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ID PMID Title PublicationDate abstract
32325182 Network pharmacology approach to elucidate possible action mechanisms of Sinomenii Caulis 2020 Jul 15 ETHNOPHARMACOLOGICAL RELEVANCE: Sinomenii Caulis (SC) is a well-konwn traditional Chinese medicine used for treatment of rheumatoid arthritis (RA), dermatophytosis and paralysis. Patients with RA are usually secondary to osteoporosis, but the potential protective effect of SC on osteoporosis (OP) is seldom reported and its possible action mechanism is little known. AIM: The purpose of this study was to demonstrate the anti-osteoporosis effects of SC extract and alkaloids in prednisolone (Pre)-induced OP of zebrafish, and then to explore the potential mechanism of SC on system level by network pharmacology. METHODS: Firstly, zebrafish OP model was established to investigate the anti-osteoporosis effect of SC. Secondly, the targets of SC and OP from multiple databases were collected, and Compound-Target-Pathway network based on protein-protein interaction (PPI) was constructed. Moreover, gene enrichment and annotation were performed via the DAVID server. Finally, the reliability of the network pharmacology prediction results in Pre-induced OP of zebrafish was verified by qRT-PCR. RESULTS: The results indicated that SC extract and alkaloids have remarkable ability to promote bone formation of cranial bones and reduce TRAP contents in Pre-induced OP of zebrafish. 32 OP-related ingredients in SC and 77 OP-related targets were screened from multiple databases, and 15 OP-related pathways were enriched by the KEGG database. Further experimental validation indicated that SC extract and alkaloids could regulate the expression of MAPK14, CASP3, CXCL8, IL-1β, IL6, PTGS2, TNF-α, ESR1, and MMP9 for treatment of OP. CONCLUSION: In summary, we conducted an integrative analysis to provide convincing evidence that SC may partially alleviate OP by inhibiting pro-inflammatory cytokines and regulating of RANK/RANKL/OPG system.
32013232 Impact of Janus Kinase Inhibition with Tofacitinib on Fundamental Processes of Bone Healin 2020 Jan 29 Both inflammatory diseases like rheumatoid arthritis (RA) and anti-inflammatory treatment of RA with glucocorticoids (GCs) or non-steroidal anti-inflammatory drugs (NSAIDs) negatively influence bone metabolism and fracture healing. Janus kinase (JAK) inhibition with tofacitinib has been demonstrated to act as a potent anti-inflammatory therapeutic agent in the treatment of RA, but its impact on the fundamental processes of bone regeneration is currently controversially discussed and at least in part elusive. Therefore, in this study, we aimed to examine the effects of tofacitinib on processes of bone healing focusing on recruitment of human mesenchymal stromal cells (hMSCs) into the inflammatory microenvironment of the fracture gap, chondrogenesis, osteogenesis and osteoclastogenesis. We performed our analyses under conditions of reduced oxygen availability in order to mimic the in vivo situation of the fracture gap most optimal. We demonstrate that tofacitinib dose-dependently promotes the recruitment of hMSCs under hypoxia but inhibits recruitment of hMSCs under normoxia. With regard to the chondrogenic differentiation of hMSCs, we demonstrate that tofacitinib does not inhibit survival at therapeutically relevant doses of 10-100 nM. Moreover, tofacitinib dose-dependently enhances osteogenic differentiation of hMSCs and reduces osteoclast differentiation and activity. We conclude from our data that tofacitinib may influence bone healing by promotion of hMSC recruitment into the hypoxic microenvironment of the fracture gap but does not interfere with the cartilaginous phase of the soft callus phase of fracture healing process. We assume that tofacitinib may promote bone formation and reduce bone resorption, which could in part explain the positive impact of tofacitinib on bone erosions in RA. Thus, we hypothesize that it will be unnecessary to stop this medication in case of fracture and suggest that positive effects on osteoporosis are likely.
31862695 Lipid rafts in glial cells: role in neuroinflammation and pain processing. 2020 May Activation of microglia and astrocytes secondary to inflammatory processes contributes to the development and perpetuation of pain with a neuropathic phenotype. This pain state presents as a chronic debilitating condition and affects a large population of patients with conditions like rheumatoid arthritis and diabetes, or after surgery, trauma, or chemotherapy. Here, we review the regulation of lipid rafts in glial cells and the role they play as a key component of neuroinflammatory sensitization of central pain signaling pathways. In this context, we introduce the concept of an inflammaraft (i-raft), enlarged lipid rafts harboring activated receptors and adaptor molecules and serving as an organizing platform to initiate inflammatory signaling and the cellular response. Characteristics of the inflammaraft include increased relative abundance of lipid rafts in inflammatory cells, increased content of cholesterol per raft, and increased levels of inflammatory receptors, such as toll-like receptor (TLR)4, adaptor molecules, ion channels, and enzymes in lipid rafts. This inflammaraft motif serves an important role in the membrane assembly of protein complexes, for example, TLR4 dimerization. Operating within this framework, we demonstrate the involvement of inflammatory receptors, redox molecules, and ion channels in the inflammaraft formation and the regulation of cholesterol and sphingolipid metabolism in the inflammaraft maintenance and disruption. Strategies for targeting inflammarafts, without affecting the integrity of lipid rafts in noninflammatory cells, may lead to developing novel therapies for neuropathic pain states and other neuroinflammatory conditions.
31808359 Proximal Medial Gastrocnemius Release Versus Open Plantar Fasciotomy for the Surgical Trea 2020 Mar BACKGROUND: Plantar fasciitis is a common cause of foot pain. If conservative treatment fails, there is no consensus as to the best surgical management for recalcitrant plantar fasciitis (RPF). The aim of this study was to compare the results obtained from proximal medial gastrocnemius release (PMGR) with those obtained from open plantar fasciotomy (OPF) in terms of pain, satisfaction, health-related quality of life, and American Orthopaedic Foot & Ankle Society (AOFAS) score. METHODS: This is a prospective randomized trial conducted between 2012 and 2016. Patients with RPF for at least 9 months were included. Diagnosis was clinically made. The exclusion criteria were neuropathic heel pain; a history of previous foot fracture, surgery, or deformity; rheumatoid arthritis; or the need for long-term analgesic administration. After ruling out other conditions with magnetic resonance or ultrasound imaging, patients were randomized to be operated on with OPF or PMGR independently of the Silfverskjold test. Follow-up was carried out for up to 1 year. The AOFAS, visual analog scale (VAS) for pain, SF-36, and Likert scale for satisfaction were used to evaluate the results obtained. The analysis was done with 21 patients in the OPF group and 15 in the PMGR group. The demographic data (age, sex, body mass index, duration of symptoms, and positivity to the Silfverskjold test) of the groups were comparable. RESULTS: No differences were found in terms of the AOFAS (P = .24), VAS (P = .14), or any item of the SF-36. Satisfaction was very good in 85.8% of the PMGR group and 89.5% of the OPF group (P = .27). Faster recovery was observed in the PMGR group. CONCLUSION: OPF and PMGR provided good results for patients with RPF. Neither was superior to the other relative to pain, AOFAS score, satisfaction, or the SF-36. We recommend PMGR as the first option in RPF surgical management in order to avoid potential biomechanical complications related to OPF. LEVEL OF EVIDENCE: Level I, therapeutic randomized controlled trial.
31755595 The role of Interleukin 1 receptor antagonist in mesenchymal stem cell-based tissue repair 2020 Mar Interleukin (IL)-1 receptor antagonist (IL-1Ra), a naturally occurring antagonist of IL-1α/IL-1β signaling pathways, has been attributed to the immunosuppressive effects of mesenchymal stem cells (MSCs). MSCs, in IL-1Ra-dependent manner, suppressed production of IL-1β in dermal macrophages, induced their polarization in anti-inflammatory M2 phenotype, attenuated antigen-presenting properties of dendritic cells (DCs), and promoted expansion of immunosuppressive T regulatory cells in the skin, which resulted in enhanced repair of the nonhealing wounds. Reduced activation of inflammasome and suppressed production of IL-1β in macrophages were mainly responsible for beneficial effects of MSC-derived IL-1Ra in alleviation of acute lung injury, dry eye syndrome, and corneal injury. Through the production of IL-1Ra, MSCs reduced migration of DCs to the draining lymph nodes and attenuated generation of inflammatory Th1 and Th17 cells that resulted in alleviation of fulminant hepatitis and rheumatoid arthritis. MSCs, in IL-1Ra-dependent manner, reduced liver fibrosis by suppressing production of Type I collagen in hepatic stellate cells. IL-1Ra was, at least partially, responsible for enhanced proliferation of hepatocytes and chondrocytes in MSC-treated animals with partial hepatectomy and osteoarthritis. Despite of these beneficial effects, IL-1Ra-dependent inhibition of IL-1α/IL-1β-signaling significantly increased risk of infections. Therefore, future experimental and clinical studies should delineate potential side effects of MSC-derived IL-1Ra before IL-1Ra-overexpressing MSCs could be used as a potentially new therapeutic agent for the treatment of acute and chronic inflammatory diseases.
31688984 Integrating complement into the molecular pathogenesis of Hidradenitis Suppurativa. 2020 Jan Complement inhibition has been identified as a potential therapeutic target for multiple inflammatory disorders including Hidradenitis Suppurativa (HS). It is currently unclear how complement integrates into our current model of molecular pathogenesis in HS and whether it represents a central component of pathogenesis, or a neutrophil-associated bystander. Levels of C5a in serum and tissue correlate with disease activity and degree of neutrophilic infiltrates in HS. C5a has been associated with Th17 immune axis activation in psoriasis, rheumatoid arthritis and Crohn's disease with strong similarities to TH17 activation in HS. Porphyromonas species (which are identified in the HS microbiome) are able to cleave inactive C5 into C5a implicating the cutaneous microbiome as an activator of complement. C3a and C5a are associated with activation of the NLRP3 inflammasome, implicated in the inflammatory drive in HS. Complement receptors are present upon dendritic cells, monocytes, fibroblasts and adipocytes, which may broaden the potential contribution of complement to multiple aspects of HS pathogenesis. Dysregulation of complement receptor pathways has been documented in obesity, insulin resistance and polycystic ovarian syndrome leading to the possibility that complement may explain the epidemiological associations between these conditions and HS. The therapeutic potential of complement inhibitors in HS may be related to the therapeutic target (complement receptor or complement subunit) and the presence of alternate receptors (such as C5aR2) or ligands (including C3a, PAMPs and DAMPs). Integrating complement into the known pathogenesis of HS may aid in explaining the contradictory results between Phase 2 studies of C5a antagonists. It also allows for the identification of existing knowledge gaps to target further clinical investigation and research.
32829915 Inhibition of porcine epidemic diarrhea virus (PEDV) replication by A77 1726 through targe 2020 Dec Porcine epidemic diarrhea (PED) virus (PEDV) is a coronavirus that primarily infects porcine intestinal epithelial cells and causes severe diarrhea and high fatality in piglets. A77 1726 is the active metabolite of leflunomide, a clinically approved anti-rheumatoid arthritis (RA) drug. A77 1726 inhibits the activity of protein tyrosine kinases (PTKs), p70 S6 kinase (S6K1), and dihydroorotate dehydrogenase (DHO-DHase). Whether A77 1726 can control coronavirus infections has not been investigated. Here we report that A77 1726 effectively restricted PEDV replication by inhibiting Janus kinases (JAKs) and Src kinase activities but not by inhibiting DHO-DHase and S6K1 activities. Overexpression of Src, JAK2 or its substrate STAT3 enhanced PEDV replication and attenuated the antiviral activity of A77 1726. Our study demonstrates for the first time the ability of A77 1726 to control coronavirus replication by inhibiting PTK activities. Leflunomide has potential therapeutic value for the control of PEDV and other coronavirus infections.
33658993 TRPM7 Kinase Is Essential for Neutrophil Recruitment and Function via Regulation of Akt/mT 2020 During inflammation, neutrophils are one of the first responding cells of innate immunity, contributing to a fast clearance of infection and return to homeostasis. However, excessive neutrophil infiltration accelerates unsolicited disproportionate inflammation for instance in autoimmune diseases such as rheumatoid arthritis. The transient-receptor-potential channel-kinase TRPM7 is an essential regulator of immune system homeostasis. Naïve murine T cells with genetic inactivation of the TRPM7 enzyme, due to a point mutation at the active site, are unable to differentiate into pro-inflammatory T cells, whereas regulatory T cells develop normally. Moreover, TRPM7 is vital for lipopolysaccharides (LPS)-induced activation of murine macrophages. Within this study, we show that the channel-kinase TRPM7 is functionally expressed in neutrophils and has an important impact on neutrophil recruitment during inflammation. We find that human neutrophils cannot transmigrate along a CXCL8 chemokine gradient or produce reactive oxygen species in response to gram-negative bacterial lipopolysaccharide LPS, if TRPM7 channel or kinase activity are blocked. Using a recently identified TRPM7 kinase inhibitor, TG100-115, as well as murine neutrophils with genetic ablation of the kinase activity, we confirm the importance of both TRPM7 channel and kinase function in murine neutrophil transmigration and unravel that TRPM7 kinase affects Akt1/mTOR signaling thereby regulating neutrophil transmigration and effector function. Hence, TRPM7 represents an interesting potential target to treat unwanted excessive neutrophil invasion.
33328268 Does the presence of cranial contrast spread during a sacroiliac joint injection predict s 2021 Mar BACKGROUND: The innervation of the sacroiliac joint (SIJ) is complex, with a dual innervation originating from the lumbosacral plexus anteriorly as well as the sacral lateral branches posteriorly. Nociceptors are found in intra-articular structures as well as periarticular structures. In patients with SIJ pain, a fluoroscopy-guided SIJ injection is usually performed posteriorly into the bottom one-third of the joint with local anesthetic and corticosteroids, but this does not always reach all intra-articular structures. The correlation between a cranial contrast spread and clinical success is undetermined in patients with SIJ pain. METHODS: In a tertiary referral pain center, electronic medical records of patients who underwent an SIJ injection were retrospectively analyzed. Only patients with at least three positive provocation maneuvers for SIJ pain were selected. Contrast images of the SIJ were classified as with or without cranial spread on fluoroscopy as a marker of intra-articular injection. Clinical success was defined as ≥50% improvement in the patient's global perceived effect after 3-4 weeks. The primary outcome was defined as the correlation between cranial contrast spread and clinical success after an SIJ injection. RESULTS: 128 patients in total were included. In 68 patients (53.1%) fluoroscopy showed cranial contrast spread. Clinical success was higher in patients with cranial spread of contrast (55 of 68, 81%) versus those without (35 of 60, 58%) (p=0.0067). In a multivariable analysis with age, gender, presence of rheumatoid arthritis, side, and number of positive provocation maneuvers, the cranial spread of contrast remained the only independent factor of clinical success (p=0.006; OR 3.2, 95% CI 1.4 to 7.7). CONCLUSION: In patients with SIJ pain, identified by positive pain provocation maneuvers, cranial contrast spread as a marker of intra-articular injection, with subsequent injection of 3 mL of local anesthetic and methylprednisolone 40 mg, was significantly correlated with clinical success up to 4 weeks. Therefore, attempts should be made to reach this final needle position before injecting local anesthetic and corticosteroids. This result needs to be confirmed in a high-quality prospective trial.
33072083 Human Chondrocyte Activation by Toxins From Premolis semirufa, an Amazon Rainforest Moth C 2020 Pararamosis is a disease that occurs due to contact with the hairs of the larval stage of the Brazilian moth Premolis semirufa. Envenomation induces osteoarticular alterations with cartilage impairment that resembles joint synovitis. Thus, the toxic venom present in the caterpillar hairs interferes with the phenotype of the cells present in the joints, resulting in inflammation and promoting tissue injury. Therefore, to address the inflammatory mechanisms triggered by envenomation, we studied the effects of P. semirufa hair extract on human chondrocytes. We have selected for the investigation, cytokines, chemokines, matrix metalloproteinases (MMPs), complement components, eicosanoids, and extracellular matrix (ECM) components related to OA and RA. In addition, for measuring protein-coding mRNAs of some molecules associated with osteoarthritis (OA) and rheumatoid arthritis (RA), reverse transcription (RT) was performed followed by quantitative real-time PCR (RT-qPCR) and we performed the RNA-sequencing (RNA-seq) analysis of the chondrocytes transcriptome. In the supernatant of cell cultures treated with the extract, we observed increased IL-6, IL-8, MCP-1, prostaglandin E2, metalloproteinases (MMP-1, MMP-2, MMP-3 and MMP-13), and complement system components (C3, C4, and C5). We noticed a significant decrease in both aggrecan and type II collagen and an increase in HMGB1 protein in chondrocytes after extract treatment. RNA-seq analysis of the chondrocyte transcriptome allowed us to identify important pathways related to the inflammatory process of the disease, such as the inflammatory response, chemotaxis of immune cells and extracellular matrix (ECM) remodeling. Thus, these results suggest that components of Premolis semirufa hair have strong inflammatory potential and are able to induce cartilage degradation and ECM remodeling, promoting a disease with an osteoarthritis signature. Modulation of the signaling pathways that were identified as being involved in this pathology may be a promising approach to develop new therapeutic strategies for the control of pararamosis and other inflammatory joint diseases.
32994431 Microtiter plate-based antibody-competition assay to determine binding affinities and plas 2020 Sep 29 C-X-C chemokine receptor type 4 (CXCR4) is involved in several intractable disease processes, including HIV infection, cancer cell metastasis, leukemia cell progression, rheumatoid arthritis, asthma and pulmonary fibrosis. Thus, CXCR4 represents a promising drug target and several CXCR4 antagonizing agents are in preclinical or clinical development. Important parameters in drug lead evaluation are determination of binding affinities to the receptor and assessment of their stability and activity in plasma or blood of animals and humans. Here, we designed a microtiter plate-based CXCR4 antibody competition assay that enables to measure inhibitory concentrations (IC(50) values) and affinity constants (K(i) values) of CXCR4 targeting drugs. The assay is based on the observation that most if not all CXCR4 antagonists compete with binding of the fluorescence-tagged CXCR4 antibody 12G5 to the receptor. We demonstrate that this antibody-competition assay allows a convenient and cheap determination of binding affinities of various CXCR4 antagonists in living cells within just 3 h. Moreover, the assay can be performed in the presence of high concentrations of physiologically relevant body fluids, and thus is a useful readout to evaluate stability (i.e. half-life) of CXCR4 ligands in serum/plasma, and even whole human and mouse blood ex vivo. Thus, this optimized 12G5 antibody-competition assay allows a robust and convenient determination and calculation of various important pharmacological parameters of CXCR4 receptor-drug interaction and may not only foster future drug development but also animal welfare by reducing the number of experimental animals.
32879894 Polymorphonuclear Cell Chemotaxis and Suicidal NETosis: Simultaneous Observation Using fML 2020 Chemotaxis and the formation of suicidal neutrophil extracellular traps (suicidal NETosis) are key functions of polymorphonuclear cells (PMNs). Neutrophil extracellular traps in particular are known to be significantly involved in the severity of inflammatory and immunological disorders such as rheumatoid arthritis and Crohn's disease. Therefore, detailed knowledge of PMNs is essential for analyzing the mechanisms involved in, and developing new therapies for, such diseases. To date, no standard method to analyze these cell activities has been established. This study used in vitro live cell imaging to simultaneously observe and analyze PMN functions. To demonstrate this, the effects of phorbol-12-myristat-13-acetat (PMA, 0.1-10 nM), N-formylmethionine-leucyl-phenylalanine (fMLP, 10 nM), and protein kinase C inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7) on PMN chemotaxis and suicidal NETosis were studied. PMA (1 nM-10 nM) resulted in significant concentration-dependent behavior in chemotaxis and an earlier onset of maximum oxidative burst and NET formation of up to 44%. When adding H7, PMA-triggered PMN functions were reduced, demonstrating that all three functions rely mostly on protein kinase C (PKC) activity, while PKC is not essential for fMLP-induced PMN activity. Thus, the method here described can be used to objectively quantify PMN functions and, especially through the regulation of the PKC pathway, could be useful in further clinical studies of immunological disorders.
32781284 Hydrogen sulfide: An endogenous regulator of the immune system. 2020 Nov Hydrogen sulfide (H(2)S) is now recognized as an endogenous signaling gasotransmitter in mammals. It is produced by mammalian cells and tissues by various enzymes - predominantly cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST) - but part of the H(2)S is produced by the intestinal microbiota (colonic H(2)S-producing bacteria). Here we summarize the available information on the production and functional role of H(2)S in the various cell types typically associated with innate immunity (neutrophils, macrophages, dendritic cells, natural killer cells, mast cells, basophils, eosinophils) and adaptive immunity (T and B lymphocytes) under normal conditions and as it relates to the development of various inflammatory and immune diseases. Special attention is paid to the physiological and the pathophysiological aspects of the oral cavity and the colon, where the immune cells and the parenchymal cells are exposed to a special "H(2)S environment" due to bacterial H(2)S production. H(2)S has many cellular and molecular targets. Immune cells are "surrounded" by a "cloud" of H(2)S, as a result of endogenous H(2)S production and exogenous production from the surrounding parenchymal cells, which, in turn, importantly regulates their viability and function. Downregulation of endogenous H(2)S producing enzymes in various diseases, or genetic defects in H(2)S biosynthetic enzyme systems either lead to the development of spontaneous autoimmune disease or accelerate the onset and worsen the severity of various immune-mediated diseases (e.g. autoimmune rheumatoid arthritis or asthma). Low, regulated amounts of H(2)S, when therapeutically delivered by small molecule donors, improve the function of various immune cells, and protect them against dysfunction induced by various noxious stimuli (e.g. reactive oxygen species or oxidized LDL). These effects of H(2)S contribute to the maintenance of immune functions, can stimulate antimicrobial defenses and can exert anti-inflammatory therapeutic effects in various diseases.
32766317 Mechanism of Follicular Helper T Cell Differentiation Regulated by Transcription Factors. 2020 Helping B cells and antibody responses is a major function of CD4(+)T helper cells. Follicular helper T (Tfh) cells are identified as a subset of CD4(+)T helper cells, which is specialized in helping B cells in the germinal center reaction. Tfh cells express high levels of CXCR5, PD-1, IL-21, and other characteristic markers. Accumulating evidence has demonstrated that the dysregulation of Tfh cells is involved in infectious, inflammatory, and autoimmune diseases, including lymphocytic choriomeningitis virus (LCMV) infection, inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), IgG4-related disease (IgG4-RD), Sjögren syndrome (SS), and type 1 diabetes (T1D). Activation of subset-specific transcription factors is the essential step for Tfh cell differentiation. The differentiation of Tfh cells is regulated by a complicated network of transcription factors, including positive factors (Bcl6, ATF-3, Batf, IRF4, c-Maf, and so on) and negative factors (Blimp-1, STAT5, IRF8, Bach2, and so on). The current knowledge underlying the molecular mechanisms of Tfh cell differentiation at the transcriptional level is summarized in this paper, which will provide many perspectives to explore the pathogenesis and treatment of the relevant immune diseases.
32765418 Protective Effects of PACAP in Peripheral Organs. 2020 Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide widely distributed in the nervous system, where it exerts strong neuroprotective effects. PACAP is also expressed in peripheral organs but its peripheral protective effects have not been summarized so far. Therefore, the aim of the present paper is to review the existing literature regarding the cytoprotective effects of PACAP in non-neuronal cell types, peripheral tissues, and organs. Among others, PACAP has widespread expression in the digestive system, where it shows protective effects in various intestinal pathologies, such as duodenal ulcer, small bowel ischemia, and intestinal inflammation. PACAP is present in both the exocrine and endocrine pancreas as well as liver where it reduces inflammation and steatosis by interfering with hepatic pathology related to obesity. It is found in several exocrine glands and also in urinary organs, where, with its protective effects being mainly published regarding renal pathologies, PACAP is protective in numerous conditions. PACAP displays anti-inflammatory effects in upper and lower airways of the respiratory system. In the skin, it is involved in the development of inflammatory pathology such as psoriasis and also has anti-allergic effects in a model of contact dermatitis. In the non-neuronal part of the visual system, PACAP showed protective effects in pathological conditions of the cornea and retinal pigment epithelial cells. The positive role of PACAP has been demonstrated on the formation and healing processes of cartilage and bone where it also prevents osteoarthritis and rheumatoid arthritis development. The protective role of PACAP was also demonstrated in the cardiovascular system in different pathological processes including hyperglycaemia-induced endothelial dysfunction and age-related vascular changes. In the heart, PACAP protects against ischemia, oxidative stress, and cardiomyopathies. PACAP is also involved in the protection against the development of pre-senile systemic amyloidosis, which is presented in various peripheral organs in PACAP-deficient mice. The studies summarized here provide strong evidence for the cytoprotective effects of the peptide. The survival-promoting effects of PACAP depend on a number of factors which are also shortly discussed in the present review.
32731768 Association of Rs231775 Genetic Variant of Cytotoxic T-lymphocyte Associated Protein 4 wit 2021 Nov BACKGROUND: Alopecia Areata (AA) is a common inflammatory immune-mediated non-scarring hair loss; however, the exact genetic susceptibility remains to be clarified. Cytotoxic T-lymphocyte Associated Protein 4 (CTLA4) has emerged as a central and critically important modulator of immune responses and is believed to play a crucial rule in AA pathogenesis. OBJECTIVES: To investigate the association of CTLA4 variant (rs231775) within codon 17 with AA risk and outcomes. METHODS: Genetic analyses of the rs231775 SNP of CTLA4 gene were performed in 186 males (93 AA patients and 93 controls). RESULTS: The rs231775 CTLA4 variant was significantly higher in AA patients in comparison with control subjects especially among heterozygous and dominant model. This association varied significantly with disease severity. CONCLUSIONS: Individuals with homozygosity of rs231775 CTLA4 variant represented AA disease risk and increased severity than their counterparts.Abbreviations: AA: Alopecia areata; CTLA4: Cytotoxic T-lymphocyte Associated Protein 4; SNP: Single nucleotide polymorphism; LADA: Latent autoimmune diabetes in adults; SLE: Systemic lupus erythematosus; SCU: Suez Canal University; SALT: Severity of Alopecia Tool; DNA: Deoxyribonucleic acid; RT-PCR: Real-time polymerase chain reaction, HWE: Hardy-Weinberg equation; RA: rheumatoid arthritis.
32682372 Therapeutic and Mechanistic Approaches of Tridax Procumbens Flavonoids for the Treatment o 2020 Homeostasis of bone is closely regulated by the balanced activities between the bone resorbing activity of osteoclast cells and bone-forming ability of osteoblast cells. Multinucleated osteoclasts degrade bone matrix and involve in the dynamic bone remodelling in coordination with osteoblasts. Disruption of this regulatory balance between these cells or any imbalance in bone remodelling caused by a higher rate of resorption over construction of bone results in a decrease of bone matrix including bone mineral density (BMD). These osteoclast-dominant effects result in a higher risk of bone crack and joint demolition in several bone-related diseases, including osteoporosis and rheumatoid arthritis (RA). Tridax procumbens is a very interesting perennial plant and its secondary metabolites called here T. procumbens flavonoids (TPFs) are well-known phytochemical agents owing to various therapeutic practices such as anti-inflammatory, anti-anaemic and anti-diabetic actions. This review designed to focus the systematic convention concerning the medicinal property and mechanism of actions of TPFs for the management of bone-related diseases. Based on the current literature, the review offers evidence-based information of TPFs for basic researchers and clinicians for the prevention and treatment of bone related diseases, including osteoporosis. It also emphasizes the medical significance for more research to comprehend the cellular signalling pathways of TPFs for the regulation of bone remodelling and discusses the possible promising ethnobotanical resource that can convey the preclinical and clinical clues to develop the next generation therapeutic agents for the treatment of bonerelated disorders.
32672719 Chronic Corticosteroid Use as a Risk Factor for Perioperative Complications in Patients Un 2020 Jul BACKGROUND: Osteoarthritis may be caused by or concurrent with diseases such as rheumatoid arthritis or systemic lupus erythematosus, which rely on chronic corticosteroids regimens for treatment. If a total knee or hip arthroplasty is needed, this chronic treatment method has been associated with poorer surgical outcomes. METHODS: A retrospective analysis of data collected by the American College of Surgeons National Surgical Quality Improvement Program was conducted. The Current Procedural Terminology codes were used to identify 403,566 total knee arthroplasty and total hip arthroplasty patients who were then stratified by the use of chronic corticosteroids for univariate analysis. RESULTS: Forteen thousand seven hundred seventy-four of the patients identified were prescribed chronic corticosteroid regimens. A statistically significant difference was observed in perioperative complications for patients prescribed with corticosteroids, including higher rates of surgical site infection (P = 0.0001), occurrence of deep incisional surgical site infection (P < 0.0001), occurrences of organ space surgical site infection (P < 0.0001), wound dehiscence (P < 0.0001), general would infection (P < 0.0001), pneumonia (P < 0.0001), occurrences of unplanned intubation (P = 0.0002), urinary tract infection (P < 0.0001), and readmission (P < 0.0001). No statistically significant difference was observed in the 30-day mortality between the 2 groups (0.63), venous thromboembolic event (0.42), cerebrovascular accident (0.12), myocardial infarction (0.49), cardiac arrest (0.098), deep vein thrombosis (0.17), or sepsis (0.52). CONCLUSION: Many of the notable differences in complications may be directly attributed to the immunosuppressive nature of corticosteroids. With increased knowledge of which perioperative complications to monitor, surgeons can tailor treatment strategies to this population that reduce morbidity and improve outcomes.
32623537 Atlanto-axial rotary instability (Fielding type 1): characteristic clinical and radiologic 2021 Jun Atlanto-axial instability (AAI) is common in the connective tissue disorders, such as rheumatoid arthritis, and increasingly recognized in the heritable disorders of Stickler, Loeys-Dietz, Marfan, Morquio, and Ehlers-Danlos (EDS) syndromes, where it typically presents as a rotary subluxation due to incompetence of the alar ligament. This retrospective, IRB-approved study examines 20 subjects with Fielding type 1 rotary subluxation, characterized by anterior subluxation of the facet on one side, with a normal atlanto-dental interval. Subjects diagnosed with a heritable connective tissue disorder, and AAI had failed non-operative treatment and presented with severe headache, neck pain, and characteristic neurological findings. Subjects underwent a modified Goel-Harms posterior C1-C2 screw fixation and fusion without complication. At 15 months, two subjects underwent reoperation following a fall (one) and occipito-atlantal instability (one). Patients reported improvement in the frequency or severity of neck pain (P < 0.001), numbness in the hands and lower extremities (P = 0.001), headaches, pre-syncope, and lightheadedness (all P < 0.01), vertigo and arm weakness (both P = 0.01), and syncope, nausea, joint pain, and exercise tolerance (all P < 0.05). The diagnosis of Fielding type 1 AAI requires directed investigation with dynamic imaging. Alignment and stabilization is associated with improvement of pain, syncopal and near-syncopal episodes, sensorimotor function, and exercise tolerance.
32500484 Hidradenitis Suppurativa and Concurrent Psoriasis: Comparison of Epidemiology, Comorbidity 2020 Aug INTRODUCTION: Hidradenitis suppurativa (HS) is a chronic, debilitating, and inflammatory skin disease. The epidemiology of HS varies greatly, with an estimated prevalence ranging from 0.03% to 4% worldwide. Similar to psoriasis (PsO), HS also exhibits a systemic inflammatory nature with a spectrum of systemic comorbidities. A large health insurance claims (HICs) database is analyzed to determine the demography and epidemiology of HS, PsO, and HS with concurrent PsO (HS-PsO) patients. Furthermore, the comorbidity profiles, including the comorbidity risk of these patient populations, are analyzed. METHODS: This is a noninterventional retrospective analysis of anonymized HICs data using a subset of the Institute of Applied Health Research Berlin (InGef) database. The primary outcome is the prevalence and incidence of HS, PsO, and HS-PsO. Secondary outcomes include comorbidity profiles and a comorbidity risk analysis. RESULTS: The prevalence and incidence of HS were 0.0681% and 0.0101%, respectively. The prevalence of HS-PsO was 0.004% (6% of the total HS population). HS patients frequently suffered from arterial hypertension (45%), nicotine dependence (46%), obesity (41%), and depression (36%), which were more common in HS-PsO patients compared with HS alone. HS patients had an increased prevalence of metabolic, psychiatric, immune-mediated, and cardiovascular diseases, e.g., overweight/obesity [odds ratio (OR): 2.65, 95% confidence interval (CI) 2.37-2.96], depression (OR: 1.55, 95% CI 1.42-1.76), or seronegative rheumatoid arthritis (OR: 2.82, 95% CI 1.61-4.94) compared with the overall population. The increased risk of myocardial infarction in HS patients (OR: 4.1, 95% CI 3.5-4.8, adjusting for age/sex) was largely attributed to patient's current smoking status (OR: 1.1, 95% CI 0.8-1.5, adjusting for smoking/age/sex). CONCLUSIONS: HS patients show a broad spectrum of inflammatory and metabolic syndrome-related comorbidities, with an increased risk by concurrent PsO. Important for clinical practice, the elevated cardiovascular risk of HS patients can be largely attributed to smoking.