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ID PMID Title PublicationDate abstract
24060442 Adherence to osteoporosis regimens among men and analysis of risk factors of poor complian 2013 Sep 23 BACKGROUND: To investigate adherence and patient-specific factors associated with poor compliance with osteoporosis regimens among men. METHODS: In this retrospective chart review study, we collected data on male patients with osteoporosis treated in accordance with therapeutic recommendations. Adherence was determined by the compliance and persistence of those patients who had been dispensed an osteoporosis regimen after an index prescription. All osteoporosis regimens were considered equivalent for the purpose of investigating adherence. RESULTS: The prescriptions of 333 males met the inclusion criteria for data collection. The mean age was 68.6 ± 10.4 years. The median medication possession ratio (MPR, %) at years 1 and 2 was 90.1% (interquartile range (IQR) 19-100) and 53.7% (IQR 10.4-100), respectively; 52.3% of male patients at year 1 and 37.5% at year 2 had good compliance (defined as a MPR≧80%). The 1- and 2-year persistence rates were 45.9% and 30.0%, respectively. Patient-specific factors associated with poor compliance (MPR < 80%) during year 1 were first prescriptions given by orthopedists (odds ratio (OR) = 2.67; 95% confidence interval (CI) = 1.58-4.53; adjusted OR = 2.30, 95% CI = 1.26-4.22, p = 0.007). Male patients with rheumatoid arthritis (RA) (OR = 0.22, 95% CI = 0.06-0.78, adjusted OR = 0.19, 95% CI = 0.04-0.81, p = 0.025) and baseline bone mineral density (BMD) measurements (OR = 0.52, 95% CI = 0.32-0.85; adjusted OR = 0.51; 95% CI = 0.28-0.93, p = 0.029) were less likely to have poor compliance. CONCLUSIONS: Adherence to osteoporosis regimens in males was suboptimal in our study. Poor compliance was more likely in prescription of the first anti-osteoporotic regimen by an orthopedist. Men with RA and BMD measurements before therapy had a lower risk of non-adherence. Healthcare professionals need to target patients with specific factors to improve adherence to osteoporotic regimens.
23899415 Anti-angiogenic quassinoid-rich fraction from Eurycoma longifolia modulates endothelial ce 2013 Nov Targeting angiogenesis could be an excellent strategy to combat angiogenesis-dependent pathophysiological conditions such as cancer, rheumatoid arthritis, obesity, systemic lupus erythematosus, psoriasis, proliferative retinopathy and atherosclerosis. Recently a number of clinical investigations are being undertaken to assess the potential therapeutic application of various anti-angiogenic agents. Many of these angiogenesis inhibitors are directed against the functions of endothelial cells, which are considered as the building blocks of blood vessels. Similarly, roots of a traditional medicinal plant, Eurycoma longifolia, can be used as an alternative treatment to prevent and treat the angiogenesis-related diseases. In the present study, antiangiogenic potential of partially purified quassinoid-rich fraction (TAF273) of E. longifolia root extract was evaluated using ex vivo and in vivo angiogenesis models and the anti-angiogenic efficacy of TAF273 was investigated in human umbilical vein endothelial cells (HUVEC). TAF273 caused significant suppression in sprouting of microvessels in rat aorta with IC50 11.5μg/ml. TAF273 (50μg/ml) showed remarkable inhibition (63.13%) of neovascularization in chorioallantoic membrane of chick embryo. Tumor histology also revealed marked reduction in extent of vascularization. In vitro, TAF273 significantly inhibited the major angiogenesis steps such as proliferation, migration and differentiation of HUVECs. Phytochemical analysis revealed high content of quassinoids in TAF273. Specially, HPLC characterization showed that TAF273 is enriched with eurycomanone, 13α(21)-epoxyeurycomanone and eurycomanol. These results demonstrated that the antiangiogenic activity of TAF273 may be due to its inhibitory effect on endothelial cell proliferation, differentiation and migration which could be attributed to the high content of quassinoids in E. longifolia.
23843952 Rituximab in relapsing and progressive forms of multiple sclerosis: a systematic review. 2013 BACKGROUND: Rituximab is an anti-CD20 monoclonal antibody approved for non Hodgkin lymphoma and rheumatoid arthritis. It is being considered for the treatment of MS. OBJECTIVES: To evaluate the efficacy and safety of rituximab for MS treatment. DATA COLLECTION: Studies were selected if they were clinical trials, irrespective of the dosage or combination therapies. MAIN RESULTS: Four studies with a total of 599 patients were included. One assessed the efficacy of rituximab for primary progressive (PP) MS while the other three focused on relapsing-remitting (RR) MS. In the PPMS study, rituximab delayed time to confirmed disease progression (CDP) in pre-planned sub-group analyses. The increase in T2 lesion volume was lower in the rituximab group at week 96 compared with placebo. For the RRMS studies, an open-label phase I study found that rituximab reduced the annualized relapse rate to 0.25 from pre-therapy baseline to week 24, while in the randomized placebo-controlled phase II trial, annualized relapse rates were 0.37 in the rituximab group and 0.84 in the placebo group (p = 0.04) at week 24. Rituximab dramatically reduced the number of gadolinium-enhancing lesions on brain MRI scans for both RRMS studies. Off-label rituximab as an add-on therapy in patients with breakthrough disease on first-line agents was associated with an 88% reduction when comparing the mean number of gadolinium-enhancing lesions prior to and after the treatment. Although frequent adverse events classified as mild or moderate occurred in up to 77% of the patients, there were no grade 4 infusion-related adverse events. AUTHOR’S CONCLUSION: Despite the frequent mild/moderate adverse events related to the drug, rituximab appears overall safe for up to 2 years of therapy and has a substantial impact on the inflammatory disease activity (clinical and/or radiological) of RRMS. The effect of rituximab on disease progression in PPMS appears to be marginal.
23720862 (99m)Tc-Type II tumor necrosis receptor-Fc-interlukin-1 receptor antagonist fusion protein 2004 Tumor necrosis factor (TNF) is a proinflammatory cytokine produced by macrophages, and it plays an important role in inflammation and immune response (1). There are two types of TNF (TNF-α, TNF-β). TNF-α is mainly responsible for initiating inflammatory responses by induction of several proinflammatory cytokines, chemokines, matrix metalloproteinases, and vascular endothelial adhesion molecules that attract leukocytes known to promote inflammation. There are two types of TNF receptors: TNFR1 and TNFR2. Soluble forms of TNF receptors are released upon proteolytic cleavage of the membrane-bound TNF receptors. Soluble TNF receptors participate in limiting the availability of TNF to bind to its receptors (2, 3). Several anti-TNF monoclonal antibodies (TNF blockers) to further reduce circulating TNF have been approved by the United States Food and Drug Administration (FDA) for the treatment of a variety of inflammatory diseases (4, 5). The interleukin-1 family consists of two proinflammatory cytokines, IL-1α and IL-1β, which bind to two IL-1 receptors (IL-1R1 and IL-1R2), and an IL-1R antagonist (IL-1ra), which is mainly produced by activated macrophages and tissue macrophages (6). IL-1α and IL-1β are important mediators of the inflammatory response and hematopoiesis, and they are involved in a variety of cellular activities, including cell proliferation, differentiation, and apoptosis. IL-1 is involved in chronic inflammatory diseases and in neuropathological conditions (7, 8). The balancing act of IL-1 and IL-1ra plays an important role in the regulation of inflammation and immune responses (9). IL-1ra has been shown to be effective as an anti-inflammatory treatment in several chronic inflammatory diseases and stroke (10, 11). A human recombinant, non-glycosylated form of the human IL-1ra (rhIL-1ra, Anakinra) has been approved by the FDA for the treatment of rheumatoid arthritis (12). IL-1β and TNF-α exhibit additive or synergistic effects in promoting pathophysiological processes observed in many inflammatory diseases (13). A dual domain TNFR2-Fc-IL-1ra fusion protein was constructed by joining TNFR2 and IL-1ra cDNA to the Fc fragment of human IgG(1) cDNA in an expression plasmid (14). The amino-terminal segment binds to TNF, and the carboxyl-terminal sequence binds to the IL-1R. Liu et al. (14) radiolabeled TNFR2-Fc-IL-1ra with (99m)Tc via 2-iminothiolane reduction to produce (99m)Tc-TNFR2-Fc-IL-1ra for use with single-photon emission computed tomography (SPECT) imaging of inflammation in mice.
23577057 RNAi-mediated silencing of Atp6i and Atp6i haploinsufficiency prevents both bone loss and 2013 Periodontal disease affects about 80% of adults in America, and is characterized by oral bacterial infection-induced gingival inflammation, oral bone resorption, and tooth loss. Periodontitis is also associated with other diseases such as rheumatoid arthritis, diabetes, and heart disease. Although many efforts have been made to develop effective therapies for this disease, none have been very effective and there is still an urgent need for better treatments and preventative strategies. Herein we explored for the first time the possibility that adeno-associated virus (AAV)-mediated RNAi knockdown could be used to treat periodontal disease with improved efficacy. For this purpose, we used AAV-mediated RNAi knockdown of Atp6i/TIRC7 gene expression to target bone resorption and gingival inflammation simultaneously. Mice were infected with the oral pathogen Porphyromonas gingivalis W50 (P. gingivalis) in the maxillary periodontium to induce periodontitis. We found that Atp6i depletion impaired extracellular acidification and osteoclast-mediated bone resorption. Furthermore, local injection of AAV-shRNA-Atp6i/TIRC7 into the periodontal tissues in vivo protected mice from P. gingivalis infection-stimulated bone resorption by >85% and decreased the T-cell number in periodontal tissues. Notably, AAV-mediated Atp6i/TIRC7 knockdown also reduced the expression of osteoclast marker genes and inflammation-induced cytokine genes. Atp6i(+/-) mice with haploinsufficiency were similarly protected from P. gingivalis infection-stimulated bone loss and gingival inflammation. This suggests that AAV-shRNA-Atp6i/TIRC7 therapeutic treatment may significantly improve the health of millions who suffer from P. gingivalis-mediated periodontal disease.
23383699 Best practices in specialty pharmacy management. 2013 Jan BACKGROUND: Specialty pharmacy is a growing area of research, utilization, and cost. Because of the unique nature of the diseases treated by specialty pharmaceuticals, such as cancer and rheumatoid arthritis, novel management approaches are needed. Advocate Physician Partners (APP) is an entity within the Advocate Health Care Health System in the Chicago and the central Illinois area. It coordinates the care management and managed care contracting between the Advocate Health Care System and more than 4,000 physicians on the medical staffs of Advocate hospitals. APP has experienced a per-member-per-month (PMPM) increase of less than  3% in oncology intravenous medications spend in 2012. This spend refers to the intravenous medications covered under the medical benefits for APP's health maintenance organization (HMO) population. The spend has consistently been less than national projections, and we believe this is tied to the adoption of several key best practices. Prior to instituting the best practices, the yearly percentage increases for oncology spending were 5.52% (2007 to 2008), 9.39% (2008 to 2009), and 5.29% (2009 to 2010). After instituting best practices during the first quarter of 2011, the increases in PMPM were 3.11% (2010 to 2011) and 2.11% (2011 to 2012), which were below previous years. OBJECTIVE: To describe the best practices of specialty pharmacy management adopted by APP, specifically (a) establishing a content expert and governing bodies, (b) ensuring compliance with policies, and (c) providing educational resources. METHODS: APP has several key result areas (KRAs). One KRA was compliance with appropriate utilization of intravenous oncology protocols for its HMO population. The protocols for each medication outline the appropriate indication and patient population. These protocols were developed and reviewed by the APP Pharmacy and Technology (PT) committee. The PT-approved indications reflect FDA indications and indications found in national guidelines. The APP KRA target for the utilization of protocols was 80%. The compliance for completing the protocols that correspond to these medications was calculated by tabulating the number of paid claims over the number of completed protocols, resulting in a compliance percentage. APP defined noncompliance as any utilization not outlined in the protocol. Another KRA was physician feedback. APP requires that physicians complete a certain number of continuing medical education (CME) programs provided by APP each year. Feedback from physicians, provided at the end of the CME, were tabulated and utilized for further programs. Additionally, APP strived to increase physician engagement by placing them in key roles that oversaw clinical and business aspects of the organization. In order to meet the KRAs, investigate inappropriate utilization, and become better involved in engaging oncology specialists, APP invested in an oncology clinical pharmacist position. The primary responsibility of the oncology clinical pharmacist was to be a specialty drug resource for the organization with a focus on provider education. The oncology clinical pharmacist was deemed the content expert who developed clinical protocols, educated providers, and encouraged compliance with organizational policies and procedures as it pertained to the KRAs. RESULTS: Since establishing the oncology clinical pharmacist position, APP has seen an increase in protocol compliance. Prior to the institution of this position, the protocol compliance was 62%. In less than 1 year after hiring the oncology clinical pharmacist, the compliance percentage spiked to over 80%. APP has several committees and boards that oversee the clinical and business aspects of the organization. By placing physicians in chairmanship positions of the committees, APP has seen the benefit of handling difficult patient decisions and increased compliance with policies. Lastly, extensive provider education has led to an improved physician satisfaction in the educational initiatives of APP. Greater than 80% of the physicians felt the CME content was relevant to their practices; the content would likely have a positive impact on their practices; and the clinical content was evidence based and accepted by the medical community. CONCLUSIONS: By hiring an oncology clinical pharmacist, engaging physicians by placing them in key roles, and providing more specialist-specific education, APP has improved its KRAs and compliance percentages. APP achieved success in containing expenditures for oncology intravenous medications by implementing key best practices combined with traditional management strategies.
23329394 Targeting the B7 family of co-stimulatory molecules: successes and challenges. 2013 Feb As more patient data is cross-referenced with animal models of disease, the primary focus on T(h)1 autoreactive effector cell function in autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis, has shifted towards the role of T(h)17 autoreactive effector cells and the ability of regulatory T cells (T(reg)) to modulate the pro-inflammatory autoimmune response. Therefore, the currently favored hypothesis is that a delicate balance between T(h)1/17 effector cells and T(reg) cell function is critical in the regulation of inflammatory autoimmune disease. An intensive area of research with regard to the T(h)1/17:T(reg) cell balance is the utilization of blockade and/or ligation of various co-stimulatory or co-inhibitory molecules, respectively, during ongoing disease to skew the immune response toward a more tolerogenic/regulatory state. Currently, FDA-approved therapies for multiple sclerosis patients are all aimed at the suppression of immune cell function. The other favored method of treatment is a modulation or deletion of autoreactive immune cells via short-term blockade of activating co-stimulatory receptors via treatment with fusion proteins such as CTLA4-Ig and CTLA4-FasL. Based on the initial success of CTLA4-Ig, there are additional fusion proteins that are currently under development. Examples of the more recently identified B7/CD28 family members are PD-L1, PD-L2, inducible co-stimulatory molecule-ligand (ICOS-L), B7-H3, and B7-H4, all of which may emerge as potential fusion protein therapeutics, each with unique, yet often overlapping functions. The expression of both stimulatory and inhibitory B7 molecules seems to play an essential role in modulating immune cell function through a variety of mechanisms, which is supported by findings that suggest each B7 molecule has developed its own indispensable niche in the immune system. As more data are generated, the diagnostic and therapeutic potential of the above B7 family-member-derived fusion proteins becomes ever more apparent. Besides defining the biology of these B7/CD28 family members in vivo, additional difficulty in the development of these therapies lies in maintaining the normal immune functions of recognition and reaction to non-self-antigens following viral or bacterial infection in the patient. Further complicating the clinical translation of these therapies, the mechanism of action identified for a particular reagent may depend upon the method of immune-cell activation and the subset of immune cells targeted in the study.
25457839 Pregnancy level of estrogen attenuates experimental autoimmune encephalomyelitis in both o 2014 Dec 15 Pregnancy suppressive effect on autoimmune diseases including Multiple Sclerosis and Rheumatoid Arthritis may result from high levels of sex steroids such as estrogen and estriol. This study was designed to reveal the molecular and cellular mechanisms underlying the effect of estrogen on MS alleviation. Female C57BL/6 mice were immunized with MOG35-55. Clinical scores and other relevant parameters were monitored daily. Brain and spinal cord histology was performed to measure lymphocyte infiltration and central nervous system demyelination. Th1/Th2/Th17 and Treg cell profiles were determined through ELISA, flow cytometry, and real-time PCR. Transcription factor expression levels in the CNS were assessed by real-time PCR and T cell differentiation was explored through flow cytometry examination. Pregnancy and pregnancy level of estrogen alleviated clinical manifestations in EAE induced mice, reduced CNS demyelination and cell infiltration, suppressed spleen T cell proliferation, enhanced production of anti-inflammatory cytokines in splenocytes and increased the percentage of Th2 and Treg cells. Furthermore, the results of real-time PCR for transcription factors and related cytokines of Th1/Th2/Th17 and Treg cells in CNS showed reduced expression levels of Th1 and Th17 transcription factors, including T-bet and ROR-γt, and decreased Th1 and Th17 cytokines including IFN-γ, TNF-α, IL-17 and IL-23. These results are the first to indicate that pregnancy and pregnancy level of estrogen ameliorate the EAE condition by favoring Treg and Th2 differentiation through induced expression of Foxp3 and GATA3 in the CNS. Moreover, pregnancy and pregnancy level of estrogen decreased mRNA levels of T-bet and ROR-γt in the CNS.
25448930 Spectroscopic analysis of the impact of oxidative stress on the structure of human serum a 2015 Feb 5 Oxygen metabolism has an important role in the pathogenesis of rheumatoid arthritis (RA). Reactive oxygen species (ROS) are produced in the course of cellular oxidative phosphorylation and by activated phagocytic cells during oxidative bursts, exceed the physiological buffering capacity and result in oxidative stress. ROS result in oxidation of serum albumin, which causes a number of structural changes in the spatial structure, may influence the binding and cause significant drug interactions, particularly in polytherapy. During the oxidation modification of amino acid residues, particularly cysteine and methionine may occur. The aim of the study was to investigate the influence of oxidative stress on human serum albumin (HSA) structure and evaluate of possible alterations in the binding of the drug to oxidized human serum albumin (oHSA). HSA was oxidized by a chloramine-T (CT). CT reacts rapidly with sulfhydryl groups and at pH 7.4 the reaction was monitored by spectroscopic techniques. Modification of free thiol group in the Cys residue in HSA was quantitatively determined by the use of Ellman's reagent. Changes of albumin conformation were examined by comparison of modified (oHSA) and nonmodified human serum albumin (HSA) absorption spectra, emission spectra, red-edge shift (REES) and synchronous spectroscopy. Studies of absorption spectra indicated that changes in the value of absorbance associated with spectral changes in the region of 200-250 nm involve structural alterations in peptide backbone conformation. Synchronous fluorescence spectroscopy technique confirmed changes of position of tryptophanyl and tyrosyl residues fluorescent band caused by CT. Moreover analysis of REES effect allowed to observe structural changes caused by CT in the region of the hydrophobic pocket containing the tryptophanyl residue. Effect of oxidative stress on binding of anti-rheumatic drugs, sulfasalazine (SSZ) and sulindac (SLD) in the high and low affinity binding sites was investigated by spectrofluorescence, ITC and (1)H NMR spectroscopy, respectively. SSZ and SLD change the affinity of each other to the binding site in non- and modified human serum albumin. The presence of SLD causes the increase of association constant (Ka) of SSZ-oHSA system and the strength of binding and the stability of the complexes has been observed while in the presence of SSZ a displacement of SLD from the SLD-HSA has been recorded. The analysis of (1)H NMR spectral parameters i.e. changes of chemical shifts of the drug indicate that the presence of SSZ and SLD have a mutual influence on changes in the affinity of human serum albumin binding site and this competition takes place not only due to the additional drug but also to the oxidation of HSA.
25345743 Establishment of a novel cell-based assay for screening small molecule antagonists of huma 2014 Nov AIM: Blockade of interleukin-6 (IL-6) or its receptor (IL-6R) is effective in preventing the progression of autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis. In the present study, we established a novel cell-based assay for identifying small molecule IL-6R antagonists. METHODS: HEK293A cells were transfected with recombinant plasmids pTaglite-SNAP-IL6R and pABhFc-IL6 to obtain membrane-bound IL-6R and recombinant human IL-6 coupled with human Fc fragment (rhIL-6), respectively. A novel screening assay based on the interaction between IL-6R and rhIL-6 was established, optimized and validated. The stability of the assay was also assessed by calculating the Z'-factor. RESULTS: RhIL-6 dose-dependently bound to IL-6R expressed at HEK293A cell surface. The IC50 value of the known antagonist ab47215 was 0.38±0.08 μg/mL, which was consistent with that obtained using the traditional method (0.36±0.14 μg/mL). The value of Z'-factor was 0.68, suggesting that the novel assay was stable for high throughput screening. A total of 474 compounds were screened using the novel screening assay, and 3 compounds exhibited antagonistic activities (IC50=8.73±0.28, 32.32±9.08, 57.83±4.24 μg/mL). Furthermore, the active compounds dose-dependently inhibited IL-6-induced proliferation of 7TD1 cells, and reduced IL-6-induced STAT3 phosphorylation in U937 cells. CONCLUSION: A novel cell-based screening assay for identifying small molecule IL-6R antagonists was established, which simplifies the procedures in traditional cellular ELISA screening and profiling and reduces the costs.
25329869 Pharmacokinetic comparisons of benzoylmesaconine in rats using ultra-performance liquid ch 2014 Oct 17 Wutou decoction is widely used in China because of its therapeutic effect on rheumatoid arthritis. Benzoylmesaconine (BMA), the most abundant component of Wutou decoction, was used as the marker compound for the pharmacokinetic study of Wutou decoction. The aim of the present study was to compare the pharmacokinetics of BMA in rats after oral administration of pure BMA and Wutou decoction. Pure BMA (5 mg/kg) and Wutou decoction (0.54 g/kg, equivalent to 5 mg/kg BMA) were orally administered to rats with blood samples collected over 10 h. Quantification of BMA in rat plasma was achieved using sensitive and validated ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Specifically, the half-life (T1/2) and mean residence time values of pure BMA were 228.3 ± 117.0 min and 155.0 ± 33.2 min, respectively, whereas those of BMA in Wutou decoction were decreased to 61.8 ± 35.1 min and 55.8 ± 16.4 min, respectively. The area under the curve (AUC) of BMA after administration of Wutou decoction was significantly decreased (five-fold) compared with that of pure BMA. The results indicate that the elimination of BMA in rats after the administration of Wutou decoction was significantly faster compared with that of pure BMA.
25319439 Listeria monocytogenes-associated biliary tract infections: a study of 12 consecutive case 2014 Oct At present, little is known regarding Listeria monocytogenes-associated biliary tract infection, a rare form of listeriosis.In this article, we will study 12 culture-proven cases reported to the French National Reference Center for Listeria from 1996 to 2013 and review the 8 previously published cases.Twenty cases were studied: 17 cholecystitis, 2 cholangitis, and 1 biliary cyst infection. Half were men with a median age of 69 years (32-85). Comorbidities were present in 80%, including cirrhosis, rheumatoid arthritis, and diabetes. Five patients received immunosuppressive therapy, including corticosteroids and anti-tumor necrosis factor biotherapies. Half were afebrile. Blood cultures were positive in 60% (3/5). Gallbladder histological lesions were analyzed in 3 patients and evidenced acute, chronic, or necrotic exacerbation of chronic infection. Genoserogroup of the 12 available strains were IVb (n=6), IIb (n=5), and IIa (n=1). Their survival in the bile was not enhanced when compared with isolates from other listeriosis cases. Adverse outcome was reported in 33% (5/15): 3 deaths, 1 recurrence; 75% of the patients with adverse outcome received inadequate antimicrobial therapy (P=0.033).Biliary tract listeriosis is a severe infection associated with high mortality in patients not treated with appropriate therapy. This study provides medical relevance to in vitro and animal studies that had shown Listeria monocytogenes ability to survive in bile and induce overt biliary infections.
25196213 CDr10b inhibits the expression of cyclooxygenase-2 and inducible nitric oxide synthase ind 2014 Nov 5 The pathophysiological processes of inflammation can lead to a host of diseases, such as periodontitis, atherosclerosis, rheumatoid arthritis, and even cancer. The dysregulated inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) activation play important roles in the development of certain inflammatory diseases. Here, we investigated the effects of CDr10b which is originally developed for a microglia staining probe on inflammation, by modulating NF-κB activation and iNOS and COX-2 expression induced by lipopolysaccharide (LPS) in murine macrophages. The CDr10b suppressed NF-κB activation and iNOS and COX-2 expression induced by LPS. All the results suggest that CDr10b is a promising novel agent for the treatment of inflammatory diseases.
25164081 Peptidyl arginine deiminase-4 activation exacerbates kidney ischemia-reperfusion injury. 2014 Nov 1 Peptidyl arginine deiminase (PAD)4 is a nuclear enzyme that catalyzes the posttranslational conversion of arginine residues to citrulline. Posttranslational protein citrullination has been implicated in several inflammatory autoimmune diseases, including rheumatoid arthritis, colitis, and multiple sclerosis. Here, we tested the hypothesis that PAD4 contributes to ischemic acute kidney injury (AKI) by exacerbating the inflammatory response after renal ischemia-reperfusion (I/R). Renal I/R injury in mice increased PAD4 activity as well as PAD4 expression in the mouse kidney. After 30 min of renal I/R, vehicle-treated mice developed severe AKI with large increases in plasma creatinine. In contrast, mice pretreated with PAD4 inhibitors (2-chloroamidine or streptonigrin) had significantly reduced renal I/R injury. Further supporting a critical role for PAD4 in generating ischemic AKI, mice pretreated with recombinant human PAD4 (rPAD4) protein and subjected to mild (20 min) renal I/R developed exacerbated ischemic AKI. Consistent with the hypothesis that PAD4 regulates renal tubular inflammation after I/R, mice treated with a PAD4 inhibitor had significantly reduced renal neutrophil chemotactic cytokine (macrophage inflammatory protein-2 and keratinocyte-derived cytokine) expression and had decreased neutrophil infiltration. Furthermore, mice treated with rPAD4 had significantly increased renal tubular macrophage inflammatory protein-2 and keratinocyte-derived cytokine expression as well as increased neutrophil infiltration and necrosis. Finally, cultured mouse kidney proximal tubules treated with rPAD4 had significantly increased proinflammatory chemokine expression compared with vehicle-treated cells. Taken together, our results suggest that PAD4 plays a critical role in renal I/R injury by increasing renal tubular inflammatory responses and neutrophil infiltration after renal I/R.
25112565 How does mental-physical multimorbidity express itself in lived time and space? A phenomen 2014 Oct Mental-physical multimorbidity (the co-existence of mental and physical ill health) is highly prevalent and associated with significant impairments and high healthcare costs. While the sociology of chronic illness has developed a mature discourse on coping with long term physical illness the impact of mental and physical health have remained analytically separated, highlighting the need for a better understanding of the day-to-day complexities encountered by people living with mental-physical multimorbidity. We used the phenomenological paradigm of the lived body to elucidate how the experience of mental-physical multimorbidity shapes people's lifeworlds. Nineteen people with chronic obstructive pulmonary disease (COPD) and depression (defined as a score ≥8 on depression scale of Hospital Anxiety and Depression Scale) were recruited from secondary NHS care and interviewed at their homes. Data were analysed phenomenologically using van Manen's lifeworld existential framework of the lived body, lived time, lived space, lived relations. Additionally, we re-analysed data (using the same framework) collected from 13 people recruited from secondary NHS care with either COPD, rheumatoid arthritis, heart disease, or type 1 or type 2 diabetes and depression. The phenomenology of mental-physical multimorbidity was articulated through embodied and emotional encounters with day-to-day life in four ways: [a] participants' perception of lived time and lived space contracted; [b] time and [c] space were experienced as liminal categories, enforcing negative mood and temporal and spatial contraction; and [d] time and space could also be customised to reinstate agency and self-determination. Mental-physical multimorbidity negatively impacts on individuals' perceptions of lived time and lived space, leading to a loss of agency, heightened uncertainty, and poor well-being. Harnessing people's capacity to modify their experience of time and space may be a novel way to support people with mental-physical multimorbidity to live well with illness.
25036790 Multi-dimensional target profiling of N,4-diaryl-1,3-thiazole-2-amines as potent inhibitor 2014 Sep 12 Eicosanoids like leukotrienes and prostaglandins play a considerable role in inflammation. Produced within the arachidonic acid (AA) cascade, these lipid mediators are involved in the pathogenesis of pain as well as acute and chronic inflammatory diseases like rheumatoid arthritis and asthma. With regard to the lipid cross-talk within the AA pathway, a promising approach for an effective anti-inflammatory therapy is the development of inhibitors targeting more than one enzyme of this cascade. Within this study, thirty N-4-diaryl-1,3-thiazole-2-amine based compounds with different substitution patterns were synthesized and tested in various cell-based assays to investigate their activity and selectivity profile concerning five key enzymes involved in eicosanoid metabolism (5-, 12-, 15-lipoxygenase (LO), cyclooxygenase-1 and -2 (COX-1/-2)). With compound 7, 2-(4-phenyl)thiazol-2-ylamino)phenol (ST-1355), a multi-target ligand targeting all tested enzymes is presented, whereas compound 9, 2-(4-(4-chlorophenyl)thiazol-2-ylamino)phenol (ST-1705), represents a potent and selective 5-LO and COX-2 inhibitor with an IC50 value of 0.9 ± 0.2 μM (5-LO) and a residual activity of 9.1 ± 1.1% at 10 μM (COX-2 product formation). The promising characteristics and the additional non-cytotoxic profile of both compounds reveal new lead structures for the treatment of eicosanoid-mediated diseases.
24971753 A novel function for lysyl oxidase in pluripotent mesenchymal cell proliferation and relev 2014 Lysyl oxidase is a multifunctional enzyme required for collagen biosynthesis. Various growth factors regulate lysyl oxidase during osteoblast differentiation, subject to modulation by cytokines such as TNF-α in inflammatory osteopenic disorders including diabetic bone disease. Canonical Wnt signaling promotes osteoblast development. Here we investigated the effect of Wnt3a and TNF-α on lysyl oxidase expression in pluripotent C3H10T1/2 cells, bone marrow stromal cells, and committed osteoblasts. Lysyl oxidase was up-regulated by a transcriptional mechanism 3-fold in C3H10T1/2 cells, and 2.5-fold in bone marrow stromal cells. A putative functional TCF/LEF element was identified in the lysyl oxidase promoter. Interestingly, lysyl oxidase was not up-regulated in committed primary rat calvarial- or MC3T3-E1 osteoblasts. TNF-α down-regulated lysyl oxidase both in Wnt3a-treated and in non-treated C3H10T1/2 cells by a post-transcriptional mechanism mediated by miR203. Non-differentiated cells do not produce a collagen matrix; thus, a novel biological role for lysyl oxidase in pluripotent cells was investigated. Lysyl oxidase shRNAs effectively silenced lysyl oxidase expression, and suppressed the growth of C3H10T1/2 cells by 50%, and blocked osteoblast differentiation. We propose that interference with lysyl oxidase expression under excess inflammatory conditions such as those that occur in diabetes, osteoporosis, or rheumatoid arthritis can result in a diminished pool of pluripotent cells which ultimately contributes to osteopenia.
24677326 Enhanced immunoprotective effects by anti-IL-17 antibody translates to improved skeletal p 2014 Sep Activated T cell has a key role in the interaction between bone and immune system. T cells produce proinflammatory cytokines, including receptor activator of NF-κB ligand (RANKL), tumor necrosis factor α (TNF-α), and interleukin 17 (IL-17), all of which augment osteoclastogenesis. RANKL and TNF-α are targeted by inhibitors such as denosumab, a human monoclonal RANKL antibody, and infliximab, which neutralizes TNF-α. IL-17 is also an important mediator of bone loss, and an antibody against IL-17 is undergoing phase II clinical trial for rheumatoid arthritis. Although there are a few studies showing suppression of Th17 cell differentiation and induction of regulatory T cells (Tregs) by infliximab, the effect of denosumab remains poorly understood. In this study, we investigated the effects of anti-TNF-α, anti-RANKL, or anti-IL-17 antibody administration to estrogen-deficient mice on CD4(+) T-cell proliferation, CD28 loss, Th17/Treg balance and B lymphopoesis, and finally, the translation of these immunomodulatory effects on skeletal parameters. Adult Balb/c mice were treated with anti-RANKL/-TNF-α/-IL-17 subcutaneously, twice a week, postovariectomy (Ovx) for 4 weeks. Animals were then autopsied; bone marrow cells were collected for FACS and RNA analysis and serum collected for ELISA. Bones were dissected for static and dynamic histomorphometry studies. We observed that although anti-RANKL and anti-TNF-α therapies had no effect on Ovx-induced CD4(+) T-cell proliferation and B lymphopoesis, anti-IL-17 effectively suppressed both events with concomitant reversal of CD28 loss. Anti-IL-17 antibody reduced proinflammatory cytokine production and induced Tregs. All three antibodies restored trabecular microarchitecture with comparable efficacy; however, cortical bone parameters, bone biomechanical properties, and histomorphometry were best preserved by anti-IL-17 antibody, likely attributable to its inhibitory effect on osteoblast apoptosis and increased number of bone lining cells and Wnt10b expression. Based on the superior immunoprotective effects of anti-IL-17, which appears to translate to a better skeletal preservation, we propose beginning clinical trials using a humanized antibody against IL-17 for treatment of postmenopausal osteoporosis.
24616831 Omega 3 fatty acids as a host modulator in chronic periodontitis patients: a randomised, d 2014 Feb PURPOSE: Periodontitis is an infectious disease caused predominantly by gram-negative anerobes. The host inflammatory response to these bacteria causes alveolar bone loss that is characterized as periodontitis. Omega-3 fatty acids (ω-3 FAs) have anti-inflammatory properties, thus have been used to treat some chronic inflammatory diseases such as cardiovascular disease and rheumatoid arthritis. We aimed to evaluate the effect of dietary supplementation with ω-3 FAs as a host modulating agent in patients with chronic periodontitis. METHODS: Sixty otherwise healthy subjects with moderate and severe chronic periodontitis were enrolled in our randomised, double-blind, placebo-controlled trial. The control group (CG, n=30) was treated with scaling and root planing (SRP) and given a placebo; the treatment group (TG, n=30) was treated with SRP and dietary supplementation of ω-3 FAs (one 300 mg tablet daily for 12 weeks). Periodontal clinical parameters and serum C-reactive protein (CRP) levels were evaluated in all patients at baseline, a 6-week and 12-week period after treatment. RESULTS: A significant reduction in the gingival index, sulcus bleeding index, pocket depth, and clinical attachment level was found in the TG compared to the CG at a 12-week period. However, no statistically significant changes in serum CRP levels were found. CONCLUSIONS: Our findings suggest that ω-3 FAs can successfully reduce gingival inflammation, pocket depth, and attachment level gain. Dietary supplementation with ω-3 FAs may have potential benefits as a host modulatory agent in the prevention and/or adjunctive management of chronic periodontitis.
24587984 Infliximab reverses suppression of cholesterol efflux proteins by TNF-α: a possible mecha 2014 Tumor necrosis factor- (TNF-) α is a proinflammatory proatherogenic cytokine. Infliximab, an anti-TNF-α monoclonal antibody, is effective in treating rheumatoid arthritis. However, its impact on cardiovascular burden and lipid transport is unclear. The present study investigates the effect of TNF-α and infliximab on reverse cholesterol transport (RCT) proteins. Uptake of modified lipoproteins by macrophages in the vasculature leads to atherogenic foam cell formation. RCT is mediated by proteins including ATP binding cassette transporters A1 (ABCA1), G1 (ABCG1), liver X receptor- (LXR-) α, and 27-hydroxylase. RCT counteracts lipid overload by ridding cells of excess cholesterol. THP-1 human monocytes were incubated with either TNF-α alone or TNF-α with infliximab. Expression of proteins involved in cholesterol efflux was analyzed. TNF-α significantly reduced both ABCA1 and LXR-α mRNA (to 68.5 ± 1.59%, P < 0.05, and 41.2 ± 0.25%, P < 0.01, versus control set as 100%, resp.). Infliximab nullified the TNF-α effect. Results were confirmed by Western blot. Infliximab abolished the increase in foam cells induced by TNF-α. TNF-α treatment significantly reduces ABCA1 and LXR-α expression in monocytes, thus bringing about a proatherogenic state. The anti-TNF drug infliximab, commonly used in rheumatology, restored RCT proteins. This is the first report of an atheroprotective effect of infliximab on RCT in monocytes.