Network pharmacology and computer-aided drug design to explored potential targets of Lianhua Qingwen and Qingfei Paidu decoction for COVID-19.

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, has spread globally, affecting people's lives worldwide and hindering global development. Traditional Chinese Medicine (TCM) plays a unique role in preventing and treating COVID-19. Representative prescriptions for the COVID-19 treatment, Lianhua Qingwen (LHQW) and Qingfei Paidu Decoction (QFPD), effectively alleviate COVID-19 symptoms, delaying its progression and preventing its occurrence. Despite the extensive similarity in their therapeutic effects, the mechanisms and advantages of LHQW and QFPD in in treating mild-to-moderate COVID-19 remain elusive. To characterize the mechanisms of LHQW and QFPD in treating COVID-19, we used integrated network pharmacology and system biology to compare the LHQW and QFPD components, active compounds and their targets in Homo sapiens. LHQW and QFPD comprise 196 and 310 active compounds, some of which have identical targets. These targets are enriched in pathways associated with inflammation, immunity, apoptosis, oxidative stress, etc. However, the two TCM formulas also have specific active compounds and targets. In LHQW, arctiin, corymbosin, and aloe-emodin target neurological disease-related genes (GRM1 and GRM5), whereas in QFPD, isofucosterol, baicalein, nobiletin, oroxylin A, epiberberine, and piperlonguminine target immunity- and inflammation-related genes (mTOR and PLA2G4A). Our findings indicate that LHQW may be suitable for treating mild-to-moderate COVID-19 with nervous system symptoms. Moreover, QFPD may effectively regulate oxidative stress damage and inflammatory symptoms induced by SARS-CoV-2. These findings may provide references for the clinical application of LHQW and QFPD.

Ironing Out the Details: How Iron Orchestrates Macrophage Polarization.

Iron fine-tunes innate immune responses, including macrophage inflammation. In this review, we summarize the current understanding about the iron in dictating macrophage polarization. Mechanistically, iron orchestrates macrophage polarization through several aspects, including cellular signaling, cellular metabolism, and epigenetic regulation. Therefore, iron modulates the development and progression of multiple macrophage-associated diseases, such as cancer, atherosclerosis, and liver diseases. Collectively, this review highlights the crucial role of iron for macrophage polarization, and indicates the potential application of iron supplementation as an adjuvant therapy in different inflammatory disorders relative to the balance of macrophage polarization.

Dietary supplementation with N-carbamylglycinate (CGly) improved feed source proline absorption and reproductive performance in sows.

Nutrient requirements are increased in the late-gestation period due to the faster growth of the foetal-placental unit and maternal erythrocyte mass. Glycine, proline and arginine are important amino acids that could improve foetal growth and development. The present study aims to investigate the effects of a derivative of glycine (N-carbamylglycinate, CGly) on the amino acid profiles and reproductive performances of late gestation sows. Thirty-two multiparous gestating sows (∼d 80) were selected, and randomly assigned into two groups: (1) control and (2) treatment (CGly, 800 mg kg-1) from day 85 of gestation to parturition. The serum amino acid profiles at day 110 of gestation and reproductive performance were investigated. The results showed that dietary supplementation of CGly in the late gestation period significantly improved the levels of glycine (p < 0.05) and proline (p < 0.01) in the serum of the perinatal sows, and thereafter improved the litter birth weights (p < 0.05) and number born alive (p < 0.1). Based on the in vitro studies, the improvement of proline levels is probably due to the induced expression of SLC6A20 and SLC38A2. Further studies should focus on the details of amino acid absorption, especially the competitive and cooperative absorption processes for different amino acids and derivatives.

Effect of Dietary Copper on Intestinal Microbiota and Antimicrobial Resistance Profiles of Escherichia coli in Weaned Piglets.

Copper is an essential microelement for animals, and not only it has been used as a feed additive at pharmacological doses in swine production to improve growth performance, but it also has an effect on intestinal microbes by enhancing host bacterial resistance. However, there are few reports on the effects of pharmacological doses of copper on intestinal microorganisms and the antimicrobial resistance profiles of pathogenic bacteria, such as Escherichia coli, in pigs. Therefore, this study aimed to investigate the effects of pharmacological doses of copper on the microbial communities in the hindgut and the antimicrobial resistance profiles of E. coli in weaned piglets. Twenty-four healthy weaned piglets aged 21 ± 1 days and with an average weight of 7.27 ± 0.46 kg were randomly divided into four groups. The control group was fed a basal diet, while the treatment groups were fed a basal diet supplemented with 20, 100, or 200 mg copper/kg feed, in the form of CuSO4. Anal swabs were collected at 0, 21, and 42 days of the trial, and E. coli was isolated. Meanwhile, the contents of the ileum and cecum from the control and 200 mg copper/kg feed groups were collected at 21 and 42 days for microbial community analysis and E. coli isolation. All isolated E. coli strains were used for antimicrobial resistance profile analysis. A pharmacological dose of copper did not significantly change the diversity, but significantly affected the composition, of microbial communities in the ileum and cecum. Moreover, it affected the microbial metabolic functions of energy metabolism, protein metabolism, and amino acid biosynthesis. Specifically, copper treatment increased the richness of E. coli in the hindgut and the rates of E. coli resistance to chloramphenicol and ciprofloxacin. Moreover, the rate of E. coli resistance to multiple drugs increased in the ileum of pigs fed a pharmacological dose of copper. Thus, a pharmacological dose of copper affected the composition of the microbial community, increased the antimicrobial resistance rates of intestinal E. coli, and was most likely harmful to the health of piglets at the early stage after weaning.

A new species of Eostyloceros (Cervidae, Artiodactyla) from the Late Miocene of the Linxia Basin in Gansu, China.

A new species, Eostyloceros hezhengensis sp. nov., is established based on a skull with its cranial appendages collected from the Late Miocene Liushu Formation of the Linxia Basin in Gansu Province, northwestern China. It is a large-sized muntjak with a distinct longitudinal ridge along the lateral margin of the frontal bone that joins the antler pedicle. The pedicle is short, cylindrical, robust, and extends posteriorly from the rear of the orbit. The anterior and posterior branches arise from the burr and diverge at an angle of 30°. The posterior branch is relatively long, and its tip is strongly curved posteriorly. The anterior branch is straight and situated anteromedially from the posterior branch. The posterior branch is lateromedially compressed, and the anterior branch has a circular cross section. The morphological observation together with a cladistic and a principal component analysis indicate that E. hezhengensis is more basal than any known species of the genus Eostyloceros in having shorter pedicles, a lower position of the fork above the burr, more slender anterior branches, and a small angle between the anterior and posterior branches. Its age is the middle Late Miocene, corresponding to the late Bahean.

The eIF4E/eIF4G interaction inhibitor 4EGI-1 augments TRAIL-mediated apoptosis through c-FLIP Down-regulation and DR5 induction independent of inhibition of cap-dependent protein translation.

The small molecule 4EGI-1 was identified as an inhibitor of cap-dependent translation initiation owing to its disruption of the eIF4E/eIF4G association through binding to eIF4E. 4EGI-1 exhibits growth-inhibitory and apoptosis-inducing activity in cancer cells; thus, we were interested in its therapeutic efficacy in human lung cancer cells. 4EGI-1, as a single agent, inhibited the growth and induced apoptosis of human lung cancer cells.When combined with the death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), enhanced apoptosis-induced activity was observed. As expected, 4EGI-1 inhibited eIF4E/eIF4G interaction and reduced the levels of cyclin D1 and hypoxia-inducing factor-1alpha (HIF-1alpha), both of which are regulated by a cap-dependent translation mechanism. Moreover, 4EGI-1 induced CCAAT/enhancer-binding protein homologous protein-dependent DR5 expression and ubiquitin/proteasome- mediated degradation of cellular FLICE-inhibitory protein (c-FLIP). Small interfering RNA-mediated blockade of DR5 induction or enforced expression of c-FLIP abrogated 4EGI-1's ability to enhance TRAIL-induced apoptosis, indicating that both DR5 induction and c-FLIP down-regulation contribute to enhancement of TRAIL-induced apoptosis by 4EGI-1. However, inhibition of eIF4E/eIF4G interaction by knockdown of eIF4E effectively reduced the levels of cyclin D1 and HIF-1alpha but failed to induce DR5 expression, downregulate c-FLIP levels, or augment TRAIL-induced apoptosis. These results collectively suggest that 4EGI-1 augments TRAIL-induced apoptosis through induction of DR5 and down-regulation of c-FLIP, independent of inhibition of cap-dependent protein translation.

Enzymatic properties of a new peptide deformylase from pathogenic bacterium Leptospira interrogans.

Peptide deformylase (LiPDF), a target protein for antibacterial agents from pathogenic bacteria Leptospira interrogans was identified and purified. Enzymatic studies including kinetics and inhibition revealed new inspiring highlights. The purified active enzyme was a dimer and showed a hyperbolic progress plot when the substrate was low but an excess substrate inhibition effect in higher substrate concentration. Variants on the metal-binding ligand-Cys102 were constructed to verify the indispensable attribute. Also the variant, LiPDF with the insertion residues (R(70)Y(71)P(72)G(73)T(74) P(75)D(76)V(77)) between the conserved motif 1 and motif 2 excised, was constructed and displayed no marked changes on enzymatic features. The results of atom absorbance proved that it contains a tightly bound Zn2+ rather than Fe2+ in E. coliPDF that is an essential cofactor for its high catalytic activity.