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Eric H J Verschuren, Sami G Mohammed, Wouter N Leonhard, Caro Overmars-Bos, Kimberly A M Veraar, Joost G J Hoenderop, René J M Bindels, Dorien J M Peters, Francisco J Arjona
The PKD1 gene encodes polycystin-1 (PC1), a mechanosensor triggering intracellular responses upon urinary flow sensing in kidney tubular cells. Mutations in PKD1 lead to autosomal dominant polycystic kidney disease (ADPKD). The involvement of PC1 in renal electrolyte handling remains unknown since renal electrolyte physiology in ADPKD patients has only been characterized in cystic ADPKD. We thus studied the renal electrolyte handling in inducible kidney-specific Pkd1 knockout (iKsp-Pkd1-/-) mice manifesting a pre-cystic phenotype...
May 16, 2018: American Journal of Physiology. Renal Physiology
Y-F Xia, H-J Chu, G-F Kuang, G-J Jiang, Y-C Che
OBJECTIVE: To investigate the anti-tumor effect of acridone against breast cancer in vivo and provide a therapeutic agent for treatment of breast cancer. MATERIALS AND METHODS: The nude mice xenografted tumor model was established by MCF-7 cells. The mice were randomly divided into four groups. The mice in each group (n=6) were intraperitoneally injected with 0.1 mg/kg saline (low-dose), 0.5 mg/kg (middle-dose) and 1.0 mg/kg (high-dose) of acridone for 21 days, respectively...
April 2018: European Review for Medical and Pharmacological Sciences
Vachiranee Limviphuvadh, Chee Seng Tan, Fumikazu Konishi, Piroon Jenjaroenpun, Joy Shengnan Xiang, Yuliya Kremenska, Yar Soe Mu, Nicholas Syn, Soo Chin Lee, Ross A Soo, Frank Eisenhaber, Sebastian Maurer-Stroh, Wei Peng Yong
BACKGROUND: Single Nucleotide Polymorphisms (SNPs) can influence patient outcome such as drug response and toxicity after drug intervention. The purpose of this study is to develop a systematic pathway approach to accurately and efficiently predict novel non-synonymous SNPs (nsSNPs) that could be causative to gemcitabine-based chemotherapy treatment outcome in Singaporean non-small cell lung cancer (NSCLC) patients. METHODS: Using a pathway approach that incorporates comprehensive protein-protein interaction data to systematically extend the gemcitabine pharmacologic pathway, we identified 77 related nsSNPs, common in the Singaporean population...
May 11, 2018: BMC Cancer
Boglárka Zámbó, Zsuzsa Bartos, Orsolya Mózner, Edit Szabó, György Várady, Gyula Poór, Márton Pálinkás, Hajnalka Andrikovics, Tamás Hegedűs, László Homolya, Balázs Sarkadi
The ABCG2 membrane protein is a key xeno- and endobiotic transporter, modulating the absorption and metabolism of pharmacological agents and causing multidrug resistance in cancer. ABCG2 is also involved in uric acid elimination and its impaired function is causative in gout. Analysis of ABCG2 expression in the erythrocyte membranes of healthy volunteers and gout patients showed an enrichment of lower expression levels in the patients. By genetic screening based on protein expression, we found a relatively frequent, novel ABCG2 mutation (ABCG2-M71V), which, according to cellular expression studies, causes reduced protein expression, although with preserved transporter capability...
May 10, 2018: Scientific Reports
Wenlong Li, Rolf W Sparidans, Yaogeng Wang, Maria C Lebre, Els Wagenaar, Jos H Beijnen, Alfred H Schinkel
Lorlatinib (PF-06463922) is a promising oral anaplastic lymphoma kinase (ALK) and ROS1 inhibitor currently in Phase III clinical trials for treatment of non-small cell lung cancer (NSCLC) containing an ALK rearrangement. With therapy-resistant brain metastases a major concern in NSCLC, lorlatinib was designed to have high membrane and blood-brain barrier permeability. We investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, and the multispecific drug-metabolizing enzyme CYP3A in plasma pharmacokinetics and tissue distribution of lorlatinib using genetically modified mouse strains...
May 9, 2018: International Journal of Cancer. Journal International du Cancer
Li Yang, Manjun Li, Fang Wang, Chen Zhen, Min Luo, Xiaona Fang, Hong Zhang, Jianye Zhang, Qingshan Li, Liwu Fu
BACKGROUND/AIMS: Multidrug resistance (MDR) triggered by ATP binding cassette (ABC) transporters, such as ABCB1, ABCC1, and ABCG2, is a key obstacle for successful cancer chemotherapy. There is currently no FDA-approved MDR modulator that can be used in clinic. Ceritinib, a selective ALK inhibitor, has been approved as the second-line treatment for ALK-positive non-small cell lung cancer. Here, we examined the role of ceritinib in leukemia associated MDR in therapy. METHODS: The cell proliferation was detected by MTT assay...
May 5, 2018: Cellular Physiology and Biochemistry
Ao Wu, Jiaoli Zhang, Liyan Zeng, Feng Li, Zhaoguang Dong, Yanling Feng, Xiaofang Jia, Jun-O Jin, Lijun Zhang
BACKGROUND: ATP-binding cassette sub-family G member 2 (ABCG2), an ABC transport protein involved in the efflux of anticancer compounds, has been reported to have altered expression levels in several cancers including breast, colon, and gastric cancer, etc. However, its expression change (up- or down-regulated in cancer) is still contradictory. METHODS: We performed immunohistochemistry to examine ABCG2 expression in the microarray with 90 pairs of colon cancer and their adjacent normal tissues...
March 1, 2018: Clinical Laboratory
Maiko Abumiya, Akiko Mita, Saori Takahashi, Tomoko Yoshioka, Yoshihiro Kameoka, Naoto Takahashi, Masatomo Miura
We investigated the effects of polymorphisms in NR1I2 (7635A>G, 8055C>T), CYP3A4 (20230G>A), ABCB1 (1199G>A, 1236C>T, 2677G>T/A, 3435C>T), and ABCG2 (421C>A) on the mean plasma trough concentrations (C0 ) of bosutinib at the steady-state in 30 Japanese patients with chronic myeloid leukemia. Bosutinib C0 values were monitored using high-performance liquid chromatography. The median coefficient of variation (CV) value of the bosutinib C0 for one patient (intrapatient) during bosutinib therapy was 25...
May 7, 2018: Medical Oncology
Majda Vrkić Kirhmajer, Viola Macolić Šarinić, Livija Šimičević, Iva Ladić, Krešimir Putarek, Ljiljana Banfić, Nada Božina
Up to the beginning of 2018, a total of eight cases describing rare but clinically important drug interactions between rosuvastatin and ticagrelor which resulted in rhabdomyolysis have been noted in the Global World Health Organization (WHO) adverse drug reaction (ADR) database (VigiBase) as well as in available literature. There are several possible factors which could contribute to the onset of rhabdomyolysis: old age, initially excessive rosuvastatin dose, drug-drug interactions (DDI) on metabolic enzymes (CYPs and UGTs) and drug transporter levels (ABCB1, ABCG2, OATP1B1) and pharmacogenetic predisposition...
May 7, 2018: Basic & Clinical Pharmacology & Toxicology
Yuyi Wang, Ming Jiang, Chi Du, Yang Yu, Yanyang Liu, Mei Li, Feng Luo
Lung cancer is one of the most l ethal types of cancer, and its poor prognosis is primarily due to drug resistance and cancer recurrence. As it is associated with a low five-year survival rate, lung cancer stem cells (LCSCs) have been the subject of numerous recent studies. For these studies of LCSCs, lung cancer cell lines are more commonly used than lung cancer tissues obtained from patients, as they are easier to acquire. The methods utilized for the identification of LCSCs from lung cancer cell lines include fluorescence activated cell sorting (FACS), magnetic activated cell sorting (MACS), sphere-forming assay and bacterial surface display library screening...
May 2018: Oncology Letters
Adviti Naik, Aida Al-Yahyaee, Nada Abdullah, Juda-El Sam, Noura Al-Zeheimi, Mahmoud W Yaish, Sirin A Adham
BACKGROUND: Neuropilin-1 (NRP-1), a non-tyrosine kinase glycoprotein receptor, is associated with poor prognosis breast cancer, however transcriptomic changes triggered by NRP-1 overexpression and its association with chemoresistance in breast cancer have not yet been explored. METHODS: BT-474 NRP-1 variant cells were generated by stable overexpression of NRP-1 in the BT-474 breast cancer cell line. RNA sequencing and qRT-PCR were conducted to identify differentially expressed genes...
May 5, 2018: BMC Cancer
Juan Chen, Qi-Biao Su, Yu-Qian Tao, Jia-Ming Qin, Yi Zhou, Shan Zhou, Hong-Liang Li, Zhuo-Jia Chen, Ya-Fang Zhou, Lie-Min Zhou, Xue-Ding Wang, Min Huang
Valproic acid (VPA), a widely used antiepileptic drug, is characterized by intensive inter-individual variability in concentration. Both efflux and influx transporters are reported to play important roles in the disposition of VPA, however, no comprehensive investigation into the association of the single nucleotide polymorphism (SNP) in ABC/SLC families with VPA concentration are reported. In the present study, we investigated the association of 12 SNPs in ABCC2, ABCC4, ABCG2, MCT1, MCT2, and OATP2B1 in 187 Chinese patients with epilepsy on VPA monotherapy with the trough concentrations of VPA...
May 1, 2018: Die Pharmazie
Zhizhen Qin, Shoubao Wang, Yihuang Lin, Ying Zhao, Shengqian Yang, Junke Song, Tao Xie, Jinlong Tian, Song Wu, Guanhua Du
A mangiferin aglycon derivative J99745 has been identified as a potent xanthine oxidase (XOD) inhibitor by previous in vitro study. This study aimed to evaluate the hypouricemic effects of J99745 in experimental hyperuricemia mice, and explore the underlying mechanisms. Mice were orally administered 600 mg/kg xanthine once daily for 7 days and intraperitoneally injected 250 mg/kg oxonic acid on the 7th day to induce hyperuricemia. Meanwhile, J99745 (3, 10, and 30 mg/kg), allopurinol (20 mg/kg) or benzbromarone (20 mg/kg) were orally administered to mice for 7 days...
March 2018: Acta Pharmaceutica Sinica. B
Shinsuke Noguchi, Chiaki Nakaseko, Kaichi Nishiwaki, Hitoshi Ogasawara, Kohshi Ohishi, Michihide Tokuhira, Masaaki Noguchi, Hideo Kimura, Hiroshi Handa, Kinuko Mitani, Masatomo Miura, Hisashi Wakita, Naoto Takahashi
The purpose of this clinical trial was to evaluate the efficacy of 2-year consolidation therapy using nilotinib (NIL) for achieving a molecular response (MR4.5 , BCR-ABL1 IS  ≤ 0.0032% on the International Scale) in patients with chronic myeloid leukemia in the chronic phase (CML-CP) who had achieved a major molecular response (MMR, BCR-ABL1 IS  ≤ 0.1%) with imatinib (IM). We recruited 76 Japanese patients for this trial. Nilotinib 300 mg, twice daily, was administered for 2 years, and 74 patients were evaluated in the study...
April 30, 2018: International Journal of Hematology
Onat Kadioglu, Mohamed Saeed, Victor Kuete, Henry J Greten, Thomas Efferth
Drug resistance is one of the main reasons of chemotherapy failure. Therefore, overcoming drug resistance is an invaluable approach to identify novel anticancer drugs that have the potential to bypass or overcome resistance to established drugs and to substantially increase life span of cancer patients for effective chemotherapy. Oridonin is a cytotoxic diterpenoid isolated from Rabdosia rubescens with in vivo anticancer activity. In the present study, we evaluated the cytotoxicity of oridonin toward a panel of drug-resistant cancer cells overexpressing ABCB1, ABCG2, or ΔEGFR or with a knockout deletion of TP53...
2018: Frontiers in Pharmacology
Bin Yan, Shuang Liu, Ying Shi, Na Liu, Ling Chen, Xiang Wang, Desheng Xiao, Xiaoli Liu, Chao Mao, Yiqun Jiang, Weiwei Lai, Xing Xin, Can-E Tang, Dixian Luo, Tan Tan, Jiantao Jia, Yating Liu, Rui Yang, Jun Huang, Hu Zhou, Yan Cheng, Ya Cao, Weishi Yu, Kathrin Muegge, Yongguang Tao
Most cancer patients receive radiotherapy in the course of their disease and the occurrence of radioresistance is associated with poor prognosis. The molecular pathways that drive enhanced tumorigenic potential during the development of radioresistance are poorly understood. Here, we demonstrate that aryl hydrocarbon receptor (AhR) plays a vital role in the maintenance of cancer stem-like properties. AhR promotes the cancer stem-like phenotype and drives metastasis by directly targeting the promoters of 'stemness' genes, such as the ATP-binding cassette sub-family G member 2 (ABCG2) gene...
April 30, 2018: Cell Death & Disease
Chao-Yuan Tang, Li-Xin Zhu, Jian-Dong Yu, Zhi Chen, Man-Cang Gu, Chao-Feng Mu, Qi Liu, Yang Xiong
In order to explore the mechanism of the reversing multidrug resistance (MDR) phenotypes by β-elemene (β-ELE) in doxorubicin (DOX)-resistant breast cancer cells (MCF-7/DOX), both the functionality and quantity of the ABC transporters in MCF-7/DOX were studied. Bioluminescence imaging (BLI) was used to study the efflux of d-luciferin potassium salt, the substrate of ATP-binding cassette transporters (ABC transporters), in MCF-7/DOX cells treated by β-ELE. At the same time three major ABC transport proteins and genes-related MDR, P-glycoprotein (P-gp, ABCB1) and multidrug resistance-associated protein 1 (MRP, ABCC1) as well as breast cancer resistance protein (BCRP, ABCG2) were analyzed by q-PCR and Western blot...
April 25, 2018: European Journal of Pharmaceutical Sciences
Yan Li, Lingjuan He, Xiuzhen Huang, Shirin Issa Bhaloo, Huan Zhao, Shaohua Zhang, Wenjuan Pu, Xueying Tian, Yi Li, Qiaozhen Liu, Wei Yu, Libo Zhang, Xiuxiu Liu, Kuo Liu, Juan Tang, Hui Zhang, Dongqing Cai, Ralf H Adams, Qingbo Xu, Kathy O Lui, Bin Zhou
Background -Whether the adult mammalian heart harbors cardiac stem cells (CSCs) for regeneration of cardiomyocytes is an important yet contentious topic in the field of cardiovascular regeneration. The putative myocyte stem cell populations recognized without specific cell markers such as the cardiosphere-derived cells or with markers such as Sca1+ , Bmi1+ , Isl1+ or Abcg2+ CSCs have been reported. Moreover, it remains unclear whether putative CSCs with unknown or unidentified markers exist and give rise to de novo cardiomyocytes in the adult heart...
April 26, 2018: Circulation
Markus Grube, Paul Hagen, Gabriele Jedlitschky
Neurosteroids, comprising pregnane, androstane, and sulfated steroids can alter neuronal excitability through interaction with ligand-gated ion channels and other receptors and have therefore a therapeutic potential in several brain disorders. They can be formed in brain cells or are synthesized by an endocrine gland and reach the brain by penetrating the blood-brain barrier (BBB). Especially sulfated steroids such as pregnenolone sulfate (PregS) and dehydroepiandrosterone sulfate (DHEAS) depend on transporter proteins to cross membranes...
2018: Frontiers in Pharmacology
Faisal Alowaidi, Saeed Mujahid Hashimi, Naif Alqurashi, Reem Alhulais, Saso Ivanovski, Bernadette Bellette, Adrian Meedenyia, Alfred Lam, Stephen Wood
To date two questions that remain unanswered regarding cancer are the following: i) how is it initiated, and ii) what is the role that cancer stem cells (CSCs) play in the disease process? Understanding the biology of CSCs and how they are generated is pivotal for the development of successful treatment regimens. To date, the lack of a representative cell model has prevented the successful identification and eradication of CSCs in vivo. The current methods of CSC identification are dependent on the protocol used to generate these cells, which has introduced variation and made the identification process more complicated...
April 23, 2018: Oncology Reports
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