Drug Target Insights最新文献

{"title":"Effects of zaprinast and rolipram on olfactory and visual memory in the social transmission of food preference and novel object recognition tests in mice.","authors":"Furuzan Akar, Oguz Mutlu, Ipek K Celikyurt, Emine Bektas, Mehmet H Tanyeri, Guner Ulak, Pelin Tanyeri, Faruk Erden","doi":"10.4137/DTI.S14813","DOIUrl":"10.4137/DTI.S14813","url":null,"abstract":"<p><p>The role of phosphodiesterase (PDE) inhibitors in central nervous system has been investigated and shown to stimulate neuronal functions and increase neurogenesis in Alzheimer patients. The aim of this study is to investigate effect of PDE5 inhibitor zaprinast and PDE4 inhibitor rolipram on visual memory in novel object recognition (NOR) test, on olfactory memory in social transmission of food preference (STFP) test, and also on locomotion and anxiety in open field test in naive mice. Male Balb-c mice were treated intraperitoneally (i.p.) with zaprinast (3 and 10 mg/kg), rolipram (0.05 and 0.1 mg/kg), or physiological saline. Zaprinast (10 mg/kg) significantly increased cued/non-cued food eaten compared to control group, while rolipram had a partial effect on retention trial of STFP test. Zaprinast (10 mg/kg) and rolipram (0.05 and 0.1 mg/kg) significantly increased ratio index (RI) compared to control group in retention trial of NOR test. There was no significant effect of zaprinast and rolipram on total distance moved, speed, and center zone duration in open field test. Results of this study revealed that both zaprinast and rolipram enhanced visual memory in NOR test, however zaprinast exerted a significant memory-enhancing effect compared to rolipram in STFP test in mice. </p>","PeriodicalId":11326,"journal":{"name":"Drug Target Insights","volume":"8 ","pages":"23-9"},"PeriodicalIF":2.7,"publicationDate":"2014-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4137/DTI.S14813","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32363561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Antidepressant Agomelatine Improves Memory Deterioration and Upregulates CREB and BDNF Gene Expression Levels in Unpredictable Chronic Mild Stress (UCMS)-Exposed Mice.","authors":"Esen Gumuslu,&nbsp;Oguz Mutlu,&nbsp;Deniz Sunnetci,&nbsp;Guner Ulak,&nbsp;Ipek K Celikyurt,&nbsp;Naci Cine,&nbsp;Furuzan Akar,&nbsp;Hakan Savlı,&nbsp;Faruk Erden","doi":"10.4137/DTI.S13870","DOIUrl":"https://doi.org/10.4137/DTI.S13870","url":null,"abstract":"<p><p>Agomelatine, a novel antidepressant with established clinical efficacy, acts as an agonist of melatonergic MT1 and MT2 receptors and as an antagonist of 5-HT2C receptors. The present study was undertaken to investigate whether chronic treatment with agomelatine would block unpredictable chronic mild stress (UCMS)-induced cognitive deterioration in mice in passive avoidance (PA), modified elevated plus maze (mEPM), novel object recognition (NOR), and Morris water maze (MWM) tests. Moreover, the effects of stress and agomelatine on brain-derived neurotrophic factor (BDNF) and cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) messenger ribonucleic acid (mRNA) levels in the hippocampus was also determined using quantitative real-time polymerase chain reaction (RT-PCR). Male inbred BALB/c mice were treated with agomelatine (10 mg/kg, i.p.), melatonin (10 mg/kg), or vehicle daily for five weeks. The results of this study revealed that UCMS-exposed animals exhibited memory deterioration in the PA, mEPM, NOR, and MWM tests. The chronic administration of melatonin had a positive effect in the PA and +mEPM tests, whereas agomelatine had a partial effect. Both agomelatine and melatonin blocked stress-induced impairment in visual memory in the NOR test and reversed spatial learning and memory impairment in the stressed group in the MWM test. Quantitative RT-PCR revealed that CREB and BDNF gene expression levels were downregulated in UCMS-exposed mice, and these alterations were reversed by chronic agomelatine or melatonin treatment. Thus, agomelatine plays an important role in blocking stress-induced hippocampal memory deterioration and activates molecular mechanisms of memory storage in response to a learning experience. </p>","PeriodicalId":11326,"journal":{"name":"Drug Target Insights","volume":"8 ","pages":"11-21"},"PeriodicalIF":2.7,"publicationDate":"2014-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4137/DTI.S13870","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32181751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Silico Molecular Characterization of Cysteine Protease YopT from Yersinia pestis by Homology Modeling and Binding Site Identification.","authors":"Md Anayet Hasan,&nbsp;S M Alauddin,&nbsp;Mohammad Al Amin,&nbsp;Suza Mohammad Nur,&nbsp;Adnan Mannan","doi":"10.4137/DTI.S13529","DOIUrl":"https://doi.org/10.4137/DTI.S13529","url":null,"abstract":"<p><p>Plague is a major health concern and Yersinia pestis plays the central causal role in this disease. Yersinia pestis has developed resistance against the commonly available drugs. So, it is now a key concern to find a new drug target. Cysteine protease YopT enzyme is an important factor used by Yersinia pestis for pathogenesis in its host and it has the anti-phagocytic function of removal of C-termini lipid modification. The 3D structure of cysteine protease YopT of Yersinia pestis was determined by means of homology modeling through multiple alignments followed by intensive optimization and validation. The modeling was done by Phyre 2 and refined by ModRefiner. The obtained model was verified with structure validation programs such as PROCHECK, verify 3D and ERRAT for reliability. Interacting partners and active sites were also determined. PROCHECK analysis showed that 93% of the residues are in the most favored region, 5.9% are in the additional allowed region and 1.1% are in the generously allowed region of the Ramachandran plot. The verify 3D value of 0.78 indicates that the environmental profile of the model is good. SOPMA is employed for calculation of the secondary structural features of cysteine protease YopT. Active site determination through CASTp proposes that this protein can be utilized as a potential drug target. However, these findings should further be confirmed by wet lab studies for a targeted therapeutic agent design against Yersinia pestis. </p>","PeriodicalId":11326,"journal":{"name":"Drug Target Insights","volume":"8 ","pages":"1-9"},"PeriodicalIF":2.7,"publicationDate":"2014-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4137/DTI.S13529","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32117668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microscopic colitis and reproductive factors related to exposure to estrogens and progesterone.","authors":"Bodil Roth,&nbsp;Jonas Manjer,&nbsp;Bodil Ohlsson","doi":"10.4137/DTI.S12889","DOIUrl":"https://doi.org/10.4137/DTI.S12889","url":null,"abstract":"<p><p>Microscopic colitis (MC) often debuts around or after menopause and is divided into lymphocytic- and collagenous colitis. The aim of this study was to examine whether factors influencing sex hormone levels differed between subgroups of MC as well as between patients and controls. A self-administered questionnaire about parity was completed which included questions surrounding age at first childbirth, menarche and menopause, the use of oral contraceptives, and hormonal replacement therapy. Patients with lymphocytic colitis had children less often compared to those with collagenous colitis (OR = 0.20, 95% CI = 0.05-0.86), however no differences were observed between patients with persistent or transient disease. Patients were less often older than 15 years of age at menarche (OR = 0.48, 95% CI = 0.26-0.91) and were younger at menopause (OR = 0.30, 95% CI = 0.16-0.56) compared with controls. Thus, no obvious association between factors influencing sex hormone levels and presence of MC could be found. </p>","PeriodicalId":11326,"journal":{"name":"Drug Target Insights","volume":"7 ","pages":"53-62"},"PeriodicalIF":2.7,"publicationDate":"2013-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4137/DTI.S12889","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31817729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hsp60 chaperonin acts as barrier to pharmacologically induced oxidative stress mediated apoptosis in tumor cells with differential stress response.","authors":"Upasana Sarangi,&nbsp;Manish Kumar Singh,&nbsp;Kanugovi Vijaya Vittal Abhijnya,&nbsp;Lebaka Prasanna Anjaneya Reddy,&nbsp;Badabagni Siva Prasad,&nbsp;Vikrant Vinay Pitke,&nbsp;Khanderao Paithankar,&nbsp;Amere Subbarao Sreedhar","doi":"10.4137/DTI.S12513","DOIUrl":"https://doi.org/10.4137/DTI.S12513","url":null,"abstract":"<p><p>Mitochondrial functions play a central role in energy metabolism and provide survival fitness to both normal and tumor cells. Mitochondrial chaperonin Hsp60 is involved in both pro- and anti-apoptotic functions, but how Hsp60 senses the mitochondria selective oxidative stress response is unknown. In this study, by using rotenone, an irreversible inhibitor of oxidative phosphorylation against IMR-32 and BC-8 tumor cells containing differential heat shock transcriptional machinery, we studied whether the oxidative stress response is related to Hsp60. The accelerated cytotoxicity in response to rotenone has been correlated with enhanced production of O2 (•-), H2O2, reactive oxygen species, and Hsp60 translocation from the mitochondria to the cytoplasm. The inability of cells to resist oxidative stress mediated Hsp60 translocation appeared to depend on mitochondrial oxyradical scavenging system and Bax translocation. A delayed oxidative stress response in hsp60 shRNA-treated cells was found to be due to increased mitochondrial translocation of Hsp60 on shRNA pre-sensitization. Overexpression of Hsp60 failed to protect cells from oxidative stress due to a lack of its mitochondrial retention upon post-rotenone treatment. These results also revealed that Hsp60 mitochondrial localization is indispensable for decreasing O2 (•-) levels, but not H2O2 and ROS levels. However, cycloheximide treatment alone induced Hsp60 translocation, while rotenone combination delayed this translocation. In contrast to oxidative stress, MG132 and 17AAG treatments showed mitochondrial retention of Hsp60; however, MG132 combination either with hsp60 shRNA or 17AAG induced its translocation. Additionally, overexpression of Huntingtin gene also resulted in Hsp60 mitochondrial accumulation. We suggest that Hsp60 may act as a barrier to pharmacological targeting of mitochondria. </p>","PeriodicalId":11326,"journal":{"name":"Drug Target Insights","volume":"7 ","pages":"35-51"},"PeriodicalIF":2.7,"publicationDate":"2013-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4137/DTI.S12513","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31725348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"P-glycoprotein Inhibition for Optimal Drug Delivery.","authors":"Md Lutful Amin","doi":"10.4137/DTI.S12519","DOIUrl":"https://doi.org/10.4137/DTI.S12519","url":null,"abstract":"<p><p>P-glycoprotein (P-gp), an efflux membrane transporter, is widely distributed throughout the body and is responsible for limiting cellular uptake and the distribution of xenobiotics and toxic substances. Hundreds of structurally diverse therapeutic agents are substrates to it and it impedes the absorption, permeability, and retention of the drugs, extruding them out of the cells. It is overexpressed in cancer cells and accountable for obstructing cell internalization of chemotherapeutic agents and for developing transporter mediated resistance by cancer cells during anti-tumor treatments. As it jeopardizes the success of drug delivery and cancer targeting, strategies are being developed to overcome P-gp mediated drug transport. This concise review represents a brief discussion on P-gp mediated drug transport and how it hinders the success of various therapies. Its main focus is on various strategies used to tackle this curb in the field of drug delivery and targeting. </p>","PeriodicalId":11326,"journal":{"name":"Drug Target Insights","volume":"7 ","pages":"27-34"},"PeriodicalIF":2.7,"publicationDate":"2013-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4137/DTI.S12519","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31722089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microscopic Colitis is Associated with Several Concomitant Diseases.","authors":"Bodil Roth,&nbsp;Jonas Manjer,&nbsp;Bodil Ohlsson","doi":"10.4137/DTI.S12109","DOIUrl":"https://doi.org/10.4137/DTI.S12109","url":null,"abstract":"<p><p>Microscopic colitis (MC) is a disease with intestinal mucosal inflammation causing diarrhea, affecting predominantly middle-aged women. The etiology is unknown, but increased prevalence of autoimmune diseases in these patients has been described, although not compared with controls or adjusted for confounding factors. The aim of this study was to examine the prevalence of common diseases in patients with MC and controls from the general population. Hypertension, rheumatoid arthritis, asthma or bronchitis, ischemia, and diabetes mellitus were more prevalent in patients than in controls. The prevalence of gastric ulcer and cancer did not differ between the groups. Besides corticosteroids, many patients were also being treated with proton pump inhibitors, antidepressant drugs, angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists, statins, thyroid hormones, and beta-blockers. More patients than controls were former or current smokers (72.5% versus 57.7%). Thus, MC patients have an increased prevalence of several diseases, not only of autoimmune origin. </p>","PeriodicalId":11326,"journal":{"name":"Drug Target Insights","volume":"7 ","pages":"19-25"},"PeriodicalIF":2.7,"publicationDate":"2013-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4137/DTI.S12109","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31705685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of hepatocyte growth factor on skeletal myoblast transplantation late after myocardial infarction.","authors":"Stacy B O'Blenes,&nbsp;Audrey W Li,&nbsp;Chris Bowen,&nbsp;Drew Debay,&nbsp;Mohammed Althobaiti,&nbsp;James Clarke","doi":"10.4137/DTI.S11802","DOIUrl":"https://doi.org/10.4137/DTI.S11802","url":null,"abstract":"<p><p>In clinical studies, skeletal myoblast (SKMB) transplantation late after myocardial infarction (MI) has minimal impact on left ventricular (LV) function. This may be related to our previous observation that the extent of SKMB engraftment is minimal in chronic MI when compared to acute MI, which correlates with decreased hepatocyte growth factor (HGF) expression, an important regulator of SKMB function. Here, we investigated delivery of exogenous HGF as a strategy for augmenting SKMB engraftment late after MI. Rats underwent SKMB transplantation 4 weeks after coronary ligation. HGF or vehicle control was delivered intravenously during the subsequent 2 weeks. LV function was assessed by MRI before and 2 weeks after SKMB transplantation. We evaluated HGF delivery, SKMB engraftment, and expression of genes associated with post-MI remodeling. Serum HGF was 6.2 ± 2.4 ng/mL after 2 weeks of HGF infusion (n = 7), but undetectable in controls (n = 7). LV end-diastolic volume and ejection fraction did not improve with HGF treatment (321 ± 27 mm(3), 42% ± 2% vs. 285 ± 33 mm(3), 43% ± 2%, HGF vs. control). MIs were larger in HGF-treated animals (50 ± 7 vs. 30 ± 6 mm(3), P = 0.046), but the volume of engrafted SKMBs or percentage of MIs occupied by SKMBs did not increase with HGF (1.7 ± 0.3 mm(3), 4.7% ± 1.9% vs. 1.4 ± 0.4 mm(3), 5.3% ± 1.6%, HGF vs. control). Expression of genes associated with post-infarction remodeling was not altered by HGF. Delivery of exogenous HGF failed to augment SKMB engraftment and functional recovery in chronic MI. Expression of genes associated with LV remodeling was not altered by HGF. Alternative strategies to enhance engraftment of SKMB must be explored to optimize the clinical efficacy of SKMB transplantation.</p>","PeriodicalId":11326,"journal":{"name":"Drug Target Insights","volume":"7 ","pages":"9-17"},"PeriodicalIF":2.7,"publicationDate":"2013-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4137/DTI.S11802","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31450188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antibodies against gonadotropin-releasing hormone in patients with posterior laryngitis.","authors":"Hillevi Pendleton,&nbsp;Ragnar Alm,&nbsp;Gunilla Nordin Fredrikson,&nbsp;Bodil Ohlsson","doi":"10.4137/DTI.S10837","DOIUrl":"https://doi.org/10.4137/DTI.S10837","url":null,"abstract":"<p><p>Patients with functional gastrointestinal disorders express antibodies against gonadotropin-releasing hormone (GnRH) in serum. One common cause of posterior laryngitis (PL) is extra-esophageal reflux, but a functional etiology has also been suggested. The aim of this study was to scrutinize patients with PL with regard to the presence of GnRH antibodies and to examine the association between antibodies and symptoms and reflux. Consecutive PL patients were included after examination. Serum was analyzed for the presence of antibodies using an enzyme-linked immunosorbent assay (ELISA) method and expressed as relative units (RU). Two age- and gender-matched healthy subjects per case served as controls. The prevalence of IgM GnRH antibodies in patients was 35% compared with 28% in controls (P = 0.06), with higher levels in patients (0.8 (0.3-2.2) RU) than in controls (0.2 (0.1-0.6) RU) (P = 0.007). The corresponding IgG antibody prevalences were 43% and 4%, respectively (P = 0.001), with no difference in levels (P = 0.70). There was no association between antibodies and clinical findings.</p>","PeriodicalId":11326,"journal":{"name":"Drug Target Insights","volume":"7 ","pages":"1-8"},"PeriodicalIF":2.7,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4137/DTI.S10837","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31229985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug Target Exploitable Structural Features of Adenylyl Cyclase Activity in Schistosoma mansoni.","authors":"Andreas N Mbah,&nbsp;Henri L Kamga,&nbsp;Omotayo R Awofolu,&nbsp;Raphael D Isokpehi","doi":"10.4137/DTI.S10219","DOIUrl":"https://doi.org/10.4137/DTI.S10219","url":null,"abstract":"<p><p>The draft genome sequence of the parasitic flatworm Schistosoma mansoni (S. mansoni), a cause of schistosomiasis, encodes a predicted guanosine triphosphate (GTP) binding protein tagged Smp_059340.1. Smp_059340.1 is predicted to be a member of the G protein alpha-s subunit responsible for regulating adenylyl cyclase activity in S. mansoni and a possible drug target against the parasite. Our structural bioinformatics analyses identified key amino acid residues (Ser53, Thr188, Asp207 and Gly210) in the two molecular switches responsible for cycling the protein between active (GTP bound) and inactive (GDP bound) states. Residue Thr188 is located on Switch I region while Gly210 is located on Switch II region with Switch II longer than Switch I. The Asp207 is located on the G3 box motif and Ser53 is the binding residue for magnesium ion. These findings offer new insights into the dynamic and functional determinants of the Smp_059340.1 protein in regulating the S. mansoni life cycle. The binding interfaces and their residues could be used as starting points for selective modulations of interactions within the pathway using small molecules, peptides or mutagenesis.</p>","PeriodicalId":11326,"journal":{"name":"Drug Target Insights","volume":"6 ","pages":"41-58"},"PeriodicalIF":2.7,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4137/DTI.S10219","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31033666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}