Role and possible mechanism of estrogen receptor α down-regulation leading to damage of TM4 Sertoli cell connectivity in mice / 中国药理学通报

Aim To investigate the role of autophagy in the dysfunction of testicular TM4 cell junction induced by ERα down-regulation. Methods TM4 cells were treated with different concentrations of E R a inhibitor ICI182780 (ICI), and the proliferative activity of TM4 cells was detected by CCK-8 method. The number and morphological changes of TM4 cells were observed by light microscope. The levels of E R a, junction function related proteins and autophagy marker proteins were detected by Western blot. The expression and localization of Cx43 were detected by immunofluorescence staining. The cells were treated with chloroquine (CQ) and ICI for 24 h. The expression levels of autophagy and junction function related proteins were detected by Western blot. Results When ICI concentration was 50 nmol • L ~ or above, the cell viability decreased significantly. The increase of cell vacuoles in ICI group was observed by light microscope. Compared with normal control group, the protein expression levels of E R a, ZO-1, occludin, claudin-11, p-catenin and Cx43 in ICI groups significantly dropped, while the expression levels of N-cadherin and E-cadherin had no significant changes; LC3 II significantly rose, while p62 expression significantly fell. The results of immunofluorescence showed that the fluorescence expression of Cx43 in ICI group decreased significantly, but the position of CX43 did not change significantly. Compared with ICI group, the expression levels of LC3 II, p62, Cx43, ZO-1 and β-Catenin significantly increased. Conclusions The down-regulation of E R a leads to damage of TM4 cell junction function, which may be related to the activation of autophagy.

Effects of high-fat diet on testicular germ cell apoptosis in mice through endoplasmic reticulum stress / 中国药理学通报

Aim To study the effects of high-fat diet on testicular germ cell apoptosis in mice through endoplasmic reticulum stress. Methods C57BL/6J male mice were assigned into normal group and high-fat diet group randomly, with six mice in each group. The mice in normal group or high-fat diet group were fed with regular or high-fat diet continuously for five months. The mice were weighed, anesthetized, and euthanized to collect testicular and epididymal tissue for analysis. The testicular tissue was weighed and their indices were calculated. Epididymal tissue was collected for semen analysis. The morphological alterations of testicular tissue were observed using hematoxylin-eosin ( HE ) staining. The apoptosis of germ cells was detected by TUNEL staining and the apoptotic indices were calculated. The expression levels of apoptosis and endoplasmic reticulum stress-related proteins in testicular tissue were detected by Western blot. The protein expression and localization of GRP78 in testicular tissue were further detected by immunofluorescence. Results The results showed that compared to the normal group, the high-fat diet group had a significant increase in body weight, a significant decrease in testicular index, sperm concentration, and sperm vability, loose arrangement of germ cells, significant thinning of the seminiferous epithelium, no significant change in the diameter of seminiferous tubules, a significant increase in germ cell apoptosis , with an increased apoptosis index, and significant increase in expression of Bax and cleaved-caspase-12,and a significant decrease in Bcl-2 protein expression. The expression levels of GRP78 , p-IREl, XBP1, and ATF6a proteins were significantly up-regulated, while p-PERK, p-eIF2a, ATF4 protein expression showed no significant changes. Immunofluorescence results further showed a significant increase in the expression of GRP78 protein in the testicular tissue,with no significant changes in the expression location. Conclusions High-fat diet can induce the apoptosis of mouse testicular germ cells, and the mechanism may be related to the activation of endoplasmic reticulum stress IRE1 and ATF6 signaling pathway.

Progress in Clinical Research on Gonadotropin-Releasing Hormone Receptor Antagonists for the Treatment of Prostate Cancer.

Gonadotropin-releasing hormone (GnRH) receptor agonists are still the most commonly used androgen deprivation treatment (ADT) drugs for prostate cancer in clinical practice. Currently, the GnRH receptor antagonists used for endocrine therapy for prostate cancer primarily include degarelix and relugolix (TAK-385). The former is administered by subcutaneous injection, while the latter is an oral drug. Compared to GnRH agonists, GnRH antagonists reduce serum testosterone levels more rapidly without an initial testosterone surge or subsequent microsurges. This review focuses on the mechanism of action of GnRH antagonists and agonists, the developmental history of GnRH antagonists, and emerging data from clinical studies of the two antagonists used as endocrine therapy for prostate cancer.

Fat fraction quantification of lumbar spine: comparison of T1-weighted two-point Dixon and single-voxel magnetic resonance spectroscopy in diagnosis of multiple myeloma.

PURPOSE: We aimed to investigate the value of T1-weighted two-point Dixon technique and single-voxel magnetic resonance spectroscopy (MRS) in diagnosis of multiple myeloma (MM) through quantifying fat content of vertebral marrow. METHODS: A total of 30 MM patients and 30 healthy volunteers underwent T1-weighted two-point Dixon and single-voxel MRS imaging. The fat fraction map (FFM) was reconstructed from the Dixon images using the equation FFM = Lip/In, where Lip represents fat maps and In represents in-phase images. The fat fraction (FF) of MRS was calculated by using the integral area of Lip peak divided by the sum of integral area of Lip peak and water peak. RESULTS: FF values measured by the Dixon technique and MRS were significantly decreased in MM patients (45.99%±3.39% and 47.63%±4.38%) compared with healthy controls (64.43%±0.96% and 76.22%±1.91%) (P < 0.001 with both methods). FF values measured by Dixon technique were significantly positively correlated to those measured by MRS in MM (r = 0.837, P < 0.001) and healthy control group (r = 0.735, P < 0.001), respectively. There was no significant difference between area under the curve (AUC) obtained by the Dixon technique (0.878±0.047; range, 0.785 to 0.971; optimal cutoff, 56.35 for healthy controls vs. MM) and MRS (0.883±0.047; range, 0.791 to 0.974; optimal cutoff, 61.00 for healthy controls vs. MM). The ability of Dixon technique to differentiate MM group from healthy controls was equivalent to single-voxel MRS. CONCLUSION: Regarding detection of fat contents in vertebral bone, T1-weighted two-point Dixon technique exhibited equivalent performance to single-voxel MRS in the diagnosis of multiple myeloma. Moreover, two-point Dixon is a more convenient and stable technique for assessing bone marrow changes in MM patients than single-voxel MRS.