Preparation of 4-sulfonylcalix6arene-modified cotton for uranium contamination removal / 中国辐射卫生

Objective To prepare 4-sulfonylcalix[6]arene-modified cotton fibers for adsorption and removal of uranium based on the specific complexation of calix[6]arene with uranium (VI). Methods Chemical grafting was used for the modification of cotton, which reacted with α-bromoisobutyryl bromide, glycidyl methacrylate, and 4-sulfonylcalix[6]arene. Scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and infrared spectroscopy (FTIR) were used to characterize the structure of 4-sulfonylcalix[6]arene-modified cotton (Cotton S-C[6]a). A Franz diffusion cell was used to simulate uranium-contaminated skin. Laser fluorimetry was used to determine the uranium content. Results SEM, XPS, and FTIR showed that cotton fibers were successfully grafted with 4-sulfonylcalix[6]arene. The optimal conditions of Cotton S-C[6]a for the adsorption of uranium (VI) was pH 4.0, duration of 20 min, and 20 mg of adsorbent. The adsorption process fitted well with pseudo-secondary-order kinetics. The uranium removal efficiency of Cotton S-C[6]a was up to 78.46% in aqueous solution and 81.72% on skin. Conclusion The synthesized Cotton S-C[6]a is highly efficient in the removal of uranium (VI) in solution and on contaminated skin.

Discovery of novel exceptionally potent and orally active c-MET PROTACs for the treatment of tumors with MET alterations

Various c-mesenchymal-to-epithelial transition (c-MET) inhibitors are effective in the treatment of non-small cell lung cancer; however, the inevitable drug resistance remains a challenge, limiting their clinical efficacy. Therefore, novel strategies targeting c-MET are urgently required. Herein, through rational structure optimization, we obtained novel exceptionally potent and orally active c-MET proteolysis targeting chimeras (PROTACs) namely D10 and D15 based on thalidomide and tepotinib. D10 and D15 inhibited cell growth with low nanomolar IC50 values and achieved picomolar DC50 values and >99% of maximum degradation (Dmax) in EBC-1 and Hs746T cells. Mechanistically, D10 and D15 dramatically induced cell apoptosis, G1 cell cycle arrest and inhibited cell migration and invasion. Notably, intraperitoneal administration of D10 and D15 significantly inhibited tumor growth in the EBC-1 xenograft model and oral administration of D15 induced approximately complete tumor suppression in the Hs746T xenograft model with well-tolerated dose-schedules. Furthermore, D10 and D15 exerted significant anti-tumor effect in cells with c-METY1230H and c-METD1228N mutations, which are resistant to tepotinib in clinic. These findings demonstrated that D10 and D15 could serve as candidates for the treatment of tumors with MET alterations.

Human protein tyrosine phosphataseβand its inhibitors:research advances / 国际药学研究杂志

Human protein tyrosine phosphataseβ(HPTPβ)is an endothelial cell-specific receptor protein tyrosine phospha?tase(PTP). HPTPβplays an important role in regulating pathophysiological processes such as angiogenesis and cell-to-cell adherens junction,and is taken as a novel target for developing new antiatherosclerosis and antitumor drugs. In this review,the latest research progress in the structure,physiological functions and small molecular inhibitors of HPTPβis summarized.

Targeted drugs of differentiated thyroid cancer:research advances / 国际药学研究杂志

Differentiated thyroid cancer is a common endocrine malignancy,and its incidence has increased rapidly in the past 10 years.Although most patients have a good prognosis when treated with traditional methods,it is difficult to achieve satisfactory results for a small part of refractory thyroid cancer. With the understanding of the pathogenesis of thyroid cancer gradually improving to the molecular level,targeting therapy based on mechanisms and molecular targets have become a frontier area in the treatment of re?fractory thyroid cancer. Up to now,a variety of molecular targets has been found to be closely related to the incidence of thyroid can?cer,and their effectiveness and safety has been verified by clinical trials. A number of targeted drugs of refractory thyroid cancer have been found through a method of target-based drug design,and have come into clinical trials or clinical applications. The representative drugs,sorafenib and lenvatinib,were approved for the treatment of refractory differentiated thyroid cancer,which provides a new hope for the treatment of advanced thyroid cancer.

Suppression of epipolythiodioxopiperazine compound C87 on growth of tumor cells and its effect on production of reactive oxygen species / 中国药理学与毒理学杂志

OBJECTIVE To study the effect of epipolythiodioxopiperazine compound C87 on tumor cell proliferation and explore the potential mechanisms. METHODS Tumor cells were exposed to C87 0.05-1 μmol.L-1 for 24, 48 and 72 h, cell viability was determined by sulforhodamine B (SRB) assay and the half growth inhibition (Gl50 ) was calculated. After treatment with C87 0.1-2.5 μmol.L-1 for 6 h, or C87 2.5 μmol.L-1 for 0-6 h, the generation of reactive oxygen species (ROS) was measured using the compound 2′,7′-dichlorofluoresceindiacetate and flow cytometry analysis. After treatment with C87 2.5 μmol.L-1 , either alone or with antioxidant N-acetylcysteine (NAC), for 6 h, the generation of ROS was measured by flow cytometry analysis. Tumor cells were exposed to C87 0.05-1 μmol.L-1 , either alone or with NAC, for 24 and 48 h, while cell viability was determined by SRB assay. RESULTS The cell viability was significantly reduced following exposure to C87 0.05-1 μmol.L-1 for 24, 48 and 72 h in a concentration-dependent manner in A549, HCT116, HeLa and SMMC7721 cells(P<0.05). At 72 h, the value of r2 was 0.946, 0.989, 0.973 and 0.984(P<0.05), respectively. The cell viability was significantly reduced following exposure to C87 1 μmol.L-1 for 24 - 72 h in a time-dependent manner in A549, HCT116, HeLa and SMMC7721 cells(P<0.05). The value of r2 was 0.983, 0.956, 0.951 and 0.873(P<0.05), respectively. The generation of ROS was increased after exposure to C87 0.25-2.5 μmol.L-1 in a concentration-dependent manner in HCT116 and HeLa cells for 6 h (r2 = 0.760, P = 0.045: r2 = 0.987, P=0.001), and after exposure to C87 2.5 μmol.L-1 in a time-dependent manner in HCT116 and HeLa cells for 0.5-6 h (r2 = 0.886, P = 0.017: r2 = 0.994, P = 0.000).The C87-induced ROS generation could be blocked by NAC in HCT116 and HeLa cells(P<0.05). The C87 induced cell death could be blocked by NAC 5 and 10 mmol.L-1 , and the Gl50 value was 1.446 and 1.134 μmol.L-1 for 24 h (the Gl50 value of C87 group was 0.513 μmol.L-1 ), and 0.882 and 1.166 μmol.L-1 for 48 h (the Gl50 value of C87 group was 0.333 μmol.L-1 ). CONCLUSION The novel epipolythiodioxopiperazine derivative C87 exerts potent antitumor activity in vitro, possibly via triggering ROS production.

ReIationships between sodium channeI NaV 1.7 and pain / 中国药理学与毒理学杂志

Voltage-gated sodium channels (NaV1.1-NaV1.9) play important roles in the generation and maintenance of electrical excitability. NaV1.7 is preferentially expressed in peripheral somatic sensory neurons and sympathetic ganglion neurons. ln humans, gain-of-function mutations of SCN9A gene, which encodes NaV1.7, cause inherited neuropathic pain, whereas loss-of-function mutations result in a congenital indifference to pain without motor, cognitive and cardiac deficits. The effects of some analge-sics are associated, at least in part, with the NaV1.7 and selective NaV1.7 inhibitors have also been demonstrated to be analgesic in animal models. NaV1.7 has emerged as a potential target for the treat-ment of pain.

Mechanism of opioid receptor ubiquitination and its effect on receptor function / 中国药理学与毒理学杂志

Opioid receptors, as an important member of G protein coupled receptors (GPCR), are the binding targets of endogenous opioid peptides and exogenous opiates. The activation of opioid receptors influences the nervous system, immune physiology and endocrine system. However, prolonged activation of opioid receptors is likely to produce opioid tolerance, leading to opioid addiction. Receptor endocytosis and sorting into the recycling pathway contribute to recovery of cellular opioid responsiveness. Recent studies have revealed that GPCR can be modulated by ubiquitination which plays a unique roles in governing GPCR trafficking. Moreover, ubiquitination of the opioid receptors (μ, κand δ) is increased after stimulation of most opioid agonists. Mutation of the ubiquitin sites affects the internalization and degradation of opioid receptors, which contributes to changes in signal pathways and regulation of opioid receptors. ln this paper, ubiquitination of opioid receptors and the fundamental role of ubiquitination in trafficking of opioid receptors are reviewed.

Reactivation of nanoparticulated HI-6 on acetylcholinesterase activity in soman poisoned mice / 中国药理学与毒理学杂志

OBJECTIVE Based on different drug loading models,three types of nanoparticulated HI-6 were prepared and their reactivations on inhibited acetylcholinesterase (AChE)in peripheral and central nervous syste ms were evaluated and compared in so man-intoxicated mice.METHODS Three kinds of nano-reactivators including HI-6 loaded human serum albunin nanoparticle (HSA-HI-6 NP),HI-6 absorptive mesoporous silica nanoparticle(MSN-HI-6),polylactico-glycolic acid nanoparticle coated HI-6 (PLGA-HI-6 NP)were prepared.The characteristic of all blank nanocarriers was observed through elec-tron microscope.HI-6 release rate of nano-reactivators was also determined in vitro.Then the reactiva-tion rate of nano-reactivators at a constant HI-6 dosage(22 mg·kg -1 )on so man-inhabited AChE both in blood and brain was assessed the so man intoxicated mice(120 μg·kg -1 ,sc).RESULTS All the syn-thetic nanocarriers met the de mand for nanodrug use in vivo.The rate of HI-6 release of nano-reactiva-tors was HI-6 >HSA-HI-6 NPs >MSN-HI-6 >PLGA-HI-6 NP in vitro.On the reactivations of so man-inhibited mice blood AChE,the free HI-6 and HSA-HI-6 NPs,as well as MSN-HI-6 showed co mparable reactivation rates(20% -30%)but were greater than that of PLGA-HI-6 NPs (6.2%)(P <0.01 ). However on the reactivations of so man-inhibited mice brain AChE,the reactivation rate of HSA-HI-6 NP (15.3%)was significantly higher than that of PLGA-HI-6 NP(3.3%)and free HI-6(6.3)(P<0.01 ).In addition,MSN-HI-6 group had a significant reactivation rate compared to PLGA-HI-6 NPs(P <0.01 ). But there was no statistic difference between MSN-HI-6 and free HI-6.CONCLUSION The reactivation potency changed obviously with different drug loading models and HSA-HI-6 NPs had the most potent reactivation on so man-inhibited AChE in both blood and brain.