Advances in the prevention and treatment of postoperative delirium by acupuncture: A review.

Postoperative delirium is a common postoperative complication of neurocognitive dysfunction, especially in elderly surgical patients. Postoperative delirium not only damages patients' recovery but also increases social costs. Therefore, its prevention and treatment has essential clinical and social significance. However, due to its intricate pathogenesis and limited pharmacological interventions, the effective prevention and treatment of postoperative delirium remains a thorny problem. As traditional acupuncture therapy has been shown to be an effective treatment in many neurological disorders, and in recent years, it has begun to be clinically used as an intervention for postoperative delirium. Although most clinical and animal studies confirm that multiple types of acupuncture interventions can alleviate or prevent postoperative delirium by relieving acute postoperative pain, reducing the consumption of anesthetics and analgesics, attenuating neuroinflammation and neuronal lesions, while more evidence-based medical evidence and clinical validation are needed for these encouraging effects.

The Intraoperative Median Effective Dose of Oxytocin for Preventing Uterine Atony in Parturients with a Prior History of Caesarean Delivery.

BACKGROUND AND OBJECTIVE: While oxytocin is commonly used for the prevention of uterine atony, its pharmacology may be affected by a prior history of caesarean delivery. The objective of this study was to determine the 50% effective dose (ED50) of bolus oxytocin after caesarean delivery in parturients with and without prior caesarean delivery. METHODS: This was a parallel-group, double-blind, dose-response study using Dixon's up-and-down sequential allocation method to estimate the ED50 of bolus-administered oxytocin in parturients having caesarean delivery under combined spinal-epidural anaesthesia (CSE). Twenty-seven parturients with a history of prior caesarean delivery (With-PCD group) and 26 parturients with no such history (Without-PCD group) were enrolled. Oxytocin was administered as an intravenous bolus at a starting dose of 0.5 units, which was then increased or decreased by 0.25 units at a time. Uterine tone was assessed by the obstetrician as either 'adequate' or 'inadequate' 3 min after delivery of the fetus. Adverse effects, administration of additional uterotonic agents, and estimated blood loss were recorded. RESULTS: The ED50 of oxytocin was greater in the With-PCD group than in the Without-PCD group (0.95 units [95% CI 0.82-1.08] vs. 0.55 units [95% CI 0.38-0.73], P < 0.001). The overall incidence of adverse effects was higher in the With-PCD group than in the Without-PCD group (33.3% vs. 7.7%, P = 0.02). CONCLUSION: The initial bolus dose of oxytocin needed to prevent uterine atony was higher in parturients with prior caesarean delivery than in parturients without prior caesarean delivery. Uterine scarring may contribute to the increased oxytocin requirements of the former group. TRIAL REGISTRATION NUMBER: ChiCTR1900023474; investigator: Wei CN; date of registration: 30 May 2019.

Dual-Band Dual-Mode Button Antenna for On-Body and Off-Body Communications.

A dual-band dual-mode button antenna for body centric communications is presented. At the lower band, a spiral inverted-F antenna is designed with omnidirectional radiation pattern for on-body communication. At the upper band, the high-order mode of the inverted-F antenna is utilized together with a metal reflector to realize broadside radiation for off-body communication. For demonstration, a prototype is implemented. The measured peak gains on the phantom at the lower and upper bands are -0.6 and 4.3 dBi, respectively. The antenna operating on the phantom has measured efficiencies of 46.3% at the lower band and 69.3% at the upper band. The issue of specific absorption rate (SAR) is studied. The maximum transmitted power under the SAR regulation of 1.6 W/kg is found to be 26.4 dB·m, which is high enough for body centric communications. In addition, the transmission performance between two proposed antennas mounted on the body is investigated by measuring the transmission loss. With an overall miniaturized size, the robust button antenna could be integrated in clothes and be a potential candidate for wireless body area network applications.

MicroRNA-93-5p increases multidrug resistance in human colorectal carcinoma cells by downregulating cyclin dependent kinase inhibitor 1A gene expression.

Multidrug resistance (MDR) impedes successful chemotherapy in colorectal carcinoma (CRC) and emerging evidence suggests that microRNAs (miRs) are involved in the development of MDR. In the present study, the role of miR-93-5p in the modulation of drug resistance in CRC was investigated using HCT-8 and MDR HCT-8/vincristine (VCR) cell lines. The results demonstrated upregulated expression of miR-93-5p and MDR protein 1 (MDR1) in HCT-8/VCR cells, compared with the parental HCT-8 cells. Furthermore, cyclin-dependent kinase inhibitor 1A (CDKN1A) was identified as a potential target of miR-93-5p using miR target analysis tools, including PicTar, TargetScan and miRanda. In addition, inhibition of miR-93-5p expression in HCT-8/VCR cells markedly downregulated MDR1 gene expression, upregulated CDKN1A gene expression and induced cell cycle arrest in G1. Conversely, the overexpression of miR-93-5p in HCT-8/VCR cells upregulated MDR1 gene expression, downregulated CDKN1A gene expression and promoted G1/S transition. Furthermore, the in vitro drug sensitivity assay performed suggested that downregulation of miR-93-5p enhanced the sensitivity of HCT-8/VCR cells to VCR, while the upregulation of miR-93-5p decreased the sensitivity of HCT-8 cells to VCR. In conclusion, the results of the present study suggest that miR-93-5p serves a role in the development of MDR through downregulating CDKN1A gene expression in CRC.

Role of LAP+CD4+ T cells in the tumor microenvironment of colorectal cancer.

AIM: To investigate the abundance and potential functions of LAP+CD4+ T cells in colorectal cancer (CRC). METHODS: Proportions of LAP+CD4+ T cells were examined in peripheral blood and tumor/paratumor tissues of CRC patients and healthy controls using flow cytometry. Expression of phenotypic markers such as forkhead box (Fox)p3, cytotoxic T-lymphocyte-associated protein (CTLA)-4, chemokine CC receptor (CCR)4 and CCR5 was measured using flow cytometry. LAP-CD4+ and LAP+CD4+ T cells were isolated using a magnetic cell-sorting system and cell purity was analyzed by flow cytometry. Real-time quantitative polymerase chain reaction was used to measure expression of cytokines interleukin (IL)-10 and transforming growth factor (TGF)-ß. RESULTS: The proportion of LAP+CD4+ T cells was significantly higher in peripheral blood from patients (9.44% ± 3.18%) than healthy controls (1.49% ± 1.00%, P < 0.001). Among patients, the proportion of LAP+CD4+ T cells was significantly higher in tumor tissues (11.76% ± 3.74%) compared with paratumor tissues (3.87% ± 1.64%, P < 0.001). We also observed positive correlations between the proportion of LAP+CD4+ T cells and TNM stage (P < 0.001), distant metastasis (P < 0.001) and serum level of carcinoembryonic antigen (P < 0.05). Magnetic-activated cell sorting gave an overall enrichment of LAP+CD4+ T cells (95.02% ± 2.87%), which was similar for LAP-CD4+ T cells (94.75% ± 2.76%). In contrast to LAP-CD4+ T cells, LAP+CD4+ T cells showed lower Foxp3 expression but significantly higher levels of CTLA-4, CCR4 and CCR5 (P < 0.01). LAP+CD4+ T cells expressed significantly larger amounts of IL-10 and TGF-ß but lower levels of IL-2, IL-4, IL-17 and interferon-γ, compared with LAP-CD4+ T cells. CONCLUSION: LAP+CD4+ T cells accumulated in the tumor microenvironment of CRC patients and were involved in immune evasion mediated by IL-10 and TGF-ß.

Th22 cell accumulation is associated with colorectal cancer development.

AIM: To investigate the expression of Th22 cells and related cytokines in colorectal cancer (CRC) tissues, and the probably mechanism. METHODS: CRC tumor and paratumor tissues were collected to detect the expression levels of Th22 cells and of related cytokines by immunohistochemistry, flow cytometry and real-time quantitative polymerase chain reaction (RT-qPCR). Interleukin (IL)-22 alone or with a STAT3 inhibitor was co-cultured with RKO cells in vitro to study the effects of IL-22 on colon cancer cells. IL-22 alone or with a STAT3 inhibitor was injected into a BALB/c nude mouse model with subcutaneously transplanted RKO cells to study the effects of IL-22 on colon cancer growth. RESULTS: The percentage of Th22 cells in the CD4(+) T subset was significantly higher in tumor tissues compared with that in paratumor tissues (1.47% ± 0.083% vs 1.23% ± 0.077%, P < 0.05) as determined by flow cytometry. RT-qPCR analysis revealed that the mRNA expression levels of IL-22, aryl hydrocarbon receptor, CCL20 and CCL22 were significantly higher in tumor tissues compared with those in paratumor tissues. CCL27 mRNA also displayed a higher expression level in tumor tissues compared with that in paratumor tissues; however, these levels were not significantly different (2.58 ± 0.93 vs 2.30 ± 0.78, P > 0.05). IL-22 enhanced colon cancer cell proliferation in vitro and displayed anti-apoptotic effects; these effects were blocked by adding a STAT3 inhibitor. IL-22 promoted tumor growth in BALB/c nude mice; however, this effect was reversed by adding a STAT3 inhibitor. CONCLUSION: Th22 cells that accumulate in CRC may be associated with the chemotactic effect of the tumor microenvironment. IL-22 is associated with CRC development, most likely via STAT3 activation.

Electroacupuncture improves survival in rats with lethal endotoxemia via the autonomic nervous system.

BACKGROUND: Recent advances have indicated a complex interplay between the autonomic nervous system and the innate immune system. Targeting neural networks for the treatment of sepsis is being developed as a therapeutic strategy. Because electroacupuncture at select acupoints can modulate activities of the autonomic nervous system, we tested the hypothesis that electroacupuncture at specific acupoints could modulate systemic inflammatory responses and improve survival via its impact on the autonomic nervous system in a rat model of sepsis. METHODS: Sprague-Dawley male rats received electroacupuncture for 45 min before and at 1, 2, or 4 h after a lethal dose of intraperitoneal lipopolysaccharide injection (6 mg/kg). Outcomes included survival and systemic cytokine responses. Also, the possible roles of neural circuitry, including the hypothalamic-pituitary-adrenal axis and the autonomic nervous system, were evaluated. RESULTS: Electroacupuncture pretreatment at the Hegu acupoints significantly attenuate systemic inflammatory responses and improve survival rate from 20% to 80% in rats with lethal endotoxemia. Such a site-specific effect requires the activation of muscarinic receptors in the central nervous system, but not increasing central sympathetic tone. In the periphery synergistic, rather than independent, action of the sympathetic and parasympathetic systems is also necessary. CONCLUSIONS: Electroacupuncture pretreatment has a dramatic survival-enhancing effect in rats with lethal endotoxemia, which involves the activation of efferent neural circuits of the autonomic nervous system (e.g., cholinergic antiinflammatory pathway). This approach could be developed as a prophylactic treatment for sepsis or perioperative conditions related to excessive inflammation.

High-dose vs low-dose proton pump inhibitors for upper gastrointestinal bleeding: a meta-analysis.

AIM: To evaluate the efficacy of high-dose proton pump inhibitors (PPIs) vs low-dose PPIs for patients with upper gastrointestinal bleeding. METHODS: PubMed, Embase, the Cochrane Library, and Web of Science were searched to identify relevant randomized controlled trials (RCTs). Eligible trials were RCTs that compared high-dose PPI with low-dose PPI following endoscopic hemostasis. The primary endpoint was rebleeding; secondary endpoints were patient numbers that needed surgery, and mortality. The meta-analysis was performed with a fixed effects model or random effects model. RESULTS: Nine eligible RCTs including 1342 patients were retrieved. The results showed that high-dose intravenous PPI was not superior to low-dose intravenous PPI in reducing rebleeding [odds ratio (OR) = 1.091, 95% confidential interval (CI): 0.777-1.532], need for surgery (OR = 1.522, 95% CI: 0.643-3.605) and mortality (OR = 1.022, 95% CI: 0.476-2.196). Subgroup analysis according to different region revealed no difference in rebleeding rate between Asian patients (OR = 0.831, 95% CI, 0.467-1.480) and European patients (OR = 1.263, 95% CI: 0.827-1.929). CONCLUSION: Low-dose intravenous PPI can achieve the same efficacy as high-dose PPI following endoscopic hemostasis.

Systematic review of D2 lymphadenectomy versus D2 with para-aortic nodal dissection for advanced gastric cancer.

AIM: To evaluate the feasibility and therapeutic effects of para-aortic nodal dissection (PAND) for advanced gastric cancer. METHODS: Randomized controlled trials (RCTs) and non-randomized studies comparing D2 + PAND with D2 lymphadenectomy were identified using a pre-defined search strategy. Five-year overall survival rate, post-operative mortality, and wound degree of surgery between the two operations were compared by using the methods provided by the Cochrane Handbook for Systematic Reviews of Interventions. RESULTS: Four RCTs (1120 patients) and 4 non-randomized studies (901 patients) were identified. Meta-analysis showed that there was no significant difference between these two groups in 5-year overall survival rate [risk ratio (RR) 1.04 (95% CI: 0.93-1.16) for RCTs and 0.96 (95% CI: 0.83-1.10) for non-randomized studies] and post-operative mortality [RR 0.99 (95% CI: 0.44-2.24) for RCTs and 2.06 (95% CI: 0.69-6.15) for non-randomized studies]. There was a significant difference between these two groups in wound degree of surgery, operation time was significantly longer [weighted mean difference (WMD) 195.32 min (95% CI: 114.59-276.05) for RCTs and 126.07 min (95% CI: 22.09-230.04) for non-randomized studies] and blood loss was significantly greater [WMD 301 mL (95% CI: 151.55-450.45) for RCTs and 302.86 mL (95% CI: 127.89-477.84) for non-randomized studies] in D2 + PAND. CONCLUSION: D2 + PAND can be performed as safely as standard D2 resection without increasing post-operative mortality but fail to benefit overall survival in patients with advanced gastric cancer.

Baroreflex sensitivity is impaired in patients with obstructive jaundice.

BACKGROUND: Obstructive jaundice is associated with enhanced susceptibility to hypotensive shock, renal failure, and toxic effects of endotoxin, which results in high perioperative morbidity and mortality. Since the normal arterial baroreflex function is necessary for hemodynamic homeostasis and improving survival in sepsis, this study aimed to determine whether baroreflex sensitivity was impaired in jaundiced patients. METHODS: Thirty-five patients with obstructive jaundice scheduled for surgery were included, and 30 nonjaundiced patients served as controls. A modified Oxford pharmacologic technique was used for evaluating baroreflex sensitivity immediately before the surgery. Potential factors that may affect baroreflex sensitivity in jaundice, such as liver biochemistry, plasma concentrations of methionine-enkephalin, atrial natriuretic peptide and nitrate, were also measured. RESULTS: Patients with obstructive jaundice had decreased sensitivity in both the sympathetic and vagal components of the baroreflex, as compared with the controls (P < 0.01). There was a significant inverse correlation between plasma atrial natriuretic peptide concentration and decreased sympathetic baroreflex sensitivity in the jaundiced group (r = -0.44, P = 0.008). CONCLUSIONS: Baroreflex sensitivity is impaired in patients with obstructive jaundice, which may contribute to their enhanced susceptibility to the well-known perioperative complications. The underlying mechanisms for such a change may be associated with an increased level of plasma atrial natriuretic peptide.

Outcome of surgical management of the bladder in advanced colorectal cancer.

BACKGROUND: To evaluate morbidity, mortality, and long-term survival in patients undergoing partial or total cystectomy during en bloc resection for locally advanced colorectal cancer. METHODS: This study retrospectively evaluated the outcome of combined bladder resection for colorectal cancer in our department. RESULTS: Patients (n=33) with colorectal tumors adherent to the bladder were followed. Overall morbidity was 11/33 (33.3%). Histological staging demonstrated inflammatory adhesion in 54.5% (18/33) and invasion in 45.6% (15/33). Morbidity was significantly higher in those that had undergone total cystectomy than in those that had undergone partial cystectomy (4/5 vs 7/28, P=0.033). The local recurrence has no difference the between total cystectomy group and the partial cystectomy group (1/5 vs 8/28, P=1.000). Overall 5-year survival rate was 39.4% (13/33). Mean survival time was 46.6875 month. There was no difference in 5-year survival between patients with inflammatory adhesion vs those with tumorous infiltration between colorectal tumor and bladder (P=0.7389). CONCLUSION: Survival after surgery for colorectal cancer is not influenced by the need to excise part or all of the urinary bladder in case it is contiguous to a colorectal tumor. Experienced surgeons in urology and colon and rectal surgery should be left to decide on the surgical options to be employed.

[Photosynthesis and active-oxygen-scavenging enzyme activities in rice varieties with different phosphorus efficiency under phosphorus stress].

Using six rice varieties with different phosphorus (P) use efficiency as the materials, the photosynthesis and active-oxygen-scavenging enzyme activities of the rice varieties under different P conditions were studied. Under deficient P condition, the photosynthetic rate (Pn) and soluble protein content (pro) were all gradually decreased with the growth process in the six tested varieties. The Pn and pro were always lower under deficient P condition than those under sufficient P condition. The Pn (ranging from 10.06-10.83 micromol CO2 x m(-2) x s(-1)), chlorophyll content (ranging from 3.32-3.56 mg x g(-1) FM) and pro (ranging from 33.08-33.95 mg x g(-1) FM) were all the highest in varieties with high-P efficiency, then in varieties with mid-P efficiency, and the lowest in varieties with low-P efficiency. There were no obvious differences on stomatal conductance (Gs) among the varieties. Meanwhile, the superoxide dismutase (SOD) activities of the tested varieties were all decreased with the process of deficient P stress. The SOD activities were also shown to be the highest in the varieties with high-P efficiency, then in the varieties with mid-P efficiency, and the lowest in the varieties with low-P efficiency under deficient P conditions. The malondialdehyde (MDA) contents in the tested varieties showed a reverse pattern of the SOD activities, with the highest in varieties with low-P efficiency and lowest in varieties with high-P efficiency. There was not an obvious change pattern on POD activity among the tested varieties under different P conditions. Under deficient P condition, the higher SOD activity and lower peroxidation degree of cell membrane system play important roles in improving the photosynthesis of the varieties with high-P efficiency.

[Expression of P33ING1, P53 and their relationship with apoptosis in anal canal carcinoma].

OBJECTIVE: To explore the expressions of P33ING1, P53 and their relationships with apoptosis in anal canal carcinoma (ACC). METHODS: The expressions of P33ING1, P53 proteins were measured by immunohistochemistry method (SP method), and apoptosis was detected in 42 cases with ACC, 36 cases with anal canal adenoma (ACA) or anal canal papilloma (ACP), and 40 cases with paraanal inflammatory mass(PAIM). RESULTS: The positive expression rates of P33ING1 and P53 proteins were 40.5% (17/42), 97.2% (35/36) and 97.5% (39/40), 50.0% (21/42), 22.2% (8/36) and 27.5% (11/40) respectively, and the average apoptosis indexes(AI) were (10.27+/- 1.23) per thousand, (42.75+/- 0.98) per thousand and (42.67+/- 1.04) per thousand respectively in ACC, ACA or ACP and PAIM. There were significant differences in the positive expression rates of P33ING1, P53 and apoptosis index between ACC and the other two groups respectively (P< 0.05). Among 21 cases of ACC with positive expression of P53 protein,there were 18 cases with P33ING1 negative expression. CONCLUSIONS: P33ING1 expression decrease in ACC, which may play an important role in the carcinogenesis and progression of ACC. P33ING1 and P53 may have an synergistic effect of suppressing cell growth and accelerating cell apoptosis.

Meta-analysis of short-term outcomes after laparoscopic resection for rectal cancer.

BACKGROUND: Laparoscopic resection (LR) has become increasingly popular for the management of rectal cancer. Despite a decade of experience, the safety and efficacy of LR for rectal cancer remains to be established. This report performs a meta-analysis to compare LR with conventional open resection (CR) in patients with rectal cancer. METHODS: Using a defined search strategy, studies directly comparing CR with LR for rectal cancer were identified. The data for patients with rectal cancer treated with both approaches were extracted and used in our meta-analysis. Open surgery and laparoscopic surgery were compared in terms of postoperative mortality, morbidity, complications, oncological clearance, operating time, and time before recovery to a normal diet. RESULTS: Compared with CR, LR is associated with lower morbidity rates [OR 0.63 (0.41, 1.96) P=0.03], longer operating times [weighted mean difference 1.59 (1.20, 1.98) P<0.00001], similar mortality rates, wound healing disorder rates, urinary disorder rates, cardiopulmony disease rates, all leakage rates, all abscess rates and a positive rate of margin. CONCLUSION: LR is associated with less postoperative morbidity, but longer operation time. A prospective randomized controlled trial is warranted to fully investigate these and other outcome measures.

Genetic alterations and expression of inhibitor of growth 1 in human sporadic colorectal cancer.

AIM: To explore the effect and significance of inhibitor of growth 1 (ING1) gene in carcinogenesis and progression of human sporadic colorectal cancer. METHODS: mRNA expression, mutation, and loss of heterozygosity (LOH) of ING1 gene in 35 specimens of sporadic colorectal cancer tissues and the matched normal mucous membrane tissues were detected by semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), PCR-single strain conformation polymorphism (PCR-SSCP) and PCR-simple sequence length polymorphism (PCR-SSLP) using microsatellite markers, respectively. RESULTS: The average ratios of light intensities of p33(ING1b) and p47(ING1a) mRNA expression in the cancerous tissues were significantly lower than those in normal tissues. The difference between the two mRNA splices was not significant in the matched tissues. In addition, the ratios of light intensities of p33(ING1b) and p47(ING1a) mRNA expression in the cancerous tissues of Dukes' stages C and D were significantly lower than those in cancerous tissues of Dukes' stages A and B. However, no mutation of ING1 gene was detected in all 35 cases; only 4 cases of LOH (11.4%) were found. CONCLUSION: p33(ING1b) and p47(ING1a) mRNA expressions are closely related with the carcinogenesis and progression of human sporadic colorectal cancer. No mutation of ING1 gene is found, and there are only few LOH in sporadic colorectal cancers. These might not be the main reasons for the down regulation of ING1 expression. Its low expression may happen in transcription or post-transcription.

Awakening concentration of desflurane is decreased in patients with obstructive jaundice.

BACKGROUND: Some studies suggest that behavioral complications of cholestasis, such as fatigue and pruritus, may be associated with altered neurotransmission in the brain. Because inhaled anesthetics primarily act on ion channels and receptors on the neuronal cell membrane and alter synaptic transmission in the central nervous system, it is possible that altered sensitivity to inhaled anesthetics may occur in cholestatic patients. Therefore, the authors compared the minimum alveolar concentration (MAC)-awake of desflurane in obstructive jaundiced patients with the MACawake in nonjaundiced patients. METHODS: Patients underwent inhalational induction of anesthesia with desflurane. MACawake was determined in each patient by observing the response to a verbal command (open eyes on request). An end-tidal anesthetic concentration was maintained at an initial target level of 1.4% for 15 min before a command. If a positive response was observed, the concentration of desflurane was increased by 0.1% and again kept constant for 15 min. The verbal command was then continued. This process was repeated until an end-tidal concentration was reached at which the patient did not respond to command. The anesthetic concentration midway between the value permitting the response and that just preventing the response was defined as MACawake for each patient. RESULTS: The MACawake of desflurane for patients with obstructive jaundice (1.78 +/- 0.19%) was significantly less than those observed for the control group (2.17 +/- 0.25%; P < 0.001) and correlated significantly with serum total bilirubin (r = -0.67, P = 0.0004). CONCLUSIONS: The MACawake of desflurane is reduced in obstructive jaundiced patients compared with nonjaundiced controls.

Potential inhibition of cytochrome P450 3A4 by propofol in human primary hepatocytes.

AIM: Hepatic cytochrome P450 isoenzymes constitute a superfamily of hemoproteins that play a major role in the metabolism of endogenous compounds and in the detoxification of xenobiotic molecules. P450 3A4 is one of the most important forms in human being, and mediates the metabolism of around 70 % of therapeutic drugs and endogenous compounds. Propofol, a widely used intravenous anesthetic drug, is known to inhibit cytochrome P450 activities in isolated rat hepatocytes. The goal of this study was to evaluate the potential efficacy of propofol on P450 3A4 in a dose-dependent manner to understand its drug-drug interaction. METHODS: Hepatocytes were isolated from liver specimens from hepatic angioma patients undergone hepatic surgery. Primary incubated hepatocytes were treated with 0, 0.01, 0.05, 0.1, 0.5, and 1.0 mM propofol for 24 hours. P450 3A4 activity was measured with Nash's colorimetry. The protein expression was assessed by Western blot analysis. RESULTS: A dose-dependent inhibitory effect of propofol was observed in cytochrome P450 3A4 activity. A minimal dosage of propofol (0.01 mM) induced a significant inhibition of P450 3A4 activity, although its regular dosages (0.01-0.1 mM) showed no inhibitory effect on the cellular protein expression of P450 3A4. CONCLUSION: Propofol may be a potential CYP3A4 inhibitor as this anesthetic can inhibit isoenzyme activity significantly and reduce the metabolic rate of CYP3A4 substrates. This inhibition occurs at post-expression level, and concentration of propofol used clinically does not affect CYP3A4 protein expression. propofol may thus induce drug interaction of cytochrome P450 3A4 activity at the dosage used clinically.

Different alterations of cytochrome P450 3A4 isoform and its gene expression in livers of patients with chronic liver diseases.

AIM: To determine whether parenchymal cells or hepatic cytochrome P450 protein was changed in chronic liver diseases, and to compare the difference of CYP3A4 enzyme and its gene expression between patients with hepatic cirrhosis and obstructive jaundice, and to investigate the pharmacologic significance behind this difference. METHODS: Liver samples were obtained from patients undergoing hepatic surgery with hepatic cirrhosis (n=6) and obstructive jaundice (n=6) and hepatic angeioma (controls, n=6). CYP3A4 activity and protein were determined by Nash and western blotting using specific polychonal antibody, respectively. Total hepatic RNA was extracted and CYP3A4cDNA probe was prepared according the method of random primer marking, and difference of cyp3a4 expression was compared among those patients by Northern blotting. RESULTS: Compared to control group, the CYP3A4 activity and protein in liver tissue among patients with cirrhosis were evidently reduced. (P<0.01) Northern blot showed the same change in its mRNA levels. In contrast, the isoenzyme and its gene expression were not changed among patients with obstructive jaundice. CONCLUSION: Hepatic levels of P450s and its CYP3A4 isoform activity were selectively changed in different chronic liver diseases. CYP3A4 isoenzyme and its activity declined among patients with hepatic cirrhosis as expression of cyp3a4 gene was significantly reduced. Liver's ability to eliminate many clinical therapeutic drug substrates would decline consequently. These findings may have practical implications for the use of drugs in patients with cirrhosis and emphasize the need to understand the metabolic fate of therapeutic compounds. Elucidation of the reasons for these different changes in hepatic CYP3A4 may provide insight into more fundamental aspects and mechanisms of imparied liver function.