Evaluation of liver cell proliferation during ciprofibrate-induced hepatocarcinogenesis

To determine if the carcinogenic potential of peroxisome proliferators is dependent upon their ability to induce cell proliferation, we have investigated the extent of cell proliferation in the livers of rats fed ciprofibrate, a peroxisome proliferator. Male rats were maintained on a diet containing ciprofibrate (0.025% w/w) and killed at selected intervals following 1 week of continuous [3H]thymidine labeling. Evaluation of labeling indices demonstrated a significant increase in cell proliferation during the first week but not in rats killed at the end of 5 and 20 weeks of treatment. Increases in hepatocyte nuclear labeling were found at 40 and 70 weeks of ciprofibrate administration which coincided with the appearance in livers of putative preneoplastic and neoplastic lesions. In a short-term feeding study, ciprofibrate and ethoxyquin were fed to rats at a dietary concentration of 0.025% and 0.5%, respectively, either alone or in combination for 7 days. Ciprofibrate and ethoxyquin either alone or in combination produced marked hepatomegaly and a significant increase in DNA synthesis as demonstrated by [3H]thymidine incorporation and autoradiographic studies. DNA synthesis in the group receiving ciprofibrate and ethoxyquin simultaneously, was slightly more than in animals that received either compound alone, suggesting a synergistic effect, although chronic feeding of these agents together resulted in inhibition of liver carcinogenesis (Rao, M. S. et al. (1984) Cancer Res., 44, 1072-1076). The results of this study further suggest that cell proliferation induced by peroxisome proliferators may be less important in carcinogenesis than peroxisome proliferation induced by these compounds.     

Effect of the peroxisome proliferators ciprofibrate and perfluorodecanoic acid on hepatic cell proliferation and toxicity in Sprague--Dawley rats

The objective of this study was to compare the effects of perfluorodecanoicacid (PFDA) and ciprofibrate on the induction of hepatic toxicityand on hepatocellular proliferation in rats. In the first study,rats were first subjected to partial hepatectomy and then injectedwith [³H]thymidine (20 µCi/injection) at 23, 24, 25, 47,48 and 49 h afterwards. After a 2 week recovery period, ratswere injected with one of four levels of PFDA (03, 1.0, 3.0or 10 mg/kg/injection) in four i.p. doses every 14 days, orwere fed 0.01% or 0.003% ciprofibrate. Six days after the lastPFDA injection and three days before the animals were killed,an osmotic minipump containing 20 mg/ml 5-bromo-2’-deoxyuridine(BrdU) was implanted s.c for the measurement of DNA synthesis.Peroxisomal fatty acyl-CoA oxidase activity was significantlyenhanced in both PFDA and ciprofibrate-treated groups in a dose-dependentmanner. Hepatotoxicity, measured as the loss of [³H]thymldinefrom hepatic DNA, was not significantly affected by any of thetreatments. Hepatic DNA synthesis was significantly increasedonly in rats receiving the highest dose of PFDA. In order todetermine the time course of ciprofibrate- and PFDA-inducedcell proliferation, we conducted another study with more timepoints. Rats were fed 0.01% ciprofibrate or were injected every14 days with 3 or 10 mg PFDA/kg body weight for 10 days, 24days, 6 weeks, 26 weeks or 54 weeks. Cell proliferation wasquantified as in the first study. Ciprofibrate increased cellproliferation at the early but not the later time points, whereasPFDA increased cell proliferation at most times throughout thestudy. This study demonstrates that PFDA and ciprofibrate donot selectively induce hepatic toxicity and that their effectson cell proliferation do not correlate with their carcinogenicor promoting activities.     

Induction of peroxisome proliferation and hepatic tumours in C57BL/6N mice by ciprofibrate, a hypolipidaemic compound

The hepatic effects of ciprofibrate, a potent peroxisome proliferator, were evaluated in male C57BL/6N mice, a mouse strain with very low incidence of spontaneous liver tumour development. Dietary feeding of ciprofibrate (0.0125% or 0.025% w/w) for 2 weeks resulted in a marked proliferation of peroxisomes (9-fold increase) and several-fold increase (8- to 10-fold) in the activity of peroxisomal beta-oxidation enzymes. Feeding ciprofibrate at 0.025% concentration for 15 months followed by a 0.0125% for 6 months led to the development of hepatic adenomas in 8/14 (57%) and hepatocellular carcinomas (HCC) in 3/14 (21%) mice. In mice given 0.0125% ciprofibrate for 18 months 5 of 8 (62%) and 3 of 8 (37%) developed adenomas and HCC respectively. Similar to the findings observed in rats, both the adenomas and HCC were negative for gamma-glutamyltranspeptidase. These results in C57BL/6N mice of hepatocarcinogenic effect of ciprofibrate, a non-genotoxic chemical, indicate that peroxisome proliferation can be used as a reliable parameter to evaluate the carcinogenicity of hypolipidaemic compounds.     

Lack of carcinogenicity of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) in cynomolgus monkeys.

The carcinogenic potential of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) was evaluated in cynomolgus monkeys. The animals received MeIQx, beginning at the age of one year, at doses of 10 or 20 mg/kg body weight by gavage five times a week for 84 months and were autopsied 8 months thereafter. Although sporadic development of aberrant crypt foci in the colon and glutathione S-transferase pi-positive foci in the liver as well as hyperplastic changes of the lymphatic tissue in the lung and gastro-intestinal tract were observed in several monkeys, this was not treatment-related. No neoplastic or preneoplastic lesions were found in other organs. Serum chemistry data and organ weights were also within the normal ranges. From these data, it is concluded that MeIQx is not carcinogenic in the cynomolgus monkey under the conditions examined. This lack of carcinogenicity is probably related to the poor activation of MeIQx due to the lack of constitutive expression of CYP1A2 as well as an inability of other cytochrome P450s to catalyze N-hydroxylation of MeIQx in the cynomolgus monkey.     

丙戊酸钠联合地西他滨治疗骨髓增生异常综合征疗效分析

目的 探讨丙戊酸钠联合地西他滨治疗骨髓增生异常综合征(MDS)的有效性和安全性.方法 选择2012年2月至2017年2月山西大医院血液科收治的42例MDS患者为研究对象.将患者按照随机数字表法分为对照组(21例)和试验组(21例),对照组接受地西他滨治疗,剂量20 mg·m-2·d-1,2 h完成静脉滴注,连续治疗5 d,4周为1个疗程;试验组在使用地西他滨治疗的基础上,口服丙戊酸钠0.2 g/次,3次/d,1周后加量至0.4 g/次,3次/d.两组均至少进行4个疗程的治疗.出现严重的不良反应或疾病明显进展时停用,治疗后每4周复查一次骨髓涂片,评价疗效.并分别于治疗前后用荧光定量聚合酶链反应检测患者骨髓细胞中ASXL1、DNMT3A、TET2的表达情况.结果 试验组与对照组的总体治疗反应率分别为76.2%(16/21)和57.1%(12/21),差异有统计学意义(P<0.05);两组的总缓解率分别为47.6%(10/21)和38.1%(8/21),差异无统计学意义(P>0.05);两组患者均有轻微的药物不良反应,不良反应发生率分别为42.9%(9/21)和38.1%(8/21),差异无统计学意义(P>0.05);治疗后两组TET2 mRNA、DNMT3A mRNA含量较治疗前下降,差异均具有统计学意义(P<0.05),但两组间治疗后比较差异无统计学意义(P>0.05);对照组ASXL1 mRNA含量较治疗前无显著变化,试验组患者的ASXL1 mRNA含量较治疗前下降,差异有统计学意义(P<0.05).结论 丙戊酸钠联合地西他滨治疗MDS效果良好,不良反应轻微,且对MDS相关基因TET2、DNMT3A以及ASXL1的表达均有影响.     

Lack of Carcinogenicity of 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) in Cynomolgus Monkeys

The carcinogenic potential of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) was evaluated in cynomolgus monkeys. The animals received MeIQx, beginning at the age of one year, at doses of 10 or 20 mg/kg body weight by gavage five times a week for 84 months and were autopsied 8 months thereafter. Although sporadic development of aberrant crypt foci in the colon and glutathione S-transferase π-positive foci in the liver as well as hyper plastic changes of the lymphatic tissue in the lung and gastro-intestinal tract were observed in several monkeys, this was not treatment-related. No neoplastic or preneoplastic lesions were found in other organs. Serum chemistry data and organ weights were also within the normal ranges. From these data, it is concluded that MeIQx is not carcinogenic in the cynomolgus monkey under the conditions examined. This lack of carcinogenicity is probably related to the poor activation of MeIQx due to the lack of constitutive expression of CYP1A2 as well as an inability of other cytochrome P450s to catalyze N- hydroxylation of MeIQx in the cynomolgus monkey.     

缺氧对人乳腺癌细胞系MCF-7生物学行为的影响

目的:研究缺氧对人乳腺癌细胞系MCF-7的生物学行为,增殖、侵袭能力的影响。通过影响缺氧诱导因子1α(hypoxic-induciblefactor1α,HIF-1α)的表达,检验其在这一过程中的作用,并进一步探讨作用机制。方法:慢病毒感染细胞,干扰乳腺癌细胞系MCF-7中HIF-1α的表达,得到HIF-1α表达正常的乳腺癌细胞系MCF-7-NC和HIF-1α表达受干扰的细胞系MCF-7-HIF△。分别低氧培养及化学药物诱导缺氧,用MTT法检测2组细胞系在缺氧和正常培养条件下的增殖能力,ANOVA检验检测其增殖能力的区别。Transwell实验检验缺氧和正常培养条件下人乳腺癌细胞的侵袭能力,计数通过Transwell小室的细胞,ANOVA检验检测细胞侵袭能力的区别。共聚焦免疫荧光法检测缺氧后2组乳腺癌细胞的上皮和间质标记物的表达,检验细胞系是否发生了上皮-间质转化(epithelial-mesenchymaltransition,EMT)。结果:MTT实验结果:正常表达HIF-1α的MCF-7-NC的增殖能力在缺氧后与正常培养条件下相比明显减弱,其差别具有统计学意义(P<0.05)。HIF-1α表达受干扰的MCF-7-HIF△的增殖能力在缺氧和正常培养条件下相比无显著区别。Transwell实验检测细胞的侵袭能力,缺氧后正常表达HIF-1α的MCF-7-NC的侵袭能力较正常培养的细胞明显增强,其差别具有统计学意义(P<0.05)。HIF-1α表达受干扰的MCF-7-HIF△侵袭能力在缺氧和正常培养下无显著区别。缺氧后,正常表达HIF-1α的细胞系MCF-7-NC发生上皮-间质转化(epithelial-mesenchymaltransition,EMT)。共聚焦荧光染色显示:在诱导缺氧后,正常表达HIF-1α的MCF-7-NC细胞极性发生变化,呈长梭形改变,上皮标志物人广谱角蛋白(pan-cytokeratin,P-CK)表达下调,间质标志物人α平滑肌动蛋白(α-SMA)表达上调;而HIF-1α表达受干扰的MCF-7-HIF△无明显EMT变化。结论:在体外条件下,缺氧可以引起乳腺癌细胞系MCF-7增殖能力减弱、侵袭能力增强,可以诱导乳腺癌细胞MCF-7发生EMT,干扰缺氧诱导因子亚基HIF-1α的表达,则缺氧对乳腺癌细胞增殖、侵袭的影响消失。     

In vivoEffect of Recombinant Human Leukemia Inhibitory Factor in Primates

Leukemia inhibitory factor(LIF) is known to be a causative factor for cacbexia and thrombocytosis in nude mice bearing human cancer cells. In the present study, we investigated whether recombinant human (rh) LIF can induce these biological activities in a primate model. rhLIF was synthesized by the expression of LIF protein in Escherichia coli . rhLIF (5, 20, or 80μ/kg) was administered subcutaneously twice daily to cynomolgus monkeys for 14 consecutive days. A remarkable decrease of body weight (10%) was observed in the 80μg/kg/day group. Approximately two-fold increases in platelet counts were observed at doses higher than 5 /μg/kg/day when compared with control counts. These biological effects disappeared soon after the cessation of rhLIF treatment. Macroscopically, a remarkable reduction in subcutaneous fatty tissues and severe splenomegaly were observed. The results of this study demonstrate that rhLIF induces weight loss and thrombocytosis in a primate model.     

Peroxisome proliferators increase ethanol catabolism through utilization of the catalase pathway

We investigated the effects of ciprofibrate, a potent peroxisome proliferator, on ethanol metabolism in mice. The blood alcohol levels of mice fed a liquid diet containing both ciprofibrate and ethanol were markedly depressed compared with mice fed the ethanol-containing diet alone. Ciprofibrate markedly induced enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase, hydrogen peroxide, and to a lesser extent catalase in both control and ethanol-diet fed mice. Northern blot analysis indicated no significant upregulation of cytochrome P450IIE1 mRNA by ciprofibrate. Our study suggests that peroxisome proliferators increase ethanol catabolism through hydrogen peroxide production, thus allowing utilization of the catalase pathway. These findings indicate that catalase has the potential to provide a significant pathway for ethanol metabolism under conditions of peroxisome proliferation.     

西达本胺对利妥昔单抗耐药 B 细胞淋巴瘤增殖的影响及作用机制

目的 探讨组蛋白去乙酰化酶（HDAC）抑制剂西达本胺在体外对利妥昔单抗耐药的B细胞淋巴瘤细胞增殖的影响及其可能的作用机制。方法 采用不同浓度西达本胺、利妥昔单抗单药或联合作用于淋巴瘤Jeko-1和Jeko-1/R细胞,采用CCK-8法检测细胞增殖情况;RT-PCR检测CD20 mRNA表达水平;Western blot法检测组蛋白H3、H4的乙酰化水平。结果 25 μg/mL、50 μg/mL、100 μg/mL和200 μg/mL利妥昔单抗在48 h可呈剂量依赖式抑制Jeko-1细胞增殖,组间差异有统计学意义（F=38.533,P<0.001）,且细胞增殖抑制率均高于Jeko-1/R细胞（均P<0.001）。4 μmol/L、8 μmol/L和16 μmol/L西达本胺在48 h呈剂量依赖式抑制Jeko-1和Jeko-1/R细胞增殖,组间差异有统计学意义（F=17.968,P=0.003;F=51.456,P<0.001）,但不同浓度西达本胺作用Jeko-1和Jeko-1/R细胞的增殖抑制率差异均无统计学意义（均P>0.05）。西达本胺（8 μmol/L）联合利妥昔单抗（100 μg/mL）分别处理Jeko-1和Jeko-1/R细胞48 h,与单药西达本胺比较,联合处理后细胞增殖抑制率均增高（P<0.001）。西达本胺在48 h呈剂量依赖式上调Jeko-1/R细胞CD20 mRNA表达和组蛋白H3和H4乙酰化水平（P<0.001）。结论 西达本胺可抑制耐药B细胞淋巴瘤Jeko-1/R细胞增殖,其作用机制可能与上调组蛋白H3、H4乙酰化水平及CD20 mRNA表达有关。     

Effects of PPAR and RXR ligands in semaphorin 6B gene expression of human MCF-7 breast cancer cells

This study tests the hypothesis that the activators of peroxisome proliferator-activated receptors (PPARs) and 9-cis-retinoic acid receptor (RXR) regulate human semaphorin 6B (Sema6B) gene expression. The human MCF-7 breast adenocarcinoma cell line was chosen because it expresses Sema6B at a high level. The Sema6B mRNA level was analyzed by RT-PCR and the semaphorin 6B protein content was determined using a polyclonal antibody that we have produced and characterized. Treatments with fenofibrate (a PPARalpha activator) and troglitazone (a PPARgamma ligand) strongly decreased the Sema6B mRNA. The drop in Sema6B mRNA level and in protein content was more important when the treatment combined the action of fenofibrate or troglitazone and 9-cis-retinoic acid. On the other hand, no significant change was observed in the Sema6B mRNA and protein levels when the cells were exposed to the combined action of GW610742 (a PPARbeta activator) and 9-cis-retinoic acid. These data suggest that PPARalpha/RXR and PPARgamma/RXR heterodimers are involved in the regulation of Sema6B gene expression and open new perspectives concerning the participation of these nuclear receptors in cell recognition and migration.     

Bevacizumab in clinical practice: prescribing appropriateness relative to national indications and safety

The aim of this study was to describe the clinical use of bevacizumab in Lombardy (9.5 million inhabitants), Italy, during 2006-2007 in patients with metastatic colorectal cancer (mCRC) to evaluate compliance with the Italian Medicine Agency (AIFA) indications, the incidence of adverse events, and the survival rate. We performed computerized record linkage among three different Lombardy health care databases: File F registry, Regional discharge database, and Registry Office records. Patients were classified into approved and off-label uses according to the AIFA indications. Treatment with bevacizumab was administered to 780 patients, of whom 81.7% (n = 637) had mCRC. Among these, 37.8% (n = 241) of patients received the drug in observance of AIFA indications. Overall, ～10% of patients had serious treatment-related toxicities (fistula, 3.5%; venous thromboembolism, 2.8%; hemorrhage, 1.9%; intestinal perforation and arterial thromboembolism, <1%). The 1-year survival rate was 74.3% and the 2-year survival rate was 39.2%. The median survival time was 20.5 months, and there were no meaningful differences between gender and age groups. There was a gap between the bevacizumab approved indication and clinical practice pattern: overall, less than one half of the patients received bevacizumab in observance with the regulatory indication. The main reason for nonadherence to the indication was use as a second-line or advanced line of therapy. The incidence of serious adverse events and the survival rates of mCRC patients were similar to those reported in clinical trials.     

In vivo distribution of a carcinogenic hepatic peroxisome proliferator: whole-body autoradiography of [14C]ciprofibrate in the mouse

The distribution of radiolabel in male mice was studied by whole-bodyautoradiography at intervals after oral administration of [¹⁴C]ciprofibrate,a carcinogenic hepatic peroxisome proliferator. Radioactivitywas rapidly taken up by the liver and to a lesser extent bythe brown fat within 9 h after oral dosing of ciprofibrate.The radioactivity levels in blood, interstitial fluid and fatdecreased during the first 3 days after dosing, but the liverremained densely labeled. Between 3 and 27 days after dosing,liver exhibited a stippled pattern as a result of heavier labelingapparently around the central veins. The relatively low levelsof radiolabel in extra-hepatic tissues observed after oral dosing,together with the prolonged retention in this region of theliver, is consistent with the hepatotropic effects (i.e. hepaticperoxisome proliferation and development of liver tumors) exertedby this compound.     

New Protocol of Intermittent Androgen Deprivation Therapy for Patients With Metastatic Prostate Cancer: A Retrospective Study

BackgroundThe optimal points for halting and resuming treatment in intermittent androgen deprivation therapy (IADT) for metastatic prostate cancer patients are controversial.Patients and MethodsIn the 65 metastatic prostate cancer patients in group 1, androgen deprivation therapy was stopped when prostate-specific antigen (PSA) levels reached a nadir and was resumed when PSA levels doubled and ≥ 1.0 ng/mL (new protocol). In the 62 patients in group 2, androgen deprivation therapy was stopped 3 months after PSA = 0.2 ng/mL and resumed at PSA ≥ 4.0 ng/mL (Chinese Urological Association guideline). The total IADT duration, overall on-treatment and off-treatment time, tumor clinical progression ratio, performance status improvement, and treatment-related adverse effects were retrospectively analyzed.ResultsIn groups 1 and 2, the median total IADT durations were 51 and 46.5 months (significant difference, P = .006), median overall on-treatment times were 28 and 27.5 months (no significant difference, P > .05), and median overall off-treatment times were 23 and 19 months (significant difference, P < .001), respectively. Multivariate Cox regression analysis indicated that patients in group 1 had significantly higher progression-free-survival (hazard ratio, 0.634; P = .014). Two cases of clinical progression occurred group 1 and 5 in group 2; there was no significant difference (P > .05). There were no significant differences between the groups in terms of performance status improvement and treatment-related adverse effects.ConclusionThe new protocol was found to be beneficial, showing less biochemical/clinical progression, satisfactory performance status, and acceptable treatment-related adverse effects.     

Lack of expression of glutathione-S-transferase P, gamma-glutamyl transpeptidase, and alpha-fetoprotein messenger RNAs in liver tumors induced by peroxisome proliferators

Many structurally unrelated nonmutagenic peroxisome proliferators induce altered areas, neoplastic nodules, and hepatocellular carcinomas in rats. Unlike the lesions induced by genotoxic hepatocarcinogens, these lesions do not stain positively for the phenotypic markers gamma-glutamyl transpeptidase (GGT) and glutathione-S-transferase P (GST-P). To ascertain whether the absence of immunocytochemically detectable GST-P and GGT proteins in peroxisome proliferator-induced neoplastic lesions is due to the absence of specific mRNAs, we analyzed the total RNA isolated from hepatocellular carcinomas induced by three different peroxisome proliferators (ciprofibrate, Wy-14643, and BR-931) and the genotoxic carcinogens, 2-acetylaminofluorene and aflatoxin B1 (AFB), for the presence of GST-P, GGT, and alpha-fetoprotein (AFP) mRNAs. Northern and dot blot analysis of total RNA isolated from liver tumors induced by three different peroxisome proliferators revealed no detectable GST-P, GGT, and AFP mRNAs. GST-P mRNA was also not detected in a transplantable hepatocellular carcinoma established from a liver tumor induced by ciprofibrate. In contrast, GST-P mRNA levels were high in primary liver tumors induced by both 2-acetylaminofluorene and AFB and the two transplantable hepatocellular carcinomas established from such tumors. By immunoblot method, GST-P protein was found to be abundant in both primary and transplantable liver tumors induced by genotoxic carcinogens but not in those derived from peroxisome proliferator treatment. The GGT and AFP mRNAs were also not found in all 18 liver tumors induced by peroxisome proliferators that were analyzed and also in the ciprofibrate-derived transplantable liver tumor. The expression of GGT and AFP genes in liver tumors induced by 2-acetylaminofluorene and AFB was variable. These studies with peroxisome proliferators show that the GST-P and GGT gene derepression is not essential for the hepatocarcinogenesis or successful tumor transplantation. Further characterization of the molecular basis for the differential expression, particularly of the GST-P gene in liver tumors, may help identification of the critical event(s) in hepatocarcinogenesis by genotoxic carcinogens and nongenotoxic peroxisome proliferators.     

Peroxisome proliferation and lipid peroxidation in rat liver

Male F344 rats were fed a diet containing the peroxisome proliferators 2-[4-(2,2-dichlorocyclopropyl)phenoxy]-2-methylpropionic acid [ciprofibrate (0.025%)] or [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid [Wy-14643 (0.1%)] for up to 14 months to determine whether hepatic peroxisome proliferation caused by these agents results in the induction of membrane lipid peroxidation in the liver. Peroxidative damage of membrane lipids from whole liver, postnuclear, heavy-particle, microsomal, and nuclear membranes was evaluated by determining the extent of formation of conjugated dienes (ultraviolet absorption, 233 nm). Increased generation of diene conjugates was noted in whole-liver, postnuclear, and heavy-particle membrane lipids of rats fed peroxisome proliferators for 6 months or longer when compared to controls. An additional, more intense absorption profile in the ultraviolet absorption range of approximately 276 nm was noted in the membrane lipids derived from whole liver, postnuclear, and heavy particle pellets, but not in the nuclear and microsomal membrane lipids of livers with peroxisome proliferation. Although the exact chemical nature of this delta 276 nm peak is not clear, it is attributed to the formation of ketone dienes and/or conjugated trienes. The excess lipid peroxidation correlates with the previous observation of accumulation of abundant quantities of lipofuscin in hepatocytes of rats chronically exposed to peroxisome proliferators. The generation of conjugated dienes and ketone dienes and/or trienes together with increased levels of H2O2 generation by peroxisomal enzymes, and decreased levels of hepatic glutathione peroxidase, glutathione reductase, and glutathione-S-transferases, enzymes responsible for the defense against H2O2 damage, suggest the occurrence of membrane lipid peroxidation and oxidative stress in livers of rats treated with carcinogenic peroxisome proliferators.     

Moderate exercise training attenuates aging-induced cardiac inflammation,hypertrophy and fibrosis injuries of rat hearts

Aging is the most important risk factor in cardiovascular disease (CVD), which is the leading causes of death worldwide and the second major cause of death in Taiwan. The major factor in heart failure during aging is heart remodeling, including long-term stress-induced cardiac hypertrophy and fibrosis. Exercise is good for aging heart health, but the impact of exercise training on aging is not defined. This study used 3-, 12- and 18-month-old rats and randomly divided each age group into no exercise training control groups (C3, A12 and A18) and moderate gentle swimming exercise training groups (E3, AE12 and AE18). The protocol of exercise training was swimming five times weekly with gradual increases from the first week from 20 to 60 min for 12 weeks. Analyses of protein from rat heart tissues and sections revealed cardiac inflammation, hypertrophy and fibrosis pathway increases in aged rat groups (A12 and A18), which were improved in exercise training groups (AE12 and AE18). There were no heart injuries in young rat hearts in exercise group E3. These data suggest that moderate swimming exercise training attenuated aging-induced cardiac inflammation, hypertrophy and fibrosis injuries of rat hearts.