Quinacrine: An Effective Addition to the Treatment of Refractory Cutaneous Lupus Erythematosus

Summary@#Treatment of refractory cutaneous lupus is challenging. When conventional therapy, including hydroxychloroquine (HCQ), corticosteroids and immunosuppressants, has failed, the addition of quinacrine may be a promising option. We describe a case of refractory chronic cutaneous lupus erythematosus (CCLE) who responded well to quinacrine.

Virtual Screening for Potential Inhibitors of NS3 Protein of Zika Virus

Zika virus (ZIKV) is a mosquito borne pathogen, belongs to Flaviviridae family having a positive-sense single-stranded RNA genome, currently known for causing large epidemics in Brazil. Its infection can cause microcephaly, a serious birth defect during pregnancy. The recent outbreak of ZIKV in February 2016 in Brazil realized it as a major health risk, demands an enhanced surveillance and a need to develop novel drugs against ZIKV. Amodiaquine, prochlorperazine, quinacrine, and berberine are few promising drugs approved by Food and Drug Administration against dengue virus which also belong to Flaviviridae family. In this study, we performed molecular docking analysis of these drugs against nonstructural 3 (NS3) protein of ZIKV. The protease activity of NS3 is necessary for viral replication and its prohibition could be considered as a strategy for treatment of ZIKV infection. Amongst these four drugs, berberine has shown highest binding affinity of –5.8 kcal/mol and it is binding around the active site region of the receptor. Based on the properties of berberine, more similar compounds were retrieved from ZINC database and a structure-based virtual screening was carried out by AutoDock Vina in PyRx 0.8. Best 10 novel drug-like compounds were identified and amongst them ZINC53047591 (2-(benzylsulfanyl)-3-cyclohexyl-3H-spiro[benzo[h]quinazoline-5,1'-cyclopentan]-4(6H)-one) was found to interact with NS3 protein with binding energy of –7.1 kcal/mol and formed H-bonds with Ser135 and Asn152 amino acid residues. Observations made in this study may extend an assuring platform for developing anti-viral competitive inhibitors against ZIKV infection.

Effect of quinacrine on inflammatory reaction of blood system induced by microwave irradiation / 中国实验血液学杂志

This work was aimed to investigate the effect of quinacrine on peripheral granulocytes and lymphocytes, interleukin 1 (IL-1) and interleukin 6 (IL-6) in peripheral blood serum of inflammatory reaction induced by microwave irradiation, and observe the protective effect of quinacrine against microwave irradiation injury. BALB/c mice were suffered from microwave irradiation with the total intensity of 50 mW/cm(2) for 30 minutes, at 1 hour before irradiation quinacrine (12.6 mg/kg or 50.4 mg/kg) was orally administrated. Mice received same volume of water for injection instead of quinacrine were named as microwave irradiation group (MR group), and mice received no microwave irradiation but stayed in microwave irradiation environment also for 30 min were set as control. After microwave irradiation, mice were sacrificed and peripheral blood cells were analyzed with cytoanalyzer, and mice serum interleukin-1β, interleukin-6 were detected by radioimmunoassay. The results showed that microwave irradiation increased the count of peripheral granulocytes and lymphocyte along with prolongation of time, while the increase of these cells in mice administrated quinacrine was markedly delayed. The level of IL-1β in serum of mice was significantly increased after 1 day of microwave irradiation (50 mW/cm(2)), and recovered to normal level after 7 days. The 2 concentrations of quinacrine (12.6 mg/kg, 50.4 mg/kg) could suppress level of IL-1β in serum induced by microwave irradiation. The level of IL-6 in serum of mice was gradually increased after microwave irradiation with intensity of 50 mW/cm(2) for 7 days, but quinacrine administration could delay the rise of IL-6 level, specially within time of 2 days. It is concluded that the quinacrine administration can delay the increase of peripheral granulocytes and lymphocytes inducted by microwave irradiation, and may partially suppress the rise of IL-1β and IL-6 in serum. The results of this study suggest that the quinacrine can provide some protective effect against microwave irradiation injury.

Avaliação das concentrações de zinco no aparelho reprodutor feminino por ativação neutrônica instrumental / Assessment of zinc concentration in the female reproductive system by instrumental neutron activation

A esterilização feminina não cirúrgica por meio da aplicação intracervical de pastilhas de cloridrato de quinacrina foi considerada um método contraceptivo definitivo de baixo custo, seguro e eficaz. O zinco, presente no útero e nas tubas uterinas, inibe a ação da quinacrina. A adição de cobre aumenta a eficácia da quinacrina, reduzindo o risco de gravidez devido às falhas de obstrução das tubas uterinas. O cobre neutraliza o efeito deletério do zinco, aumentando a eficácia do método. Para obter o mapeamento da concentração de zinco no aparelho reprodutor feminino, amostras de útero e de tubas uterinas foram analisadas por ativação neutrônica instrumental. Os resultados obtidos são apresentados neste trabalho.

Nonsurgical female sterilization through the transcervical insertion of quinacrine pellets was considered a definitive, low-cost, safe and effective contraceptive method. The zinc, present in both uterus and Fallopian tubes, inhibit the action of quinacrine. The addition of copper increases the efficacy of quinacrine, thus reducing the risk of pregnancy due to the failure to obstruct the Fallopian tubes. The copper neutralized the deleterious effect of the zinc and so the treatment efficacy is increased. In order to obtain a mapping to study the zinc concentration in the female reproductive system, samples of both uterus and Fallopian tubes were analyzed by neutron activation. The results are here reported.

Determination of sex from tooth pulp tissue

This study was carried out to determine the reliability of sex determination from teeth pulp tissue. This study was carried on 60 maxillary and mandibular premolars and permanent molars [30 male teeth and 30 female teeth] which were indicated for extraction. The teeth were categorized into three groups of 20 each [10 from males and 10 from females].Group 1-pulp tissue from teeth examined immediately after extraction. Group 2-and Group 3-pulp tissue examined from teeth one and five month after extraction, respectively. Teeth was sectioned and pulpal cells were stained with quinacrine dihydrochloride. The cells were observed with fluorescent microscope for fluorescent body. Gender was determined by identification of Y chromosome fluorescence in dental pulp. Freshly extracted teeth and for those examined one month later, sensitivity, specificity, positive predictive value, negative predictive value, and efficiency were all 100%. The fluorescent Y body test is shown to be a reliable, simple, and cost-effective technique for gender identification in the immediate postmortem period up to one month

Role of the PLA2-Activated Neutrophilic Oxidative Stress in Oleic Acid-Induced Acute Lung Injury / 결핵및호흡기질환

BACKGROUND: The underlying pathogenesis of fat embolism-induced acute lung injury (ALI) has not been elucidated. In the present study, the pathogenesis of fat embolism-induced ALI was probed in association with neutrophilic oxidative stress in oleic acid (OA)-induced ALI of S-D rats. METHODS: OA was injected intravenously to provoke ALI in experimental rats. Five hours later, indices of ALI were measured to confirm the role of the neutrophilic respiratory burst. The effect of an inhibition of phospholipase A2 (PLA2) was also evaluated. RESULTS: The accumulation of neutrophils in the lung due to OA caused increased neutrophilic oxidative stress in lung, which was ameliorated by mepacrine. What were the results from inhibition of PLA2. CONCLUSION: Excess neutrophilic oxidative stress contributes to OA-induced ALI, which is lessened by the inhibition of PLA2.

Ischemia/reperfusion Lung Injury Increases Serum Ferritin and Heme Oxygenase-1 in Rats

Intestinal ischemia/reperfusion (I/R) is one of common causes of acute lung injury (ALI). Early and accurate diagnosis of patients who are like to develop serious acute respiratory distress syndrome (ARDS) would give a therapeutic advantage. Ferritin and heme oxygenase-1 (HO-1) are increased by oxidative stress and are potential candidates as a predictive biomarker of ARDS. However, the mechanisms responsible for the increases of ferritin and HO-1, and their relationship to ALI, are unclear. In order to elucidate the interactions between ferritin and HO-1, we studied the changes in ferritin and HO-1 levels in serum and bronchoalveolar lavage (BAL) fluid after intestinal I/R injury in rats. Leukocyte number and protein contents in BAL fluid were elevated following I/R, and the increases were attenuated by mepacrine pretreatment. Both serum ferritin and HO-1 concentrations were progressively elevated throughout the 3 h observation period. Mepacrine pretreatment attenuated the increase of serum and BAL fluid ferritin concentrations, but did not suppress the increase of serum HO-1. Moreover, BAL fluid HO-1 levels did not change after I/R or after mepacrine pretreated I/R compared with sham rats. Unlike ferritin, HO-1 levels are not exactly matched with the ALI. Therefore, there might be a different mechanism between the changes of ferritin and HO-1 in intestinal I/R-induced ALI model.

Desenvolvimento de metodologia para fabricação de pastilhas de cobre para utilização em esterilização feminina não cirúrgica com quinacrina / Development of methods for the manufacturing of copper pellets to use inquinacrine female non-surgical sterilization

Objetivo: A esterilização feminina não cirúrgica por meio da aplicação intracervical de pastilhas de quinacrina foi considerada um método contraceptivo definitivo, de baixo custo, seguro e eficaz, e é sabido que a adição do cobre aumenta a eficácia da quinacrina. Com o objetivo de produzir pastilhas de cobre a serem aplicadas juntamente com pastilhas de quinacrina, foi desenvolvido, no Centro de Desenvolvimento daTecnologia Nuclear da Comissão Nacional de Energia Nuclear (CDTN/CNEN), um processo para sua fabricação. Material e métodos: Utilizou-se póde cobre metálico esferoidal e amido de milho e empregaram-se as mesmas técnicas de metalurgia do pó empregada na fabricação de pastilhas combustíveis nucleares. Resultados: Foi possível definir o teor ideal de amido de milho para diminuir o intertravamento entre as partículas metálicas de cobre que propicia uma adequada desagregação das pastilhas quando umidificada, de modo a criar no útero um ambiente rico em cobre antes da dissolução das pastilhas de quinacrina. Conclusões: Foram, então, produzidas 200 pastilhas de cobre com 6% em peso de amido de milho, para viabilizar um projeto de pesquisa da Faculdade de Medicina da Universidade Federal de Minas Gerais sobre esterilização feminina não cirúrgica com quinacrina. São descritas as técnicas, os testes e os resultados do desenvolvimento desta metodologia.

Objectives: Non-surgical female sterilization through the transcervical insertion of quinacrine pellets was considered a definitive, low-cost, safe and effective contraceptive method. The addition of copper increases the efficacy of quinacrine, reducing the risk of pregnancy due to a failure in the obstruction’s procedure of the Fallopian tubes. In order to produce copper pellets to be applied together with the quinacrine pellets, a manufacturing procedure was developed at Centro de Desenvolvimento da Tecnologia Nuclear da Comissão Nacional de Energia Nuclear (CDTN/CNEN). Material and Methods: It was used spheroidal metallic copper and corn starch and the same technics of powder metallurgy employed to the fabrication of nuclear fuel pellets. Results: It was possible to defi ne the ideal corn starch content to decrease the interlock degree between the metallic copperparticles that provide an appropiate desintegration of the pellets when humidfied in order to create in the uterus an environment rich in copper before the quinacrine pellet dissolution. Conclusions: Two hundred copper pellets were produced with 6% by weight of corn starch to make possible a research project of Faculdade de Medicina of Universidade Federal de Minas Gerais about non-surgical female sterilization with quinacrina. The techniques, tests and results of the developed methodology are here presented.

STAT3 is involved in phosphatidic acid-induced Bcl-2 expression in HeLa cells

Phosphatidic acid (PA), the product of a PLD-mediated reaction, is a lipid second messenger that participates in various intracellular signaling events and is known to regulate a growing list of signaling proteins. We found that Bcl-2 was upregulated by PA treatment in HeLa cells. However, how PA upregulates Bcl-2 expression has not yet been studied. In this study, we tried to discover the mechanisms of Bcl-2 up-regulation by PA treatment in HeLa cells. Treatment with PA resulted in significantly increased expression of Bcl-2 in HeLa cells. Moreover, PA-induced Bcl-2 expression was blocked by mepacrine, an inhibitor of PLA2, but not by propranolol, an inhibitor of PA phospholyhydrolase (PAP). Treatment of 1,2-dipalmitoryl-sn-glycero-3-phosphate (DPPA) also increased Bcl-2 expression. These results indicate that Bcl-2 expression is mediated by lysophosphatidic acid (LPA), not by arachidonic acid (AA). Thereafter, we used MEK1/2 inhibitor, PD98059 to investigate the relationship between ERK1/2 MAPK and PA-induced Bcl-2 expression. PA-induced Bcl-2 expression was decreased when ERK1/2 was inhibited by PD98059. The transcription factor such as STAT3 which is controlled by ERK1/2 MAPK was increased along with Bcl-2 expression when the cells were treated with PA. Furthermore, STAT3 siRNA treatments inhibited PA-induced Bcl-2 expression, suggesting that STAT3 (Ser727) is involved in PA-induced Bcl-2 expression. Taken together, these findings indicate that PA acts as an important mediator for increasing Bcl-2 expression through STAT3 (Ser727) activation via the ERK1/2 MAPK pathway.

Update Treatment of Dementia: Focus on Pharmacologic Treatment

Dementia is an increasingly common diagnosis in our population, and the numbers are expected to rise exponentially in coming years. Within the past decades research has progressed rapidly on multiple fronts, including epidemiology, etiology, pathology, diagnosis, and treatment. This article reviews the evidence for the effecacy of various pharmacologic treatments on dementia. Acetylcholinesterase inhibitors and NMDA antagonist are effective in patients with Alzheimer's disease. Benefit for vitamine E, anti-inflammatory drugs and ginko biloba have been suggested, but supporting evidence is not strong. And although antipsychotics have efficacy and safety in the treatment of aggression, agitation, and psychosis in patients with Alzheimer's disease, adverse effects limit their overall effectiveness. SSRI and atypical antipsychotic agents are frequently used to manage behavioral abnormalities associated with frontotemporal dementia. Cholinesterase inhibitors and levodopa have been reported to improve hallucination, cognition, apathy in dementia with Lewy bodies. And pharmacological intervention was largely ineffective in the management of corticobasal degeneration. Phenothiazine, quinacrine are being evaluated as treatment for CJD patients in trials. Cholinergic deficits in vascular dementia are due to ischemia of basal forebrain nuclei and of cholinergic pathways and can be treated with the use of the cholinesterase inhibitors. Future studies, directed to distinct causal and pathological factors, will be needed to enable therapeutic advances in dementia. Larger, well-controlled treatment studies are required to reach more definitive conclusions about treatment efficacy.

Actualidades en la terapéutica en giardiosis / State of the art in the treatment of giardiasis

Giardia lamblia, el protozoo intestinal patógeno más frecuentemente diagnosticado a escala mundial, se reconoce como uno de los agentes causantes de diarrea en el niño que puede llegar hasta trastornos que comprometen su adecuado crecimiento. En el tratamiento de esta parasitosis se involucran un número de agentes antiparasitarios, entre los que se destacan: los 5-nitroimidazoles, los nitrofuranos, la quinacrina, los benzimidazoles, entre otros. En el presente artículo, se hace una revisión de las principales características de estas drogas frente a Giardia, teniendo en consideración su eficacia terapéutica.

Prophylactic effect of quinacrine against experimental heatstroke / 药学学报

The present study is to assess the prophylactic effect of quinacrine (QA) , an anti-malarial drug, against heatstroke in rats. Conscious rats were orally given equal volume normal saline or QA (dissolved in normal saline and final dosage for rats was 4.5, 9.0 and 18 mg x kg(-1)). An hour later rats were put into a warm water circulated hot chamber (41.0 +/- 0.5) degrees C. Rectal temperature (core temperature, T(co)) of rats in hot chamber was continuously monitored by a thermocouple. T(co) and survival time of rats showed that QA pre-treatment postponed the hyperthermia, and increased the survival time of rats in hot chamber. Primary striatum neurons' culture from new born rats was maintained with D-MEM and 10% FBS. After immuno-cytochemistry identification with antibodies against neural specific proteins, culture received 20 micromol x L(-1) QA only for 1 h and followed by 43.0 degrees C heat treatment for another hour, or 20 micromol x L(-1) QA for 1 h followed by 43.0 degrees C heat treatment for another hour. Control culture received heat treatment only. Cultures were labeled with the fluorescent indicator DPH and the relative membrane fluidity of neurons was measured with the help of fluorescent polarized spectrophotometer. [3H] Arachidonic acid (AA) labeled membrane of E. Coli cells was used as substrate to determine cPLA2 activity of neurons. Gas chromatography and mass spectrum were also employed to detect on the level of fatty acids level in rat striatum neurons. Results from cells indicated that inhibition of cPLA2, reduction the release of active fatty acids such as AA, and possibly, stabilization of the cell membrane which was disturbed by hot treatment, may contribute to the mechanism underlying heat protection and heatstroke preventive effects of quinacrine.

Changes of Serum Ferritin in Acute Lung Injury Induced by Intestinal Ischemia/Reperfusion

Serum ferritin levels are increased in subjects at-risk for or with acute lung injury (ALI), and there are observations to suggest that increases in serum ferritin levels may help predict the development of ALI in at-risk individuals. To deepen our understanding of increases of serum ferritin and their relationship to the development of ALI, we measured serum ferritin levels before and after intestinal ischemia/reperfusion (I/R) injury in rats, and found that serum ferritin levels increased significantly following I/R. Increases in serum and lavage ferritin levels paralleled increases in lung inflammation (lavage leukocyte numbers and tissue myeloperoxidase activities) and lung leak (lavage protein levels). In contrast, pre-treatment of rats with mepacrine (60 mg/kg, i.p.), a phospholipase A2 inhibitor, attenuated not only I/R-induced serum and lavage ferritin increases, but also the development of ALI. These findings indicate that, besides of human subjects with ALI, serum ferritin levels increase early on also in an animal model of ALI. Therefore, serum and lavage ferritin can be a candidate for early biomarker of ALI.

Doença de Creutzfeldt-Jakob forma Heidenhain: relato de caso com achados de ressonância magnética e DWI / Creutzfeldt-Jakob disease, Heidenhain variant: case report with MRI (DWI) findings

A doença de Creutzfeldt-Jakob (CJD) é uma forma de demência pré-senil de rápida evolução, geralmente fatal em um ano. Casos autóctones no Brasil têm sido raramente descritos assim como achados de ressonância magnética. Mulher, natural de Ponta Grossa PR, branca , 54 anos , foi admitida no serviço em outubro de 2001 com quadro de amaurose bilateral cortical progressiva desde há 1 mês do internamento. Nunca viajou ao exterior e foi somente submetida a uma cirurgia de redução do estômago, para obesidade. História familial sem relato de casos semelhantes. Logo após o internamento a paciente desenvolveu quadro de disfasia mista, hemiparesia flácida direita, com movimentos coreoatetóticos e crises parciais motoras. Paciente evoluiu com quadro demencial progressivo; atualmente, acamada, torporosa, dependente de alimentação enteral, recebendo mepacrina, fenitoína e clorpromazina , estabilizando o quadro até final de maio de 2002. Exames laboratoriais negativos ou normais. Pesquisa de proteína 14-3-3 no líquor foi positiva; enolase-neurônio-específica no líquor foi normal. Estudo genético do gen PRNP não revelou mutação descrita anteriormente. EEG (23/10/2001) revelou intensa atividade irritativa hemisfério cerebral esquerdo. Estudo de ressonância magnética revelou áreas de hipersinal em T2 e FLAIR em regiões temporal esquerda e bioccipital; gânglios da base normal. Imagens de DWI mostraram hipersinal nas mesmas áreas.Outro EEG (15/03/2002) revelou padrão periódico de ondas trifásicas sugestivos de CJD. A paciente fez uso de mepacrina associado a clorpromazina com aparente estabilização do quadro, até seu óbito por complicações infecciosas pulmonares em abril de 2003.

Protective effect of Quinacrine on striatum neurons from heat treatment injury / 中国应用生理学杂志

<p><b>AIM</b>To study the protective effect of Quinacrine(QA) on rat striatum neurons from the injury caused by heat environment treatment, to probe the relationship between cell membrane injury and cellular injury protection, and to seek the possibility of QA as a preventive agent to heat injury.</p><p><b>METHODS</b>Primary cultured striatum neurons from newborn rats were pretreated with QA at different concentration for 1 h, and then heat-treated at 43 degrees C for another 1 h. Cell necrosis was detected by Trypan blue staining, and apoptosis was evaluated through Activated Caspase-3 dye and TdT dye.</p><p><b>RESULTS</b>Heat treatment effected the survival of striatum neurons and resulted in great number of cell death, which was mainly mediated by cell necrosis process. It was shown that treatment of QA itself had little effect on the survival of striatum neurons, while QA pretreatment decreased cellular necrosis caused by following heat treatment.</p><p><b>CONCLUSION</b>QA protects striatum neurons from heat environment injury at about 20 pmol/L, and the protection may mediated by reduction of necrosis.</p>

The Role of ATP on Reactive Oxygen Species Generation and Cellular Proliferation in BV-2 Cells

PURPOSE: Adenosine triphosphate (ATP) evokes several cellular responses in microglia including propagation. However, the role of the purinoceptor on ROS generation in microglia is unclear. In order to determine the action of the purinoceptor in microglia, the effects of ATP on ROS generation and cellular proliferation in BV-2 murine microglial cells were evaluated. An additional aim of this study was to investigate signal transduction pathways using several inhibitors. METHODS: The [Ca2+] was measured using Ca2+ sensitive indicator, Fura-2/AM. ROS production was observed by fluorescence-confocal microscope and cell proliferation was evaluated by counting cell number. RESULTS: ATP increased the intracellular calcium levels ([Ca2+]i) in BV-2 cells in a dose-dependent manner. This increase was attenuated by pretreatment with a calcium chelator (EGTA) and a phospholipase C (PLC) inhibitor (U-73122) while the protein tyrosine kinase (PTK) inhibitor (genistein) had no inhibitory effects. To identify the effects of the nucleotides, ROS generation was observed in the nucleotide-stimulated BV-2 cells. The treatment with 100 M ATP induced ROS generation, but 100 M adenosine and 100 M UTP did not. To investigate the signal transduction pathway in ATP-induced ROS generation, several inhibitors were pretreated before adding ATP. ATP- induced ROS production was blocked by pretreatment with either 0.5 mM EGTA or 10 M U73122 while 40 M genistein had an inhibitory effect on ATP action. Correspondingly, 40 M KN62 (CaM kinase II inhibitor), 1 M sphingosine (protein kinase C inhibitor), 1 nM DPI (NADPH oxidase inhibitor) and 50 M mepacrine (phospholipase A2 inhibitor) could suppress ATP-induced ROS generation. The effects of ATP on cell proliferation was observed 3 days after ATP treatment and its peak velocity after 4 days. NF-kB activation was observed after the cells were incubated with 0.1 mM ATP. The maximal level of NF-kB activation was obtained with 0.3 mM ATP while higher concentrations were less effective. CONCLUSION: Overall, we conclude that ATP in BV-2 cells induces ROS generation and cell propagation. The signal transduction pathways including calcium, CaM kinase II, PLC, protein kinase C, phospholipase A2 and NADPH oxidase are involved in ATP-induced ROS generation.

Location of quinacrine pellets in different positions of non-surgical female sterilization.

OBJECTIVE: To compare quinacrine pellets distribution in the uterine cavity between women standing up promptly after insertion and those lying down for a further 30-minutes. DESIGNS: Randomized controlled trial MATERIAL AND METHOD: Twenty women who, desired interval female sterilization, were equally randomized into 2 groups. Quinacrine pellets were inserted twice, one month apart in both groups. Transvaginal ultrasonography (TVS) was performed after insertion in order to locate the position of the quinacrine pellets. In group I, the TVS was performed after the women stood up promptly. In group II, the TVS was performed after the women lay down for 30-minute. The distribution of quinacrine pellets, measured from the uterine fundus to the lowest pellet, were compared. RESULTS: There was no difference at the baseline and 30 minutes measurement of both groups. In the first insertion, there was statistical difference of the distance of the quinacrine pellets when compared in the same group immediately and the 30-minute measurement (Gr 1: 19.10+/-3.28 mm vs 22.30+/-3.50 mm); (Gr 2: 18.70+/-3.40 mm vs 24.40+/-5.95 mm). In the same manner, the authors found statistical difference in the same group of the second insertion (Gr 1: 21.80+/-5.39 mm vs 24.70+/-7.24 mm); (Gr 2 : 20.89+/-4.78 mm vs 28.30+/-7.59 mm) CONCLUSIONS: There was statistical difference of quinacrine pellet distribution in uterine cavity after time. However, body movement did not effect the position of the pellets. The failure rate of quinacrine pellet insertion for non-surgical female sterilization may not be explained by the changes of position after insertion.

Effects of betamethasone, sulindac and quinacrine drugs on the inflammatory neoangiogenesis response induced by polyurethane sponge implanted in mouse

In this study, we showed the effect of the betamethasone, sulindac and quinacrine alone or combined, on the inflammatory angiogenesis promoted by polyurethane sponge on mice. The main finding reported here is that the formation of new blood vessels was strongly inhibited by low concentration of betamethasone, sulindac or quinacrine, whether alone or in combination. It is known that steroidal anti-inflammatory drugs inhibit the enzymes required for the production of prostaglandins through a nuclear glucocorticoid receptor (GR) mediated mechanism. This mechanism may occur in endothelial cells as well. Considering that activity of cyclo-oxigenases 1 and 2 is inhibited by sulindac, and that these enzymes are located in the stromal tissue, we propose that the anti-angiogenic effect of these agents may occur via inhibition of both COX isoforms. On the other hand, quinacrine inhibited PLA2 activity, and we propose here that the anti-angiogenic effect occurs via inhibition of the enzyme PLA2. The potentiated effect of the association of betamethasone, sulindac and quinacrine may have some therapeutic benefit in the control of pathological angiogenesis. Further studies are required to validate these propositions

Phospholipase A2 Contributes to Hemorrhage-induced Acute Lung Injury Through Neutrophilic Respiratory Burst / 결핵

BACKGROUND: The present study was carried out in association with neutrophilic respiratory burst in the lung in order to clarify the pathogenesis of acute respiratory distress syndrome(ARDS) following acute severe hemorrhage. Because oxidative stress has been suggested as one of the principal factors causing tissue injury, the role of free radicals from neutrophils was assessed in acute hemorrhage-induced lung injury. METHOD: In Sprague-Dawley rats, hemorrhagic shock was induced by withdrawing blood(20 ml/kg of B.W) for 5 min and the hypotensive state was sustained for 60 min. To determine the mechanism and role of oxidative stress associated with phospholipase A2(PLA2) by neutrophils, the level of lung leakage, pulmonary myeloperoxidase(MPO), and the pulmonary PLA2 were measured. In addition, the production of free radicals was assessed in isolated neutrophils by cytochemical electron microscopy in the lung. RESULTS: In hypotensive shock-induced acute lung injury, the pulmonary MPO, the level of lung leakage and the production of free radicals were higher. The inhibition of PLA2 with mepacrine decreased the pulmonary MPO, level of lung leakage and the production of free radicals from neutrophils. CONCLUSION: A. neutrophilic respiratory burst is responsible for the oxidative stress causing acute lung injury followed by acute, severe hemorrhage. PLA2 activation is the principal cause of this oxidative stress.

Inhibition of Phospholipase A2 Ameliorates the Acute Lung Injury Induced by E Coli Endotoxin via Reduced Production of Oxygen Free Radicals in the Lung / 대한마취과학회지

BACKGROUND: In order to understand the pathogenetic mechanism of sepsis-induced acute lung injury, inhibition of phospholipase A2 (PLA A2) was carried out in an endotoxin-induced septic lung model. METHODS: Sprague-Dawley rats were divided three groups; sham group, endotoxin group (instillation of E coli endotoxin, 100microgram/rat, type 017) and mepacrine group (the non-specific PLA2 inhibitor, 50 ml/kg intraperitoneal injection after endotoxin treatment). Five hours after endotoxin treatment, protein contents, neurophils counts, gamma-glutamyl transpeptidase (GGT) activity and surfactant concentrations in the bronchoalveolar fluid (BAL), meyloperoxidase (MPO) and PLA2 activity in the lung were measured. A morphological study for the effect of the endotoxin and mepacirne, and a cytochemical electron microscopy for detection of hydrogen peroxide in the lung were also performed. RESULTS: Endotoxin increased the concentrations of protein, the number of neutrophils, and GGT activity in the BAL fluid, MPO and PLA2 activity in the lung but mepacrine decreased these parameters (P < 0.001). The light density of surfactant was increased by the endotoxin (P < 0.001), but mepacrine diminished this pathological change. In the light microscopic findings, the endotoxin caused pulmonary accumulation of neutrophils, atelectasis and transudation of intravascular protein was observed. In contrast, mepacrine lessened these pathological findings. In ultrastructural findings, adhesion of neutrophils to endothelial cells, necroses of type II cells and endothelial cells, and the damage of lamellar bodies were observed after the endotoxin treatment, which recovered with mepacrine. In the cytochemical electron microscopy for detection of hydrogen peroxide in the lung, the deposits of cerrous perhydroxide were increased by the endotoxin but mepacrine decreased deposits of cerrous perhydroxide. CONCLUSIONS: Inhibition of PLA2 in an endotoxin induced acute lung leak showed protection against oxidative stress by a diminution of neutrophilic respiratory bursts and a decreased production of free radicals. It is suggested that PLA2 has a pivotal role in causing acute oxidative stress in endotoxin induced acute lung injury.