Synthesis and biological evaluation of 4-phenyl-5-quinolinyl substituted isoxazole analogues as potent cytotoxic and tubulin polymerization inhibitors against ESCC.

The identification of chemically different inhibitors that target the colchicine site of tubulin is still of great value for cancer treatment. Combretastatin A-4(CA-4), a naturally occurring colchicine-site binder characterized by its structural simplicity and biological activity, has served as a structural blueprint for the development of novel analogues with improved safety and therapeutic efficacy. In this study, a library of forty-eight 4-phenyl-5-quinolinyl substituted triazole, pyrazole or isoxazole analouges of CA-4, were synthesized and evaluated for their cytotoxicity against Esophageal Squamous Cell Carcinoma (ESCC) cell lines. Compound C11, which features a 2-methyl substitution at the quinoline and carries an isoxazole ring, emerged as the most promising, with 48 h IC50s of less than 20 nmol/L against two ESCC cell lines. The findings from EBI competitive assay, CETA, and in vitro tubulin polymerization assay of C11 are consistent with those of the positive control colchicine, demonstrating the clear affinity of compound C11 to the colchicine binding site. The subsequent cellular-based mechanism studies revealed that C11 significantly inhibited ESCC cell proliferation, arrested cell cycle at the M phase, induced apoptosis, and impeded migration. Experiments conducted in vivo further confirmed that C11 effectively suppressed the growth of ESCC without showing any toxicity towards the selected animal species. Overall, our research suggests that the tubulin polymerization inhibitor incorporating quinoline and the isoxazole ring may deserve consideration for cancer therapy.

Discovery of the 2,4-disubstituted quinazoline derivative as a novel neddylation inhibitor for tumor therapy.

Overactivation of neddylation has been found in a number of common human tumor-related diseases. In recent years, targeting the neddylation pathway has become an appealing anti-cancer strategy, and it is critical to find neddylation inhibitors with novel structures and higher efficacy. Here, we present the discovery of novel inhibitors of the NEDD8-activating enzyme (NAE) and their antitumor activity in vitro. All synthesized 1,4-disubstituted piperidine compounds were evaluated for antiproliferative activity against MGC-803, MCF-7, A549, and KYSE-30 cells. Among five representative compounds, III-26 bearing a quinazoline motif was identified as the lead one due to the fact that it significantly hindered the neddylation of Cullin1. Cellular mechanisms elucidated that III-26 inhibited the proliferation, migration, and invasion of UBC12-overexpressed MGC-803 cell lines, as well as induced apoptosis and arrested the cell cycle at G2/M phase. Importantly, III-26 reduced NAE activity, thus selectively preventing neddylation of Cullin3 and Cullin1 over other Cullin members. At a dose of 4 µM, III-26 virtually entirely blocked UBC12-NEDD8 conjugation in MGC-803 cells. Our molecular modeling and kinetic investigation suggested that this compound may function as a non-covalent inhibitor of NAE.

Discovery of novel tranylcypromine-based derivatives as LSD1 inhibitors for gastric cancer treatment.

As an important epigenetic regulator, histone lysine specific demethylase 1 (LSD1) has become an attractive target for the discovery of anticancer agents. In this work, a series of tranylcypromine-based derivatives were designed and synthesized. Among them, compound 12u exhibited the most potent inhibitory potency on LSD1 (IC50 = 25.3 nM), and also displayed good antiproliferative effects on MGC-803, KYSE450 and HCT-116 cells with IC50 values of 14.3, 22.8 and 16.3 µM, respectively. Further studies revealed that compound 12u could directly act on LSD1 and inhibit LSD1 in MGC-803 cells, thereby significantly increasing the expression levels of mono-/bi-methylation of H3K4 and H3K9. In addition, compound 12u could induce apoptosis and differentiation, inhibit migration and cell stemness in MGC-803 cells. All these findings suggested that compound 12u was an active tranylcypromine-based derivative as a LSD1 inhibitor that inhibited gastric cancer.

Phloroglucinol inhibits oxytocin-induced contraction in rat gastric circular muscle and uterine smooth muscle.

Phloroglucinol is commonly used to alleviate dysmenorrhoea and stomach cramps. However, there is little evidence of phloroglucinol in the mechanism of primary dysmenorrhoea (PD) development. In this study, a PD rat model was established. The effects of phloroglucinol on the contraction of rat gastric circular muscle and uterine smooth muscle induced by oxytocin (OT) were investigated. The writhing response, and levels of oestradiol (E2), prostaglandin e2 (PGE2), and prostaglandin f2α (PGF2α) were determined. The protein and mRNA levels of OT receptor (OTR) were detected. OT showed a significant promoting effect on gastric circular muscle and uterine smooth muscle contraction. However, phloroglucinol strongly inhibited the contraction induced by 10-6 mol/L of OT. We also found that phloroglucinol reduced writhing response and attenuated uterine damage. Compared to the blank group, E2 and PGF2α were significantly increased, but PGE2 was significantly decreased in the PD model group. Phloroglucinol was found to reverse the changes of E2, PGF2α and PGE2. Moreover, phloroglucinol reduced the protein and mRNA levels of OTR. In conclusion, phloroglucinol could attenuate PD and inhibit the contraction of rat gastric circular muscle and uterine smooth muscle induced by OT. The mechanism might be related with the regulation of OTR expression.IMPACT STATEMENTWhat is already known on this subject? Phloroglucinol is commonly used to alleviate dysmenorrhoea and stomach cramps. However, there is little evidence of phloroglucinol in the mechanism of primary dysmenorrhoea (PD) development.What do the results of this study add? Phloroglucinol could attenuate PD and inhibit the contraction of rat gastric circular muscle and uterine smooth muscle induced by OT. The underlying mechanisms of phloroglucinol for PD treatment may be associated with OTR.What are the implications of these findings for clinical practice and/or further research? These findings provide novel ideas for the role of phloroglucinol in PD development.

Associations of perfluoroalkyl and polyfluoroalkyl substances with gestational hypertension and blood pressure during pregnancy: A cohort study.

Previous studies have reported inconsistent associations between perfluoroalkyl and polyfluoroalkyl substances (PFAS) and gestational hypertension (GH) and blood pressure (BP) during pregnancy. Herein, we aimed to evaluate individual and overall effects of PFAS on GH and longitudinal BP measures during pregnancy. We included 826 pregnant women from the Jiashan Birth Cohort established between 2016 and 2018. Concentrations of thirteen PFAS were quantified using plasma samples collected within 16 weeks of gestation. Longitudinal BP measures were obtained from medical records, and more than nine measurements were available for 85.60% of participants. GH was defined as new-onset hypertension occurring after 20 weeks of gestation. Logistic regression models were used to examine the effect of PFAS on GH, while generalized estimating equation models evaluated the average effect of PFAS on BP in each trimester. The potential effect modification by fetal sex was also examined. Bayesian kernel machine regression (BKMR) and quantile g-computation (QgC) were implemented to explore the overall effect of the PFAS mixture. PFOA, PFOS, and PFHxS presented the highest median concentrations of 11.99, 8.81 and 5.43 ng/mL, respectively. Overall, 5.57% of subjects developed GH. PFOS, PFDA, PFUdA, and PFDoA were significantly associated with lower GH odds, and odds ratios ranged between 0.62 and 0.68. We noted associations between PFAS and lower systolic BP and diastolic BP in the third trimester, with PFDA and PFUdA exhibiting the effect on systolic BP only in pregnant women carrying a female fetus. These associations were further confirmed by BKMR and QgC, showing an inverse overall effect of the PFAS mixture. Higher concentrations of PFAS during early pregnancy were associated with lower GH risk and longitudinal BP measures in the third trimester in a population with relatively high exposure levels. Fetal sex might modify the effects of PFDA and PFUdA on systolic BP in the third trimester.

Association of pre-pregnancy body mass index and gestational weight gain with neonatal anogenital distance in a Chinese birth cohort.

BACKGROUND: This study aimed to investigate the associations of pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) with anogenital distance (AGD) among newborns. METHODS: The study included 556 mother-newborn pairs from the Jiashan birth cohort. AGD was measured as AGDAP (from the center of the anus to the anterior base of the penis, where the penile tissue meets the pubic bone) and AGDAS (from the center of the anus to the posterior base of the scrotum, where the skin changes from rugate to smooth) in males and AGDAC (from the center of the anus to the clitoris) and AGDAF (from the center of the anus to the posterior convergence of the fourchette) in females. Multiple linear regression models were used to estimate the associations of pre-pregnancy BMI and GWG, with AGD. RESULTS: After adjusting for pre-pregnancy BMI and other potential confounders, male newborns whose mothers had excessive GWG had shorter AGDAP than those whose mothers had normal GWG. Male newborns whose mothers had normal pre-pregnancy BMI and inadequate/excessive GWG had shorter AGDAP than the reference group where mothers had normal pre-pregnancy BMI and GWG in stratified analyses. CONCLUSION: Gestational weight gain during pregnancy was associated with AGD in newborns in this birth cohort.

In China, the prevalence of underweight and overweight/obesity remained high among women. Appropriate pre-pregnancy body mass index (BMI) and gestation weight gain (GWG) were critical to reduce the risk of adverse birth outcomes. The anogenital distance (AGD) was measured as an indicator of neonatal reproductive function and was associated with adverse reproductive outcomes in adults. Thus, we investigated the associations of both sub-optimal pre-pregnancy BMI, as well as GWG, with AGD among newborns to draw a picture about their effect on offspring reproductive health.A total of 556 mother-newborns were included in the study from the Jiashan birth cohort in China. We extracted information about maternal lifestyles, social demographic characteristics, diet, and medical history from questionnaires conducted during 8­16 gestational weeks and medical records. AGD among newborns was measured within 3 days of delivery.We found that maternal excessive GWG was associated with shorter AGD in male newborns after adjusting for maternal pre-pregnancy BMI in multiple linear regression models. The study also suggested that maternal inadequate GWG was associated with a shorter AGD in male newborns, which needed to be corroborated in further studies with a larger sample size.In conclusion, health professionals shall implement sufficient intervention to prevent suboptimal GWG during prenatal checkups.

Discovery of N-aryl sulphonamide-quinazoline derivatives as anti-gastric cancer agents in vitro and in vivo via activating the Hippo signalling pathway.

Hippo signalling pathway plays a crucial role in tumorigenesis and cancer progression. In this work, we identified an N-aryl sulphonamide-quinazoline derivative, compound 9i as an anti-gastric cancer agent, which exhibited potent antiproliferative ability with IC50 values of 0.36 µM (MGC-803 cells), 0.70 µM (HCT-116 cells), 1.04 µM (PC-3 cells), and 0.81 µM (MCF-7 cells), respectively and inhibited YAP activity by the activation of p-LATS. Compound 9i was effective in suppressing MGC-803 xenograft tumour growth in nude mice without obvious toxicity and significantly down-regulated the expression of YAP in vivo. Compound 9i arrested cells in the G2/M phase, induced intrinsic apoptosis, and inhibited cell colony formation in MGC-803 and SGC-7901 cells. Therefore, compound 9i is to be reported as an anti-gastric cancer agent via activating the Hippo signalling pathway and might help foster a new strategy for the cancer treatment by activating the Hippo signalling pathway regulatory function to inhibit the activity of YAP.

Review of NEDDylation inhibition activity detection methods.

NEDDylation is a post-translational modification of a protein, which transfers Ubiquitin like protein NEDD8 (Neuronal Precursor Cell-expressed Developmentally Down-regulated Protein 8) to the lysine residue of the product through a three-stage enzymatic reaction, and widely regulates many biological processes, such as cell cycle signal transduction and immune recognition. In the past ten years, we have witnessed tremendous progress in the study of protein ubiquitination modification, from modification mechanisms to drug development. Which suggests that inhibition of NEDDylation is an effective way to inhibit tumor. A variety of biological detection methods have been developed during the development of the inhibitor. In this review, we briefly introduced the modification process and substrates of NEDDylation, and discussed detection methods of NEDDylation activity in detail. This review will provide an up-to-date and comprehensive review of the methods for detecting NEDDylation activity that will contribute to NEDDylation inhibitor development.

Prenatal plasma concentrations of Perfluoroalkyl and polyfluoroalkyl substances and neuropsychological development in children at four years of age.

OBJECTIVE: Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are persistent pollutants and have endocrine disruptive and neurotoxic effects. The association between maternal PFAS concentrations and neuropsychological development in children is inconclusive. The present study aimed to examine the effect of maternal PFAS concentrations on neuropsychological development in 4-years-old children. METHODS: We used data from Shanghai-Minhang Birth Cohort, which recruited pregnant women at 12-16 gestational weeks. Among 981 women having PFAS measurement, 533 mother-child pairs were included in the study. A total of eight PFASs were measured, including perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonate (PFHxS), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUdA), perfluorododecanoic acid (PFDoA), and perfluorotridecanoic acid (PFTrDA). When infants turned 4 years old, mothers were asked to complete the Ages and Stages Questionnaires® (ASQ) to assess neuropsychological development of their children. Poisson regression model with robust variance estimates was used to examine the association between maternal PFAS concentrations and each developmental subscale of the ASQ. RESULTS: Prenatal plasma concentrations of most PFASs tended to be associated with increased risk of development problem in personal-social skills, including PFHxS, PFOS, PFOA, PFNA, PFDA, and PDUdA, and the associations for PFNA and PFDA were significant (per natural log unit increase: RRPFNA = 1.92, 95% CI: 1.21, 3.05; RR PFDA = 1.66, 95% CI: 1.17, 2.37). In stratified analyses by child' sex, the consistent pattern of higher risk of developmental problems in personal-social skills associated with most PFASs was mainly observed among girls (RRPFOS = 2.56, 95% CI: 1.20, 5.45; RRPFOA = 9.00, 95% CI: 3.82, 21.21; RRPFNA = 3.11, 95% CI: 1.36, 7.13; RRPFDA = 2.20, 95% CI: 1.21, 4.00; RRPFUdA = 2.44, 95% CI: 1.14, 5.20; RRPFDoA = 1.62, 95% CI: 1.04, 2.54). Boys with higher maternal PFOA concentrations had a decreased risk of developmental problems in gross motor skills (RR = 0.47, 95% CI: 0.25, 0.89). CONCLUSION: Prenatal plasma PFAS concentrations were associated with neuropsychological development in girls at 4 years of age, mainly in the subset of personal-social skills.

Interactions between Nitrogen and Silicon in Rice and Their Effects on Resistance toward the Brown Planthopper Nilaparvata lugens.

Nitrogen (N) and silicon (Si) are two important nutritional elements required for plant growth, and both impact host plant resistance toward insect herbivores. The interaction between the two elements may therefore play a significant role in determining host plant resistance. We investigated this interaction in rice (Oryza sativa L.) and its effect on resistance to the herbivore brown planthopper Nilaparvata lugens (BPH). Our results indicate that high-level (5.76 mM) N fertilization reduced Si accumulation in rice leaves, and furthermore, this decrease was likely due to decreased expression of Si transporters OsLsi1 and OsLsi2. Conversely, reduced N accumulation was observed at high N fertilization levels when Si was exogenously provided, and this was associated with down-regulation of OsAMT1;1 and OsGS1;1, which are involved in ammonium uptake and assimilation, respectively. Under lower N fertilization levels (0.72 and/or 1.44 mM), Si amendment resulted in increased OsNRT1:1, OsGS2, OsFd-GOGAT, OsNADH-GOGAT2, and OsGDH2 expression. Additionally, bioassays revealed that high N fertilization level significantly decreased rice resistance to BPH, and the opposite effect was observed when Si was provided. These results provide additional insight into the antagonistic interaction between Si and N accumulation in rice, and the effects on plant growth and susceptibility to herbivores.