Archiv für Experimentelle Pathologie und Pharmakologie (N-S ARCH PHARMACOL)

Publisher: Springer Verlag

Journal description

Naunyn-Schmiedeberg's Archives of Pharmacology was founded in 1873 as "Archiv für experimentelle Pathologie und Pharmakologie" by B. Naunyn O. Schmiedeberg E. Klebs. In cooperation with colleagues it was edited by L. Krehl W. Straub W. Heubner and others; from Vol. 208 No. 2 on edited in cooperation with the Deutsche Pharmakologische Gesellschaft. Vols. 1-158 (1930) Leipzig F.C.W. Vogel Vols. 159-196 (1940) Berlin F.C.W. Vogel; from Vol. 197 on Berlin Springer. Vols. 110 to 253 "Naunyn-Schmiedebergs Archiv für experimentelle Pathologie und Pharmakologie"; from Vol. 254 (1966) to 263 "Naunyn-Schmiedebergs Archiv für Pharmakologie und experimentelle Pathologie"; from Vol. 264 (1969) to 271 "Naunyn-Schmiedebergs Archiv für Pharmakologie"; from Vol. 272 (1972) "Naunyn-Schmiedeberg's Archives of Pharmacology". As of Vol. 343 (1991) edited on behalf of the Deutsche Gesellschaft für Pharmakologie und Toxikologie; from Vol. 349 (1994) Deutsche Gesellschaft für experimentelle und klinische Pharmakologie und Toxikologie e.V.

Current impact factor: 2.36

Impact Factor Rankings

2015 Impact Factor Available summer 2015
2013 / 2014 Impact Factor 2.36
2012 Impact Factor 2.147
2011 Impact Factor 2.647
2010 Impact Factor 2.5
2009 Impact Factor 2.631
2008 Impact Factor 2.83
2007 Impact Factor 2.161
2006 Impact Factor 2.779
2005 Impact Factor 2.098
2004 Impact Factor 1.963
2003 Impact Factor 2.101
2002 Impact Factor 2.566
2001 Impact Factor 2.472
2000 Impact Factor 2.869
1999 Impact Factor 2.414
1998 Impact Factor 2.2
1997 Impact Factor 2.492
1996 Impact Factor 2.679
1995 Impact Factor 3.04
1994 Impact Factor 2.813
1993 Impact Factor 3
1992 Impact Factor 3.227

Impact factor over time

Impact factor
Year

Additional details

5-year impact 2.23
Cited half-life 0.00
Immediacy index 0.53
Eigenfactor 0.01
Article influence 0.62
Website Naunyn-Schmiedeberg's Archives of Pharmacology website
Other titles Naunyn-Schmiedeberg's archives of pharmacology (Online), Archives of pharmacology
ISSN 0028-1298
OCLC 43450808
Material type Document, Periodical, Internet resource
Document type Internet Resource, Computer File, Journal / Magazine / Newspaper

Publisher details

Springer Verlag

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    • Author's post-print on any open access repository after 12 months after publication
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    • Articles in some journals can be made Open Access on payment of additional charge
  • Classification
    ​ green

Publications in this journal

  • Archiv für Experimentelle Pathologie und Pharmakologie 05/2015; DOI:10.1007/s00210-015-1119-0
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    ABSTRACT: Cardiopulmonary bypass (CPB) often is required for the operative correction of congenital heart defects in small infants. Unfortunately, CPB is associated with injury of inner organs such as the brain, kidney, lung, and liver. Renal failure and increase in liver enzymes are typical side effects observed after CPB. Here, we investigate whether organ protection of the kidney and liver can be achieved with the application of minocycline, which is known-besides its anti-infective effects-to act as a poly-ADP-ribose-polymerase inhibitor. Twenty-nine 4-week-old Angler Sattelschwein-piglets (8-15 kg) were divided into four groups: control group (n = 8), CPB group (n = 9), minocycline-control group (n = 6), and the minocycline-CPB group (n = 6). CPB groups were thoracotomized and underwent CPB for 120 min (cross-clamp, 90 min; reperfusion, 30 min) followed by a 90-min recovery time. The control groups also were thoracotomized but not connected to CPB. The minocycline group received 4 mg/kg minocycline before and 2 mg/kg after CPB. In the kidneys, CPB histologically resulted in widening of Bowman's capsule, and-mainly in tubules-formation of poly-ADP-ribose, nitrosylation of tyrosine-residues, nuclear translocation of hypoxia-induced factor HIF-1α, and of apoptosis-inducing factor (AIF). In addition, we found significantly less ATP in the kidney and significantly increased plasma urea and creatinine. Similar but gradually attenuated changes were found in the liver together with significantly elevated de-Ritis coefficient. These changes in the kidney and liver were significantly diminished by minocycline (except AIF in the liver which was similar in all groups). In conclusion, CPB causes damage in the kidney and-to a lower degree-in the liver, which can be attenuated by minocycline.
    Archiv für Experimentelle Pathologie und Pharmakologie 03/2015; DOI:10.1007/s00210-015-1115-4
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    ABSTRACT: The mechanism of a lower incidence of dermatological manifestations in patients treated with enalapril compared to patients treated with other ACE-inhibitors, e.g., captopril, is not known. The finding that prolidase plays an important role in collagen biosynthesis and that some angiotensin-converting enzyme inhibitors affect prolidase activity led us to evaluate its effect on collagen biosynthesis in cultured human skin fibroblasts. Since insulin-like growth factor (IGF-I) and transforming growth factor beta 1 (TGF-β1) are the most potent stimulators of both collagen biosynthesis and prolidase activity, and prolidase is regulated by β1 integrin signaling, the effect of enalapril and enalaprilat on IGF-IR, TGF-β1, and β1 integrin receptor expressions was evaluated. Cells were treated with milimolar concentrations (0.3 and 0.5 mM) of enalapril and enalaprilat for 24 h. The activity of prolidase was determined by colorimetic assay. Collagen biosynthesis was evaluated by radiometric assay. Expression of signaling proteins was evaluated using Western blot. It was found that enalapril- and enalaprilat-dependent increase in prolidase activity and expression was accompanied by parallel increase in collagen biosynthesis. The exposure of the cells to 0.5 mM enalapril and enalaprilat contributed to increase in IGF-IR and α2β1 integrin receptor as well as TGF-β1 and NF-κB p65 expressions. Enalapril- and enalaprilat-dependent increase of collagen biosynthesis in fibroblasts results from increase of prolidase activity and expression, which may undergo through activation of α2β1 integrin and IGF-IR signaling as well as upregulation of TGF-β1 and NF-κB p65, the inhibitor of collagen gene expression.
    Archiv für Experimentelle Pathologie und Pharmakologie 03/2015; DOI:10.1007/s00210-015-1114-5
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    ABSTRACT: Members of the family of transient receptor potential (TRP) channels have been implicated in the pathophysiology of a host of lung diseases. The role of these multimodal cation channels in lung homeostasis is thought to stem from their ability to respond to changes in mechanical stimuli (i.e., shear and stretch), as well as to various protein and lipid mediators. The vanilloid subfamily member, TRPV4, which is highly expressed in the majority of lung cell types, is well positioned for critical involvement in several pulmonary conditions, including edema formation, control of pulmonary vascular tone, and the lung response to local or systemic inflammatory insults. In recent years, several pharmacological inhibitors of TRPV4 have been developed, and the current generation of compounds possess high affinity and specificity for TRPV4. As such, we have now entered a time where the therapeutic potential of TRPV4 inhibitors can be systematically examined in a variety of lung diseases. Due to this fact, this review seeks to describe the current state of the art with respect to the role of TRPV4 in pulmonary homeostasis and disease, and to highlight the current and future roles of TRPV4 inhibitors in disease treatment. We will first focus on genera aspects of TRPV4 structure and function, and then will discuss known roles for TRPV4 in pulmonary diseases, including pulmonary edema formation, pulmonary hypertension, and acute lung injury. Finally, both promising aspects and potential pitfalls of the clinical use of TRPV4 inhibitors will be examined.
    Archiv für Experimentelle Pathologie und Pharmakologie 03/2015; 388(4):421. DOI:10.1007/s00210-014-1058-1
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    ABSTRACT: Epidemiological data suggest that the consumption of polyphenol-rich foods reduces the incidence of cancer, coronary heart disease, and inflammation. Chlorogenic acid (CGA), an ester of caffeic and quinic acids, is one of the most abundant polyphenol compounds in human diet with proven biological effectiveness both in vitro and in vivo. The aim of the study is to investigate the possible anti-inflammatory effect of CGA in the gastrointestinal (GI) tract and its mechanism of action. We used a well-established model of colitis, induced by intracolonic (i.c.) administration of trinitrobenzenesulfonic acid (TNBS) in mice. The anti-inflammatory effect of CGA in the colon was evaluated based on the clinical and macroscopic and microscopic parameters. To investigate the mechanism of protective action of CGA, myeloperoxidase (MPO), H2O2, and NF-κB levels were assessed in the colon tissue. CGA administered i.c. at the dose of 20 mg/kg (two times daily) protected against TNBS-induced colitis more effectively than the same dose administered orally (p.o.), as evidenced by significantly lower macroscopic and ulcer scores. Furthermore, CGA (20 mg/kg, i.c.) reduced neutrophil infiltration, as demonstrated by decreased MPO activity. Moreover, CGA suppressed activation of NF-κB, as evidenced by lower levels of phospho-NF-κB/NF-κB ratio in the tissue. CGA did not affect the oxidative stress pathways. CGA exhibits anti-inflammatory properties through reduction of neutrophil infiltration and inhibition of NF-κB-dependent pathways. Our results suggest that CGA may have the potential to become a valuable supplement in the treatment of GI diseases.
    Archiv für Experimentelle Pathologie und Pharmakologie 03/2015; DOI:10.1007/s00210-015-1110-9
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    ABSTRACT: Hyperlipidemia is regarded as independent risk factor in the development of ischemic heart disease, and it can increase the myocardial susceptibility to ischemia-/reperfusion (I/R)-induced injury. Hyperlipidemia attenuates the cardioprotective response of ischemic preconditioning (IPC). The present study investigated the effect of zinc supplements in the attenuated cardioprotective effect of ischemic preconditioning in hyperlipidemic rat hearts. Hyperlipidemia was induced in rat by feeding high-fat diet (HFD) for 6 weeks then the serum lipid profile was observed. In experiment, the isolated Langendorff rat heart preparation was subjected to 4 cycles of ischemic preconditioning (IPC), then 30 min of ischemia followed by 120 min of reperfusion. Myocardial infarct size was elaborated morphologically by triphenyltetrazolium chloride (TTC) staining and biochemically by lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) release from coronary effluent and left ventricular collagen content. However, the effect of zinc supplement, i.e., zinc pyrithione (10 μM) perfused during reperfusion for 120 min, significantly abrogated the attenuated cardioprotective effect of ischemic preconditioning in hyperlipidemic rat heart whereas administration of chelator of this zinc ionophore, i.e., N,N,N',N'-tetrakis(2-pyridylmethyl)ethylene diamine (TPEN; 10 μM), perfused during reperfusion 2 min before the perfusion of zinc pyrithione abrogated the cardioprotective effect of zinc supplement during experiment in hyperlipidemic rat heart. Thus, the administration of zinc supplements limits the infarct size, LDH, and CK-MB and enhanced the collagen level which suggests that the attenuated cardioprotective effect of IPC in hyperlipidemic rat is due to zinc loss during reperfusion caused by ischemia/reperfusion.
    Archiv für Experimentelle Pathologie und Pharmakologie 03/2015; DOI:10.1007/s00210-015-1105-6
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    ABSTRACT: Glucocorticoids are hormones released in response to stress that are involved in various physiological processes including immune functions. One immune-modulating mechanism is achieved by the Kv1.3 voltage-dependent potassium channel, which is expressed highly in lymphocytes including effector memory T lymphocytes (TEM). Although glucocorticoids are known to inhibit Kv1.3 function, the detailed inhibitory mechanism is not yet fully understood. Here we studied the rapid non-genomic effects of cortisone and hydrocortisone on the human Kv1.3 channel expressed in Xenopus oocytes. Both cortisone and hydrocortisone reduced the amplitude of the Kv1.3 channel current in a concentration-dependent manner. Both cortisone and hydrocortisone rapidly and irreversibly inhibited Kv1.3 currents, eliminating the possibility of genomic regulation. Inhibition rate was stable relative to the degree of depolarization. Kinetically, cortisone altered the activating gate of Kv1.3 and hydrocortisone interacted with this channel in an open state. These results suggest that cortisone and hydrocortisone inhibit Kv1.3 currents via a non-genomic mechanism, providing a mechanism for the immunosuppressive effects of glucocorticoids.
    Archiv für Experimentelle Pathologie und Pharmakologie 03/2015; DOI:10.1007/s00210-015-1109-2
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    ABSTRACT: Pancreatic cancer is a devastating disease with a poor prognosis. It ranks as the fourth or fifth most common cancer in men and women and has the lowest 5-year survival rate. Therefore, there is an urgent need to develop novel therapeutic agents for pancreatic cancer. Longikaurin E (LE), which is derived from the traditional herbal medicine Rabdosia longituba, had been reported to have anti-proliferative and pro-apoptotic properties in several types of cancers. In this study, we investigated the cytotoxic properties of LE against pancreatic cancer cells and explored the mechanism behind the observed apoptosis. Pancreatic cancer cell lines cultured in the presence of LE exhibited dose- and time-dependent growth suppression by clone formation, methylthiazoltetrazolium assay, lactate dehydrogenase cytotoxicity assay, and fluorescence-activated cell sorting analysis, respectively. In addition, these culture conditions also induced the generation of cellular reactive oxygen species (ROS). In order to determine the mechanisms underlying LE-induced cytotoxicity, we used reverse transcription polymerase chain reaction and Western blot analysis in the pancreatic cancer cell line PANC1. The results showed that the expression of Bax was noticeably upregulated and the expression levels of Bcl-2, Bcl-XL, survivin, and c-Myc were significantly downregulated. We also observed increased p38 phosphorylation and decreased phosphorylation of the PI3K/AKT pathway. Interestingly, we also found that LE activated caspase-3. However, N-acetyl-L-cysteine, a kind of antioxidant, reversed all of these cellular activities. In conclusion, this study suggested that LE induced apoptosis of pancreatic cancer cells via ROS generation to modulate the p38 and PI3K/AKT pathways and could be a promising anti-pancreatic agent.
    Archiv für Experimentelle Pathologie und Pharmakologie 03/2015; DOI:10.1007/s00210-015-1107-4
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    ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is closely linked to insulin resistance, oxidative stress, and cytokine imbalance. Boswellic acids, a series of pentacyclic triterpene molecules that are produced by plants in the genus Boswellia, has been traditionally used for the treatment of a variety of diseases. This study aimed at evaluating the protective effect of boswellic acids in a model of diet-induced NAFLD in rats in comparison to the standard insulin sensitizer, pioglitazone. Rats were fed with a high-fat diet (HFD) for 12 weeks to induce NAFLD. Starting from week 5, rats received boswellic acids (125 or 250 mg/kg) or pioglitazone parallel to the HFD. Feeding with HFD induced hepatic steatosis and inflammation in rats. In addition, liver index, insulin resistance index, activities of liver enzymes, and serum lipids deviated from normal. Further, serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and cyclooxygenase 2 were elevated; this was associated with an increase in hepatic expression of inducible nitric oxide synthase (iNOS) and formation of 4-hydroxy-2-nonenal (HNE). Rats treated with boswellic acids (125 or 250 mg/kg) or pioglitazone showed improved insulin sensitivity and a reduction in liver index, activities of liver enzymes, serum TNF-α and IL-6 as well as hepatic iNOS expression and HNE formation compared to HFD group. Furthermore, at the cellular level, boswellic acids (250 mg/kg) ameliorated the expression of thermogenesis-related mitochondrial uncoupling protein-1 and carnitine palmitoyl transferase-1 in white adipose tissues. Data from this study indicated that boswellic acids might be a promising therapy in the clinical management of NAFLD if appropriate safety and efficacy data are available.
    Archiv für Experimentelle Pathologie und Pharmakologie 02/2015; DOI:10.1007/s00210-015-1102-9
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    ABSTRACT: Resistance to chemotherapy is the major problem in cancer treatment. Cholangiocarcinoma (CCA) is the tumor arising from the bile duct epithelium. The disease is characterized by very poor prognosis and rarely responds to current radiotherapy or chemotherapy. Transcription factor Nrf2 is activated by oxidative stress and electrophiles and contributes to cytoprotection in normal cells as well as cancer cells. Inhibition of Nrf2 can enhance the sensitivity of cancer cells to chemotherapeutic agents, although this sensitizing effect is variable depending on the cancers. In this study, we selected three CCA cell lines with different Nrf2 expression levels, detected by immunocytofluorescent staining. Chemotherapeutic agents variably induced the expression of antioxidant and xenobiotic metabolizing genes including Nrf2, NQO1, HO-1, GCLC, and GSTP1. Knockdown of Nrf2 expression by siRNA suppressed protein expression of Nrf2-regulated genes and enhanced the sensitivity to 5-fluorouracil and gemcitabine of CCA cells in both high and low basal Nrf2 expression. Cells with more resistance to chemotherapeutic agents gained more chemosensitizing effect by Nrf2 inhibition than the sensitive cells. The IC50 of the chemotherapeutic agents was also significantly reduced and the maximal cytotoxic effect was increased. Suppression of Nrf2 signaling may be a strategy to increase the efficacy of chemotherapy to CCA.
    Archiv für Experimentelle Pathologie und Pharmakologie 02/2015; DOI:10.1007/s00210-015-1101-x
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    ABSTRACT: Docetaxel was the first chemotherapeutic agent to increase survival time in patients with androgen-resistant prostate cancer. However, it provides only a modest increase in survival and is associated with significant toxicity. Therefore, there is an urgent need to identify potential adjunct therapies. Given the key role of autophagy in both tumour survival and chemoresistance, the impact of autophagy modulation on docetaxel toxicity was tested in vitro. PC-3 and LNCaP cells were pre-treated with the autophagy inhibitor 3-methyladenine (5 mM) and then exposed to various concentrations (0-100 μM) of docetaxel. Cytoxic effects of docetaxel were measured using resazurin reduction to resorufin, whilst autophagy and apoptosis was measured using monodansylcadaverine, annexin V and caspase-3, respectively. Docetaxel produced significant toxicity in PC-3 cells but was not toxic to LNCaP cells. Pre-treatment with the autophagy inhibitor, 3-methyladenine (5 mM) significantly protected PC-3 cells against docetaxel-induced cytotoxicity, increased autophagosome formation and apoptosis measured using monodansylcadaverine, annexin V and caspase-3 fluorescence, respectively. In contrast, 3-methyladenine was toxic by itself in LNCaP cells and also increased autophagic vesicle formation and apoptosis but did not influence docetaxel toxicity in these cells. These paradoxical effects of 3-methyladenine were largely independent of reactive oxygen species production. We show here that modulation of autophagy may influence docetaxel-induced toxicity in prostate cancer cells and these effects may differ between cell lines.
    Archiv für Experimentelle Pathologie und Pharmakologie 02/2015; DOI:10.1007/s00210-015-1104-7
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    ABSTRACT: 4-Hydroxy-2-nonenal (4-HNE) is a major reactive aldehyde formed by lipid peroxidation, and it plays an important role in the pathogenesis of several vascular diseases, including diabetes mellitus. In this study, we examined the effects of 4-HNE on the vasodilatory mechanisms of rat retinal arterioles. The retinal vasodilator responses were assessed by measuring the diameter of retinal arterioles in the fundus images. Intravitreal injection of 4-HNE significantly prevented the vasodilation of retinal arterioles induced by the β2-adrenoceptor agonist salbutamol but not the nitric oxide donor (±)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (NOR3). Iberiotoxin, an inhibitor of large-conductance KCa (BKCa) channels, significantly reduced the salbutamol-induced vasodilation of retinal arterioles. The vasodilator effect of BMS-191011, a BKCa channel opener, on retinal arterioles was significantly attenuated by 4-HNE. These results suggest that 4-HNE attenuates retinal vasodilator responses to β2-adrenoceptor agonists through the impairment of the BKCa pathway. The direct effect of 4-HNE on retinal blood vessels may, therefore, contribute to the retinal vascular dysfunction observed in patients with diabetes mellitus.
    Archiv für Experimentelle Pathologie und Pharmakologie 02/2015; 388(5). DOI:10.1007/s00210-015-1099-0
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    ABSTRACT: Ischemic-reperfusion (I/R) is a major event in the pathogenesis of ischemic heart disease that leads to higher rate of mortality. The study has been designed to investigate the therapeutic potential and molecular mechanism of vitamin P and digoxin in I/R-induced myocardial infarction in isolated rat heart preparation by using Langendorff apparatus. The animals were treated with vitamin P (50 and 100 mg/kg; p.o.) and digoxin (500 μg/kg) for 5 consecutive days. Digoxin served as a positive control in the present study. On the sixth day, the heart was harvested and induced to 30 min of global ischemia followed by 120 min of reperfusion using Langendorff apparatus. The coronary effluent was collected at different time intervals (i.e. basal, 1, 15, 30, 45, 60 and 120 min.) for the assessment of myocardial contractility function. In addition, creatine kinase-M and B subunits (CK-MB), lactate dehydrogenase (LDH1) and Na(+)-K(+)-ATPase activity along with oxidative tissue biomarkers (i.e. thio-barbituric acid reactive substances (TBARS) and reduced glutathione (GSH)) changes were estimated. The I/R of myocardium produced decrease in coronary flow rate; increase in CK-MB, LDH1 and Na(+)-K(+)-ATPase activity along with increase in TBARS and decrease in GSH levels as compared to normal group. The treatment with vitamin P (100 mg/kg) and digoxin (500 μg/kg) have produced a significant (p < 0.05) ameliorative effect against I/R induced above functional, metabolic and tissue biomarkers changes. Vitamin P has an ameliorative potential against I/R induced myocardial functional changes. It may be due to its free radical scavenging and anti-infarct property via inhibition of Na(+)-K(+)-ATPase activity. Therefore, it can be used as a potential therapeutic medicine for the management of cardiovascular disorders.
    Archiv für Experimentelle Pathologie und Pharmakologie 02/2015; DOI:10.1007/s00210-015-1103-8
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    ABSTRACT: Intravesical administration of the cytotoxic drug doxorubicin is a common treatment for superficial carcinoma of the bladder, but it is associated with significant urological adverse effects. The aim of this study was to identify doxorubicin-induced changes in the local mechanisms involved in regulating bladder function. As a model of intravesical doxorubicin administration in patients, doxorubicin (1 mg/mL) was applied to the luminal surface of porcine bladders for 60 min. Following treatment, the release of urothelial/lamina propria mediators (acetylcholine (Ach), ATP and prostaglandin E2 (PGE2) and contractile responses of isolated tissue strips was investigated. Doxorubicin pretreatment did not affect contractile responses of detrusor muscle to carbachol, but did enhance neurogenic detrusor responses to electrical field stimulation (219 % at 5 Hz). Contractions of isolated strips of urothelium/lamina propria to carbachol were also enhanced (30 %) in tissues from doxorubicin pretreated bladders. Isolated strips of urothelium/lamina propria from control bladders demonstrated a basal release of all three mediators (Ach > ATP > PGE2), with increased release of ATP when tissues were stretched. In tissues from doxorubicin-pretreated bladders, the basal release of ATP was significantly enhanced (sevenfold), while the release of acetylcholine and PGE2 was not affected. The application of luminal doxorubicin, under conditions that mimic intravesical administration to patients, affects urothelial/lamina propria function (increased contractile activity and ATP release) and enhances efferent neurotransmission without affecting detrusor smooth muscle. These actions would enhance bladder contractile activity and sensory nerve activity and may explain the adverse urological effects observed in patients following intravesical doxorubicin treatment.
    Archiv für Experimentelle Pathologie und Pharmakologie 02/2015; DOI:10.1007/s00210-015-1097-2
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    ABSTRACT: In a lipopolysaccharide (LPS)-induced rat model of sepsis (endotoxaemia), we previously demonstrated that pravastatin reduced microvascular inflammation via increased endothelial nitric oxide synthase III (NOSIII). This study aimed to determine whether atorvastatin, the most commonly used statin for lowering cholesterol, exerted beneficial pleiotropic effects via a similar mechanism. The mesenteric microcirculation of anaesthetised male Wistar rats (308 ± 63 g, n = 54) was prepared for fluorescent intravital microscopy. Over 4 h, animals received intravenous (i.v.) administration of either saline, LPS (150 μg kg(-1) h(-1)) or LPS + atorvastatin (200 μg kg(-1) s.c., 18 and 3 h before LPS), with/without the non-specific NOS inhibitor L-NG-Nitroarginine Methyl Ester (L-NAME) (10 μg kg(-1) h(-1)) or NOSII-specific inhibitor 1400 W (20 μg kg(-1) min(-1)). LPS decreased mean arterial blood pressure (MAP) (4 h, control 113 ± 20 mmHg; LPS 70 ± 23 mmHg), being reversed by atorvastatin (105 ± 3 mmHg) (p < 0.05). LPS also increased macromolecular leak measured after 100 mg kg(-1) of i.v FITC-BSA (arbitrary grey level adjacent to venules), which again was attenuated by atorvastatin (control 1.9 ± 4.0; LPS 12.0 ± 2.4; LPS + atorvastatin 4.5 ± 2.2) (p < 0.05). Furthermore, immunohistochemistry identified that atorvastatin decreased LPS-induced upregulation of endothelial cell NOSII expression, but NOSIII was unchanged in all groups. Atorvastatin improved MAP and reduced microvascular inflammation during endotoxaemia, associated with a reduction of pro-inflammatory NOSII. This differs from previous studies, whereby pravastatin increased expression of NOSIII. Thus preoperative statins have beneficial anti-inflammatory effects during endotoxaemia, but careful consideration must be given to the specific statin being used.
    Archiv für Experimentelle Pathologie und Pharmakologie 02/2015; 388(5). DOI:10.1007/s00210-015-1100-y
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    ABSTRACT: Coronary heart disease remains a leading cause of death in the world. The demand on targeting therapy to reduce myocardial ischemia/reperfusion (I/R) injury is still urgent. The pathogenesis of I/R-induced myocardial injury is complicated. Reactive oxygen species (ROS) generation and inflammatory response activation participate in the development of I/R injury. Cell death occurs and finally leads to myocardial infarction. A newly phenolic aporphine alkaloid derivative, TM-1-1DP, was synthesized in our team. We aimed to investigate the effect of novel compound on myocardial I/R injury. Rats were subjected to 1-h coronary artery occlusion and followed by 2-h reperfusion. Adult rat cardimoycyte was isolated for the cell study, and H2O2 was added into culture medium to induce ROS stress. As compared to the sham group, TM-1-1DP-treated rats had better cardiac performance in association with less infarct size and cardiac injury markers after myocardial I/R. The protective effect is associated with the inhibition of inflammatory response, cell death-related pathway (caspase-3 and TNF-α), and the activation of AKT-eNOS pathway. The finding was further coincided with the cell study. TM-1-1DP treatment significantly alleviated ROS production and improved cell viability in cardiomyocyte after H2O2 exposure. The action of TM-1-1DP is via a nitric oxide (NO)-dependent manner, since NOS inhibitor, L-NAME, abolished the protective effect. We provide a new insight into this therapeutic potential for phenolic aporphine alkaloid in myocardial I/R.
    Archiv für Experimentelle Pathologie und Pharmakologie 02/2015; 388(5). DOI:10.1007/s00210-015-1098-1
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    ABSTRACT: Parkinson's disease (PD) is a chronic, progressive neurodegenerative disorder characterized by motor impairments and loss of dopaminergic neurons in the substantia nigra. FLZ (formulated as: N-2-(4-hydroxy-phenyl)-ethyl]-2-(2, 5-dimethoxy-phenyl)-3-(3-methoxy-4-hydroxy-phenyl)-acrylamide) is a novel synthetic derivative of squamosamide from a Chinese herb and has been proven to protect dopaminergic neurons in subacute PD models. However, whether FLZ has a neuroprotective effect on chronic PD model is still unknown. The present study was designed to verify the neuroprotection of FLZ on chronic PD mouse model induced by MPTP combined with probenecid (MPTP/p). The results showed that treatment of mice with FLZ for 9 weeks significantly improved motor behavior and dopaminergic neuronal function of mice injected with MPTP/p. The beneficial effects of FLZ attributed to the elevation of dopaminergic neuron number, dopamine level, and tyrosine hydroxylase (TH) activity, as well as decrease of α-synuclein (α-Syn) expression, α-Syn phosphorylation, nitration, and aggregation. Moreover, FLZ decreased the interaction between α-Syn and TH, which eventually improved dopaminergic neuronal function. Mechanistic study demonstrated that FLZ increased Akt and mTOR phosphorylation, suggesting that FLZ activated Akt/mTOR signaling pathway and this might be involved in the neuroprotection of FLZ. The present results provided more elaborate in vivo evidences to support the neuroprotective effect of FLZ on dopaminergic neurons of chronic PD mouse model and the potential of FLZ to be developed as new drug to treat PD.
    Archiv für Experimentelle Pathologie und Pharmakologie 02/2015; 388(5). DOI:10.1007/s00210-015-1094-5