Discovery of deoxyandrographolide and its novel effect on vascular senescence by targeting HDAC1.

Aconitum carmichaelii (Fuzi) is a traditional Chinese medicine that has been widely used in the clinic to save the dying life for over several thousand years. However, the medicinal components of Fuzi in treating vascular senescence (VS) and its potential mechanism remain unclear. In this study, a network pharmacology method was used to explore the possible components and further validated by experiments to get a candidate compound, deoxyandrographolide (DA). DA restrains aging biomarkers, such as p16, p21, γH2A.X, and p53 in vitro and in vivo blood co-culture studies. Histone deacetylase 1 (HDAC1), mouse double minute2 (MDM2), cyclin-dependent kinase 4, and mechanistic target of rapamycin kinase (mTOR) are predicted to be the possible targets of DA based on virtual screening. Subsequent bio-layer interferometry results indicated that DA showed good affinity capability with HDAC1. DA enhances the protein expression of HDAC1 in the angiotensin II-induced senescence process by inhibiting its ubiquitination degradation. Loss of HDAC1 by CRISPR/Cas9 leads to the disappearance of DA's anti-aging property. The enhancement of HDAC1 represses H3K4me3 (a biomarker of chromosomal activity) and improves chromosome stability. RNA sequencing results also confirmed our hypothesis. Our evidence illuminated that DA may achieve as a novel compound in the treatment of VS by improving chromosome stability.

Extraction optimization, structural characterization and potential alleviation of hyperuricemia by flavone glycosides from celery seeds.

Celery seeds are commonly used as condiments and in herbal teas with high medicinal value. In the present study, we investigated the contents of extracts derived under different extraction conditions and determined the optimal conditions for only extracting flavone glycosides from celery seeds. The compositional analysis identified three primary flavone glycosides in the ethanolic extract, and apiin, graveobioside A, and graveobioside B were isolated. Apigenin, luteolin, and chrsyeriol were obtained by the acid hydrolysis of flavone glycosides under high-temperature conditions. Here we investigated the inhibitory activity of apigenin and apiin on xanthine oxidase by reducing the rate of oxidative cytochrome C and found that both apigenin and apiin reduced cytochrome C production, except for low concentrations of apiin. In vivo analysis with hyperuricemia mice and rats showed that apiin had excellent uric acid-lowering effects and high dose-dependence, while apigenin was relatively slightly uric acid-lowering. In addition, the flavone glycoside extracts from celery seeds exhibited similar effects of reducing uric acid with apiin. Surprisingly, in hyperuricemia rats, the uric acid-lowering effects of high-dose apiin and flavone glycoside extracts were almost comparable to that of allopurinol. Besides, our experimental results showed that apigenin could improve uric acid clearance by increasing the glomerular filtration capacity, which was reflected in reducing the renal function parameters SUN and SCr; also, apiin showed better results. This study also showed that celery seeds have a unique medicinal value in treating hyperuricemia and that the flavone glycoside extracts from celery seeds can be developed as medicine for hyperuricemia.

Challenges and potential for improving the druggability of podophyllotoxin-derived drugs in cancer chemotherapy.

Covering: up to 2020As a main bioactive component of the Chinese, Indian, and American Podophyllum species, the herbal medicine, podophyllotoxin (PTOX) exhibits broad spectrum pharmacological activity, such as superior antitumor activity and against multiple viruses. PTOX derivatives (PTOXs) could arrest the cell cycle, block the transitorily generated DNA/RNA breaks, and blunt the growth-stimulation by targeting topoisomerase II, tubulin, or insulin-like growth factor 1 receptor. Since 1983, etoposide (VP-16) is being used in frontline cancer therapy against various cancer types, such as small cell lung cancer and testicular cancer. Surprisingly, VP-16 (ClinicalTrials NTC04356690) was also redeveloped to treat the cytokine storm in coronavirus disease 2019 (COVID-19) in phase II in April 2020. The treatment aims at dampening the cytokine storm and is based on etoposide in the case of central nervous system. However, the initial version of PTOX was far from perfect. Almost all podophyllotoxin derivatives, including the FDA-approved drugs VP-16 and teniposide, were seriously limited in clinical therapy due to systemic toxicity, drug resistance, and low bioavailability. To meet this challenge, scientists have devoted continuous efforts to discover new candidate drugs and have developed drug strategies. This review focuses on the current clinical treatment of PTOXs and the prospective analysis for improving druggability in the rational design of new generation PTOX-derived drugs.

Virtual Screening and Biomolecular Interactions of CviR-Based Quorum Sensing Inhibitors Against Chromobacterium violaceum.

The rise of bacterial multi drug resistance becomes a global threat to the mankind. Therefore it is essential to find out alternate strategies to fight against these "super bugs." Quorum sensing (QS) is a cell-to-cell communication mechanism by which many bacteria regulate their biofilm and virulence factors expression to execute their pathogenesis. Hence, interfering the quorum sensing is an effective alternate strategy against various pathogens. In this study, we aimed to find out potential CviR-mediated quorum sensing inhibitors (QSIs) against Chromobacterium violaceum. Virtual screening from a natural products database, in vitro biofilm and violacein inhibition assays have been performed. Biofilm formation was investigated using confocal microscopy and gene expression studies were carried out using qRT-PCR. Further, to study the biomolecular interaction of QSIs with purified CviR Protein (a LuxR homologue), microscale thermophoresis (MST) analysis was performed. Results suggested that phytochemicals SPL, BN1, BN2, and C7X have potential GScore when compared to cognate ligand and reduced the biofilm formation and violacein production significantly. Especially, 100 µM of BN1 drastically reduced the biofilm formation about 82.61%. qRT-PCR studies revealed that cviI, cviR, vioB, vioC, vioD genes were significantly down regulated by QSIs. MST analysis confirmed the molecular interactions between QSIs and purified CviR protein which cohere with the docking results. Interestingly, we found that BN2 has better interaction with CviR (Kd = 45.07 ±1.90 nm). Overall results suggested that QSIs can potentially interact with CviR and inhibit the QS in a dose dependent manner. Since, LuxR homologs present in more than 100 bacterial species, these QSIs may be developed as broad spectrum anti-infective drugs in future.

Effects of dietary supplementation with an expressed fusion peptide bovine lactoferricin-lactoferrampin on performance, immune function and intestinal mucosal morphology in piglets weaned at age 21 d.

Lactoferrin has antimicrobial activity associated with peptide fragments lactoferricin (LFC) and lactoferrampin (LFA) released on digestion. These two fragments have been expressed in Photorhabdus luminescens as a fusion peptide linked to protein cipB. The construct cipB-LFC-LFA was tested as an alternative to antimicrobial growth promoters in pig production. Sixty piglets with an average live body weight of 5.42 (sem 0.59) kg were challenged with enterotoxigenic Escherichia coli and randomly assigned to four treatment groups fed a maize-soyabean meal diet containing either no addition (C), cipB at 100 mg/kg (C+B), cipB-LFC-LFA at 100 mg/kg (C+L) or colistin sulfate at 100 mg/kg (C+CS) for 3 weeks. Compared with C, dietary supplementation with C+L for 3 weeks increased daily weight gain by 21 %, increased recovery from diarrhoea, enhanced serum glutathione peroxidase (GPx), peroxidase (POD) and total antioxidant content (T-AOC), liver GPx, POD, superoxide dismutase and T-AOC, Fe, total Fe-binding capacity, IgA, IgG and IgM levels (P < 0.05), decreased the concentration of E. coli in the ileum, caecum and colon (P < 0.05), increased the concentration of lactobacilli and bifidobacteria in the ileum, caecum and colon (P < 0.05), and promoted development of the villus-crypt architecture of the small intestine. Growth performance was similar between C+L- and C+CS-supplemented pigs. The present results indicate that LFC-LFA is an effective alternative to the feed antibiotic CS for enhancing growth performance in piglets weaned at age 21 d.