Menopause is associated with dyslipidemia and an increased risk of cardio-cerebrovascular disease. The classic view assumes that the underlying mechanism of dyslipidemia is attributed to an insufficiency of estrogen. In addition to a decrease in estrogen, circulating follicle-stimulating hormone (FSH) levels become elevated at menopause. In this study, we find that blocking FSH reduces serum cholesterol via inhibiting hepatic cholesterol biosynthesis. First, epidemiological results show that the serum FSH levels are positively correlated with the serum total cholesterol levels, even after adjustment by considering the effects of serum estrogen. In addition, the prevalence of hypercholesterolemia is significantly higher in peri-menopausal women than that in premenopausal women. Furthermore, we generated a mouse model of FSH elevation by intraperitoneally injecting exogenous FSH into ovariectomized (OVX) mice, in which a normal level of estrogen (E2) was maintained by exogenous supplementation. Consistently, the results indicate that FSH, independent of estrogen, increases the serum cholesterol level in this mouse model. Moreover, blocking FSH signaling by anti-FSHβ antibody or ablating the FSH receptor (FSHR) gene could effectively prevent hypercholesterolemia induced by FSH injection or high-cholesterol diet feeding. Mechanistically, FSH, via binding to hepatic FSHRs, activates the Gi2α/β-arrestin-2/Akt pathway and subsequently inhibits the binding of FoxO1 with the SREBP-2 promoter, thus preventing FoxO1 from repressing SREBP-2 gene transcription. This effect, in turn, results in the upregulation of SREBP-2, which drives HMGCR nascent transcription and de novo cholesterol biosynthesis, leading to the increase of cholesterol accumulation. This study uncovers that blocking FSH signaling might be a new strategy for treating hypercholesterolemia during menopause, particularly for women in peri-menopause characterized by FSH elevation only.

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To discover novel BChE inhibitors, a hierarchical virtual screening protocol followed by biochemical evaluation was applied. The most potent compound 8012-9656 (eqBChE IC 50 = 0.18 ± 0.03 μM, hBChE IC 50 = 0.32 ± 0.07 μM) was purchased and synthesized. It inhibited BChE in a noncompetitive manner and could occupy the binding pocket forming diverse interactions with the target. 8012-9656 was proven to be safe in vivo and in vitro and showed comparable performance in ameliorating the scopolamine-induced cognition impairment to tacrine. Additionally, treatment with 8012-9656 could almost entirely recover the Aβ 1−42 (icv)-impaired cognitive function to the normal level and showed better behavioral performance than donepezil. The evaluation of the Aβ 1−42 total amount confirmed its anti-amyloidogenic profile. Moreover, 8012-9656 possessed blood−brain barrier (BBB) penetrating ability, a long T 1/2 , and low intrinsic clearance. Hence, the novel potential BChE inhibitor 8012-9656 can be considered as a promising lead compound for further investigation of anti-AD agents.

PURPOSE. To determine the roles of dopamine D2 receptors (D2Rs) and dopamine D1 receptors (D1Rs) in the inhibition of form-deprivation myopia (FDM) by the nonselective dopamine agonist apomorphine (APO) in D2R-knockout (D2R-KO) and D1R-KO mice. METHODS.Retinal layer thicknesses and electroretinograms (ERGs) were analyzed in KO mice and in D2R and D1R antagonist-treated mice. D2R-KO or D1R-KO mice and wild-type (WT) littermates were subjected to form deprivation during postnatal weeks 5 to 8. Both groups were intraperitoneally injected daily with either APO (5 lg/g body weight) dissolved in 1 lg/ lL ascorbic acid or vehicle alone. Refraction, vitreous chamber depth (VCD), and axial length (AL), among other parameters, were measured prior to and at the end of the treatment period.RESULTS. The retinal layer thicknesses and ERGs in KO mice were similar to those treated with D2R and D1R antagonists. APO administration in WT mice inhibited the development of FDM by approximately 80%. FDM in D2R-KO mice was inhibited approximately 50% compared with WT mice and was further inhibited by APO to a level similar to that in APO-treated WT mice. FDM development in D1R-KO mice was similar to that in WT mice and was not affected by APO administration. The changes in VCD and AL were consistent with refraction data.CONCLUSIONS. In mice, APO-mediated FDM inhibition was abolished by D1R KO but not D2R KO. This indicates the specificity of D1Rs for the pharmacologic inhibitory effect of APO on FDM and a nonessential role of D2Rs in this process in mice.

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Histone demethylation is a vital process in epigenetic regulation of gene expression. A number of histone demethylases are present to control the methylated states of histone. Among these enzymes, KDM4s are one subfamily of JmjC KDMs and play important roles in both normal and cancer cells. The discovery of KDM4s inhibitors is a potential therapeutic strategy against different diseases including cancer. Here, we summarize the development of KDM4s inhibitors and some related pharmaceutical information to provide an update of recent progress in KDM4s inhibitors.

Background: Neo-tetraploid rice (NTR) is a new tetraploid rice germplasm that developed from the crossing and directional selection of different autotetraploid rice lines, which showed high fertility and promising yield potential. However, systematic yield assessment, genome composition and functional variations associated with fertility and yield remain elusive. Results: Two season's field trials of 15 NTRs and 27 autotetraploid rice (ATR) lines revealed that the improvement of YPP (yield per plant, 4.45 g increase) were significantly associated with the increase of SS (seed setting, 29.44% increase), and yield and seed setting of NTRs improved significantly compared to parental lines. Whole genome resequencing of 13 NTR sister lines and their parents at about 48.63 depth were conducted and genome compositions were illustrated using inherited chromosomal blocks. Interestingly, 222 non-parental genes were detected between NTRs and their low fertility parental lines, which were conserved in 13 NTRs. These genes were overlapped with yield and fertility QTLs, and RNA-Seq analysis revealed that 81 of them were enriched in reproductive tissues. CRISPR/Cas9 gene knockout was conducted for 9 non-parental genes to validate their function. Knockout mutants showed on an average 25.63% and 4.88 g decrease in SS and YPP, respectively. Notably, some mutants showed interesting phenotypes, e.g., kin7l (kinesin motor gene) and kin14m (kinesin motor gene), bzr3 (BES1/BZR1 homolog) and nrfg4 (neo-tetraploid rice fertility related gene) exhibited 44.65%, 24.30%, 24.42% and 28.33% decrease in SS and 8.81 g, 4.71 g, 5.90 g, 6.22 g reduction in YPP, respectively. Conclusion: Comparative genomics provides insights into genome composition of neo-tetraploid rice and the genes associated with fertility and yield will play important role to reveal molecular mechanisms for the improvement of tetraploid rice.

Herein, we report a series of selective sub-nanomolar inhibitors against butyrylcholinesterase (BChE). These compounds, bearing a novel N-benzyl benzamide scaffold, inhibited BChE with IC 50 from picomolar to nanomolar. The inhibitory activity was confirmed by the surface plasmon resonance assay, showing a sub-nanomolar K D value, which revealed that the compounds exert the inhibitory effect through directly binding to BChE. Several compounds showed neuroprotective effects verified by the oxidative damage model. Furthermore, the safety of S11-1014 and S11-1033 was demonstrated by the in vivo acute toxicity test. In the behavior study, 0.5 mg/kg S11-1014 or S11-1033 exhibited a marked therapeutic effect, which was almost equal to the treatment with 1 mg/kg rivastigmine, against the cognitive impairment induced by Aβ 1−42 . The pharmacokinetics studies characterized the metabolic stability of S11-1014. Thus, N-benzyl benzamide inhibitors are promising compounds with drug-like properties for improving cognitive dysfunction, providing a potential strategy for the treatment of Alzheimer's disease.