Tingli Dazao Xiefei Decoction ameliorates asthma in vivo and in vitro from lung to intestine by modifying NO-CO metabolic disorder mediated inflammation, immune imbalance, cellular barrier damage, oxidative stress and intestinal bacterial disorders.

ETHNOPHARMACOLOGICAL RELEVANCE: Asthma is a chronic airway inflammatory disease. Current treatment of mainstream medications has significant side effects. There is growing evidence that the refractoriness of asthma is closely related to common changes in the lung and intestine. The lungs and intestines, as sites of frequent gas exchange in the body, are widely populated with gas signaling molecules NO and CO, which constitute NO-CO metabolism and may be relevant to the pathogenesis of asthma in the lung and intestine. The Chinese herbal formula Tingli Dazao Xiefei Decoction (TD) is commonly used in clinical practice to treat asthma with good efficacy, but there are few systematic evaluations of the efficacy of asthma on NO-CO metabolism, and the mode of action of its improving effect on the lung and intestine is unclear. AIM OF THE STUDY: To investigate the effect of TD on the lung and intestine of asthmatic rats based on NO-CO metabolism. MATERIALS AND METHODS: In vivo, we established a rat asthma model by intraperitoneal injection of sensitizing solution with OVA atomization, followed by intervention by gavage administration of TD. We simultaneously examined alterations in basal function, pathology, NO-CO metabolism, inflammation and immune cell homeostasis in the lungs and intestines of asthmatic rats, and detected changes in intestinal flora by macrogenome sequencing technology, with a view to multi-angle evaluation of the treatment effects of TD on asthmatic rats. In vitro, lung cells BEAS-2B and intestinal cells NCM-460 were used to establish a model of lung injury causing intestinal injury using LPS and co-culture chambers, and lung cells or intestinal cells TD-containing serum was administered to intervene. Changes in inflammatory, NO-CO metabolism-related, cell barrier-related and oxidative stress indicators were measured in lung cells and intestinal cells to evaluate TD on intestinal injury by way of amelioration and in-depth mechanism. RESULTS: In vivo, our results showed significant basal functional impairment in the lung and intestine of asthmatic rats, and an inflammatory response, immune cell imbalance and intestinal flora disturbance elicited by NO-CO metabolic disorders were observed (P < 0.05 or 0.01). The administration of TD was shown to deliver a multidimensional amelioration of the impairment induced by NO-CO metabolic disorders (P < 0.05 or 0.01). In vitro, the results showed that LPS-induced lung cells BEAS-2B injury could cause NO-CO metabolic disorder-induced inflammatory response, cell permeability damage and oxidative stress damage in intestinal cells NCM-460 (P < 0.01). The ameliorative effect on intestinal cells NCM-460 could only be exerted when TD-containing serum interfered with lung cells BEAS-2B (P < 0.01), suggesting that the intestinal ameliorative effect of TD may be exerted indirectly through the lung. CONCLUSION: TD can ameliorate NO-CO metabolism in the lung and thus achieve the indirectly amelioration of NO-CO metabolism in the intestine, ultimately achieving co-regulation of lung and intestinal inflammation, immune imbalance, cellular barrier damage, oxidative stress and intestinal bacterial disorders in asthma in vivo and in vitro. Targeting lung and intestinal NO-CO metabolic disorders in asthma may be a new therapeutic idea and strategy for asthma.

Significant change of cytochrome P450s activities in patients with hepatocellular carcinoma.

The lack of information concerning individual variation in drug-metabolizing enzymes is one of the most important obstacles for designing personalized medicine approaches for hepatocellular carcinoma (HCC) patients. To assess cytochrome P450 (CYP) in the metabolism of endogenous and exogenous molecules in an HCC setting, the activity changes of 10 major CYPs in microsomes from 105 normal and 102 HCC liver tissue samples were investigated. We found that CYP activity values expressed as intrinsic clearance (CLint) differed between HCC patients and control subjects. HCC patient samples showed increased CLint for CYP2C9, CYP2D6, and CYP2E1 compared to controls. Meanwhile, CYP1A2, CYP2C8, and CYP2C19 CLint values decreased and CYP2A6, CYP2B6, and CYP3A4/5 activity was unchanged relative to controls. For patients with HCC accompanied by fibrosis or cirrhosis, the same activity changes were seen for the CYP isoforms, except for CYP2D6 which had higher values in HCC patients with cirrhosis. Moreover, CYP2D6*10 (100C>T), CYP2C9*3 (42614 A>C), and CYP3A5*3 (6986A>G) polymorphisms had definite effects on enzyme activities. In the HCC group, the CLint of CYP2D6*10 mutant homozygote was decreased by 95% compared to wild-type samples, and the frequency of this homozygote was 2.8-fold lower than the controls.In conclusion, the activities of CYP isoforms were differentially affected in HCC patients. Genetic polymorphisms of some CYP enzymes, especially CYP2D6*10, could affect enzyme activity. CYP2D6*10 allelic frequency was significantly different between HCC patients and control subjects. These findings may be useful for personalizing the clinical treatment of HCC patients as well as predicting the risk of hepatocarcinogenesis.

Chemical constituents from endophytic fungus Fusarium oxysporum.

A new oxysporidinone analogue (1) and a new 3-hydroxyl-2-piperidinone derivative (2), along with the known compounds (-)-4,6'-anhydrooxysporidinone (3), (+)-fusarinolic acid (4), gibepyrone D (5), beauvercin (6),cerevisterol (7), fusaruside (8), and (2S,2'R,3R,3'E,4E,8E)-1-O-D-glucopyranosyl-2-N-(2'-hydroxy-3'-octadecenoyl)-3-hydroxy-9-methyl-4,8-sphingadienine (9) were isolated from Fusarium oxysporum. Compounds 1-9 were evaluated for cytotoxicity using the MTT method against cancer cell lines, PC-3, PANC-1, and A549. Beauvericin showed cytotoxicity against PC-3, PANC-1, and A549 with IC(50) value of 49.5 ± 3.8, 47.2 ± 2.9, and 10.4 ± 1.6µM, respectively. Beauvericin also exhibited anti-bacterial activity towards methicillin-resistant Staphylococcus aureus (MIC=3.125 µg/mL) and Bacillus subtilis (MIC=3.125 µg/mL).