Cen Liu’s research while affiliated with Beijing University of Chinese Medicine and other places

Rat sarcoma (RAS), as a frequently mutated oncogene, has been studied as an attractive target for treating RAS-driven cancers for over four decades. However, it is until the recent success of kirsten-RAS (KRAS)G12C inhibitor that RAS gets rid of the title "undruggable". It is worth noting that the therapeutic effect of KRASG12C inhibitors on different RAS allelic mutations or even different cancers with KRASG12C varies significantly. Thus, deep understanding of the characteristics of each allelic RAS mutation will be a prerequisite for developing new RAS inhibitors. In this review, the structural and biochemical features of different RAS mutations are summarized and compared. Besides, the pathological characteristics and treatment responses of different cancers carrying RAS mutations are listed based on clinical reports. In addition, the development of RAS inhibitors, either direct or indirect, that target the downstream components in RAS pathway is summarized as well. Hopefully, this review will broaden our knowledge on RAS-targeting strategies and trigger more intensive studies on exploiting new RAS allele-specific inhibitors.

Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is an evolutionarily conserved protein kinase and the most studied member of the Dual-specificity tyrosine-regulated kinase (DYRK) family. It has been shown that it participates in the development of plenty of diseases, and both the low or high expression of DYRK1A protein could lead to disorder. Thus, DYRK1A is recognized as a key target for the therapy for these diseases, and the studies on natural or synthetic DYRK1A inhibitors have become more and more popular. Here, we provide a comprehensive review for DYRK1A from the structure and function of DYRK1A, the roles of DYRK1A in various types of diseases, including diabetes mellitus, neurodegenerative diseases, and kinds of cancers, and the studies of its natural and synthetic inhibitors.

Oxidative stress disrupts the homeostasis of the redox state in cells and induces apoptosis. Prolonged oxidative stress can impair the normal function of cells, tissues, and organs and lead to the development of several diseases. H-2 was synthesized by derivatising N-Alkylamides (NAAs) from Anacyclus pyrethrum (L.) DC, which is commonly used in the treatment of vitiligo in Uyghurs. The antioxidant activity and potential molecular mechanisms of H-2 were investigated using Caenorhabditis elegans (C. elegans) and mouse melanoma cell B16-F10 models. The in vivo anti-vitiligo activity of H-2 was studied using C57BL/6 mice. The results showed that H-2 could increase the survival time of nematodes under oxidative stress, promote the nuclear localization of DAF-16, and enhance the expression of Superoxide Dismutase 3 (SOD-3) in nematodes thereby activating the antioxidant enzyme system. H-2 could affect the survival rate of age-1 and akt-1 mutants under oxidative stress. H-2 could reverse the oxidative stress damage by reducing the reactive oxygen species (ROS) content in the Hydrogen peroxide (H2O2) -induced oxidative stress damage model of mouse melanoma cells B16-F10. In addition, it was also able to increase the number of melanocytes in the hair follicles of vitiligo model mice and improve the phenomenon of skin damage in mice. In conclusion, our findings suggest that H-2 can alleviate oxidative stress damage in C. elegans and B16-F10, which may be associated with oxidative stress, suppression of antioxidant defences, and transcription factors DAF-16/FOXO, providing beneficial evidence for the application of H-2 in the vitiligo treatment.

As a glucagon (GCG) receptor (GCGR) and glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) dual agonist, oxyntomodulin (OXM) has been attracting scientific attentions due to its efficacies of suppressing appetite, increasing energy expenditure, and inducing body weight loss in obese humans. Based on the scaffold of native OXM, specific helix-favoring amino acids substitutions and the consequent salt bridge formations were believed to offer enhanced and balanced GCGR/GLP-1R activations through increasing α-helical conformation. Novel OXM analogues are obtained by intramolecular lactam stapling of positions [Glu16 & Lys20] or [Lys17 & Glu21] to further strengthen conformationally constrained stabilization. Even though the lactam staple does not provide additional dual GCGR/GLP-1R activations in vitro, the stapled OXM analogues are firstly reported to have higher or lower anti-PANC-1 cell proliferation activity, meanwhile which has no obvious inhibitory effect on the proliferation of Hela cells. Therefore, it is speculated that the stapled analogues may have the potential to inhibit the proliferation of specific cancer cell types. Among the stapled peptides as well as their precursors, analogue 6 has the most prominent anti-PANC-1 proliferation activity with the IC50 value of 115.1 μmol/L. Its mechanism of actions including effective signal pathways should be worth further investigations in future.

Purpose Pinocembrin is a dihydroflavonoid, which is widely found in several plant species. Although pinocembrin has good pharmacological activity, it has poor water solubility and low bioavailability. Therefore, we have modified the structure of pinocembrin with a combination of different amino acids to solve this problem. Moreover, the effect of the antiaging activity of them has not been explored. We aim to investigate the effect of pinocembrin and its amino acid derivatives on the aging of Caenorhabditis elegans. Methods Pinocembrin was spliced with different amino acids in order to obtain their corresponding derivatives. The preliminary research of pinocembrin and its amino acid derivatives on antiaging effect was studied by using the C. elegans model. Among all the compounds, the one shows the best antiaging effect was then studied on antiaging mechanism. The protective effect on nematodes under emergency conditions was explained by detecting the ROS content and sod-3p::GFP fusion protein expression in nematodes; the possible anti-aging mechanism of nematodes was determined by DAF-16 nuclear localization experiment and the survival curve of transgenic nematodes model under stress conditions. Results Pb-3 showed the best effect on increasing tolerance to thermal and oxidative stress and reduce the accumulation of lipofuscin. In the assay of C. elegans, pb-3 reduced intracellular ROS accumulation. Application of pb-3 to the transgenic mutant TJ356 induced the translocation of the transcription factor DAF-16 from the cytosol to the nucleus, and modulated the expression of SOD-3 (downstream genes of daf-16), which regulates longevity in C. elegans. Moreover, pb-3 did not prolong the lifespan of daf-16, age-1, daf-2 and hsp16.2 mutants, suggesting that these genetic pathways are involved in mediating the antiaging effects of pb-3. Conclusion The antioxidant and antiaging properties of pb-3 may involve in the DAF-16/FOXO transcription process. Pinocembrin amino acid derivatives might be a novel agent for antiaging therapy.

[This corrects the article DOI: 10.2147/DDDT.S330223.].

Harmine is a beta-carboline and harmala alkaloid with extensive bioactivities. However, its toxicity, especially in neural system, is not systematically assessed and the toxic mechanism is not yet clear. Using Caenorhabditis elegans (C. elegans) as a model system, we found that harmine exhibited dosage dependent (0, 5, 10, 20, 40, 80, 160, and 320 μmol/L) toxic effect, such as growth inhibition, egg laying defects, shortened life span and increased mortality. Although harmine did not result in obvious structural alterations in neurite or death of neurons, it did show direct acetylcholinesterase inhibition activity. Further, we found that harmine treatment decreased worm pharyngeal pump rate and lowered the content of nitric oxide (NO) in worm body, implying foraging disorders, which is an indicator of acetylcholinergic neuron activity inhibition. Besides, network pharmacology and molecular docking reveals that acetylcholinesterase is one of the major neural toxicity targets as well. Above all, harmine can directly inhibit the activity of acetylcholinesterase, leading to excessive accumulation of acetylcholine, which may be one of the harmine neurotoxicity mechanisms.

Background N-Alkylamides (NAAs), derived from Anacyclus pyrethrum (L.) DC, have potential anti-tumor effects. To explore the molecular mechanism and chemo-preventive capacity of NAAs, we synthesized an NAA (H-10) and evaluated whether it could inhibit the proliferation of B16, HepG2, HeLa, and HCT116 cancer cells in 2D culture. Methods To evaluate the antiproliferative activity of H-10 in 2D and 3D culture of BD, HepG2, HeLa, and HCT116 cells, multicellular tumor spheroids were constructed to more accurately reflect the cell tumor environment. To visualize nuclear changes related to apoptosis, Hoechst 33258 staining and propidium iodide-Annexin V double staining were performed. Results Compound H-10 strongly inhibited the growth of all tested cell lines. Hoechst 33258 staining and propidium iodide-Annexin V double staining revealed that H-10 did not cause morphological alterations in the nuclei and moderately induced late apoptosis only when treated at 180 μM. The strongest inhibitory effect was observed in HCT116 cells. Flow cytometry analysis indicated that treatment of HCT116 cells with compound H-10 resulted in robust cell growth arrest in G2 phase in 2D and 3D cell culture; in 3D-cultured HCT116 cells, growth arrest occurred in G1 phase. Treatment with compound H-10 also significantly suppressed angiogenesis of chick chorioallantoic membrane in vivo. Conclusion Treatment with compound H-10 strongly affected clonogenic survival (in the long-term) and migration of HCT116 cells. Therefore, H-10, a compound of NAAs may be useful for treating cancer because of its anti-neoplastic effect and easy synthesis.