The role of CYP2C19 in amitriptyline N -demethylation in Chinese subjects

May 1, 2002, 12:00 am

≫ Next: Countermeasures of heavy metal pollution

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Abstract

Objective. To determine the role of cytochrome P₄₅₀ (CYP)2C19 in N-demethylation of amitriptyline (AT) in healthy Chinese subjects.

Methods. One hundred and one subjects were genotyped for CYP2C19 using polymerase chain reaction-restriction fragment length polymorphism analysis. Twelve unrelated adult men (19.7±0.6 years, 61.8±3.8 kg) were chosen and orally given a single dose of 50 mg AT, and the blood samples were drawn from a forearm vein at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, and 96 h after AT administration. Plasma concentrations of AT and nortriptyline (NT) were determined using high-performance liquid chromatography with an ultraviolet detector.

Results. The mean area under the plasma concentration–time curve (AUC_AT) of CYP2C19 poor metabolizers (PMs, n=6) was significantly higher than that of CYP2C19 extensive metabolizers (EMs, n=6) (2207±501 ng/ml·h^–1 vs 1596±406 ng/ml·h^–1, P<0.05). In contrast, the mean AUC_NT(0–∞) of PMs was significantly lower than that of EMs (294±70 ng/ml·h^–1 vs 684±130 ng/ml·h^–1, P<0.0001). Other pharmacokinetic parameters such as clearance, half-life, maximum plasma concentration, and time to peak plasma concentration showed no significant difference between PMs and EMs (0.41±0.12 l /h·kg^–1 vs 0.50±0.15 l /h·kg^–1, 25.0±6.2 h vs 24.1±4.4 h, 96±25 ng/ml vs 75±27 ng/ml, 4.0±1.4 h vs 3.7±1.5 h, respectively).

Conclusion. The genetic defects of CYP2C19 have a significant effect on AT pharmacokinetics, and CYP2C19 plays an important role in N-demethylation of AT in vivo at a clinically therapeutic dose.

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Countermeasures of heavy metal pollution

December 1, 2013, 12:00 am

≫ Next: Pharmacological Modulation of Cytotoxicity and Cellular Uptake of Anti-cancer Drugs by PDE5 Inhibitors in Lung Cancer Cells

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Abstract

This article gives a review on heavy metal pollution prevention and control, and it also discusses heavy metal pollutant discharge, prediction and evaluation of environmental impact, and pollution prevention and monitoring.

Pharmacological Modulation of Cytotoxicity and Cellular Uptake of Anti-cancer Drugs by PDE5 Inhibitors in Lung Cancer Cells

January 1, 2014, 12:00 am

≫ Next: Apolipoprotein E polymorphism is associated with lower extremity deep venous thrombosis: color-flow Doppler ultrasound evaluation

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ABSTRACT

Purpose

Previous research has led to the recognition of a cGMP signaling pathway governing drug transport. This study is to investigate whether inhibitors of phosphodiesterase type 5 (PDE5), which increase intracellular cGMP levels, modulate the cytotoxicity and uptake of anti-cancer drugs in cancer cells.

Methods

The experiments were conducted with and without PDE5 inhibitors: dipyridamole, vardenafil, and/or sildenafil. The cytotoxicity of doxorubicin, cisplatin and oxaliplatin was determined in multiple cancer cell lines derived from different tissues. The cellular uptake of structurally diverse compounds was further examined in lung cancer cells with and without various endocytotic inhibitors. The tumor accumulation and the anti-tumor effect of trastuzumab were examined in a lung cancer xenograft mouse model.

Results

Dipyridamole could modulate the cytotoxicity of doxorubicin, cisplatin, and oxaliplatin in cancer cells. Particularly, PDE5 inhibitors increased cellular uptake of structurally diverse compounds into lung cancer cells both in vitro and in vivo. The effect of vardenafil on drug uptake could be blocked by endocytotic inhibitors. The growth of lung cancer xenograft in nude mice was significantly suppressed by addition of vardenafil to trastuzumab treatment.

Conclusion

PDE5 inhibitors may increase the efficacy of anti-cancer drugs by increasing endocytosis-mediated cellular drug uptake, and thus serve as adjuvant therapy for certain cancers such as lung cancer.

Apolipoprotein E polymorphism is associated with lower extremity deep venous thrombosis: color-flow Doppler ultrasound evaluation

January 24, 2014, 12:00 am

≫ Next: Role of solute carriers in response to anticancer drugs

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Abstract

Introduction

Apolipoprotein E (apoE) is a member of apolipoprotein family, and its gene polymorphisms seem to have some impact among patients with cardiovascular disease. However, its role in the lower extremity deep venous thrombosis (LEDVT) has not been well studied. The objective of this study was to investigate the potential association between APOE gene polymorphisms and LEDVT.

Materials and methods

A hospital-based case–control study was conducted in 300 patients with LEDVT by color-flow Doppler ultrasound and 300 age- and gender-matched healthy controls. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay was applied to assess the APOE gene polymorphisms.

Results

Patients with LEDVT had a significantly higher frequency of APOE E3/E4 genotype [odds ratio (OR) =1.48, 95% confidence interval (CI) = 1.05, 2.10; P = 0.03] than healthy controls. When stratifying by family history of LEDVT, it was found that patients with positive family history of LEDVT had a significantly higher frequency of APOE E3/E4 genotype (OR =1.68, 95% CI = 1.04, 0.95; P = 2.70). When stratifying by smoking status, presence of varicose veins, type 2 diabetes mellitus and any hormone administration before, no significant differences were found in any groups.

Conclusion

Our study suggested that APOE E3/E4 genotype was associated with a higher LEDVT risk. Additional studies are needed to confirm this finding.

Role of solute carriers in response to anticancer drugs

May 27, 2014, 12:00 am

≫ Next: Study on soil heavy metals contamination of a lead refinery

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Abstract

Membrane transporters play critical roles in moving a variety of anticancer drugs across cancer cell membrane, thereby determining chemotherapy efficacy and/or toxicity. The retention of anticancer drugs in cancer cells is the result of net function of efflux and influx transporters. The ATP-binding cassette (ABC) transporters are mainly the efflux transporters expressing at cancer cells, conferring the chemo-resistance in various malignant tumors, which has been well documented over the past decades. However, the function of influx transporters, in particular the solute carriers (SLC) in cancer cells, has only been recently well recognized to have significant impact on cancer therapy. The SLC transporters not only directly bring anticancer agents into cancer cells but also serve as the uptake mediators of essential nutrients for tumor growth and survival. In this review, we concentrate on the interaction of SLC transporters with anticancer drugs and nutrients, and their impact on chemo-sensitivity or -resistance of cancer cells. The differential expression patterns of SLC transporters between normal and tumor tissues may be well utilized to achieve specific delivery of chemotherapeutic agents.

Study on soil heavy metals contamination of a lead refinery

December 1, 2014, 12:00 am

≫ Next: Aging increases the susceptibility of cisplatin-induced nephrotoxicity

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Abstract

The contents of Pb, Cd, Cr, As, and Hg was investigated in the neighboring areas of a lead smelting enterprise and the metals contamination of soil was evaluated with the methodologies of the single factor index and Nemerow integrated index. It is found that the content of heavy metals in the neighboring areas has no obvious difference from the reference points. And the soil contamination of heavy metals varies by elements, the contamination index follows the pollution order: Cd>Hg>Cr>As>Pb. The pollution degree of Cd is at high level and Hg at low level, but Cr and As reached the warning level. Therefore, the lead smelting enterprises should not only control lead but also other heavy metals as Cd.

Aging increases the susceptibility of cisplatin-induced nephrotoxicity

November 3, 2015, 12:00 am

≫ Next: Moderately increased maternal dietary energy intake delays foetal skeletal muscle differentiation and maturity in pigs

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Abstract

Cisplatin (CDDP) nephrotoxicity is one of the most common side effects in cancer treatment, causing the disruption of chemotherapy. In this study, we analyzed the influence of nongenetic factors on CDDP-induced nephrotoxiciy using the data from 182 CDDP-treated and 52 carboplatin (CBP)-treated patients. The mean change of eGFR (100 % to baseline) in CDDP-treated patients was −9.2 %, which was significantly lower than that in the population with CBP therapy. By using the chi-squared test and multivariate logistic regression analysis, age (≥50 years) is found associated with CDDP-induced nephrotoxicity, with odds ratio (OR) of 9.167 and 11.771, respectively. Three- and 18-month-old mice were employed to study the age-dependent susceptibility of CDDP-induced nephrotoxicity. Biochemical parameters, histopathogical examination, and mRNA biomarkers indicated that old mice were subjected to more severe kidney injury. In addition, old mice accumulated more CDDP in kidney than young mice, and the protein level of CDDP efflux transporter, MATE1, in aged mice kidney was 35 % of that in young mice. Moreover, inflammatory receptor TLR4 was higher in the kidney of old mice, indicating the alteration of inflammatory signaling in old mice. After CDDP administration, the induced alterations of TNF-α, ICAM-1, and TLR4 were more extensive in old mice. To summarize, aging increased the susceptibility of CDDP-induced renal function decline or nephrotoxicity.

Moderately increased maternal dietary energy intake delays foetal skeletal muscle differentiation and maturity in pigs

June 1, 2016, 12:00 am

≫ Next: Hamilton-Jacobi Equations on Graph and Applications

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Abstract

Objectives

This study aimed to evaluate the effects of moderately increased maternal dietary energy intake during gestation on foetal skeletal muscle development and metabolism with pig as a model.

Methods

Twelve primiparous purebred Large White sows (initial body weight 135.5 ± 1.6 kg) were allocated to one of two energy intake treatments: normal-energy-intake group (Con, 30.96 MJ DE/day) as recommended by the National Research Council (NRC; 2012) and high-energy-intake group (HE, 34.15 MJ DE/day). The nutritional treatments were introduced from mating to day 90 of gestation. On day 90 of gestation, foetuses were examined by morphological, biochemical and molecular analysis of the longissimus muscle. Umbilical vein serum hormones were measured.

Results

Sow body weight was increased in HE group compared with Con group (P < 0.05), whereas foetal myofibre density was decreased (P < 0.05). Meanwhile, protein concentration, creatine kinase and lactate dehydrogenase activities and umbilical vein serum triiodothyronine (T3) concentration were decreased in HE foetuses (P < 0.05). Maternal HE diets decreased the mRNA abundance of muscle growth-related genes, myosin heavy-chain (MYH/MyHC) genes (MYH2 and MYH1) and insulin-like growth factor 1 and insulin growth factor-binding protein 5 (P < 0.05). Furthermore, the protein expressions of myogenic differentiation factor 1, myogenin and fast-MyHC isoforms were reduced in HE foetuses (P < 0.05).

Conclusion

Our results suggest that moderately increased maternal dietary energy intake delays the differentiation and maturation in skeletal muscle of the foetus on day 90 of gestation.

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Hamilton-Jacobi Equations on Graph and Applications

May 17, 2017, 12:00 am

≫ Next: Indinavir Alters the Pharmacokinetics of Lamivudine Partially via Inhibition of Multidrug and Toxin Extrusion Protein 1 (MATE1)

≪ Previous: Moderately increased maternal dietary energy intake delays foetal skeletal muscle differentiation and maturity in pigs

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Abstract

This paper introduces a notion of gradient and an infimal-convolution operator that extend properties of solutions of Hamilton Jacobi equations to more general spaces, in particular to graphs. As a main application, the hypercontractivity of this class of infimal-convolution operators is connected to some discrete version of the log-Sobolev inequality and to a discrete version of Talagrand’s transport inequality.

Indinavir Alters the Pharmacokinetics of Lamivudine Partially via Inhibition of Multidrug and Toxin Extrusion Protein 1 (MATE1)

January 4, 2018, 12:00 am

≫ Next: The dysregulation of tRNAs and tRNA derivatives in cancer

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Abstract

Purpose

Lamivudine, a characterized substrate for human multidrug and toxin extrusion protein 1 (hMATE1) in vitro, was commonly used with indinavir as a therapy against human immunodeficiency virus (HIV). We aimed to investigate whether mouse MATE1 is involved in the disposition of lamivudine in vivo, and whether there is any transporter-mediated interaction between indinavir and lamivudine.

Methods

The role of MATE1 in the disposition of lamivudine was determined using Mate1 wild type (+/+) and knockout (−/−) mice. The inhibitory potencies of indinavir on lamivudine uptake mediated by OCT2 and MATE1 were determined in human embryonic kidney 293 (HEK 293) cells stably expressing these transporters. The role of MATE1 in the interaction between indinavir and lamivudine in vivo was determined using Mate1 (+/+) and Mate1 (−/−) mice.

Results

The plasma concentrations and tissue accumulation of lamivudine were markedly elevated in Mate1 (−/−) mice as compared to those in Mate1 (+/+) mice. Indinavir significantly increased the pharmacokinetic exposure of lamivudine in mice; however, the effect by indinavir was significantly less pronounced in Mate1 (−/−) mice as compared to Mate1(+/+) mice.

Conclusion

MATE1 played an important role in lamivudine pharmacokinetics. Indinavir could cause drug-drug interaction with lamivudine in vivo via inhibition of MATE1 and additional mechanism.

The dysregulation of tRNAs and tRNA derivatives in cancer

May 9, 2018, 12:00 am

≫ Next: Clinical evaluation of a panel of multiplex quantitative real-time reverse transcription polymerase chain reaction assays for the detection of 16 respiratory viruses associated with community-acquired pneumonia

≪ Previous: Indinavir Alters the Pharmacokinetics of Lamivudine Partially via Inhibition of Multidrug and Toxin Extrusion Protein 1 (MATE1)

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Abstract

Transfer RNAs (tRNAs), traditionally considered to participate in protein translation, were interspersed in the entire genome. Recent studies suggested that dysregulation was observed in not only tRNAs, but also tRNA derivatives generated by the specific cleavage of pre- and mature tRNAs in the progression of cancer. Accumulating evidence had identified that certain tRNAs and tRNA derivatives were involved in proliferation, metastasis and invasiveness of cancer cell, as well as tumor growth and angiogenesis in several malignant human tumors. This paper reviews the importance of the dysregulation of tRNAs and tRNA derivatives during the development of cancer, such as breast cancer, lung cancer, and melanoma, aiming at a better understanding of the tumorigenesis and providing new ideas for the treatment of these cancers.

Clinical evaluation of a panel of multiplex quantitative real-time reverse transcription polymerase chain reaction assays for the detection of 16 respiratory viruses associated with community-acquired pneumonia

June 30, 2018, 12:00 am

≫ Next: Selective Inhibition on Organic Cation Transporters by Carvedilol Protects Mice from Cisplatin-Induced Nephrotoxicity

≪ Previous: The dysregulation of tRNAs and tRNA derivatives in cancer

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Abstract

We developed a panel of multiplex quantitative real-time reverse transcription polymerase chain reaction (mqRT-PCR) assay consisting of seven internally controlled qRT-PCR assays to detect 16 different respiratory viruses. We compared the new mqRT-PCR with a previously reported two-tube mRT-PCR assay using 363 clinical sputum specimens. The mqRT-PCR assay performed comparably with the two-tube assay for most viruses, offering the advantages of quantitative analysis, easier performance, lower susceptibility to contamination, and shorter turnaround time in laboratories equipped with conventional real-time PCR instrumentation, and it could therefore be a valuable tool for routine surveillance of respiratory virus infections in China.

Selective Inhibition on Organic Cation Transporters by Carvedilol Protects Mice from Cisplatin-Induced Nephrotoxicity

September 6, 2018, 12:00 am

≫ Next: Metagenomic analysis of viral nucleic acid extraction methods in respiratory clinical samples

≪ Previous: Clinical evaluation of a panel of multiplex quantitative real-time reverse transcription polymerase chain reaction assays for the detection of 16 respiratory viruses associated with community-acquired pneumonia

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Abstract

Purpose

The organic cation transporters (OCTs) and multidrug and toxin extrusions (MATEs), located in the basolateral and apical membrane of proximal tubular cells respectively, are crucial determinants of renal elimination and/or toxicity of cationic drugs such as cisplatin. The purpose of this study was to discover selective OCT inhibitors over MATEs, and explore their potential to protect against cisplatin-induced nephrotoxicity that is clinically common.

Methods

The inhibition by select compounds on the uptake of the probe substrate metformin was assessed in HEK293 cells overexpressing human OCT2, OCT1, MATE1, MATE2-K, and mouse Oct2, Oct1, and Mate1. Furthermore, the effects of carvedilol on organic cation transporter-mediated cellular and renal accumulation of metformin and cisplatin, and particularly the toxicity associated with cisplatin, were investigated in HEK293 cells and mice.

Results

Five selective OCT inhibitors were identified through the screening of forty-one drugs previously reported as the inhibitors of OCTs and/or MATEs. Among them, carvedilol showed the most selectivity on OCTs over MATEs (IC₅₀: 3.6 μM for human OCT2, 103 μM for human MATE1 and 202 μM for human MATE2-K) in the cellular assays in vitro, with the selectivity in mice as well. Moreover, carvedilol treatment could significantly decrease cisplatin accumulation and ameliorate its toxicity both in vitro in cells and in vivo in mouse kidney.

Conclusions

Our data indicate that selective inhibition of OCTs by carvedilol may protect from cisplatin-induced nephrotoxicity by restraining the cellular entry of cisplatin via OCTs, while having no impact on its elimination through MATEs.

Metagenomic analysis of viral nucleic acid extraction methods in respiratory clinical samples

October 25, 2018, 12:00 am

≫ Next: Irinotecan Alters the Disposition of Morphine Via Inhibition of Organic Cation Transporter 1 (OCT1) and 2 (OCT2)

≪ Previous: Selective Inhibition on Organic Cation Transporters by Carvedilol Protects Mice from Cisplatin-Induced Nephrotoxicity

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Abstract

Background

Numerous protocols for viral enrichment and genome amplification have been created. However, the direct identification of viral genomes from clinical specimens using next-generation sequencing (NGS) still has its challenges. As a selected viral nucleic acid extraction method may determine the sensitivity and reliability of NGS, it is still valuable to evaluate the extraction efficiency of different extraction kits using clinical specimens directly.

Results

In this study, we performed qRT-PCR and viral metagenomic analysis of the extraction efficiency of four commonly used Qiagen extraction kits: QIAamp Viral RNA Mini Kit (VRMK), QIAamp MinElute Virus Spin Kit (MVSK), RNeasy Mini Kit (RMK), and RNeasy Plus Micro Kit (RPMK), using a mixed respiratory clinical sample without any pre-treatment. This sample contained an adenovirus (ADV), influenza virus A (Flu A), human parainfluenza virus 3 (PIV3), human coronavirus OC43 (OC43), and human metapneumovirus (HMPV). The quantity and quality of the viral extracts were significantly different among these kits. The highest threshold cycle(Ct)values for ADV and OC43 were obtained by using the RPMK. The MVSK had the lowest Ct values for ADV and PIV3. The RMK revealed the lowest detectability for HMPV and PIV3. The most effective rate of NGS data at 67.47% was observed with the RPMK. The other three kits ranged between 12.1–26.79% effectiveness rates for the NGS data. Most importantly, compared to the other three kits the highest proportion of non-host reads was obtained by the RPMK. The MVSK performed best with the lowest Ct value of 20.5 in the extraction of ADV, while the RMK revealed the best extraction efficiency by NGS analysis.

Conclusions

The evaluation of viral nucleic acid extraction efficiency is different between NGS and qRT-PCR analysis. The RPMK was most applicable for the metagenomic analysis of viral RNA and enabled more sensitive identification of the RNA virus genome in respiratory clinical samples. In addition, viral RNA extraction kits were also applicable for metagenomic analysis of the DNA virus. Our results highlighted the importance of nucleic acid extraction kit selection, which has a major impact on the yield and number of viral reads by NGS analysis. Therefore, the choice of extraction method for a given viral pathogen needs to be carefully considered.

Irinotecan Alters the Disposition of Morphine Via Inhibition of Organic Cation Transporter 1 (OCT1) and 2 (OCT2)

October 25, 2018, 12:00 am

≫ Next: Downregulation of DAPK1 promotes the stemness of cancer stem cells and EMT process by activating ZEB1 in colorectal cancer

≪ Previous: Metagenomic analysis of viral nucleic acid extraction methods in respiratory clinical samples

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Abstract

Purpose

The organic cation transporters (OCTs) and multidrug and toxin extrusions (MATEs) together are regarded as an organic cation transport system critical to the disposition and response of many organic cationic drugs. Patient response to the analgesic morphine, a characterized substrate for human OCT1, is highly variable. This study was aimed to examine whether there is any organic cation transporter-mediated drug and drug interaction (DDI) between morphine and commonly co-administrated drugs.

Methods

The uptake of morphine and its inhibition by six drugs which are commonly co-administered with morphine in the clinic were assessed in human embryonic kidney 293 (HEK293) cells stably expressing OCT1, OCT2 and MATE1. The in vivo interaction between morphine and the select irinotecan was determined by comparing the disposition of morphine in the absence versus presence of irinotecan treatment in mice.

Results

The uptake of morphine in the stable HEK293 cells expressing human OCT1 and OCT2 was significantly increased by 3.56 and 3.04 fold, respectively, than that in the control cells, with no significant uptake increase in the cells expressing human MATE1. All of the six drugs examined, including amitriptyline, fluoxetine, imipramine, irinotecan, ondansetron, and verapamil, were inhibitors of OCT1/2-mediated morphine uptake. The select irinotecan significantly increased the plasma concentrations and decreased hepatic and renal accumulation of morphine in mice.

Conclusions

Morphine is a substrate of OCT1 and OCT2. Clinician should be aware that the disposition of and thus the response to morphine may be altered by co-administration of an OCT1/2 inhibitor, such as irinotecan.

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Downregulation of DAPK1 promotes the stemness of cancer stem cells and EMT process by activating ZEB1 in colorectal cancer

November 20, 2018, 12:00 am

≫ Next: Novel metformin-containing resin promotes odontogenic differentiation and mineral synthesis of dental pulp stem cells

≪ Previous: Irinotecan Alters the Disposition of Morphine Via Inhibition of Organic Cation Transporter 1 (OCT1) and 2 (OCT2)

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Abstract

Cancer stem cells (CSCs) and epithelial–mesenchymal transition (EMT) play an important role in the metastasis and chemoresistance in the context of colorectal cancer (CRC). Downregulation of death associated protein kinase 1 (DAPK1) may promote metastasis and chemoresistance of cancer cells through various mechanisms. However, the association between DAPK1 and CSCs or EMT has not been explored. In this study, we demonstrated that DAPK1 was associated with elevated stemness of CSCs in patients with CRC. Silencing of DAPK1 in CRC cell lines promoted the metastasis and chemoresistance due to increased stemness of CSCs and enhanced mesenchymal phenotype, an effect that was mediated via activation of the transcription factor, zinc finger E-box binding homeobox 1 (ZEB1). Blockade of this signaling pathway attenuated the stemness of CSCs and rescued the EMT process. DAPK1–ZEB1 may lie at the interface of TGF-β and WNT pathways and participate in both CSCs and EMT process. Targeted therapies aimed at DAPK1–ZEB1 pathway may inhibit the chemoresistance and metastasis of CRC.

Key messages

• Downregulation of DAPK1 promotes chemoresistance and metastasis of CRC.

• Inhibition of DAPK1 promotes the stemness of cancer stem cells and EMT process.

• DAPK1–ZEB1 may lie at the interface of TGF-β and WNT pathways.

• DAPK1–ZEB1 participates in both CSCs and EMT process.

Novel metformin-containing resin promotes odontogenic differentiation and mineral synthesis of dental pulp stem cells

November 21, 2018, 12:00 am

≫ Next: The LRP6 functional mutation rs2302685 contributes to individual susceptibility to alcoholic liver injury related to the Wnt/β-catenin-TCF1-CYP2E1 signaling pathway

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Abstract

This represents the first report on the development of metformin-containing dental resins. The objectives were to use the resin as a carrier to deliver metformin locally to stimulate dental cells for dental tissue regeneration and to investigate the effects on odontogenic differentiation of dental pulp stem cells (DPSCs) and mineral synthesis. Metformin was incorporated into a resin at 20% by mass as a model system. DPSC proliferation attaching on resins was evaluated. Dentin sialophosphoprotein (DSPP), dentin matrix phosphoprotein 1 (DMP-1), alkaline phosphatase (ALP), and runt-related transcription factor 2 (Runx2) genes expressions were measured. ALP activity and alizarin red staining (ARS) of mineral synthesis by the DPSCs on resins were determined. DPSCs on metformin-containing resin proliferated well (mean ± SD; n = 6), and the number of cells increased by 4-fold from 1 to 14 days (p > 0.1). DSPP, ALP, and DMP-1 gene expressions of DPSCs on metformin resin were much higher than DPSCs on control resin without metformin (p < 0.05). ALP activity of metformin group was 70% higher than that without metformin at 14 days (p < 0.05). Mineral synthesis by DPSCs on metformin-containing resin at 21 days was 9-fold that without metformin (p < 0.05). A novel metformin-containing resin was developed, achieving substantial enhancement of odontoblastic differentiation of DPSCs and greater mineral synthesis. The metformin resin is promising for deep cavities and perforated cavities to stimulate DPSCs for tertiary dentin formation, for tooth root coatings with metformin release for periodontal regeneration, and for root canal fillings with apical lesions to stimulate bone regeneration.

The LRP6 functional mutation rs2302685 contributes to individual susceptibility to alcoholic liver injury related to the Wnt/β-catenin-TCF1-CYP2E1 signaling pathway

June 1, 2019, 12:00 am

≫ Next: Respiratory virus associated with surgery in children patients

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Abstract

Low-density lipoprotein receptor-related protein 6 (LRP6) is an important coreceptor in the Wnt/β-catenin upstream signaling pathway. Rs2302685 is a common functional mutation of LRP6 that has been previously associated with reduced alcoholic liver injury among alcoholic liver disease (ALD) patients, and the present research was designed to study the underlying mechanisms of that finding. A total of 107 ALD patients and 138 non-ALD patients were recruited from hospitalized alcoholics in China. Their venous blood samples were collected for DNA extraction and genotyped using Sequenom MassARRAY. We found that the rs2302685 mutation, which impaired the function of LRP6, was present in higher frequency among alcoholics with ALD than those without ALD. We also conducted a mouse model experiment in which LRP6^(+/−) knockdown mice and LRP6^(+/+) wild-type mice received daily intragastric doses of ethanol (2.4 g/kg) as well as a larger dose of ethanol (4 g/kg) every 7 days for 28 days. The mouse blood and liver specimens were subsequently collected for laboratory analysis, and cell experiments were performed to compare the inhibition, activation, over-expression, and siRNA of LRP6 in the treatment versus the control HL7702 cells. Expression of the targeted molecules was detected by real-time PCR or western blot analysis. Stably transfected cells with pRL3-CYP2E1 vector were used to further study the underlying mechanisms. The total bile acid (TBA), direct bilirubin, total bilirubin (TBIL), aspartate aminotransferase (AST), mitochondrial aspartate aminotransferase, and AST/ALT values were significantly lower in carriers of the rs2302685 mutation than in the wild-type patients, by 63.4, 60.6, 82.1, 44.8, 45.7, and 21.4%, respectively. Compared to the LRP6^(+/+) wild-type mice, the LRP6^(+/−) knockdown mice had lower ALT, TBIL, TBA, and ALB/GLO values, as well reduced liver tissue damage, in accordance with their reduced expressions of LRP6, β-catenin, and CYP2E1. In HL7702 cells exposed to ethanol, AST, ALT, lipid accumulation, and ROS generation decreased in cells that were treated with LRP6 inhibitors or siRNA but increased in cells treated with LRP6 activators or over-expressed LRP6. TCF1 was the transcriptional factor most likely to connect the LRP6-Wnt/β-catenin signaling pathway to the regulation of CYP2E1. We concluded that the LRP6 functional mutation rs2302685 contributes to individual differences in susceptibility to alcoholic liver injury related to the Wnt/β-catenin-TCF1-CYP2E1 signaling pathway.

Respiratory virus associated with surgery in children patients

June 17, 2019, 12:00 am

≫ Next: Lack of Association of Generic Brittle Status with Genetics and Physiologic Measures in Patients with Epilepsy

≪ Previous: The LRP6 functional mutation rs2302685 contributes to individual susceptibility to alcoholic liver injury related to the Wnt/β-catenin-TCF1-CYP2E1 signaling pathway

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Abstract

Background

Viral respiratory infection (VRI) is a common contraindication to elective surgery. Asymptomatic shedding among pediatric surgery patients (PSPs) could potentially lead to progression of symptomatic diseases and cause outbreaks of respiratory diseases. The aim of this study is to investigate the incidence of infection among mild symptomatic PSP group and asymptomatic PSP group after surgical procedure.

Methods

We collected the induced sputum from enrolled 1629 children (under 18 years of age) with no respiratory symptom prior to pediatric surgery between March 2017 and February 2019. We tested 16 different respiratory virus infections in post-surgery mild symptomatic PSP group and asymptomatic PSP group using a quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR) assay panel. We analyzed symptom data and quantitative viral load to investigate the association between viruses, symptoms and viral quantity in qRT-PCR-positive PSPs.

Results

Out of 1629 children enrolled, a total of 204 respiratory viruses were present in 171 (10.50%) PSPs including 47 patients with mild symptoms and 124 with no symptoms after surgery. Commonly detected viruses were human rhino/enterovirus (HRV/EV, 42.19%), parainfluenza virus 3 (PIV3, 24.48%), coronavirus (CoV NL63, OC43, HKU1, 11.46%), and respiratory syncytial virus (RSV, 9.9%). PIV3 infection with a higher viral load was frequently found in PSPs presenting with mild symptoms, progressing to pneumonia with radiographic evidence after surgery. HRV/EV were the most commonly detected pathogens in both asymptomatic and mild symptomatic PSPs. CoV (OC43, HKU1) infections with a higher viral load were mostly observed in asymptomatic PSPs progressing to alveolar or interstitial infiltration.

Conclusions

Our study suggested that PIV3 is a new risk factor for VRI in PSPs. Employing a more comprehensive, sensitive and quantitative method should be considered for preoperative testing of respiratory viruses in order to guide optimal surgical timing.

Lack of Association of Generic Brittle Status with Genetics and Physiologic Measures in Patients with Epilepsy

February 26, 2020, 12:00 am

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Abstract

Purpose

A patient was denoted to be generic brittle (GB) if they had a negative opinion about generics (e.g. prior history of a switch problem) or took the innovator brand of their most problematic anti-epileptic drug (AED) when generic was available. The aim of this hypothesis-generating study was to assess possible genetic and physiologic differences between GB and not GB patients with epilepsy.

Methods

Patients (n = 148) with epilepsy were previously characterized as being either GB or not GB. Blood was collected from each subject for genotyping and physiologic testing. Genotyping for 24 single nucleotide polymorphisms (SNPs) and two copy number variants (CNVs) was performed across 12 genes in each patient. Forty-four physiologic tests were conducted in each patient. Chi square analysis was performed to assess for associations between genotyping results and GB status, as well as between physiologic test results and GB status.

Results

No SNP or CNV discriminated GB status in genetic analysis (genotype or allele frequency). Physiologic test results in this study were not associated with GB status.

Conclusions

Questions from neurologists and patients about generics is frequently based on applicability of generic drug standards to individual subjects. However, findings here in patients with epilepsy did not uncover genetic or physiologic reasons that explained which patients were GB and which were not GB.