Selective Estrogen Receptor Modulation by Larrea nitida on MCF-7 Cell Proliferation and Immature Rat Uterus

Larrea nitida is a plant that belongs to the Zygophyllaceae family and is widely used in South America to treat inflammatory diseases, tumors and menstrual pain. However, its pharmacological activity remains unclear. In this study we evaluated the property of selective estrogen receptor modulator (SERM) of Larrea nitida extracts (LNE) as a phytoestrogen that can mimic, modulate or disrupt the actions of endogenous estrogens, depending on the tissue and relative amount of other SERMs. To investigate the property of SERM of LNE, we performed MCF-7 cell proliferation assays, estrogen response element (ERE)-luciferase reporter gene assay, human estrogen receptor (hER) binding assays and in vivo uterotrophic assay. To gain insight into the active principles, we performed a bioassay-guided analysis of LNE employing solvents of various polarities and using classical column chromatography, which yielded 16 fractions (LNs). LNE showed high binding affinities for hERα and hERβ with IC₅₀ values of 1.20 ×10⁻⁷ g/ml and 1.00×10⁻⁷ g/ml, respectively. LNE induced 17β-estradiol (E2)-induced MCF-7 cell proliferation, however, it reduced the proliferation in the presence of E2. Furthermore, LNE had an atrophic effect in the uterus of immature rats through reducing the expression level of progesterone receptor (PR) proteins. LN08 and LN10 had more potent affinities for binding on hER α and β than other fractions. Our results indicate that LNE had higher binding affinities for hERβ than hERα, and showed SERM properties in MCF-7 breast cancer cells and the rat uterus. LNE may be useful for the treatment of estrogen-related conditions, such as female cancers and menopause.     

Effects of Epimedii Herba on a Rat Model of Hypothyroidism Induced by PTU (6-propyl, 2-thiouracil)

Objectives: The symptoms of hypothyroidism are fatigue, cold intolerance, arthralgia, muscle cramps, dry skin, etc. Although hypothyroidism is a relatively common endocrinical disease, we do have many difficulties treating it effectively. The symptoms of hypothyroidism are similar to those of Yang deficiency in Oriental medicine. Epimedii Herba is a popular herb that has the effect of tonifying the kidney and strengthening Yang in Oriental medicine. In this study, we investigated the therapeutic effects of Epimedii Herba on a rat model of hypothyroidism induced by PTU (6-propyl, 2-thiouracil).Methods: Twenty-four (24) two-month-old Spargue-Dawley (SD) rats were divided into 4 groups: 1) normal (n=6), 2) PTU-induced hypothyroidism control (n=6), 3) hypothyroidism rat treated with Epimedii Herba (n=6), 4) hypothyroidism rat treated with levothyroxine (n=6). PTU was administered for 4 weeks. Epimedii Herba and levothyroxine were administered for 2 weeks after PTU had been administered for 2 weeks, for a total duration of 4 weeks. At the end of the experiment, blood samples from all the rats were taken from their hearts and were analyzed.Results: In comparison with the normal group, the PTU-induced control group significantly showed hypothyroidism with low T3 and T4 and with high TSH. In the Epimedii Herba group, T4 was significantly increased (p < 0.05). There was no significant difference in TSH between the Epimedii Herba treatment group and the control group and no significant differences were observed in biochemical lab tests and weight between the Epimedii Herba group and the control group.Conclusions: These results suggest that Epimedii Herba could help thyroid cells to produce thyroid hormones. No significant side effects related with Epimedii Herba were found, suggesting that it is safe to administer. According to these results, Epimedii Herba may be a safe alternative medicine for the treatment of hypothyroidism.Key Words: Epimedii Herba; 6-propyl, 2-thiouracil; hypothyroidism     

Senp2 expression was induced by chronic glucose stimulation in INS1 cells,and it was required for the associated induction of Ccnd1 and Mafa

Post-translational modification by bonding of small ubiquitin-like modifier (SUMO) peptides influences various cellular functions, and is regulated by SUMO-specific proteases (SENPs). Several proteins have been suggested to have diverse impact on insulin synthesis and secretion through SUMO modification in β cells. However, the role of SUMO modification in β cell mass has not been established. Here, we examined the changes in expression of Senp in INS1 cells and pancreatic islets under diabetes-relevant stress conditions and associated changes in β cell mass. Treatment with 25 mM glucose for 72 h induced Senp2 mRNA expression but not that of Senp1 in INS1 cells. Immunohistochemical staining with anti-SENP2 antibody on human pancreas sections revealed that SENP2 was localized in the nucleus. Moreover, in a patient with type 2 diabetes, SENP2 levels were enhanced, especially in the cytoplasm. Senp2 cytoplasmic levels were also increased in islet cells in obese diabetic mice. Cell number peaked earlier in INS1 cells cultured in high-glucose conditions compared to those cultured in control media. This finding was associated with increased Ccnd1 mRNA expression in high-glucose conditions, and siRNA-mediated Senp2 suppression abrogated it. Mafa expression, unlike Pdx1, was also dependent on Senp2 expression during high-glucose conditions. In conclusion, Senp2 may play a role in β cell mass in response to chronic high-glucose through Cyclin D1 and Mafa.