酶类药物现状、问题及展望

随着生物制药的迅速发展,许多酶类药物应运而生,在治疗代谢疾病、心血管疾病、癌症等诸多疾病上发挥着越来越重要的作用。但是酶类药物也存在一些不足,如潜在的免疫原性、较短的体内半衰期,以及较差的组织靶向性,影响了酶类药物的疗效和应用。为克服这些缺点,人们已开发出多种技术,如通过糖基化、聚乙二醇修饰等分子工程技术提升酶蛋白药效,另一方面酶基因疗法也已成功用于多种酶缺陷疾病的治疗。基于酶类药物的迅速发展和广泛的应用前景,本文对酶类药物的现状进行较详细的阐述,并对酶类药物的优势、所存在的问题及未来发展趋势进行分析和评述。     

Development and validation of robust metabolism-related gene signature in the prognostic prediction of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common malignant tumours worldwide. Given metabolic reprogramming in tumours was a crucial hallmark, several studies have demonstrated its value in the diagnostics and surveillance of malignant tumours. The present study aimed to identify a cluster of metabolism-related genes to construct a prediction model for the prognosis of HCC. Multiple cohorts of HCC cases (466 cases) from public datasets were included in the present analysis. (GEO cohort) After identifying a list of metabolism-related genes associated with prognosis, a risk score based on metabolism-related genes was formulated via the LASSO-Cox and LASSO-pcvl algorithms. According to the risk score, patients were stratified into low- and high-risk groups, and further analysis and validation were accordingly conducted. The results revealed that high-risk patients had a significantly worse 5-year overall survival (OS) than low-risk patients in the GEO cohort. (30.0% vs. 57.8%; hazard ratio [HR], 0.411; 95% confidence interval [95% CI], 0.302–0.651; p < 0.001) This observation was confirmed in the external TCGA-LIHC cohort. (34.5% vs. 54.4%; HR 0.452; 95% CI, 0.299–0.681; p < 0.001) To promote the predictive ability of the model, risk score, age, gender and tumour stage were integrated into a nomogram. According to the results of receiver operating characteristic curves and decision curves analysis, the nomogram score possessed a superior predictive ability than conventional factors, which indicate that the risk score combined with clinicopathological features was able to achieve a robust prediction for OS and improve the individualized clinical decision making of HCC patients. In conclusion, the metabolic genes related to OS were identified and developed a metabolism-based predictive model for HCC. Through a series of bioinformatics and statistical analyses, the predictive ability of the model was approved.     

Quantitative Detection of 15 Serum Bile Acid Metabolic Products by LC/MS/MS in the Diagnosis of Primary Biliary Cholangitis

To determine 15 bile acid metabolic products in human serum by liquid chromatography-tandem mass spectrometry (LC/MS/MS) and value their diagnostic outcome in primary biliary cholangitis (PBC). Serum from 20 healthy controls and 26 patients with PBC were collected and went LC/MS/MS analysis of 15 bile acid metabolic products. The test results were analyzed by bile acid metabolomics, and the potential biomarkers were screened and their diagnostic performance was judged by statistical methods such as principal component and partial least squares discriminant analysis and area under curve (AUC). 8 differential metabolites can be screened out: Deoxycholic acid (DCA), Glycine deoxycholic acid (GDCA), Lithocholic acid (LCA), Glycine ursodeoxycholic acid (GUDCA), Taurolithocholic acid (TLCA), Tauroursodeoxycholic acid (TUDCA), Taurodeoxycholic acid (TDCA), Glycine chenodeoxycholic acid (GCDCA). The performance of the biomarkers was evaluated by the AUC, specificity and sensitivity. In conclusion, DCA, GDCA, LCA, GUDCA, TLCA, TUDCA, TDCA and GCDCA were identified as eight potential biomarkers to distinguish between healthy people and PBC patients by multivariate statistical analysis, which provided reliable experimental basis for clinical practice.     

Poleward increase in feeding efficiency of leafminer Stigmella lapponica (Lepidoptera: Nepticulidae) in a latitudinal gradient crossing a boreal forest zone

Damage to plant communities imposed by insect herbivores generally decreases from low to high latitudes. This decrease is routinely attributed to declines in herbivore abundance and/or diversity, whereas latitudinal changes in per capita food consumption remain virtually unknown. Here, we tested the hypothesis that the lifetime food consumption by a herbivore individual decreases from low to high latitudes due to a temperature-driven decrease in metabolic expenses. From 2016 to 2019, we explored latitudinal changes in multiple characteristics of linear (gallery) mines made by larvae of the pygmy moth, Stigmella lapponica, in leaves of downy birch, Betula pubescens. The mined leaves were larger than intact leaves at the southern end of our latitudinal gradient (at 60°N) but smaller than intact leaves at its northern end (at 69°N), suggesting that female oviposition preference changes with latitude. No latitudinal changes were observed in larval size, mine length or area, and in per capita food consumption, but the larval feeding efficiency (quantified as the ratio between larval size and mine size) increased with latitude. Consequently, S. lapponica larvae consumed less foliar biomass at higher latitudes than at lower latitudes to reach the same size. Based on space-for-time substitution, we suggest that climate warming will increase metabolic expenses of insect herbivores with uncertain consequences for plant–herbivore interactions.     

Utilization of metabolic scope in relation to feeding and activity by individual and grouped zebrafish, Brachydanio rerio (Hamilton-Buchanan)

Metabolic scope and its utilization in relation to feeding and activity were measured in individual and grouped zebrafish (weight range, 430–551 mg) at 24° C by respirometry. Mean maximum metabolic rate, induced by swimming to exhaustion, R_max(i), was 1223 (s.d. , 157) mg O₂, kg^?1 h^?1 for individuals. Standard metabolic rate, R_s. was 364 mg O₂ kg^?1 h^?1, as estimated by extrapolating to zero activity from measurements of unfed, spontaneously active individuals. Mean routine metabolic rate, R_rout, of individuals was 421 (s.d. , 58) mg O₂, kg_-1 h_-1. The mean voluntary maximum metabolic rate, R_max(v), following transfer of minimally exercised fish to the respirometer, was 1110 (s.d. , 83) mg O₂ kg ^?1 h^?1 for groups of six fish, and was not significantly different from the value measured for individuals, 1066 (s.d. , 122) mg O₂, kg^?1 h^?1. Grouped fish acclimated to the respirometer more slowly than individual fish and exhibited significantly higher R_rout, apparently a result of greater social interaction and activity in groups. Mean R_rout for groups was 560 (s.d. , 78) mg O₂, kg^?1 h^?1. While groups of zebrafish fed a ration of 5% wet body weight day^?1 exhibited consistently higher metabolic rates than fish fed rations of 2.5% wet body weight day^?1 the high ration group still used only a maximum of 77% of the metabolic scope. Zebrafish of the size studied do not appear to demonstrate a high degree of conflict in utilization of metabolic scope by different respiratory components. The metabolic rates measured for zebrafish are among the highest yet measured for fish of similar size and at similar temperatures.     

Genetic metabolic polymorphisms and the risk of cancer: a review of the literature

The purpose of this paper is to systematically analyse the design and results of epidemiological studies on the association between various types of cancer (lung, bladder, breast, colon, stomach) and four genetically-based metabolic polymorphisms, involved in the metabolism of several carcinogens (glutathione-S-transferase M1, debrisoquine hydroxylase, N acetyltransferase, aryl hydrocarbon hydroxylase). These inherited polymorphisms usually cause modifications in the quality or quantity of the relevant enzymes. Such enzymes are involved in the activation/inactivation of known carcinogens and seem to modify the extent to which carcinogens interact with DNA in target tissues. Two enzymes, debrisoquine hydroxylase and aryl hydrocarbon hydroxylase, activate procarcinogens to carcinogens (phase I enzymes). The other two, glutathione-S-transferase M1 and N-acetyltransferase, mainly detoxity carcinogenic substances (phase II enzymes). Because of their role as host factors (modulating the action of carcinogens), it has been hypothesized that subjects presenting a specific phenotype for such polymorphisms could be at a greater risk of developing various types of cancer. A number of epidemiological studies have investigated such associations, often with discordant results. We examine and discuss the design of the studies, and present a meta-analysis of the available data.     

Human Interindividual Variability in Cancer Risks—Technical and Management Challenges

Existing risk assessment procedures for carcinogens are intended to be “conservative” in the uncertainty dimension—giving estimates that are expected to be higher than true risks for typical people. However, these procedures do not consider the likely variability in susceptibility among individual people. This paper updates previous estimates of the likely extent of this variability for metabolically activated, genetically-acting carcinogens based on recent information on human interindividual variability in metabolic activation, detoxification, and DNA repair. The resulting expected skewness of cancer risk distributions is estimated using Monte Carlo simulations of both variability and uncertainty.

Some risk management implications are:

1. When evaluating the fairness of a particular risk distribution, managers need to gain familiarity with a three-dimensional characterization—X level of risk, for the Yth percentile individual (addressing variability) with Z degree of confidence (addressing uncertainty).

2. To the extent that variability distributions are skewed (e.g., with a long tail extending to high values) population mean risks will tend to exceed risks for median individuals. Together with the skewness in uncertainty distributions, this implies that “expected value” estimates of aggregate population risks—the estimates of interest for cost benefit analyses—are likely to be closer to traditional upper confidence limit risk estimates than has often been assumed in the past.

Regulation of energy metabolism in liver

Energy metabolism in liver has to cope with the special tasks of this organ in intermediary metabolism. Main ATP-generating processes in the liver cell are the respiratory chain and glycolysis, whereas main ATP-consuming processes are gluconeogenesis, urea synthesis, protein synthesis, ATPases and mitochondrial proton leak. Mitochondrial respiratory chain in the intact liver cell is subject to control mainly by substrate (hydrogen donors, ADP, oxygen) transport and supply and proton leak/slip. Whereas hormonal control is mainly on substrate supply to mitochondria, proton leak/slip is supposed to play an important role in the modulation of the efficiency of oxidative phosphorylation.     

Seasonal activity and energetics of two species of varanid lizards in tropical Australia

The field metabolic rates (FMR) and rates of water flux were measured in two species of varanid lizards over five periods of the year in tropical Australia. The energetics of these species were further investigated by directly measuring activity (locomotion) and body temperatures of free-ranging animals by radiotelemetry, and by measuring standard metabolic rate (over a range of body temperatures) and activity metabolism in the laboratory. Seasonal differences in the activity and energetics were found in these goannas despite similar, high daytime temperatures throughout the year in tropical Australia. Periods of inactivity were associated with the dry times of the year, but the onset of this period of inactivity differed with respect to habitat even within the same species. Varanus gouldii, which inhabit woodlands only, were inactive during the dry and late dry seasons. V. panoptes that live in the woodland had a similar seasonal pattern of activity, but V. panoptes living near the floodplain of the South Alligator River had their highest levels of activity during the dry season when they walked long distances to forage at the receding edge of the floodplain. However, during the late dry season, after the floodplain had dried completely, they too became inactive. For V. gouldii, the rates of energy expenditure were 196 kJ kg^–1 day^–1 for active animals and 66 kJ kg^–1 day^–1 for inactive animals. The rates of water influx for these groups were respectively 50.7 and 19.5 ml kg^–1 day^–1. For V. panoptes, the rates of energy expenditure were 143 kJ kg^–1 day^–1 for active animals and 56 kJ kg^–1 day^–1 for inactive animals. The rates of water influx for these two groups were respectively 41.4 and 21.0 ml kg^–1 day^–1. We divided the daily energy expenditure into the proportion of energy that lizards used when in burrows, out of burrows but inactive, and in locomotion for the two species during the different seasons. The time spent in locomotion by V. panoptes during the dry season is extremely high for a reptile (mean of 3.5 h/day spent walking), and these results provide an ecological correlate to the high aerobic capacity found in laboratory measurements of some species of varanids.