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Potential Therapeutic Approach (potential + therapeutic_approach)
Selected AbstractsModulation of angiogenesis is effective in a model of rheumatoid arthritisJOURNAL OF ANATOMY, Issue 5 2002A. O. Afuwape A feature of rheumatoid arthritis (RA) is prominent hyperplasia of the synovium, which results in an increased distance between the invasive pannus and the existing synovial vasculature. Concomitantly the hyperplastic tissue imposes an augmented metabolic demand on the pre-existing vasculature. As a consequence the synovium in RA becomes hypoxic, resulting in an increased rate of formation of new blood vessels, to supply nutrients and oxygen. Targeting the vasculature in RA is a potential therapeutic approach in RA. VEGF, a key vascular permeability and angiogenic factor, is expressed in RA. In this study we utilised adenovirus expressing the secreted form of the extracellular domain of the Flt-1 VEGF receptor (sFlt-1) to inhibit VEGF in the collagen-induced arthritis (CIA) model, to determine whether blocking the effects of vegf might be an effective treatment for RA. AdvsFlt-1, administered intravenously on the first day of arthritis, significantly suppressed CIA. For example, on d 6 of arthritis the mean increase in paw thickness, which reflects oedema, for untreated and null adenovirus-treated animals was 0.23 ± 0.05 mm and 0.38 ± 0.08, respectively, compared to 0.07 ± 0.05 for AdvsFlt-1-treated mice (P < 0.001 vs. Adv0-treated and untreated mice by 2-way anova). Western blot analyses revealed the presence of a 100-kDa band, corresponding to human sFlt-1, in liver extracts from arthritic mice infected with AdvsFlt-1 at 24 h but not 72 h after infection. This band was absent in liver extracts from Adv0-infected mice and all synovial extracts. Measurement of protein levels by ELISA demonstrated the presence of sFlt-1 in liver, synovium and serum, although levels declined by 72 h post infection. These data suggest efficient but transient expression of sFlt-1. Sera from adenovirus infected mice were found to contain antiviral antibodies and additionally, sera from AdvsFlt-1-infected but not Adv0-infected mice recognised human recombinant sFlt-1. These observations demonstrate that adenoviral mediated delivery of human sFlt-1 leads to transient gene expression and suppression of CIA. This effect is reduced later in the course of disease due to the expression of antiadenovirus as well as antisFlt-1 antibodies. Future studies will assess the effect of combination treatment, using AdvsFlt-1 together with anti-TNF(antibody, to prolong the beneficial effects of VEGF blockade. These results suggest that blocking the pro-angiogenic and permeability action of VEGF may be beneficial for treatment of RA. [source] Inhibition of west nile virus replication by retrovirus-delivered small interfering RNA in human neuroblastoma cellsJOURNAL OF MEDICAL VIROLOGY, Issue 5 2008Yongbo Yang Abstract West Nile virus (WNV) has been responsible for the largest outbreaks of arboviral encephalitis in U.S. history. No specific drug is currently available for the effective treatment of WNV infection. To exploit RNA interference as a potential therapeutic approach, a Moloney murine leukemia virus-based retrovirus vector was used to effectively deliver WNV-specific small interfering RNA (siRNA) into human neuroblastoma HTB-11 cells. Viral plaque assays demonstrated that transduced cells were significantly refractory to WNV replication, as compared to untransduced control cells (P,<,0.05), which correlated with the reduced expression of target viral genes and respective viral proteins. Therefore, retrovirus-mediated delivery of siRNA for gene silencing can be used to study the specific functions of viral genes associated with replication and may have potential therapeutic applications. J. Med. Virol. 80:930,936, 2008. © 2008 Wiley-Liss, Inc. [source] Reversing interleukin-2 inhibition mediated by anti,double-stranded DNA autoantibody ameliorates glomerulonephritis in MRL- lpr/lpr miceARTHRITIS & RHEUMATISM, Issue 8 2010Ying-Chyi Song Objective Our previous study demonstrated that anti,double-stranded DNA (anti-dsDNA) antibodies involved in lupus nephritis down-regulate the production of interleukin-2 (IL-2) in T cells, which in turn, contributes to the defective production of cytotoxic cells and to activation-induced cell death in vitro. To reveal novel molecular targets for lupus therapy, the molecular mechanisms of IL-2 down-regulation by anti-dsDNA were studied. Methods Anti-dsDNA monoclonal antibody (mAb) 9D7 was used to study the molecular mechanisms of IL-2 production in vitro. Treatment with arginine-rich peptide, a penetration inhibitor, was used to verify the effect of internalization of anti-dsDNA on the production of IL-2. The signaling pathway for IL-2 expression induced by anti-dsDNA was analyzed by using kinase inhibitors. The therapeutic effects of these inhibitors were evaluated in MRL- lpr/lpr mice. Results Inhibition of IL-2 production in activated Jurkat cells and human T cells pretreated with mAb 9D7 was reversed by treatment with the arginine-rich peptide. Levels of pAkt and phosphorylated glycogen synthase kinase 3 (pGSK-3) were reduced in activated Jurkat cells that had been pretreated with mAb 9D7. The inhibition of IL-2 production by mAb 9D7 was counteracted by pretreating the cells with LiCl (a GSK-3 inhibitor). However, IL-2 reduction was not recovered in the cells pretreated with ERK and JNK inhibitors. Furthermore, MRL- lpr/lpr mice injected with LiCl or with arginine-rich peptide restored the IL-2 production and reduced the manifestations of lupus. Conclusion These findings suggest that penetration of T cells by anti-dsDNA may inhibit IL-2 production by activating GSK-3. Moreover, blocking GSK-3 activation as well as inhibiting anti-dsDNA penetration is a potential therapeutic approach for lupus. [source] Aggregation characteristics of ovalbumin in ,-sheet conformation determined by spectroscopyBIOPOLYMERS, Issue 2 2002Raimon Sabaté Abstract Protein misfolding and aggregation are involved in a number of the so-called "conformational" diseases (e.g., transmissible spongiform encephalopathies and Alzheimer disease). The development of rational strategies to interfere with aggregation is a potential therapeutic approach that requires complete knowledge of the aggregation process. We studied the aggregation of ovalbumin in ,-sheet conformation using mainly the spectral changes in the spectra of two dyes (Congo Red and pinacyanol) caused by the aggregates. We assumed a linear model of polymerization that fit to the experimental data. The critical aggregation constant, concentration of half-aggregation, nucleation parameter, growth parameter, and number of aggregation and free energy changes (total and per residue) were determined as aggregation-related parameters. ,-Ovalbumin aggregates in a cooperative way. Moreover, the differences between such parameters obtained with Congo Red and pinacyanol suggest that each dye interacts with the protein in its own way. © 2002 John Wiley & Sons, Inc. Biopolymers (Biospectroscopy) 67: 113,120, 2002 [source] Killing tumor cells through their surface ,2 -microglobulin or major histocompatibility complex class I moleculesCANCER, Issue 7 2010Jing Yang PhD Abstract Targeted antibody-based therapy has been used successfully to treat cancers. Recent studies have demonstrated that tumor cells treated with antibodies specific for ,2 -microglobulin (,2M) or major histocompatibility complex (MHC) class I molecules undergo apoptosis in vitro and in vivo (mouse models). Antibodies against ,2M or MHC class I induce tumor cell apoptosis by 1) recruiting MHC class I molecules to lipid rafts and activating LYN kinase and the signal-transducing enzyme phospholipase C-,2-dependent c-Jun N-terminal kinase signaling pathway and 2) expelling interleukin 6 and insulin-like growth factor 1 receptors out of lipid rafts and inhibiting the growth and survival factor-induced activation of the phosphatidylinositol 3-kinase/Akt and extracellular signal-related kinase pathways. Consequently, mitochondrial integrity is compromised, and the caspase-9-dependent cascade is activated in treated tumor cells. However, although ,2M and MHC class I are expressed on normal hematopoietic cells, which is a potential safety concern, the monoclonal antibodies were selective to tumor cells and did not damage normal cells in vitro or in human-like mouse models. These findings suggest that targeting ,2M or MHC class I by using antibodies or other agents offers a potential therapeutic approach for ,2M/MHC class I-expressing malignancies. Cancer 2010. © 2010 American Cancer Society. [source] HIGH GLUCOSE-INDUCED HUMAN UMBILICAL VEIN ENDOTHELIAL CELL HYPERPERMEABILITY IS DEPENDENT ON PROTEIN KINASE C ACTIVATION AND INDEPENDENT OF THE Ca2+,NITRIC OXIDE SIGNALLING PATHWAYCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 9 2005Lei Dang SUMMARY 1.,Endothelial barrier dysfunction plays a pivotal role in the pathogenesis of diabetic vascular complications. The precise molecular mechanisms by which hyperglycaemia causes the increased permeability in endothelial cells are not yet well understood. In the present study, we investigated whether high concentrations of glucose induce endothelial permeability through the activation of protein kinase C (PKC) and/or the calcium,nitric oxide (NO) signalling pathway in human umbilical vein endothelial cells (HUVEC). 2.,Endothelial permeability was measured by albumin diffusion across endothelial monolayers under the stimuli of high glucose (HG; 20 mmol/L), 100 nmol/L phorbol-myristate-acetate (PMA) or 100 nmol/L histamine. The intracellular calcium concentration ([Ca2+]i) was detected in HUVEC using the fluorescent probe fura-2 AM. The effects of PKC inhibitors (LY379196 and hypocrellin A) and the NO synthase (NOS) inhibitor NG -monomethyl- l -arginine (l -NMMA) on endothelial permeability and [Ca2+]i were determined. 3.,High glucose and PMA increased endothelial permeability associated with decreased [Ca2+]i, whereas histamine triggered significant increases in endothelial permeability, accompanied by increases in [Ca2+]i in HUVEC. Hypocrellin A (HA) and LY379196 reversed both HG- and histamine-induced endothelial permeability. The NOS inhibitor l -NMMA only abolished histamine- and not HG-induced endothelial permeability. Neither LY379196, HA nor l -NMMA had any significant effects on alterations in [Ca2+]i caused by HG and histamine. 4.,These results indicate that increased endothelial permeability in HUVEC induced by HG is dependent on PKC activity and is independent of the [Ca2+]i,NO pathway. Increased endothelial permeability due to other inflammatory factors, such as histamine, may also be mediated by the PKC pathway. Thus, PKC inhibitors would be a potential therapeutic approach to endothelial dysfunction induced by hyperglycaemia, as well as other inflammatory factors, in diabetes. [source] Duchenne's muscular dystrophy: animal models used to investigate pathogenesis and develop therapeutic strategiesINTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 4 2003C.A. Collins Summary., Duchenne's muscular dystrophy (DMD) is a lethal childhood disease caused by mutations of the dystrophin gene, the protein product of which, dystrophin, has a vital role in maintaining muscle structure and function. Homologues of DMD have been identified in several animals including dogs, cats, mice, fish and invertebrates. The most notable of these are the extensively studied mdx mouse, a genetic and biochemical model of the human disease, and the muscular dystrophic Golden Retriever dog, which is the nearest pathological counterpart of DMD. These models have been used to explore potential therapeutic approaches along a number of avenues including gene replacement and cell transplantation strategies. High-throughput screening of pharmacological and genetic therapies could potentially be carried out in recently available smaller models such as zebrafish and Caenorhabditis elegans. It is possible that a successful treatment will eventually be identified through the integration of studies in multiple species differentially suited to addressing particular questions. [source] Molecular basis for the antiandrogen withdrawal syndromeJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2004Hiroshi Miyamoto Abstract In patients with prostate cancer who manifest disease progression during combined androgen blockade therapy, discontinuation of antiandrogen treatment might result in prostate-specific antigen decline, often associated with clinical improvement. The response called antiandrogen withdrawal syndrome is thus acknowledged as a general phenomenon. However, molecular mechanisms responsible for this syndrome are not completely understood. This article outlines the proposed mechanisms, including alterations of androgen receptor gene and its coregulatory proteins and activation of the signal transduction pathway, and the potential therapeutic approaches based on the specific mechanisms. © 2003 Wiley-Liss, Inc. [source] Oxidative stress: A cause and therapeutic target of diabetic complicationsJOURNAL OF DIABETES INVESTIGATION, Issue 3 2010Eiichi Araki Abstract Oxidative stress is defined as excessive production of reactive oxygen species (ROS) in the presence of diminished anti-oxidant substances. Increased oxidative stress could be one of the common pathogenic factors of diabetic complications. However, the mechanisms by which hyperglycemia increases oxidative stress are not fully understood. In this review, we focus on the impact of mitochondrial derived ROS (mtROS) on diabetic complications and suggest potential therapeutic approaches to suppress mtROS. It has been shown that hyperglycemia increases ROS production from mitochondrial electron transport chain and normalizing mitochondrial ROS ameliorates major pathways of hyperglycemic damage, such as activation of polyol pathway, activation of PKC and accumulation of advanced glycation end-products (AGE). Additionally, in subjects with type 2 diabetes, we found a positive correlation between HbA1c and urinary excretion of 8-hydroxydeoxyguanosine (8-OHdG), which reflects mitochondrial oxidative damage, and further reported that 8-OHdG was elevated in subjects with diabetic micro- and macro- vascular complications. We recently created vascular endothelial cell-specific manganese superoxide dismutase (MnSOD) transgenic mice, and clarified that overexpression of MnSOD in endothelium could prevent diabetic retinopathy in vivo. Furthermore, we found that metformin and pioglitazone, both of which have the ability to reduce diabetic vascular complications, could ameliorate hyperglycemia-induced mtROS production by the induction of PPAR, coactivator-1, (PGC-1,) and MnSOD and/or activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK). We also found that metformin and pioglitazone promote mitochondrial biogenesis through the same AMPK,PGC-1, pathway. Taking these results, mtROS could be the key initiator of and a therapeutic target for diabetic vascular complications. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00013.x, 2010) [source] Neuropharmacology of addiction,setting the sceneBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2008A J Lawrence Addiction is a complex disorder, affecting not only the individual addict, but also their family and the community at large. While therapeutic strategies are available for the treatment of some forms of substance abuse/dependence, these are not without problems and are not universally efficacious. Moreover, in some instances (for example, cocaine addiction), there are still no medications specifically registered as treatment options. In this themed issue of the British Journal of Pharmacology, we highlight a number of addictions from a pharmacological perspective, with an emphasis on both mechanism and potential therapeutic approaches that are either under development or reflect preclinical work. As such, the authors endeavour to describe the latest thinking on the neural theory of addiction and corresponding novel pharmacotherapeutic targets, and in this way to set the stage for future advances in research and drug development. In addition, we have also attempted to draw attention to the clinicians' perspective in terms of the interface between basic science and care provision. British Journal of Pharmacology (2008) 154, 259,260; doi: 10.1038/bjp.2008.131; published online 14 April 2008 [source] Survival outcomes for clonal evolution in chronic myeloid leukemia patients on second generation tyrosine kinase inhibitor therapy,CANCER, Issue 11 2010Dushyant Verma MD Abstract BACKGROUND: Clonal evolution is frequently detected in patients developing resistance to imatinib. The outcome of patients with clonal evolution treated with second generation tyrosine kinase inhibitors is not known. METHODS: The authors analyzed the outcome of 177 CML patients after second tyrosine kinase inhibitor therapy. RESULTS: Ninety-five patients were in chronic phase, 30 had clonal evolution, 28 were in accelerated phase (AP), and 24 were in AP plus clonal evolution. Major cytogenetic response rates were 58%, 54%, 28%, and 13%; 2-year overall survival (OS) rates were 86%, 73%, 68%, and 33%; and 2-year event-free survival (EFS) rates were 69%, 67%, 31%, and 8%, respectively. The hematologic and cytogenetic response rates, OS, and EFS were no different between patients in chronic phase with clonal evolution and patients with chronic phase and no clonal evolution. However, clonal evolution had a significant adverse impact when associated with other features of AP. On multivariate analysis, clonal evolution had no independently significant effect on achieving major cytogenetic response on the second generation tyrosine kinase inhibitors. The factors predicting increasing major cytogenetic response to second generation tyrosine kinase inhibitors were prior achievement of major cytogenetic response with imatinib, higher hemoglobin levels, no splenomegaly, lower percentage of Philadelphia chromosome-positive metaphases, and no prior chemotherapy. CONCLUSIONS: Clonal evolution constitutes a heterogeneous entity with variable outcome with second generation tyrosine kinase inhibitors, with trisomy 8, chromosome 17, and complex abnormalities having the worst outcome, regardless of the number of metaphases involved. The molecular events behind these abnormalities and potential therapeutic approaches directed at them need to be defined. Cancer 2010. © 2010 American Cancer Society. [source] | |||||||||||||