Biological and molecular characterization of pydiflumetofen and phenamacril dual-resistant Fusarium graminearum strains.

BACKGROUND: Fusarium head blight (FHB) caused by Fusarium graminearum species complex (FGSG) remains a major challenge to cereal crops and resistance to key fungicides by the pathogen threatens control efficacy. Pydiflumetofen, a succinate dehydrogenase inhibitor, and phenamacril, a cyanoacrylate fungicide targeting myosin I, have been applied to combat this disease. Nonetheless, emergence of pydiflumetofen resistance in a subset of field isolates alongside laboratory-induced facile generation of phenamacril-resistant isolates signals a critical danger of resistance proliferation. RESULTS: Our study investigates the development of dual resistance to these fungicides in F. graminearum. Utilizing pydiflumetofen-resistant (PyR) and -sensitive (PyS) isolates, we obtained dual-resistant (PyRPhR) and phenamacril-resistant (PySPhR) mutants on potato sucrose agar containing phenamacril. Mutation rates for phenamacril resistance were comparable between pydiflumetofen-resistant and -sensitive isolates, implying independent pathways for resistance development. The mutants compromised in fungal growth, competitive viability and deoxynivalenol production, suggesting fitness penalties for the dual-resistant mutants. However, no cross-resistance was found with tebuconazole or fludioxonil. In addition, we characterized four critical amino acid changes (S217L, C423R, K537T, E420G) in the Myo1 that were verified to confer phenamacril resistance in F. graminearum. CONCLUSION: This research indicates the possibility of resistance development for both pydiflumetofen and phenamacril in F. graminearum and emphasizes the need for fungicide resistance management for FHB. © 2024 Society of Chemical Industry.

New strategy for rational use of antihypertensive drugs in clinical practice in high-altitude hypoxic environments.

High-altitude hypoxic environments have critical implications on cardiovascular system function as well as blood pressure regulation. Such environments place patients with hypertension at risk by activating the sympathetic nervous system, which leads to an increase in blood pressure. In addition, the high-altitude hypoxic environment alters the in vivo metabolism and antihypertensive effects of antihypertensive drugs, which changes the activity and expression of drug-metabolizing enzymes and drug transporters. The present study reviewed the pharmacodynamics and pharmacokinetics of antihypertensive drugs and its effects on patients with hypertension in a high-altitude hypoxic environment. It also proposes a new strategy for the rational use of antihypertensive drugs in clinical practice in high-altitude hypoxic environments. The increase in blood pressure on exposure to a high-altitude hypoxic environment was mainly dependent on increased sympathetic nervous system activity. Blood pressure also increased proportionally to altitude, whilst ambulatory blood pressure increased more than conventional blood pressure, especially at night. High-altitude hypoxia can reduce the activities and expression of drug-metabolizing enzymes, such as CYP1A1, CYP1A2, CYP3A1, and CYP2E1, while increasing those of CYP2D1, CYP2D6, and CYP3A6. Drug transporter changes were related to tissue type, hypoxic degree, and hypoxic exposure time. Furthermore, the effects of high-altitude hypoxia on drug-metabolism enzymes and transporters altered drug pharmacokinetics, causing changes in pharmacodynamic responses. These findings suggest that high-altitude hypoxic environments affect the blood pressure, pharmacokinetics, and pharmacodynamics of antihypertensive drugs. The optimal hypertension treatment plan and safe and effective medication strategy should be formulated considering high-altitude hypoxic environments.

Relationship between blood-brain barrier changes and drug metabolism under high-altitude hypoxia: obstacle or opportunity for drug transport?

The blood-brain barrier is essential for maintaining the stability of the central nervous system and is also crucial for regulating drug metabolism, changes of blood-brain barrier's structure and function can influence how drugs are delivered to the brain. In high-altitude hypoxia, the central nervous system's function is drastically altered, which can cause disease and modify the metabolism of drugs in vivo. Changes in the structure and function of the blood-brain barrier and the transport of the drug across the blood-brain barrier under high-altitude hypoxia, are regulated by changes in brain microvascular endothelial cells, astrocytes, and pericytes, either regulated by drug metabolism factors such as drug transporters and drug-metabolizing enzymes. This article aims to review the effects of high-altitude hypoxia on the structure and function of the blood-brain barrier as well as the effects of changes in the blood-brain barrier on drug metabolism. We also hypothesized and explore the regulation and potential mechanisms of the blood-brain barrier and associated pathways, such as transcription factors, inflammatory factors, and nuclear receptors, in regulating drug transport under high-altitude hypoxia.

High-altitude Hypoxia Influences the Activities of the Drug-Metabolizing Enzyme CYP3A1 and the Pharmacokinetics of Four Cardiovascular System Drugs.

(1) Background: High-altitude hypoxia has been shown to affect the pharmacokinetic properties of drugs. Although there is a high incidence of cardiovascular disease among individuals living in high-altitude areas, studies on the effect of high-altitude hypoxia on the pharmacokinetic properties of cardiovascular drugs are limited. (2) Methods: The aim of this study was to evaluate the pharmacokinetics of nifedipine, bosentan, simvastatin, sildenafil, and their respective main metabolites, dehydronifedipine, hydroxybosentan, simvastatin hydroxy acid, and N-desmethyl sildenafil, in rats exposed to high-altitude hypoxia. Additionally, the protein and mRNA expression of cytochrome P450 3A1 (CYP3A1), a drug-metabolizing enzyme, were examined. (3) Results: There were significant changes in the pharmacokinetic properties of the drugs in rats exposed to high-altitude hypoxia, as evidenced by an increase in the area under the curve (AUC) and the half-life (t1/2z) and a decrease in total plasma clearance (CLz/F). However, most of these changes were reversed when the rats returned to a normoxic environment. Additionally, there was a significant decrease in CYP3A1 expression in rats exposed to high-altitude hypoxia at both the protein and mRNA levels. (4) Conclusions: High-altitude hypoxia suppressed the metabolism of the drugs, indicating that the pharmacokinetics of the drugs should be re-examined, and the optimal dose should be reassessed in patients living in high-altitude areas.

Bacterial Communities in the Endophyte and Rhizosphere of White Radish (Raphanus sativus) in Different Compartments and Growth Conditions.

Endophyte resources have important research value in multiresistance breeding, ecological protection, germicide development, and other fields. In this study, high-throughput sequencing (Illumina-MiSeq) technology was employed to analyse the diversity and community composition of white radish (Raphanus sativus) endophytes and rhizosphere bacteria in different compartments and cultivation conditions, including greenhouse and open field cultivation, at both the phylum and genus levels. Alpha diversity index analysis showed that the bacterial richness and diversity values of rhizosphere bacteria were higher than those of endophytes in different compartments. NMDS analysis and microbial co-occurrence network analysis showed that apart from the similarity in the endophytic bacterial composition of the leaf and root endosphere, the endophytic bacterial composition in flesh and epidermis of radish were also more similar. The dominant endophytic bacteria in white radish were Proteobacteria, Bacteroidetes, and Actinomycetes at the phylum level. We analyzed the effects of different ecological compartments and two cultivation environments on radish microorganisms, and found that ecological compartments played an important role, which was related to the mechanism of microbial assembly in plants. The same facility cultivation can also improve the diversity of radish microorganisms in different ecological compartments, and change the biomarkers that play a major role in rhizosphere microorganisms and endophytes of radish. Bacteria plays an important role in the process of plant growth, and the study of endophytes enriches the understanding of microbial diversity in white radish, which helps to provide insight into the ecological function and interaction mechanisms of plants and microorganisms.

Colonization and Interaction of Bacteria Associated With Chinese Chives Affected by Ecological Compartments and Growth Conditions.

Chinese chive has a long history of planting in China. At present, there are many studies on endophytic bacteria and rhizosphere microorganisms of Chinese chive, but the effects of ecological compartment and growth conditions on bacterial communities in Chinese chives are unclear. Here, we aimed to elucidate the differences in bacterial a-diversity, ß-diversity, community structure, core species differences, interaction networks and predicted metabolic functions among bacterial communities in different ecological compartments (the phylloplane, leaf endosphere, stem endosphere, root endosphere, and rhizosphere) in Chinese chives in an open field, a solar greenhouse, an arched shed, and a hydroponic system. Sixty samples were collected from these five ecological compartments under four growth conditions, and we compared the bacterial profiles of these groups using 16S rRNA sequencing. We evaluated the differences in diversity and composition among bacterial communities in these ecological compartments, analyzed the bacterial interaction patterns under the different growth conditions, and predicted the bacterial metabolic pathways in these ecological compartments and growth conditions. The results showed that the effects of ecological compartments on bacterial diversity, community composition, interaction network pattern, and functional expression of Chinese chives were greater than those of growth condition. Ecological compartments (R 2 = 0.5292) could better explain bacterial community division than growth conditions (R 2 = 0.1056). The microbial interaction networks and indicator bacteria in different ecological compartments showed that most of the bacteria that played the role of key nodes (OTUs) in each ecological compartment were bacteria with high relative abundance in the compartment. However, the bacteria that played the role of key nodes (OTUs) in bulbs were not Proteobacteria with the highest relative abundance in the compartment, but Actinobacteria that were significantly enriched in the root endosphere and rhizosphere ecological compartments. In addition, interactions among bacteria were interrupted in the hydroponic system, and specific bacterial communities and interaction patterns in Chinese chives varied among growth conditions. Prediction of metabolic functions indicated that plant metabolic activity related to stress responses and induction of system resistance was greater in belowground ecological compartments.

Exposure to High-Altitude Environment Is Associated with Drug Transporters Change: microRNA-873-5p-Mediated Alteration of Function and Expression Levels of Drug Transporters under Hypoxia.

Hypoxia is the main characteristic of a high-altitude environment, affecting drug metabolism. However, so far, the mechanism of microRNA (miRNA) involved in the regulation of drug metabolism and transporters under high-altitude hypoxia is still unclear. This study aims to investigate the functions and expression levels of multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein 2 (MRP2), breast cancer resistance protein (BCRP), peptide transport 1 (PEPT1), and organic anion-transporting polypeptides 2B1 (OATP2B1) in rats and colon cancer (Caco-2) cells after exposure to high-altitude hypoxia. The protein and mRNA expression of MDR1, MRP2, BCRP, PEPT1, and OATP2B1 were determined by Western blot and qPCR. The functions of MDR1, MRP2, BCRP, PEPT1, and OATP2B1 were evaluated by determining the effective intestinal permeability and absorption rate constants of their specific substrates in rats under high-altitude hypoxia, and uptake and transport studies were performed on Caco-2 cells. To screen the miRNA associated with hypoxia, Caco-2 cells were examined by high throughput sequencing. We observed that the miR-873-5p was significantly decreased under hypoxia and might target MDR1 and pregnane X receptor (PXR). To clarify whether miR-873-5p regulates MDR1 and PXR under hypoxia, Caco-2 cells were transfected with mimics or inhibitors of miR-873-5p and negative control (NC). The function and expression of drug transporters were found to be significantly increased in rats and Caco-2 cells under hypoxia. We found that miR-873-5p regulated MDR1 and PXR expression. Herein, it is shown that miRNA may affect the expression of drug transporter and nuclear receptor under hypoxia. SIGNIFICANCE STATEMENT: This study explores if alterations to the microRNAs (miRNAs), induced by high-altitude hypoxia, can be translated to altered drug transporters. Among miRNAs, which show a significant change in a hypoxic environment, miR-873-5p can act on the multidrug resistance protein 1 (MDR1) gene; however, there are multiple miRNAs that can act on the pregnane X receptor (PXR). This study speculates that the miRNA-PXR-drug transporter axis is important in the physiological disposition of drugs.

Pharmacokinetics of Acetaminophen and Metformin Hydrochloride in Rats After Exposure to Simulated High Altitude Hypoxia.

The pharmacokinetic characteristics of drugs were altered under high altitude hypoxia, thereby affecting the absorption, distribution, metabolism, and excretion of drug. However, there are few literatures on the pharmacokinetic changes of antipyretic and pain-relieving drugs and cardiovascular system drugs at high altitude. This study aimed to evaluate the pharmacokinetics of acetaminophen and metformin hydrochloride in rats under simulated high altitude hypoxia condition. Mechanically, the protein and mRNA expression of uridine diphosphate glucuronyltransferase 1A1 (UGT1A1) and organic cation transporter 2 (OCT2) were investigated by enzyme linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. Compared with the normoxia group, the t1/2 and AUC of acetaminophen were significantly increased, and the CL/F was significantly decreased in rats after exposure to simulated high altitude hypoxia. The t1/2 of metformin hydrochloride was significantly increased by simulated high altitude hypoxia. No significant differences in AUC and CL/F of metformin hydrochloride were observed when comparing the hypoxia group with the normoxia group. The protein and mRNA expression of UGT1A1 and OCT2 were decreased significantly under hypoxia in rats. This study found obvious changes in the pharmacokinetics of acetaminophen and metformin hydrochloride in rats after exposure to simulated high altitude hypoxia, and they might be due to significant decreases in the expressions of UGT1A1 and OCT2. To sum up, our data suggested that the pharmacokinetics of acetaminophen and metformin hydrochloride should be reexamined, and the optimal dose should be reassessed under hypoxia exposure.

A Decade's Review of miRNA: A Center of Transcriptional Regulation of Drugmetabolizing Enzymes and Transporters under Hypoxia.

BACKGROUND: Hypoxia has a negative effect on the cardiovascular system, nervous system, and metabolism, which contributes to potential changes in drug absorption, distribution, metabolism, and excretion (ADME). However, hypoxia can also alter the expression of microRNA (miRNA), thereby regulating drug-metabolizing enzymes, transporters, and ADME genes, such as hypoxia-inducible factor, inflammatory cytokine, nuclear receptor, etc. Therefore, it is crucial to study the role of miRNA in the regulation of drug-metabolizing enzymes and transporters under hypoxia. METHODS: A systematic review of published studies was carried out to investigate the role of miRNA in the regulation of drug-metabolizing enzymes and transporters under hypoxia. Data and information on expression changes in miRNA, drug-metabolizing enzymes, and transporters under hypoxia were analyzed and summarized. RESULTS: Hypoxia can up or down-regulate the expression of miRNA. The effect of hypoxia on Cytochrome P450 (CYP450) is still a subject of debate. The widespread belief is that hypoxia decreased the activity and expression of CYP1A1, CYP1A2, CYP2E1, and CYP3A1 and increased those of CYP3A6 and CYP2D1 in rats. Hypoxia increased the expression of a multidrug resistance-associated protein, breast cancer resistance protein, peptide transporter, organic cation transporter, and organic anion transporter. miRNA negatively regulated the expression of drugmetabolizing enzymes and transporters. CONCLUSION: The findings of this review indicated that miRNA plays a key role in the expression changes of drugmetabolizing enzymes and transporters under hypoxia.

Regulation of High-Altitude Hypoxia on the Transcription of CYP450 and UGT1A1 Mediated by PXR and CAR.

Little is known about what roles the pregnane X receptor (PXR) and constitutive androstane receptor (CAR) play in drug metabolism in high-altitude hypoxia. Likewise, the potential interaction of nuclear receptors and drug metabolism enzymes during drug metabolism of high-altitude hypoxia is not fully understood. In this work, we investigated the effects of high-altitude hypoxia on transcriptional regulation of cytochrome P450 (CYP450) and UDP-glucuronosyltransferase 1A1 (UGT1A1) genes mediated by PXR and CAR proteins. The protein and mRNA expressions of CYP450, UGT1A1, PXR, and CAR were determined by enzyme-linked immunosorbent assay and qPCR in rats and HepG2 cell lines under hypoxia. Hypoxia potently inhibited the CYP450 isoforms, UGT1A1, PXR, and CAR protein and mRNA expression. To clarify whether PXR and CAR regulate various genes involved in drug metabolism of high-altitude hypoxia, we investigated the expression of CYP1A2, CYP2C9, CYP2E1, CYP3A4, and UGT1A1 using a dual-luciferase reporter assay after treatment with Ketoconazole (KCZ) and Retinoic acid (RA), or silenced PXR and CAR gene expression. In HepG2 cells, hypoxia, KCZ, and RA inhibited CYP450 isoforms and UGT1A1 expression. Activation of PXR and CAR in cells treated with 6-(4-chlorophenyl)-imidazo (2,1-b) thiazole-5-carbaldehyde (CITCO) and rifampicin (Rif) resulted in the enhancement of CYP450 isoforms, UGT1A1, PXR, and CAR. In contrast, this effect was not observed under hypoxia. Taken together, our results suggest that hypoxia inhibits CYP1A2, CYP2C9, CYP2E1, CYP3A4, and UGT1A1 expression via the PXR and CAR regulatory pathway.

Protection against X-Ray Irradiation Injury by Chinese Caterpillar Medicinal Mushroom Ophiocordyceps sinensis (Ascomycetes) Polysaccharides in Mice.

Polysaccharides are one of the main active ingredients of Ophiocordyceps sinensis, a traditional Chinese medicinal mushroom. In this study, we investigated the protective effect of O. sinensis polysaccharides (CSPs) against X-ray irradiation in mice. The results indicated that CSPs improved survival rates and times in radiation-injured mice, accelerated the recovery of white blood cells, increased the organ index of thymus and spleen, and increased the DNA content in bone marrow cells. CSPs also increased the activity of superoxide dismutase, decreased the production of malondialdehyde, and reversed the increase in catalase and glutathione peroxidase activity induced by irradiation. Treatment with 100, 200, and 400 mg/kg body weight CSPs caused a significant decrease in the protein and messenger RNA expression of extracellular regulated protein kinase (ERK1), c-Jun N-terminal kinase (JNK1), and p38 mitogen-activated protein kinase (MAPK) after irradiation. Our results demonstrate that CSPs protect mice from injury after exposure to X-ray irradiation, and that this effect may be exerted via the mitogen-activated protein kinase pathway. These findings may provide a basis for the use of CSPs as an effective radioprotector or an alternative strategy in reducing irradiation-induced injury.

Effects of Radiation on Drug Metabolism: A Review.

BACKGROUND: Radiation is the fourth most prevalent type of pollution following the water, air and noise pollution. It can adversely affect normal bodily functions. Radiation alters the protein and mRNA expression of drugmetabolizing enzymes and drug transporters and the pharmacokinetic characteristics of drugs, thereby affecting drug absorption, distribution, metabolism, and excretion. Therefore, it is important to study the pharmacokinetic changes in drugs under radiation. METHODS: To update data on the effects of ionizing radiation and non-ionizing radiation caused by environmental pollution or clinical treatments on the protein and mRNA expression of drug-metabolizing enzymes and drug transporters. Data and information on pharmacokinetic changes in drugs under radiation were analyzed and summarized. RESULTS: The effect of radiation on cytochrome P450 is still a subject of debate. The widespread belief is that higherdose radiation increased the expression of CYP1A1 and CYP1B1 of rat, zebrafish or human, CYP1A2, CYP2B1, and CYP3A1 of rat, and CYP2E1 of mouse or rat, and decreased that of rat's CYP2C11 and CYP2D1. Radiation increased the expression of multidrug resistance protein, multidrug resistance-associated protein, and breast cancer resistance protein. The metabolism of some drugs, as well as the clearance, increased during concurrent chemoradiation therapy, whereas the half-life, mean residence time, and area under the curve decreased. Changes in the expression of cytochrome P450 and drug transporters were consistent with the changes in the pharmacokinetics of some drugs under radiation. CONCLUSION: The findings of this review indicated that radiation caused by environmental pollution or clinical treatments can alter the pharmacokinetic characteristics of drugs. Thus, the pharmacokinetics of drugs should be rechecked and the optimal dose should be re-evaluated after radiation.

Regulation of X-Ray Irradiation on the Activity and Expression Levels of CYP1A2 and CYP2E1 in Rats.

The objective of this study was to investigate the regulation of X-ray irradiation and its effect on the activity and protein and mRNA expression levels of CYP1A2 and CYP2E1 in rats. Rats were randomly divided into 0 Gy (control), 1 Gy (low-dose irradiation), and 5 Gy (high-dose irradiation) groups. CYP1A2 and CYP2E1 activity was evaluated from changes in pharmacokinetic parameters of caffeine and chlorzoxazone, respectively. The plasma concentrations of the probe drugs were determined by high-performance liquid chromatography (HPLC). Enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (PCR) tests were used to analyze the protein and mRNA expression levels of CYP1A2 and CYP2E1, respectively. The AUC0-12 of caffeine was decreased by 1.7- and 2.5-fold, and the CL was increased by 1.8- and 2.6-fold in the 1 Gy and 5 Gy groups, respectively, compared to the 0 Gy group. The AUC0-10 of chlorzoxazone was 1.4- and 1.8-fold lower, and the CL was 1.4- and 1.9-fold higher in the 1 Gy and 5 Gy groups, respectively, compared to the 0 Gy group. The metabolism of caffeine and chlorzoxazone increased under X-ray irradiation as CL levels increased and AUC levels decreased, suggesting that CYP1A2 and CYP2E1 activity is enhanced in rats after X-ray irradiation. Compared to that of the 0 Gy group, the protein expression level of CYP1A2 was measured as 28.3% and 38.9% higher in the 1 Gy and 5 Gy groups, respectively. The protein expression level of CYP2E1 was 48.4% higher in the 5 Gy group compared to the 0 Gy group, and there was no statistically significant difference between 0 Gy and 1 Gy. Compared to the 0 Gy group, the mRNA expression level of CYP1A2 was 200% and 856.3% higher in the 1 Gy and 5 Gy group, respectively, whereas the mRNA expression level of CYP2E1 was 89.0% and 192.3% higher in the 1 Gy and 5 Gy groups, respectively. This study reveals significant changes in the activity and protein and mRNA expression levels of CYP1A2 and CYP2E1 in rats after exposure to X-ray irradiation.

Effects of yak-activated protein on hematopoiesis and related cytokines in radiation-induced injury in mice.

The aim of the present study was to investigate the protective effects of yak-activated protein on hematopoiesis and cytokine function in radiation-induced injury in mice. A total of 180 Kunming mice were randomly divided into three groups (A, B and C). Of these, 60 were randomly divided into a normal control group, a radiation model group, a positive control group and 3 yak-activated protein groups (high, medium and low dose groups; 10, 5 and 2.5 mg/kg, respectively). The other 120 mice were used for the subsequent experiments on days 7 and 14 following radiation. Yak-activated protein was administered orally to mice in the treatment groups and an equal volume of saline was administered orally to mice in the normal control and radiation model groups for 14 days. The positive control group received amifostine (150 mg/kg) via intraperitoneal injection. With the exception of the control group, the groups of mice received a 5 Gy quantity of X-radiation evenly over their whole body once. Changes in the peripheral hemogram, thymus and spleen indices, DNA content in the bone marrow, interleukin (IL)-2 and IL-6 levels, and the expression levels of B cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) following irradiation were assessed. The low dose of yak-activated protein significantly increased Spleen indices in mice 14 days after irradiation and the high and middle dose of yak-activated protein significantly increased Thymus indices in mice 14 days after irradiation (P<0.05) compared with the control group. In addition, hemogram results increased gradually in the low-yak-activated protein dose group and were significantly higher 7 days after irradiation compared with the radiation model group (P<0.05). The DNA content in the bone marrow was markedly increased in the yak-activated protein groups, and increased significantly in the low dose group at 7 days post-irradiation compared with the radiation model group (P<0.05). The IL-2 content was significantly increased in the yak-activated protein groups (P<0.05). Furthermore, Bcl-2 expression was increased and Bax expression was decreased (P<0.05). These results suggest that yak-activated protein exerts protective effects against radiation-induced injury in mice. The optimal effects of yak-activated protein were observed in the medium dose group 14 days after irradiation.

Pharmacokinetics of Lidocaine Hydrochloride Metabolized by CYP3A4 in Chinese Han Volunteers Living at Low Altitude and in Native Han and Tibetan Chinese Volunteers Living at High Altitude.

To investigate the pharmacokinetics of lidocaine hydrochloride metabolized by cytochrome P450 3A4 (CYP3A4) in Chinese Han volunteers living at low altitude (LA) and in native Han and Tibetan Chinese volunteers living at high altitude, lidocaine hydrochloride 10 mg was given by intramuscular injection to 3 groups: Han volunteers living at LA, and native Han and Tibetan volunteers living at a high altitude. Blood samples were collected before the (baseline) study drug was given and at 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0 h after study drug administration. Lidocaine hydrochloride in plasma was determined by RP-HPLC. Pharmacokinetics parameters of lidocaine hydrochloride showed that there were no significant difference between the native Han and Tibetan volunteers, but the t(1/2) was 29.8 and 29.8% higher in 2 groups, respectively, than in the LA group. To study related mechanism, the effects of exposure to chronic high-altitude hypoxia (CHH) on the activity and expression of CYP3A1 were examined in rats. Rats were divided into LA, chronic moderate altitude hypoxia, and CHH groups. CHH caused significant decreases in the activity and protein and mRNA expression of rat CYP3A1 in vivo. This study found significant changes in the disposition of lidocaine hydrochloride in native healthy Tibetan and Han Chinese subjects living at a high altitude in comparison to healthy Han Chinese subjects living at LA, it might be due to significant decreases in the activity and protein and mRNA expression of CYP3A4 under CHH condition.

Protective Effect of Lycium ruthenicum Murr. Against Radiation Injury in Mice.

The protective effect of Lycium ruthenicum Murr. against radiation injury was examined in mice. Kunming mice were randomly divided into a control group, model group, positive drug group and L. ruthenicum high dose (8 g/kg), L. ruthenicum middle dose (4 g/kg), L. ruthenicum low dose (2 g/kg) treatment groups, for which doses were administered the third day, seventh day and 14th day after irradiation. L. ruthenicum extract was administered orally to the mice in the three treatment groups and normal saline was administered orally to the mice in the control group and model group for 14 days. The positive group was treated with amifostine (WR-2721) at 30 min before irradiation. Except for the control group, the groups of mice received a 5 Gy quantity of X-radiation evenly over their whole body at one time. Body weight, hemogram, thymus and spleen index, DNA, caspase-3, caspase-6, and P53 contents were observed at the third day, seventh day, and 14th day after irradiation. L. ruthenicum could significantly increase the total red blood cell count, hemoglobin count and DNA contents (p < 0.05). The spleen index recovered significantly by the third day and 14th day after irradiation (p < 0.05). L. ruthenicum low dose group showed a significant reduction in caspase-3 and caspase-6 of serum in mice at the third day, seventh day, and 14th day after irradiation and L. ruthenicum middle dose group experienced a reduction in caspase-6 of serum in mice by the seventh day after irradiation. L. ruthenicum could decrease the expression of P53. The results showed that L. ruthenicum had protective effects against radiation injury in mice.

[Protective Effect of Lycium ruthenicum on Peripheral Blood System Against Radiation Injury in Mice].

OBJECTIVE: To study the protective effect of Lycium ruthenicum on peripheral blood system against radiation injury in mice. METHODS: Kunming mice were randomly divided into control group, model group, positive group and Lycium ruthenicum high dose (8 g/kg), middle dose (4 g/kg) and low dose (2 g/kg)treatment groups that experimented three days after irradiation. In the same way, groups were set at 7 days and 14 days after irradiation respectively. Lycium ruthenicum extract were administered orally to the mice in the three Lycium ruthenicum treatment groups and normal saline were administered orally to the mice in control group and model group for 14 days. Positive group were treated with radioprotective agent amifostine (WR-2721) at 30 min before irradiation. Except control group, mice in other groups received quantity of 5 Gy X-radiation whole body evenly with one time. Hemogram, organ index, DNA, Caspase-3, Caspase-6 and P53 contents were observed at the 3rd, 7th and 14th day after irradiation. RESULTS: Lycium ruthenicum significantly increased the total red blood cell count, hemoglobin count, the indexes of spleen and thymus and bone marrow DNA contents (P < 0.05), as well as decreased Caspase-3 and Caspase-6 contents in serum and the expression of P53 in intestinal crypt epithelial cells. CONCLUSION: The results showed that Lycium ruthenicum had protective effects on peripheral blood system against radiation injury in mice.

The activity, protein, and mRNA expression of CYP2E1 and CYP3A1 in rats after exposure to acute and chronic high altitude hypoxia.

The effects of exposure to acute and chronic high altitude hypoxia on the activity and expression of CYP2E1 and CYP3A1 were examined in rats. Rats were divided into low altitude (LA, 400 m), acute moderate altitude hypoxia (AMH, 2800 m), chronic moderate altitude hypoxia (CMH, 2800 m), acute high altitude hypoxia (AHH, 4300 m), and chronic high altitude hypoxia groups (CHH, 4300 m). Probe drugs were administrated orally to all five groups. Then the serum concentration of probe drug and its metabolite was determined by RP-HPLC. The activity of CYP2E1 and CYP3A1 was evaluated using the ratio of the metabolite to chlorzoxazone and testosterone, respectively. ELISA and real-time PCR were used to analyze the protein and mRNA expression of CYP2E1 and CYP3A1 in liver microsomes, respectively. Chronic high altitude hypoxia caused significant decreases in the activity and protein and mRNA expression of rat CYP2E1 and CYP3A1 in vivo. Acute high altitude hypoxia was not found to change the activity, protein or mRNA expression of rat CYP2E1 or CYP3A1. This study showed significant changes in the activity and protein and mRNA expression of CYP2E1 or CYP3A1 in rats after exposure to chronic high altitude hypoxia.

Effect of exposure to acute and chronic high-altitude hypoxia on the activity and expression of CYP1A2, CYP2D6, CYP2C9, CYP2C19 and NAT2 in rats.

We investigated the effect of exposure to acute and chronic high-altitude hypoxia (AHH and CHH) on the activity and expression of CYP1A2, CYP2D6, CYP2C9, CYP2C19 and NAT2 in rats. The rats were divided into plain (400 m), acute middle-altitude hypoxia (2,800 m), chronic middle-altitude hypoxia (2,800 m), AHH (4,300 m) and CHH (4,300 m). After probe drugs had been orally administered to the rats of the 5 groups, the serum or urine concentration of the probe drug and its metabolite was determined by reversed-phase HPLC. The activity of cytochrome P450 isozyme and NAT2 was evaluated by the ratio of the metabolite to the probe drug. The ELISA and real-time PCR were used to analyze the protein and mRNA expression of cytochrome P450 isozyme and NAT2, respectively. AHH and CHH caused significant decreases in the activity and protein and mRNA expression of rat CYP1A2 in vivo. AHH downregulates the activity and mRNA expression of rat NAT2 in vivo, and CHH upregulates the activity and protein and mRNA expression of rat CYP2D6. AHH and CHH did not change the expression of CYP2C9 and CYP2C19 in rats. This study found significant changes in the activity and protein and mRNA expression of CYP1A2, CYP2D6 and NAT2 in rats in the special environment of high-altitude hypoxia.