The predictive value of nontraditional lipid parameters for intracranial and extracranial atherosclerotic stenosis: a hospital-based observational study in China.

BACKGROUND: Ischemic strokes are primarily caused by intracranial and extracranial atherosclerotic stenosis. Nontraditional lipid parameters broaden traditional lipid profiles, better reflect the metabolism and interaction between different lipid components, and optimize the predictive ability of lipid profiles for atherosclerotic diseases. This research was carried out to investigate the predictive value of nontraditional lipid parameters for intracranial or extracranial atherosclerotic stenosis. METHODS: The investigation collected data from inpatients who underwent cervical vascular ultrasonography, carotid CTA, cerebral artery CTA or MRA, and brain MRI or CT from December 2014 to December 2021. The nontraditional lipid parameters were calculated by collecting traditional lipid parameters. To evaluate the predictive power of nontraditional lipid parameters, logistic regression and receiver operating characteristic curve (ROC) analyses were performed. RESULTS: Based on the inclusion and exclusion criteria, 545 patients were included. According to the imaging results, inpatients were divided into two groups, including no intracranial or extracranial atherosclerotic stenosis (n = 250) and intracranial or extracranial atherosclerotic stenosis (AS, n = 295). Among them, AS was further divided into three subgroups: intracranial atherosclerotic stenosis (ICAS), extracranial atherosclerotic stenosis (ECAS) and combined intracranial and extracranial atherosclerotic stenosis (IECAS). Logistic regression analysis showed that nontraditional lipid parameters, including the atherogenic index of plasma (AIP), TG/HDL-C, remnant cholesterol (RC), nonhigh-density lipoprotein cholesterol (non-HDL-C), lipoprotein combine index (LCI), atherogenic coefficient (AC), Castelli's index-I (CRI-I) and Castelli's index-II (CRI-II), were significantly correlated with intracranial or extracranial atherosclerotic stenosis (P < 0.05). Compared with other nontraditional lipid parameters, regardless of adjusting for potential confounding factors, AIP had a greater OR value in ICAS (OR = 4.226, 95% CI: 1.681-10.625), ECAS (OR = 2.993, 95% CI: 1.119-8.003) and IECAS (OR = 4.502, 95% CI: 1.613-12.561). ROC curve analysis revealed that nontraditional lipid parameters had good predictive power for intracranial or extracranial atherosclerotic stenosis. CONCLUSIONS: This Chinese hospital-based study demonstrates that nontraditional lipid parameters (AIP, LCI, RC, CRI-II, AC, CRI-I and non-HDL-C) are effective predictors of intracranial and extracranial atherosclerotic stenosis, of which AIP may be a significant risk factor for predicting atherosclerotic arterial stenosis in the intracranial or extracranial regions.

Design, synthesis, and in vitro antitumor activity of 6-aryloxyl substituted quinazoline derivatives.

Quinazoline derivatives are a class of important antitumor drugs known as small molecule inhibitors that include epidermal growth factor receptor (EGFR) inhibitors. Based on the structure of poziotinib, a series of 6-aryloxyl substituted quinazoline derivatives were designed and synthesized. The in vitro antitumor activities of the compounds were evaluated by the 3-(4,5-dimethyl-thiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) method using the human gastric cancer N87 (HER2), nonsmall-cell lung cancer H1975 (EGFRT790M/L858R), and A549 (EGFRWT) cell lines. The most promising compound 4m exhibited potent antitumoral activities with IC50 values of 6.3 nM and 7.5 nM for N87 and H1975 cell lines, respectively. Meanwhile, it was less potent against A549 cancer cells with an IC50 value of 29.9 µM. The molecular docking results suggested that compound 4m has different binding modes to the wild-type and mutated EGFR.

The Synthesis, Structural Modification and Mode of Anticancer Action of Evodiamine: A Review.

BACKGROUND: Finding novel antitumor reagents from naturally occurring alkaloids is a widely accepted strategy. Evodiamine, a tryptamine indole alkaloid isolated from Evodia rutaecarpa, has a wide range of biological activities, such as anti-tumor, anti-inflammation, and anti-bacteria. Hence, research on the structural modification of evodiamine will facilitate the discovery of new antitumor drugs. OBJECTIVE: The recent advances in the synthesis of evodiamine, and studies on the drug design, biological activities, and structure-activity-relationships of its derivatives, published in patents and primary literature, are reviewed in this paper. METHODS: The literature, including patents and follow-up research papers from 2015 to 2020, related to evodiamine is searched in the Scifinder, PubMed, Espacenet, China National Knowledge Infrastructure (CNKI), and Wanfang databases. The keywords are evodiamine, synthesis, modification, anticancer, mechanism. RESULTS: The synthesis of evodiamine is summarized. Then, structural modifications of evodiamine are described, and the possible modes of action are discussed. CONCLUSION: Evodiamine has a 6/5/6/6/6 ring system, and the structural modifications are focused on rings A, D, E, C5, N-13, and N-14. Some compounds show promising anticancer potentials and warrant further study.

The Design, Synthesis and Evaluation of Rho-kinase Inhibitory Activity of 4-aryl-thiazole-2-amines.

Rho-associated kinases (ROCK) are a class of serine/threonine kinases that play important roles in various biological processes. ROCK are becoming attractive targets for drug designing. A novel scaffold was designed according to molecular hybridization strategy, then a series of 4-aryl-5-aminomethyl-thiazole-2-amines were synthesized, and their inhibitory activities on ROCK were screened by enzyme-linked immunosorbent assay (ELISA). The results showed that 4-aryl-5-aminomethyl-thiazole-2-amines derivatives displayed certain ROCK II inhibitory activities. The IC50 value of the most potent compound 4v was found to be 20 nM. The preliminary structure-activity-relationship investigation showed that compounds with 4-pyridine substitution were generally found to be more potent than compounds with 3-pyridine substitution. The molecular docking studies indicated that more optimization work needs to conduct to obtain more potent ROCK inhibitors.

Design, synthesis, and biological evaluation of urea-based ROCK2 inhibitors.

A series of urea-based ROCK2 inhibitors were design and synthesized. The inhibitory activity on ROCK2 was screened by enzyme-linked immunosorbent assay (ELISA). The study results showed that the urea derivatives exhibited certain ROCK2 inhibitory activity. The most potent compound 10p showed ROCK2 inhibitory activity with the IC50  value of 0.03 µM. A preliminary structure-activity relationship was then summarized. The molecular docking studies showed that further optimization needs to conduct to obtain more potent ROCK inhibitors.

Speciation, controlling steps and pathways of silver release from the sludge generated from coagulation of wastewater spiked with silver nanoparticles.

Sludge generated in wastewater treatment facilities is an integral part for the introduction of silver nanoparticles (AgNPs) to the terrestrial environment, which would cause some adverse ecosystem responses. The understanding of silver release process from the sludge is important to evaluate their risks. In this study, the amount and speciation of the released silver were investigated by taking the sludge generated by wastewater coagulation with AgNPs added (denoted as sludgeC-AgNPs) an example, and kinetic analysis and density functional theory (DFT) calculations were first used to explore the controlling steps and pathways about the silver release. The results showed that sludgeC-AgNPs could release the dissolved silver and the colloidal silver. Beside Cl-, Ca2+ in the leaching solution could enhance the silver release of sludgeC-AgNPs, especially for the colloidal silver. The released colloidal silver restricted in size from 40 nm to 100 nm with irregular shape. Although the oxidative dissolution of Ag0 was the origin of the silver release pathways from the sludgeC-AgNPs, the silver diffusion was the controlling step due to the spontaneous binding between silver and the hydrolysates of polyaluminium chloride in sludgeC-AgNPs. However, Ca2+ in the leaching solution could occupy the binding site of silver on sludgeC-AgNPs, which would increase the diffusion rate of silver over the oxidative rate of Ag0. With this condition, the controlling step of silver release from sludgeC-AgNPs turned to the oxidative dissolution of Ag0. Our findings are important to assess the fate of AgNPs in wastewater treatment as well as sludge applications.

Design, synthesis, and antitumor activity evaluation of pretubulysin analogs.

Pretubulysin, a biosynthetic precursor of the tubulysins, shows potent biological activity in a variety of tumor cell lines. Although there are several total synthesis routes to tubulysin and pretubulysin reported, the commercialization still has been hampered due to the complexity of the structure. To find structurally simpler pretubulysin analogs, a series of 2-(3-(methylamino)propyl)thiazole-4-carboxamides are designed and synthesized, and their anticancer activities are screened using MCF-7 (breast cancer), and NCI-H157 (lung cancer) cell lines. Taxol (IC50  = 0.01 µM) and pretubulysin are used as the control. Compounds 8c (IC50  = 0.05 µM, MCF-7; 0.09 µM, NCI-H157) and 8h (IC50  = 0.01 µM, MCF-7; 0.02 µM, NCI-H157) exhibited certain antitumor activities comparable to those of Taxol. The urea analogs of pretubulysin might represent a promising scaffold for the further development of novel antitumor drugs.

The role of natural organic matter in the silver release from sludge generated from coagulation of wastewater spiked with silver nanoparticles.

Sludge is an integral part in the migration pathway of silver nanoparticles (AgNPs) from manufacture to the terrestrial environment. However, the detailed information on the role of natural organic matters (NOMs) remains limited. In this study, the sludge generated from coagulation of wastewater spiked with AgNPs (denoted as sludgeC-AgNPs) was taken as the model. Effects of humic acid (HA), alginate (AA) and bovine serum albumin (BSA) on the release amount, dynamics and speciation of silver from the sludgeC-AgNPs were investigated by a series of leaching experiments. The results showed that HA, AA and BSA in the leaching solution could enhance the silver release from the sludgeC-AgNPs. The concentrations of the dissolved and colloidal silver in the BSA solution were the highest at the initial stage of dynamic leaching. The controlling step of the silver release was internal diffusion in the HA and AA solution, while the release of dissolved silver was controlled by both chemical reaction and internal diffusion in the BSA solution. In addition, the released colloidal silver fractions in the BSA solution contained more particles with size >50 nm compared with the HA and AA solutions. The results suggested that the properties of NOMs may be the key factor affecting the transfer of AgNPs from the sludge to the terrestrial environment.

Design, synthesis and biological evaluation of 4-aryl-5-aminoalkyl-thiazole-2-amines derivatives as ROCK II inhibitors.

A series of 4-aryl-5-aminoalkyl-thiazole-2-amines were designed and synthesized, and their inhibitory activity on ROCK II was screened by enzyme-linked immunosorbent assay (ELISA). The results showed that 4-aryl-5-aminomethyl-thiazole-2-amines derivatives had certain ROCK II inhibitory activities. Compound 10l showed ROCK II inhibitory activity with IC50 value of 20 nM.

Synthesis and Evaluation of Biological Properties of 2-Amino-thiazole-4-carboxamides: Amide Linkage Analogues of Pretubulysin.

Pretubulysin is a bio-precursor of highly toxic tetrapeptide tubulysins. Although pretubulysin has a much simpler chemical structure, it has similar anti-mitotic potency. A series of 2-amino-thiazole-4-carboxamides were designed and synthesized based on the structure of cemadotin. These are all novel compounds and their structures are characterized by 1H-NMR, 13C-NMR, and high resolution (HR)MS. The antitumor activities of these compounds were screened using the methyl thiazolyl tetrazolium colorimetric (MTT) cell viability method in MCF7 (breast cancer) and NCI-H1650 (lung cancer) cells. All the synthesized compounds 6a-n showed moderate anti-proliferation activities. Compounds 6m exhibited antitumor activity with the IC50 value of 0.47 and 1.1 µM in MCF7 and NCI-H1650 cells, respectively.

The removal of silver nanoparticle by titanium tetrachloride and modified sodium alginate composite coagulants: floc properties, membrane fouling, and floc recycle.

In this study, a modified sodium alginate (MSA) composited with TiCl4 was used to treat the synthetic Ag nanoparticles (AgNPs) water in coagulation-ultrafiltration process. The floc properties and membrane fouling of TiCl4 and MSA composite coagulants (TiCl4 + MSA) were investigated by a laser diffraction instrument and ultrafiltration fouling model. The recycle of the AgNP-containing flocs was evaluated by XRD and photocatalytic experiments. The results showed that TiCl4 + MSA could achieve better coagulation performance than TiCl4 alone with AgNP and DOC removal up to 97 and 59% at the optimum condition (pH = 5 and dosage = 12 mg TiCl4/L). TiCl4 + MSA produced larger and looser flocs than TiCl4 and TiCl4 + SA composite coagulant (TiCl4 + SA), which was benefit for the inhibition of subsequence membrane fouling. The strongly attached external fouling resistance (Ref-s) and the reversible internal fouling resistance (Rif-r) of TiCl4 + MSA were only 43 and 39.2% of those achieved by TiCl4 at the optimal coagulation condition. Besides, the adopted AgCl-TiO2 could be recycled from AgNP-containing flocs. And MSA could promote the form of TiO2 anatase. It gives us a possible way for silver nanoparticle recycle.