Introduction of fluorine to phenyl group of 4-(2-pyrimidinylamino)benzamides leading to a series of potent hedgehog signaling pathway inhibitors

In present study, a novel series of fluorine containing 4-(2-pyrimidinylamino)benzamide analogues were designed and synthesized. The hedgehog (Hh) signaling inhibitory activities for these compounds were evaluated by a luciferase reporter method. The preliminary SAR was discussed and many compounds showed potent Hh signaling inhibitory activities. Compound 15h displayed the most potent inhibitory activity, with an IC₅₀ of 0.050 nM. This paper finds the introduction of fluorine to the 4-(2-pyrimidinylamino)benzamide scaffold can lead to a novel series of potent Hh signaling pathway inhibitors.     

Identification of highly potent and selective PI3Kδ inhibitors

Selective PI3Kδ inhibitors have recently been hypothesized to be appropriate immunosuppressive agents for the treatment of immunological disorders such as rheumatoid arthritis. However, few reports have highlighted molecules that are highly selective for PI3Kδ over the other PI3K isoforms. In this letter, isoform and kinome selective PI3Kδ inhibitors are presented. The Structural Activity Relationship leading to such molecules is outlined.     

Association Between Tumor Necrosis Factor-α and Diabetic Peripheral Neuropathy in Patients with Type 2 Diabetes: a Meta-Analysis

Tumor necrosis factor-α (TNF-α) is a cell signaling protein involved in systemic inflammation, and is also an important cytokine in the acute phase reaction. Several studies suggested a possible association between TNF-α and diabetic peripheral neuropathy (DPN) in type 2 diabetic patients, but no accurate conclusion was available. A systematic review and meta-analysis of observational studies was performed to comprehensively assess the association between serum TNF-α levels and DPN in type 2 diabetic patients. We searched Pubmed, Web of Science, Embase, and China Biology Medicine (CMB) databases for eligible studies. Study-specific data were combined using meta-analysis. Fourteen studies were finally included into the meta-analysis, which involved a total of 2650 participants. Meta-analysis showed that there were obviously increased serum TNF-α levels in DPN patients compared with type 2 diabetic patients without DPN (standard mean difference [SMD]?=?1.203, 95 % CI 0.795–1.611, P?<?0.001). There were also obviously increased levels of serum TNF-α in diabetic patients with DPN when compared with healthy controls (SMD?=?2.364, 95 % CI 1.333–3.394, P?<?0.001). In addition, there were increased serum TNF-α levels in painful DPN patients compared with painless DPN patients (SMD?=?0.964, 95 % CI 0.237–1.690, P?=?0.009). High level of serum TNF-α was significantly associated with increased risk of DPN in patients with type 2 diabetes (odds ratio [OR]?=?2.594, 95 % CI 1.182–5.500, P?=?0.017). Increased serum levels of TNF-α was not associated with increased risk of painful DPN in patients with type 2 diabetes (OR?=?2.486, 95 % CI 0.672–9.193, P?=?0.172). Sensitivity analysis showed that there was no obvious change in the pooled estimates when omitting single study by turns. Type 2 diabetic patients with peripheral neuropathy have obviously increased serum TNF-α levels than type 2 diabetic patients without peripheral neuropathy and healthy controls, and high level of serum TNF-α may be associated with increased risk of peripheral neuropathy independently. Further prospective cohort studies are needed to assess the association between TNF-α and DPN.     

有机氯农药在大滨鹬和红腹滨鹬体内的富集程度

为探讨东亚-澳大利西亚迁徙路线上的鸻鹬类体内有机氯农药的含量及来源,本研究以该迁徙路线上的大滨鹬(Calidris tenuirostris)和红腹滨鹬(C.canutus)为研究对象,用索氏提取法对这两种鸟的胸肌和皮下脂肪中的有机污染物进行萃取,并用气相色谱法对19种有机氯农药进行检测。结果表明,HCHs、DDTs、硫丹Ⅱ等14种有机氯农药在大滨鹬和红腹滨鹬的组织中均有不同程度的检出,所有样品中的含量最高值达1 573.5 ng/g脂重;在检出的14种有机氯农药中,α-HCH、β-HCH、γ-HCH、p,p′-DDE、硫丹Ⅱ、硫丹硫酸酯和/或p,p′-DDT的检出率达100%;在大滨鹬的肌肉组织、红腹滨鹬的肌肉和脂肪组织中,p,p′-DDE的残留量最高;而在大滨鹬的脂肪组织中硫丹硫酸酯和/或p,p′-DDT的含量最高;目标物中的艾氏剂、异狄氏剂、七氯、反式氯丹等未达检出限或含量较低。我们对比了不同物种及不同组织样本中有机氯农药的富集程度,红腹滨鹬的肌肉组织中HCHs的沉积量显著高于大滨鹬,而大滨鹬的脂肪组织中硫丹硫酸酯和/或p,p′-DDT的含量显著高于红腹滨鹬。此外,分别对比两个物种的肌肉组织和脂肪组织中有机氯农药沉积量,部分有机氯农药在脂肪组织中的沉积量显著高于肌肉组织,说明相比于肌肉组织,有机氯农药可能更易于在脂肪组织中累积。     

Histone acetylation and reactive oxygen species are involved in the preprophase arrest induced by sodium butyrate in maize roots

Histone acetylation plays a critical role in controlling chromatin structure, and reactive oxygen species (ROS) are involved in cell cycle progression. To study the relationship between histone acetylation and cell cycle progression in plants, sodium butyrate (NaB), a histone deacetylase (HDAC) inhibitor that can cause a significant increase in histone acetylation in both mammal and plant genomes, was applied to treat maize seedlings. The results showed that NaB had significant inhibition effects on different root zones at the tissue level and caused cell cycle arrest at preprophase in the root meristem zones. This effect was accompanied by a dramatic increase in the total level of acetylated lysine 9 on histone H3 (H3K9ac) and acetylated lysine 5 on histone H4 (H4K5ac). The exposure of maize roots in NaB led to a continuous rise of intracellular ROS concentration, accompanied by a higher electrolyte leakage ratio and malondialdehyde (MDA) relative value. The NaB-treated group displayed negative results in both TdT-mediated dUTP nick end labelling (TUNEL) and γ-H2AX immunostaining assays. The expression of topoisomerase genes was reduced after treatment with NaB. These results suggested that NaB increased the levels of H3K9ac and H4K5ac and could cause preprophase arrest accompanied with ROS formation leading to the inhibition of DNA topoisomerase.