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Novel therapeutic approaches targeting L-type amino acid transporters for cancer treatment

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World Journal of Gastrointestinal Oncology 2017年第1期9卷 21-29页

作者： Keitaro Hayashi Naohiko Anzai Department of pharmacology and toxicology Dokkyo Medical University School of Medicine Department of pharmacology Chiba University Graduate School of Medicine

L-type amino acid transporters(LATs) mainly assist the uptake of neutral amino acids into cells. Four LATs(LAT1, LAT2, LAT3 and LAT4) have so far been identified. LAT1(SLC7A5) has been attracting much attention in the field of cancer research since it is commonly up-regulated in various cancers. Basic research has made it increasingly clear that LAT1 plays a predominant role in malignancy. The functional significance of LAT1 in cancer and the potential therapeutic application of the features of LAT1 to cancer management are described in this review.

关键词： LAT1 Amino acid transporter Molecular target drug Amino acid starvation response Signal transduction

Polymorphisms of the oxidant enzymes glutathione S-transferase and glutathione reductase and their association with resistance of Plasmodium falciparum isolates to antimalarial drugs

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Asian Pacific Journal of Tropical Medicine 2010年第9期3卷 673-677页

作者： Raewadee Wisedpanichkij Wanna Chaicharoenkul Poonuch Mahamad Prapichaya Prompradit Kesara Na-Bangchang pharmacology and toxicology Unit Graduate Program in Biomedical SciencesThammasat UniversityThailand

Objective:To investigate the association between amplification of the two regulatory genes controlling glutathione(GSH) levels,glutathione reductase(PfGR) and glutathione S-transferase (PfGST) genes and sensitivity of Plasmodium falciparum(***) isolates collected from different malaria endemic areas of Thailand to standard antimalarial ***:A total of 70 *** isolates were collected from endemic areas of multi-drug resistance (Tak,Chantaburi and Ranong Provinces) during the year *** in vitro assessment of antimalarial activity of *** clones(K1- and Dd2 chloroquine resistant and 3D7- chloroquine sensitive) and isolates to chloroquine,quinine,mefloquine and arteusnate was performed based on SYBR Green modified ***:68(97.14%),11(15.71%) and 28(40%) isolates respectively were classified as chloroquine-,quinine- and mefloquine-resistant isolates. With this limited number of *** isolates included in the analysis,no significant association between amplification of PfGST gene and sensitivity of the parasite to chloroquine, quinine,mefloquine and quinine was *** on PCR analysis,Dd2,Kl and 3D7 clones all contained only one copy of the PfGST *** isolates(70) also carried only one copy number of PfGST *** appears to be an association between amplification of PfGR gene and chloroquine *** 3D7 and Dd2 clones were found to carry only one PfGR gene copy, whereas the K1 clone carried two gene ***:Chloroquine resistance is likely to be a consequence of multi-factors and enzymes in the GSH system may be partly involved. Larger number of parasite isolates are required to increase power of the hypothesis testing in order to confirm the involvement of both genes as well as other genes implicated in glutathione metabolism in conferring chloroquine resistance.

关键词： Plasmodium falciparum Drug resistance Glutathione reductase(PfGR) Glutathione S-transferase(P/GST)

Behind the curtain of non-coding RNAs; long non-coding RNAs regulating hepatocarcinogenesis

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World Journal of Gastroenterology 2018年第5期24卷 549-572页

作者： Aya El Khodiry Menna Afify Hend M El Tayebi Genetic pharmacology Research group Clinical Pharmacy Unit department of Pharmacology and toxicology faculty of Pharmacy and biotechnology German University in Cairo

Hepatocellular carcinoma(HCC) is one of the most common and aggressive cancers worldwide. HCC is the fifth common malignancy in the world and the second leading cause of cancer death in Asia. Long non-coding RNAs(lncRNAs) are RNAs with a length greater than 200 nucleotides that do not encode proteins. lncRNAs can regulate gene expression and protein synthesis in several ways by interacting with DNA, RNA and proteins in a sequence specific manner. They could regulate cellular and developmental processes through either gene inhibition or gene activation. Many studies have shown that dysregulation of lncRNAs is related to many human diseases such as cardiovascular diseases, genetic disorders, neurological diseases, immune mediated disorders and cancers. However, the study of lncRNAs is challenging as they are poorly conserved between species, their expression levels aren't as high as that of m RNAs and have great interpatient variations. The study of lncRNAs expression in cancers have been a breakthrough as it unveils potential biomarkers and drug targets for cancer therapy and helps understand the mechanism of pathogenesis. This review discusses many long non-coding RNAs and their contribution in HCC, their role in development, metastasis, and prognosis of HCC and how to regulate and target these lncRNAs as a therapeutic tool in HCC treatment in the future.

关键词： tumor suppressor genes oncogenes Long non-coding RNAs proliferation hepatocellular carcinoma metastasis

Epigenetic regulation of insulin-like growth factor axis in hepatocellular carcinoma

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World Journal of Gastroenterology 2016年第9期22卷 2668-2677页

作者： Hend Mohamed El Tayebi Ahmed Ihab Abdelaziz The Molecular Pathology Research group Department of Pharmacology and Toxicology Faculty of Pharmacy and Biotechnology German University in Cairo

The insulin-like growth factor(IGF) signaling path-way is an important pathway in the process of hepa-tocarcinogenesis,and the IGF network is clearly dysregulated in many cancers and developmental *** hepatocellular carcinoma(HCC),only a minority of patients are eligible for curative treatments,such as tumor resection or liver ***,there is a high recurrence of HCC after surgical tumor *** research efforts have focused on targeting IGF axis members in an attempt to find therapeutic options for many health *** this review,we shed lights on the regulation of members of the IGF axis,mainly by micro RNAs in *** RNAs in HCC attempt to halt the aberrant expression of the IGF network,and a single micro RNA can have multiple downstream targets in one or more signaling *** micro RNAs is a relatively new approach for identifying an efficient radical cure for HCC.

关键词： Hepatocellular carcinoma Insulin-like growth factors Insulin-like growth factor receptors Epigenetics microRNAs

Effect of extract of Abrus precatorius on blood glucose concentration of alloxan induced diabetic Albino Wistar Rats

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Asian Pacific Journal of Tropical Medicine 2009年第6期2卷 16-17页

作者： Georgewill OA Georgewill UO Department of pharmacology and toxicology

Objective:To evaluate the effect of extract of Abrus precatorius on blood glucose of alloxan induced albino wistar ***:Experimental animals received daily oral administration of extract of Abrus precatorius for 14 *** effect of 200 mg/kg dose was studied during the treatment ***:There was a significant reduction in blood glucose concentration(P groups as 5.0±0.3 for normal control,7.0±0.4 for diabetic control group and 4.0±0.2 for diabetic treated group. Conclusion:The findings of this study suggest that extract of Abrus precatorius has hypoglycemic effect.

关键词： Abrus precatorius Hypoglycemia Diabetes Hyperglycemia

Inhibition of cytochrome P450 by furanocoumarins in grapefruit juice and herbal medicines

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Acta Pharmacologica Sinica 2004年第2期25卷 3-10页

作者： Lian-qing GUO1, Yasushi YAMAZOE2Department of Clinical pharmacology, Jinling Hospital, Nanjing 210002, China 2Division of Drug Metabolism and Moleculartoxicology, graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan Department of Clinical pharmacology Jinling Hospital Nanjing 210002 Division of Drug Metabolism and Molecular toxicology Graduate School of Pharmaceutical Sciences Tohoku University Sendai 980-8578 日本

Furanocoumarins (psoralens) exist in various plants and some of them are used to cure skin diseases. Thesechemicals draw attentions recently because of their abilities to arouse drug interaction through inhibition of cyto-chrome P450. Grapefruit juice is a well-known example for food-drug interaction. But in vitro and in vivo studieshave shown that the causative components are mainly furanocoumarin derivatives with geranyloxy side chains. Invitro experiments confirmed that furanocoumarins from grapefruit juice are both competitive and mechanism-based inhibitors of CYP3A4. Although the inhibition appeared to be stronger in the dimers than that in the monomers,all contribute comprehensively to the grapefruit juice-drug interaction. Further experiments with other furanocoumarinsand related citrus fruits or umbelliferous herbal medicines indicate that drug interaction might also occur with stuffsother than grapefruit juice, especially with traditional medicine.

关键词： psoralens grapefruit juice herbal medicine enzyme inhibitors cytochrome P-450 enzyme system drug interaction

Synthesis and Crystal Structure of 7α-[(R)-1-Hydroxyl-1-methyl-3-(thien-2-yl)- propyl]-6,14-endoethanotetrahydrothebaine

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Chinese Journal of Structural Chemistry 2005年第9期24卷 1021-1024页

作者：刘河刘春河吴波陈兰福仲伯华 No. 7 Department Beijing Institute of Pharmacology and Toxicology Beijing 100850 China

The crystal structure of 7α-[（R）-1-hydroxyl-1-methyl-3-（thien-2-yl）propyl]-6,14-endoethanotetrahydrothebaine （C29H37NO4S, Mr=495.66） has been determined by single-crystal X-ray diffraction analysis. The crystal belongs orthorhombic, space group P212121 with α=10.063（4）, b=12.571（5）, c=19.626（8）A°, V=2482.9（17）A°^3, Z=4, Dc=1.326 g/cm^3,μ=0.167 mm^-1, F（000）=1064, the final R=0.0537 and wR=0.0888. The C（7） substituent is l-hy-droxyl-1-methyl-3-（thienyl-2-）propyl group adopting R-configuration. The N-methyl group is located at the equatorial position as expected. The crystal structure shows the presence of intra- molecular hydrogen bonds, O（1）-H（1）…O（2）.

关键词： thebaine crystal structure grignard reaction

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Resolution and Crystal Structure of 9α-(3-Azabicyclo[3,3,1]nonanyl)- 2′-cyclopentyl-2′-hydroxyl-2′-thienylacetate

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Chinese Journal of Structural Chemistry 2006年第5期25卷 547-551页

作者： LIU He HAN Xiang-Yu ZHANG Yan-Ping ZHONG Bo-Hua LIU Ke-Liang Beijing Institute of pharmacology and toxicology 27 Taiping Road Beijing 100850 China

The crystal structure of 9α-（3-azabicyclo[3,3,1]nonanyl）-2′-cyclopentyl-2′-hydro- xyl-2′-thienylacetate （C16H27NO3S, Mr = 349.48） has been determined by single-crystal X-ray diffraction analysis. The crystal belongs to orthorhombic, space group P212121 with a = 14.937（3）, b = 8.1673（16）, c = 15.423（3） ,A, V = 1881.5（6） ,A^3, Z = 4, Dc =1.234 g/cm^3, μ = 0.188 mm^-1, F（000） = 752, the final R = 0.0468 and wR = 0.1251. The bicyclo[3,3,1]nonane ring system adopts the most favored twin-chair conformation. The crystal structure shows the existence of intramolecular O-H…O hydrogen bonds by which a one-dimensional chain structure is formed.

关键词： optical resolution crystal structure muscarinic receptor antagonist

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Exploitation of the nicotinic anti-inflammatory pathway for the treatment of epithelial inflammatory diseases

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World Journal of Gastroenterology 2006年第46期12卷 7451-7459页

作者： David A Scott Michael Martin Oral Health and Systemic Disease Research group and Department of Pharmacology and Toxicology University of Louisville Kentucky United States Oral Health and Systemic Disease Research group and Department of Microbiology and Immunology University of Louisville Kentucky United States

Discoveries in the first few years of the 21st century have led to an understanding of important interactions between the nervous system and the inflammatory response at the molecular level, most notably the acetylcholine （ACh）- triggered,α7-nicotinic acetylcholine receptor （α7nAChR）- dependent nicotinic antinflammatory pathway. Studies using the α7nAChR agonist, nicotine, for the treatment of mucosal inflammation have been undertaken but the efficacy of nicotine as a treatment for inflammatory bowel diseases remains debatable. Further understanding of the nicotinic anti-inflammatory pathway and other endogenous anti-inflammatory mechanisms is required in order to develop refined and specific therapeutic strategies for the treatment of a number of inflammatory diseases and conditions, including periodontitis, psoriasis, sarcoidosis, and ulcerative colitis.

关键词： α7-nicotinic acetylcholine receptor Inflammation Mucosa Nicotine Nicotinic anti-inflammatory pathway Tobacco smoking