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ID PMID Title PublicationDate abstract
31463594 Somatostatin receptor imaging by SPECT and PET in patients with chronic inflammatory disor 2019 Nov OBJECTIVE: To review the literature on the clinical application of radiolabeled somatostatin receptor scintigraphy (SRS) by SPECT and PET in adults with chronic inflammatory diseases. RESEARCH DESIGN: Systematic review of published observational studies between 1993 and 2017. DATA COLLECTION AND ANALYSIS: The Cochrane Central Register of Controlled Trials, MedLine, EMBASE, PubMed, Google Scholar, OVID, EBSCO, Scopus, and Web of Science were used to search for studies on the use of SRS in adults with chronic inflammatory diseases. A team of reviewers independently screened for eligible studies. Quality of evidence was assessed by QUADAS approach. RESULTS: Eligible papers included 38 studies. Studied populations were heterogeneous, and patients were classified according to the diagnosed disease: endothelial inflammation, rheumatoid arthritis, cardiac allograft rejection, granulomatous diseases, small vessel vasculitis, idiopathic pulmonary fibrosis, sarcoidosis, and thyroid exophthalmopathy. Because of many quality differences between studies, it was not possible to pool data, and a narrative synthesis is reported. CONCLUSION: Results highlight the value of SRS to detect active inflammation in several chronic inflammatory conditions, despite the bias related to the index test, showing lack of standardization of the scintigraphic technique and high variability of methods used to clinically evaluate inflammatory condition.
31416681 Activin-A in the regulation of immunity in health and disease. 2019 Nov The TGF-β superfamily of cytokines plays pivotal roles in the regulation of immune responses protecting against or contributing to diseases, such as, allergy, autoimmunity and cancer. Activin-A, a member of the TGF-β superfamily, was initially identified as an inducer of follicle-stimulating hormone secretion. Extensive research over the past decades illuminated fundamental roles for activin-A in essential biologic processes, including embryonic development, stem cell maintenance and differentiation, haematopoiesis, cell proliferation and tissue fibrosis. Activin-A signals through two type I and two type II receptors which, upon ligand binding, activate their kinase activity, phosphorylate the SMAD2 and 3 intracellular signaling mediators that form a complex with SMAD4, translocate to the nucleus and activate or silence gene expression. Most immune cell types, including macrophages, dendritic cells (DCs), T and B lymphocytes and natural killer cells have the capacity to produce and respond to activin-A, although not in a similar manner. In innate immune cells, including macrophages, DCs and neutrophils, activin-A exerts a broad range of pro- or anti-inflammatory functions depending on the cell maturation and activation status and the spatiotemporal context. Activin-A also controls the differentiation and effector functions of Th cell subsets, including Th9 cells, T(FH) cells, Tr1 Treg cells and Foxp3(+) Treg cells. Moreover, activin-A affects B cell responses, enhancing mucosal IgA secretion and inhibiting pathogenic autoantibody production. Interestingly, an array of preclinical and clinical studies has highlighted crucial functions of activin-A in the initiation, propagation and resolution of human diseases, including autoimmune diseases, such as, systemic lupus erythematosus, rheumatoid arthritis and pulmonary alveolar proteinosis, in allergic disorders, including allergic asthma and atopic dermatitis, in cancer and in microbial infections. Here, we provide an overview of the biology of activin-A and its signaling pathways, summarize recent studies pertinent to the role of activin-A in the modulation of inflammation and immunity, and discuss the potential of targeting activin-A as a novel therapeutic approach for the control of inflammatory diseases.
31243880 Sinomenine exerts antitumour effect in gastric cancer cells via enhancement of miR-204 exp 2019 Nov Gastric carcinoma (GC) is a pernicious neoplasm with high morbidity and mortality. Sinomenine (SIN) has long been exploited to heal rheumatoid arthritis. Recently, SIN has been discovered to exert the antitumour functions in diverse cancers. However, the impacts of SIN on GC remain indistinct. We attempted to expose the antitumour effect of SIN on GC. MKN45 and SGC-7901 cells were administered with SIN for 24 hours, cell viability, proliferation, apoptosis, migration, invasion and the associated proteins in the above processes were examined via exploiting CCK-8, BrdU, flow cytometry, Transwell and Western blot. MiR-204 expression in GC tumour tissues, different GC cell lines and SIN-stimulated GC cells was investigated by executing RT-qPCR. The above cell biological processes were reassessed after transfection with miR-204 inhibitor. The latent mechanisms were probed by examining AMPK and Wnt/β-catenin pathways. We found that SIN memorably repressed cell proliferation, evoked apoptosis and affected CyclinD1, Bcl-2, Bax and cleaved-caspase-3 expression in MKN45 and SGC-7901 cells. Cell migration, invasion and expression of MMP-9 and Vimentin were all restrained by SIN stimulation. The increase of miR-204 was discovered in GC tissues and SIN-treated MKN45 and SGC-7901 cells. But suppression of miR-204 was observed in AGS, MKN28, MKN45 and SGC-7901 cells. Suppression of miR-204 overturned the inhibitory functions of SIN in MKN45 and SGC-7901 cells. Besides, SIN prohibited AMPK and Wnt/β-catenin pathways via enhancement of miR-204. In conclusion, these findings suggested that SIN exerted the antitumour activity in GC cells by hindering AMPK and Wnt/β-catenin pathways via enhancement of miR-204.
31243781 UPLC-Q-TOF/MS characterization of efficacy substances on osteoblasts differentiation and f 2019 Oct Wang-Bi tablet (WB) is popularly used for the treatment of rheumatoid arthritis. However, few studies have been carried out on its active ingredients and mechanism. In this study, the effect of WB medicated serum on the changes in differentiation and function in osteoblast was investigated, the results showed that WB induced the production of ALP and mineralized nodules to promote the final maturation of osteoblasts and enhance the function of osteoblasts. The potential mechanism may that WB significantly inhibits gene expressions of RANKL and miR-141, up-regulates the gene expressions of RUNX2 and OPG, decreases expression of DKK-1 and increases levels of β-catenin protein to promote the activation of Wnt/β-catenin signaling pathways, which enhances osteogenesis and bone repair function. To investigate which compounds contributed to the activity and mechanisms, a total of 138 compounds were characterized from WB, and 13 parent molecules and eight metabolites in rat serum were rapidly characterized by UPLC-Q-TOF/MS. Total glycosides of paeony, loganin, α-linolenic acid, linoleic acid and naringin from WB may contribute to the actions on osteoblasts according to our study and literature review. Our research provides a method to explore the bioactive ingredients and action mechanisms of WB.
31166662 Comparison of Varying Corticosteroid Type, Dose, and Volume for the Treatment of Pain in S 2019 Jul OBJECTIVE: To systematically evaluate the scientific literature examining the effect of corticosteroid type, dose, and volume of small- and intermediate-size joint injections on pain and function. TYPE: Narrative review. LITERATURE SURVEY: Medline (PubMed), Cochrane Central Register of Controlled Trial, and SportDiscus databases were searched. METHODOLOGY: Inclusion criteria included prospective studies evaluating pain- and/or function-related improvements following a corticosteroid injection of a small- or intermediate-size joint. SYNTHESIS: A total of 28 articles were included, all studying patients with osteoarthritis and/or rheumatoid arthritis. Eleven studies were randomized-controlled trials comparing corticosteroid injections to a control treatment and three were randomized trials comparing corticosteroid dose or type; the rest were prospective case series without a control. Most studies used 10 to 20 mg of methylprednisolone or triamcinolone for small joints and 20 to 40 mg for intermediate joints; wrist joints were the only joint studied that directly compared doses-20 mg was noninferior to 40 mg. Triamcinolone hexacetonide was found to be superior to methylprednisolone in the interphalangeal finger joints in a single randomized-controlled trial; no other studies compared steroid types in any joint. No studies evaluated the effect of volume on clinical outcomes. CONCLUSIONS: Very few studies directly examine the effect of corticosteroid type, corticosteroid dose, or injectate volume on clinical outcomes for small- or intermediate-size joint arthralgia. Future studies are needed to better elucidate the most effective treatment protocols. LEVEL OF EVIDENCE: IV.
35521419 Identification of key transporters mediating uptake of aconitum alkaloids into the liver a 2019 May 20 Aconite as a commonly used herb has been extensively applied in the treatment of rheumatoid arthritis, as pain relief, as well as for its cardiotonic actions. Aconitum alkaloids have been shown to be the most potent ingredients in aconite, in terms of efficacy against disease, but they are also highly toxic. Apart from neurological and cardiovascular toxicity exposed, the damage to hepatocytes and nephrocytes with long-term use of aconitum alkaloids should also be carefully considered. This study attempted to investigate the critical role of uptake transporters mediating the transport of aconitum alkaloids into the liver and the kidneys. The resulting data revealed that hOATP1B1, 1B3, hOCT1 and hOAT3 were mainly involved in the uptake of aconitum alkaloids. Additionally, the inhibitory effects of bioactive ingredients of liquorice on uptake transporters were screened and further confirmed by determining the IC(50) values. The in vitro study suggested that liquorice might lower the toxicity of aconite by reducing its exposure in the liver and/or kidneys through inhibition of uptake transporters. Eventually, the in vivo study was indicative of detoxification of liquorice by decreasing the exposure of aconitine as representative compound in liver after co-administration, even though the exposure in kidney altered was less significant. In summary, hOATP1B1, 1B3, hOCT1 and hOCT3 were determined as the key uptake transporters mediating the transport process of aconitum alkaloids into the liver and/or kidneys, and liquorice may alleviate the toxicity caused by reduction of exposure through inhibition of those key uptake transporters.
31085395 The qualitative and quantitative analyses of Gelsemium elegans. 2019 Aug 5 Gelsemium elegans is a traditional Chinese medicine that has been used to treat eczema, bruises, rheumatoid arthritis and skin ulcers for many years, and alkaloids are its major active and toxic constituents. This study aimed to comprehensively assess the quality of G. elegans samples including different plant parts and origins using ultra high-performance liquid chromatography coupled with photo-diode array and quadrupole time-of-flight mass spectrometry (UHPLC-PDA-QTOF/MS) and high-performance liquid chromatography coupled with UV detector (HPLC-UV). Firstly, the UHPLC-PDA-QTOF/MS approach was developed for the characterization of alkaloids in G. elegans and understanding the differences between multiple groups of samples. Based on the exact mass information, the fragmentation characteristics and the retention time of compounds, 38 alkaloids were identified or tentatively identified. 24 potential chemical markers for differentiating different plant parts of G. elegans were selected through PCA and OPLS/PLS-DA analysis. Secondly, a heatmap visualization was employed for clarifying the distribution of 24 selected alkaloids with high response in the UV. The roots, stems and leaves from Yunnan Province possess relatively consistent alkaloids composition, respectively. Most compounds in the root have a higher content than stems and leaves. Thirdly, a HPLC-UV approach was developed for quantitative analysis of three major alkaloids (gelsemine, koumine and gelsenicine) of G. elegans, and the results showed remarkable variation in the contents of these constituents. While, the contents of three alkaloids fluctuate relatively less in the stem. These results indicated that integrated chemical profiling and quantitative analysis of alkaloids in G. elegans from different plant parts and origins could be assessed by this method, which would establish the foundation for the application of G. elegans.
31062890 Enantioseparation of flurbiprofen enantiomers using chiral ionic liquids by liquid-liquid 2019 Jun Flurbiprofen is a kind of nonsteroidal anti-inflammatory drug, which has been widely used in clinic for treatment of rheumatoid arthritis and osteoarthritis. It has been reported that S-flurbiprofen shows good performance on clinic anti-inflammatory treatment, while R-enantiomer almost has no pharmacological activities. It has important practical values to obtain optically pure S-flurbiprofen. In this work, chiral ionic liquids, which have good structural designability and chiral recognize ability, were selected as the extraction selector by the assistance of quantum chemistry calculations. The distribution behaviors of flurbiprofen enantiomers were investigated in the extraction system, which was composed of organic solvent and aqueous phase containing chiral ionic liquid. The results show that maximum enantioselectivity up to 1.20 was attained at pH 2.0, 25°C using 1,2-dichloroethane as organic solvent, 1-butyl-3-methylimidazole L-tryptophan ([Bmim][L-trp]) as chiral selector. The racemic flurbiprofen initial concentration was 0.2 mmol L(-1) , and [Bmim][L-trp] concentration was 0.02 mol L(-1) . Furthermore, the recycle of chiral ionic liquids has been achieved by reverse extraction process of the aqueous phase with chiral selector, which is significant for industrial application of chiral ionic liquids and scale-up of the extraction process.
31037141 Gold Clusters Prevent Inflammation-Induced Bone Erosion through Inhibiting the Activation 2019 Inflammation-induced bone erosion is a major pathological factor in several chronic inflammatory diseases that often cause severe outcomes, such as rheumatoid arthritis and periodontitis. Plenty of evidences indicated that the inflammatory bone destruction was attributed to an increase in the number of bone-resorbing osteoclasts. However, anti-resorptive therapy alone failed to prevent bone loss in an inflammatory condition. Conventional anti-inflammation treatments are usually intended to suppress inflammation only, but ignore debilitating the subsequent bone destruction. Therefore, inhibition of proinflammatory activation of osteoclastogenesis could be an important strategy for the development of drugs aimed at preventing inflammatory bone destruction. Methods: In this study, we synthesized a peptide coated gold cluster to evaluate its effects on inflammatory osteoclastogenesis in vitro and inflammation-induced bone destruction in vivo. The in vitro anti-inflammation and anti-osteoclastogenesis effects of the cluster were evaluated in LPS-stimulated and receptor activator of nuclear factor κB ligand (RANKL) stimulated macrophages, respectively. The LPS-induced expression of crucial pro-inflammation cytokines and RANKL-induced osteoclastogenesis as well as the activation of NF-κB pathway in both situations were detected. The inflammation-induced RANKL expression and subsequent inflammatory bone destruction in vivo were determined in collagen-immunized mice. Results: The gold cluster strongly suppresses RANKL-induced osteoclast formation via inhibiting the activation of NF-κB pathway in vitro. Moreover, treatment with the clusters at a dose of 5 mg Au/kg.bw significantly reduces the severity of inflammation-induced bone and cartilage destruction in vivo without any significant toxicity effects. Conclusion: Therefore, the gold clusters may offer a novel potent therapeutic stratagem for inhibiting chronic inflammation associated bone destruction.
31024321 Inhibitory Effect of KP-A038 on Osteoclastogenesis and Inflammatory Bone Loss Is Associate 2019 Excessive osteoclastic activity results in pathological bone resorptive diseases, such as osteoporosis, periodontitis, and rheumatoid arthritis. As imidazole-containing compounds possess extensive therapeutic potential for the management of diverse diseases, we synthesized a series of imidazole derivatives and investigated their effects on osteoclast differentiation and function. In the present study, we found that a novel imidazole derivative, KP-A038, suppressed receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclastogenesis and bone-resorbing activity in vitro and attenuated lipopolysaccharide (LPS)-induced bone destruction in vivo. KP-A038 significantly inhibited the induction of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) and the expression of its target genes, including tartrate-resistant acid phosphatase (Acp5), cathepsin K (Ctsk), dendritic cell-specific transmembrane protein (Dcstamp), and matrix metallopeptidase 9 (Mmp9). KP-A038 upregulated the expression of negative regulators of osteoclast differentiation, such as interferon regulatory factor-8 (Irf8) and B-cell lymphoma 6 (Bcl6). Consistently, KP-A038 downregulated the expression of B lymphocyte-induced maturation protein-1 (Blimp1 encoded by Prdm1), a repressor for Irf8 and Bcl6. Moreover, administration of KP-A038 reduced LPS-induced bone erosion by suppressing osteoclast formation in vivo. Thus, our findings suggest that KP-A038 may serve as an effective therapeutic agent for the treatment and/or prevention of bone loss in pathological bone diseases, including osteoporosis and periodontitis.
31000797 The IL-23/IL-17 pathway in human chronic inflammatory diseases-new insight from genetics a 2019 May Chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, spondyloarthritis, and psoriasis cause significant morbidity and are a considerable burden for the patients in terms of pain, impaired function, and diminished quality of life, as well as for society, because of the associated high health-care costs and loss of productivity. Our limited understanding of the pathogenic mechanisms involved in these diseases currently hinders early diagnosis and the development of more specific and effective therapies. The past years have been marked by considerable progress in our insight of the genetic basis of many diseases. In particular, genome-wide association studies (GWAS) performed with thousands of patients have provided detailed information about the genetic variants associated with a large number of chronic inflammatory diseases. These studies have brought to the forefront many genes linked to signaling pathways that were not previously known to be involved in pathogenesis, pointing to new directions in the study of disease mechanisms. GWAS also provided fundamental evidence for a key role of the immune system in the pathogenesis of these diseases, because many of the identified loci map to genes involved in different immune processes. However, the mechanisms by which disease-associated genetic variants act on disease development and the targeted cell populations remain poorly understood. The challenge of the post-GWAS era is to understand how these variants affect pathogenesis, to allow translation of genetic data into better diagnostics and innovative treatment strategies. Here, we review recent results that document the importance of the IL-23/IL-17 pathway for the pathogenesis of several chronic inflammatory diseases and summarize data that demonstrate how therapeutic targeting of this pathway can benefit affected patients.
30981079 PPAR-γ agonist pioglitazone protects against IL-17 induced intervertebral disc inflammati 2019 Jul Interleukin-17 (IL-17) is the production of T helper type 17 (Th17) cells and has been reported to play a pro-inflammatory role in the immunopathogenesis of intervertebral disc degeneration. Peroxisome proliferator-activated receptor γ (PPAR-γ) activators display anti-inflammatory and anti-degeneration roles in osteoarthritis and rheumatoid arthritis. However, the expression level of PPAR-γ and related regulatory mechanisms in the nucleus pulposus tissues are not clear. Herein we report that PPAR-γ was down-regulated both in the nucleus pulposus tissue of intervertebral disc degeneration patient and in the cultured nucleus pulposus cells stimulated with IL-17. This study was undertaken to investigate the potential therapeutic effect of pioglitazone, as a PPAR-γ ligand, and its underlying molecular mechanism in IL-17-induced human intervertebral disc degeneration model in vitro. Our results indicate that pioglitazone administration suppressed the production of pro-inflammatory cytokines and down-regulated the mRNA expression levels of inflammatory mediators in the cultured human nucleus pulposus cells and tissue. Consistently, pioglitazone decreased the levels of metalloproteinase and maintained the expression of critical matrix components, such as aggrecan and type II collagen. Moreover, the activation of NF-κB signaling in the nucleus pulposus tissue during the intervertebral disc degeneration development was antagonized by pioglitazone administration. In conclusion, our current findings provide scientific evidence for the assessment of pioglitazone as a potential therapeutic approach to treat the intervertebral disc degeneration.
30959217 Emerging role of air pollution in autoimmune diseases. 2019 Jun Autoimmune diseases (ADs) are a broad spectrum of disorders featured by the body's immune responses being directed against its own tissues, resulting in prolonged inflammation and subsequent tissue damage. Recently, the exposure to ambient air pollution has been implicated in the occurrence and development of ADs. Mechanisms linking air pollution exposures and ADs mainly include systemic inflammation, increased oxidative stress, epigenetic modifications induced by exposures and immune response caused by airway damage. The lung may be an autoimmunity initiation site in autoimmune diseases (ADs). Air pollutants can bind to the Aryl hydrocarbon receptor (AHR) to regulate Th17 and Treg cells. Oxidative stress and inducible bronchus associated lymphoid tissue caused by the pollutants can influence T, B cells, resulting in the production of proinflammatory cytokines. These cytokines stimulate B cell and dendritic cells, resulting in a lot of antibodies and self-reactive T lymphocytes. Moreover, air pollutants may induce epigenetic changes to contribute to ADs. In this review, we will concern the associations between air pollution and immune-inflammatory responses, as well as mechanisms linking air pollution exposure and autoimmunity. In addition, we focus on the potential roles of air pollution in major autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), and type 1 diabetes mellitus (T1DM).
30949178 Dissecting Integrin Expression and Function on Memory B Cells in Mice and Humans in Autoim 2019 Immunological memory ensures life-long protection against previously encountered pathogens, and in mice and humans the spleen is an important reservoir for long-lived memory B cells (MBCs). It is well-established that integrins play several crucial roles in lymphocyte survival and trafficking, but their involvement in the retention of MBCs in secondary lymphoid organs, and differences between B cell subsets in their adhesion capacity to ICAM-1 and/or VCAM-1 have not yet been confirmed. Here, we use an autoimmune mouse model, where MBCs are abundant, to show that the highest levels of LFA-1 and VLA-4 amongst B cells are found on MBCs. In vivo blockade of VLA-4 alone or in combination with LFA-1, but not LFA-1 alone, causes a release of MBCs from the spleen into the blood stream. In humans, we find that in peripheral blood, spleens, and tonsils from healthy donors the highest expression levels of the integrins LFA-1 and VLA-4 are also found on MBCs. Consistent with this, we found MBCs to have a higher capacity to adhere to ICAM-1 and VCAM-1 than naïve B cells. In patients with the autoimmune disease rheumatoid arthritis, it is the MBCs that have the highest levels of LFA-1 and VLA-4; moreover, compared with healthy donors, naïve B and MBCs of patients receiving anti-TNF medication have enhanced levels of the active form of LFA-1. Commensurate levels of the active αL subunit can be induced on B cells from healthy donors by exposure to the integrin ligands. Thus, our findings establish the selective use of the integrins LFA-1 and VLA-4 in the localization and adhesion of MBCs in both mice and humans.
30903782 Lateral instability of the knee joint and disorder of the ankle joint extension disorder i 2019 OBJECTIVE: Introducion: The flexion of the knee joints in the movement of the squat may be accompanied by physiological varus deformity that increases smoothly with the lowering of the center of gravity, followed by a return to the starting position. Observing the disturbances of the physiological movement of the knee joints in the frontal plane, the authors correlated them with the mobility of the ankles in the sagittal plane. The aim: To show the relationship of knee joint motion disorders in the frontal plane with the movement of the ankle joints in the sagittal plane in the movement of the squat. The authors asked themselves about the number of subjects with the physiological mobility of both joints in the given planes and in what part of the subjects there are disorders and whether they relate to the ipsi or the contralateral part of the body. There was also the question of whether and in which group there are deviations not meeting the above criteria. PATIENTS AND METHODS: Materials and methods: 20 healthy right-handed men aged 25-35 were examined with physiological mobility of lower limb joints, confirmed in a physiotherapeutic study. Exclusion criteria included: polyarticular laxity, systemic diseases, rheumatoid arthritis, osteoarthritis. The subjects performed a three-time squat after putting in the Biomech measuring system inertial sensors on the lower limbs and the pelvis. Assessment was related to the movement of the knee joint in the frontal plane with the movement of the ankle joint in the sagittal plane. RESULTS: Results: Alternating deformity with right knee valgus occurred in 16 people in the right knee joint (80% of subjects) and in 6 men in the left knee joint (30% of subjects). Three subjects (15%) had a degenerative disorder in both knee joints. The others presented physiological mobility or single (not correlating) disturbances in the mobility of selected joints. CONCLUSION: Conclusions: The tests confirmed that the ankle joint is functionally connected to the dysfunctional knee joint on the opposite side, despite various surfaces of mutual movement. Dysfunction of the knee joint is about 10 ° reduction of varus deformity during squat during maximum flexion of the knee joint and again varus deformation when lifting the center of gravity, which ends in distortion until the starting position. These deflections are accompanied by a decrease in the opposite ankle extension at the time of knee valgus deformity in the maximum flexion. The above dysfunctions occurred in 100% instability of the non-dominant knee joint, and on the dominant side in 63%.
30801189 In Silico Exploration of the Molecular Mechanism of Cassane Diterpenoids on Anti-inflammat 2019 May 28 Cassane diterpenoids (CAs), recognized as main constituents of many medical plants of the genus Caesalpinia, exhibit diverse bioactivities, including anti-inflammatory and immunomodulatory activity, and also showed a therapeutic effect on rheumatoid arthritis (RA) according to previous work, including ours. In this study, 102 CA compounds were selected to explore the possible molecular mechanism of this class of natural products on anti-inflammatory and immunomodulatory activity using RA as a disease model through a series of in silico methods: chemical-similarity-based target prediction, molecular docking, and molecular dynamics (MD) simulation. As a consequence, four signaling pathways (TCR signaling pathway, TLR signaling pathway, VEGF signaling pathway, and osteoclast differentiation pathway) by which CAs exert their effect on inflammation and immunomodulation were identified. Furthermore, the binding modes of CAs complexing with several crucial targets, which were picked out by credible docking results and took part in these signaling pathways, were explored by MD simulations. This is the first time that the molecular mechanism of the anti-RA activity of natural CAs has been investigated with in silico methods, and these findings might explain the activity of CAs on anti-inflammation and immunomodulation, which could supply a valuable reference for drug design research on CAs.
30775575 Acute and sub-acute toxicity of aqueous extract of aerial parts of Caralluma dalzielii N. 2019 Jan Caralluma dalzielii N. E. Brown (Asclepiadaceae) is a cactus-like shaped shrub widely used in traditional medicine for the treatment of rheumatoid arthritis, diabetes, infertility and impotence. The present study evaluated the potential toxicity of aqueous extract of aerial parts of Caralluma dalzielii (AECD) through acute and sub-acute oral administration in mice and rats. During acute toxicity study, female mice and rats were orally administered with AECD at single doses of 175, 500 and 2000 mg/kg according to OECD Guidelines 425. Sub-acute toxicity of AECD (150, 300 and 600 mg/kg p.o) was studied by daily dosing of Wistar rats of both sexes for 28 days. The acute toxicity study revealed no lethal effects and behavioural signs of toxicity at the tested doses indicating that LD(50) is greater than 2000 mg/kg. In sub-acute study, a significant reduction in the body weight (p < 0.05), feed and water (p < 0.001) intake of the rats were observed. A significant (p < 0.05) increase in lymphocytes, mean platelet volume counts and alanine aminotransferase were also observed. Histopathological analysis showed mild liver cell distortion in female rats treated at 600 mg/kg of AECD. These results show low toxicity of AECD on short-term use and liver toxicity on long-term use.
30654118 Potential diagnostic value of a type X collagen neo-epitope biomarker for knee osteoarthri 2019 Apr OBJECTIVE: Phenotypic changes of chondrocytes toward hypertrophy might be fundamental in the pathogenesis of osteoarthritis (OA), of which type X collagen (Col10) is a well-known marker. The purpose was to develop a specific immunoassay for blood quantification of a newly identified neo-epitope of type Col10 to assess its diagnostic value for radiographic knee OA. METHODS: A neo-epitope of Col10 was identified in urine samples from OA patients. A monoclonal antibody against the neo-epitope was produced in Balb/C mice. The enzyme responsible for the cleavage was identified. Immunohistochemical detection of this neo-epitope was performed on human OA cartilage. An immunoassay (Col10neo) was developed and quantified in two clinical studies: the C4Pain-003 and the NYU OA progression study. Receiver operating characteristic curve (ROC) curve analysis was carried out to evaluate the discriminative power of Col10neo between OA and rheumatoid arthritis (RA). RESULTS: A neo-epitope specific mAb was produced. The Cathepsin K-generated neo-epitope was localized to the pericellular matrix of chondrocytes, while its presence was extended and more prominent in superficial fibrillation in the cartilage with advanced degradation. In the C4Pain study, a higher level of Col10neo was seen in subjects with greater KL grade. The group of the highest tertile of Col10neo included more subjects with KL3-4. In the NYU study, Col10neo was statistically higher in OA than control or RA. ROC curve analysis revealed area under the curve was 0.88 (95% CI 0.81-0.94). CONCLUSION: Our findings indicate that Col10neo linked to hypertrophic chondrocytes could be used as a diagnostic biochemical marker for knee OA.
30605855 In silico drug design of inhibitor of nuclear factor kappa B kinase subunit beta inhibitor 2019 Feb Inhibitor of nuclear factor kappa B kinase subunit beta (IKK-β), a specific regulator of nuclear factor-κB (NF-κB), is considered a valid target to design novel candidate drugs to treat rheumatoid arthritis and various cancers. In the present study, quantitative structure-activity relationships (QSAR) and molecular docking techniques were used to screen for new IKK-β inhibitors from a series of 2-acylamino-3-aminothienopyridine analogs. During the two-dimensional QSAR phase, the statistical model partial least square was selected from among two alternatives (r(2) = 0.868, q(2) (cross-validation) = 0.630). Descriptors with positive or negative contributions were derived from the created model. To build of three-dimensional QSAR models, we used three different fingerprints as analysis precepts for molecular clustering and the subsequent division of training sets and test sets. The best model, which used fingerprint model definition language public keys, was selected for further prediction of the compounds' activities. Favorable physicochemical, structural, electrostatic, and steric properties were derived from the created QSAR models and then used for drug design with an in-house library. Amongst the designed compounds, compounds B01 and B02 showed good predicted activities. Furthermore, after a selecting the protein structure and docking method, docking studies were carried out to reveal the detailed interactions between the ligands and the target protein. Binding affinity was measured and sorted using the value of "-CDOCKER_ENERGY". The high -CDOCKER_ENERGY values of compounds B01 (41.6134 kcal/mol) and B02 (40.1366 kcal/mol) indicated their prominent docking affinities.
30518476 Predicting Costs Exceeding Bundled Payment Targets for Total Joint Arthroplasty. 2019 Mar BACKGROUND: The Center for Medicare and Medicaid Services has instituted bundled reimbursement models for total joint arthroplasty (TJA), which includes target prices for each procedure. Some patients exceed these targets; however, currently there are no tools to accurately predict this preoperatively. We hypothesized that a validated comorbidity index combined with patient demographics would adequately predict excess cost-of-care prior to hospitalization. METHODS: Two thousand eighty-four primary unilateral TJAs performed at a single tertiary center were retrospectively examined. Data were extracted from medical records and a predictive model was built from 30 comorbidities and 7 patient demographic factors (age, gender, race, body mass index, American Society of Anesthesiologists score, smoking status, and marital status). Following parameter selection, a final multivariable model was created, with a corresponding nomogram for interactive visualization of probability for excess cost. RESULTS: Six hundred twelve patients (29%) had cost-of-care exceeding the target price. The final model demonstrated adequate predictive discrimination for cost-of-care exceeding the target price (area under the receiver operator characteristic curve: 0.747). Factors associated with excess cost included age, gender, marital status, American Society of Anesthesiologists score, body mass index, and race, as well as 7 Elixhauser comorbidities (alcohol use, rheumatoid arthritis, diabetes, electrolyte disorders, neurodegenerative disorders, psychoses, and pulmonary circulatory disorders). CONCLUSION: A novel patient model composed of a subset of validated comorbidities and demographic variables provides adequate discrimination in predicting excess cost within bundled payment models for TJA. This not only helps identify patients who would benefit from preoperative optimization, but also provides evidence for modification of future bundled reimbursement models to adjust for nonmodifiable risk factors.