Adriamycin-treated Group Research Articles

TRNA-Derived Fragments in Podocytes with Adriamycin-Induced Injury Reveal the Potential Mechanism of Idiopathic Nephrotic Syndrome.

Idiopathic nephrotic syndrome (INS) is a disease involving injury to podocytes in the glomerular filtration barrier, and its specific causes have not been elucidated. Transfer RNA-derived fragments (tRFs), products of precise tRNA cleavage, have been indicated to play critical roles in various diseases. Currently, there is no relevant research on the role of tRFs in INS. This study intends to explore the changes in and importance of tRFs during podocyte injury in vitro and to further analyze the potential mechanism of INS. Differentially expressed tRFs in the adriamycin-treated group were identified by high-throughput sequencing and further verified by quantitative RT-PCR. In total, 203 tRFs with significant differential expression were identified, namely, 102 upregulated tRFs and 101 downregulated tRFs (q < 0.05, ∣log2FC | ≥2). In particular, AS-tDR-008924, AS-tDR-011690, tDR-003634, AS-tDR-013354, tDR-011031, AS-tDR-001008, and AS-tDR-007319 were predicted to be involved in podocyte injury by targeting the Gpr, Wnt, Rac1, and other genes. Furthermore, gene ontology analysis showed that these differential tRFs were strongly associated with podocyte injury processes such as protein binding, cell adhesion, synapses, the actin cytoskeleton, and insulin-activate receptor activity. KEGG pathway analysis predicted that they participated in the PI3K-Akt signaling pathway, Wnt signaling pathway, and Ras signaling pathway. It was reported that these pathways contribute to podocyte injury. In conclusion, our study revealed that changes in the expression levels of tRFs might be involved in INS. Seven of the differentially expressed tRFs might play important roles in the process of podocyte injury and are worthy of further study.

Therapeutic efficacy of bone marrow derived mesenchymal stromal cells versus losartan on adriamycin-induced renal cortical injury in adult albino rats

BackgroundRenal disease is a major health problem. Recent studies have reported the efficacy of stem cell therapy in nephropathy animal models. Aim of the workThis study was designed to investigate the therapeutic effectiveness of bone marrow–derived mesenchymal stromal cells (MSCs) versus losartan in the treatment of renal alterations induced by adriamycin (ADR). Materials and methodsThirty-five adult male albino rats were divided into four groups. Group I was the control group. Group II (adriamycin-treated group),which included ten rats that were injected with a single dose of adriamycin (15 mg/kg) intraperitoneally, was subdivided into subgroup IIa and IIb and they were sacrificed 1 week and 5 weeks after adriamycin injection, respectively. Group III was the adriamycin + losartan–treated group and 1 week after adriamycin injection five rats received 10 mg/kg of losartan orally and daily for 4 weeks. Group IV was the adriamycin + MSC–treated group); five rats were injected with adriamycin as group II then supplied with MSCs at a dose of 1 × 106 cells suspended in 0.5 mL of phosphate-buffered saline (PBS) per rat in the tail vein 1 week after adriamycin injection. Rats of this group were sacrificed 4 weeks after the stem cell injection. Blood urea nitrogen and serum creatinine were measured. Samples from renal cortex were processed for light and electron microscope examination. As regards light microscope, sections were stained with hematoxylin and eosin (H-E), periodic acid–Schiff (PAS), masson trichrome, proliferating cell nuclear antigen (PCNA) and Caspase-3 immunohistochemical stains. Morphometrical and statistical analyses were also conducted. ResultsExamination of adriamycin-treated group revealed deterioration of renal functions and various degrees of renal structural alterations as vacuolated cytoplasm, dark nuclei and detached epithelial lining. Administration of losartan partially improved ADR-induced kidney dysfunction, whereas MSCs denoted a more ameliorative role evidenced by structural and functional recovery. ConclusionMSCs have a relevant therapeutic potential against ADR-induced renal damage. MSCs may accomplish this role by decreasing caspase-3 expression and increasing proliferating cell nuclear antigen staining which influence the regeneration of the kidney.

Effects of adriamycin and candesartan on the collagen and elastin of the aorta in rats.

IntroductionIt has been reported that the chemotherapeutic agent, adriamycin, not only has an effect on the myocardium but also on the arteries. The aim of this study is to elucidate effects of adriamycin and an angiotensin receptor blocker, candesartan, on collagen and elastin of the aorta in rats.MethodsTwenty four male 8-week-old Wistar-Kyoto rats were divided into four groups: control (C) group, adriamycin-treated (AD) group, candesartan-treated (CA) group, and adriamycin- and candesartan-treated (AD + CA) group. Adriamycin of 2.5 mg/kg/wk was administered intraperitoneally one time per week for 6 weeks, and candesartan of 10 mg/kg/day was administered orally everyday for 6 weeks. After 6 weeks, the rats were sacrificed and the aortas were harvested. Hematoxylin-eosin staining, Verhoff’s elastic, and Goldner’s trichrome staining were performed for histopathologic analyses. Tunica media thickness, collagen, and elastic area fractions were measured quantitatively with a computerized digital image analyzer.ResultsTunica media thickness in the CA and AD + CA groups was significantly lesser than that in the C and AD groups, respectively. The AD and AD + CA groups had a tendency of lower elastin area fraction than the C and CA groups, respectively. Collagen area fraction in the AD + CA group was significantly lower than that in the AD group. There were no significant differences of collagen/elastin ratio between groups.ConclusionsThese findings suggest that adriamycin has a tendency of decreasing the quantity of elastin fibers and candesartan cannot mitigate the effects of adriamycin on elastin fibers.Electronic supplementary materialThe online version of this article (doi:10.1186/2056-5909-1-2) contains supplementary material, which is available to authorized users.

Adriamycin-induced autophagic cardiomyocyte death plays a pathogenic role in a rat model of heart failure

Background The mechanisms underlying heart failure induced by adriamycin are very complicated and still unclear. The aim of this study was to investigate whether autophagy was involved in the progression of heart failure induced by adriamycin, so that we can develop a novel treatment strategy for heart failure. Methods 3-methyladenine (3MA), a specific inhibitor on autophagy was used in a heart failure model of rats induced by adriamycin. Neonatal cardiomyocytes were isolated from Sprague–Dawley rat hearts and randomly divided into controls, an adriamycin-treated group, and a 3MA plus adriamycin-treated group. We then examined the morphology, expression of beclin 1 gene, mitochondrial permeability transition (MPT), and Na +–K + ATPase activity in vivo. We also assessed cell viability, mitochondrial membrane potential changes and counted autophagic vacuoles in cultured cardiomyocytes. In addition, we analyzed the expression of autophagy associated gene, beclin 1 using RT-PCR and Western blotting in an animal model. Results 3MA significantly improved cardiac function and reduced mitochondrial injury. Furthermore, adriamycin induced the formation of autophagic vacuoles, and 3MA strongly downregulated the expression of beclin 1 in adriamycin-induced failing heart and inhibited the formation of autophagic vacuoles. Conclusion Autophagic cardiomyocyte death plays an important role in the pathogenesis of heart failure in rats induced by adriamycin. Mitochondrial injury may be involved in the progression of heart failure caused by adriamycin via the autophagy pathway.

Inhibition action of bufalin on human transplanted hepatocellular tumor and its effects on expressions of Bcl-2 and Bax proteins in nude mice

To investigate the anti-tumor effect of bufalin and its regulation on Bcl-2 and Bax proteins in orthotopically transplanted tumor of human hepatocellular carcinoma in nude mice. Orthotopically transplanted tumor of human hepatocellular carcinoma was established in nude mice. The mice were randomly divided into five groups: high-dose bufalin-treated group (1.5 mg/kg), medium-dose bufalin-treated group (1 mg/kg), low-dose bufalin-treated group (0.5 mg/kg), adriamycin-treated group (8.0 mg/kg), and normal saline-treated group. After 25 days, mice were sacrificed. The tumor volume was measured, and the pathological changes of tumor tissues were detected by HE staining to observe the tumor necrosis degree. Cell morphological changes were also observed by an electron microscopy. Label index of tumor cell apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), and the expressions of Bcl-2 and Bax proteins were determined by immunohistochemical method. The tumor volume in the bufalin-treated groups was shrunk significantly compared with that in the normal saline-treated group (P<0.01). The survival time of the bufalin-treated groups was prolonged compared with that of the adriamycin-treated group and the normal saline-treated group P<0.05. Apoptotic characteristics could be seen in tumor tissues of the bufalin-treated groups. The label index of tumor cell apoptosis in the bufalin-treated groups (5.87+/-2.13, 8.86+/-2.96 and 10.60+/-3.42 in low-, medium- and high-dose groups respectively) was higher than that in the adriamycin-treated group (3.28+/-0.98) (P<0.05, P<0.01). The expression of Bax was up-regulated, while no changes were detected as to Bcl-2 protein in tumors of the bufalin-treated groups. Bufalin has significant anti-tumor effect on the orthotopically transplanted tumor of human hepatocellular carcinoma in nude mice. Its effect might be related to up-regulation of Bax protein and inducement of the tumor cell apoptosis.

THE CLASSIC: Amputation and Adriamycin in Primary Osteosarcoma

THE CLASSIC: Amputation and Adriamycin in Primary Osteosarcoma

Serial Assessment of Myocardial Properties Using Cyclic Variation of Integrated Backscatter in an Adriamycin-Induced Cardiomyopathy Rat Model

Although adriamycin (Doxorubicin) is one of the most effective and useful antineoplastic agents for the treatment of a variety of malignancies, its repeated administration can induce irreversible myocardial damage and resultant heart failure. Currently, no marker to detect early cardiac damage is available. The purpose of this study was to investigate whether an assessment of the acoustic properties of the myocardium could enable the earlier detection of myocardial damage after adriamycin chemotherapy. Forty Wistar rats were treated with adriamycin (2 mg/kg, i.v.) once a week for 2, 4, 6 or 8 weeks consecutively. Left ventricular ejection fraction (LVEF) was calculated using M-mode echocardiography data. The magnitude of cardiac cycle dependent variation of integrated backscatter (CVIB) of the myocardium was measured in the mid segment of the septum and in the posterior wall of the left ventricle, using a real time two dimensional integrated backscatter imaging system. LVEF was significantly lower in the adriamycin-treated 8-week group than in the controls (75 ± 9 vs 57 ± 8%, p < 0.05). Myocyte damage was only seen in the 8-week adriamycin-treated group. However, no significant changes of CVIB were observed between baseline or during follow-up in the ADR or control group. In conclusion, serial assessment of the acoustic properties of the myocardium may not be an optimal tool for the early detection of myocardial damage after doxorubicin chemotherapy in a rat model.

Cell death in the early adriamycin rat model.

The adriamycin rat model (ARM) exhibits many features of the VACTERL association. Adriamycin is a cytotoxic drug used in cancer chemotherapy. Although its exact mode of action is not clear, it is presumed to have a similar cytotoxic role in the developing embryo. Lysotracker red (LT) is a dye that stains phagolysosomes and apoptotic bodies and allows entire rodent embryos to be stained for apoptosis. We hypothesised that there was increased cell death in adriamycin-exposed embryos. To investigate this hypothesis, adriamycin (1.75 mg/kg) was given intraperitoneally to rats on days 7, 8, and 9 of pregnancy. A control group was given saline on the same schedule. Embryos were recovered at 3, 12, 24, and 48 h following the last dose and also at term (21 days) to confirm that the usual incidence of congenital anomalies found in the ARM was obtained in our animal model. Embryos were embedded in resin, sectioned, and studied by light microscopy. Embryos from the 3-h and 24-h groups were studied using LT and confocal microscopy to search for evidence of apoptosis. All term newborns (100%) from the adriamycin-treated group demonstrated the typical abnormalities found in the ARM, i.e., oesophageal atresia, multiple gastrointestinal atresias, vertebral malformations, absent tails, ureterohydronephrosis, etc. In the 9.5-day adriamycin group there was no difference in appearance between the experimental and control embryos. Specifically, no cellular debris or increased cell turnover indicative of adriamycin cytotoxicity was observed in the experimental group. At day 10.5, 90% of embryos from two separate litters had evidence of notochordal distortion and tethering to the gut or gut-tube abnormalities. These findings were not observed in the control embryos. Confocal microscopy and LT examination of the embryos from litters killed at 3 and 24 h following the last dose of adriamycin demonstrated no evidence of increased cell death in adriamycin-exposed embryos compared to control embryos. The absence of significant apoptosis in the developing embryos in the immediate period following administration of adriamycin suggests that the teratogenic effect of adriamycin is not caused by cell death.

In Vivo and In Vitro Efficacy of an Acid-Sensitive Albumin Conjugate of Adriamycin Compared to the Parent Compound in Murine Renal-Cell Carcinoma

This investigation is part of a continuing effort to develop effective drug delivery systems for anticancer agents using human serum proteins as drug carriers. The purpose of the present study was to compare the in vitro and in vivo activity of Adriamycin and an acid-sensitive Adriamycin-albumin conjugate (A-HYD2) in murine renal-cell carcinoma (RENCA). The inhibitory efficacy of A-HYD in RENCA cells in vitro was approximately fourfold lower as compared to Adriamycin. In a first in vivo experiment the efficacy of AHYD2 was compared to free Adriamycin at equitoxic doses (doses: 2 x 12 mg/kg for Adriamycin; 4 x 12 mg/kg for A-HYD2, iv over a period of 2 weeks; beginning therapy at day 7 after tumor inoculation: 10 Balb/ c mice per group). Seven of the eight surviving mice in the Adriamycin-treated group manifested clearly visible kidney tumors and ascites at the end of the experiment. In contrast, the 10 mice treated with A-HYD2 showed a complete remission in all cases, with no visible primary tumor. In a second experiment, therapy was started on day 10 to allow for the development of lung metastases, and the efficacy of the compounds was compared at equimolar and equitoxic doses (doses: 2 x 12 mg/kg for Adriamycin; 2 x 12 mg/kg and 4 x 12 mg/kg for A-HYD2, iv over a period of 2 weeks; 6 mice per group). After 24 days mice treated with Adriamycin or A-HYD2 at equimolar doses showed distinct kidney tumors and metastases in the lungs, with the number of metastases being twice as high in the Adriamycin-compared to the conjugatetreated group. Mice treated with A-HYD2 at equitoxic doses, however, showed a complete remission in all cases and no macroscopically visible metastases in the lungs. In summary, the data are a first identication that therapy with acid-sensitive albumin-Adriamycin conjugates could be a promising approach of treating renal-cell cancer.

Abnormal beta-adrenergic transmembrane signaling in rabbits with adriamycin-induced cardiomyopathy.

We investigated alterations in the beta-adrenergic receptor-adenylate cyclase system in rabbits with congestive heart failure induced by adriamycin cardiotoxicity. A dose of 24 mg/kg adriamycin was administered over 16 weeks in 16 rabbits. Five of them died and 4 of them could not tolerate the full dose of adriamycin. Complete data were obtained in the remaining 7 rabbits. Another 7 rabbits received physiological saline for the same period and served as controls. Plasma norepinephrine concentration increased in adriamycin-treated rabbits, but not in the control rabbits. Cardiac output was lower in the adriamycin-treated group than in the control group. Both the left and right ventricular end-diastolic pressure were higher in the adriamycin-treated group. The density of myocardial beta-adrenergic receptors and the norepinephrine content were reduced in both ventricles in the adriamycin-treated group. Basal and isoproterenol-, sodium fluoride- and forskolin-stimulated adenylate cyclase activities were lower in the adriamycin-treated group. Thus, alterations in beta-adrenergic signaling occurred in both ventricles in animals with chronic biventricular failure induced by adriamycin. These may be the result of post-receptor abnormalities, including abnormalities of guanine nucleotide-binding proteins or of the catalytic unit of adenylate cyclase.

Renal norepinephrine spillover and baroreflex responses in evolving heart failure

Renal sympathetic nerve activity (RSNA), as assessed by norepinephrine (NE) spillover, was examined in conscious rabbits with adriamycin-induced cardiomyopathic heart failure (n = 5) and in control rabbits (n = 5). Each rabbit was studied after 4 and 6 wk of adriamycin (2 mg.kg-1.wk-1) or vehicle under resting conditions and in response to changes in mean arterial pressure (MAP) produced by infusions of sodium nitroprusside and phenylephrine. Basal renal NE spillover rate was significantly increased after 4 wk of adriamycin treatment compared with controls (24.2 +/- 2.5 vs. 15.2 +/- 2.4 ng/min, P less than 0.05). At this stage the two groups had similar systemic hemodynamics and renal blood flows. The baroreflex-renal NE spillover response to hypotension in the adriamycin-treated group showed a significant upward shift. After 6 wk of adriamycin treatment, there were significant falls in resting MAP (74 +/- 3 vs. 86 +/- 2 mmHg, P less than 0.01) and renal blood flow (78 +/- 6 vs. 109 +/- 8 ml/min, P less than 0.05). At this stage of established heart failure, resting renal NE spillover rate remained elevated but there was significant blunting of the baroreflex-renal NE spillover response. These results suggest that, in this model of low-output heart failure, there is an early increase in resting renal sympathetic activity that is sustained. The baroreflex-renal NE spillover curve changes during the course of development of heart failure.

Differences in the effects of angiotensin converting enzyme inhibitors with or without a thiol group in chronic renal failure in rats

1. We have investigated the effects of the non-renin-mediated actions of angiotensin converting enzyme inhibitors on the progression of chronic renal failure accelerated by hypertension. For this purpose, we studied the effects of captopril (a thiol-containing angiotensin converting enzyme inhibitor), enalapril (an angiotensin converting enzyme inhibitor without a thiol group) and cysteine (a thiol-containing amino acid which has no angiotensin converting enzyme-inhibitory action) in adriamycin-treated rats with deoxycorticosterone acetate-salt hypertension, in which the renin-angiotensin system was suppressed. 2. There were no significant differences in blood pressure between these groups and the control group [adriamycin-treated group with deoxycorticosterone acetate-salt loading, 206 +/- 7 mmHg (27.4 +/- 0.9 kPa) at week 10]. 3. Massive proteinuria occurred in all groups. At the end of the experiment (at week 10), urinary protein excretion was significantly reduced in the captopril and cysteine groups compared with the control group. No manifest improvements appeared in the enalapril group. 4. Levels of serum creatinine and blood urea nitrogen increased progressively. At week 10, the increases in the serum levels of creatinine were less in the captopril (87 +/- 16 mmol/l) and cysteine (80 +/- 19 mmol/l) groups than in the control group (124 +/- 27 mmol/l) (P less than 0.01). No marked differences were found between the control and enalapril groups. 5. Captopril and cysteine caused more than a three-fold reduction in the focal glomerulosclerosis score when compared with that in the control group, but enalapril did not decrease the score. The extent of tubulointerstitial change was parallel with the focal glomerulosclerosis score. 6. We conclude that the thiol group is possibly involved in the mechanism of the beneficial effects of some angiotensin converting enzyme inhibitors on the progression of chronic renal failure exacerbated by hypertension.

Effects of Adriamycin on the Radiation Response of Murine Hematopoietic Stem Cells

The effects of adriamycin on radiation response of murine hematopoietic stem cells are studied using the spleen colony technique. Doses of adriamycin causing little cell kill did not affect the radiation survival curve. When dosage sufficient to result in 35% survival (0.8 mg) was given, the shoulder of the radiation survival curve disappeared without any change in the D0. When tested using divided doses of radiation, repair was not inhibited. Further, the trough seen in controls when the two doses of radiation were separated by 8-12 hr was not seen in the adriamycin-treated group. In fact, with these fractionation schemes survival in the presence of the drug was greater than in its absence.