Active components and molecular mechanism of Syringa oblata Lindl. in the treatment of endometritis based on pharmacology network prediction.

Antibiotic treatment of endometritis was limited by the inevitable antibiotic residues and risk of bacterial resistance. Therefore, the development of safe and effective strategies for endometritis treatment is urgently needed. Syringa oblata Lindl. (SOL) showed great pharmacological potential against endometritis. However, the active components and underlying mechanism of SOL for endometritis treatment remain indeterminate. In our study, the active components and possible molecular mechanism of SOL against endometritis were predicted through computer data mining and biological networks construction. It was predicted that the main active components of SOL were luteolin, kaempferol, oleanolic acid, and rutin, and their anti-endometritis effect was mainly attributed to the TLRs/NF-κB signaling pathway. Furthermore, a green and efficient deep eutectic solvent combined with ultrasound-assisted extraction (DES-UAE) was performed and optimized to obtain high contents of total flavonoid, rutin, and luteolin. The four predicted active components in the SOL extracts were qualitatively and quantitatively analyzed by LC/MS and HPLC. Finally, the pharmacological effects of SOL and active components have been verified by Staphylococcus aureus-endometritis models in mice. H&E staining and bacterial load in uterus tissues assays initially validated the pharmacodynamic effects of SOL, and quantitative real-time PCR (RT-qPCR) and ELISA results confirmed that SOL and four active components could ameliorate the uterus injury caused by Staphylococcus aureus, the mechanism of action is related to the TLRs/NF-κB signaling pathway.

Correction: Inhibition of Stat3 signaling pathway by nifuroxazide improves antitumor immunity and impairs colorectal carcinoma metastasis.

Since publication of this article, the authors have noticed that there were errors in Fig. 1b (the CT 26 cells colony formation images) and Fig. 7c (the vehicle group images). As a result of the misfiling of the data during preparation of figures, incorrect images were inadvertently inserted in these figures.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Genome-Wide Identification and Characterization of the GmSnRK2 Family in Soybean.

Sucrose non-fermenting-1 (SNF1)-related protein kinase 2s (SnRK2s) that were reported to be involved in the transduction of abscisic acid (ABA) signaling, play important roles in response to biotic and abiotic stresses in plants. Compared to the systemic investigation of SnRK2s in Arabidopsisthaliana and Oryza sativa, little is known regarding SnRK2s in soybean, which is one of the most important oil and protein crops. In the present study, we performed genome-wide identification and characterization of GmSnRK2s in soybean. In summary, 22 GmSnRK2s were identified and clustered into four groups. Phylogenetic analysis indicated the expansion of SnRK2 gene family during the evolution of soybean. Various cis-acting elements such as ABA Response Elements (ABREs) were identified and analyzed in the promoter regions of GmSnRK2s. The results of RNA sequencing (RNA-Seq) data for different soybean tissues showed that GmSnRK2s exhibited spatio-temporally specific expression patterns during soybean growth and development. Certain GmSnRK2s could respond to the treatments including salinity, ABA and strigolactones. Our results provide a foundation for the further elucidation of the function of GmSnRK2 genes in soybean.

Inhibition of Stat3 signaling pathway by nifuroxazide improves antitumor immunity and impairs colorectal carcinoma metastasis.

Colorectal carcinoma (CRC) is the one of the most common cancers with considerable metastatic potential, explaining the need for new drug candidates that inhibit tumor metastasis. The signal transducers and activators of the transcription 3 (Stat3) signaling pathway has an important role in CRC and has been validated as a promising anticancer target for CRC therapy. In the present study, we report our findings on nifuroxazide, an antidiarrheal agent identified as an inhibitor of Stat3. Our studies showed that nifuroxazide decreased the viability of three CRC cell lines and induced apoptosis of cancer cells in a concentration-dependent manner. Moreover, western blot analysis demonstrated that the occurrence of its apoptosis was correlated with the activation of Bax and cleaved caspase-3, and decreased the expression of Bcl-2. In addition, nifuroxazide markedly impaired CRC cell migration and invasion by downregulating phosphorylated-Stat3Tyr705, and also impaired the expression of matrix metalloproteinases (MMP-2 and MMP-9). Furthermore, our studies showed that nifuroxazide also significantly inhibited the tumor metastasis in lung and abdomen metastasis models of colon cancer. Meanwhile, nifuroxazide functionally reduced the proliferation index, induced tumor apoptosis and impaired metastasis. Notably, nifuroxazide reduced the number of myeloid-derived suppressor cells in the blood, spleens and tumors, accompanied by the increased infiltration of CD8+ T cells in the tumors. Importantly, a marked decrease in the number of M2-type macrophages in tumor in the abdomen metastasis model was also observed. Taken together, our results indicated that nifuroxazide could effectively inhibit tumor metastasis by mediating Stat3 pathway and it might have a therapeutic potential for the treatment of CRC.

Discovery of novel N-(5-(tert-butyl)isoxazol-3-yl)-N'-phenylurea analogs as potent FLT3 inhibitors and evaluation of their activity against acute myeloid leukemia in vitro and in vivo.

FLT3 inhibitors have been explored as a viable therapy for acute myeloid leukemia (AML). However, the clinical outcomes of these FLT3 inhibitors were underwhelming except AC220. Therefore, the development of novel FLT3 inhibitors with high potency against both FLT3-WT and FLT3-ITD mutants are strongly demanded at the present time. In this study, we designed and synthesized a series of novel N-(5-(tert-butyl)isoxazol-3-yl)-N'-phenylurea derivatives as FLT3 inhibitors. SAR studies focused on the fused rings led to the discovery of a series of compounds with high potency against FLT3-ITD-bearing MV4-11 cells and significantly inhibitory activity toward FLT3. Among these compounds, N-(5-(tert-butyl)isoxazol-3-yl)-N'-(4-(7-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl)urea (16i), displayed acceptable aqueous solubility, desirable pharmacokinetic profile and high cytotoxicity selectivity against MV4-11 cells. This compound can inhibit phosphorylation of FLT3 and induce apoptosis in a concentration-dependent manner. Further in vivo antitumor studies showed that 16i led to complete tumor regression in the MV4-11 xenograft model at a dose of 60 mg/kg/d while without observable body weight loss. This study had provided us a new chemotype of FLT3 inhibitors as novel therapic candidates for AML.

Discovery of imidazo[2,1-b]thiazole HCV NS4B inhibitors exhibiting synergistic effect with other direct-acting antiviral agents.

The design, synthesis, and SAR studies of novel inhibitors of HCV NS4B based on the imidazo[2,1-b]thiazole scaffold were described. Optimization of potency with respect to genotype 1b resulted in the discovery of two potent leads 26f (EC50 = 16 nM) and 28g (EC50 = 31 nM). The resistance profile studies revealed that 26f and 28g targeted HCV NS4B, more precisely the second amphipathic α helix of NS4B (4BAH2). Cross-resistance between our 4BAH2 inhibitors and other direct-acting antiviral agents targeting NS3/4A, NS5A, and NS5B was not observed. For the first time, the synergism of a series of combinations based on 4BAH2 inhibitors was evaluated. The results demonstrated that our 4BAH2 inhibitor 26f was synergistic with NS3/4A inhibitor simeprevir, NS5A inhibitor daclatasvir, and NS5B inhibitor sofosbuvir, and it could also reduce the dose of these drugs at almost all effect levels. Our study suggested that favorable effects could be achieved by combining 4BAH2 inhibitors such as 26f with these approved drugs and that new all-oral antiviral combinations based on 4BAH2 inhibitors were worth developing to supplement or even replace current treatment regimens for curing HCV infection.

Reductions in myeloid-derived suppressor cells and lung metastases using AZD4547 treatment of a metastatic murine breast tumor model.

BACKGROUND: AZD4547, a small-molecule inhibitor targeting the tyrosine kinase of Fibroblast Growth Factor Receptors (FGFRs), is currently under phase II clinical study for human subjects having breast cancer, while the underlying mechanism remains elusive. The aim of this study is to explore the potential mechanism by which AZD4547 inhibits breast tumor lung metastases at the level of the tumor microenvironment. METHODS: First, through in vitro experiments, we investigated the efficacy of the FGFRs inhibitor AZD4547 on 4T1 tumor cells for their proliferation, apoptosis, migration, and invasion. Second, by in vivo animal experiments, we evaluated the effects of AZD4547 on tumor growth and lung metastases in 4T1 tumor-bearing mice. Finally, we examined the impact of AZD4547 on the infiltration of myeloid-derived suppressor cells (MDSCs) in lung, spleens, peripheral blood and tumor. RESULTS: Through this study we found that AZD4547 could efficiently suppress tumor 4T1 cells through restraining their proliferation, blocking migration and invasion, and inducing apoptosis in vitro. In animal model we also demonstrated that AZD4547 was able to inhibit tumor growth and lung metastases, consistent with the decreased MDSCs accumulation in the tumor and lung tissues, respectively. Moreover, the reduced number of MDSCs in peripheral blood and spleens were also observed in the AZD4547-treated mice. Importantly, through the AZD4547 treatment, the CD4(+) and CD8(+) T-cells were significantly increased in tumor and spleens. CONCLUSION: Our studies showed that AZD4547 can inhibit breast cancer cell proliferation, induce its apoptosis and block migration and invasion in vitro and suppress tumor growth and lung metastases by modulating the tumor immunologic microenvironment in vivo.

Synthesis and biological evaluation of 1,2,4-triazole and 1,3,4-thiadiazole derivatives as potential cytotoxic agents.

A series of new 3-amino-5-sulfanyl-1,2,4-triazole and 2-amino-5-sulfanyl-1,3,4-thiadiazole derivatives have been synthesized and their cytotoxicities were evaluated on a panel of human cancer cell lines (BxPC-3, H1975, SKOV-3, A875, HCT116, etc.). The best one (compound 5m) exhibited activities with IC50 values ranging from 0.04 to 23.6 µM against nine human cancer cell lines. Further biological evaluation indicated that DNA replication was blocked by treatment with compound 5m in HCT116 cells.

N-[(4-Carbamoylphen-yl)carbamothio-yl]-2,3,4,5-tetra-fluoro-benzamide.

In the title compound, C(15)H(9)F(4)N(3)O(2)S, the N,N'-disubstituted thio-urea fragment adopts a cis,trans geometry, stabilized by an intra-molecular N-H⋯O hydrogen bond to the carbonyl O atom of the tetra-fluoro-benzoyl group. The central thio-urea group makes dihedral angles of 47.79 (7) and 35.54 (8)° with the two aromatic rings. In the crystal, mol-ecules are linked via N-H⋯O and N-H⋯S hydrogen bonds into two-dimensional polymeric structures parallel to (100). In turn, π-π stacking inter-actions between tetra-fluoro-benzene and benzene units [centroid-centroid distance = 3.996 (10) Å; dihedral angle = 13.60 (8)°] organize these two-dimensional assemblies into a three-dimensional framework.