Gossypol inhibits 5α-reductase 1 and 3α-hydroxysteroid dehydrogenase: Its possible use for the treatment of prostate cancer.

Gossypol is a yellow polyphenol isolated from cotton seeds. It has the antitumor activity and it is being tested to treat prostate cancer. However, its underlying mechanisms are still not well understood. The present study investigated the inhibitory effects of gossypol acetate on rat 5α-reductase 1, 3α-hydroxysteroid dehydrogenase, and retinol dehydrogenase 2 for androgen metabolism. Rat 5α-reductase 1, 3α-hydroxysteroid dehydrogenase, and retinol dehydrogenase 2 were expressed in COS-1 cells. Immature Leydig cells that contain these enzymes were isolated from 35-day-old male Sprague Dawley rats. The potency and mode of action of gossypol acetate to inhibit these enzymes in both enzyme-expressed preparations and immature Leydig cells were examined. Molecular docking study of gossypol on the crystal structure of 3α-hydroxysteroid dehydrogenase was performed. Gossypol acetate inhibited 5α-reductase 1 and 3α-hydroxysteroid dehydrogenase with IC50 values of 3.33 ±â€¯0.07 and 0.52 ±â€¯0.06 × 10-6 M in the expressed enzymes as well as 8.512 ±â€¯0.079 and 1.032 ±â€¯0.068 × 10-6 M in intact rat immature Leydig cells, respectively. Gossypol acetate inhibited rat 5α-reductase 1 in a noncompetitive mode and 3α-hydroxysteroid dehydrogenase in a mixed mode when steroid substrates were supplied. Gossypol acetate weakly inhibited retinol dehydrogenase 2 with IC50 value over 1 × 10-4 M. Molecular docking analysis showed that gossypol partially bound to the steroid-binding site of the crystal structure of rat 3α-hydroxysteroid dehydrogenase. Gossypol acetate is a potent inhibitor of rat 5α-reductase 1 and 3α-hydroxysteroid dehydrogenase, possibly inhibiting the formation of androgen in the prostate cancer cells.

Combined Virtual Screening and Substructure Search for Discovery of Novel FABP4 Inhibitors.

Fatty acid-binding protein 4 (FABP4, AFABP) is a potential drug target for diabetes and atherosclerosis. In this study, a series of novel FABP4 inhibitors were discovered through combining virtual screening and substructure search. Seventeen compounds exhibited FABP4 inhibitory activities with IC50 < 10 µM, among which 11 compounds showed high selectivity against FABP3. The best compound 36b displayed an IC50 value of 1.5 µM. Molecular docking and point mutation studies revealed that Gln95, Arg126, and Tyr128 play key roles for these compounds binding with FABP4. Interestingly, Gln95 seems to be essential for conformation stability of FABP4. The new scaffolds of these compounds and their interaction mechanisms binding with FABP4 should provide an important clue for the further development of novel FABP4 inhibitors.

Suppression of rat and human androgen biosynthetic enzymes by apigenin: Possible use for the treatment of prostate cancer.

Apigenin is a natural flavone. It has recently been used as a chemopreventive agent. It may also have some beneficial effects to treat prostate cancer by inhibiting androgen production. The objective of the present study was to investigate the effects of apigenin on the steroidogenesis of rat immature Leydig cells and some human testosterone biosynthetic enzyme activities. Rat immature Leydig cells were incubated for 3h with 100µM apigenin without (basal) or with 1ng/ml luteinizing hormone (LH), 10mM 8-bromoadenosine 3',5'-cyclic monophosphate (8BR), and 20µM of the following steroid substrates: 22R-hydroxychloesterol (22R), pregnenolone (P5), progesterone (P4), and androstenedione (D4). The medium levels of 5α-androstane-3α, 17ß-diol (DIOL), the primary androgen produced by rat immature Leydig cells, were measured. Apigenin significantly inhibited basal, 8BR, 22R, PREG, P4, and D4 stimulated DIOL production in rat immature Leydig cells. Further study showed that apigenin inhibited rat 3ß-hydroxysteroid dehydrogenase, 17α-hydroxylase/17, 20-lyase, and 17ß-hydroxysteroid dehydrogenase 3 with IC50 values of 11.41±0.7, 8.98±0.10, and 9.37±0.07µM, respectively. Apigenin inhibited human 3ß-hydroxysteroid dehydrogenase and 17ß-hydroxysteroid dehydrogenase 3 with IC50 values of 2.17±0.04 and 1.31±0.09µM, respectively. Apigenin is a potent inhibitor of rat and human steroidogenic enzymes, being possible use for the treatment of prostate cancer.

Optical coherence tomography and histopathology of macular uveitis.

PURPOSE: Spectral-domain optical coherence tomography (SD-OCT) is a noninvasive technique that can provide high-resolution images of macular morphology. The purpose of this study was to examine the pathological mechanism of uveitis and compare the changes in the macula of uveitis patients and the histopathological features of experimentally induced uveitis in mice. METHODS: Macular OCT was performed on 78 eyes of 51 patients of the Eye Hospital of Shandong University of Traditional Chinese Medicine, China, with apparent uveitis changes. C57BL/6 mice were injected with interphotoreceptor retinoid-binding protein (IRBP)-specific T cells from naïve mice immunized with complete Freund adjuvant IRBP(1-20) to induce uveitis. The disease was monitored by indirect fundoscopy. The eyes of the mice with experimental autoimmune uveitis (EAU) were enucleated 18 days after injection and classified according to pathological characteristics. RESULTS: The characteristics of uveitis were classified into six categories. Macular edema was detected in 48 eyes (61.5%); macular epiretinal membrane in 22 eyes (28.2%); choroidal neovascularization and macular lamellar holes in 4 eyes (5.1%), respectively; macular atrophy in 10 eyes (12.8%); and serous neuroepithelium detachment in 22 eyes (28.2%). As in human patients, pathological examinations of mouse EAU showed inflammation, folds, and atrophy of the outer part of the neuroretina, choroidal neovascularization with hemorrhagic retinal detachment, serous neuroepithelium detachment, and epiretinal membrane formation. CONCLUSIONS: Macular OCT of uveitis patients can display different morphological characteristics. Mouse EAU can simulate human uveitis. The comparative analysis of macular OCT in human uveitis and transfer EAU histopathology changes could provide important information on the pathogenesis of human uveitis.

Early clinical evaluation of AcrySof ReSTOR multifocal intraocular lens for treatment of cataract.

PURPOSE: To evaluate the efficacy, safety and early visual quality of the AcrySof ReSTOR multifocal intraocular lens (IOL) following cataract surgery. SETTING: Eye Center of Shandong University of Traditional Chinese Medicine, Jinan Shierming Eye Hospital, Jinan, Shandong, China. METHODS: After small-incision phacoemulsification, AcrySof ReSTOR IOLs were implanted in 20 subjects (40 eyes, ReSTOR group). Monofocal IOLs were implanted in 18 subjects (36 eyes, control group). Three to six months following bilateral implantation, visual acuity, depth of focus, corneal astigmatism, contrast sensitivity, glare sensitivity, visual field and spherical aberration were compared between the groups. A subjective outcome questionnaire was also completed by the subjects. RESULTS: Uncorrected near visual acuity 0.5 or better was achieved by 92.5% of the ReSTOR eyes. In the monofocal eyes, only 33.3% of the eyes achieved uncorrected near visual acuity of 0.5 or better. There was no statistical difference between corrected near, distance visual acuity, and uncorrected distance visual acuity in the 2 groups (p > 0.05). In patients with visual acuity 0.5 or better, the depth of focus was 4.87 +/- 1.09 and 2.08 +/- 0.69 dpt in the ReSTOR and control groups, respectively. The contrast sensitivity, glare sensitivity and visual field of both groups were similar (p > 0.05). The spherical aberration of the 2 groups was similar (t = -0.37, p = 0.71). Visual disturbances were minimal with only 1 patient in each group complaining of glare at night. CONCLUSION: The AcrySof ReSTOR multifocal IOL is a safe and effective treatment for cataracts.