scholarly journals Spironolactone Inhibits Cardiomyocyte Hypertrophy by Regulating the Ca2+/Calcineurin/p-NFATc3 Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Xin Wang ◽  
Wenting Zhang ◽  
Jingtao Na ◽  
Yanping Huo ◽  
Yacheng Wang ◽  
...  

This study aimed to investigate the protective effect and molecular mechanism of spironolactone in isoproterenol-induced cardiomyocyte hypertrophy. In this study, primary cardiomyocytes were extracted from the heart of neonatal rats. After stable culture, they were processed with isoproterenol alone or isoproterenol (10 μM) combined with different doses (low dose of 10 μM and high dose of 50 μM), and the cellular activity was determined by MTT experiment. The volume of cells was measured with an inverted microscope and CIAS-1000 cell image analysis system. The mRNA expression levels of ANP and BNP in cells were explored by RT-qPCR. The levels of ANP and BNP proteins and NFATc3 phosphorylation in the nucleus were detected by western blot. The extracellular Ca2+ concentration and CaN activity were measured by colorimetry with the kit. Isoproterenol significantly enlarged the volume of cardiomyocytes ( p < 0.001 ), upregulated mRNA and expression levels of ANP and BNP proteins ( p < 0.001 ), increased extracellular Ca2+ concentration and CaN activity ( p < 0.001 ), and upregulated NFATc3 phosphorylation in the nucleus ( p < 0.001 ). The volume of cells treated with isoproterenol combined with different doses of spironolactone significantly decreased compared with those treated with isoproterenol alone ( p < 0.001 ). mRNA and expression levels of ANP and BNP proteins downregulated significantly ( p < 0.001 ). The extracellular Ca2+ ( p < 0.01 ) concentration and CaN activity ( p < 0.001 ) decreased significantly, and NFATc3 phosphorylation in the nucleus downregulated significantly ( p < 0.001 ). There was no significant difference in cell volume ( p = 0.999 ), ANP and BNP mRNA ( p = 0.695 ), expression levels of proteins, CaN activity (0.154), and NFATc3 phosphorylation in the nucleus between the cells treated with isoproterenol combined with high-dose spironolactone and those in the control group. In conclusion, spironolactone can reverse isoproterenol-induced cardiomyocyte hypertrophy by inhibiting the Ca2+/CaN/NFATc3 pathway.

2021 ◽  
Vol 36 (4) ◽  
pp. 263-272
Author(s):  
Areej A. Mohammed ◽  
Aisha F. Bonaama ◽  
Souad A. M. Moftah ◽  
Ameerah T. Ramadhan ◽  
Abdulsalam M. A. Bolhaj ◽  
...  

This study was carried out to investigate the effect of two different doses of oxytocin on weight. Adult male rabbits (15) were weighed and provided with food twice daily for 3 weeks to determine the amount of food consumed daily and the time spent feeding by each rabbit.  After 3 weeks the rabbits were weighed and divided randomly into 3groups: the control group, the low dose group, and the high dose group. The animals were injected daily for 3 weeks. During that time the amount of food consumed and the time spent feeding in both periods were determined. After the end of the treatment period the rabbits were weighed, and sacrificed. The results of this study showed that before treatment the rabbits consumed more food in the evening period than they did in the afternoon period. The mean time spent feeding in the evening period was slightly higher than that spent in the afternoon period; however, this difference was not statistically significant. After treatment, there was still significant difference between the means of the consumed food in the afternoon and the evening period for the control group. The mean amounts of food consumed in both periods by the treated groups were slightly reduced, but this reduction was not statistically significant. Furthermore, the mean time spent feeding in the evening period was slightly higher than that of the afternoon period for the 3 groups; however, these differences were not significant. The mean weight of the control group was slightly increased after treatment with the hormone; and the mean weights of the treated groups were slightly reduced after treatment. However, changes in body weighs were not statistically significant.


2020 ◽  
Vol 23 (1) ◽  
pp. 89-101 ◽  
Author(s):  
A. Samimi ◽  
E. Sakhaee ◽  
F. Iranmanesh

This experimental, prospective, randomised, and blinded study aimed to perform comparative evaluation of electrocardiographic (ECG) effects of different doses xylazine and medetomidine in dromedary calves after intravenous (IV) administration. A total of twenty five clinically and paraclinically healthy male dromedary calves aged 15±2 weeks and weighing 95±5.5 kg were assigned randomly to five different groups (four experimental and one control). Groups XL and XH received a low (0.2 mg kg-1) and high (0.4 mg kg-1) dose of xylazine hydrochloride and groups ML and MH received a low (10 µg kg-1) and high (20 µg kg-1) dose of medetomidine hydrochloride once, IV. Finally, the control group (C) received normal saline in the same manner. ECG indices were evaluated on post treatment 0, 5, 10, 15, 30, 60, 90, 120 min, and 24 h. There was no significant difference in heart rate (HR) in all experimental groups at T90. HR was significantly lower after high doses than after low doses of medetomidine and xylazine at T120. HR was significantly lower in XH than in other groups of study at T24. At T90 QRS amplitude in XH was statistically lower than in control and XL groups. Analysis of P wave duration revealed that in MH and XH it was significantly longer than in ML, XL and control at T5. Duration of P wave in control group was significantly shorter than in all experimental groups from T10 to T90. RR interval duration was significantly shorter at T5 and T10 in control group compared to experimental groups. At T120, RR interval duration in MH and XH was considerably longer than that in ML, XL, and control. Compared with control group, cardiac arrhythmia scores were significantly lower than in all experimental groups from T5 to T60. At T90 and T120 in MH and XH, cardiac arrhythmia scores were significantly higher than those of XL, ML, and control. According to our findings, using low dose of medetomidine (10 µg kg-1) and xylazine (0.2 mg kg-1) was suggested in comparison with high dose of medetomidine (20 µg kg-1) and xylazine (0.4 mg kg-1) in dromedary calves with cardiac diseases in the field.


Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1382-1382
Author(s):  
Anna Hecht ◽  
Daniel Nowak ◽  
Florian Nolte ◽  
Verena Nowak ◽  
Julia Oblaender ◽  
...  

Abstract Introduction: Insulin-like growth factor binding proteins (IGFBP) are carriers of insulin-like growth factors (IGFs). They prolong their half-life and modulate their availability and activity. The IGF-signaling system has been shown to have an important role in various solid cancers and hematologic malignancies. High levels of IGFBP2 and IGFBP7 have been associated with chemoresistance, relapse and inferior survival in different leukemias. Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML), which has been reported to have increased expression of IGFBP2. However, there is no data on its impact on prognosis. In addition, no data exist on IGFBP7 in APL. The aim of this study was to elucidate the influence on prognosis of both candidate genes in APL patients. Methods: Expression levels of IGFBP2 und IGFBP7 were retrospectively analysed in bone marrow (BM) samples at the time of initial diagnosis from 69 APL patients (42 female, 27 male) after informed consent. Median age of patients was 46 years (range 19 to 82 years). All patients were diagnosed and treated in the German AML Cooperative Group (AMLCG) studies. Treatment consisted of simultaneous ATRA and double induction chemotherapy including high dose ara-C, one cycle of consolidation chemotherapy and 3 years monthly maintenance chemotherapy. In patients older than 60 years, the second induction cycle was at the discretion of the treating physician. Three patients (4%) received an induction of ATRA and an anthracycline without ara-C. BM samples of 22 healthy volunteers served as a control group. Multiplex reverse transcriptase quantitative real-time PCR (qRT-PCR) was performed on a LightCycler® 480 (Roche, Mannheim, Germany) PCR system. Glucose-6-phosphat isomerase was used as a housekeeping gene. For quantification of relative expression values a modified delta-delta CT calculation model according to Pfaffl was used after determination of PCR efficiencies. cDNA from the cell line K562 served as a calibrator in each run. All reactions were performed in triplicates. IGFBP2 expression groups were defined as follows: Patients with IGFBP2 expression below or equal the 25th percentile (IGFBP2low) were compared to patients with higher IGFBP2 expression (IGFBP2high). Overall survival (OS), relapse free survival (RFS) and the cumulative incidence of relapse (CIR) were calculated using the Kaplan-Meier method and a log-rank test was used to compare differences between the groups (p < 0.05). Results: Expression levels of IGFBP2 did not differ between APL patients and healthy controls. However, there was a significantly higher relapse rate in APL patients with low IGFBP2 expression (CIR: 25% in the IGFBP2low group vs. 5% in the IGFBP2high group; p=0.04). Accordingly, RFS of patients in the IGFBP2low group was also inferior (41% vs. 81% in the IGFBP2high group; p=0.0002; Fig. 1). The OS of patients who had responded to induction therapy was also influenced by IGFBP2 expression (OS of responders: 61% for IGFBP2low vs. 83% for IGFBP2high; p=0.02). However, there was no significant difference in the analysis of OS of all patients including patients who suffered early death. In contrast to these findings, IGFBP7 was expressed significantly lower in APL patients compared to healthy controls (p<0.0001) but there was no association with outcome of APL patients. Conclusion: Of the two analysed IGFBP family members only IGFBP2 showed impact on the prognosis of APL patients. Remarkably, IGFBP2 was not overexpressed compared to healthy controls in our patient cohort. The reason might be that whole BM samples of healthy controls were used instead of subpopulations. Still, among the APL patients cohort its expression showed a strong influence on prognosis especially on relapse rate and RFS. To find low expression as a negative prognostic marker is surprising as for leukemias only high expression has been reported as a negative factor. However, IGFBP2 has been proposed to suppress tumor development through binding IGFs and preventing IGF-receptor driven tumorigenesis. This is supported by the fact that the IGFBP2 promotor is hypermethylated in various types of cancer. In summary, we identified low IGFBP2 expression as a novel prognostic marker for APL. Further investigations are warranted to clarify its possible role in leukemia. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.


Author(s):  
Meilinah Hidayat ◽  
Sijani Prahastuti ◽  
Estherolita Dewi ◽  
Dewi Safitri ◽  
Siti Farah Rahmawati ◽  
...  

ABSTRACTObjective: As an antiobesity therapy, combination extracts of Detam 1 soybean and Jati Belanda will be consumed for a long time; therefore, theirtoxicities to the liver need to be investigated. To determine the effect of subchronic toxicity test of combination of ethanol extract of Detam 1 soybean(EEDS) and ethanol extract of Jati Belanda (EEJB) on liver function with parameters: Alanine transaminase (ALT), macroscopic, and histopathologicalof liver.Methods: This study was conducted on 120 Wistar rats (60 males and 60 females), 90 days (treatment group) and 120 days (satellite group). Ratswere divided into six treatment groups (3 test materials, 1 control, and 2 satellites); each group included 10 males and 10 females.Results: ALT levels of treatment groups (low dose, medium, and high), both males and females were lower than the control group (p<0.05). Thetreatment groups demonstrated a good effects effect on liver function. Liver weight of all groups showed no significant difference compared with thecontrol group (p>0.05). Results of histopathological score interpretation of male and female liver rats of low dose groups were not disturbed; middledose groups were slightly disturbed and high dose groups were damaged. Satellite high doses of male groups were disrupted, while female groupswere not.Conclusion: The combination of EEDS and EEJB has a good effect on liver function, did not lead to change organ weight and at low doses did not causerenal histopathology damage in rats after 90 days administration.Keywords: Combination of soybean Jati Belanda, Toxicity subchronic test, Function, Weight, Histopathology, Liver.


2007 ◽  
Vol 7 (3) ◽  
pp. 212-217 ◽  
Author(s):  
Sabaheta Hasić ◽  
Radivoj Jadrić ◽  
Emina Kiseljaković ◽  
Zakira Mornjaković ◽  
Mira Winterhalter-Jadrić

In our investigation, we used short-time model of myocardial infarction of rats induced by high dose of isoproterenol (ISP). We investigated cardiac troponin T blood level (cTnT) and histological characteristics of rat myocardium. ISP, single, intraperitoneal dose 250 mg/kg was given to male, adult, Wistar rats (n=12). Rats were distributed depending on their body weight in subgroups: ISP I (BW 260-280g) and ISP II (BW 250-400g). Control group (n=9) was treated with intraperitoneal dose of 0,95% NaCl. Cardiac TnT was measured by electrochemiluminiscence (ECLA) sandwich immunoassay in rat serum 4 hours after ISP application. Rats’ hearts were dissected and examined by qualitative histological method (HE). Statistical significance was set at 0,05. There was significant difference in cTnT of ISP II (p=0,0001) vs. control and ISP I (p<0,05) vs. control. Significant difference was beetween ISP I and ISP II subgroups (p<0.001). The accent of histological changes of myocardium was on nuclei of cell. Cells showed acydophilic changes and nuclei disappearance as signs of coagulative necrosis development. Extensivity of histological changes were different beetween ISP I and ISP II subgroup. Used dose of ISP induced development of myocardial necrosis in rats. Suben-docardial portion of myocardium was more vulnerability than subepicardial portion. Rats of ISP II had more extensive histological changes than these in ISP I. Administered doses of ISP enabled cTnT utilization as a marker of myocardial necrosis.


2020 ◽  
Author(s):  
fujuan qiu ◽  
Chen Yong ◽  
Qiu Fujuan ◽  
Zhao Xiaofeng ◽  
Xiao Changhong

Abstract Background To determine whether any differences of AIM2 inflammasome expression levels between rheumatoid arthritis (RA) and osteoarthritis (OA) and investigate the effects of AIM2 when transferred into RA fibroblast-like synoviocytes (RA-FLS).Methods Serum AIM2 levels between OA and RA patients were compared by ELISA. Different expression levels of AIM2, ASC, Caspase-1 and IL-1β between RA and OA synovium were semi-quantified by RT-qPCR and immunohistochemical (IHC) staining. IHC staining were recorded by H scores, and determine the correlation with ESR and CRP levels of RA patients. SiRNA AIM2 was transferred to RA-FLS and observe its effects on proliferation and migration by MTT assay and transwell test respectively.Results In RA sera, no significant difference was observed between OA and RA patients. However, in affected knee synovium, AIM2, ASC, Caspase-1 and IL-1β were expressed higher in RA than that of OA. Plus, H score of AIM2, ASC, and IL-1β were positively correlated to ESR and CRP levels in RA patients. After transferred AIM2 siRNA to FLS and incubation for 48 hours, the proliferation of FLS were significantly inhibited, and the apoptosis rate were significantly increased compared to FLS in control group. However, no effect on migration was detected.Conclusions AIM2 participated in the proliferation of FLS, and might be a potential target for therapy.


2019 ◽  
Vol 17 ◽  
pp. 205873921984406
Author(s):  
Tao Zheng ◽  
Qingyun Zhou ◽  
Zhe Chen ◽  
Qinning Wang

The study aimed to study the correlation between expression levels of interleukin-37 (IL-37), granulocyte macrophage colony-stimulating factor (GM-CSF), and C-reactive protein (CRP) in peripheral blood and the status of atherosclerosis (AS) and plaque stability and to confirm the clinical significance of these inflammatory factors in the pathogenesis of AS. A total of 64 AS patients (case group) were selected and divided into unstable plaque group (group A, 28 cases) and stable plaque group (group B, 36 cases) according to the color ultrasonography results of arterial vessels. At the same time, 30 healthy subjects were classified into the control group. General information of the enrolled subjects was collected, including levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), CRP, and homocysteine (Hcy). The expression levels of IL-37 and GM-CSF in the serum of peripheral blood samples collected from these subjects were measured by enzyme-linked immunosorbent assay (ELISA). There was no significant difference between the case group and the control group in the levels of TC, TG, HDL, and LDL ( P > 0.05). However, the expression level of Hcy in the case group was significantly higher than that in the control group ( P < 0.05). Compared with the control group, the expression levels of IL-37, GM-CSF, and CRP in the case group were significantly increased ( P < 0.05). In addition, compared with group B, the expression level of GM-CSF in group A was significantly increased ( P < 0.05), while no significant difference was detected between group A and group B in the expression levels of IL-37 and CRP ( P > 0.05). In conclusion, inflammatory factors IL-37, GM-CSF, CRP, and Hcy were all involved in the pathogenesis of AS, and the increased levels of GM-CSF were closely related to the progress of unstable plaques. These results may aid the early diagnosis/treatment of AS.


2019 ◽  
Vol 74 (2) ◽  
pp. 353-370 ◽  
Author(s):  
Li Tian ◽  
Weibin Qian ◽  
Qiuhai Qian ◽  
Wei Zhang ◽  
Xinrui Cai

Abstract Gingerol, a biologically active component in ginger, has shown antiemetic properties. Our study aimed to explore the underlying mechanisms of gingerol on protecting rats and minks from chemotherapy-induced nausea and vomiting. The preventive impact of gingerol was evaluated in the pica model of rats and the vomiting model of minks induced by cisplatin at every 6 h continuously for a duration of 72 h. Animals were arbitrarily separated into blank control group, simple gingerol control group, cisplatin control group, cisplatin + metoclopramide group, cisplatin + three different doses gingerol group (low-dose; middle-dose; high-dose). The area postrema as well as ileum damage were assessed using H&E stain. The levels of 5-TH, 5-HT3 receptor, TPH, SERT, SP, NK1 receptor, PPT, NEP, DA, D2R, TH, and DAT were determined using immunohistochemistry or qRT-PCR in rats and minks. All indicators were measured in the area postrema along with ileum. The kaolin intake by rats and the incidence of CINV of minks were significantly decreased after pretreatment with gingerol in a dosage-dependent way for the duration of 0–24-h and 24–72-h. Gingerol markedly decreased the levels of 5-TH, 5-HT3 receptor, TPH, SP, NK1 receptor, PPT, DA, D2R, TH, alleviated area postrema as well as ileum damage, and increased the accumulation of SERT, NEP, DAT in the area postrema along with ileum of rats and minks. Gingerol alleviates cisplatin-induced kaolin intake of rats and emesis of minks possibly by regulating central and peripheral 5-HT system, SP system and DA system. Graphic abstract


2018 ◽  
Vol 52 (4) ◽  
pp. 185-191
Author(s):  
Tomomi Nobashi ◽  
Tsuneo Saga ◽  
Yuji Nakamoto ◽  
Yoichi Shimizu ◽  
Sho Koyasu ◽  
...  

AbstractObjective. This study investigated whether the metformin (Met)-induced enhanced intestinal uptake of 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) is reduced by loperamide, a long-acting anti-diarrheal agent. Methods. Mean18F-FDG uptake in the mouse small intestine and colon with Met exposure was compared with that in control mice. In the Met group, high-dose (1.0 mg/kg body weight) and low-dose (0.1 mg/kg body weight) loperamide were introduced, and18F-FDG uptake in the small intestine and colon was compared with that of control mice administered high-dose loperamide. The percent injected dose of18F-FDG per gram of tissue (%ID/g) in the extracted tissues was then determined. Results.18F-FDG uptake increased significantly in the small intestine (0.64±0.06 vs. 1.01±0.15, p=0.040) and, especially, the colon (0.46±0.13 vs. 2.16±0.51, p<0.001) after Met exposure. Neither high-dose nor low-dose loperamide significantly reduced18F-FDG uptake in the small intestine (0.82±0.31 vs. 0.84±0.22, p=0.93 and 0.78±0.25 vs. 0.70±0.15, p=0.13, respectively) or colon (2.13±0.41 vs. 1.67±0.55, p=0.063 and 1.77±0.39 vs. 1.80±0.25, p=0.56, respectively). The colonic %ID/g was significantly higher in Met groups irrespective of loperamide introduction than in control group, whereas the significant difference in the small intestine was observed only between Met and control groups. Conclusion. Metformin increased18F-FDG uptake in intestines especially in colon. Loperamide administration partially, but not sufficiently, suppresses the Met-induced increased colonic uptake of18F-FDG.


2003 ◽  
Vol 14 (1) ◽  
pp. 12-15 ◽  
Author(s):  
Natasha Magro-Érnica ◽  
Osvaldo Magro-Filho ◽  
Idelmo Rangel-Garcia

The aim of this paper was to evaluate if the placement of microfibrillar collagen hemostat (MCH) into a dental socket interfered with healing. General anesthesia was administered to 30 adult male Albinus Wistar rats and the maxillary right central incisor was extracted. In the control group after each tooth was extracted, the socket was sutured. In the MCH group after each tooth was extracted, MCH was placed into the socket before suturing. Postoperatively, 5 animals were sacrificed from each group at 7, 21 and 28 days. The right maxilla was removed from each animal and histologic slides were stained with Masson's trichromic and hematoxylin and eosin. Quantitative and qualitative analyses were done. The percentage of bone area in the dental socket was quantified using the Image Lab 98 image analysis system. The bone area formation for the control and MCH groups was: 8.1% and 3.3% at 7 days, 34.4% and 33% at 21 days and 41% and 41.3% at 28 days, respectively. We concluded that MCH interferes with the beginning of dental socket healing but does not interfere with the final healing of the dental socket.


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