Forecasting annual natural gas consumption via the application of a novel hybrid model.

Accurate prediction of natural gas consumption (NGC) can offer effective information for energy planning and policy-making. In this study, a novel hybrid forecasting model based on support vector machine (SVM) and improved artificial fish swarm algorithm (IAFSA) is proposed to predict annual NGC. An adaptive learning strategy based on sigmoid function is introduced to improve the performance of traditional artificial fish swarm algorithm (AFSA), which provides a dynamic adjustment for parameter moving step step and visual scope visual. IAFSA is used to obtain the optimal parameters of SVM. In addition, the annual NGC data of China is selected as an example to evaluate the prediction performance of the proposed model. Experimental results reveal that the proposed model in this study outperforms the benchmark models such as artificial neural network (ANN) and partial least squares regression (PLS). The mean absolute percentage error (MAPE), root mean squared error (RMSE), and mean absolute error (MAE) values are as low as 0.512, 1.4958, and 1.0940. Finally, the proposed model is employed to predict NGC in China from 2020 to 2025.

Acetaminophen-Induced Liver Injury Alters Expression and Activities of Cytochrome P450 Enzymes in an Age-Dependent Manner in Mouse Liver.

Drug-induced liver injury (DILI) is a global medical problem. The risk of DILI is often related to expression and activities of drug-metabolizing enzymes, especially cytochrome P450s (P450s). However, changes on expression and activities of P450s after DILI have not been determined. The aim of this study is to fill this knowledge gap. Acetaminophen (APAP) was used as a model drug to induce DILI in C57BL/6J mice at different ages of days 10 (infant), 22 (child), and 60 (adult). DILI was assessed by levels of alanine aminotransferase and aspartate aminotransferase in plasma with a confirmation by H&E staining on liver tissue sections. The expression of selected P450s at mRNA and protein levels was measured by real-time polymerase chain reaction and liquid chromatography-tandem mass spectrometry, respectively. The activities of these P450s were determined by the formation of metabolites from probe drugs for each P450 using ultraperformance liquid chromatography-quadrupole time of flight mass spectrometry. DILI was induced at mild to severe levels in a dose-dependent manner in 200, 300, and 400 mg/kg APAP-treated groups at child and adult ages, but not at the infant age. Significantly decreased expression at mRNA and protein levels as well as enzymatic activities of CYP2E1, 3A11, 1A2, and 2C29 were found at child and adult ages. Adult male mice were more susceptible to APAP-induced liver injury than female mice with more decreased expression of P450s. These results suggest that altered levels of P450s in livers severely injured by drugs may affect the therapeutic efficacy of drugs, which are metabolized by P450s, more particularly for males. SIGNIFICANCE STATEMENT: The current study in an animal model demonstrates that acetaminophen-induced liver injury results in decreased expression and enzyme activities of several examined drug-metabolizing cytochrome P450s (P450s). The extent of such decreases is correlated to the degree of liver injury severity. The generated data may be translated to human health for patients who have drug-induced liver injury with decreased capability to metabolize drugs by certain P450s.

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 Cyp2c29 and 3a11) 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.

Exogenous dopamine induces dehydroepiandrosterone sulfotransferase (rSULT2A1) in rat liver and changes the pharmacokinetic profile of moxifloxacin in rats.

Dehydroepiandrosterone sulfotransferase (SULT2A1) plays an important role in the detoxification of hydroxyl-containing xenobitotics and in the regulation of the biological activities of hydroxysteroids. Although dopamine (DA) is a vital neurotransmitter, DA also has some special functions in outer peripheral system and takes effect by binding with dopamine receptors including five subtypes (D1-D5). The objective of this study was to investigate the effect of exogenous DA on both the regulation of rSULT2A1 (rat SULT2A1) and the pharmacokinetics of moxifloxacin which is a specific substrate of rSULT2A1. After different doses of DA (0, 2, 10 and 100 mg/kg/d) were administrated to both male and female rats for 7 days, the activity, protein level and mRNA expression of rSULT2A1 increased significantly. Moreover, both Cmax and AUC of moxifloxacin decreased and AUC of moxifloxacin sulfate conjugate metabolite increased significantly when moxifloxacin was administered to rats with DA pretreatment. Additionally, D1 expression in liver and cAMP concentration also increased after the treatment with DA. Overall these results suggest that exogenous DA may induce rSULT2A1 in rat liver and may further change the pharmacokinetic characteristics of some substrates of SULT2A1, and the activation of D1-like receptor is probably involved in rSULT2A1 induction by DA.

Dopamine D1 receptor activation induces dehydroepiandrosterone sulfotransferase (SULT2A1) in HepG2 cells.

AIM: Dopamine receptors are present in the nervous system and also widely distributed in the periphery. The aim of this study was to investigate the role of D1 subtype dopamine receptors (DRD1) in the regulation of dehydroepiandrosterone sulfotransferase (SULT2A1) in HepG2 cells. METHODS: HepG2 cells were treated with DRD1 agonists with or without DRD1 antagonist for 9 d. DRD1 and SULT2A1 mRNA expression, protein expression, and SULT2A1 activity were detected using RT-PCR, Western blotting and HPLC, respectively. The level of cAMP was measured using a commercial kit. RESULTS: All the 5 DR subtypes (DRD1-DRD5) were found to be expressed in HepG2 cells. Treatment of HepG2 cells with the specific DRD1 agonists SKF82958 (2.5 µmol/L) or SKF38393 (5 and 50 µmol/L) significantly increased the mRNA and protein expression of both DRD1 and SULT2A1, and increased SULT2A1 activity and cAMP levels. These effects were partially blocked by co-treatment with the specific DRD1 antagonist SCH23390 (2.5 µmol/L). In addition, transfection of HepG2 cells with DRD1-specific siRNAs decreased DRD1 mRNA expression by 40%, which resulted in the reduction of SULT2A1 mRNA expression by 60%, protein expression by 40%, and enzyme activity by 20%. CONCLUSION: DRD1 activation upregulates DRD1 and SULT2A1 expression and SULT2A1 activity in HepG2 cells, suggesting that the DRD1 subtype may be involved in the metabolism of drugs and xenobiotics through regulating SULT2A1.

Inhibition of EGFR autophosphorylation plays an important role in the anti-breast cancer efficacy of the dithiocarbamate derivative TM208.

AIM: To investigate the effects of a novel dithiocarbamate derivative TM208 on human breast cancer cells as well as the pharmacokinetic characteristics of TM208 in human breast cancer xenograft mice. METHODS: Human breast cancer MCF-7 and MDA-MB-231 cells were treated with TM208 or a positive control drug tamoxifen. Cell proliferation was examined using SRB and colony formation assays. Cell apoptosis was analyzed with Annexin V-FITC/PI staining assay. Protein expression was examined with Western blot, ELISA and immunohistochemical analyses. MCF-7 breast cancer xenograft nude mice were orally administered TM208 (50 or 150 mg·kg(-1)·d(-1)) or tamoxifen (50 mg·kg(-1)·d(-1)) for 18 d. On d 19, the tumors were collected for analyses. Blood samples were collected from the mice treated with the high dose of TM208, and plasma concentrations of TM208 were measured using LC-MS/MS. RESULTS: Treatment of MCF-7 and MDA-MB-231 cells with TM208 dose-dependently inhibited the cell proliferation and colony formation in vitro (the IC50 values were 36.38 ± 3.77 and 18.13 ± 0.76 µmol/L, respectively). TM208 (20-150 µmol/L) dose-dependently induced apoptosis of both the breast cancer cells in vitro. In MCF-7 breast cancer xenograft nude mice, TM208 administration dose-dependently reduced the tumor growth, but did not result in the accumulation of TM208 or weight loss. TM208 dose-dependently inhibited the phosphorylation of EGFR and ERK1/2 in both the breast cancer cells in vitro as well as in the MCF-7 xenograft tumor. CONCLUSION: Inhibition of EGFR autophosphorylation plays an important role in the anticancer effect of TM208 against human breast cancer.