liver index, lower aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in the peripheral blood, elevate superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities, and decrease malonaldehyde (MDA) and 8-hydroxy-2-deoxyguanosine (8-OHdG) contents in the peripheral blood and liver. Furthermore, Anwulignan could upregulate the expression of p38 mitogen-activated protein kinase (MAPK), Nrf2, and HO-1 in the liver, increase the HepG2 cell viability, and decrease caspase-3 contents in liver. Conclusion: Anwulignan has protective effects against the hepatic injury induced by D-gal, which may be related to its antioxidant capacity through activating p38 MAPK–Nrf2–HO-1 pathway, increases the injured cell viability, and decreases the caspase-3 contents in liver. Keywords: Schisandra, antioxidant capacity, caspase-3

Schisantherin A (SCA) was evaluated for possible function in restoring the learning and memory impairment induced by D-galactose in mice. ICR mice were treated with D-galactose subcutaneously (220 mg·kg

Schisandrin B (SchB) is an active lignan component from Schisandra chinensis Turcz. Baill that has been long used as Traditional Chinese Medical Herb in the prescriptions for "tranquilizing the mind and overcoming anxiety". Given that SchB is one of the most abundant ingredients of Schisandra chinensis Baill, we examined the sedative and hypnotic effects of SchB and explored the underlying mechanism. The results showed that SchB can significantly decrease mouse locomotor activities and improved sleeping quality index, including increased number of sleeping mice treated with the subthreshold dose of pentobarbital sodium, increased sleep time, shortened sleep latency and prolonged sleep duration. We found that SchB could significantly elevate the level of γ-aminobutyric acid (GABA) and reduce the level of glutamic acid(Glu)in the peripheral blood of mice as well as in the cerebral cortex, hippocampus, hypothalamus of rats, resulting in the increased ratio of GABA/Glu. GABA receptor inhibitor picrotoxin could antagonize the effect of SchB on the sleep latency and duration in the mice treated with the threshold dose of pentobarbital sodium. Furthermore, SchB up-regulates the expression of GABA

Introduction Red ginseng (RG) is one of the main processed products of the roots and rhizomes of Panax ginseng C.A. Meyer and is used for anti-ageing. But how metabonomic influences of RG on the progress of ageing are less researched. Objective A metabonomic method was developed to study the characters of the ageing process and the effects of total ginsenosides of red ginseng (TGRG) on the progress of ageing. Methods Urine samples from four different ages (4, 12, 18 and 24 months old) of rats and interference after TGRG were analysed by rapid resolution liquid chromatography coupled with quadruple-time-of-flight mass spectrometry (RRLC-Q-TOF-MS) and multivariate statistical analysis were performed for the pattern recognition and characteristic metabolites identification. Results Fourteen potential biomarkers were found and identified by MS/MS analysis by referring to authentic chemicals. The analysis of metabolic pathways indicated that the reduced energy and lipid metabolism, the decline of kidney function and amino acids metabolism disorders were the main features of ageing. After TGRG administration, lipid and amino acids metabolism of 18 and 24 month-old rats were adjusted to restore a younger level, and nine related biomarkers in the ageing process reset to a younger level were recognised. Conclusion These changes showed that TGRG may produce an anti-ageing effect by intervening in the lipid metabolism and correcting the amino acid metabolism disorders in ageing rats.

Background Schisandra, a globally distributed plant, has been widely applied for the treatment of diseases such as hyperlipidemia, fatty liver and obesity in China. In the present work, a rapid resolution liquid chromatography coupled with quadruple-time-of-flight mass spectrometry (RRLC-Q-TOF-MS)-based metabolomics was conducted to investigate the intervention effect of Schisandra chinensis lignans (SCL) on hyperlipidemia mice induced by high-fat diet (HFD). Methods Hyperlipidemia mice were orally administered with SCL (100 mg/kg) once a day for 4 weeks. Serum biochemistry assay of triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c) and high-density lipoprotein cholesterol (HDL-c) was conducted to confirm the treatment of SCL on lipid regulation. Metabolomics analysis on serum samples was carried out, and principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) were carried out for the pattern recognition and characteristic metabolites identification. The relative levels of critical regulatory factors of liver lipid metabolism, sterol regulatory element-binding proteins (SREBPs) and its related gene expressions were measured by quantitative real-time polymerase chain reaction (RT-PCR) for investigating the underlying mechanism. Results Oral administration of SCL significantly decreased the serum levels of TC, TG and LDL-c and increased the serum level of HDL-c in the hyperlipidemia mice, and no effect of SCL on blood lipid levels was observed in control mice. Serum samples were scattered in the PCA scores plots in response to the control, HFD and SCL group. Totally, thirteen biomarkers were identified and nine of them were recovered to the normal levels after SCL treatment. Based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis, the anti-hyperlipidemia mechanisms of SCL may be involved in the following metabolic pathways: tricarboxylic acid (TCA) cycle, synthesis of ketone body and cholesterol, choline metabolism and fatty acid metabolism. Meanwhile, SCL significantly inhibited the mRNA expression level of hepatic lipogenesis genes such as SREBP-1c, fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC), and decreased the mRNA expression of liver X receptor α (LXRα). Moreover, SCL also significantly decreased the expression level of SREBP-2 and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) in the liver of hyperlipidemia mice. Conclusion Anti-hyperlipidemia effect of SCL was confirmed by both serum biochemistry and metabolomics analysis. The mechanism may be related to the down-regulation of LXRα/SREBP-1c/FAS/ACC and SREBP2/HMGCR signaling pathways.

Background Hepatoprotective effects of Chinese herbal medicine Schisandra Chinensis (Schisandra) have been widely investigated. However, most studies were focused on its lignan extracts. We investigated the effects of Schisandra polysaccharide (SCP) in a mouse model of non-alcoholic fatty liver disease (NAFLD), and studied its effect on sterol regulatory element binding proteins (SREBPs) and the related genes. Methods The mouse model of NAFLD was established by feeding mice with a high-fat diet for 16 weeks. Effect of SCP-treatment (100 mg/kg, once daily for 12 weeks) on biochemical parameters and liver histopathology was assessed. Relative levels of sterol regulatory element-binding proteins (SREBPs) and their gene expressions were determined by quantitative real-time polymerase chain reaction and Western Blot. Results SCP significantly reduced the liver index by 12.0%. Serum levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol, alanine aminotransferase and aspartate aminotransferase were decreased by 31.3, 28.3, 42.8, 20.1 and 15.5%, respectively. Serum high-density lipoprotein cholesterol was increased by 26.9%. Further, SCP lowered hepatic TC and TG content by 27.0% and 28.3%, respectively, and alleviated fatty degeneration and necrosis of liver cells. A significant downregulation of mRNA and protein expressions of hepatic lipogenesis genes, SREBP-1c, fatty acid synthase and acetyl-CoA carboxylase, and the mRNA expression of liver X receptor α (LXRα) was observed in NAFLD mice treated with SCP. SCP also significantly reduced the hepatic expression of SREBP-2 and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). Conclusion These findings demonstrate the hepatoprotective effects of SCP in a mouse model of NAFLD; the effects may be mediated via downregulation of LXRα/SREBP-1c/FAS/ACC and SREBP-2/HMGCR signaling pathways in the liver.

Purpose: We determined the effects of vorinostat (suberoylanalide hydroxamic acid) and/or MK-0457 (VX-680), an Aurora kinase inhibitor on the cultured human (HL-60, OCI-AML3, and K562) and primary acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML), as well as on the murine pro-B BaF3 cells with ectopic expression of the unmutated and mutant forms of Bcr-Abl. Experimental Design: Following exposure to MK-0457 and/or vorinostat, apoptosis, loss of viability, as well as activity and levels of Aurora kinase and Bcr-Abl proteins were determined. Results: Treatment with MK-0457 decreased the phosphorylation of Aurora kinase substrates including serine (S)10 on histone H3 and survivin, and led to aberrant mitosis, DNA endoreduplication as well as apoptosis of the cultured human acute leukemia HL-60, OCI-AML3, and K562 cells. Combined treatment with vorinostat and MK-0457 resulted in greater attenuation of Aurora and Bcr-Abl (in K562) kinase activity and levels as well as synergistically induced apoptosis of OCI-AML3, HL-60, and K562 cells. MK-0457 plus vorinostat also induced synergistic apoptosis of BaF3 cells with ectopic overexpression of wild-type or mutant Bcr-Abl. Finally, cotreatment with MK-0457 and vorinostat induced more loss of viability of primary AML and imatinib-refractory CML than treatment with either agent alone, but exhibited minimal toxicity to normal CD34+ progenitor cells. Conclusions: Combined in vitro treatment with MK-0457 and vorinostat is highly active against cultured and primary leukemia cells. These findings merit in vivo testing of the combination against human AML and CML cells, especially against imatinib mesylate–resistant Bcr-AblT315I–expressing CML Cells.

Nuclear receptors (NRs) are a large family of ligand-dependent transcription factors that regulate important physiological processes. To activate or repress genes assembled naturally as chromatin, NRs recruit two distinct enzymatic activities, namely histone-modifying enzymes and ATP-dependent chromatin remodeling complexes, to alter local chromatin structure at target gene promoters. In this review, we examine the functional relationship between ATP-dependent chromatin remodeling complexes and NRs in the context of transcriptional regulation. Using the steroid-responsive mouse mammary tumor virus promoter as a model system, we discuss in detail the molecular mechanisms underlying the recruitment of these complexes and subsequent chromatin structure changes catalyzed by this group of enzymes. In addition, we extend the discussion to other NR-regulated promoters including the pS2 promoter. Finally, we summarize specific principles governing this critical relationship, identify unanswered questions and discuss the potential application of these principles in rational drug design.

Amiodarone, which is generally classified as class III antiarrhythmic drug in the Vaughan Williams classification, is widely used for the treatments of refractory arrhythmias. However, we previously reported that intravenous infusion of amiodarone (6.67 mg/kg per hour) did not suppress arrhythmias induced by coronary ligation/reperfusion in dogs. In this study, we examined effects of a prior oral loading of amiodarone on arrhythmias induced by coronary ligation/reperfusion. Sixteen female beagle dogs (8.5 – 12.5 kg) were divided into two groups; one group was given amiodarone (40 mg/kg, orally, n = 8), and the other was given empty gelatin capsules (n = 8) 2 h before the operation. Dogs were anesthetized with pentobarbital and artificially ventilated. The left chest was opened, and the left anterior descending coronary artery was ligated for 30 min and then reperfused. The mean plasma concentration of amiodarone was over 1.3 μg/ml. Although the prior oral loading of amiodarone did not change the QT interval, amiodarone suppressed the number of ectopic beats during coronary ligation and the incidence of ventricular fibrillation during coronary ligation and reperfusion periods (P

HMG-CoA reductase inhibitors (statins) have been shown to decrease cardiovascular mortality. Since ventricular tachyarrhythmias are closely related to cardiovascular mortality, we tested effects of the hydrophilic statin pravastatin and the lipophilic statin fluvastatin in a rat arrhythmia model of ischemia/reperfusion and simultaneously measured serum total cholesterol level. Anesthetized rats were subjected to 5-min ischemia and 10-min reperfusion after chronic administration of oral pravastatin (0.02, 0.2, or 2 mg/kg), fluvastatin (0.2, 2, or 4 mg/kg), or vehicle for 22 days, once daily. The acute effect of pravastatin (0.2 or 2 mg/kg, once orally) was also observed. Chronically administrated pravastatin significantly reduced the incidence of ischemia-induced ventricular tachycardia (VT) from 70% (control) to 9% at 2 mg/kg, and it reduced the incidence of reperfusion-induced lethal ventricular fibrillation (VF) from 90% (control) to 20% at 0.2 mg/kg. Acute pravastatin and chronically administrated fluvastatin had no significant effect on these arrhythmias. There were no significant changes in blood pressure, heart rate, QT interval, and serum cholesterol among pravastatin-, fluvastatin-, and vehicle-treated groups. Hydrophilic pravastatin prevented reperfusion-induced lethal VF in anesthetized rats by chronic administration independent of its cholesterol lowering effect. This may be a new beneficial role of pravastatin in decreasing cardiovascular mortality.

The mutant JAK2V617F tyrosine kinase (TK) is present in the majority of patients with BCR-ABL–negative myeloproliferative neoplasms (MPNs). JAK2V617F activates downstream signaling through the signal transducers and activators of transcription (STAT), RAS/mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3 (PI3)/AKT pathways, conferring proliferative and survival advantages in the MPN hematopoietic progenitor cells (HPCs). Treatment with the pan-histone deacetylase (HDAC) inhibitor panobinostat (PS) is known to inhibit the chaperone function of heat shock protein 90, as well as induce growth arrest and apoptosis of transformed HPCs. Here, we demonstrate that PS treatment depletes the autophosphorylation, expression, and downstream signaling of JAK2V617F. Treatment with PS also disrupted the chaperone association of JAK2V617F with hsp90, promoting proteasomal degradation of JAK2V617F. PS also induced apoptosis of the cultured JAK2V617F-expressing human erythroleukemia HEL92.1.7 and Ba/F3-JAK2V617F cells. Treatment with the JAK2 TK inhibitor TG101209 attenuated JAK2V617F autophosphorylation and induced apoptosis of HEL92.1.7 and Ba/F3-JAK2V617F cells. Cotreatment with PS and TG101209 further depleted JAK/STAT signaling and synergistically induced apoptosis of HEL92.1.7 and Ba/F3-JAK2V617F cells. Cotreatment with TG101209 and PS exerted greater cytotoxicity against primary CD34+ MPN cells than normal CD34+ HPCs. These in vitro findings suggest combination therapy with HDAC and JAK2V617F inhibitors is of potential value for the treatment of JAK2V617F-positive MPN.

Pan-histone deacetylase inhibitors, for example, vorinostat and panobinostat (LBH589; Novartis Pharmaceuticals, East Hanover, NJ), have shown clinical efficacy against advanced cutaneous T-cell lymphoma (CTCL). However, the molecular basis of this activity remains unclear. HDAC7, a class IIA histone deacetylase (HDAC), is overexpressed in thymocytes, where it represses expression of the proapoptotic nuclear orphan receptor Nur77. Here, we demonstrate that treatment with panobinostat rapidly inhibits the in vitro and intracellular activity, as well as the mRNA and protein levels of HDAC7, and induces expression and translocation of Nur77 to the mitochondria. There, Nur77 converts death resistance protein Bcl-2 into a killer protein, promoting cell death of cultured and patient-derived human CTCL cells. Treatment with panobinostat improved survival of athymic nude mice implanted with human CTCL cells. Ectopic expression of Nur77 induced apoptosis and sensitized HH cells to panobinostat, whereas combined knockdown of Nur77 and its family member Nor1 was necessary to inhibit panobinostat-induced apoptosis of CTCL cells. Cotreatment with the Bcl-2/Bcl-xL antagonist ABT-737 decreased resistance and synergistically induced apoptosis of human CTCL cells. These findings mechanistically implicate HDAC7 and Nur77 in sensitizing human CTCL cells to panobinostat as well as suggest that cotreatment with an anti–Bcl-2 agent would augment the anti-CTCL activity of panobinostat.

To investigate the possible participation of angiotensin II receptor 1 (AT(1) receptor) in pressor response induced by IL-1beta in the paraventricular nucleus (PVN) of hypothalamus.The experiments were performed on adult Wistar rats. Mean arterial pressure (MAP) were recorded during microinjection of different doses of IL-1beta, IL-1beta together with Losartan, an AT1 receptor antagonist, or Ang II pre-treated with IL-1beta into PVN. Rats microinjected with saline were served as controls in all experiments.Microinjection of IL-1beta (0.1 or 0.2 ng) resulted in increases in blood pressure in a dose-dependent manner, and the pressor effect caused by administration of IL-1beta (0.2 ng) could be attenuated by pre-treatment with AT(1) receptor antagonist (100 ng Losartan). A subpressor dose of IL-1beta (0.05 ng) could augment the pressor response induced by microinjection of Ang II (10 ng).The present results provide support that central infusion of IL-1beta increases blood pressure and the pressor response requires stimulation of AT(1) receptors. It is also shown that IL-1beta has the effect of increasing the magnitude of pressor response induced by Ang II in PVN.

We have reported that chronically administered pravastatin prevented coronary artery reperfusion-induced lethal ventricular fibrillation (VF) in anesthetized rats without lowering the serum cholesterol level. The present study was undertaken to evaluate whether pravastatin prevents ischemia-induced lethal VF, simultaneously examining myeloperoxidase (MPO) activity in ischemic myocardial tissues. Anesthetized rats were subjected to 30-min ischemia and 60-min reperfusion after chronic administration of pravastatin (0.02, 0.2, and 2mg/kg), fluvastatin (2 and 4 mg/kg), or vehicle for 22 days, orally, once daily. ECG and blood pressure were continually recorded, and MPO was measured by a spectrophotometer. Pravastatin and fluvastatin significantly (P

SEA0400 (2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline), a novel and selective inhibitor of Na+/Ca2+ exchanger, was investigated for its possible antiarrhythmic effects on arrhythmias of Ca2+ overload induced by coronary ligation/reperfusion and by digitalis in the dog. SEA0400 (1.0 mg/kg) did not change the hemodynamics but slightly prolonged the QRS duration (P

We investigated the mRNA and protein expression of fibronectin and stromelysin-1 (matrix metalloproteinase-3, MMP-3) by trabecular cells treated with growth factors present in primary and secondary aqueous humors. Serum-deprived trabecular cells were incubated for 48 hr or 7 days in medium containing either primary or secondary aqueous humor growth factors or in serum-free medium. We extracted total RNA, performed reverse transcription-polymerase chain reaction using primer pairs for fibronectin, stromelysin-1 and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and quantified the products. We utilized Western blotting to detect and quantify fibronectin and stromelysin-1 protein. Compared to controls, expression of fibronectin mRNA by trabecular cells was increased by 50 and 100% after incubation in primary aqueous humor growth factors for 48 hr or 7 days, respectively, and 50 and 130% after incubation in secondary aqueous humor growth factors. Stromelysin-1 mRNA expression was decreased by 25 and 50% after incubation in primary aqueous humor growth factors for 48 hr or 7 days, respectively, and 80 and 85% after incubation for 48 hr or 7 days, respectively, in secondary aqueous humor growth factors. Fibronectin protein increased 3.5-fold and 6-fold after incubation for 48 hr with primary or secondary aqueous humor growth factors, respectively; after 7 days, the level increased 4- and 7-folds, respectively. Stromelysin-1 protein was not detectable by western blotting. The up-regulation of fibronectin mRNA by trabecular cells exposed to growth factors present in secondary aqueous humor augmented by the down-regulation of stromelysin-1 mRNA contributed to the accumulation of fibronectin. Our findings open the possibility that induction of stromelysin-1 gene expression in the trabecular meshwork of glaucomatous eyes could effectively reduce buildup of fibronectin in the aqueous outflow pathway to decrease outflow resistance in glaucomatous states of the eye.

A cDNA encoding mouse pseudouridine synthase 3 (mPus3p) has been cloned. The predicted protein has 34% identity with yeast pseudouridine synthase 3 (Pus3), an enzyme known to form pseudouridine at positions 38 and 39 in yeast tRNA. The cDNA is 1.7 kb, and when used as a probe on a Northern blot of total RNA from mouse tissues or cells in culture, a band at 1.8 kb was observed. The open reading frame codes for a protein of 481 amino acids with a predicted molecular mass of 55 552 Da. When mPus3p was in vitro translated and used in reactions with tRNA substrates from both yeast and humans, uridines at position 39 were modified to pseudouridine. In a tRNA substrate with a uridine at position 38 (human tRNA(Leu)), there was very slight formation of pseudouridine at that position after incubation with mPus3p.

1. The antiarrhythmic and haemodynamic effects of three class III antiarrhythmic drugs, MS-551, sematilide and dofetilide, were examined in the coronary artery, ligation-reperfusion model of pentobarbitone-anaesthetized rats, a species deficient in functional cardiac IK. MS-551 is a non-selective potassium channel blocker, while both sematilide and dofetilide are selective delayed rectifier potassium (K) channel (IK) blockers. 2. Before coronary ligation, 3 and 10 mg kg-1 MS-551 decreased the heart rate by 6% (P < 0.01) and 12% (P < 0.01), and increased mean arterial pressure (MAP) by 14% (P < 0.05) and 33% (P < 0.01), respectively. Sematilide at 10 and 30 mg kg-1 also decreased the heart rate by 4% (P < 0.01) and 9% (P < 0.01), respectively, and the higher dose of 30 mg kg-1 decreased MAP by 29% (P < 0.01). Dofetilide, 1 mg kg-1, decreased the heart rate (P < 0.01), but had no significant effect on MAP. 3. The QT interval was increased by 10% (P < 0.01) and 31% (P < 0.01), when 3 and 10 mg kg-1 MS-551 were given. Sematilide and dofetilide had no effect on the QT interval. 4. Immediately after reperfusion, lethal ventricular fibrillation (VF) was induced in 80% of the saline group. MS-551 at 3 and 10 mg kg-1, reduced the incidence of lethal VF to 50% and 20% (P < 0.05). Neither dofetilide 1 mg kg-1 nor sematilide (10 and 30 mg kg-1) decreased the incidence of lethal VF (70%, 80% and 50%, respectively). None of the three drugs had any effect on the occurrence of reperfusion-induced VT or the total incidence of VF. However, 10 mg kg-1 MS-551 delayed the onset of reperfusion-induced VF (27 +/- 5 s compared with 12 +/- 2 s of the control group, P < 0.05). 5. In conclusion, in rats which are deficient in cardiac IK MS-551 prolonged the QT interval and reduced the incidence of sustained VF after reperfusion. Blockade of channels other than IK might participate in the defibrillatory effect of MS-551. Sematilide and dofetilide, which are selective IK blockers, did not increase the QT interval nor did they show antiarrhythmic effects Mechanisms other than K channel block may be involved in the different effects of the three drugs on blood pressure.

Dofetilide, a new class III antiarrhythmic agent, was tested in various kinds of canine ventricular arrhythmias to compare its effects with those of other class III agents. Ventricular arrhythmia models used were induced by two-stage coronary ligation, digitalis, epinephrine, coronary ligation and reperfusion, and programmed electrical stimulation (PES). Dofetilide (100 micrograms/kg intravenously) did not suppress automaticity arrhythmias induced by two-stage coronary ligation and epinephrine or the coronary ligation and reperfusion arrhythmias, but suppressed the reentry arrhythmia induced by PES in dogs with old myocardial infarction (MI). This effect was associated with a prolongation of QT interval. Dofetilide also showed antiarrhythmic effect in some dogs with digitalis arrhythmia. Dofetilide increased QT interval and showed negative chronotropic effect like that of other class III drugs, but was different in antiarrhythmic profiles from those of other class III agents such as D-sotalol, E-4031, and MS-551 in that it did not prevent the occurrence of ventricular fibrillation (VF) immediately after coronary reperfusion and had some antiarrhythmic effects on digitalis arrhythmia.