As one of the most serious hereditary neuromuscular disease, spinal muscular atrophy (SMA) is caused by the loss or mutation of survival motor neuron 1 (SMN1) gene. It leads to a decrease in the level of SMN protein and a consequent loss of alpha neurons and progressive muscle atrophy resulting in the progressive muscle weakness, the significant disability and the shortened lifespan. Up till now, only three drugs have been approved for SMA, including the gene therapy drug onasemnogene abeparvovec. The antisense oligonucleotide drug nusinersen and and the small molecule chemical drug risdiplam were briefly introduced. Some representative samples of the small molecule chemical drugs and antisense oligonucleotide drugs targeting SMN2 in the clinical trial or preclinical research phases were also reviewed.

Proton nuclear magnetic resonance (¹H NMR) based metabolomics was applied to characterize the fecal metabolic profiles of chronic unpredictable mild stress (CUMS)-depression (CUMS-D) and CUMS-resilience (CUMS-R) rats. The fecal biomarkers and metabolic pathways involved in CUMS-D and CUMS-R were screened and identified, revealing the underlying mechanisms of two different responses of the body to the same stresses. Firstly, the classic depression model, i.e. CUMS, was constructed. According to the fecal metabolomics profiles, the model rats were divided into two groups, i.e. the CUMS-D group and the CUMS-R group. And then, the depression statuses of CUMS-D rats and CUMS-R rats were verified by their sucrose preference rates. Lastly, multivariate data analysis was applied to clarify the fecal biomarkers and corresponding metabolic pathways involving in CUMS-D and CUMS-R. The results show that compared with the control rats, the sucrose preference rates of CUMS-D rats were significantly reduced. By contrast, the sucrose preference rates of CUMS-R rats had no significant difference. At the same time, CUMS-D and CUMS-R showed both unique and shared biomarkers and pathways. Three pathways are significantly related to CUMS-D, including taurine and hypotaurine metabolism, alanine, aspartate and glutamate metabolism, and arginine and proline metabolism. Glycerolipid metabolism and tryptophan metabolism are specific pathways related to CUMS-R. This study explores the mechanisms of the emergence of susceptible and resilience of rats under the same stimulus from a metabolomics perspective. The current findings provide not only a new perspective for studying depression, and personalized and precision treatments in clinic, but also the research and development of antidepressants.

Hepatocellular carcinoma (HCC) is a common malignant tumor worldwise. The incidence rate of HCC is high and is easy to metastasis and recurrence, which seriously affects human health. Traditional chemical drugs have some challenges such as toxicity, side effects, and multidrug resistance, thus it is urgent to find new drugs and effective targets. Here we synthesized a novel chemical, protonic bis-phenanthroline (H-BP), and the antitumor effect was investigated in the study. The results showed that H-BP could selectively inhibit the proliferation of tumor cells and cause HCC apoptosis. And also, in HCC tumor-bearing mice, H-BP could effectively prevent the growth of tumor mass, even completely eliminate the tumor at medium dose (5 mg·kg^-1) and high dose (10 mg·kg^-1), and meanwhile H-BP has no significant effect on the body weight of mice. The experimental protocol was approved by the Animal Ethics Committee of Southwest University, and the experimental operation was strictly carried out in accordance with the ethical principles of animal use and care. Mechanism studies showed that H-BP induced HCC apoptosis was related to down-regulation the expression of pleomorphic adenoma gene like-2 (PLAGL2), a oncogene transcription factor, resulting in the down-regulation of PLAGL2 downstream proteins hypoxia inducible factor and β-catenin. This study not only introduces the dimerization method to form novel compounds that will provide a new approach for drug design, but also suggests that PLAGL2 may be an effective target in tumor therapy.

On the basis of the Uncaria transcriptome, specific primers were designed for UrSTR. The full-length cDNA of UrSTR (GeneBank: OL310251) was 1 541 bp, encoding 345 amino acid residues, and the promoter region sequence of UrSTR (GeneBank: OL310252) was 1 179 bp. Phylogenetic tree is revealed that UrSTR had a closest relationship with STR from Ophiorrhiza pumila and Ophiorrhiza japonica. Localization of UrSTR protein is revealed located in the vacuole membrane. Plant-care analysis indicated that the promoter region sequence of UrSTR, covering multiple light, stress and hormone-response cis-regulatory elements, and verified transcriptional activity. The results of SDS-PAGE show that pET-28a-UrSTR recombinant protein was successfully expressed, and the size was anticipated. The UrSTR prokaryotic expression system needs to be optimized in the later stage. The research lays the foundation for further purification to study its structure and functional characterization of the UrSTR protein.

Drug-induced long QT syndrome (LQTS) has become an important clinical research topic, and the occurrence of acquired long QT syndrome (acLQTS) is mainly caused by drug inhibition of the human ether-α-go-go related gene (hERG) channel. The hERG gene encodes the α subunit of the fast-activating delayed rectifying potassium ion channel (Ikr), which plays an important role in the process of action potential phase 3 repolarization and is also the target of most antiarrhythmic drugs. The purpose of this study was to investigate the effect of hydroxyrutaecarpine (HRU) on the hERG channel and to evaluate its cardiotoxicity. The whole cell patch clamp technique was used to detect the effects of HRU on the current and kinetics of the hERG channel, and to confirm the binding site on the hERG channel. PCR was used to determine the effect of HRU on hERG mRNA expression. Western blotting was used to detect the effects of HRU on the expression of hERG protein and transcription factor Sp1. Immunofluorescence was used to confirm the effects of HRU on localization and expression of hERG protein and transcription factor Sp1. Studies have shown that transient HRU can inhibit hERG current and shorten the inactivation time constant. Its binding sites to the hERG channel are F656 and Y652. After incubation for 24 h, HRU can reduce the expression of hERG protein, inhibit the hERG current, reduce the level of hERG mRNA, and reduce the expression of transcription factor Sp1 in the nucleus and hERG protein in the cytoplasm. Immunofluorescence experiments also showed the same results suggesting that the inhibition of Sp1 expression by HRU is the cause of the decreased expression of hERG mRNA. In conclusion, the acute inhibition of HRU accelerates the channel inactivation process and reduces the inactivation time constant by binding to the F656 and Y652 sites in the hERG channel, thus reducing the hERG current. In addition, HRU also inhibits the expression of hERG protein, mainly by inhibiting the expression of transcription factor Sp1, the transcription function of hERG channel protein is down-regulated, so that the hERG protein is reduced.

Flavonoids is one of the biggest families of the plant-derived secondary metabolites with structural diversity. Until now, over 10 000 kinds of flavonoids with distinct structures have been purified and identified from plants, and some of them possess a range of important pharmacological effects, such as anticancer, anti-inflammatory and so on. So far, a number of genes and enzymes responsible for the biosynthesis of flavonoids have been reported, especially, a great of progress has been achieved in the synthetic biology of flavonoids in the recent years. Herein, based upon a brief introduction on the biosynthesis of flavonoids, this review summarizes the research advances in synthetic biology of flavonoids in the past two decades (2001-2021), highlighting the cell factories construction of the representative flavonoids. And, a brief discussion and prospects of the relevant metabolic bottlenecks and optimizing strategies are proposed.

Effective supplementation of probiotics can be beneficial to intestinal health, but in situ analysis of probiotics activity has rarely been reported. In this study, by coupling fluorescein 5-isothiocyanate (FITC) and 5(6)-carboxytetramethylrhodamine N-succinimidyl ester (5(6)-TAMRA-SE) with D-lysine, two fluorescent D-amino acids (FDAAs) probes were obtained: green probe (fluorescein-D-lysine, FDL) and red probe (TAMRA-D-lysine, TDL). Then, we tried to label the three kinds of probiotics, Lactobacillus acidophilus (LA), Lactobacillus casei (LC) and Veillonella atypica (VA) in vitro. FDAAs was applied to the labeling of intestinal flora in mice, and a method was established to investigate the oral survival rate of three commonly used probiotics. All animal experiments were approved by the Animal Ethics Committee of Guangzhou University of Chinese Medicine. The results show that the two synthetic FDAAs can be non-toxic and 100% for the in vitro labeling of the three probiotics. Known by FDAAs two-step labeling of oral probiotics, the high survival rate of LA was 92.30% ± 1.67%. The survival rates of VA and LC are similar, 84.13% ± 4.06% and 82.27% ± 2.43%, respectively. This study can quickly compare the changes of colonization survival rate of different probiotics in vivo, provide theoretical support for the in situ colonization activity of probiotics in the intestine, and guide the rational drug use of clinical probiotics.

In this study, we investigated the inhibitory effects of bufalin on proliferation, migration and invasion of PC3 cells in vitro, and preliminarily explored the molecular mechanism of epithelial-mesenchymal transformation (EMT) inhibited by bufalin. The viability of PC3 cells was evaluated by MTT assay, and the migration and invasion abilities of PC3 cells were detected by wound healing and Transwell assay. Western blot was used to detect the expression of EMT and integrin family proteins. The results showed that the half maximal inhibitory concentration (IC₅₀) value of bufalin against PC3 cells was 0.26 ± 0.03 μmol·L^-1. After bufalin treatment, the migration rate of PC3 cells slowed down (P < 0.05), the number of PC3 cells passing through the microporous membrane decreased (P < 0.05), which indicated that bufalin could inhibit the proliferation, migration and invasion of PC3 cells in a concentration-dependent manner. We found that bufalin could affect the expression of EMT-related proteins, including up-regulation of E-cadherin and down-regulation of N-cadherin, β-catenin, matrix metalloproteinase 9 (MMP9), matrix metalloproteinase 2 (MMP2), c-myc and Snail. Bufalin also inhibited the expression of integrin family proteins, including integrin α2 (ITGA2), integrin β1 (ITGB1), integrin β3 (ITGB3), integrin β5 (ITGB5), Yes-associated protein/transcriptional coactivator with a PDZ-binding motif (YAP/TAZ) and integrin-linked kinase (ILK). In addition, bufalin could also inhibit the protein expression level of phospho-focal adhesion kinase (p-FAK)/FAK, phospho-steroid receptor coactivator (p-Src)/Src and phospho-protein kinase B (p-Akt)/Akt. These results suggested that bufalin might inhibit the proliferation, metastasis and invasion of prostate cancer PC3 cells through the FAK/Src/phosphoinositide 3-kinase (PI3K)/Akt pathway. Therefore, bufalin provides reference value for the development of therapeutic drugs for prostate cancer.

Fe-based metal-organic frameworks (MOFs) are a class of polymer crystals formed by the combination of Fe ions or Fe clusters with organic ligands through coordination bonds. At present, Fe-based MOFs can be mainly prepared by solvothermal synthesis, ultrasonic synthesis, microwave synthesis, and dry-gel conversion, etc. Fe-based MOFs have the characteristics of strong drug loading capacity of inorganic nano-carrier and high safety of organic nano-carrier, and have good tumor targeting and the capacity of inducting tumor's ferroptosis, which have high potential in the delivery of antitumor drugs. Recently, Fe-based MOFs have also been developed with various functions such as imaging, magnetic hyperthermia, photothermal therapy, photodynamic therapy, and intelligent response, which can facilitate diagnosis and monitor drug distribution while delivering antitumor drugs, and can produce synergistic antitumor effects combined with thermotherapy and phototherapy, and can also control the precise release of drugs. Reviewing the advances in the synthesis methods, characteristics as well as functions and types of Fe-based MOFs can provide a basis for the further applications of Fe-based MOFs in antitumor drug delivery.

Two compounds were isolated from 95% ethanol extract of the gum resin of Boswellia carterii by silica gel column chromatography (CC) and high-performance liquid chromatography (HPLC). Their structures were identified with IR, UV, NMR and HR-ESI-MS spectroscopic data as 7α-hydroxy-3, 11-dioxo- tirucalla-8, 24-dien-21-oic acid (1) and 21β-hydroxy-3-acetyl-11-keto-β-boswellic acid (2). In addition, their absolute configurations were also identified by ECD calculations. Among them, compound 1 is a new compound and the absolute configuration of compound 2 is confirmed by ECD calculation for the first time.