Design, synthesis and antitumor activity evaluation of novel indole acrylamide derivatives as IMPDH inhibitors.

Inosine 5'-monophosphate dehydrogenase (IMPDH; EC1.1.1.205) is the rate-limiting enzyme of GMP biosynthesis. The inhibition of IMPDH limits the growth and survival of tumors. Based on the systematic summary of clinical IMPDH inhibitors, 38 acrylamide derivatives with differently substituted indoles at the 3-position as the core scaffold were designed and synthesized. In addition, the actions of these compounds at the enzyme and cellular levels were evaluated. An MTT assay with different kinds of cells was used to assess the cytotoxic activities of compounds 14e and 14n, which displayed potent hIMPDH2 inhibitory activities (IC50 = 4.207 and 2.948 µM, respectively). Biological evaluation indicated that target compounds 14e and 14n displayed the most significant effects on SW480 human colon cancer cells (IC50 = 15.34 ± 0.06 and 15.31 ± 0.09 µM, respectively), and it was determined that these compounds are effective and valuable IMPDH inhibitors for cancer intervention.

Identification of Novel Artemisinin Hybrids Induce Apoptosis and Ferroptosis in MCF-7 Cells.

A series of novel 1,3,4-oxadiazole-artemisinin hybrids have been designed and synthesized. An MTT assay revealed that most of tested hybrids showed more enhanced anti-proliferative activities than artemisinin, among which A8 had the superior potency with IC50 values ranging from 4.07 µM to 9.71 µM against five tested cancer cell lines. Cell colony formation assays showed that A8 could inhibit significantly more cell proliferation than artemisinin and 5-fluorouracil. Further mechanism studies reveal that A8 induces apoptosis and ferroptosis in MCF-7 cells in a dose-dependent manner, and CYPs inhibition assays reveal that A8 has a moderate inhibitory effect on CYP1A2 and CYP3A4 in the human body at 10 µM. The present work indicates that hybrid A8 may merit further investigation as a potential therapeutic agent.

The binocular intraocular lens power difference in eyes with different axial lengths.

AIM: To investigate the binocular intraocular lens (IOL) power difference in eyes with short, normal, and long axial lengths (AL) using Lenstar LS 900 optical biometry. METHODS: A total of 716 (1432 eyes) participants were included. The groups were categorized into short (group A: AL<22 mm), normal (group B: 22 mm≤AL≤25 mm), and long AL groups (group C: AL>25 mm). The central corneal thickness (CCT), anterior chamber depth (ACD), lens thickness (LT), AL, anterior corneal keratometry, white-to-white (WTW), pupil diameter (PD), as well as IOL power calculated using embedded Barrett formula were assessed. Bland-Altman plots were used to test the agreement of the binocular parameters. RESULTS: In group A, the CCT of the right eye was significantly thinner than that of the left eye (P=0.044) with a difference of -2±8 µm [95% limits of agreement (LoA), -17.8 to 13.2 µm]. For group B, the PD and IOL power in the right eye were significantly lower than those of the left eye (P=0.001, <0.001) with a difference of -0.05±0.32 mm (95%LoA, -0.68 to 0.58 mm) and -0.18±1.01 D (95%LoA, -2.2 to 1.8 D). The AL of right eye was longer than that of the left eye (P=0.002) with a difference of 0.04±0.25 mm (95%LoA, -0.45 to 0.52 mm). No significant difference was observed for all the binocular parameters in group C. The percentage of participants with binocular IOL power difference within ±0.5 D were 62% (31/50), 68.3% (339/496), and 38.8% (66/170) in groups A, B, and C, respectively. CONCLUSION: The binocular parameters related to IOL power are in good agreement, but the binocular IOL power difference of more than half of participants with long AL is more than 0.50 D.

Mechanism of Shengmai Injection on Anti-Sepsis and Protective Activities of Intestinal Mucosal Barrier in Mice.

OBJECTIVE: To study the mechanism of Shengmai Injection (SMI, ) on anti-sepsis and protective activities of intestinal mucosal barrier. METHODS: The contents of 11 active components of SMI including ginsenoside Rb1, Rb2, Rb3, Rd, Re, Rf, Rg1, Rg2, ophioposide D, schisandrol A and schisantherin A were determined using ultra-performance liquid chromatography. Fifty mice were randomly divided into the blank, the model, the low-, medium- and high-dose SMI groups (0.375, 0.75, 1.5 mL/kg, respectively) by random number table, 10 mice in each group. In SMI group, SMI was administrated to mice daily via tail vein injection for 3 consecutive days, while the mice in the blank and model groups were given 0.1 mL of normal saline. One hour after the last SMI administration, except the blank group, the mice in other groups were intraperitoneally injected with lipopolysaccharide (LPS) saline solution (2 mL/kg) at a dosage of 5 mL/kg for development of endotoxemia mice model. The mice in the blank group were given the same volume of normal saline. Inflammatory factors including interferon-γ (INF-γ), tumor necrosis factor-α (TNF-α), interleukin (IL)-2 and IL-10 were measured by flow cytometry. Myosin light-chain kinase (MLCK), nuclear factor κB (NF-κB) levels, and change of Occludin proteins in jejunum samples were analyzed by Western blot. RESULTS: The decreasing trends of INF-γ, TNF-α and IL-2 were found in serum of SMI treatment groups. In SMI-treated mice, the content of Occludin increased and MLCK protein decreased compared with the model group (P<0.05 or P<0.01). The content of cellular and nuclear NF-κB did not change significantly (P>0.05). CONCLUSION: SMI may exert its anti-sepsis activity mainly through NF-κB-pro-inflammatory factor-MLCK-TJ cascade.

TRIM65 supports bladder urothelial carcinoma cell aggressiveness by promoting ANXA2 ubiquitination and degradation.

Clinically, most of human urothelial carcinoma of the bladder (UCB)-related deaths result from tumor metastasis, but the underlying molecular mechanisms are largely unknown. Recently, a growing number of tripartite motif (TRIM) family members have been suggested to be important regulators for tumorigenesis. However, the impact of most TRIM members on UCB pathogenesis is unclear. In this study, TRIM65 was first screened as an important oncogenic factor of UCB from the Cancer Genome Atlas (TCGA) database and was validated by a large cohort of clinical UCB tissues. By in vitro and in vivo experiments, we demonstrated that TRIM65 promotes UCB cell invasive and metastatic capacities. Notably, we showed that TRIM65 modulates cytoskeleton rearrangement and induces UCB cells epithelial-mesenchymal transition by the ubiquitination of ANXA2, ultimately leading to an enhanced invasiveness of UCB cells. Importantly, UCBs with high expression of TRIM65 and low expression of ANXA2 showed the poorest outcome. Collectively, our results suggest that the overexpression of TRIM65 has an essential oncogenic role via ubiquitination of ANXA2 in UCB pathogenesis, and that such could be used as a novel prognostic marker and/or therapeutic target for UCB.