Utilizing integrating network pharmacological approaches to investigate the potential mechanism of Ma Xing Shi Gan Decoction in treating COVID-19.

Beginning in December 2019, coronavirus disease 2019 (COVID-19), due to 2019-nCoV infection, emerged in Wuhan and spread rapidly throughout China and even worldwide. Employing combined therapy of modern medicine and traditional Chinese medicine has been proposed, in which Ma Xing Shi Gan Decoction (MXSGD) was recommended as a basic prescription and applied widely in the clinical treatment of COVID-19. We investigated the underlying mechanism of MXSGD in treating COVID-19 utilizing the approaches of integrating network pharmacology. A total of 97 active ingredients of MXSGD were screened out, and 169 targets were predicted. The protein-protein interaction network exhibited hub targets of MXSGD, such as Heat shock protein 90, RAC-alpha serine/threonine-protein kinase, Transcription factor AP-1, Mitogen-activated protein kinase 1, Cellular tumor antigen p53, Vascular endothelial growth factor A, and Tumour necrosis factor. Gene Ontology functional enrichment analysis demonstrated that the biological processes altered within the body after taking MXSGD were closely related to the regulation of such processes as the acute inflammatory response, chemokine production, vascular permeability, response to oxygen radicals, oxidative stress-induced apoptosis, T cell differentiation involved in the immune response, immunoglobulin secretion, and extracellular matrix disassembly. KEGG enrichment analysis indicated that the targets of MXSGD were significantly enriched in inflammation-related pathways, immunomodulation-related pathways, and viral infection-related pathways. The therapeutic mechanisms of MXSGD on COVID-19 may primarily involve the following effects: reducing inflammation, suppressing cytokine storm, protecting the pulmonary alveolar-capillary barrier, alleviating pulmonary edema, regulating the immune response, and decreasing fever.

In vitro and in vivo digestibility of corn starch for weaned pigs: Effects of amylose:amylopectin ratio, extrusion, storage duration, and enzyme supplementation.

The objective of this study was to investigate the effects of amylose (AM):amylopectin (AP) ratio, extrusion, storage duration, and enzyme supplementation on starch digestibility of corn. Three corn varieties with high (0.60; HA), medium (0.44; MA), and low (0.39; LA) AM:AP ratios, respectively, were selected from 74 corn samples to evaluate the in vitro and in vivo digestibility of starch. In Exp. 1, during wk 4 after extrusion, resistant starch (RS) content of the 3 selected corn varieties (LA, MA, and HA) increased (P < 0.05) each week and starch digestibility in vitro decreased as storage time increased (P < 0.05). The AM:AP ratio affected the formation of RS (P < 0.01). The RS content of the 3 corn varieties was ranked as LA < MA < HA in each week (P < 0.05). Correlation analysis showed that AM:AP ratio and storage duration were both positively correlated with RS content (P < 0.01). Furthermore, a significant quadratic relation was found between storage duration and RS content in each corn variety as well as storage duration and digestibility. Starch digestibility was negatively correlated with RS content (P < 0.001). In Exp. 2, digestion trials were performed on cannulated pigs with BW of 13.20 ± 0.94 kg. Extrusion increased ileal digestibility of GE and starch of either HA or LA compared with the enzyme-supplemented diets (P < 0.001). Enzyme supplementation did not improve ileal energy and starch digestibility. The ileal digestibility of starch and GE of LA varieties was greater than HA samples (P < 0.05). The results implied that AM:AP ratio and storage duration after extrusion may be important determinants of RS formation and digestibility of starch for corn. In addition, RS content could be an important indicator of digestibility of starch in extruded corn. Using a lower AM:AP ratio corn or reducing the storage duration of extruded corn would help to reduce the formation of RS and improve the starch bioavailability of corn for piglets.

Effect of dietary phytate and phytase on metabolic change of blood and intestinal mucosa in chickens.

The objective of this study was to investigate the effect of dietary phytate and phytase on the metabolic parameters of lipid, protein, enzyme, electrolyte in the blood or intestinal mucosa of broiler chickens. Diets containing phytate phosphorus (0.22% or 0.44%) with phytase supplementation (0, 500 or 1000 U/kg) were administrated to 504 Cobb chicks for 4 weeks. Results showed that the serum concentrations of total cholesterol (T-CHO), albumin, albumin/globulin, total superoxide dismutase (T-SOD), total antioxidant capacity (T-AOC) and glutamic pyruvic transaminase (GPT) were decreased by 9-41% in high phytate diets (p < 0.05) and the concentrations of blood P, K, Fe, Cu, Zn and Mg were decreased by 4-14% for birds fed high phytate diets (p < 0.05), whereas inclusion of phytase compensated these adverse influences. In the duodenum, phytate decreased the level of T-AOC by 13% (p < 0.05), whereas phytase increased the levels of T-SOD, T-AOC and alkaline phosphatase (ALP) by 9-16% (p < 0.05). Also, in the jejunum, diets with high phytate showed lower activity of T-SOD, T-AOC and glutamic oxaloacetic transaminase (GOT) (p < 0.05), and phytase increased T-SOD, T-AOC and ALP (p < 0.05). However, phytase decreased transaminase activity in the low phytate basal diets (p < 0.05). This study suggests that dietary phytate can adversely interfere with the metabolisms of lipid and protein, as well as the antioxidation of blood and intestinal cells, while phytase supplementation may compensate these effects for broiler chickens.

Effect of diet containing phytate and phytase on the activity and messenger ribonucleic acid expression of carbohydrase and transporter in chickens.

The effect of dietary phytate and phytase on carbohydrase activity and hexose transport was investigated in broiler chickens. Diets containing phytate P (2.2 or 4.4 g/kg) with different phytase dose rates (0, 500, or 1,000 phytase units/kg) were fed to 504 female Cobb chicks for 3 wk. Diets containing high phytate concentrations depressed (P < 0.05) BW and G:F, whereas phytase supplementation improved (P < 0.05) the performance of birds. In the duodenum, phytate decreased (P < 0.05) the activities of disaccharidases, Na(+)K(+)-ATPase, and glucose concentrations by 5 to 11%, but phytase enhanced (P < 0.05) the concentrations of amylase, sucrase, maltase, Na(+)K(+)-ATPase, and glucose by 5 to 30%. In the jejunum, phytate decreased (P < 0.05) the concentrations of amylase, sucrase, Na(+)K(+)-ATPase, and glucose by 10 to 22%, and phytase alleviated the negative effect of phytate on the above variables. Ingestion of diets containing phytate also decreased (P < 0.05) serum amylase activity and glucose concentration, and phytase enhanced (P < 0.05) serum concentrations of amylase, sucrase, maltase, Na(+)K(+)-ATPase, and glucose. There were also interactions (P < 0.05) between phytate and phytase on the concentrations of serum amylase, duodenal amylase, sucrase, and jejunal glucose. Enzymatic analysis at a molecular level showed that neither phytate nor phytase influenced the mRNA expression of sucrase-isomaltase in the small intestine. Also, the investigation into the sodium glucose cotransporter gene may challenge the mechanism by which phytate interferes with glucose utilization, as partly indicated by bird performance, and transmembrane transport because diets containing increased phytate upregulated (P < 0.05) the mRNA expression of the sodium glucose cotransporter gene in duodenum and did not influence it in the jejunum. These results indicate that phytate can impair endogenous carbohydrase activity and digestive competence, and phytase can ameliorate these effects for chickens.

Efficacy of phytases on egg production and nutrient digestibility in layers fed reduced phosphorus diets.

The effects of phytases on the performance of layers and the ileal nutrient digestibility of corn-, soybean-, and by-product meal-based diets were assessed with 320 Hy-Line brown layers from 23 to 28 wk of age. Layers were grouped randomly into 5 treatments, with 8 replicates per treatment and 8 layers per replicate. The 5 diets consisted of a positive control diet with adequate Ca (3.30%), total P (0.50%), and nonphytate P (NPP; 0.28%), and a negative control diet with Ca reduced by 0.12%, total P reduced by 0.14%, NPP reduced by 0.13%, and 3 phytases (phytase A derived from Aspergillus niger, and phytases B and C derived from Escherichia coli) supplemented at 300 phytase units/kg of feed, respectively. Egg production and feed intake were recorded daily, and eggshell quality and ileal nutrient digestibility were measured at the end of a 6-wk feeding period. The results revealed that the reduction of Ca and P from the positive control diet significantly depressed feed intake, egg mass, eggshell hardness, and the digestibility of N, Ca, P, and amino acids (P < 0.05). Phytase supplementation in the negative control diet improved the digestibility of P and Ca by 11.08 and 9.81% (P < 0.05), respectively, whereas it improved the digestibility of amino acids by 2 to 8% (P < 0.05). However, the digestibility of most amino acids was not restored to the levels of the positive control diet by the application of phytases. Supplementing phytases in the negative control diet improved the rate of lay, egg mass, and egshell quality to the levels of birds fed the positive control diet. These results suggest that supplementing phytases can improve the digestibility not only of Ca and P, but also of amino acids in layers fed a corn-, soybean-, and by-product-based diet.

Effect of parathyroid hormone-related peptide supplementation of soy protein formulas in the neonatal pig model.

PTH-related peptide (PTHrP) is found in all milks, including human and pig. To define a role for PTHrP in milk, 2-day-old piglets were randomized to receive soy formula devoid of PTHrP or supplemented with 1 nM synthetic PTHrP(1-86) (n = 8 per group). The number of serum samples with detectable PTHrP by immunoassay (Incstar) and radiometric assay (Nichols) was 9 of 33 and 3 of 13 in PTHrP- and 8 of 27 and 3 of 15 in PTHrP+ formula-fed piglets and 8 of 14 and 7 of 12 in naturally suckling piglets, respectively. Serum and urine concentrations of calcium and magnesium and total and bone alkaline phosphatase were similar in both groups at 3, 6, 10, and 17 days of age. No differences were seen in bone mineral content of the tibia measured by single-photon absorptiometry (BMC 0.22 +/- 0.06 and 0.22 +/- 0.10) or dual x-ray absorption (BMC 1.43 +/- 0.36 and 1.31 +/- 0.78) either in vivo or on excised bone or by measurement of Ca, Mg, or P content or total bone ash (1.26 +/- 0.26 and 1.38 +/- 0.28 mg). Intestinal histology, serum intestinal alkaline phosphatase, and net absorption and retention of Ca, Mg, and P in balances from age 11-17 days were all similar. As in humans, however, a developmental pattern was seen for phosphorus regulation in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Rational design of potent, bioavailable, nonpeptide cyclic ureas as HIV protease inhibitors.

Mechanistic information and structure-based design methods have been used to design a series of nonpeptide cyclic ureas that are potent inhibitors of human immunodeficiency virus (HIV) protease and HIV replication. A fundamental feature of these inhibitors is the cyclic urea carbonyl oxygen that mimics the hydrogen-bonding features of a key structural water molecule. The success of the design in both displacing and mimicking the structural water molecule was confirmed by x-ray crystallographic studies. Highly selective, preorganized inhibitors with relatively low molecular weight and high oral bioavailability were synthesized.