Physapubescin I from husk tomato suppresses SW1990 cancer cell growth by targeting kidney-type glutaminase.

Kidney-type glutaminase (KGA), catalyzing the hydrolysis of glutamine to glutamate for energy supply, is over-expressed in many cancers and has been regarded as a new therapeutic target for cancers. Physapubescin I was isolated from the fruits of the edible herb Physalis pubescens L., commonly named as "husk tomato or hairy groundcherry", and was predicted to be a potential KGA inhibitor through structure-based virtual ligand screening. Enzyme inhibition assays, microscale thermophoresis (MST) and cellular thermal shift assay (CETSA) experiments have demonstrated the high efficiency and specificity of physapubescin I targeting KGA. EdU proliferation, Hoechst 33258 staining and cytotoxicity assays indicated that physapubescin I could inhibit cancer cell proliferation and promote apoptosis more effectively than the known KGA inhibitor, BPTES. Knockdown of KGA by siRNA reduced the inhibition of physapubescin I to SW1990 cells. Meanwhile, physapubescin I impaired glutamine metabolism in SW1990 cells with increasing intracellular level of glutamine, and correspondingly decreasing glutamate and its downstream metabolites, which may account for its inhibition of cancer cell proliferation and proapoptosis. Physapubescin I also showed significant tumor growth inhibition and low toxicity in a SW1990 xenograft mouse model. Collectively, physapubescin I may serve as a potential drug candidate or lead compound for cancer therapy by targeting KGA.

Assessing the effects of short-term traffic restriction policies on traffic-related air pollutants.

The implementation of short-term traffic restriction policies (TRPs) during major events positively influences the traffic emission reduction. However, few studies explore the impact of diesel vehicle emissions on air quality during short-term TRP. In particular, the intertwined influences of short-term TRP and Spring Festival remains unclear. Based on Beijing 2022 Olympic Games, this study analyzed the spatiotemporal changes in urban air quality and diesel vehicle emission during short-term TRP. The results showed that the TRPs and Spring Festival contributed equally to the improvement of air quality and reduction of diesel vehicle emissions. The "interruption-recovery" pattern of short-term TRPs is characterized by a longer duration and a slower decline/recovery rate. Additionally, the individual contribution rate of diesel vehicle emissions to urban air pollutants was 15-20 % higher than that of meteorological factors during short-term TRPs.

Safety and efficacy of hyaluronic acid injectable filler in the treatment of nasolabial fold wrinkle: a randomized, double-blind, self-controlled clinical trial.

INTRODUCTION: The injectable skin fillers available for soft tissue augmentation are constantly growing, providing esthetic surgeons with more options in the treatment of scars, lines, and wrinkles. Hyaluronic acid (HA)-derived injectable fillers are ideal to reduce the appearance of nasolabial folding. This study investigated the efficacy and safety of the commercially available HA filler from Maxigen Biotech Inc. (MBI-FD) in the treatment of nasolabial folds (NLFs). METHODS: We analyzed 1,4-butanediol diglycidyl ether (BDDE) residues and injection force test and observed the protein content in MBI-FD, and then was cultured in fibroblast L929 cells and examined for cytotoxicity. Finally, 95 healthy participants underwent dermal filler injection therapy to evaluate the efficacy and safety for 24 and 52 weeks, respectively. RESULTS: BDDE residues in MBI-FD was <0.125 µg/mL. MBI-FD was fitted using 27- and 30-G injection needles with an average pushing force of 14.30 ± 2.07 and 36.43 ± 3.11 N, respectively. Sodium hyaluronate protein in MBI-FD was 7.19 µg/g. The cell viabilities of 1× and 0.5× MBI-FD were 83.25% ± 3.58% and 82.23% ± 1.85%, respectively, indicating MBI-FD had no cytotoxicity, and decreased NLF wrinkles with no serious adverse events. CONCLUSION: MBI-FD is an effective filler for tissue augmentation of the NLFs and may be a suitable candidate as an injectable dermal filler for tissue augmentation in humans in the future.

Design, synthesis and biological evaluation of novel HSP70 inhibitors: N, N'-disubstituted thiourea derivatives.

As novel heat shock protein 70 (HSP70) inhibitors, N, N'-disubstituted thiourea derivatives were designed and synthesized based on the X-ray structure of the ATPase domain (nucleotide binding domain, NBD). An ATPase activity inhibition assay revealed that these compounds effectively inhibited HSP70 ATPase activity. The results revealed that the compounds 370/371/374/379/380//392/394/397/404/405 and 407 can inhibit the HSP70 ATPase turnover with high percentages of inhibition: 50.42, 38.46, 50.45, 44.12, 47.13, 50.50, 40.95, 65.36, 46.23, 35.78, and 58.37 in 200 µM, respectively. Significant synergies with lapatinib were observed for compound 379 and compound 405 in the BT474 breast cancer cell line. A structure-function analysis revealed that most of the thiourea derivatives exhibited cooperative action with lapatinib in the BT474 cancer cell line and the BT/Lap(R)1.0 lapatinib-resistant cell line. HSP70 inhibitors may be developed as synergetic drugs in drug-resistant cancer therapy.

Novel nonquaternary reactivators showing reactivation efficiency for soman-inhibited human acetylcholinesterase.

Soman is a highly toxic nerve agent with strong inhibition of acetylcholinesterase (AChE), but of the few reactivators showing antidotal efficiency for soman-inhibited AChE presently are all permanently charged cationic oximes with poor penetration of the blood-brain barrier. To overcome this problem, uncharged reactivators have been designed and synthesized, but few of them were efficient for treating soman poisoning. Herein, we used a dual site biding strategy to develop more efficient uncharged reactivators. The ortho-hydroxylbenzaldoximes were chosen as reactivation ligands of AChE to prevent the secondary poisoning of AChE, and simple aromatic groups were used as peripheral site ligands of AChE, which were linked to the oximes in a similar way as that found in the reactivator HI-6. The in vitro experiment demonstrated that some of the resulting conjugates have robust activity against soman-inhibited AChE, and oxime 8b was highlighted as the most efficient one. Although not good as HI-6 in vitro, these new compounds hold promise for development of more efficient centrally acting reactivators for soman poisoning due to their novel nonquaternary structures, which are predicted to be able to cross the blood-brain barrier.

Antagonism of transforming growth factor-Beta signaling inhibits fibrosis-related genes.

In the fibrotic process, the transforming growth factor-beta1 (TGF-beta1)/Smad3 (Sma- and Mad-related protein 3) signaling plays a central role. To screen for antagonists of TGF-beta1/Smad3 signaling and to investigate their effects on the genes related to fibrosis, we construct a molecular model with a luciferase reporter gene. Results showed that both SB-431542 [4-(5-benzo[1,3]dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)-benzamide] and small interference RNA (siRNA) against Smad3 could dose-dependently suppress the reporter gene. More importantly, they both significantly inhibited the expression of plasminogen activator inhibitor-type 1 (PAI-1) and type I collagenalpha1 (Col Ialpha1) genes in rat hepatic stellate cells. Thus, SB-431542 and Smad3/siRNA may be potential therapeutics for fibrosis.