Xanthones from Calophyllum Polyanthum Wallich ex Choisy with CYP1 Enzymes Inhibitory Activity.

Three new xanthone compounds, 1,3,5-trihydroxy-2-(2-hydroxy-3-methylbut-3-enyl)-4-(3-methylbut-2-enyl)xanthone (1), toxyloxanthone E (2), dehydrocycloguanandin B (3) along with 15 known xanthones (4-18) were isolated from the aerial parts of Calophyllum polyanthum Wall. ex Choisy. Their structures were fully characterised using spectroscopic data, as well as comparison with the previous literature data. All isolated compounds had inhibitory effects against CYP1A1, CYP1A2 and CYP1B1 enzymes at working concentration of 10 µM, 1 µM and 10 µM, respectively. Among them, compounds 10, 11, and 12 exhibited better CYP1A2 enzyme inhibitory effects than that of the positive control α-naphthoflavone, with 51.05 %, 56.82 % and 44.93 % inhibition, respectively.

Inhibition of CYP1A1 Alleviates Colchicine-Induced Hepatotoxicity.

Colchicine, a natural compound extracted from Colchicum autumnale, is a phytotoxin, but interestingly, it also has multiple pharmacological activities. Clinically, colchicine is widely used for the treatment of gouty arthritis, familial Mediterranean fever, cardiovascular dysfunction and new coronary pneumonia. However, overdose intake of colchicine could cause lethal liver damage, which is a limitation of its application. Therefore, exploring the potential mechanism of colchicine-induced hepatotoxicity is meaningful. Interestingly, it was found that CYP1A1 played an important role in the hepatotoxicity of colchicine, while it might also participate in its metabolism. Inhibition of CYP1A1 could alleviate oxidative stress and pyroptosis in the liver upon colchicine treatment. By regulating CYP1A1 through the CASPASE-1-GSDMD pathway, colchicine-induced liver injury was effectively relieved in a mouse model. In summary, we concluded that CYP1A1 may be a potential target, and the inhibition of CYP1A1 alleviates colchicine-induced liver injury through pyroptosis regulated by the CASPASE-1-GSDMD pathway.

Metabolomics reveals that sulfotransferase 1 may regulate colchicine-induced liver injury.

Colchicine is widely used to treat gouty arthritis for years. Previous studies showed that colchicine overdose can cause liver damage, yet the mechanism underlying its hepatotoxicity remains unclear. In this study, hepatotoxicity of colchicine was investigated in vivo. Metabolomic analysis of colchicine metabolites and endogenous metabolites was performed using Ultra High Performance Liquid Chromatography (UHPLC) - mass spectrometry (MS). Seventeen metabolites of colchicine were identified, including 3 novel sulfated metabolites. Meanwhile, endogenous sulfated metabolites were found to be decreased by colchicine. Colchicine might regulate sulfotransferase 1 (SULT1) through perixisome proliferation-activated receptor ɑ (PPARα), and inhibition of SULT1 reduced the levels of sulfated metabolites of colchicine. Inhibition of SULT1 aggravated colchicine-induced liver injury, whereas activation of SULT1 attenuated its liver injury. The supplementation of endogenous sulfated metabolites indoxyl sulfate (IS) or p-cresol sulfate (PCS) alleviated colchicine-induced liver injury through modulation of the CASPASE-1-gasdermin D (GSDMD) pathway. These results indicated that colchicine might cause hepatotoxicity through inhibition of SULT1and decreased production of bioactive sulfated endogenous metabolites IS and PCS. Our results provided evidence for potential therapeutic targets and agents to prevent liver injury caused by colchicine. Targeting the SULT1 enzyme and administration of IS and PCS may be useful in alleviating colchicine hepatotoxicity.

Parabacteroides distasonis ameliorates hepatic fibrosis potentially via modulating intestinal bile acid metabolism and hepatocyte pyroptosis in male mice.

Parabacteroides distasonis (P. distasonis) plays an important role in human health, including diabetes, colorectal cancer and inflammatory bowel disease. Here, we show that P. distasonis is decreased in patients with hepatic fibrosis, and that administration of P. distasonis to male mice improves thioacetamide (TAA)- and methionine and choline-deficient (MCD) diet-induced hepatic fibrosis. Administration of P. distasonis also leads to increased bile salt hydrolase (BSH) activity, inhibition of intestinal farnesoid X receptor (FXR) signaling and decreased taurochenodeoxycholic acid (TCDCA) levels in liver. TCDCA produces toxicity in mouse primary hepatic cells (HSCs) and induces mitochondrial permeability transition (MPT) and Caspase-11 pyroptosis in mice. The decrease of TCDCA by P. distasonis improves activation of HSCs through decreasing MPT-Caspase-11 pyroptosis in hepatocytes. Celastrol, a compound reported to increase P. distasonis abundance in mice, promotes the growth of P. distasonis with concomitant enhancement of bile acid excretion and improvement of hepatic fibrosis in male mice. These data suggest that supplementation of P. distasonis may be a promising means to ameliorate hepatic fibrosis.

Chitosan-poloxamer-based thermosensitive hydrogels containing zinc gluconate/recombinant human epidermal growth factor benefit for antibacterial and wound healing.

Chitosan/poloxamer-based thermosensitive hydrogels containing zinc gluconate/recombinant human epidermal growth factor (ZnG/rhEGF@Chit/Polo) were developed as a convenient, safe and effective dressing for skin wound treatment. Their fabrication procedure and characterization were reported, and their morphology was examined by a scanning electron microscope. Antibacterial and biofilms activities were evaluated by in vitro tests to reveal the inhibitory effects and scavenging activity on the biofilms of Staphylococcus aureus and Pseudomonas aeruginosa. ZnG/rhEGF@Chit/Polo was also investigated as a potential therapeutic agent for wound healing therapy. In vivo wound healing studies on rats for 21 days proves that ZnG/rhEGF@Chit/Polo supplements the requisite Zn2+ and rhEGF for wound healing to promote the vascular remodeling and collagen deposition, facilitate fibrogenesis, and reduce the level of interleukin 6 for wound basement repair, and thus is a good wound therapy.

Evaluation of the synergetic effect of Yupingfeng san and Flos Sophorae Immaturus based on free radical scavenging capacity.

OBJECTIVE: This study aimed to determine the optimal extraction process and examine whether the combination of Flos Sophorae Immaturus (FSI) and Yupingfeng san (YPS) has a synergistic effect on free radical scavenging capacity. DESIGN AND METHODS: The time of immersion and extraction and the ratios (material/solvent) of the combination of YPS and FSI were optimized on the basis of polysaccharide and flavonoid yields via orthogonal design. The optimal result was used in the 1,1-diphenyl-1-picrylhydrazyl (DPPH) assay and animal experiments to test the antioxidant activity, which is reflected by superoxide dismutase, malondialdehyde, glutathione peroxidase, and total antioxidant capacity serum levels. The optimal extraction process was determined using various ingredients to obtain complex extracts with high active ingredient content and antioxidant activity. DPPH assay results showed that the optimized ingredients have antioxidant effects, and the combination had better antioxidation function than YPS in vitro. The combination also showed synergistic antioxidant activity compared with YPS in vivo. CONCLUSIONS: The combination of YPS and FSI had a synergistic antioxidant effect in vitro. The optimized extracts had antioxidant effects in vivo. These results indicated that YPS could be used with FSI to improve its antioxidant capacity in the body on the basis of free radical scavenging capacity.

Synthesis, Characterization, and Pharmacodynamics Study of Enrofloxacin Mesylate.

INTRODUCTION: Enrofloxacin is used in the treatment of a wide variety of bacterial infections in mammals. However, its poor solubility limits the clinical use. METHODS: In order to improve the solubility of enrofloxacin, the enrofloxacin mesylate (EM) were obtained by a chemical synthesis method. The characterization of EM was carried out using ultraviolet scan (UV), synchronous thermal analysis (SDT), fourier transform infrared spectrometer (FTIR) and mass spectrometry (MS), nuclear magnetic resonance (NMR) and X-ray powder diffraction analysis (XRPD). Acute toxicity of EM in Kunming mice was studied. Besides, pharmacokinetic studies were performed in New Zealand rabbits at a single oral dose of 10 mg/kg, and the antibacterial activity of EM was also evaluated. RESULTS: EM was successfully synthesized and purified. The stoichiometric ratio of mesylate to enrofloxacin was 1:1 and the aqueous solubility of EM was 483.01±4.06 mg/mL, the solubility of EM was about 2000 times higher than enrofloxacin. The oral lethal dose (LD50) of EM was 1168.364 mg/kg, and the pharmacokinetics indicated that the oral relative bioavailability of EM was about 1.79 times and 1.48 times higher than that of enrofloxacin and enrofloxacin hydrochloride, respectively. In addition, the in vitro antibacterial activity of EM was not significantly changed compared with enrofloxacin and enrofloxacin hydrochloride. CONCLUSION: EM has higher solubility, low toxicity for oral use, and increases the oral bioavailability in rabbit. This study may be of benefit for the development of new enrofloxacin drugs.

Isobologram Analysis: A Comprehensive Review of Methodology and Current Research.

Drug combination is a common method for clinical disease treatment. Whether the combination of drugs is reasonable often affects the result of the disease treatment. Many methods have been used to evaluate interaction between drugs to date. Isobologram analysis has been mathematically proven and widely used to evaluate drug interactions. In this paper, the principle of isobologram analysis and its application in drug interaction evaluation are summarized. The applications of the similar cotoxicity coefficient and fractional inhibitory concentration index in the evaluation of drug interaction are also reviewed. This work is expected to evaluate the effect of formulations scientifically and provide scientific judgment standards for the development of formulations and clinical drug compatibility.