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Potential Therapeutic Agents (potential + therapeutic_agent)
Selected AbstractsDiscovery and Potency Optimization of 2-Amino-5-arylmethyl-1,3-thiazole Derivatives as Potential Therapeutic Agents for Prostate CancerARCHIV DER PHARMAZIE, Issue 7 2009Mikhail Krasavin Abstract A new chemical series was identified via high-throughput screening as having antiproliferative activity on DU-145 human prostate carcinoma cell line (hit compound potency , 2.9 ,M). Medicinal chemistry optimization of two peripheral diversity vectors of the hit molecule, independently, led to SAR generalizations and identification of the ,best' moieties. The latter were merged in a single compound that exhibited an over 100-fold better potency than the hit compound. For the most potent compounds it was confirmed that the observed antiproliferative potency was not associated with the compounds' non-specific cytotoxicity. [source] ChemInform Abstract: Discovery and Potency Optimization of 2-Amino-5-arylmethyl-1,3-thiazole Derivatives as Potential Therapeutic Agents for Prostate Cancer.CHEMINFORM, Issue 45 2009Mikhail Krasavin Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] Oligonucleotide N3,,P5, Phosphoramidates and Thio -Phoshoramidates as Potential Therapeutic AgentsCHEMISTRY & BIODIVERSITY, Issue 3 2010Sergei Abstract Nucleic acids analogues, i.e., oligonucleotide N3,,P5, phosphoramidates and N3,,P5, thio -phosphoramidates, containing 3,-amino-3,-deoxy nucleosides with various 2,-substituents were synthesized and extensively studied. These compounds resist nuclease hydrolysis and form stable duplexes with complementary native phosphodiester DNA and, particularly, RNA strands. An increase in duplexes' melting temperature, ,Tm, relative to their phosphodiester counterparts, reaches 2.2,4.0° per modified nucleoside. 2,-OH- (RNA-like), 2,- O -Me-, and 2,- ribo -F-nucleoside substitutions result in the highest degree of duplex stabilization. Moreover, under close to physiological salt and pH conditions, the 2,-deoxy- and 2,-fluoro-phosphoramidate compounds form extremely stable triple-stranded complexes with either single- or double-stranded phosphodiester DNA oligonucleotides. Melting temperature, Tm, of these triplexes exceeds Tm values for the isosequential phosphodiester counterparts by up to 35°. 2,-Deoxy-N3,,P5, phosphoramidates adopt RNA-like C3,- endo or N -type nucleoside sugar-ring conformations and hence can be used as stable RNA mimetics. Duplexes formed by 2,-deoxy phosphoramidates with complementary RNA strands are not substrates for RNase H-mediated cleavage in vitro. Oligonucleotide phosphoramidates and especially thio -phosphoramidates conjugated with lipid groups are cell-permeable and demonstrate high biological target specific activity in vitro. In vivo, these compounds show good bioavailability and efficient biodistribution to all major organs, while exerting acceptable toxicity at therapeutically relevant doses. Short oligonucleotide N3,,P5, thio -phosphoramidate conjugated to 5,-palmitoyl group, designated as GRN163L (Imetelstat), was recently introduced as a potent human telomerase inhibitor. GRN163L is not an antisense agent; it is a direct competitive inhibitor of human telomerase, which directly binds to the active site of the enzyme and thus inhibits its activity. This compound is currently in multiple Phase-I and Phase-I/II clinical trials as potential broad-spectrum anticancer agent. [source] Melittin prevents liver cancer cell metastasis through inhibition of the Rac1-dependent pathway,HEPATOLOGY, Issue 6 2008Shujing Liu Melittin, a water-soluble toxic peptide derived from bee venom of Apis mellifera was reported to have inhibitory effects on hepatocellular carcinoma (HCC). However, its role in antimetastasis and the underlying mechanism remains elusive. By utilizing both HCC cell lines and an animal model based assay system, we found that Rac1, which has been shown to be involved in cancer cell metastasis, is highly expressed in aggressive HCC cell lines and its activity correlated with cell motility and cytoskeleton polymerization. In addition, Rac1-dependent activity and metastatic potential of aggressive HCC cells are remarkably high in both cellular and nude mouse models. We provide evidence here that melittin inhibits the viability and motility of HCC cells in vitro, which correlates with its suppression of Rac1-dependent activity, cell motility, and microfilament depolymerization. Furthermore, melittin suppresses both HCC metastasis and Rac1-dependent activity in nude mouse models. The specificity of the effect of melittin on Rac1 was confirmed in HCC cells both in vitro and in vivo. Conclusion: Melittin inhibits tumor cell metastasis by reducing cell motility and migration via the suppression of Rac1-dependent pathway, suggesting that melittin is a potential therapeutic agent for HCC. (HEPATOLOGY 2008;47:1964,1973.) [source] Melatonin as a potential therapeutic agent in psychiatric illnessHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 5 2009Maria D. Maldonado Abstract The aim of this review was to summarize the potential use of melatonin in the treatment of mental disorders, specifically bipolar disorders, depression, and schizophrenia. To date, melatonin has been most commonly used in psychiatry because of its hypnotic, rhythm resynchronizing, and antioxidant actions. Here, we examine other properties of the melatonin including its anti-inflammatory, antinociceptive, anxiolytic, and drug detoxification actions as well as its protective effects against neural loss. The brain is an intricate sensory and motor organ which receives information from both the external and internal environments. It transduces information into complex chemical and electrical signals which are transmitted throughout the central nervous system (CNS) and the organism. The pathogenesis of mental disorders remains ambiguous and neuroinflammation has been proposed as a causative agent. We consider the potential contributions of melatonin as therapeutic agent in CNS and during neuroinflammation in mental disorders. Copyright © 2009 John Wiley & Sons, Ltd. [source] Novel indoloquinoline derivative, IQDMA, inhibits STAT5 signaling associated with apoptosis in K562 cellsJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 6 2008Sheng-Huei Yang Abstract N,-(11H-indolo[3,2-c]quinolin-6-yl)- N,N -dimethylethane-1,2-diamine (IQDMA), an indoloquinoline derivative, synthesized in our laboratory, has been demonstrated to be an effective antitumor agent in human leukemia cells. In the present study, treatment with IQDMA inhibited phosphorylation of epidermal growth factor receptor (EGFR), Src, Bcr-Abl, and Janus-activated kinase (JAK2) in a time-dependent manner. IQDMA also degraded JAK2 protein. Moreover, signal transducer and activator of transcription 5 (STAT5) signaling were also blocked by IQDMA. However, IQDMA did not inhibit other oncogenic and tumor survival pathways such as those mediated by Akt and extracellular signal-regulated kinase 1/2. Furthermore, IQDMA upregulated the expression of p21 and p27 and downregulated the expression of cyclin D1, myeloid cell leukemia-1(Mcl-1), Bcl-XL, and vascular endothelial growth factor (VEGF). Taken together, these results indicate that IQDMA causes significant induction of apoptosis in K562 cells via downregulation of EGFR, Src, Bcr-Abl, JAK2, and STAT5 signaling and modulation of p21, p27, cyclin D1, Mcl-1, Bcl-XL, and VEGF proteins. Thus, IQDMA appears to be a potential therapeutic agent for treating leukemia K562 cells. © 2008 Wiley Periodicals, Inc. J Biochem Mol Toxicol 22:396,404, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20254 [source] Protective effects of baicalin on ligature-induced periodontitis in ratsJOURNAL OF PERIODONTAL RESEARCH, Issue 1 2008X. Cai Background and Objective:, Baicalin is a flavonoid compound purified from the medicinal plant, Scutellaria baicalensis Georgi, and has been reported to possess anti-inflammatory and antioxidant activities. The purpose of this study was to test the ability of baicalin to influence the progression of experimental periodontitis in rats, as well as the expression of cyclooxygenase-2 and inducible nitric oxide synthase. Material and Methods:, Adult male Sprague,Dawley rats were subjected to placement of a nylon thread around the bilateral lower first molars and killed after 7 d. Baicalin (50, 100 or 200 mg/kg) was supplied to the animals by oral gavage, starting 1 d before the induction of periodontitis. The ligature group consisted of rats subjected to periodontitis and receiving vehicle (0.5% carboxymethylcellulose) alone. The alveolar bone loss and the area fraction occupied by collagen fibers were assessed. The expression of cyclooxygenase-2 and inducible nitric oxide synthase protein in the gingiva were detected by immunohistochemistry and western blotting. Results:, Baicalin-treated groups presented with lower alveolar bone loss than that of the ligature group, reaching statistical significance at the dose of 200 mg/kg (p = 0.009). The area fraction of collagen fibers was significantly higher in the baicalin (200 mg/kg)-treated group than in the ligature group (p = 0.047). Baicalin treatment significantly down-regulated the protein expression for cyclooxygenase-2 (p = 0.000) and inducible nitric oxide synthase (p = 0.003), compared with the ligature group. Conclusion:, Baicalin protects against tissue damage in ligature-induced periodontitis in rats, which might be mediated, in part, by its inhibitory effect on the expression of cyclooxygenase-2 and inducible nitric oxide synthase. These activities could support the continued investigation of baicalin as a potential therapeutic agent in periodontal disease. [source] Carcinoembryonic antigen-related cell adhesion molecule (CEACAM)-binding recombinant polypeptide confers protection against infection by respiratory and urogenital pathogensMOLECULAR MICROBIOLOGY, Issue 5 2005Darryl J. Hill Summary The human-specific pathogens Neisseria meningitidis, N. gonorrhoea, Haemophilus influenzae and Moraxella catarrhalis share the property of targeting the carcinoembryonic antigen (CEA)-related cell adhesion molecules (CEACAMs) expressed on human epithelia. CEACAMs are signalling receptors implicated in cell adhesion and regulation of several physiological functions. Their targeting by pathogens can lead to tissue invasion. Although the CEACAM-binding ligands of the bacteria are structurally diverse, they target a common site on the receptor. We have generated a recombinant polypeptide that blocks the interactions of the mucosal pathogens with human epithelial cells and antibodies against it inhibit M. catarrhalis interactions with the receptor. As such, it is a potential antimicrobial agent to prevent infection via a strategy unlikely to promote bacterial resistance and a vaccine candidate against M. catarrhalis. In addition, it could serve more widely as a novel research tool and as a potential therapeutic agent in CEACAM-based physiological disorders. [source] Neuroprotective effects of 3,5-dicaffeoylquinic acid on hydrogen peroxide-induced cell death in SH-SY5Y cellsPHYTOTHERAPY RESEARCH, Issue 3 2005Sung-Soo Kim Abstract Oxidative stress plays an important role in the pathological processes of a variety of neurodegenerative diseases. The neuroprotective effects of 3,5-diCQA and 3,4-diCQA, two caffeoylquinic acid derivatives present in Dipsacus asper, on hydrogen peroxide (H2O2)-induced neuronal cell damage were evaluated in this study. SH-SY5Y cells treated with H2O2 exhibited a decrease in survival and intracellular glutathione and also an increase in the caspase-3 activity. However, pretreatment of cells with 3,5-diCQA attenuated the neuronal death and caspase-3 activation induced by H2O2. In addition, 3,5-diCQA restored H2O2 -induced depletion of intracellular glutathione. 3,5-diCQA showed significant protective effects although it could not completely suppress H2O2 -induced cell injury to control levels. The data suggest that 3,5-diCQA might be a potential therapeutic agent for treating or preventing neurodegenerative diseases implicated with oxidative stress. Copyright © 2005 John Wiley & Sons, Ltd. [source] The Effect of Korean Red Ginseng Extract on the Relaxation Response in Isolated Rabbit Vaginal Tissue and Its MechanismTHE JOURNAL OF SEXUAL MEDICINE, Issue 9 2008Sun-Ouck Kim MD ABSTRACT Introduction., Ginseng is an herbal medicine with a variety of biological activities. Aim., The purpose of this study was to investigate the effect of Korean red ginseng (KRG) extract on the relaxation response in isolated rabbit vaginal tissue and its mechanism as a potential therapeutic agent for female sexual dysfunction. Method., Strips of rabbit vagina were mounted in organ chambers to measure isometric tension. After the strips were precontracted with phenylephrine, the contractile responses to KRG extract (1,20 mg/mL), nitric oxide inhibitor (N[omega]-nitro-L-arginine methyl ester [L-NAME]), an inhibitor of soluble guanylate cyclase (methylene blue), an inhibitor of Ca2+ -activated K+ channels (tetraethylammonium [TEA]), and an adenosine triphosphate (ATP)-sensitive K+ channel blocker (glybenclamide) were examined. Main Outcome Measures., The relaxation of the vaginal tissue strip was assessed after treating KRG extract or other chemicals. Results., KRG (1,20 mg/mL) extract relaxed the vaginal tissue strip in a dose-dependent manner up to 85%. The relaxation effect was significantly inhibited by L-NAME (30 µM) and methylene blue (30 µM) (P < 0.05). In addition, KRG inhibited the contraction induced by depolarization with 10, 20, and 40 mM KCl. The KRG-induced relaxation effect was significantly inhibited by TEA (300 µM) (P < 0.05), and not by glybenclamide (30 µM). Conclusions., These data show that KRG extract has a relaxing effect on rabbit vaginal smooth muscle tissue. These effects might be mediated partly through the NO pathway and hyperpolarization via Ca2+ -activated K+ channels. Kim S-O, Kim MK, Lee H-S, Park JK, and Park K. The effect of Korean red ginseng extract on the relaxation response in isolated rabbit vaginal tissue and its mechanism. J Sex Med 2008;5:2079,2084. [source] S-allylcysteine, a water-soluble garlic derivative, suppresses the growth of a human androgen-independent prostate cancer xenograft, CWR22R, under in vivo conditionsBJU INTERNATIONAL, Issue 4 2007Qingjun Chu OBJECTIVE To evaluate the effect of S-allylcysteine (SAC) on CWR22R, a human androgen-independent (AI) prostate cancer xenograft, in nude mice. Despite extensive research worldwide there is no effective way to control the growth of prostate cancer, and we previously reported that SAC and S-allylmercaptocysteine (SAMC), two water-soluble derivatives of garlic, inhibit cancer cell invasion through restoration of E-cadherin expression in vitro. MATERIALS AND METHODS The effects of SAC on tumour cell proliferation markers such as Ki-67 and proliferating cell nuclear antigen, and apoptotic regulators including Bcl-2 and cleaved caspase-3, were assessed by immunohistochemical staining. The inhibitory effects of SAC on prostate cancer invasion was examined by immunoreactivity of E-cadherin and its binding proteins ,, , and ,-catenins. The serum prostate-specific antigen (PSA) level at three different times (initiation, middle and end of treatment) and toxicity of SAC on several organs after treatment were assessed. RESULTS Treatment with SAC resulted in inhibition of the growth of CWR22R, with no detectable toxic effect on nude mice. The SAC-induced growth reduction was correlated with a concurrent reduction in serum PSA level and proliferation rate of xenografts, together with an inhibition of invasion through the restoration of E-cadherin and ,-catenin expression. Furthermore, the apoptotic rate of SAC-treated tumours increased together with a decrease in Bcl-2 and increase in cleaved caspase-3. CONCLUSION These results suggest that this garlic-derived compound might be a potential therapeutic agent for suppressing AI prostate cancer. [source] Growth hormone secretagogue receptor antagonists as potential therapeutic agents for obesityDRUG DEVELOPMENT RESEARCH, Issue 2 2005Hongyu Zhao Abstract Safe and efficacious medicines for obesity treatment are greatly needed. As an endogenous ligand of growth hormone secretagogue receptor 1a (GHS-R 1a), ghrelin is the only known circulating orexigen. Administration of ghrelin causes food intake and body weight increase in both rodents and humans, whereas inhibiting its actions by antibodies, peptide antagonists, and anti-sense oligonucleotides leads to decreased food intake and weight loss. Recent progress in developing nonpeptidyl small molecule GHS-R antagonists is reviewed in this article. Drug Dev. Res. 65:50,54, 2005. © 2005 Wiley-Liss, Inc. [source] Role of the Bone Marrow Microenvironment in Multiple Myeloma,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 11 2002G. David Roodman M.D., Ph.D. Abstract On June 26,27, 2001, the Sixth Research Roundtable in Multiple Myeloma, entitled "The Role of the Bone Microenvironment in Multiple Myeloma," was held and focused on the biology of cell-to-cell interactions, the mediators of bone disease, and novel treatment strategies for myeloma. Studies on cell-cell interactions showed that vascular cell adhesion molecule 1, expressed by local endothelial and stromal cells, binds to tumor cell surface integrins in which expression may be increased by tumor cell-derived chemokines such as macrophage inflammatory protein (MIP) 1,. These adhesive interactions increase production and release of vascular endothelial growth factor (VEGF). Studies on myeloma bone disease showed the ligand for receptor activator of nuclear transcription factor-,B (RANKL) was expressed on tumor cells and stromal cells associated with myeloma cells and was critical for osteoclast-induced osteolysis. Blockade of RANKL suppressed osteoclast maturation, bone resorption, and tumor development. Bisphosphonates, in addition to reducing osteoclast mobility and inducing osteoclast apoptosis, also decreased tumor cell adhesion to stroma. Immunomodulatory drugs such as thalidomide analogues targeted these tumor cell-stromal cell interactions, blocking both secretion of cytokines and activation of intracellular signaling pathways required for tumor survival and growth. These agents induced tumor cell apoptosis, decreased neovascularization, and potentiated natural killer cell activity. The proteasome inhibitor PS-341 also prevented expression of adhesion molecules and cytokines and triggered tumor cell apoptosis, even in drug-resistant cell lines, while showing minimal activity in healthy cells. In addition, potential therapeutic agents under investigation, which included RANKL antagonists, protein prenylation inhibitors, and osteoblast growth factors, were discussed. [source] Synthetic approaches to 4,8-dimethyl-5,-(N -pyridiniummethyl)- 4,,5,-dihydropsoralens and 4,8-dimethyl-5,- (N -aminomethyl)- 4,,5,-dihydropsoralens,,JOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 4 2001Marilyn S. Whittemore New synthetic approaches to 4,8-dimethyl-5,-(N -pyridiniummethyl)-4,,5,-dihydropsoralens and 4,8-dimemyl-5,-(N -aminomethyl)-4,,5,-dihydropsoralens are described. The 5,-halomethyl-4,,5,-dihydro-psoralen precursors are formed by electrophilic ring closures of 4,8-dimethyl-6-allyl-7-hydroxycoumarin. The ring-closure reactions may also be applied to the synthesis of 5,-halomethyl-4-methyl-4,,5,-dihydroangelicins. The compounds are potential therapeutic agents for improved psoralen ultraviolet A radiation treatment. [source] Blood,brain barrier efflux transportJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 9 2003Pamela L. Golden Abstract Efflux transport at the blood,brain barrier (BBB) limits the brain tissue exposure to a variety of potential therapeutic agents, including compounds that are relatively lipophilic and would be predicted to permeate the endothelial lining of the brain microvasculature. Recent advances in molecular and cell biology have led to identification of several specific transport systems at the blood,brain interface. Refinement of classical pharmacokinetic experimentation has allowed assessment of the structural specificity of transporters, the impact of efflux transport on brain tissue exposure, and the potential for drug,drug interactions at the level of BBB efflux transport. The objective of this minireview is to summarize efflux transporter characteristics (location, specificity, and potential inhibition) for transport systems identified in the BBB. A variety of experimental approaches available to ascertain or predict the impact of efflux transport on net brain tissue uptake of substrates also are presented. The potential impact of efflux transport on the pharmacodynamics of agents acting in the central nervous system are illustrated. Finally, general issues regarding the role of identifying efflux transport as part of the drug development process are discussed. © 2003 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:1739,1753, 2003 [source] Inhibitors and antagonists of bacterial quorum sensingMEDICINAL RESEARCH REVIEWS, Issue 1 2009Nanting Ni Abstract Bacteria can regulate community-wide behaviors including biofilm formation, virulence, conjugation, sporulation, and swarming motility through a process called quorum sensing. Inhibitors and antagonists of bacterial quorum sensing are important research tools and potential therapeutic agents. In this review, we have summarized recent developments in this area. © 2008 Wiley Periodicals, Inc. Med Res Rev, 29, No. 1, 65,124, 2009 [source] Competitive AMPA receptor antagonistsMEDICINAL RESEARCH REVIEWS, Issue 2 2007Daniela Catarzi Abstract Glutamic acid (Glu) is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) where it is involved in the physiological regulation of different processes. It has been well established that excessive endogenous Glu is associated with many acute and chronic neurodegenerative disorders such as cerebral ischaemia, epilepsy, amiotrophic lateral sclerosis, Parkinson's, and Alzheimer's disease. These data have consequently added great impetus to the research in this field. In fact, many Glu receptor antagonists acting at the N -methyl- D -aspartic acid (NMDA), 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA), and/or kainic acid (KA) receptors have been developed as research tools and potential therapeutic agents. Ligands showing competitive antagonistic action at the AMPA type of Glu receptors were first reported in 1988, and the systemically active 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo[f]quinoxaline (NBQX) was first shown to have useful therapeutic effects in animal models of neurological disease in 1990. Since then, the quinoxaline template has represented the backbone of various competitive AMPA receptor antagonists belonging to different classes which had been developed in order to increase potency, selectivity and water solubility, but also to prolong the "in vivo" action. Compounds that present better pharmacokinetic properties and less serious adverse effects with respect to the others previously developed are undergoing clinical evaluation. In the near future, the most important clinical application for the AMPA receptor antagonists will probably be as neuroprotectant in neurodegenerative diseases, such as epilepsy, for the treatment of patients not responding to current therapies. The present review reports the history of competitive AMPA receptor antagonists from 1988 up to today, providing a systematic coverage of both the open and patent literature. © 2006 Wiley Periodicals, Inc. [source] Current trends in the structure,activity relationship studies of the endogenous agouti-related protein (AGRP) melanocortin receptor antagonistMEDICINAL RESEARCH REVIEWS, Issue 5 2005Andrzej M. Wilczynski Abstract Agouti-related protein (AGRP) is an endogenous antagonist of the melanocortin-3 and -4 (MC3R and MC4) G-protein coupled receptors. The 87,132 amino acid C-terminal domain of hAGRP possesses five disulfide bridges and a well-defined three-dimensional structure that displays full biological activity as compared to the full-length protein. Based on the NMR structure of the C-terminal AGRP(87,132), a novel mini-protein, referred to as "Mini-AGRP" was designed that exhibited receptor binding affinity and antagonism similar to that of the parent hAGRP(87,132) protein. It was demonstrated that this new-engineered protein autonomously folds to the inhibitor cystine knot (ICK) motif. As this AGRP is a novel mammalian protein involved in energy homeostasis and possibly other physiological functions remaining to be identified, structure-function studies are starting to emerge toward the understanding of how this unique protein putatively interacts with the melanocortin receptors with the objective of designing potential therapeutic agents for in vivo physiological studies. This article summarizes the progress to date of AGRP-based structure,activity relationships and putative ligand,receptor interactions. © 2005 Wiley Periodicals, Inc. [source] Relationship between antimicrobial proteins and airway inflammation and infection in cystic fibrosisPEDIATRIC PULMONOLOGY, Issue 4 2009Scott D. Sagel MD Abstract Antimicrobial proteins are important in lung defense and are potential therapeutic agents in chronic airways infection such as seen in cystic fibrosis (CF). In preparation for future clinical studies, we sought (1) to determine levels of three antimicrobial proteins [lactoferrin, lysozyme, and secretory leukoprotease inhibitor (SLPI)] in the CF airway and (2) to examine the relationships between these antimicrobial proteins and airway inflammation and infection. We examined bronchoalveolar lavage fluid (BALF) from 45 individuals with CF and 23 disease control individuals. Airway inflammation was measured through BALF neutrophil counts and neutrophil elastase activity. Infection was assessed through quantitative counts of CF-related bacterial pathogens. BALF lysozyme activity and lactoferrin levels were elevated in individuals with CF compared to controls whereas SLPI levels were not different between the groups. Among the CF subjects, lysozyme activity and lactoferrin increased with age while SLPI decreased with age. Lysozyme activity and lactoferrin concentrations correlated positively with neutrophil counts but not with bacterial colony counts. SLPI levels were inversely related to both neutrophil counts and bacterial colony counts. This study provides information concerning the levels of antimicrobial proteins present in the CF airway that are relevant to future clinical trials of these compounds and demonstrates clear relationships between antimicrobial protein-specific levels and airway inflammation and infection. Pediatr Pulmonol. 2009; 44:402,409. © 2009 Wiley-Liss, Inc. [source] Specific GABAA agonists and partial agonistsTHE CHEMICAL RECORD, Issue 6 2002Povl Krogsgaard-Larsen Abstract The GABAA receptor system is implicated in a number of neurological and psychiatric diseases, making GABAA receptor ligands interesting as potential therapeutic agents. Only a few different classes of structures are currently known as ligands for the GABA recognition site on the hetero-pentameric GABAA receptor complex, reflecting the very strict structural requirements for GABAA receptor recognition and activation. Within the series of compounds showing agonist activity at the GABAA receptor site that have been developed, most of the ligands are structurally derived from the GABAA agonists muscimol, THIP, or isoguvacine, which we developed in the initial stages of the project. Using recombinant GABAA receptors, functional selectivity was demonstrated for a number of compounds, including THIP, showing highly subunit-dependent potency and maximal response. In light of the interest in partial GABAA receptor agonists as potential therapeutics, structure,activity studies of a number of analogs of 4-PIOL, a low-efficacy partial GABAA agonist derived from THIP, have been performed. In this connection, a series of GABAA ligands has been developed that exhibit pharmacological profiles from moderately potent low-efficacy partial GABAA agonist activity to potent and selective antagonist effects. Very little information is available on direct-acting GABAA receptor agonists in clinical studies. However, the results of clinical studies on the effect of the partial GABAA agonist THIP on human sleep patterns show that the functional consequences of a direct-acting agonist are different from those seen after the administration of GABAA receptor modulators, such as benzodiazepines and barbiturates. © 2002 The Japan Chemical Journal Forum and Wiley Periodicals, Inc., Chem Rec 2: 419,430; 2002: Published online in Wiley Interscience (www.interscience.wiley.com) DOI 10.1002/tcr.10040 [source] Vasopressin receptor antagonists: pharmacological tools and potential therapeutic agentsAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 2 2006J. O. Streefkerk Summary 1 The present survey deals with the development and applications of non-peptidergic vasopressin receptor antagonists. 2 The existence of at least three vasopressin receptors (V1, V2 and V3 respectively) is firmly established. 3 V1 -receptors play a relevant role in the regulation of vascular tone, whereas V2 -receptors are known to mediate the antidiuretic activity of vasopressin at the level of the renal collecting ducts. The V3 -receptor appears to be involved in the release of the adreno-corticotropic hormone. 4 Vasopressin receptor antagonists which are peptides have been known for several decades, more recently, both V1 - and V2 -receptor blockers which are non-peptidergic have been introduced, as well as agents with affinity for both V1 - and V2 -receptor subtypes. A survey of these non-peptidergic antagonists is presented here. Such compounds are useful as pharmacological tools, and they can also be thought of as therapeutic agents as therapeutic agents in cardiovascular and renal diseases. 5 Selective V1 - and V2 -receptor antagonists were used to study the interaction between vasopressin receptors and sympathetic neurones. Depending on the experimental model used this interaction can occur at either the pre- or postsynaptic sites. In both cases predominantly V1 -receptors are involved. 6 A brief survey is given of the potential use of V-receptor antagonists in the drug therapy of syndrome of inappropriate antidiuretic hormone secretion and other water retaining disorders, congestive heart failure and certain forms of hypertension (in particular in the Negroid hypertensive patients). [source] Three-dimensional culture systems for the expansion of pluripotent embryonic stem cellsBIOTECHNOLOGY & BIOENGINEERING, Issue 4 2010Michael P. Storm Abstract Mouse embryonic stem cell (ESC) lines, and more recently human ESC lines, have become valuable tools for studying early mammalian development. Increasing interest in ESCs and their differentiated progeny in drug discovery and as potential therapeutic agents has highlighted the fact that current two-dimensional (2D) static culturing techniques are inadequate for large-scale production. The culture of mammalian cells in three-dimensional (3D) agitated systems has been shown to overcome many of the restrictions of 2D and is therefore likely to be effective for ESC proliferation. Using murine ESCs as our initial model, we investigated the effectiveness of different 3D culture environments for the expansion of pluripotent ESCs. Solohill Collagen, Solohill FACT, and Cultispher-S microcarriers were employed and used in conjunction with stirred bioreactors. Initial seeding parameters, including cell number and agitation conditions, were found to be critical in promoting attachment to microcarriers and minimizing the size of aggregates formed. While all microcarriers supported the growth of undifferentiated mESCs, Cultispher-S out-performed the Solohill microcarriers. When cultured for successive passages on Cultispher-S microcarriers, mESCs maintained their pluripotency, demonstrated by self-renewal, expression of pluripotency markers and the ability to undergo multi-lineage differentiation. When these optimized conditions were applied to unweaned human ESCs, Cultispher-S microcarriers supported the growth of hESCs that retained expression of pluripotency markers including SSEA4, Tra-1,60, NANOG, and OCT-4. Our study highlights the importance of optimization of initial seeding parameters and provides proof-of-concept data demonstrating the utility of microcarriers and bioreactors for the expansion of hESCs. Biotechnol. Bioeng. 2010;107:683,695. © 2010 Wiley Periodicals, Inc. [source] Bone Affinity of a Bisphosphonate-Conjugated Protein in VivoBIOTECHNOLOGY PROGRESS, Issue 6 2000Hasan Uludag Growth factors capable of stimulating bone formation are potential therapeutic agents for osteoporosis treatment. It is essential, however, that a targeting mechanism is incorporated into the growth factors to deposit them at osseous tissue with minimal distribution to extraskeletal sites. To this end, a strategy has been developed in which a bone-seeking molecule, 1-amino-1,1-diphosphonate methane (aminoBP), was chemically conjugated to a model protein, bovine serum albumin (BSA). This study was carried out to assess the bone affinity of the conjugates in a tibia injection model. Using ovariectomized (OVX) rats, initial (3 h) retention of BSA and aminoBP-BSA were found to be equivalent when injected into the medullary cavity of tibia. After 1 day, an 8- and 12-fold higher tibiae retention of the protein was obtained in normal and OVX rats as a result of aminoBP conjugation. A similar result (,12-fold difference) was also obtained in OVX rats after 3 days. We concluded that aminoBP conjugation to BSA imparted a high bone affinity and enhanced bone retention of proteins in normal and OVX rats. [source] Characterization of apoptosis induced by protein kinase C inhibitors and its modulation by the caspase pathway in acute promyelocytic leukaemiaBRITISH JOURNAL OF HAEMATOLOGY, Issue 3 2000Hesham M. Amin Acute promyelocytic leukaemia (APL;M3) is a unique form of acute myelogenous leukaemia characterized by t(15;17) translocation. The induction of apoptosis via inhibiting protein kinase C (PKC) has been recently viewed as a promising tool for the eradication of several malignant disorders. In the present study, we investigated the effect of two different protein kinase C inhibitors, Gö6976 and safingol, on the induction of apoptosis in the APL cell line NB4 and its all trans retinoic acid (ATRA)-resistant variant NB4.306. The effect of the PKC inhibitors on leukaemic cells obtained from three APL patients was also studied. We also evaluated the possible involvement of the caspases in apoptosis induced by PKC inhibitors. Significant time- and concentration-dependent apoptotic changes were demonstrated using Gö6976 and safingol. In addition, our results demonstrated that the caspases were involved in the apoptosis induced by the PKC inhibitors. In conclusion, our study illustrates that the PKC inhibitors Gö6976 and safingol induce apoptosis in APL and hence could be potential therapeutic agents for the treatment of this disease. [source] Simplified Synthetic TMC-95A/B Analogues Retain the Potency of Proteasome Inhibitory ActivityCHEMBIOCHEM, Issue 6 2003Zhi-Qiang Yang Dr. Abstract The proteasome regulates diverse intracellular processes, including cell-cycle progression, antigen presentation, and inflammatory response. Selective inhibitors of the proteasome have great therapeutic potential for the treatment of cancer and inflammatory disorders. Natural cyclic peptides TMC-95A and B represent a new class of noncovalent, selective proteasome inhibitors. To explore the structure,activity relationship of this class of proteasome inhibitors, a series of TMC-95A/B analogues were prepared and analyzed. We found that the unique enamide functionality at the C8 position of TMC-95s can be replaced with a simple allylamide. The asymmetric center at C36 that distinguishes TMC-95A from TMC-95B but which necessitates a complicated separation of the two compounds can be eliminated. Therefore, these findings could lead to the development of more accessible simple analogues as potential therapeutic agents. [source] | ||||||||||||||||