Objective To investigate the effect of dietary saturated fat (SFA) from animal sources on the urine excretion 11-dehydro thromboxane 62 (TXB2) and 6-keto prostaglandin F la (PGF la) in 27 healthy free-living male subj...Objective To investigate the effect of dietary saturated fat (SFA) from animal sources on the urine excretion 11-dehydro thromboxane 62 (TXB2) and 6-keto prostaglandin F la (PGF la) in 27 healthy free-living male subjects aged 30 to 55 years. Methods It was a randomized crossover design. Each volunteer was randomly assigned to one of the two diets (high fat and low fat) for a period of 4 weeks, after which each subject resumed his usual diet for 2 weeks as a 'wash-out period', before being assigned to the other diet for an additional 4 weeks. Results Serum proportion of 20:4n-6 was 5% lower in the high fat (6.2% of total fatty acid) than in the low fat diet (6.5% of total fatty acid), which was associated with a significantly decreased ratio of the urinary excretion 11-dehydro TXB2 to 6-keto PGF lα (P<0.05). However, there was no significant fall in the absolute urinary excretion of 11-dehydro TXB2. Conclusions Diet rich in SFA from animal sources may influence TXA2 formation via effect on tissue proportion of 20:4n-6.展开更多
AIM: Vasodilatation and increased capillary permeability have been proposed to be involved in the pathogenesis of acute and chronic form of hepatic encephalopathy. Prostacyclin (PGI2) and nitric oxide (NO) are importa...AIM: Vasodilatation and increased capillary permeability have been proposed to be involved in the pathogenesis of acute and chronic form of hepatic encephalopathy. Prostacyclin (PGI2) and nitric oxide (NO) are important contributors to hyperdynamic circulation in portal hypertensive states. Our previous study showed that chronic inhibition of NO had detrimental effects on the severity of encephalopathy in thioacetamide (TAA)-treated rats due to aggravation of liver damage. To date, there are no detailed data concerning the effects of PGI2 inhibition on the severity of hepatic encephalopathy during fulminant hepatic failure. METHODS: Male Sprague-Dawley rats weighing 300-350 g were used. Fulminant hepatic failure was induced by intraperitoneal injection of TAA (350 mg/(kg·d) for 3 d. Rats were divided into two groups to receive intraperitoneal injection of indomethacin (5 mg/(kg·d), n = 20) or normal saline (N/S, n = 20) for 5 d, starting 2 d before TAA administration. Severity of encephalopathy was assessed by the counts of motor activity measured with Opto-Varimex animal activity meter. Plasma tumor necrosis factor-α (TNF-α, an index of liver injury) and 6-keto-PGF1α (a metabolite of PGI2) levels were measured by enzyme-linked immunosorbent assay. RESULTS: As compared with N/S-treated rats, the mortality rate was significantly higher in rats receiving indomethacin (20% vs5%, P<0.01). Inhibition of PGI2 created detrimental effects on total movement counts (indomethacin vs N/S: 438±102 vs 841±145 counts/30 min, P<0.05). Rats treated with indomethacin had significant higher plasma levels of TNPa (indomethacin vs N/S: 22±5 vs 10±1 pg/mL, P<0.05) and lower plasma levels of 6-keto-PGF1α (P<0.001), but not total bilirubin or creatinine (P>0.05), as compared with rats treated with N/S. CONCLUSION: Chronic indomethacin administration has detrimental effects on the severity of encephalopathy in TAA-treated rats and this phenomenon may be attributed to the aggravation of liver injury. This study suggests that PGI2 may provide a protective role in the development of fulminant hepatic failure.展开更多
BACKGROUND： Prostacyclin has been shown to increase portal hypertension, but the mechanism is unclear. This study aimed to investigate whether the overproduction of prostacyclin（PGI2） in cirrhosis participates in t...BACKGROUND： Prostacyclin has been shown to increase portal hypertension, but the mechanism is unclear. This study aimed to investigate whether the overproduction of prostacyclin（PGI2） in cirrhosis participates in the splanchnic vascular hyporesponsiveness to vasoconstrictors in cirrhotic rats.METHODS： Cirrhotic model was created by subcutaneous injection of 60% carbon tetrachloride（CCl4） corn oil solution combined with intermittent drinking of 5% alcohol, and agematched rats served as controls. The isolated third-generation mesenteric arterioles were used to examine the contractile response to norepinephrine. The changes in vascular diameter were observed under a microscope imaging device. The plasma concentration of 6-ketone-prostaglandin F1α（6-keto-PGF1α, a stable metabolite of PGI2） was tested via enzyme immunoassays and the expression of cyclooxygenase（COX） in mesenteric arteries was detected by Western blotting.RESULTS： In parallel with the increase of plasma 6-ketoPGF1α, the contractile response of arterioles from cirrhotic rats to norepinephrine was significantly impaired compared with that from controls. Inhibition of PGI2 or protein kinase A with indomethacin or Rp-adenosine 3＇, 5＇-cyclic monophosphothioate（Rp-cAMPS） partially reversed the vascular hypo-contractile response to norepinephrine in arterioles from cirrhotic rats.Indomethacin significantly decreased the plasma 6-keto-PGF1α.Furthermore, indomethacin significantly attenuated the effect of Rp-cAMPS on arterioles from cirrhotic rats. COX-1 expression was up-regulated in mesenteric arteries from cirrhotic rats,whereas COX-2 was not detectable in the mesenteric arteries from both cirrhotic and control rats.CONCLUSION： Enhanced COX-1 expression in cirrhotic rats resulted in elevated PGI2 production which partially contributedto the splanchnic vascular hyporesponsiveness to a vasoconstrictor via the protein kinase A pathway.展开更多
AIM To evaluate the safety and efficacy of inhaled milrinone in acute respiratory distress syndrome(ARDS).METHODS Open-label prospective cross-over pilot study where fifteen adult patients with hypoxemic failure meeti...AIM To evaluate the safety and efficacy of inhaled milrinone in acute respiratory distress syndrome(ARDS).METHODS Open-label prospective cross-over pilot study where fifteen adult patients with hypoxemic failure meeting standard ARDS criteria and monitored with a pulmonary artery catheter were recruited in an academic 24-bed medico-surgical intensive care unit. Random sequential administration of i NO(20 ppm) or nebulized epoprostenol(10 μg/mL) was done in all patients. Thereafter, inhaled milrinone(1 mg/mL) alone followed by inhaled milrinone in association with inhaled nitric oxide(iN O) was administered. A jet nebulization device synchronized with the mechanical ventilation was use to administrate the epoprostenol and the milrinone. Hemodynamic measurements and partial pressure of arterial oxygen(PaO_2) were recorded before and after each inhaled therapyadministration.RESULTS The majority of ARDS were of pulmonary cause(n = 13) and pneumonia(n = 7) was the leading underlying initial disease. Other pulmonary causes of ARDS were: Post cardiopulmonary bypass(n = 2), smoke inhalation injury(n = 1), thoracic trauma and pulmonary contusions(n = 2) and aspiration(n = 1). Two patients had an extra pulmonary cause of ARDS: A polytrauma patient and an intra-abdominal abscess Inhaled nitric oxide, epoprostenol, inhaled milrinone and the combination of inhaled milrinone and i NO had no impact on systemic hemodynamics. No significant adverse events related to study medications were observed. The median increase of PaO 2 from baseline was 8.8 mmH g [interquartile range(IQR) = 16.3], 6.0 mm Hg(IQR = 18.4), 6 mm Hg(IQR = 15.8) and 9.2 mm Hg(IQR = 20.2) respectively with i NO, epoprostenol, inhaled milrinone, and i NO added to milrinone. Only i NO and the combination of inhaled milrinone and i NO had a statistically significant effect on PaO 2. CONCLUSION When comparing the effects of inhaled NO, milrinone and epoprostenol, only NO significantly improved oxygenation. Inhaled milrinone appeared safe but failed to improve oxygenation in ARDS.展开更多
The level of 6-keto-PGF1αand thromboxane B2(TXB2) in Plasma was determined with radioimmunoassay in 58 normal subjects and 92 Patients with various cancers(including lung,hepatic,gastric,esophageal and pancreatic car...The level of 6-keto-PGF1αand thromboxane B2(TXB2) in Plasma was determined with radioimmunoassay in 58 normal subjects and 92 Patients with various cancers(including lung,hepatic,gastric,esophageal and pancreatic carcinoma).The results showed that 6-keto-PGF1α.In plasma was 10.21±2.75 Pg/ml,and TXB2 146.03±37.31 Pg/ml in normal individuals,the ratio of 6-keto-PGF1α to TXB2 was 0.07;while in cancer Patients 6-keto-PGF1αwas 27.5±16.9 Pg/ml and TXB2 315.4±173.4 Pg/ml, the ratio of 6-keto-PGF1αto TXB2 was 0.08.The values of 6-keto-PGF1αand TXB2 in plasma of cancer patients were 2.69 folds and 2.16 folds higher than that of the two groups,respectively.The difference between the two groups was statistically significant(P<0.01).It indicates that the synthesis and release of PGI2 and TXA2 of cancer tissues increases greatly as compared to the normals.The study also revealed that the size of tumor,metastasis and histological classification had no obvious relation to PGs.展开更多
In order to understand the relation between TXA2- PGI2 and secondary trauma and the effect of intra-arachnoid perfusion of dexamethasone and verapamil on alteration of TXA,-PGI, following spinal cord injury, TXB2 and ...In order to understand the relation between TXA2- PGI2 and secondary trauma and the effect of intra-arachnoid perfusion of dexamethasone and verapamil on alteration of TXA,-PGI, following spinal cord injury, TXB2 and 6-keto-PGFconcentration and pathological changes in injured site 1, 2, 4 and 6 h after injury were studied using a rabbit spinal cord injury model by Allen's weight drop method.展开更多
The endothelial cells derived from human umbilical cord vein were treated with 200 μg/ml ligustrizini. The inhibrtory rate of platelet aggregation of the supernatant from the cultured endothelial cells treated with l...The endothelial cells derived from human umbilical cord vein were treated with 200 μg/ml ligustrizini. The inhibrtory rate of platelet aggregation of the supernatant from the cultured endothelial cells treated with ligustrizini was 91% and that of superna展开更多
Objective To study the releases of endothelin-1 and prostacyclin by endothelial cells in culture and to elucidate how these releases were influenced by smoke-treated low density lipoprotein. Methods We exposed en- dot...Objective To study the releases of endothelin-1 and prostacyclin by endothelial cells in culture and to elucidate how these releases were influenced by smoke-treated low density lipoprotein. Methods We exposed en- dothelial cell cultures to native or oxidized low density lipoproteins,low density lipoproteins treated by dimethylsul- foxide-soluble particles from cigarette smoke or dimethylsulfoxide alones. The release of endothelin-1 was assayed by bioassay and the release of prostacyclin was assayed by radioimmunoassay. Results Low density lipoproteins treated by smoke significantly increased the release or endothelin-1 (P<0.025) and decreased the release of prostacyclin (P< 0.02) by endothelial cells in culture, contrast to native or dimethylsulfoxide-treated lipoproteins. Conclusion The main part or vasoconstrictor activity in conditioned medium from bovine aortic EC is endothelin-1.展开更多
ONO-1301 has been developed as a novel long-acting prostacyclin agonist with thromboxane synthase inhibitory activity. In the present study, we investigated the cerebroprotective effect of ONO-1301 on post-ischemic in...ONO-1301 has been developed as a novel long-acting prostacyclin agonist with thromboxane synthase inhibitory activity. In the present study, we investigated the cerebroprotective effect of ONO-1301 on post-ischemic injury induced by cerebral ischemia in rats. ONO-1301 (1 and 10 mg/kg) was administrated orally at reperfusion and then twice a day for 42 days. The cell damage induced by cerebral ischemia in the hippocampal CA1 was evaluated using both Nissl staining and proliferating cell nuclear antigen (PCNA) staining on the 42 days after cerebral ischemia. Activated astrocytes were evaluated using immunofluorescence staining with GFAP on the 42 days after cerebral ischemia. Spatial learning was assessed using a Morris water maze (MWM) task on the 56 days (i.e. after a 14 days washout period). ONO-1301- treated rats (1 and 10 mg/kg) significantly improved cell death in the hippocampal CA1, the number of PCNA-positive cells and astrocyte activation. The spatial learning of ONO-1301-treated rats compared with vehicle- treated rats in the MWM task. These results suggest that repeated treatment with oral ONO-1301 could prevent or limit post-ischemic brain damage. In particular, treatment with ONO-1301 within 7 days after ischemia is most effective to improve ischemic damage.展开更多
Objective:To explore the effects of prostacyclin derivatives combined with valsartan therapy on the blood biochemical indexes in patients with early hypertensive nephropathy.Methods: A total of 110 patients with hyper...Objective:To explore the effects of prostacyclin derivatives combined with valsartan therapy on the blood biochemical indexes in patients with early hypertensive nephropathy.Methods: A total of 110 patients with hypertensive nephropathy who were treated in the hospital between December 2014 and March 2017 were divided into control group (n=55) and experimental group (n=55) by random number table method. Control group received valsartan therapy, and experimental group received prostacyclin derivatives combined with valsartan therapy, which lasted for 20 weeks. The differences in the contents of renal function indexes, urinary protein indexes and endothelial injury markers were compared between the two groups before and after treatment.Results: Before treatment, the differences in the contents of renal function indexes, urinary protein indexes and endothelial injury markers were not statistically significant between the two groups. After 20 weeks of treatment, renal function indexes SCr, BUN, UA and CysC levels in peripheral blood of experimental group were lower than those of control group;urinary protein indexes ALB,β2-MG andα1-MG contents were lower than those of control group;endothelial injury markers ET-1 and E-selectin contents in peripheral blood were lower than those of control group whereas NO and CGRP contents were higher than those of control group.Conclusion: Prostacyclin derivatives combined with valsartan therapy can effectively optimize the renal function, reduce the urinary protein and alleviate the vascular endothelial injury in patients with early hypertensive nephropathy and improve the overall therapeutic effect.展开更多
Objective To investigate the interaction and c linical significance of changes in p lasma endothelin-1(ET-1)and prostacyclin(PGI 2 )concentrations in patients with isc hemic cerebral infarction.Methods Plasma ET-1and ...Objective To investigate the interaction and c linical significance of changes in p lasma endothelin-1(ET-1)and prostacyclin(PGI 2 )concentrations in patients with isc hemic cerebral infarction.Methods Plasma ET-1and 6-keto-PGF 1 α(resistant metabolite of PGI 2 )concentrations were measured in 37p atients(study group)with ischemic cerebral infarction a nd 34healthy volunteers(control group)by ra-dioimmunoassay.Results Plasma ET-1concentrations in patie nts of study group were markedly higher than that of control group(P <0.01)and 6-keto-PGF 1 αconcentrations in patients of study group were significantly lower than that of control subjects(P <0.01).Plasma ET-1concentrations in control subjects were positively correlated with 6-k eto-PGF 1 αconcentrations and no correlation i n the study group.Conclusion Both ET-1and PGI 2 are participated in patho-physiolo gic process of ischemic cerebral inf arction.ET-1is a virulence factor a nd may play a deleterious role in ischemic cerebral infarction,PGI 2 is a conservancy factor and endogenetic antagonist of ET-1.It may provid e useful therapy parameter to find out ectogenesis PGI 2 or analog for treating the patients with ischemic cerebral infarction wi th reason.展开更多
Abstract Objective To evaluate the role of increased portal pressure and portosystemic shunting in elevated level of prostacyclin (PGI 2) in portal hypertension. Methods Thirty six male Sprague Dawley rats were ...Abstract Objective To evaluate the role of increased portal pressure and portosystemic shunting in elevated level of prostacyclin (PGI 2) in portal hypertension. Methods Thirty six male Sprague Dawley rats were divided into four groups: prehepatic portal hypertension (PHPH, 8 rats), intrahepatic portal hypertension (IHPH, 9), end to side portacaval shunt (PCS, 8), and sham operated controls (SO, 11). Two weeks after surgery, free portal pressure (FPP) was measured; systemic and splanchnic hemodynamics was studied by radioactive microsphere technique and blood sample from the femoral artery was obtained to measure the level of plasma 6 keto PGF 1 α with radio immunoassay. Results The FPP (mmHg) in IHPH, PHPH, PCS and SO rats was 13.10±1.02, 12.10±1.52, 3.0±0.82 and 6.86±0.69, respectively. The value of FPP was significantly increased in IHPH, PHPH rats and significantly decreased in PCS rats when compared to SO rats. Cardiac index (CI) and portal venous inflow (PVI) were in the order of PCS>PHPH>IHPH>SO rats. Portosystemic shunting (PSS) in PCS, PHPH, IHPH was 99.7±0.29%, 76.02±20.62% and 30.34±10.18%, respectively. The concentrations of plasma 6 keto PGF 1α (ng/ml) in PHPH, IHPH, PCS and SO rats were 6.93±2.43, 5.09±2.27, 2.36±1.01 and 1.56±0.61, respectively. The concentrations of plasma PGI 2 in PHPH, IHPH and PCS rats were significantly higher than those in SO rats. Furthermore, the concentrations of plasma PGI 2 in PHPH and IHPH rats were also significantly higher than those in PCS rats. Moreover, a closed positive correlation existed between plasma PGI 2 and FPP (r=0.67, P<0.001). Conclusions The results of the present study suggest that the elevated PGI 2 in portal hypertension is mainly due to the overproduction of PGI 2 in vascular epithelium cells induced by increased portal pressure, whereas portosystemic shunting and liver dysfunction play a secondary role. In addition, the results of this study do not support that PGI 2 mediated the hyperhemodynamics in portal hypertension.展开更多
Objective To evaluate the effects of nitric oxide inhibitor on prostacyclin (PGI 2) biosynthesis and the role of PGI 2 in hyperhemodynamics of portal hypertension. Methods Sprague Dawley rats were divided into f...Objective To evaluate the effects of nitric oxide inhibitor on prostacyclin (PGI 2) biosynthesis and the role of PGI 2 in hyperhemodynamics of portal hypertension. Methods Sprague Dawley rats were divided into four groups: intrahepatic portal hypertension (IHPH) by injection of CCl 4, prehepatic portal hypertension (PHPH) by stenosis of the portal vein, end to side portacaval shunt (PCS), and sham operated controls (SO). Animals of each group were subdivided into 2 groups: systemic administration of nitric oxide inhibitor L NMMA and vehicle. The radioactive microsphere method was used for hemodynamic study. The level of plasma PGI 2 (6 keto PGF 1α ) was measured by radioimmunoassay.Results The characteristics of hyperdynamic circulatory state including increased cardiac output and splanchnic blood flow, decreased mean arterial blood pressure, total peripheral vascular resistance, and splanchnic vascular resistance were observed in IHPH, PHPH and PCS rats. The magnitude of hyperhemodynamics was in the order of PCS>PHPH>IHPH rats. The hyperdynamic circulatory state in IHPH, PHPH and PCS rats could be effectively reversed by L NMMA to the baseline values of hemodynamics in SO rats. The baseline concentrations of plasma 6 keto PGF 1α (ng/ml) in PHPH, IHPH, PCS, and SO rats were 6.93±2.43, 5.09±2.27, 2.36 ±1.01 and 1.56±0.61, respectively. The concentrations of plasma 6 Keto PGF 1α in PHPH,IHPH and PCS rats were significantly higher than those in SO rats. Moreover, the concentrations were significantly higher in PHPH and IHPH rats than in PCS rats (P<0.05). After administration of L NMMA, the concentrations of plasma 6 Keto PGF 1α (ng/ml) in PHPH, IHPH, PCS and SO rats were 7.69±2.98, 5.68 ±2.66, 5.50±0.79, 5.02±2.86, respectively. As compared to the baseline value, the concentrations of 6 keto PGF 1α rats were slightly increased in IHPH, PHPH rats (P>0.05), but significantly increased in PCS and SO rats (P<0.05).Conclusions In this study, the hyperdynamic circulatory state in portal hypertensive rats and portacaval shunt rats was completely reversed by L NNMA to normal, but the level of 6 keto PGF 1α was still elevated. The results indicate that PGI 2 is not involved in hyperhemodynamics of portal hypertension.展开更多
Background:The maintenance dosage of selexipag is categorized as low,medium or high.In order to assess the efficacy and safety of different dosages of selexipag for the risk stratification of pulmonary arterial hypert...Background:The maintenance dosage of selexipag is categorized as low,medium or high.In order to assess the efficacy and safety of different dosages of selexipag for the risk stratification of pulmonary arterial hypertension(PAH),we performed a sys-tematic review and meta-analysis.Methods:Studies assessing PAH risk stratification indices,such as the World Health Organization functional class(WHO-FC),six-minute walk distance(6MWD),N-terminal pro-B-type natriuretic peptide(NT-proBNP)level,right atrial pressure(RAP),cardiac index(CI)and mixed venous oxygen saturation(SvO2),were included.Results:Thirteen studies were included.Selexipag led to improvements in the 6MWD(MD:24.20 m,95%CI:10.74-37.67),NT-proBNP(SMD:-0.41,95%CI:-0.79-0.04),CI(MD:0.47 L/min/m^(2),95%CI:0.17-0.77)and WHO-FC(OR:0.564,95%CI:0.457-0.697).Subgroup analysis demonstrated that all three dosages improved the 6MWD.A moderate dosage led to improvements in the CI(MD:0.30 L/min/m^(2),95%CI:0.15-0.46)and WHO-FC(OR:0.589,95%CI:0.376-0.922).Within 6 months of treatment,only the WHO-FC and CI were significantly improved(OR:0.614,95%CI:0.380-0.993;MD:0.30 L/min/m^(2),95%CI:0.16-0.45,respectively).More than 6 months of treatment significantly improved the 6MWD,WHO-FC and NT-proBNP(MD:40.87 m,95%CI:10.97-70.77;OR:0.557,95%CI:0.440-0.705;SMD:-0.61,95%CI:-1.17-0.05,respectively).Conclusions:Low,medium,and high dosages of selexipag all exhibited good effects.When treatment lasted for more than 6 months,selexipag exerted obvious effects,even in the low-dosage group.This finding is important for guiding individualized treatments.展开更多
目的研究绝经后骨质疏松症患者血管舒缩活性因子前列环素(prostacyclin I2,PGI_(2))、血栓素A2(thromboxane A2,TXA_(2))在骨代谢因子Ⅰ型前胶原氨基端前肽(aminoterminal propeptide of typeⅠprocollagen,PINP)、Ⅰ型胶原交联羧基端肽...目的研究绝经后骨质疏松症患者血管舒缩活性因子前列环素(prostacyclin I2,PGI_(2))、血栓素A2(thromboxane A2,TXA_(2))在骨代谢因子Ⅰ型前胶原氨基端前肽(aminoterminal propeptide of typeⅠprocollagen,PINP)、Ⅰ型胶原交联羧基端肽(carboxyterminal cross-linked telopeptide of typeⅠcollagen,ICTP)中的作用及其相互影响的可能机制。方法便利抽样法选取2023年1月—2023年9月厦门大学附属第一医院康复医学科收治的180例女性患者为研究对象,并分为骨质疏松症组(n=90)和正常对照组(n=90)。比较2组患者血清PGI_(2)、TXA_(2)、PINP、ICTP水平,并分析PGI_(2)、TXA_(2)与PINP、ICTP的相关性。结果骨质疏松症组PGI_(2)水平为(96.00±8.25)ng/L,低于正常对照组的(158.21±8.68)ng/L,差异有统计学意义(P<0.05);骨质疏松症组TXA_(2)水平为(143.14±6.63)ng/L,高于正常对照组的(102.33±7.09)ng/L,差异有统计学意义(P<0.05)。骨质疏松症组PINP水平为(42.33±2.18)μg/L,低于正常对照组(75.38±1.86)μg/L,差异有统计学意义(P<0.05);骨质疏松症组ICTP水平为(7.13±0.41)μg/L,高于正常对照组的(3.91±0.30)μg/L,差异有统计学意义(P<0.05)。Pearson相关性分析结果显示,PGI_(2)水平与PINP水平呈正相关(r=0.982,P<0.001),而与ICTP水平呈负相关(r=-0.898,P<0.001);TXA_(2)与ICTP呈正相关(r=0.965,P<0.001),而与PINP呈负相关(r=-0.919,P<0.001)。结论骨质疏松症患者血管舒张活性因子PGI_(2)表达水平下调、血管收缩活性因子TXA_(2)表达水平上调与骨代谢活性因子PINP下降、ICTP升高紧密相关,血管活性因子中舒血管成分下调、缩血管成分升高引起局部骨代谢血管循环状态发生循环障碍的病理变化与骨质疏松症的发生具有一定的相关性。展开更多
Objective: To explore the effects of ligustrazine on proteinuria, serumcreati-nine, urinary thromboxane A_2(TxA_2), metabolism of prostacyclinI_2(PGI_2)―6-keto-PGF_(1α), and renal pathological changes of SD rats wit...Objective: To explore the effects of ligustrazine on proteinuria, serumcreati-nine, urinary thromboxane A_2(TxA_2), metabolism of prostacyclinI_2(PGI_2)―6-keto-PGF_(1α), and renal pathological changes of SD rats with passive Hermannnephritis (PHN). Methods: The PHN model was induced by intravenous injection of rabbit anti-ratrenal tubular epithelial antigen (Tub―Ag) an-tiserum to SD rats. I. P. administration ofligustrazine to rats was given every 2 d for 1 to 5 weeks. The proteinuria, creatinine, TxA_2 and6-keto-PGF_(1α) were measured by sulfosaticylic acid, picric acid, and direct radioimmunoassayrespectively. The renal pathological changes were observed under light microscope, electronicmicroscope and by direct immunofluorescence staining rabbit and rat IgG. Results: The PHN ratstreated with ligustrazine had significantly less proteinuria, serum creatinine, urinary TxA_2 andpathological changes of kidney, and more urinary 6-keto-PGF_(1α) than those without administrationof ligustrazine. Conclusion: Ligustrazine decreases proteinuria, urinary TxA_2, and renal tissueinjury and increases urinary 6-keto-PGF_(1α). These data indicate that ligustrazine may modulatethe balance of TxA_2 and PG I_2 in rat PHN model and can be used for preventing and treatingmembranous glomerulonephritis.展开更多
基金This project was supported by Department of Veterans Affairs, Australia
文摘Objective To investigate the effect of dietary saturated fat (SFA) from animal sources on the urine excretion 11-dehydro thromboxane 62 (TXB2) and 6-keto prostaglandin F la (PGF la) in 27 healthy free-living male subjects aged 30 to 55 years. Methods It was a randomized crossover design. Each volunteer was randomly assigned to one of the two diets (high fat and low fat) for a period of 4 weeks, after which each subject resumed his usual diet for 2 weeks as a 'wash-out period', before being assigned to the other diet for an additional 4 weeks. Results Serum proportion of 20:4n-6 was 5% lower in the high fat (6.2% of total fatty acid) than in the low fat diet (6.5% of total fatty acid), which was associated with a significantly decreased ratio of the urinary excretion 11-dehydro TXB2 to 6-keto PGF lα (P<0.05). However, there was no significant fall in the absolute urinary excretion of 11-dehydro TXB2. Conclusions Diet rich in SFA from animal sources may influence TXA2 formation via effect on tissue proportion of 20:4n-6.
基金Supported by the National Science Council of Taiwan (grant no. NSC 92-2314-B-075-036) Taipei Veterans General Hospital (VGH-93-212)
文摘AIM: Vasodilatation and increased capillary permeability have been proposed to be involved in the pathogenesis of acute and chronic form of hepatic encephalopathy. Prostacyclin (PGI2) and nitric oxide (NO) are important contributors to hyperdynamic circulation in portal hypertensive states. Our previous study showed that chronic inhibition of NO had detrimental effects on the severity of encephalopathy in thioacetamide (TAA)-treated rats due to aggravation of liver damage. To date, there are no detailed data concerning the effects of PGI2 inhibition on the severity of hepatic encephalopathy during fulminant hepatic failure. METHODS: Male Sprague-Dawley rats weighing 300-350 g were used. Fulminant hepatic failure was induced by intraperitoneal injection of TAA (350 mg/(kg·d) for 3 d. Rats were divided into two groups to receive intraperitoneal injection of indomethacin (5 mg/(kg·d), n = 20) or normal saline (N/S, n = 20) for 5 d, starting 2 d before TAA administration. Severity of encephalopathy was assessed by the counts of motor activity measured with Opto-Varimex animal activity meter. Plasma tumor necrosis factor-α (TNF-α, an index of liver injury) and 6-keto-PGF1α (a metabolite of PGI2) levels were measured by enzyme-linked immunosorbent assay. RESULTS: As compared with N/S-treated rats, the mortality rate was significantly higher in rats receiving indomethacin (20% vs5%, P<0.01). Inhibition of PGI2 created detrimental effects on total movement counts (indomethacin vs N/S: 438±102 vs 841±145 counts/30 min, P<0.05). Rats treated with indomethacin had significant higher plasma levels of TNPa (indomethacin vs N/S: 22±5 vs 10±1 pg/mL, P<0.05) and lower plasma levels of 6-keto-PGF1α (P<0.001), but not total bilirubin or creatinine (P>0.05), as compared with rats treated with N/S. CONCLUSION: Chronic indomethacin administration has detrimental effects on the severity of encephalopathy in TAA-treated rats and this phenomenon may be attributed to the aggravation of liver injury. This study suggests that PGI2 may provide a protective role in the development of fulminant hepatic failure.
基金supported by a grant from the Shanghai Science and Technology Commission(10411965200)
文摘BACKGROUND： Prostacyclin has been shown to increase portal hypertension, but the mechanism is unclear. This study aimed to investigate whether the overproduction of prostacyclin（PGI2） in cirrhosis participates in the splanchnic vascular hyporesponsiveness to vasoconstrictors in cirrhotic rats.METHODS： Cirrhotic model was created by subcutaneous injection of 60% carbon tetrachloride（CCl4） corn oil solution combined with intermittent drinking of 5% alcohol, and agematched rats served as controls. The isolated third-generation mesenteric arterioles were used to examine the contractile response to norepinephrine. The changes in vascular diameter were observed under a microscope imaging device. The plasma concentration of 6-ketone-prostaglandin F1α（6-keto-PGF1α, a stable metabolite of PGI2） was tested via enzyme immunoassays and the expression of cyclooxygenase（COX） in mesenteric arteries was detected by Western blotting.RESULTS： In parallel with the increase of plasma 6-ketoPGF1α, the contractile response of arterioles from cirrhotic rats to norepinephrine was significantly impaired compared with that from controls. Inhibition of PGI2 or protein kinase A with indomethacin or Rp-adenosine 3＇, 5＇-cyclic monophosphothioate（Rp-cAMPS） partially reversed the vascular hypo-contractile response to norepinephrine in arterioles from cirrhotic rats.Indomethacin significantly decreased the plasma 6-keto-PGF1α.Furthermore, indomethacin significantly attenuated the effect of Rp-cAMPS on arterioles from cirrhotic rats. COX-1 expression was up-regulated in mesenteric arteries from cirrhotic rats,whereas COX-2 was not detectable in the mesenteric arteries from both cirrhotic and control rats.CONCLUSION： Enhanced COX-1 expression in cirrhotic rats resulted in elevated PGI2 production which partially contributedto the splanchnic vascular hyporesponsiveness to a vasoconstrictor via the protein kinase A pathway.
文摘AIM To evaluate the safety and efficacy of inhaled milrinone in acute respiratory distress syndrome(ARDS).METHODS Open-label prospective cross-over pilot study where fifteen adult patients with hypoxemic failure meeting standard ARDS criteria and monitored with a pulmonary artery catheter were recruited in an academic 24-bed medico-surgical intensive care unit. Random sequential administration of i NO(20 ppm) or nebulized epoprostenol(10 μg/mL) was done in all patients. Thereafter, inhaled milrinone(1 mg/mL) alone followed by inhaled milrinone in association with inhaled nitric oxide(iN O) was administered. A jet nebulization device synchronized with the mechanical ventilation was use to administrate the epoprostenol and the milrinone. Hemodynamic measurements and partial pressure of arterial oxygen(PaO_2) were recorded before and after each inhaled therapyadministration.RESULTS The majority of ARDS were of pulmonary cause(n = 13) and pneumonia(n = 7) was the leading underlying initial disease. Other pulmonary causes of ARDS were: Post cardiopulmonary bypass(n = 2), smoke inhalation injury(n = 1), thoracic trauma and pulmonary contusions(n = 2) and aspiration(n = 1). Two patients had an extra pulmonary cause of ARDS: A polytrauma patient and an intra-abdominal abscess Inhaled nitric oxide, epoprostenol, inhaled milrinone and the combination of inhaled milrinone and i NO had no impact on systemic hemodynamics. No significant adverse events related to study medications were observed. The median increase of PaO 2 from baseline was 8.8 mmH g [interquartile range(IQR) = 16.3], 6.0 mm Hg(IQR = 18.4), 6 mm Hg(IQR = 15.8) and 9.2 mm Hg(IQR = 20.2) respectively with i NO, epoprostenol, inhaled milrinone, and i NO added to milrinone. Only i NO and the combination of inhaled milrinone and i NO had a statistically significant effect on PaO 2. CONCLUSION When comparing the effects of inhaled NO, milrinone and epoprostenol, only NO significantly improved oxygenation. Inhaled milrinone appeared safe but failed to improve oxygenation in ARDS.
文摘The level of 6-keto-PGF1αand thromboxane B2(TXB2) in Plasma was determined with radioimmunoassay in 58 normal subjects and 92 Patients with various cancers(including lung,hepatic,gastric,esophageal and pancreatic carcinoma).The results showed that 6-keto-PGF1α.In plasma was 10.21±2.75 Pg/ml,and TXB2 146.03±37.31 Pg/ml in normal individuals,the ratio of 6-keto-PGF1α to TXB2 was 0.07;while in cancer Patients 6-keto-PGF1αwas 27.5±16.9 Pg/ml and TXB2 315.4±173.4 Pg/ml, the ratio of 6-keto-PGF1αto TXB2 was 0.08.The values of 6-keto-PGF1αand TXB2 in plasma of cancer patients were 2.69 folds and 2.16 folds higher than that of the two groups,respectively.The difference between the two groups was statistically significant(P<0.01).It indicates that the synthesis and release of PGI2 and TXA2 of cancer tissues increases greatly as compared to the normals.The study also revealed that the size of tumor,metastasis and histological classification had no obvious relation to PGs.
文摘In order to understand the relation between TXA2- PGI2 and secondary trauma and the effect of intra-arachnoid perfusion of dexamethasone and verapamil on alteration of TXA,-PGI, following spinal cord injury, TXB2 and 6-keto-PGFconcentration and pathological changes in injured site 1, 2, 4 and 6 h after injury were studied using a rabbit spinal cord injury model by Allen's weight drop method.
文摘The endothelial cells derived from human umbilical cord vein were treated with 200 μg/ml ligustrizini. The inhibrtory rate of platelet aggregation of the supernatant from the cultured endothelial cells treated with ligustrizini was 91% and that of superna
文摘Objective To study the releases of endothelin-1 and prostacyclin by endothelial cells in culture and to elucidate how these releases were influenced by smoke-treated low density lipoprotein. Methods We exposed en- dothelial cell cultures to native or oxidized low density lipoproteins,low density lipoproteins treated by dimethylsul- foxide-soluble particles from cigarette smoke or dimethylsulfoxide alones. The release of endothelin-1 was assayed by bioassay and the release of prostacyclin was assayed by radioimmunoassay. Results Low density lipoproteins treated by smoke significantly increased the release or endothelin-1 (P<0.025) and decreased the release of prostacyclin (P< 0.02) by endothelial cells in culture, contrast to native or dimethylsulfoxide-treated lipoproteins. Conclusion The main part or vasoconstrictor activity in conditioned medium from bovine aortic EC is endothelin-1.
文摘ONO-1301 has been developed as a novel long-acting prostacyclin agonist with thromboxane synthase inhibitory activity. In the present study, we investigated the cerebroprotective effect of ONO-1301 on post-ischemic injury induced by cerebral ischemia in rats. ONO-1301 (1 and 10 mg/kg) was administrated orally at reperfusion and then twice a day for 42 days. The cell damage induced by cerebral ischemia in the hippocampal CA1 was evaluated using both Nissl staining and proliferating cell nuclear antigen (PCNA) staining on the 42 days after cerebral ischemia. Activated astrocytes were evaluated using immunofluorescence staining with GFAP on the 42 days after cerebral ischemia. Spatial learning was assessed using a Morris water maze (MWM) task on the 56 days (i.e. after a 14 days washout period). ONO-1301- treated rats (1 and 10 mg/kg) significantly improved cell death in the hippocampal CA1, the number of PCNA-positive cells and astrocyte activation. The spatial learning of ONO-1301-treated rats compared with vehicle- treated rats in the MWM task. These results suggest that repeated treatment with oral ONO-1301 could prevent or limit post-ischemic brain damage. In particular, treatment with ONO-1301 within 7 days after ischemia is most effective to improve ischemic damage.
文摘Objective:To explore the effects of prostacyclin derivatives combined with valsartan therapy on the blood biochemical indexes in patients with early hypertensive nephropathy.Methods: A total of 110 patients with hypertensive nephropathy who were treated in the hospital between December 2014 and March 2017 were divided into control group (n=55) and experimental group (n=55) by random number table method. Control group received valsartan therapy, and experimental group received prostacyclin derivatives combined with valsartan therapy, which lasted for 20 weeks. The differences in the contents of renal function indexes, urinary protein indexes and endothelial injury markers were compared between the two groups before and after treatment.Results: Before treatment, the differences in the contents of renal function indexes, urinary protein indexes and endothelial injury markers were not statistically significant between the two groups. After 20 weeks of treatment, renal function indexes SCr, BUN, UA and CysC levels in peripheral blood of experimental group were lower than those of control group;urinary protein indexes ALB,β2-MG andα1-MG contents were lower than those of control group;endothelial injury markers ET-1 and E-selectin contents in peripheral blood were lower than those of control group whereas NO and CGRP contents were higher than those of control group.Conclusion: Prostacyclin derivatives combined with valsartan therapy can effectively optimize the renal function, reduce the urinary protein and alleviate the vascular endothelial injury in patients with early hypertensive nephropathy and improve the overall therapeutic effect.
文摘Objective To investigate the interaction and c linical significance of changes in p lasma endothelin-1(ET-1)and prostacyclin(PGI 2 )concentrations in patients with isc hemic cerebral infarction.Methods Plasma ET-1and 6-keto-PGF 1 α(resistant metabolite of PGI 2 )concentrations were measured in 37p atients(study group)with ischemic cerebral infarction a nd 34healthy volunteers(control group)by ra-dioimmunoassay.Results Plasma ET-1concentrations in patie nts of study group were markedly higher than that of control group(P <0.01)and 6-keto-PGF 1 αconcentrations in patients of study group were significantly lower than that of control subjects(P <0.01).Plasma ET-1concentrations in control subjects were positively correlated with 6-k eto-PGF 1 αconcentrations and no correlation i n the study group.Conclusion Both ET-1and PGI 2 are participated in patho-physiolo gic process of ischemic cerebral inf arction.ET-1is a virulence factor a nd may play a deleterious role in ischemic cerebral infarction,PGI 2 is a conservancy factor and endogenetic antagonist of ET-1.It may provid e useful therapy parameter to find out ectogenesis PGI 2 or analog for treating the patients with ischemic cerebral infarction wi th reason.
文摘Abstract Objective To evaluate the role of increased portal pressure and portosystemic shunting in elevated level of prostacyclin (PGI 2) in portal hypertension. Methods Thirty six male Sprague Dawley rats were divided into four groups: prehepatic portal hypertension (PHPH, 8 rats), intrahepatic portal hypertension (IHPH, 9), end to side portacaval shunt (PCS, 8), and sham operated controls (SO, 11). Two weeks after surgery, free portal pressure (FPP) was measured; systemic and splanchnic hemodynamics was studied by radioactive microsphere technique and blood sample from the femoral artery was obtained to measure the level of plasma 6 keto PGF 1 α with radio immunoassay. Results The FPP (mmHg) in IHPH, PHPH, PCS and SO rats was 13.10±1.02, 12.10±1.52, 3.0±0.82 and 6.86±0.69, respectively. The value of FPP was significantly increased in IHPH, PHPH rats and significantly decreased in PCS rats when compared to SO rats. Cardiac index (CI) and portal venous inflow (PVI) were in the order of PCS>PHPH>IHPH>SO rats. Portosystemic shunting (PSS) in PCS, PHPH, IHPH was 99.7±0.29%, 76.02±20.62% and 30.34±10.18%, respectively. The concentrations of plasma 6 keto PGF 1α (ng/ml) in PHPH, IHPH, PCS and SO rats were 6.93±2.43, 5.09±2.27, 2.36±1.01 and 1.56±0.61, respectively. The concentrations of plasma PGI 2 in PHPH, IHPH and PCS rats were significantly higher than those in SO rats. Furthermore, the concentrations of plasma PGI 2 in PHPH and IHPH rats were also significantly higher than those in PCS rats. Moreover, a closed positive correlation existed between plasma PGI 2 and FPP (r=0.67, P<0.001). Conclusions The results of the present study suggest that the elevated PGI 2 in portal hypertension is mainly due to the overproduction of PGI 2 in vascular epithelium cells induced by increased portal pressure, whereas portosystemic shunting and liver dysfunction play a secondary role. In addition, the results of this study do not support that PGI 2 mediated the hyperhemodynamics in portal hypertension.
文摘Objective To evaluate the effects of nitric oxide inhibitor on prostacyclin (PGI 2) biosynthesis and the role of PGI 2 in hyperhemodynamics of portal hypertension. Methods Sprague Dawley rats were divided into four groups: intrahepatic portal hypertension (IHPH) by injection of CCl 4, prehepatic portal hypertension (PHPH) by stenosis of the portal vein, end to side portacaval shunt (PCS), and sham operated controls (SO). Animals of each group were subdivided into 2 groups: systemic administration of nitric oxide inhibitor L NMMA and vehicle. The radioactive microsphere method was used for hemodynamic study. The level of plasma PGI 2 (6 keto PGF 1α ) was measured by radioimmunoassay.Results The characteristics of hyperdynamic circulatory state including increased cardiac output and splanchnic blood flow, decreased mean arterial blood pressure, total peripheral vascular resistance, and splanchnic vascular resistance were observed in IHPH, PHPH and PCS rats. The magnitude of hyperhemodynamics was in the order of PCS>PHPH>IHPH rats. The hyperdynamic circulatory state in IHPH, PHPH and PCS rats could be effectively reversed by L NMMA to the baseline values of hemodynamics in SO rats. The baseline concentrations of plasma 6 keto PGF 1α (ng/ml) in PHPH, IHPH, PCS, and SO rats were 6.93±2.43, 5.09±2.27, 2.36 ±1.01 and 1.56±0.61, respectively. The concentrations of plasma 6 Keto PGF 1α in PHPH,IHPH and PCS rats were significantly higher than those in SO rats. Moreover, the concentrations were significantly higher in PHPH and IHPH rats than in PCS rats (P<0.05). After administration of L NMMA, the concentrations of plasma 6 Keto PGF 1α (ng/ml) in PHPH, IHPH, PCS and SO rats were 7.69±2.98, 5.68 ±2.66, 5.50±0.79, 5.02±2.86, respectively. As compared to the baseline value, the concentrations of 6 keto PGF 1α rats were slightly increased in IHPH, PHPH rats (P>0.05), but significantly increased in PCS and SO rats (P<0.05).Conclusions In this study, the hyperdynamic circulatory state in portal hypertensive rats and portacaval shunt rats was completely reversed by L NNMA to normal, but the level of 6 keto PGF 1α was still elevated. The results indicate that PGI 2 is not involved in hyperhemodynamics of portal hypertension.
基金Program of the National Natural Science Foundation of China,Grant/Award Number:81700045,81870042 and 82200065The Department Development Fund of Shanghai Pulmonary Hospital,Grant/Award Number:201906-0314+2 种基金The Program of Shanghai Pulmonary Hospital,Grant/Award Number:FKLY20011The Three-year Action Plan to Promote Clinical Skills and Clinical Innovation in Municipal Hospitals,Grant/Award Number:SHDC2020CR4021Young Talent Program of Shanghai Municipal Health Commission,Grant/Award Number:2022YQ070。
文摘Background:The maintenance dosage of selexipag is categorized as low,medium or high.In order to assess the efficacy and safety of different dosages of selexipag for the risk stratification of pulmonary arterial hypertension(PAH),we performed a sys-tematic review and meta-analysis.Methods:Studies assessing PAH risk stratification indices,such as the World Health Organization functional class(WHO-FC),six-minute walk distance(6MWD),N-terminal pro-B-type natriuretic peptide(NT-proBNP)level,right atrial pressure(RAP),cardiac index(CI)and mixed venous oxygen saturation(SvO2),were included.Results:Thirteen studies were included.Selexipag led to improvements in the 6MWD(MD:24.20 m,95%CI:10.74-37.67),NT-proBNP(SMD:-0.41,95%CI:-0.79-0.04),CI(MD:0.47 L/min/m^(2),95%CI:0.17-0.77)and WHO-FC(OR:0.564,95%CI:0.457-0.697).Subgroup analysis demonstrated that all three dosages improved the 6MWD.A moderate dosage led to improvements in the CI(MD:0.30 L/min/m^(2),95%CI:0.15-0.46)and WHO-FC(OR:0.589,95%CI:0.376-0.922).Within 6 months of treatment,only the WHO-FC and CI were significantly improved(OR:0.614,95%CI:0.380-0.993;MD:0.30 L/min/m^(2),95%CI:0.16-0.45,respectively).More than 6 months of treatment significantly improved the 6MWD,WHO-FC and NT-proBNP(MD:40.87 m,95%CI:10.97-70.77;OR:0.557,95%CI:0.440-0.705;SMD:-0.61,95%CI:-1.17-0.05,respectively).Conclusions:Low,medium,and high dosages of selexipag all exhibited good effects.When treatment lasted for more than 6 months,selexipag exerted obvious effects,even in the low-dosage group.This finding is important for guiding individualized treatments.
文摘目的研究绝经后骨质疏松症患者血管舒缩活性因子前列环素(prostacyclin I2,PGI_(2))、血栓素A2(thromboxane A2,TXA_(2))在骨代谢因子Ⅰ型前胶原氨基端前肽(aminoterminal propeptide of typeⅠprocollagen,PINP)、Ⅰ型胶原交联羧基端肽(carboxyterminal cross-linked telopeptide of typeⅠcollagen,ICTP)中的作用及其相互影响的可能机制。方法便利抽样法选取2023年1月—2023年9月厦门大学附属第一医院康复医学科收治的180例女性患者为研究对象,并分为骨质疏松症组(n=90)和正常对照组(n=90)。比较2组患者血清PGI_(2)、TXA_(2)、PINP、ICTP水平,并分析PGI_(2)、TXA_(2)与PINP、ICTP的相关性。结果骨质疏松症组PGI_(2)水平为(96.00±8.25)ng/L,低于正常对照组的(158.21±8.68)ng/L,差异有统计学意义(P<0.05);骨质疏松症组TXA_(2)水平为(143.14±6.63)ng/L,高于正常对照组的(102.33±7.09)ng/L,差异有统计学意义(P<0.05)。骨质疏松症组PINP水平为(42.33±2.18)μg/L,低于正常对照组(75.38±1.86)μg/L,差异有统计学意义(P<0.05);骨质疏松症组ICTP水平为(7.13±0.41)μg/L,高于正常对照组的(3.91±0.30)μg/L,差异有统计学意义(P<0.05)。Pearson相关性分析结果显示,PGI_(2)水平与PINP水平呈正相关(r=0.982,P<0.001),而与ICTP水平呈负相关(r=-0.898,P<0.001);TXA_(2)与ICTP呈正相关(r=0.965,P<0.001),而与PINP呈负相关(r=-0.919,P<0.001)。结论骨质疏松症患者血管舒张活性因子PGI_(2)表达水平下调、血管收缩活性因子TXA_(2)表达水平上调与骨代谢活性因子PINP下降、ICTP升高紧密相关,血管活性因子中舒血管成分下调、缩血管成分升高引起局部骨代谢血管循环状态发生循环障碍的病理变化与骨质疏松症的发生具有一定的相关性。
文摘Objective: To explore the effects of ligustrazine on proteinuria, serumcreati-nine, urinary thromboxane A_2(TxA_2), metabolism of prostacyclinI_2(PGI_2)―6-keto-PGF_(1α), and renal pathological changes of SD rats with passive Hermannnephritis (PHN). Methods: The PHN model was induced by intravenous injection of rabbit anti-ratrenal tubular epithelial antigen (Tub―Ag) an-tiserum to SD rats. I. P. administration ofligustrazine to rats was given every 2 d for 1 to 5 weeks. The proteinuria, creatinine, TxA_2 and6-keto-PGF_(1α) were measured by sulfosaticylic acid, picric acid, and direct radioimmunoassayrespectively. The renal pathological changes were observed under light microscope, electronicmicroscope and by direct immunofluorescence staining rabbit and rat IgG. Results: The PHN ratstreated with ligustrazine had significantly less proteinuria, serum creatinine, urinary TxA_2 andpathological changes of kidney, and more urinary 6-keto-PGF_(1α) than those without administrationof ligustrazine. Conclusion: Ligustrazine decreases proteinuria, urinary TxA_2, and renal tissueinjury and increases urinary 6-keto-PGF_(1α). These data indicate that ligustrazine may modulatethe balance of TxA_2 and PG I_2 in rat PHN model and can be used for preventing and treatingmembranous glomerulonephritis.
