cyclin-d1 and Goiter

Goiter is associated with increased oxidative stress (OS). We studied the effects of an anti-inflammatory agent, 15 deoxy-Delta12,14-prostaglandin J2 (15dPGJ2) and an antioxidant, N-acetylcysteine (NAC), on OS, thyroid function, and goiter expansion in a model of goiter induced by propylthiouracil (PTU) or perchlorate. OS was assessed by the immunodetection of 4-hydroxynonenal, thyroid function by measuring thyroxin (T4) and thyrotropin (TSH) plasma levels and detecting T4-rich thyroglobulin (Tg-I), and goiter expansion by weighing the thyroids and measuring cell proliferation (PCNA and cyclin D1 immunodetection). In both PTU and perchlorate-induced goiters, OS, TSH plasma levels, thyroid weight, and cell proliferation were strongly enhanced, whereas Tg-I expression was negative. All these parameters were reversed by NAC and 15dPGJ2 in PTU-goiters. In perchlorate-goiters, TSH plasma levels remained elevated and Tg-I-negative after NAC or 15dPGJ2 treatment. OS was reduced by NAC, but not by 15dPGJ2. In addition, NAC reduced PCNA and cyclin D1 immunostainings, as well as thyroid weight, whereas 15dPGJ2 influenced neither thyroid weight nor cell proliferation. In conclusion, NAC and 15dPGJ2 overcome PTU- but not perchlorate-induced effects. The retrieval of hormonal synthesis may result from direct chemical interactions between PTU and NAC/15dPGJ2. Although 15dPGJ2 has no effect in perchlorate-goiters, the reduction of OS by NAC is associated with altered goiter development, making OS a required condition for the growth of the thyroid gland.

Topics: Acetylcysteine; Animals; Cell Nucleus; Cell Proliferation; Cyclin D1; Female; Goiter; Organ Size; Oxidative Stress; Perchlorates; Peroxiredoxins; Proliferating Cell Nuclear Antigen; Propylthiouracil; Prostaglandin D2; Rats; Rats, Wistar; Thyroid Gland; Thyroxine

To investigate the inhibitory effects of Kangjia Pill (KJP) on the cell proliferation in rat goiter model induced by methimazole (MMI).. Fifty-six Wistar rats were randomly divided into four groups: the normal group, MMI model group (MMI), low dose of KJP group (LKJP), and high dose of KJP (HKJP). Except the normal group (20 rats), the other groups (12 rats in each) were given 0.04% (w/v) MMI through the drinking water until the end of the experiment. One week later, the rats in the LKJP and HKJP groups were given KJP by gastrogavage at the dose of 250 mg/(kg x d) and 1,000 mg/(kg x d), respectively for 12 weeks. The relative thyroid weight (mg/100 g body weight) of each rat was accessed. The expression of proliferating cell nuclear antigen (PCNA) was determined by immunohistochemistry, and the correlation analysis between the PCNA positive thyrocytes and the relative thyroid weight was performed. The expressions of PCNA and cyclin D1 were examined with Western blotting.. After KJP treatment for 12 weeks, compared with the MMI group, the relative thyroid weight of the HKJP group decreased significantly, and the positive thyrocyte populations of PCNA in the two KJP groups reduced markedly (all P<0.05). The correlation analysis showed that PCNA was closely correlated with thyrocyte proliferation (r=0.685, P<0.05). KJP significantly decreased the protein expression of PCNA and cyclin D1 in the thyroid specimens (P<0.05), the high dose showed better effects.. KJP played a therapeutic role via inhibiting cell proliferation in the rat goitrous glands.

Topics: Animals; Cell Proliferation; Cyclin D1; Disease Models, Animal; Down-Regulation; Drug Evaluation, Preclinical; Drugs, Chinese Herbal; Goiter; Male; Methimazole; Organ Size; Proliferating Cell Nuclear Antigen; Random Allocation; Rats; Rats, Wistar; Tablets; Thyroid Gland

Thyroid tumors are about 3 times more frequent in females than in males. Epidemiological studies suggest that the use of estrogens may contribute to the pathogenesis of thyroid tumors. In a very recent study a direct growth stimulatory effect of 17beta-estradiol was demonstrated in FRTL-5 rat thyroid cells. In this work the presence of estrogen receptors alpha and beta in thyroid cells derived from human goiter nodules and in human thyroid carcinoma cell line HTC-TSHr was demonstrated. There was no difference between the expression levels of estrogen receptor alpha in males and females, but there was a significant increase in expression levels in response to 17beta-estradiol. Stimulation of benign and malignant thyroid cells with 17beta-estradiol resulted in an increased proliferation rate and an enhanced expression of cyclin D1 protein, which plays a key role in the regulation of G(1)/S transition in the cell cycle. In malignant tumor cells maximal cyclin D1 expression was observed after 3 h, whereas in benign cells the effect of 17beta-estradiol was delayed. ICI 182780, a pure estrogen antagonist, prevented the effects of 17beta-estradiol. In addition, 17beta-estradiol was found to modulate activation of mitogen-activated protein (MAP) kinase, whose activity is mainly regulated by growth factors in thyroid carcinoma cells. In response to 17beta-estradiol, both MAP kinase isozymes, extracellular signal-regulated protein kinases 1 and 2, were strongly phosphorylated in benign and malignant thyroid cells. Treatment of the cells with 17beta-estradiol and MAP kinase kinase 1 inhibitor, PD 098059, prevented the accumulation of cyclin D1 and estrogen-mediated mitogenesis. Our data indicate that 17beta-estradiol is a potent mitogen for benign and malignant thyroid tumor cells and that it exerts a growth-promoting effect not only by binding to nuclear estrogen receptors, but also by activation of the MAP kinase pathway.

Topics: Adenocarcinoma; Blotting, Western; Cell Division; Cyclin D1; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Goiter; Humans; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Phosphorylation; Receptors, Estrogen; Reverse Transcriptase Polymerase Chain Reaction; Thyroid Gland; Thyroid Neoplasms; Tumor Cells, Cultured