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Lysine specific demethylase 1 (LSD1), the first identified histone demethylase, plays an important role in epigenetic regulation of gene activation and repression. The up-regulated LSD1s expression has been reported in several malignant tumors. In the current study, we designed and synthesized five series of 1,2,3-triazole-dithiocarbamate hybrids and screened their inhibitory activity toward LSD1. We found that some of these compounds, especially compound 26, exhibited the most specific and robust inhibition of LSD1. Interestingly, compound 26 also showed potent and selective cytotoxicity against LSD1 overexpressing gastric cancer cell lines MGC-803 and HGC-27, as well as marked inhibition of cell migration and invasion, compared to 2-PCPA. Furthermore, compound 26 effectively reduced the tumor growth bared by human gastric cancer cells in vivo with no signs of adverse side effects. These findings suggested that compound 26 deserves further investigation as a lead compound in the treatment of LSD1 overexpressing gastric cancer.

One new 6a,11a-dehydropterocarpan derivative, 6-O-methyl-anhydrotuberosin (1), one new 6a-hydroxypterocarpan, (6aR,11aR,11bR)-hydroxytuberosone (7), and seven known compounds including two 6a,11a-dehydropterocarpans (2 and 4), two coumestans (3 and 5), one isoflavonoid (6) and two other phenolic compounds (8 and 9) were isolated from the roots of Pueraria lobata. The structures of the isolated compounds were elucidated with spectroscopic and spectrometric methods (1 D and 2DNMR, HRESIMS). Compounds 1, 2, 4–5 showed potent LSD1 inhibitory activities with IC50 values ranging from 1.73 to 4.99 μM. Furthermore, compound 2 showed potent cytotoxicity against gastric cancer cell lines MGC-803 and BGC-823, and lung cancer cell lines H1299 and H460. [ABSTRACT FROM AUTHOR]

Two new sesquiterpenes, named selina-4(14),7,11-trien-9-ol (1) and selina-4(14),11-dien-7-ol (2), along with two known compounds were isolated from rhizomes of Atractylodes macrocephala Koidz. All structures were assigned on the basis of detailed spectroscopic analyses. The absolute configuration of 1 was established by TDDFT-ECD calculations. Compound 1 was found to moderately inhibit LSD1 activity with IC50 value of 34.0 μM. Compounds 1 and 4 exhibited a regulate effect on Keap1-Nrf2-ARE pathway. [ABSTRACT FROM AUTHOR]

Histone lysine-specific demethylase 1(LSD1) has become a promising molecular target for lung cancer therapy. Upon the screening platform for LSD1 activity, some Chinese herbal extracts were screened for LSD1 activity inhibition, and the underlying mechanism was preliminarily investigated at both molecular and cellular levels. The results of LSD1 inhibition showed that Puerariae Lobatae Radix extract can effectively reduce LSD1 expression to elevate the expression of H3 K4 me2 and H3 K9 me2 substrates in H1975 and H1299 cells. Furthermore, Puerariae Lobatae Radix was evaluated for its anti-lung cancer activity. It had a potent inhibitory ability against the proliferation and colony formation of both H1975 and H1299 cells. Flow cytometry and DAPI staining assays indicated that Puerariae Lobatae Radix can induce the apoptosis of lung cancer cells. In addition, it can significantly suppress the migration and reverse the epithelial-mesenchymal transition(EMT) process of lung cancer cells by activating E-cadherin and suppressing the expression of N-cadherin, slug and vimentin. To sum up, Puerariae Lobatae Radix displayed a robust inhibitory activity against lung cancer, and the mechanism may be related to the down-regulation of LSD1 expression to induce the cell apoptosis and suppress the cell migration and EMT process. These findings will provide new insights into the action of Puerariae Lobatae Radix as an anti-lung cancer agent and offer new ideas for the study on the anti-cancer action of Chinese medicine based on the epigenetic modification.

Objectives: Lysine-specific demethylase1 (LSD1), an important class of histone demethylases, plays a crucial role in regulation of mammalian biology. The up-regulated LSD1 expression was frequently associated with progress and oncogenesis of multiple human cancers, including non-small cell lung cancer (NSCLC). Therefore, inhibition of LSD1 may provide an attractive strategy for cancer treatment. We investigated the effect of sanguinarine against lung cancer cells as a natural alkaloid LSD1 inhibitor., Materials and Methods: The inhibition properties of sanguinarine to the recombinant LSD1 were evaluated by a fluorescence-based method. Subsequently, assays such as viability, apoptosis, clonogenicity, wound healing, and transwell were performed on H1299 and H1975 cells after treatment with sanguinarine., Results: Upon screening our in-house natural chemical library toward LSD1, we found that sanguinarine possessed a potent inhibitory effect against LSD1 with the IC50 value of 0.4 μM in a reversible manner. Molecular docking simulation suggested that sanguinarine may inactivate LSD1 by inserting into the binding pocket of LSD1 to compete with the FAD site. In H1299 and H1975 cells, sanguinarine inhibited the demethylation of LSD1, validating its cellular activity against the enzyme. Further studies showed that sanguinarine exhibited a strong capacity to suppress colony formation, inhibit migration and invasion, as well as induce apoptosis of H1299 and H1975 cells., Conclusion: Our findings present a new chemical scaffold for LSD1 inhibitors, and also provide new insight into the anti-NSCLC action of sanguinarine., Competing Interests: The authors declare that there are no conflicts of interest associated with this manuscript.

Antibiotic residues in farmland soils resulting from the application of livestock manure poses risks to the soil and water ecology associated with the spread of antibiotic resistance, thereby threatening environmental safety and human health. Here, a leaching experiment was carried out using soil(CK-T), pig manure(PM-T), cow manure(CM-T), and chicken manure(CHM-T) with the addition of tetracyclines(tetracycline, oxytetracycline, and chlortetracycline) and a control group(without antibiotics). The effects of different sources of manure on soil physical and chemical indicators and bacterial abundance under simulated leaching conditions were studied, while the migration of tetracyclines in the different treatments were also determined. The results showed that compared with the CHM-T and CM-T treatments, the tetracyclines in the PM-T treatment were more easily accumulated in the soil(residual amounts=0.90-6.91 mg·kg -1 compared to the other treatments=0.33-4.42 mg·kg -1 ). Compared with the surface soil(0-4 cm), higher concentrations of tetracyclines were detected at soil depths of 16-24 cm. Consistent with the residues of antibiotics, the concentrations of TN and NH 4 + -N in the soil with the PM-T treatment were increased by 0.044 g·kg -1 and 14.11 mg·kg -1 , respectively, which were significantly higher than other treatments. The abundance of bacteria in the soil was reduced due to the bactericidal effect of antibiotics, by 39.66% in the PM-T treatment, which was significantly higher than in the other treatments(12.38%-35.26%). Compared with other treatments, the antibiotics in the CHM-T treatment were more easily leached from the soil, with 9.91 mg of antibiotics in the leachate, which was significantly higher than the other treatments( P <0.05). TN, NH 4 + -N, tetracycline, oxytetracycline, and chlortetracycline were the first principal component factors, accounting for 54.55% of the variation, and corresponding concentrations increased with soil depth. Based on these results, tetracyclines in pig manure tended to accumulate in soil and transfer vertically along with variations in the soil microbial community. For chicken manure, relatively high concentrations of tetracyclines were detected in the soil leachate, increasing the risk of water pollution.

Lysine specific demethylase 1 (LSD1) plays a pivotal role in regulating the lysine methylation. The aberrant overexpression of LSD1 has been reported to be involved in the progression of certain human malignant tumors. Abrogation of LSD1 with RNAi or small molecule inhibitors may lead to the inhibition of cancer proliferation and migration. Herein, a series of [1,2,3]triazolo[4,5- d ]pyrimidine derivatives were synthesized and evaluated for their LSD1 inhibitory effects. The structure-activity relationship studies (SARs) were conducted by exploring three regions of this scaffold, leading to the discovery of compound 27 as potent LSD1 inhibitor (IC 50 = 0.564 μM). Compound 27 was identified as a reversible LSD1 inhibitor and showed certain selectivity to LSD1 over monoamine oxidase A/B (MAO-A/B). When MGC-803 cells were treated with compound 27 , the activity of LSD1 can be significantly inhibited, and the cell migration ability was also suppressed. Docking studies indicated that the hydrogen interaction between the nitrogen atom in the pyridine ring and Met332 could be responsible for the improved activity of 2-thiopyridine series. The [1,2,3]triazolo[4,5- d ]pyrimidine scaffold can be used as the template for designing new LSD1 inhibitors.