Selaginellin derivatives from Selaginella tamariscina and evaluation for anti-breast cancer activity.

A phytochemical investigation of Selaginella tamariscina led to the isolation of 17 selaginellin derivatives. Their inhibitory activities against breast cancer cells were screened, and preliminary structure-activity relationships were also established. Among them, dimeric selaginellin 17 showed potential activity against MDA-MB-231 cells with an IC50 value of 3.2 ± 0.1 µM, corresponding to 4-fold higher potency than the reference compound 5-FU (IC50 14.8 ± 0.2 µM). Mechanistic studies indicated that 17 could cause G2/M phase arrest in MDA-MB-231 cells and induce apoptosis accompanied by increased ROS levels.

Ginkgolide B Blocks Vascular Remodeling after Vascular Injury via Regulating Tgfß1/Smad Signaling Pathway.

Coronary artery disease (CAD) is the most prevalent cardiovascular disease worldwide, resulting in myocardial infarction (MI) and even sudden death. Following percutaneous coronary intervention (PCI), restenosis caused by vascular remodeling is always formed at the stent implantation site. Here, we show that Ginkgolide B (GB), a naturally occurring terpene lactone, effectively suppresses vascular remodeling and subsequent restenosis in wild-type mice following left carotid artery (LCA) injury. Additional experiments reveal that GB exerts a protective effect on vascular remodeling and further restenosis through modulation of the Tgfß1/Smad signaling pathway in vivo and in human vascular smooth muscle cells (HVSMAs) but not in human umbilical vein endothelial cells (HUVECs) in vitro. Moreover, the beneficial effect of GB is abolished after incubated with pirfenidone (PFD, a drug for idiopathic pulmonary fibrosis, IPF), which can inhibit Tgfß1. In Tgfß1-/- mice, treatment with pirfenidone capsules and Yinxingneizhi Zhusheye (including Ginkgolide B) fails to improve vascular remodeling and restenosis. In conclusion, our data identify that GB could be a potential novel therapeutic agent to block vessel injury-associated vascular remodeling and further restenosis and show significant repression of Tgfß1/Smad signaling pathway.

Disrupted functional networks within white-matter served as neural features in adolescent patients with conduct disorder.

BACKGROUND: Conduct disorder (CD) has been conceptualized as a psychiatric disorder associated with white-matter (WM) structural abnormalities. Although diffusion tensor imaging could identify WM structural architecture changes, it cannot characterize functional connectivity (FC) within WM. Few studies have focused on disentangling the WM dysfunctions in CD patients by using functional magnetic resonance imaging (fMRI). METHODS: The resting-state fMRI data were first obtained from both adolescent CD and typically developing (TD) controls. A voxel-based clustering analysis was utilized to identify the large-scale WM FC networks. Then, we examined the disrupted WM network features in CD, and further investigated whether these features could predict the impulsive symptoms in CD using support vector regression prediction model. RESULTS: We identified 11 WM functional networks. Compared with TDs, CD patients showed increased FCs between occipital network (ON) and superior temporal network (STN), between orbitofrontal network (OFN) and corona radiate network (CRN), as well as between deep network and CRN. Further, the disrupted FCs between ON and STN and between OFN and CRN were significantly negatively associated with non-planning impulsivity scores in CD. Moreover, the disrupted WM networks could be served as features to predict the motor impulsivity scores in CD. CONCLUSIONS: Our results provided further support on the existence of WM functional networks and could extended our knowledge about the WM functional abnormalities related with emotional and perception processing in CD patients from the view of WM dysfunction.

Overexpressing CrePAPS Polyadenylate Activity Enhances Protein Translation and Accumulation in Chlamydomonas reinhardtii.

The alga Chlamydomonas reinhardtii is a potential platform for recombinant protein expression in the future due to various advantages. Dozens of C. reinhardtii strains producing genetically engineered recombinant therapeutic protein have been reported. However, owing to extremely low protein expression efficiency, none have been applied for industrial purposes. Improving protein expression efficiency at the molecular level is, therefore, a priority. The 3'-end poly(A) tail of mRNAs is strongly correlated with mRNA transcription and protein translation efficiency. In this study, we identified a canonical C. reinhardtii poly(A) polymerase (CrePAPS), verified its polyadenylate activity, generated a series of overexpressing transformants, and performed proteomic analysis. Proteomic results demonstrated that overexpressing CrePAPS promoted ribosomal assembly and enhanced protein accumulation. The accelerated translation was further verified by increased crude and dissolved protein content detected by Kjeldahl and bicinchoninic acid (BCA) assay approaches. The findings provide a novel direction in which to exploit photosynthetic green algae as a recombinant protein expression platform.

Global analysis of protein-RNA interactions in SARS-CoV-2 infected cells reveals key regulators of infection

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19. SARS-CoV-2 relies on cellular RNA-binding proteins (RBPs) to replicate and spread, although which RBPs control SARS-CoV-2 infection remains largely unknown. Here, we employ a multi-omic approach to identify systematically and comprehensively which cellular and viral RBPs are involved in SARS-CoV-2 infection. We reveal that the cellular RNA-bound proteome is remodelled upon SARS-CoV-2 infection, having widespread effects on RNA metabolic pathways, non-canonical RBPs and antiviral factors. Moreover, we apply a new method to identify the proteins that directly interact with viral RNA, uncovering dozens of cellular RBPs and six viral proteins. Amongst them, several components of the tRNA ligase complex, which we show regulate SARS-CoV-2 infection. Furthermore, we discover that available drugs targeting host RBPs that interact with SARS-CoV-2 RNA inhibit infection. Collectively, our results uncover a new universe of host-virus interactions with potential for new antiviral therapies against COVID-19.

Development of disulfide-derived fructose-1,6-bisphosphatase (FBPase) covalent inhibitors for the treatment of type 2 diabetes.

Fructose-1,6-bisphosphatase (FBPase), as a key rate-limiting enzyme in the gluconeogenesis (GNG) pathway, represents a practical therapeutic strategy for type 2 diabetes (T2D). Our previous work first identified cysteine residue 128 (C128) was an important allosteric site in the structure of FBPase, while pharmacologically targeting C128 attenuated the catalytic ability of FBPase. Herein, ten approved cysteine covalent drugs were selected for exploring FBPase inhibitory activities, and the alcohol deterrent disulfiram displayed superior inhibitory efficacy among those drugs. Based on the structure of lead compound disulfiram, 58 disulfide-derived compounds were designed and synthesized for investigating FBPase inhibitory activities. Optimal compound 3a exhibited significant FBPase inhibition and glucose-lowering efficacy in vitro and in vivo. Furthermore, 3a covalently modified the C128 site, and then regulated the N125-S124-S123 allosteric pathway of FBPase in mechanism. In summary, 3a has the potential to be a novel FBPase inhibitor for T2D therapy.

The discovery of potential phosphopantetheinyl transferase Ppt2 inhibitors against drug-resistant Candida albicans.

With the high-frequency use or abuse of antifungal drugs, the crisis of drug-resistant fungi continues to increase worldwide; in particular, the infection of drug-resistant Candida albicans brings the great challenge to the clinical treatment. Therefore, to decelerate the spread of this resistance, it is extremely urgent to facilitate the new antifungal targets with novel drugs. Phosphopantetheinyl transferases PPTases (Ppt2 in Candida albicans) had been identified in bacterium and fungi and mammals, effects as a vital enzyme in the metabolism of organisms in C. albicans. Ppt2 transfers the phosphopantetheinyl group of coenzyme A to the acyl carrier protein Acp1 in mitochondria for the synthesis of lipoic acid that is essential for fungal respiration, so making Ppt2 an ideal target for antifungal drugs. In this study, 110 FDA-approved drugs were utilized to investigate the Ppt2 inhibition against drug-resistant Candida albicans by the improved fluorescence polarization experiments, which have enough druggability and structural variety under the novel strategy of drug repurposing. Thereinto, eight agents revealed the favourable Ppt2 inhibitory activities. Further, broth microdilution assay of incubating C. albicans with these eight drugs showed that pterostilbene, procyanidine, dichlorophen and tea polyphenol had the superior MIC values. In summary, these findings provide more valuable insight into the treatment of drug-resistant C. albicans.

Selective Th(iv) capture from a new metal-organic framework with O- groups.

Herein we report a new 4-fold interpenetrated metal-organic framework (MOF) functionalized with O- groups for selective Th(iv) capture, the activated samples 1a exhibited a high adsorption capacity for pure Th(iv) ions (Kd = 3.16 × 105 mL g-1) and the amount of metal ions adsorbed on the adsorbent was 165.61 mg g-1. A high removal efficiency of 99.75% was achieved within 10 min with an initial Th(iv) concentration of 100 mg L-1 and the adsorption data followed the pseudo-second-order model. In addition, the separation coefficient (S) of Th(iv) to metal ions with different valence states such as Th(iv)/La(iii), Th(iv)/Sm(iii), Th(iv)/Ho(iii), Th(iv)/Cd(ii) and Th(iv)/K(i) achieved values of 19.66, 26.83, 16.90, 11.26 and 255.79, respectively. Even given the fact that MOFs with O- groups showed high affinity for Pb(ii) ions, our adsorption studies for compound 1a revealed a separation coefficient (STh(IV)/Pb(II)) of 4.36. Further, the adsorption of Th(iv) ions to compound 1a was investigated by FT-IR, SEM-EDS and XPS.

System-wide Profiling of RNA-Binding Proteins Uncovers Key Regulators of Virus Infection.

The compendium of RNA-binding proteins (RBPs) has been greatly expanded by the development of RNA-interactome capture (RIC). However, it remained unknown if the complement of RBPs changes in response to environmental perturbations and whether these rearrangements are important. To answer these questions, we developed "comparative RIC" and applied it to cells challenged with an RNA virus called sindbis (SINV). Over 200 RBPs display differential interaction with RNA upon SINV infection. These alterations are mainly driven by the loss of cellular mRNAs and the emergence of viral RNA. RBPs stimulated by the infection redistribute to viral replication factories and regulate the capacity of the virus to infect. For example, ablation of XRN1 causes cells to be refractory to SINV, while GEMIN5 moonlights as a regulator of SINV gene expression. In summary, RNA availability controls RBP localization and function in SINV-infected cells.

Identification of three H1N1 influenza virus groups with natural recombinant genes circulating from 1918 to 2009.

In this study, we identify a recombinant pb1 gene, a recombinant MP segment and a recombinant PA segment. The pb1 gene is recombined from two Eurasia swine H1N1 influenza virus lineages. It belongs to a H1N1 swine clade circulating in Europe and Asia from 1999 to 2009. The mosaic MP segment descends from H7 avian and H1N1 human virus lineages and pertains to a large human H1N1 virus family circulating in Asia, Europe and America from 1918 to 2007. The recombinant PA segment originated from two swine H1N1 lineages is found in a swine H1N1 group prevailing in Asia and Europe from 1999 to 2003. These results collectively falsify the hypothesis that influenza virus do not evolve by homologous recombination. Since recombination not only leads to virus genome diversity but also can alter its host adaptation and pathogenecity; the genetic mechanism should not be neglected in influenza virus surveillance.