Activation of PXR causes drug interactions with Paxlovid in transgenic mice

Paxlovid is a nirmatrelvir (NMV) and ritonavir (RTV) co-packaged medication used for the treatment of coronavirus disease 2019 (COVID-19). The active component of Paxlovid is NMV and RTV is a pharmacokinetic booster. Our work aimed to investigate the drug/herb-drug interactions associated with Paxlovid and provide mechanism-based guidance for the clinical use of Paxlovid. By using recombinant human cytochrome P450s (CYPs), we confirmed that CYP3A4 and 3A5 are the major enzymes responsible for NMV metabolism. The role of CYP3A in Paxlovid metabolism were further verified in Cyp3a-null mice, which showed that the deficiency of CYP3A significantly suppressed the metabolism of NMV and RTV. Pregnane X receptor (PXR) is a ligand-dependent transcription factor that upregulates CYP3A4/5 expression. We next explored the impact of drug- and herb-mediated PXR activation on Paxlovid metabolism in a transgenic mouse model expressing human PXR and CYP3A4/5. We found that PXR activation increased CYP3A4/5 expression, accelerated NMV metabolism, and reduced the systemic exposure of NMV. In summary, our work demonstrated that PXR activation can cause drug interactions with Paxlovid, suggesting that PXR-activating drugs and herbs should be used cautiously in COVID-19 patients receiving Paxlovid.

The nucleocapsid protein of rice stripe virus in cell nuclei of vector insect regulates viral replication

Rice stripe virus (RSV) transmitted by the small brown planthopper causes severe rice yield losses in Asian countries. Although viral nuclear entry promotes viral replication in host cells, whether this phenomenon occurs in vector cells remains unknown. Therefore, in this study, we systematically evaluated the presence and roles of RSV in the nuclei of vector insect cells. We observed that the nucleocapsid protein (NP) and viral genomic RNAs were partially transported into vector cell nuclei by utilizing the importin α nuclear transport system. When blocking NP nuclear localization, cytoplasmic RSV accumulation significantly increased. In the vector cell nuclei, NP bound the transcription factor YY1 and affected its positive regulation to FAIM. Subsequently, decreased FAIM expression triggered an antiviral caspase-dependent apoptotic reaction. Our results reveal that viral nuclear entry induces completely different immune effects in vector and host cells, providing new insights into the balance between viral load and the immunity pressure in vector insects.

Investigation on the infection of spotted fever group Rickettsiae and Rickettsia mooseri of wild rodents in the field of plague foci in Western Yunnan / 中华地方病学杂志

Objective:To investigate the infection of spotted fever group Rickettsiae (SFGR) and Rickettsia mooseri ( R.mooseri) of wild rodents in the field of plague foci in Western Yunnan. Methods:The DNA of liver samples of 2 512 wild rodents captured from the plague foci in Lianghe County, Jianchuan County and Yulong County in Western Yunnan from 2015 to 2016 was extracted by magnetic bead method, and the heat shock protein groEL gene primers were used for nested PCR amplification. Gene sequence splicing and Blast homology comparison were performed using DNAStar 7.1 software and GenBank of the National Center for Biotechnology Information (NCBI) of the United States, respectively, and DNAStar 7.1 and MEGA 6.0 softwares were used to construct phylogenetic trees.Results:The wild rodents infected with SFGR were Mus pahari, Rattus steini, Crocidura attenuata and Suncus murinus (one for each), with a total infection rate of 0.16% (4/2 512); no R.mooseri infection was detected. The SFGR infection rates of wild rodents in the plague foci of Lianghe County and Jianchuan County were 0.49% (3/611) and 0.10% (1/1 029), respectively; no SFGR infection was detected in the wild rodents in the plague foci of Yulong County. The homology analysis showed that the homology between SFGR positive samples and reference sequences was 95.45%-100.00%; some of the groEL gene sequences were highly similar among the four positive samples, and the homology was 89.60%-97.40%. Sequence evolution analysis showed that the sequences of three SFGR positive samples from the plague focus in Lianghe County were clustered in the same branch, and the homology reached 94.40%-97.40%; one positive sample sequence from the plague focus in Jianchuan County was clustered in one branch. Conclusion:SFGR infection rate of wild rodents in the field of plague foci in Western Yunnan is low, and no R.mooseri infection is found.

Hepatitis E virus infection and gene polymorphism in murine-shaped animals of plague foci in Yunnan Province / 中华地方病学杂志

Objective:To learn about the infection and gene polymorphisms of hepatitis E virus (HEV) in murine-shaped animals of plague foci in Yunnan Province.Methods:From July to August 2019, around 16 natural villages (4 in Mile City, 6 in Mangshi and 6 in Lianghe County), which were the foci of domestic plague in Yunnan Province, the murine-shaped animals were captured by the night-time method. The liver RNA was extracted, and the target gene of rat HEV was detected by one-step real-time fluorescence quantitative PCR, and the positive rate of rat HEV was calculated. The rat HEV positive samples were amplified by PCR for further clone sequencing, and the resulting sequences were compared with the HEV sequences registered in the GenBank and a phylogenetic tree was constructed by using MegAlign and MEGA 7.0.Results:A total of 491 murine-shaped animals were captured from 3 orders, 5 families, 8 genera, 15 species, and the positive rate of rat HEV was 4.89% (24/491). Among them, the positive rate of Rattus tanezumi and Niviventer fulvescens was 9.39% (23/245) and 1/3, respectively; and other species were negative. There was a statistically significant difference in the positive rate of rat HEV between different habitats ( P = 0.014), and the positive rate of rat HEV in the habitats near the dwellings was higher than that in other habitats ( P < 0.05). The sequence comparison analysis showed that the gene sequence of P018 from Lianghe County was 100.0% homologous to the MG813927.1 sequence of the first patient with rat HEV in Hongkong, and it was clustered into the same branch with the sequences of MG813927.1 and LC549185.1 from rat, was the type HEV C. G024 from Mangshi shared a low homology (20.7% - 31.5%) with other virus strains, and it was clustered into the same branch with a HEV sequence from an avian (AY535004.1). Conclusions:Rat HEV is prevalent in murine-shaped animals of plague foci of Yunnan Province, and there may be gene polymorphisms of rat HEV. In addition, the difference infection rate may be related to the habitats.

Advances in research on microvascular invasion of liver cancer / 中华肝胆外科杂志

Liver cancer is an aggressive malignant tumor. At present, microvascular invasion (MVI) is considered to be an independent risk factor for early recurrence and metastasis of liver cancer, and it is also an important indicator for liver transplant recipient selection. Therefore, preoperative prediction of MVI has important clinical value. It is currently predicted that MVI mainly passes specific serum markers such as des-gamma-carboxyprothrombin and preoperative imaging features. This article reviews the diagnosis, occurrence, preoperative prediction, impact on prognosis and corresponding treatment methods of MVI.

Impact of obese levels on the hepatic expression of nuclear receptors and drug-metabolizing enzymes in adult and offspring mice

The prevalence of obesity-associated conditions raises new challenges in clinical medication. Although altered expression of drug-metabolizing enzymes (DMEs) has been shown in obesity, the impacts of obese levels (overweight, obesity, and severe obesity) on the expression of DMEs have not been elucidated. Especially, limited information is available on whether parental obese levels affect ontogenic expression of DMEs in children. Here, a high-fat diet (HFD) and three feeding durations were used to mimic different obese levels in C57BL/6 mice. The hepatic expression of five nuclear receptors (NRs) and nine DMEs was examined. In general, a trend of induced expression of NRs and DMEs (except for and ) was observed in HFD groups compared to low-fat diet (LFD) groups. Differential effects of HFD on the hepatic expression of DMEs were found in adult mice at different obese levels. Family-based dietary style of an HFD altered the ontogenic expression of DMEs in the offspring older than 15 days. Furthermore, obese levels of parental mice affected the hepatic expression of DMEs in offspring. Overall, the results indicate that obese levels affected expression of the DMEs in adult individuals and that of their children. Drug dosage might need to be optimized based on the obese levels.

Distribution and clinical significance of EML4-ALK fusion gene in phase Ⅰ lung cancer / 中华胸心血管外科杂志

Objective To detect the mutation frequency of EML4-ALK fusion gene in lung cancer patients, and to inves-tigate the distribution of mutation character for EML4-ALK fusion gene in Ⅰ stage lung cancer patients and clinical features as well as provide a reference for the individual treatment of lung cancer .Methods 256 fresh tumor tissue specimens of lung cancer patients were screened from the specimen bank of our hospital and all the patients had accepted the surgical treatment from February 2013 to December 2014.Total RNA was extracted and then be transcribed into cDNA, the amplification-refrac-tory mutation system(ARMS) was used to detect mutation of EML4-ALK fusion gene.The results according to the positive con-trol, negative control and RNA quality control for EML4-ALK fusion type were analyzed.Results During the 256 patients ofⅠ stage lung cancer, there were 17 patients(6.64%) had mutations in EML4-ALK fusion gene.In lung adenocarcinoma mu-tation rate(16/207, 7.73%) was higher than that of lung squamous cell mutation rate(1/39, 2.56%), lung adeno-squamous mutation rate(0/4, 0) and large cell carcinoma(0/5, 0) of the mutation rate;young lung cancer patients( <63 years) of the mutation rate(14/139, 10.07%) was significantly higher than the high age of lung cancer patients(≥63 years old) mutation rate(3/117, 2.56%), P =0.009.EML4-ALK fusion with tumor invasion and visceral pleura group incidence (9/80, 11. 25%) was significantly higher than that of non-invasive and visceral pleura group incidence rate(8/176, 4.55%), P =0.045.Conclusion The occurence of EML4-ALK fusion correlates with patients’ age as well as whether visceral pleura is in-vaded, type 1 EML4-ALK fusion was detected more in phase I lung cancer patients.

Clinical value of preventive analgesia in patients with radical gastrectomy for gastric cancer: a prospective study / 中华消化外科杂志

Objective To investigate the clinical value of preventive analgesia in patients with radical gastrectomy for gastric cancer.Methods The clinical data of 161 patients undergoing radical gastrectomy for gastric cancer at the Xijing Hospital from July 2012 to June 2013 were prospectively analyzed.A single-blind,randomized,controlled study was performed in the eligibe patients who were randomly divided into the preventive analgesia group and the control group based on a random number table.All the patients received major gastrectomy + Billroth Ⅱ anastomy or total gastrectomy + esophagojejunastomy,and then they received vein combined anesthesia and tracheal intubation.In the preventive analgesia group,10 mg dexamethasone and 200 mg parecoxib were administered by intravenous infusion before operation,7-8 mL ropivacaine (0.5％) were injected at the incisional site and transversus abdominis infiltration at open and close surgery and celecoxib was taken orally for 3 days.In the control group,vein analgesia pump was used after operation.The visual analogue scale (VAS),proportion of patients with postoperative out-off-bed activity time ＞ 8 hours,time of flatus,time of defecation and duration of hospital stay were recorded between the 2 groups.The measurement data with normal distribution were presented as x ± s.The comparison between groups was evaluated with the t test and repeated measures ANOVA.The data with skew distrubution and ordinal data were analyzed by the analysis of variance,and the count data were analyzed using the chi-square test.Results All the 161 patients who were screened for eligibility were randomly divided into the preventive analgesia group (87 patients) and the control group (74 patients).The scores of the VAS at postoperative day 1,2 and 3 were 2.8 ± 0.6,2.6 ± 0.4 and 1.8 ± 0.4 in the preventive analgesia group,and 5.3 ± 0.5,4.2 ± 0.6 and 2.4 ± 0.3 in the control group,with a significant difference between the 2 groups (F =4.25,P ＜ 0.05).The proportion of patients with postoperative first abmulation time ＞ 8 hours at postoperative day 1,2 and 3 were 8,17 and 20 in the preventive analgesia group,and 0,3 and 11 in the control group,with a significant difference between the 2 groups (x2 =7.60,10.26,3.16,P ＜ 0.05).The time of flatus,time of defecation and duration of hospital stay were (51 ± 24) hours,(61 ± 24) hours and (5.5 ± 3.0) days in the preventive analgesia group,compared with (71 ± 23) hours,(83 ± 30) hours and (6.3 ± 2.1) days in the control group,showing a significant difference between the 2 groups (t =5.32,5.04,0.17,P ＜ 0.05).All the patients in the 2 groups normally survived after surgery without respiratory depression,incision infection and adverse drug reaction.Conclusions Preventive analgesia in the perioperative treatment of patients with radical gastrectomy for gastric cancer could relieve the postoperative pain of patients,improve the bowel function and enhance the recovery of patients.Registry This study was registered with the Chinese Clinical Trial Registry with the registry number of ChiCTRTRC-11001440.

Effect of ABCE1 gene silencing on proliferation and migration of human bladder cancer cell line T24 / 中国病理生理杂志

AIM:To investigate the effect of small interfering RNA ( siRNA)-mediated ABCE1 knockdown on the survival, cell cycle and invasion of human bladder cancer cell line T24.METHODS:The siRNA against ABCE1 was constructed and transfected into the T24 cells with LipofectamineTM 2000.The expression of ABCE1 was detected by RT-PCR and Western blot.Flow cytometry was used to detect the cell cycle.The effects of ABCE1 gene silencing on prolifera-tion, migration and invasion of T24 cells were evaluated by CCK-8 assay, wound-healing assay and Transwell invasion as-say, respectively.RESULTS: Compared with control group and blank group, the mRNA and protein levels of ABCE1 were significantly decreased in experimental group after transfected with ABCE1 siRNA.The cell cycle was arrested at G0/G1 phase and the cell number in S phase was decreased in the T24 cells.Compared with control group and blank group, the proliferation of T24 cells in experimental group was inhibited significantly, and the migration and invasion abilities of T24 cells in experimental group decreased significantly.CONCLUSION:Knockdown of ABCE1 gene may decrease migration, invasion and proliferation abilities in T24 cells.

Efficacy of midazolam combined with remifentanil for lower eyelid blephamoplasty / 中华医学美学美容杂志

Objective To evaluate the efficacy of midazolam combined with remifentanil for lower eyelid blephamoplasty.Methods In a double-blind study,200 patients undergoing lower eyelid blephamoplasty were randomly and equally divided into 2 groups (100 cases each):test group (midazolam 0.05 mg/kg and remifentanil 0.5 μg/kg followed by remifentanil 0.05 μg/(kg·min) and control group (midazolam 0.05 mg/kg).Heart rate (HR),mean arterial pressure (MAP),and pulse oxygen saturation (SpO2),respiratory rate (RR),SpO2 change,operation time,recovery time,the incidence of adverse reactions and the satisfactory rate of both patients and surgeons were monitored and recorded before the medication,3 min after the medication,at beginning of the surgery,during and immediately after the surgery,and 30 min after surgery.Results Two groups of patients had no obvious difference in intraoperative MAP,HR,RR,SpO2 and postoperative recovery time (P＞0.05);the incidence of postoperative nausea and vomiting in the test group was significantly higher than that in control group (P＜0.05); Patients and surgeons satisfaction in the test group was higher than that in control group (91.3±11.6)vs (52.7±10.4) (P＜0.05).Conclusions Midazolam combined with remifentanil for lower eyelid blephamoplasty has less inhibitory effect on circulatory and respiratory functions and the patients come round fast after surgery.But there are risks of respiratory inhibition in the induce phase and nausea and vomiting in the recovery stage.

Hemodynamics of deep vein in lower limb during perioperative period of total hip arthroplasty / 中华创伤杂志

Objective To investigate hemodynamic changes of deep vein in lower limb during the perioperative period of total hip arthroplasty (THA) and early diagnosis of deep vein thrombosis (DVT). Methods Doppler ultrasound, hemorheology detection and plasma D-dimer testing were done on 62 patients treated with THA. Statistical analysis was carried out on the data of patients with or without DVT to study the early diagnosis of DVT. Results The results of Doppler ultrasound showed DVT in 8 patients. Compared with postoperative concentration of plasma D-dimer, the preoperative con-centration of plasma D-dimer was significandy higher in patients with or without DVT (P < 0.05). The levels of hemorheological indices were significantly increased at postoperative day 7 (P < 0.05). Con-clusions Doppler ultrasound combined with plasma D-dimer testing and hemorheology detection are helpful in early diagnosis of DVT.