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ID PMID Title PublicationDate abstract
16872241 Safety of etanercept in psoriasis: a critical review. 2006 Conventional systemic treatments for patients with psoriasis are associated with multiple adverse effects that require continuous monitoring. The introduction of new biological agents such as etanercept, a fully human fusion protein, has permitted individualisation of patients' treatment according to disease stage. The drug is a competitive inhibitor of tumour necrosis factor-alpha (TNFalpha) that prevents interaction between this cytokine and its cell surface receptors. Etanercept also modulates the activity of other inflammatory cytokines and does not induce complement-mediated cell lysis in vitro. The main source of information regarding etanercept safety comes from studies in patients with rheumatoid arthritis. The most common adverse effect during drug administration is mild injection site reactions. There is no increase in the overall incidence of infections compared with placebo, although there have been several reports of infections caused by intracellular organisms (Mycobacterium tuberculosis, Listeria monocytogenes, and Mycobacterium avium intracellulare). Therefore, combination of this drug with corticosteroids must be carefully monitored and should be avoided in patients with established sepsis. There are no data showing that treatment with etanercept results in an increase in the occurrence of malignant neoplasms. However, caution is recommended in use of etanercept in patients with a current or past history of demyelinating disease. Etanercept must be used with extreme caution in patients with heart failure because of several reports indicating a worsening or de novo occurrence of congestive heart failure while receiving the drug. Monitoring of autoantibodies is not currently considered necessary as they do not predict response, toxicity or autoimmune events. The presence of non-neutralising antibodies to the TNF receptor fragment or other protein components of etanercept has not been related to a decrease in drug response or adverse reactions. Etanercept does not generally modify the course of inflammatory bowel disease. When combined with other systemic therapies for psoriasis, current data do not show an increase in adverse events. In patients with hepatitis C viral infection, etanercept does not increase transaminase levels or viral load and in some instances has allowed the concomitant use of interferon which had previously been discontinued because of a worsening of psoriasis. Etanercept is rated as a US FDA category B drug in pregnancy. However, its use is not recommended in pregnant women unless the benefit-risk ratio greatly favours its use. Etanercept is not recommended for use in lactating women. Etanercept represents a relevant treatment for psoriasis, efficacious over many weeks and safe but special care should be taken to avoid the potential risks.
16701959 Solar cycles and their relationship to human disease and adaptability. 2006 In this paper, we show that 11-year solar cycle peaks predispose humans to disease, but also endow creativity and adaptability. We give several examples of diseases that are modulated by light and present evidence for an effect of intensity and variation in sunlight, primarily ultraviolet radiation (UVR), on the human genome. The birth dates of nearly 237,000 unique clients in the Maine Medicaid database collected from 1995 to 2004, inclusive, were related to solar cycle irradiance for the past seventy-one years, encompassing seven solar cycles. The sample was divided into four general categories of disease: mental/behavioral illnesses; metabolic diseases; autoimmune diseases; neoplasms. The birth months for those clients born in any given year were arranged in the form of a winter/summer ratio in order to more clearly appreciate the seasonality inherent in each disease category. Solar cycles were separated into chaotic (approximately three times as irradiant) or non-chaotic according to the Gutenberg-Richter power law and the uncertainty inherent in predicting solar storms. The results show that radiation peaks in solar cycles and particularly in chaotic solar cycles (CSCs) are associated with a higher incidence of mental disorders, suggesting the sensitivity of ectodermal embryonic tissues to UVR. Autoimmune diseases have intermediate sensitivity, while the neoplasms in the study, primarily of endoderm, appear suppressed by peak UVR intensity. The ratio of the number of clients born in CSC cycles to non-CSC cycles was highest for the more genetic mental diseases, like schizophrenia and bipolar disorder, but as that ratio decreased, the clients with diseases like multiple sclerosis and rheumatoid arthritis showed more environmental features manifested as a greater winter/summer birth month ratio that was significantly different than that of the average client in the whole data set. The paper presents evidence that latitude, e.g., variation in light, is an added stress to the immune system (especially at 53-54 degrees N. latitude) that is involved in nearly all human disease. We hypothesize that introns, the presumptive engenderers of gene control, modulate the effects of UVR, particularly for the neoplasms studied. We conclude that intermittent and largely unpredictable peak solar cycle radiation has been the fundamental engine of evolution, forcing organisms to adapt to mutagenic UVR and producing enough damage to instigate genetic variation. Probably a chance genetic mutation over 80,000 years ago produced a human brain capable of abstract thought and consciousness. The slight genetic instability that favored an adaptable, creative brain also produced other somatic variations that present phenotypically as disease, but largely expressed after natural selection (reproduction) and associated with the inexorable entropy of aging.
16652442 B cell targeted therapies in autoimmune diseases. 2006 May In addition to rheumatoid arthritis (RA), B cells are likely to play a significant role in the development of other autoimmune rheumatic diseases, such as systemic lupus erythematosus (SLE), myositis, and vasculitis. Small-vessel vasculitis subtypes may be immune complex-mediated (cryoglobulinemia) or antineutrophil cytoplasmic antibody (ANCA)-associated; ANCA may be involved in the pathogenesis of vasculitis. In SLE, both antibody-associated and antibody-independent processes are almost certainly involved. B cell activity and autoantibody production are increased, while patients often have reduced peripheral B cells and abnormal B cell profiles. B lymphocyte stimulator (BLyS) protein regulates B cell activation and differentiation. For these reasons, B cells and the molecules that activate them are potential therapeutic targets in these diseases. Recent clinical trial data from small studies of rituximab (RTX) in SLE suggest that treatment improved clinical variables and measures of disease activity in patients, including those with central nervous system SLE. With retreatment, patients whose B cells were successfully depleted continued to show improvement in clinical and laboratory variables. Preliminary data suggest that treatment with RTX may be effective in ANCA-associated vasculitis. In addition a recent study showed significant benefit with myositis. Although these studies contain small cohorts of patients, they demonstrate that B cell-modulating therapies show promise in treatment of a variety of autoimmune diseases.
16574371 Anti-inflammatory effect of Poncirus trifoliata fruit through inhibition of NF-kappaB acti 2006 Oct Mast cell-mediated allergic inflammation is involved in many diseases such as asthma, sinusitis, and rheumatoid arthritis. Mast cells induce synthesis and production of pro-inflammatory cytokines including tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 with immune regulatory properties. We investigated the effect of the fruits of Poncirus trifoliata (L.) Raf (Rutaceae) (FPT) on expression of pro-inflammatory cytokines by activated human mast cell line, HMC-1. FPT dose dependently decreased the gene expression and production of TNF-alpha and IL-6 on phorbol 12-myristate 13-acetate (PMA) and calcium ionophore A23187-stimulated HMC-1 cells. In addition, FPT attenuated PMA and A23187-induced activation of NF-kappaB indicated by inhibition of degradation of I kappa B alpha, nuclear translocation of NF-kappaB, NF-kappaB/DNA binding, and NF-kappaB-dependent gene reporter assay. Our in vitro studies provide evidence that FPT might contribute to the treatment of mast cell-derived allergic inflammatory diseases.
16536903 Suppression of matrix metalloproteinase production from synovial fibroblasts by meloxicam 2006 Mar The aim of this study was to evaluate the influence of meloxicam on the production of both matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) from human synovial fibroblasts by TNF-alpha stimulation in-vitro. Synovial fibroblasts (2 x 10(4) cells/mL) derived from patients with osteoarthritis were stimulated with 20.0 ng mL(-1) TNF-alpha in the presence of various concentrations of meloxicam. After 24 h, the culture supernatants were obtained and assayed for MMP-1, MMP-2, MMP-3, MMP-13, TIMP-1 and TIMP-2 by ELISA. mRNA expression for MMPs and TIMPs in 4-h-cultured cells were examined by real-time polymerase chain reaction. Transcriptional factor (NF-kappaB and AP-1) activation in 2-h-cultured cells was also examined by ELISA. Meloxicam could suppress MMP production in a dose-dependent manner. The minimum concentration of the agent that showed significant suppression was 0.6 x 10(-6) M for MMP-1, MMP-2 and MMP-3, and 1.3 x 10(-6) M for MMP-13. The ability of synovial fibroblasts to produce TIMPs was also suppressed by meloxicam as in the case of MMP production. Addition of meloxicam into synovial fibroblast cultures inhibited dose-dependently mRNA expression for MMPs and TIMPs, which were increased by TNF-alpha stimulation, through the suppression of NF-kappaB and AP-1 activation. The suppressive effect of meloxicam on the production of MMPs and TIMPs may partly be involved in attenuation of the clinical conditions of osteoarthritis and rheumatoid arthritis.
16451200 Inhibitory effects on HLA-DR1-specific T-cell activation by influenza virus haemagglutinin 2006 Jan Collagen (CII) 263-272 peptide, an autoantigen in rheumatoid arthritis, is a specific human leukocyte antigen (HLA)-DR1/4-binding peptide recognized by T-cell receptors (TCR). The affinity of influenza virus haemagglutinin (HA) 306-318 peptide for the antigen-binding groove of HLA-DR1/4 molecules is higher than that of CII263-272. The HLA-DR1/4-binding residues of HA306-318 are located in the region 308-317. Altered HA308-317 peptides with substitutions of TCR-contact residues may inhibit HLA-DR1/4-specific T-cell activation by blocking the antigen-binding site of HLA-DR1/4 molecules. To evaluate the role of altered HA308-317 peptides in HLA-DR1-restricted T-cell activation, we synthesized three altered HA308-317 peptides. The specific binding of altered HA308-317 peptides to HLA-DR1 molecules was examined using flow cytometry. Effects of altered HA308-317 peptides on HLA-DR1-specific T-cell hybridoma were studied by measuring T-cell proliferation and surface expression of CD69 or CD25. The results showed that altered HA308-317 peptides were able to bind to HLA-DR1 molecules and competed with CII263-272 or wildtype HA308-317 peptide. Compared with wildtype CII263-272 or HA308-317, altered HA308-317 peptides did not stimulate significant T-cell proliferation and CD69 or CD25 expression. Furthermore, the altered HA308-317 peptides inhibited HLA-DR1-specific T-cell activation induced by CII263-272 or wildtype HA308-317 peptide, which may suggest an effective therapeutic strategy in inhibition of HLA-DR1-specific T-cell responses in autoimmunity.
18957891 Epstein Barr virus-associated primary CNS lymphomas in elderly patients on immunosuppressi 2008 Nov Unlike primary central nervous system lymphomas (PCNSLs) in patients with AIDS or organ transplants, PCNSLs in the elderly are usually not considered to be mediated by Epstein Barr virus (EBV); hence, diagnostic studies for EBV are not routinely performed. We encountered 4 patients, 65 years or older, who developed EBV-associated PCNSLs and who had been treated with a variety of immunosuppressive drugs for different autoimmune/collagen vascular disorders, including autoimmune polyneuropathy (mycophenolate mofetil for 5 years), polymyositis (prednisone for 16 years with intermittent methotrexate, azathioprine, and cyclophosphamide), myasthenia gravis (azathioprine >10 years), and rheumatoid arthritis (methotrexate >10 years). All patients had multifocal, necrotic brain lesions typical of EBV-positive PCNSLs on neuroimaging. Withdrawing immunosuppressives lead to PCNSL regression in some patients. The patient who had received mycophenolate mofetil was treated successfully for his EBV-associated PCNSL with rituximab and methotrexate, but later developed fatal systemic malignant melanoma, which was likely immunosuppression related. The striking feature of these cases is the variety of underlying diseases-and hence accompanying medications-that can be associated with EBV-associated PCNSLs. They serve as a diagnostic alert for neuropathologists and suggest that increased testing of PCNSLs for EBV by immunohistochemistry or in situ hybridization may be warranted in any patient on any immunosuppressive medication, but particularly the elderly.
18757139 Mechanisms modulating inflammatory osteolysis: a review with insights into therapeutic tar 2008 Inflammatory osteolysis is a relatively frequent and incapacitating complication of rheumatoid arthritis and multiple other inflammation-associated bone diseases. It is thought to operate through an ultimate common pathway of accelerated osteoclast recruitment and activation under the control of cytokines produced in the inflammatory environment. Over the past decade, there have been major advances in our understanding of the mechanisms of osteoclastogenesis. It is now clear that the interaction of receptor activator NF-kappaB (RANK) and its ligand, RANKL, plays a central role in osteoclast formation and activity. Therefore, understanding osteoclastogenesis offers new pathways for potential therapeutic intervention in inflammatory osteolysis. The success of anti-tumor necrosis factor-alpha and interleukin-1 therapy highlights the central role that these specific cytokines play in this disease. This review outlines our current understanding of the mechanisms mediating inflammatory osteolysis and highlights potential therapeutic strategies.
18725426 Physical and mental comorbidity of headache in a nationally representative sample of US ad 2008 Sep OBJECTIVE: To investigate the contribution of comorbidity to health utilization and negative health perception in a large-scale population-based study. Comorbidity of headache with physical and mental disorders has been reported frequently in clinical samples. METHODS: This concern was addressed using combined 6-year data from the 1999 to 2004 National Health Examination and Nutrition Survey (n = 31,126 adults), nationally representative datasets of the US population. Measures of physical disorders were based on standardized interviews of chronic conditions, and mental disorders were assessed by the Composite International Diagnostic Interview for Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. RESULTS: The 3-month prevalence of severe headaches or migraine in the US general population was 22.73%, with females and young adults having greater rates than males and older adults. Adults with headache had increased odds for a variety of physical disorders (including asthma, rheumatoid arthritis, and stroke) and mental disorders (including depression, generalized anxiety disorder, and panic disorder). Adults with headache were more likely to rate their health as "fair or poor" (17.9% versus 6.1%), to seek health care four or more times in a year (43.3% versus 22.7%), and to endorse physical and mental limitations. Health utilization and negative health perception were more strongly influenced by comorbid mental disorders than physical disorders. CONCLUSIONS: The results from this nationally representative sample provide new information on the interrelationships of headache with mental and physical disorders. The greater impact of comorbid mental compared with physical disorders on healthcare utilization and health perception has important implications for the clinical evaluation and treatment of headache in the population.
18688813 Evaluation of antioxidant, antinociceptive, and anti-inflammatory activities of ethanol ex 2008 Oct Aloe species are traditionally prescribed for hypertension, burning, and rheumatoid arthritis. To elucidate the mechanism of the antihypertensive and anti-inflammatory activities of this herb, the ethanol fraction from A. saponaria Haw. was evaluated for antioxidative activity using xanthine-xanthine oxidase (XO) assay, 2,2-Diphenyl-lpicrylhydrazyl radical (DPPH) assay, lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 cell, and antinociceptive activity using a tail-flick assay and hind paw pressure assay in cisplatin-treated hyperalgesic rats. The ethanol fraction displayed potent antioxidative activities in XO assay. In addition, ethanol fractions showed potent scavenging effects in DPPH assay. We next examined whether ethanol fractions showed anti-inflammatory activities. Ethanol fractions significantly suppressed NO production from LPS-activated RAW264.7 cells. As expected, ethanol fractions dose-dependently inhibited the messenger RNA expression of inducible NO synthase (iNOS). Moreover, ethanol fractions potently suppressed the expression of cycloxygenase (COX)-2 and granulocyte-macrophage colony-stimulating factor (GM-CSF), which are stimulated by LPS in RAW264.7 cells. In addition, ethanol fractions significantly blocked cisplatin-induced hyperalgesia using tail-flick assay and hind paw pressure test in rats. Taken altogether, ethanol extracts of aloe may be useful as a functional food or as a drug against reactive oxygen species (ROS) mediated diseases.
18573841 Autoimmune diseases in patients with multiple sclerosis and their first-degree relatives: 2008 Jul BACKGROUND: Multiple sclerosis (MS) and other autoimmune diseases might cluster. Our aim was to estimate the relative risk (RR) of other autoimmune diseases among MS patients and their first-degree relatives in a population-based cohort study. METHODS: Using the Danish Multiple Sclerosis Register, the Danish Hospital Discharge Register, and the Danish Civil Registration System, we estimated RRs for 42 different autoimmune diseases in a population-based cohort of 12 403 MS patients and 20 798 of their first-degree relatives. Ratios of observed to expected numbers of autoimmune diseases, based on national sex-, age-, and period-specific incidence rates, served as measures of the RRs. RESULTS: Compared with the general population, MS patients were at an increased risk of developing ulcerative colitis (RR = 2.0 (95% confidence interval (CI): 1.4-2.8), n = 29) and pemphigoid (RR = 15.4 (CI: 8.7-27.1), n = 12) but at reduced risk of rheumatoid arthritis (RR = 0.5 (CI: 0.4-0.8), n = 28) and temporal arteritis (RR = 0.5 (CI: 0.3-0.97), n = 11). First-degree relatives of MS patients were at increased risks of Crohn's disease (RR = 1.4 (CI: 1.04-1.9), n = 44), ulcerative colitis (RR = 1.3 (CI: 0.99-1.7), n = 51), Addison's disease (RR = 3.4 (CI: 1.3-9.0), n = 4), and polyarteritis nodosa (RR = 3.7 (CI: 1.4-10.0), n = 4). PATIENTS: with MS and their first-degree relatives seem to be at an increased risk of acquiring certain other autoimmune diseases.
18479176 Comparative bioavailability of lornoxicam as single doses of quick-release tablet, standar 2008 BACKGROUND AND OBJECTIVE: Lornoxicam is an NSAID used to obtain short-term relief of acute mild to moderate pain and symptomatic relief of pain and inflammation in rheumatoid arthritis and osteoarthritis. The aim of this study was to compare and evaluate the pharmacokinetic parameters of lornoxicam 8 mg as quick-release (QR) tablet, standard tablet (ST) and intramuscular injection (IM). METHODS: Eighteen healthy volunteers (9 male, 9 female; average age 26.9 (SD 3.0) years; average body mass index 21.8 (SD 2.3) kg/m2 were randomized to three different treatment groups. Subjects received a single 8-mg dose of each lornoxicam formulation in a three-way crossover design on days 1, 8 and 15. Lornoxicam plasma concentrations were obtained from baseline to 24 hours using high-pressure liquid chromatography. The pharmacokinetic parameters area under the plasma concentration-time curve from zero to infinity (AUCinfinity), maximum plasma concentration (Cmax), time to maximum plasma concentration (tmax), terminal half-life (t1/2)) and mean residence time (MRT) were calculated. RESULTS: Lornoxicam-QR was comparable with lornoxicam-ST and lornoxicam-IM regarding AUCinfinity, t1/2 and MRT. The AUCinfinity ratio (90% CI) was 1.07 (0.94, 1.20) for lornoxicam-QR/lornoxicam-ST and 1.10 (0.97, 1.24) for lornoxicam-QR/lornoxicam-IM. Cmax and tmax did not differ between lornoxicam-QR and lornoxicam-IM (p=0.66 and 0.07, respectively). Both lornoxicam-QR and lornoxicam-IM showed significantly shorter tmax and significantly higher Cmax values than lornoxicam-ST. CONCLUSION: Lornoxicam-QR and lornoxicam-IM did not differ with respect to AUCinfinity, Cmax and tmax, but both lornoxicam-QR and lornoxicam-IM showed significantly shorter tmax and significantly higher Cmax values than lornoxicam-ST.
18038911 Anti-inflammatory mechanisms of apigenin: inhibition of cyclooxygenase-2 expression, adhes 2007 Oct The aim of this study was to clarify the anti-inflammatory mechanism of apigenin. Apigenin inhibited the collagenase activity involved in rheumatoid arthritis (RA) and suppressed lipopolysaccharide (LPS)-induced nitric oxide (NO) production in a dose dependent manner in RAW 264.7 macrophage cells. Pretreatment with apigenin also attenuated LPS-induced cyclooxygenase-2 (COX-2) expression. In addition, apigenin profoundly reduced the tumor necrosis factor-alpha (TNF-alpha)-induced adhesion of monocytes to HUVEC monolayer. Apigenin significantly suppressed the TNF-alpha-stimulated upregulation of vascular cellular adhesion molecule-1 (VCAM-1)-, intracellular adhesion molecule-1 (ICAM-1)-, and E-selectin-mRNA to the basal levels. Taken together, these results suggest that apigenin has significant anti-inflammatory activity that involves blocking NO-mediated COX-2 expression and monocyte adherence. These results further suggest that apigenin may be useful for therapeutic management of inflammatory diseases.
17963710 Application of structural dynamic approaches provide novel insights into the enzymatic mec 2008 Jan 1 Zinc dependent metalloproteinases comprise a large family of structurally homologous enzymes with a wide variety of biological roles. Originally described as proteinases involved in extracellular matrix (ECM) catabolism, these enzymes were later found to serve major roles as initiators of signaling pathways in many aspects of biology, ranging from cell proliferation, differentiation and communication, to pathological states associated with tumor metastasis, inflammation, tissue degeneration and cell death. From these enzymes, the tumor necrosis factor-α converting enzyme (TACE) stands out as a central shedding activity mediating the regulated release of a host of cytokines, receptors and other cell surface molecules. Selective drugs targeted at blocking TACE for treatment of rheumatoid arthritis and other disease indications are highly sought. Yet, the structural and chemical knowledge underlying its enzymatic activity is very limited. This is in part due to the fact that the catalytic zinc atom of metalloproteinases is usually spectroscopically silent and hence difficult to study using conventional spectroscopic and analytical tools. Most structural and biochemical studies, as well as medicinal chemistry efforts carried out so far were limited to non-dynamic structure/function characterization. Thus, to date, our mechanistic knowledge comes from theoretical calculations derived from static crystal structures from family members that are highly similar in their amino acid sequence and three-dimensional structure. This review introduces the importance of real-time quantification of biophysical properties and structural kinetic behavior applied to the study of TACE and other zinc metalloproteinases to dissect their molecular mechanisms. The molecular details that link the catalytic chemistry to key kinetic, electronic and structural events have remained elusive because of the difficulties associated with probing time-dependent structure-function aspects of enzymatic reactions. Here we discuss the use of conventional and real-time structural-spectroscopic tools to study the reactive metal site during catalysis, and initial lessons on the enzymatic mechanism that we are learning. Approaches such as the ones presented here may be useful in the design of specific inhibitors as drug candidates.
17895323 CLINICAL Review #: the role of receptor activator of nuclear factor-kappaB (RANK)/RANK lig 2007 Dec CONTEXT: Receptor activator of nuclear factor-kappaB ligand (RANKL), receptor activator of nuclear factor-kappaB (RANK), and osteoprotegerin (OPG) play a central role in bone remodeling and disorders of mineral metabolism. EVIDENCE ACQUISITION: A PubMed search was conducted from January 1992 until 2007 for basic, observational, and clinical studies in subjects with disorders related to imbalances in the RANK/RANKL/OPG system. EVIDENCE SYNTHESIS: RANK, RANKL, and OPG are members of the TNF receptor superfamily. The pathways involving them in conjunction with various cytokines and calciotropic hormones play a pivotal role in bone remodeling. Several studies involving mutations in the genes encoding RANK and OPG concluded in the discovery of a number of inherited skeletal disorders. In addition, basic and clinical studies established a consistent relationship between the RANK/RANKL/OPG pathway and skeletal lesions related to disorders of mineral metabolism. These studies were a stepping stone in further defining the role of the RANK/RANKL/OPG pathway in osteoporosis, rheumatoid arthritis, bone loss associated with malignancy-related skeletal diseases, and its relationship to vascular calcifications. Subsequently, the further understanding of this pathway led to the development of new therapeutic modalities including the human monoclonal antibody to RANKL and recombinant OPG as a target for treatment of postmenopausal osteoporosis and multiple myeloma. CONCLUSIONS: The RANK/RANKL/OPG system mediates the effects of calciotropic hormones and, consequently, alterations in their ratio are key in the development of several clinical conditions. New agents with the potential to block effects of RANKL have emerged for treatment of postmenopausal osteoporosis and malignancy-related skeletal disease.
17655275 Discovery and development of folic-acid-based receptor targeting for imaging and therapy o 2008 Jan In order to avoid the toxicities associated with prescription drug use today, we have explored novel methods for delivering drugs selectively to pathologic cells, thereby avoiding the collateral damage that accompanies their uptake by healthy cells. In this Account, we describe our quest for the ideal targeted therapeutic agent. This effort began with a search for ligands that would bind selectively to pathologic cells, displaying no affinity for healthy cells. After identification of an optimal targeting ligand, effort was focused on construction of linkers that would carry the attached drug to pathologic cells with receptors for the selected ligand. In the case of cancer, we exploited the well-characterized up-regulation of folate receptors on malignant cells to target folate-linked pharmaceuticals to cancer tissues in vivo. Drugs that have been linked to folic acid for tumor-selective drug delivery to date include (i) protein toxins, (ii) chemotherapeutic agents, (iii) gene therapy vectors, (iv) oligonucleotides (including small interfering RNA (siRNA)), (v) radioimaging agents, (vi) magnetic resonance imaging (MRI) contrast agents, (vii) liposomes with entrapped drugs, (viii) radiotherapeutic agents, (ix) immunotherapeutic agents, and (x) enzyme constructs for prodrug therapy. Current clinical trials of four folate-linked drugs demonstrate that folate receptor-targeting holds great promise for increasing the potency while reducing toxicity of many cancer therapies. In the course of developing folate-conjugated drugs for cancer, we discovered that folate receptors are also overexpressed on activated (but not resting or quiescent) macrophages. Recognizing that activated macrophages either cause or contribute to such diseases as rheumatoid arthritis, Crohn's disease, atherosclerosis, lupus, inflammatory osteoarthritis, diabetes, ischemia reperfusion injury, glomerulonephritis, sarcoidosis, psoriasis, Sjogren's disease, and vasculitis, we initiated studies aimed at developing folate-conjugated imaging and therapeutic agents for the diagnosis and treatment of such diseases. In very brief time, significant progress has been made towards identification of clinical candidates for targeted treatment of several inflammatory and autoimmune diseases. This Account summarizes the discovery and development of a variety of folate-targeted drugs for the diagnosis and therapy of cancers and inflammatory/autoimmune diseases.
17634267 In vivo angiogenesis is suppressed by unsaturated vitamin E, tocotrienol. 2007 Aug Antiangiogenic therapy using drugs and food components is a recognized strategy for the prevention of various angiogenesis-mediated disorders such as tumor growth, diabetic retinopathy, and rheumatoid arthritis. Our preliminary cell culture studies, using both bovine aortic endothelial cells and human umbilical vein endothelial cells (HUVEC) on screening for food-derived antiangiogenic compounds, showed tocotrienol (T3), an unsaturated version of vitamin E, to be a potential angiogenic inhibitor. We therefore investigaged the in vivo antiangiogenic properties of T3 using 2 well-characterized angiogenic models [mouse dorsal air sac (DAS) assay and the chick embryo chorioallantoic membrane (CAM) assay]. In the DAS assay, the increased neovascularization (angiogenesis index, 4.8 +/- 0.6) in tumor cell-implanted mice was suppressed (angiogenesis index, 2.7 +/- 0.6) by dietary supplementation of 10 mg T3-rich oil/d (equivalent to 4.4 mg T3/d). In the CAM assay, T3 (500-1000 microg/egg) inhibited new blood vessel formation on the growing CAM and increased the frequency of avascular zone (36-50%). To evaluate the antiangiogenic mechanism, we conducted cell-culture studies and found that T3 significantly reduced fibroblast growth factor -induced proliferation, migration, and tube formation in HUVEC (P < 0.05), with delta-T3 having the highest activity. Western blot analysis revealed that delta-T3 suppressed the phosphorylation of phosophoinositide-dependent protein kinase (PDK) and Akt, and increased the phosphorylation of apoptosis signal-regulating kinase and p38 in fibroblast growth factor-treated HUVEC, indicating that the antiangiogenic effects of T3 are associated with changes in growth factor-dependent phosphatidylinositol-3 kinase /PDK/Akt signaling as well as induction of apoptosis in endothelial cells. Our findings suggest that T3 has potential as a therapeutic dietary supplement for preventing angiogenic disorders, and therefore future clinical study will be required to evaluate the efficacy and safety of T3.
17535987 Genomic polymorphism at the interferon-induced helicase (IFIH1) locus contributes to Grave 2007 Aug CONTEXT: A recent large-scale analysis of nonsynonymous coding polymorphisms showed strong evidence that an alanine to threonine amino acid change at codon 946 of the interferon-induced helicase (IFIH1) gene (SNP ID rs1990760) was associated with type 1 diabetes. Previous investigations have also demonstrated that an intronic polymorphism (termed PD1.3; SNP ID rs11568821) in the programmed cell death (PDCD1) gene was associated with systemic lupus erythematosus and rheumatoid arthritis. OBJECTIVE: We sought to replicate these genetic associations in Graves' disease and autoimmune Addison's disease patient cohorts. PATIENTS AND METHODS: A total of 602 Graves' disease subjects, 214 Addison's disease subjects, and 446 healthy controls were genotyped for the IFIH1 and PDCD1 single-nucleotide polymorphisms using mass spectrometer analysis of primer extension products (Sequenom). RESULTS: The alanine-carrying allele at the IFIH1 codon 946 polymorphism was present in 796 of 1204 (66%) Graves' disease patient alleles compared with 508 of 892 (57%) control subject alleles [odds ratio 1.47 (5-95% confidence interval, 1.23-1.76); P = 1.9 x 10(-5)]. In contrast, there was no association of alleles at this marker in autoimmune Addison's disease. Neither was there evidence for association in either patient cohort at the PD1.3 polymorphism. CONCLUSIONS: We confirm a significant contribution of the Ala946Thr IFIH1 polymorphism to organ-specific autoimmune diseases, extending the range of conditions associated with this variant to include Graves' disease. This polymorphism may also contribute to several other autoimmune disorders.
17533007 Functions of TNF and its receptors in renal disease: distinct roles in inflammatory tissue 2007 May Tumor necrosis factor (TNF) alpha is a potent proinflammatory cytokine and important mediator of inflammatory tissue damage. In addition, it has important immune-regulatory functions. Many experimental studies and clinical observations support a role for TNF in the pathogenesis of acute and chronic renal disease. However, given its dual functions in inflammation and immune regulation, TNF may mediate both proinflammatory as well as immunosuppressive effects, particularly in chronic kidney diseases and systemic autoimmunity. Blockade of TNF in human rheumatoid arthritis or Crohn's disease led to the development of autoantibodies, lupus-like syndrome, and glomerulonephritis in some patients. These data raise concern about using TNF-blocking therapies in renal disease because the kidney may be especially vulnerable to the manifestation of autoimmune processes. Interestingly, recent experimental evidence suggests distinct roles for the 2 TNF receptors in mediating local inflammatory injury in the kidney and systemic immune-regulatory functions. In this review the biologic properties of TNF and its receptors, TNF receptors 1 and 2, relevant to kidney disease are summarized followed by a review of the available experimental and clinical data on the pathogenic role of the TNF system in nonimmune and immune renal diseases. Experimental evidence also is reviewed that supports a rationale for specifically blocking TNF receptor 2 versus anti-TNF therapies in some nephropathies, including immune complex-mediated glomerulonephritis.
17492939 Polyphosphate blocks tumour metastasis via anti-angiogenic activity. 2007 Aug 15 PolyP (inorganic polyphosphate) is a linear polymer of many tens or hundreds of orthophosphate residues found in a wide range of organisms, including bacteria, fungi, insects, plants and vertebrates. Despite its wide distribution in mammalian tissues and plasma, the biological functions of polyP on tumour metastasis and angiogenesis have not been previously examined. In the present study, we have shown that polyP effectively blocked in vivo pulmonary metastasis of B16BL6 cells by suppression of neovascularization, whereas it did not affect proliferation or adhesion to extracellular matrix proteins. PolyP not only inhibited bFGF (basic fibroblast growth factor)-induced proliferation and ERK (extracellular-signal-regulated kinase)/p38 MAPK (mitogen-activated protein kinase) activation of human endothelial cells, but also blocked the binding of bFGF to its cognate cell-surface receptor. Furthermore, polyP inhibited bFGF-induced in vitro and in vivo angiogenesis, suggesting that polyP possesses an anti-angiogenic activity. Since neovascularization is essential for tumour metastasis, our present findings clearly indicate that polyP has an in vivo anti-metastatic activity via its anti-angiogenic activity. Taken together with the fact that angiogenesis occurs under various normal and pathological conditions, our observations suggest that endogenous polyP may play a critical role during embryonic development, wound healing and inflammation, as well as in the progress of pathological diseases such as rheumatoid arthritis and cancer.