Drug addiction places a significant burden on society and individuals. Proteomics and metabolomics approaches pave the road for searching potential biomarkers to assist the diagnosis and treatment. This review summarized putative drug addiction-related biomarkers in proteomics and metabolomics studies and discussed challenges and prospects in future studies. Alterations of several hundred proteins and metabolites were reported when exposure to abused drug, which enriched in energy metabolism, oxidative stress response, protein modification and degradation, synaptic function and neurotrasmission, etc. Hsp70, peroxiredoxin-6 and α- and β-synuclein, as well as n-methylserotonin and purine metabolites, were promising as potential biomarker for drug addiction.
The first two authors contributed equally to this work.The ontology of imidazoline receptors was first proposed by Bousquet P in 1980s [1] and was classified as I 1 , I 2 , and I 3 (non-I 1 /I 2 ) subtypes. However, deficiency in high selective ligand restrains the illumination of I 1 imidazoline receptor functions. In 2000, Piletz JE screened human hippocampal expression library and found a strong candidate protein for I 1 imidazoline receptor, named "imidazoline receptor antisera-selected" (IRAS) [2]. Concurrently, Alahari SK discovered a protein with identical sequence as IRAS and named it as "nischarin" [3]. Afterward, this protein was proved to be similar with I 1 imidazoline receptor in tissue distribution, ligand-binding property, and intracellular signallings and mediate many processes such as hypotensive effect of rilmenidine, inhibition of opioid addiction, inhibition of cell migration, antiapoptosis, and so on [4]. Herein, we originally generated IRAS conditional knockout mice (IRAS floxed/floxed ) and IRAS null mice (IRAS À/À ), which might be valuable tools for functional exploration of IRAS/nischarin and I 1 imidazoline receptors.Mouse IRAS gene is located on chromosome 14 and scatters into 21 exons, and we generated IRAS floxed/floxed mice by flanking exon 4 with loxP sites and then obtained IRAS À/À mice by crossing EIIa-Cre mice ( Figure 1A and Data S1 for more details). As for IRAS À/À mice, genotyping with the primer pair 5loxP-f and 3loxP-r could distinguish wild-type, heterozygote, and knockout mice ( Figure 1B). Sequencing result of the PCR product from 5loxP-f and 3flank primer pair revealed that only a loxP site remained between upstream and downstream homologous arms. In RTqPCR, the amplification curve of IRAS À/À was normal when the primer pair was originated from exon 3 and exon 5; however, the product is smaller than the wild type ( Figure 1C). Moreover, the amplification curve of IRAS À/À was null when the primer pair was originated from exon 2 and exon 4 ( Figure 1D). All the results above illustrated the normal transcription and the absence of exon 4 counterpart in the transcription product of IRAS À/À mice, which resulted in a new stop code in the following exon 5. In the Western blot assay, three bands, between 95 and 130 kD, were absent in cerebellum tissue of IRAS À/À mice ( Figure 1E). As several bands that represent functional IRAS have been reported, including 85 and 33 kD in human and 67 kD in bovine, these characteristic bands were proposed to be the splicing products in mouse cerebellum. All the above declared the functional deletion of IRAS gene.The IRAS À/À mice were born small compared with wild-type littermates (Figure 2A, B). Furthermore, weights of knockout embryos at day 12.5 (0.121 g, 0.133 g, and 0.143 g) were smaller than those of wild-type littermates (0.173 and 0.173 g) ( Figure 2C). These results suggested the participation of IRAS in 978 CNS Neuroscience & Therapeutics 19 (2013) 978-981 ª 2013 John Wiley & Sons Ltd prenatal growth and the postnatal growth re...
Increasing preclinical evidence demonstrates that dopamine D3 receptor (D3R) antagonists are a potential option for the treatment of drug addiction. The reinstatement of the addiction can be triggered by environmental stimuli that acquire motivational salience through repeated associations with the drug's effects. YQA14 is a novel D3R antagonist that has exhibited pharmacotherapeutic efficacy in reducing cocaine and amphetamine reward and relapse to drug seeking in mice. In this study we investigated the effects of YQA14 on morphine-induced context-specific locomotor sensitization in mice. We showed that repeated injection of YQA14 (6.25-25 mg/kg every day ip) prior to morphine (10 mg/kg every day sc) not only inhibited the acquisition, but also significantly attenuated the expression of morphine-induced locomotor sensitization. Furthermore, in the expression phase, one single injection of YQA14 (6.25-25 mg/kg, ip) dose-dependently inhibited the expression of morphine-induced behavioral sensitization. Moreover, YQA14 inhibited the expression of morphine-induced behavioral sensitization in wild mice (WT), but not in D3R knockout (D3R) mice in the expression phase. In addition, D3R mice also displayed the reduction in the expression phase compared with WT mice. In summary, this study demonstrates that blockade or knockout of the D3R inhibits morphine-induced behavior sensitization, suggesting that D3R plays an important role in the pathogenesis and etiology of morphine addiction, and it might be a potential target for clinical management of opioid addiction.
IntroductionBortezomib, a novel proteasome inhibitor, is approved for the treatment of relapsed multiple myeloma (MM). Efficacy and safety of bortezomib is well known; however, it was necessary to validate the data in patients with different ethnic backgrounds. The efficacy and safety of bortezomib was assessed in patients from China with relapsed/refractory MM in a real-world scenario.MethodsThis prospective, non-interventional, observational study enrolled both male and female Chinese patients, aged ≥18 years and diagnosed with relapsed or refractory MM. Administration of intravenous bortezomib at 1.3 mg/m2 was recommended twice a week for 2 weeks (days 1, 4, 8 and 11), followed by a 10-day rest period (maximum of 8 cycles) and a follow-up every 12 weeks for 3 years. Efficacy assessments included best response, objective response rate (ORR), time to response, duration of response, and overall survival. Safety was also assessed.ResultsA total of 517 patients were enrolled with a median age of 58.7 years. Patients predominantly had immunoglobulin G type (46.2%) and stage III (47.8%) myeloma. Overall, 202 (42.3%) patients had partial response as best response, ORR was 88.9% and the proportion of patients exhibiting complete response was 24.7%. The median time to response observed was 27 (21–40) days. Median time to progression was 415 days and median overall survival was 475 days. Thrombocytopenia (14.4%) was the most common adverse event.ConclusionBortezomib demonstrated clinical response in majority of patients and was well tolerated in this observational study in Chinese patients with relapsed/refractory MM.Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-014-0159-z) contains supplementary material, which is available to authorized users.
Gastrointestinal (GI) cancers are among the most fatal diseases in the world. Numerous studies have demonstrated the relationship between autophagy and development of gastrointestinal cancers. However, whether autophagy-related genes can predict prognosis of GI cancers in individuals of Asian ancestry has not been defined. This study, evaluated the prognostic value of autophagy-related genes in gastrointestinal cancer. Expression profile of autophagy-related genes for 296 gastrointestinal cancer patients of Asian ancestry was downloaded from the TCGA database (TCGA-LIHC, TCGA-STAD, TCGA-ESCA, TCGA-PAAD, TCGA-COAD, TCGA-CHOL, and TCGA-READ). The prognostic value of the autophagy-related genes was evaluated using univariate Cox, LASSO, and multivariate Cox regression analyses. The risk score of the autophagy-related gene signature was calculated to assess its predictive prognostic value for GI cancers. Forty-seven differentially expressed autophagy-related genes, in Asian patients with gastrointestinal cancers, were identified. Of the 47 genes, 4 were associated with prognosis of GI cancer (SQSTM1, BIRC5, NRG3, and CXCR4). A prognostic model for GI cancer, based on the expression of the above 4 genes in the training set, showed that cancer patients were stratified into high-risk and low-risk groups ( P < 0.05 ). The utility of the model for overall survival (OS) of GI cancer patients was consistent across the entire set, training set, and test set (entire set: P = 4.568 × 10 − 4 ; train set: P = 5.718 × 10 − 3 ; test set: P = 3.516 × 10 − 2 ). The sensitivity and specificity of the ROC curve of the above prognostic model in predicting the 5-year prognosis of GI cancer was satisfactory (entire set: 0.728; train set: 0.727; test set: 0.733). Analysis of clinical samples validated the overexpression of the 4 genes (SQSTM1, BIRC5, NRG3, and CXCR4) in tumor tissues relative to paired normal tissues, consistent with bioinformatic findings. Expression of the 4 autophagy-related genes (SQSTM1, BIRC5, NRG3, and CXCR4) can accurately predict the prognosis of gastrointestinal tumors in Asian patients.
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