Quantitative Assessment of a Change of Hemosiderin Deposition with Age in Splenic Compartments of Rats.

Masuda, Tomoyuki; Satodate, Ryoichi; Tsuruga, Kinichi; Kasai, Toshifumi

doi:10.1620/tjem.170.169

Cited by 7 publications

(7 citation statements)

References 16 publications

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“…Hemosiderin deposition peaked at 12 months in the red pulp of rat spleen [33]. In our experiments, cisplatin treatment can increase the hemosiderin depositions in a short period of 2 weeks.…”

Section: Hemosiderin Deposition In the Spleen Of Patients Was Timementioning

confidence: 58%

Specific Hemosiderin Deposition in Spleen Induced by a Low Dose of Cisplatin: Altered Iron Metabolism and Its Implication as an Acute Hemosiderin Formation Model

Wang

et al. 2010

CDM

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Cisplatin is one of the commonly-used chemotherapeutic drugs to efficiently treat malignant tumors in clinic, however, the adverse effects of cisplatin such as nephrotoxicity, neurotoxcity, and hemolytic uremic syndrome are often observed at its clinical doses (~60 mg/m 2 ), which limit its broader application. In earlier studies, little attention was paid to the subtle changes in the architecture of lymphatic organs after low doses of cisplatin treatment. This paper reviews current understanding of cisplatin-induced erythrocyte injury, and presents our latest finding that a low dose of cisplatin (3.6 mg/m 2 /day, 14 days) could induce specific hemosiderin deposition in spleen of both normal and hepatoma-22 (H22) inoculated Balb/C mice. This dose of cisplatin significantly inhibited H22-induced acute ascites development. No significant toxicity was induced by this dose of cisplatin to tissues except for hemosiderin accumulation in the spleen of both normal and H22 tumor-bearing mice. Increased splenic iron content and erythrocyte injury were observed after treatment with the low dose of cisplatin. The mRNA levels of ferroportin (FPN1) and ferritin were upregulated by 25 and 5-fold in spleen, respectively. Overexpression of FPN1 and ferritin protein were also been observed at protein levels by Western blotting analysis. In addition, the mRNA expression of hepcidin was also increased, suggesting blockage of iron recycling through FPN1 in spleen with cisplatin treatment. In conclusion, cisplatin treatment damages the erythrocytes which accumulate in the red pulp of spleen with defective recycling of FPN1 and ferritin protein. Hepcidin inhibits the function of FPN1 as iron-exporter leading to iron overloaded inside ferritins of splenic cells, which are stained with abnormal hemosiderin accumulation. These results demonstrate that cisplatin-caused hemosiderin deposition in spleen provides a valuable clue for understanding the molecular basis of toxicity of cisplatin and hemosiderin accumulation and iron metabolism in vivo.

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Section: Hemosiderin Deposition In the Spleen Of Patients Was Timementioning

confidence: 58%

Specific Hemosiderin Deposition in Spleen Induced by a Low Dose of Cisplatin: Altered Iron Metabolism and Its Implication as an Acute Hemosiderin Formation Model

Wang

et al. 2010

CDM

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“…Spleens from some mice treated with either placebo or 8 contained hemosiderin-laden macrophages. These are normally present in rodent spleens 34 but may also suggest old hemorrhage somewhere in the animals. One mouse receiving 8 had evidence of a splenic infarct, which is not typical for a drug reaction but can be a thromboembolic event in cardiomyopathy.…”

Section: Resultsmentioning

confidence: 99%

Macrocyclic MEK1/2 inhibitor with efficacy in a mouse model of cardiomyopathy caused by lamin A/C gene mutation

Chordia

Hart³

et al. 2017

Bioorganic & Medicinal Chemistry

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Signaling mediated by extracellular signal-regulated kinases 1 and 2 (ERK1/2) is involved in numerous cellular processes. Mitogen-activated protein kinase kinases (MEK1/2) catalyze the phosphorylation of ERK1/2, converting it into an active kinase that regulates the expression of numerous genes and cellular processes. Inhibitors of MEK1/2 have demonstrated preclinical and clinical efficacy in certain cancers and types of cardiomyopathy. We report the synthesis of a novel, allosteric, macrocyclic MEK1/2 inhibitor that potently inhibits ERK1/2 activity in cultured cells and tissues of mice after systemic administration. Mice with dilated cardiomyopathy caused by a lamin A/C gene mutation have abnormally increased cardiac ERK1/2 activity. In these mice, this novel MEK1/2 inhibitor is well tolerated, improves left ventricular systolic function, decreases left ventricular fibrosis, has beneficial effects on skeletal muscle structure and pathology and prolongs survival. The novel MEK1/2 inhibitor described herein may therefore find clinical utility in the treatment of this rare cardiomyopathy, other types of cardiomyopathy and cancers in humans.

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“…In the spleen, Ft buildup was accompanied with an increase in both Ft-H and Ft-L gene expression, pointing to enhanced transcription of the mRNA for these proteins. However, decreased turnover cannot be ruled out since it was found previously that hemosiderin, a poorly soluble degradation product of Ft (Hoy and Jacobs 1981), accumulates in the red and white pulps of the spleen in aged rats (Masuda et al 1993).…”

Section: Discussionmentioning

confidence: 96%

Aging is an organ-specific process: changes in homeostasis of iron and redox proteins in the rat

Bulvik

Berenshtein

Konijn

et al. 2011

AGE

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Organ-specific changes of iron-and redoxrelated proteins occur with age in the rat. Ferritin, the major iron storage and detoxifying protein, as well as the proteins of the methionine-centered redox cycle (MCRC) were examined in old and young animals, and showed organ-dependent changes. In spleens and livers of aged rats, ferritin (protein) levels were greater than in young ones, and their iron saturation increased, rendering higher ferritin-bound iron (FtBI). Iron saturation of the ferritin molecule in the tongues and sternohyoids of old rats was lower but ferritin level was higher than in young rats, resulting in increased FtBI with age. Ferritin level in the esophagus of older rats was lower than in young rats but its molecular iron content higher thus the total FtBI remained the same. In the larynx, both ferritin and its iron content were the same in young and old animals. MCRC proteins were measured in livers and spleens only. With aging, methionine sulfoxide reductase A and B (MsrA and MsrB) levels in livers and spleens decreased. Thioredoxin1 (Trx) and Trx-reductase1 were elevated in old spleens, but reduced in livers. Aged spleens showed reduced Msr isozyme activity; but in the liver, its activity increased. mRNA changes with age were monitored and found to be organ specific. These organ-specific changes could reflect the different challenges and the selective pathways of each organ and its resultant capacity to cope with aging.

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Quantitative Assessment of a Change of Hemosiderin Deposition with Age in Splenic Compartments of Rats.

Cited by 7 publications

References 16 publications

Specific Hemosiderin Deposition in Spleen Induced by a Low Dose of Cisplatin: Altered Iron Metabolism and Its Implication as an Acute Hemosiderin Formation Model

Specific Hemosiderin Deposition in Spleen Induced by a Low Dose of Cisplatin: Altered Iron Metabolism and Its Implication as an Acute Hemosiderin Formation Model

Macrocyclic MEK1/2 inhibitor with efficacy in a mouse model of cardiomyopathy caused by lamin A/C gene mutation

Aging is an organ-specific process: changes in homeostasis of iron and redox proteins in the rat

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