Wnt/β-catenin signaling pathway plays an important role in the proliferation, growth, invasion, and metastasis of human cancers. Moreover, β-catenin/T-cell factor 4 (TCF4) interaction regulates the transcription of the key oncogenes in Wnt/β-catenin signaling pathway. Therefore, β-catenin/TCF4 interaction would be a promising therapeutic target for the development of highly selective anticancer agents. At present, most ongoing small-molecule inhibitors targeting β-catenin/TCF4 interaction, including PKF222-815, iCRT3/5/14, LF3, and sanguinarine, have been developed in preclinical studies for human cancer therapeutics. In this review, we summarized the research advances of up-to date inhibitors targeting β-catenin/TCF4 interaction, including the molecular structure and cellular functions of β-catenin in canonical Wnt signaling pathway. This review holds a hopeful avenue for the development of novel and highly selective Wnt inhibitors targeting β-catenin/TCF4 interaction for future anticancer strategy.

Pneumonia caused by SARS-CoV-2 has seriously threatened human life and health worldwide and caused a large number of deaths. Viral infection and acute inflammation are important causes of death, so it is particularly important to combine antiviral therapy with anti-inflammatory therapy. Glycyrrhizic acid, the main component of the glycyrrhizic root extract, has a wide range of pharmacological effects as well as high efficiency and low toxicity, its preparation has been widely used in the treatment of chronic hepatitis and other diseases. Glycyrrhizic acid can regulate the expression and release of a variety of cytokines and play a significant anti-inflammatory effect. At the same time, glycyrrhizic acid also showed significant inhibition towards a variety types of viruses. Therefore, the potential application of glycyrrhizic acid as COVID-19 treatment should be explored.

Rheumatoid arthritis (RA) is an autoimmune disease with angiogenesis, inflammatory factor infiltration and joint destruction as the main pathological features. Angiogenesis promotes the development of RA and plays an important role in its pathogenesis. The hypoxia-inducible factor (HIF)-vascular endothelial growth factor (VEGF)-angiopoietin-2 (Ang-2) signal transduction is a critical pathway to induce synovial angiogenesis. Targeting HIF-VEGF-Ang-2 signal transduction to inhibit synovial angiogenesis is a promising approach for RA treatment. This article reviews the role and mechanism of HIF-VEGF-Ang-2 signal transduction-mediated synovial angiogenesis in RA, in order to provide a new target and strategy for RA treatment.

Environmentally sensitive hydrogels are a novel formulation that has developed rapidly in recent years. It could form semi-solid with good adhesion in the topical sites based on different physiological environments. Its long local retention time is conducive for sustained drug release, and the preparation process is relatively simple and easy to realize industrialization. This review summarized the categories, commonly used polymer, and different administration routes based on the recently published literatures. According to different response factors, it can be divided into temperature, pH, ion, light, and multiple sensitive hydrogels, among which temperature-sensitive hydrogels are the most common. The most commonly used polymers include chitosan, poly N-isopropyl acrylamide, and poloxamer. There are different administration routes for environmentally sensitive hydrogels, such as transdermal, ophthalmic, nasal, oral, vaginal, rectal, injection, etc. Environmentally sensitive hydrogels have broad prospects in clinical application.

Melittin exhibits high antibacterial potency against drug-resistant bacteria. However, the clinical utility of melittin is limited by its serious hemolytic activity. Thus, the need for developing novel melittin analogues with high antimicrobial activity and low hemolytic activity has grown. We designed, synthesized, and evaluated 20 novel melittin analogues with varying hydrophobic, polar or positively charged amino acids. The results showed that 8 compounds had antimicrobial activity (MIC: 1-4 μg·mL^-1) against gram-positive pathogens equal to or better than that of melittin, and 16 compounds had low hemolytic activity (HC₅₀ ≥ 11.9 μg·mL^-1). Compounds 13 (MIC: 2-4 μg·mL^-1) and 15 (MIC: 1-2 μg·mL^-1) showed equal or better antimicrobial activity against both susceptible and resistant strains of Staphylococcus aureus and Enterococcus faecium compared to melittin (MIC: 4 μg·mL^-1). Compound 13 (HC₅₀: 24.0±4.3 μg·mL^-1) displayed noticeably decreased hemolytic activity compared to melittin (HC₅₀: 5.3±0.4 μg·mL^-1). This work established a base for further study on the structure-activity relationships and structure-toxicity relationships of melittin.

Qing-Fei-Pai-Du decoction (QFPDD) is a combination of traditional Chinese medicine and plays an important role in the treatment of coronavirus disease 2019 (COVID-19). This study investigated the inhibitory effect of QFPDD on coronavirus replication and antiviral mechanism. The cytotoxicity of QFPDD was determined by PrestoBlue cell viability assay. Quantitive reverse transcription PCR (qRT-PCR) and immunofluorescence assay (IF) were used to detect the inhibitory effects of QFPDD on coronavirus at RNA and protein levels. qRT-PCR was used to detect the adsorption and penetration of coronavirus after QFPDD treatment. The effects of QFPDD on interferon (IFN) and interferon-stimulated genes (ISGs) were also detected by qRT-PCR. The results showed that QFPDD inhibited coronavirus at RNA and protein levels in a dose-dependent manner at non-toxic concentration, and QFPDD targeted in the early stages of coronavirus infection cycle. Preliminary mechanism studies have shown that QFPDD can directly block the virus entry into the cell by inhibiting virus adsorption, and QFPDD can also play an antiviral role by up-regulating the expression of IFN and ISGs. These results indicate QFPDD as a drug potential to treat coronavirus infection.

C2H2 transcription factors play an important role in plant growth, development and the regulation of secondary metabolism. This article identifies members of the C2H2 gene family in Cannabis sativa L. at the genome level. Chromosomal location and linkage, evolutionary relationships, and identification of conserved motifs was determined from the C. sativa genome and transcriptome data using bioinformatics tools and on-line websites such as TBtools, MEGA software, NCBI, PlantTFDB, ExPASy, HMMSCAN, MEME, WoLFPSORT and PlantCARE. The results show that C. sativa contains 30 members of the C2H2 gene family (named CsC2H2-1-CsC2H2-30) distributed on 9 chromosomes. The encoded proteins range in length from 138 to 635 amino acids, and the theoretical isoelectric points range from 5.85 to 9.52. Molecular weights range from 15 909.48 to 68 445.53 Da. Transcriptome analysis showed that CsC2H2 was differentially expressed in the female flowers, bracts, leaves, and stems of the Diku variety and female flowers of nine different varieties of C. sativa. Quantitative real-time PCR verified that CsC2H2-1, CsC2H2-5, and CsC2H2-19 were significantly expressed in the female flowers and bracts of the Diku variety. This provides a theoretical basis for in-depth study of the function of the C2H2 gene family and the breeding of high-quality C. sativa varieties.

Galli Gigerii Endothelium Corneum (GGEC) represents digestion-promoting medicines with measurable effects and extensive clinical application. However, its effective components are not clear. The quality control index in the current edition of Chinese Pharmacopoeia is rather elementary and does not reflect its clinical efficacy. In this study, a bioassay method based on pepsin activity was proposed as a novel quality control method. With pepsin activity as the evaluation index, the extraction of GGEC was optimized and a method for the determination of biological potency was established by using the qualitative reaction parallel line method. The biological potency and consistency of 20 batches of GGEC were investigated. To provide scientific evidence in support of this bioassay method, two validation experiments were designed. One was to study the viscosity-reducing activity of a nutritional semi-solid paste after adding GGEC samples with differing potency. The other was to correlate the gastric residual rate in mice and pepsin activity with the alcohol soluble extract content. The results showed that the optimal preparation method was to dilute crude powder of GGEC with 50 volumes of water and subject to ultrasonic extraction at 300 W and 40 kHz for 0.5 h. The shape of the dose-response curve was similar to that of the positive control drug multienzyme tablets and the precision, intermediate precision and repeatability met the methodology requirements. The results showed that the potency of 20 batches of samples ranged from 13.49 to 34.69 U·mg^-1, with an average value of 22.21 U·mg^-1. The validation experiment demonstrated that the effect of reducing the viscosity of the nutrient paste became more significant as GGEC sample potency increased. The correlation coefficient R of gastric residual rate with pepsin potency and alcohol soluble extract content was 0.867 and 0.518, respectively, which indicated that the pepsin potency was highly correlated with in vivo activity. This study shows that a bioassay method based on pepsin activity is reliable and reproducible for GGEC and could provide reference method for the quality evaluation of other digestant herbs.

The nuclear transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) plays a crucial role in maintaining cellular redox homeostasis. The aberrant NRF2 signaling confers enhanced antioxidant capacity, which is linked to tumor progression and therapeutic resistance. The current study investigates the biological effects and molecular mechanism of tribbles homolog 3 (TRIB3), a stress-induced protein, in regulating cell survival and apoptosis in lung cancer. This study first performed the RNA sequencing data analysis with 576 lung adenocarcinoma patients from the cancer genome atlas (TCGA) database. The NRF2-antioxidant response element (ARE) signature was enriched in patients with high TRIB3 expression. Dual-luciferase reporter assay and real-time quantitative polymerase chain reaction (PCR) were used to confirm the effect of TRIB3 on the kelch-like ECH-associated protein-1 (KEAP1)-NRF2 pathway. Abrogation of TRIB3 impaired NRF2 transcriptional activity and reduced the expression of its target genes. Moreover, TRIB3 enhanced NRF2 stability via blocking KEAP1-NRF2 interaction. TRIB3-depletion promoted reactive oxygen species (ROS) production, restrained cell proliferation, and enhanced carboplatin-induced apoptosis. In addition, NRF2 overexpression recovered the tumor inhibition effect of TRIB3-depletion. Consistently, TRIB3 failed to modulate apoptosis in NRF2 depletion cells. In summary, this study shows that TRIB3 inhibits the KEAP1-NRF2 interaction and upregulates the transcriptional activity of NRF2, thereby promoting lung cancer cell proliferation and reducing the sensitivity to chemotherapy. Targeting the TRIB3-NRF2 signal axis may become a new strategy for ROS homeostasis and lung cancer treatment.

Autophagy is a lysosomal degradation pathway, and plays a crucial role in cellular homeostasis, development, immunity, tumor suppression, metabolism, prevention of neurodegeneration, and lifespan extension. Thus, pharmacological stimulation of autophagy may be an effective approach for preventing or treating certain human diseases and/or aging. Here, combined with allosteric site identification methods, high-throughput virtual screening, and in vitro activity evaluation, we found that compound 10 can activate autophagy and has good anti-MDA-MB-231 cell proliferation activity (the half maximal inhibitory concentration IC₅₀=8.25±1.53 μmol·L^-1). Subsequently, molecular docking, molecular dynamics simulation, and immunoblotting assay demonstrate that compound 10 can target and activate beclin-1. In vitro studies have shown that compound 10 can induce autophagy-associated cell death in MDA-MB-231 cells. In addition, it was found that compound 10 can induce apoptosis in MDA-MB-231 cells. Taken together, we identified the candidate compound 10 as an effective and selective targeting beclin-1 to activate autophagy as a lead compound, which provide a reference for further development and optimization of small molecule drugs targeting beclin-1 to activate autophagy for clinical treatment.