Mimicking and in vitro validating chronic inflammation in human gingival fibroblasts.

OBJECTIVE: The aim of this study was to identify and validate in vitro conditions that may mimic the translational, cytokine and chemokine profiles observed in human inflamed gingiva in vivo. DESIGN: Primary human gingiva fibroblast cells (HFIB-G) were cultured under serum starvation conditions (0 - 10 %), supplemented with increasing lipopolysaccharide (LPS) concentrations (0.1, 1, or 10 µg/ml) from two bacterial strains E. coli and P. gingivalis and 0.1, 1, or 10 ng/ml recombinant interleukin 1ß (IL-1ß), alone or in combinations. The levels of cytokines/chemokines were measured in the cell culture medium by Luminex, and gene expression was quantified by Affymetrix microarrays at 24, 48 and 72 h. RESULTS: Inflammation markers were not elevated after stimulation with P. gingivalis LPS, while E. coli LPS and IL-1ß individually increased the secretion of interleukin 6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) to the cell culture medium. IL-1ß administration also increased the secretion of several factors, including tumor necrosis factor (TNFα). However, the combination of 1 µg/ml E. coli LPS, 1 ng/ml IL-1ß and serum starvation led to increased secretion of IL-6, TNFα, in addition to other factors found in inflamed tissue. Gene expression analyses revealed that this combination not only enhanced the expression interleukins/chemokines genes but also T helper cell signaling and matrix metalloproteinases. CONCLUSION: Serum reduction in cell culture medium together with the administration of E. coli LPS and IL-1ß resulted in gene expression and secreted cytokine/chemokine profiles similar to that found in vivo during chronic inflammation.

Aqueous Extracts of Rhus trilobata Inhibit the Lipopolysaccharide-Induced Inflammatory Response In Vitro and In Vivo.

Chronic noncommunicable diseases (NCDs) are responsible for approximately 74% of deaths globally. Medicinal plants have traditionally been used to treat NCDs, including diabetes, cancer, and rheumatic diseases, and are a source of anti-inflammatory compounds. This study aimed to evaluate the anti-inflammatory effects of Rhus trilobata (Rt) extracts and fractions in lipopolysaccharide (LPS)-induced inflammation models in vitro and in vivo. The aqueous extract (RtAE) and five fractions (F2 to F6) were obtained via C18 solid-phase separation and tested in murine LPS-induced J774.1 macrophages. Key inflammatory markers, such as IL-1ß, IL-6, TNF-α, and COX-2 gene expression were measured using RT-qPCR, and PGE2 production was assessed via HPLC-DAD. The in vivo effects were tested in an LPS-induced paw edema model in Wistar rats. Results showed that RtAE at 15 µg/mL significantly decreased IL-1ß and IL-6 gene expression in vitro. Fraction F6 further reduced IL-1ß, TNF-α, and IL-6 gene expression, COX-2 expression, and PGE2 production. In vivo, F6 significantly reduced LPS-induced paw edema, inflammatory infiltration, and IL-1ß and COX-2 protein expression. Chemical characterization of F6 by UPLC/MS-QTOF revealed at least eight compounds with anti-inflammatory activity. These findings support the anti-inflammatory potential of RtAE and F6, reinforcing the medicinal use of Rt.

Interleukin-1 Beta rs16944 and rs1143634 and Interleukin-6 Receptor rs12083537 Single Nucleotide Polymorphisms as Potential Predictors of COVID-19 Severity.

Host genetic variation has been recognized as a key predictor of diverse clinical sequelae among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients. Insights into the link between the Interleukin-6 receptor (IL-6R) and Interleukin-1 beta (IL-1ß) genetic variation and severe coronavirus disease 2019 (COVID-19) are crucial for developing new predictors and therapeutic targets. We aimed to investigate the association of IL-6R rs12083537, IL-1ß rs16944, and IL-1ß rs1143634 SNPs with the severity of COVID-19. Our study was conducted on 300 COVID-19-negative individuals (control group) and 299 COVID-19-positive cases, classified into mild, moderate, and severe subgroups. Analyses of IL-1ß (rs16944, rs1143634) and IL-6R (rs12083537) SNPs' genotypes were performed using qPCR genotyping assays. The IL-1ß (rs16944) CC genotype and IL-6R (rs12083537) GG genotype were substantially related to COVID-19 severity, which was also associated with comorbidities and some laboratory parameters (p < 0.001). The IL-1ß (rs1143634) TT genotype was found to be protective. Likewise, the IL-1ß (rs16944) CC genotype was associated with increased mortality. IL-1ß rs16944 and IL-6R rs12083537 SNPs are promising potential predictors of SARS-CoV-2 disease severity. Meanwhile, the rs1143634 SNP T allele was protective against severity and mortality risk.

IL-1 receptor antagonist: etiological and drug delivery systems overview.

OBJECTIVE: This article is aims to provide an overview of studies reported in the literature to investigate the etiological role of IL-1/IL-1ra in various disease conditions and the different drug delivery systems developed to achieve IL-1ra as a possible therapeutic option. METHODS: Studies reported in PubMed, Google scholar, and other open-source literature related to etiological involvement of IL-1ra in pathophysiological conditions and various drug delivery schemes developed for IL-1ra for its efficacy evaluation as a possible treatment for different disease conditions were surveyed. RESULTS AND CONCLUSIONS: The pathophysiological conditions involving IL-1/IL-1 ra spanned CNS-related disorders, Diabetes, Cardiac disorders, Ocular disease conditions, Gastrointestinal conditions, Tumor growth & metastasis, and miscellaneous conditions. The drug delivery systems developed for IL-1ra included a commercial drug product, Gene therapy, Antibody fusions, Extended-release delivery systems, and Pegylated-IL-1ra systems.

Recurrent Pericarditis and Paradigm Shift in Cardiovascular Imaging and Targeted Therapeutics.

Recurrent pericarditis poses a significant challenge to patients and clinicians given its high morbidity and health care burden. Since the last iteration of European Society of Cardiology Guidelines in 2015, further insights have been gained into the pathophysiology, multimodality imaging assessment, and treatment of this condition. The purpose of this review is to discuss each of these aspects and highlight the role of imaging-guided therapy and interleukin-1 inhibitors in autoinflammatory phenotypes that together have transformed the care of these patients. Although future investigations are needed to optimize diagnostic surveillance and timing of therapy, recent evidence points at an encouraging paradigm shift in the treatment of recurrent pericarditis.

Targeting Inflammatory Pathways in Atherosclerosis: Exploring New Opportunities for Treatment.

PURPOSE OF THE REVIEW: This review discusses the molecular mechanisms involved in the immuno-pathogenesis of atherosclerosis, the pleiotropic anti-inflammatory effects of approved cardiovascular therapies and the available evidence on immunomodulatory therapies for atherosclerotic cardiovascular disease (ACVD). We highlight the importance of clinical and translational research in identifying molecular mechanisms and discovering new therapeutic targets. RECENT FINDINGS: The CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) trial was the first to demonstrate a reduction in cardiovascular (CV) risk with anti-inflammatory therapy, irrespective of serum lipid levels. ACVD is the leading cause of death worldwide. Although targeting principal risk factors significantly reduces CV risk, residual risk remains unaddressed. The immunological mechanisms underlying atherosclerosis represent attractive therapeutic targets. Several commonly used and non-primarily anti-inflammatory drugs (i.e. SGLT2i, and PCSK9i) exhibit pleiotropic properties. Otherwise, recent trials have investigated the blockade of primarily inflammatory compounds, trying to lower the residual risk via low-dose IL-2, PTPN22 and CD31 pathway modulation. In the era of precision medicine, modern approaches may explore new pharmacological targets, identify new markers of vascular inflammation, and evaluate therapeutic responses.

The Levels of Biomarkers Interleukin 1 (IL-1) and Brain-Derived Neurotrophic Factor (BDNF) in Non-Invasive Conventional Rehabilitation and Robotic Rehabilitation Among Brain Injury Patients: A Narrative Review.

Acquired brain injury (ABI) is becoming increasingly common in Malaysia as a result of a rise in both strokes and accidents. The present review aims to explore the levels of serum inflammatory markers of interleukin-1 (IL-1) and brain-derived neurotrophic factor (BDNF) following conventional and robotic rehabilitation regimes among ABI patients and the association between serum biomarkers with the Medical Research Council (MRC) scale for muscle strength. Online databases, namely ScienceDirect, PubMed, and Google Scholar were utilized by using search terms such as 'Definition of brain injury', 'Epidemiology of brain injury', 'Interleukin-1 in stroke', 'BDNF in stroke', 'Interleukin-1 in traumatic brain injury', 'BDNF in traumatic brain injury', 'Interleukin-1 level and robotic rehabilitation', 'BDNF and robotic rehabilitation', 'Interleukin-1 level and neurorehabilitation', and 'BDNF and neurorehabilitation'. All types of articles with different levels of evidence were included along with other relevant review articles. Articles that were not in English and were not available in the full text were excluded. The review identifies similar and no significant improvement in the treatment between conventional rehabilitation and robotic rehabilitation concerning serum biomarkers IL-1 and BDNF. This review also identifies that muscle strength and endurance training improved the level of serum BDNF in brain injury patients. Therefore, this review provides evidence of the levels of IL-1 and BDNF in non-invasive conventional rehabilitation and robotic rehabilitation among brain injury patients, as well as their relation with the MRC scale, to give a good functional outcome that will enhance the quality of life of these groups of individuals.

Molecular mechanisms of regulation of IL-1 and its receptors.

Interleukin 1 (IL-1) is a pro-inflammatory cytokine that plays a key role in the development and regulation of nonspecific defense and specific immunity. However, its regulatory influence extends beyond inflammation and impacts a range of immune and non-immune processes. The involvement of IL-1 in numerous biological processes, including modulation of inflammation, necessitates strict regulation at multiple levels. This review focuses on these regulatory processes and discusses their underlying mechanisms. IL-1 activity is controlled at various levels, including receptor binding, gene transcription, expression as inactive proforms, and regulated post-translational processing and secretion. Regulation at the level of the receptor expression - alternative splicing, tissue-specific isoforms, and gene polymorphism - is also crucial to IL-1 functional activity. Understanding these regulatory features of IL-1 will not only continue to shape future research directions but will also highlight promising therapeutic strategies to modulate the biological effects of IL-1.

Cannabiorcol as a novel inhibitor of the p38/MSK-1/NF-κB signaling pathway, reducing matrix metalloproteinases in osteoarthritis.

BACKGROUND: The bioactivity and potential medicinal applications of cannabiorcol, a lesser-known derivative of Cannabis sativa, require further investigation. Osteoarthritis (OA) is a chronic joint condition marked by gradual degradation of the cartilage and commonly associated with elevated levels of matrix metalloproteinases (MMPs). However, the influence of cannabiorcol on OA and its underlying mechanisms remains unclear. METHODS: In silico analysis investigated the key transcription factors that regulate MMP expression. A chondrocyte cell model [interleukin (IL)-1ß and IL-1⍺-treated C20A4 cell line] was established and treated with cannabiorcol. Associated cytotoxicity was assessed using a WST-8 assay. A monoiodoacetate-induced OA rat model was established and treated with cannabiorcol. Protein translocation and transactivation analyses were conducted using immunofluorescence and dual-luciferase reporter assays, respectively. Western blotting and real-time PCR analyzed relevant markers to examine cannabiorcol's effects on OA and its fundamental mechanisms. RESULTS: Cannabiorcol inhibits the expression of IL-1ß-induced MMPs compared to other cannabis-related compounds. In silico analysis revealed that the nuclear factor-kappa ß (NF-κß) and mitogen-activated protein kinase (MAPK) pathways are associated with MMP expression as key regulators. In vitro, cannabiorcol inhibits the NF-κB and p38 MAPK pathways independently cannabinoid receptors and transient receptor potential vanilloids. In vivo, cannabiorcol reduces MMP expression and ameliorates monoiodoacetate-induced OA traits in rats. CONCLUSION: Cannabiorcol inhibits IL-1ß-induced MMP expression in vitro and alleviates OA in an MIA-induced OA rat model by reducing MMP expression and inhibiting the p65/p38 axis.

Interactions between sleep, inflammation, immunity and infections: A narrative review.

BACKGROUND: Over the past decades, it has become increasingly evident that sleep disturbance contributes to inflammation-mediated disease, including depression, mainly through activation of the innate immune system and to an increased risk of infections. METHODS: A comprehensive literature search was performed in PubMed to identify relevant research findings in the field of immunity, inflammation and infections, with a focus on translational research findings from the past 5 years. RESULTS: Physiological sleep is characterized by a dynamic interplay between the immune system and sleep architecture, marked by increased innate immunity and T helper 1 (Th1) -mediated inflammation in the early phase, transitioning to a T helper 2 (Th2) response dominating in late sleep. Chronic sleep disturbances are associated with enhanced inflammation and an elevated risk of infections, while other inflammatory diseases may also be affected. Conversely, inflammation in response to infection can also disrupt sleep patterns and architecture. This narrative review summarizes current data on the complex relationships between sleep, immunity, inflammation and infections, while highlighting translational aspects. The bidirectional nature of these interactions are addressed within specific conditions such as sleep apnea, HIV, and other infections. Furthermore, technical developments with the potential to accelerate our understanding of these interactions are identified, including advances in wearable devices, artificial intelligence, and omics technology. By integrating these tools, novel biomarkers and therapeutic targets for sleep-related immune dysregulation may be identified. CONCLUSION: The review underscores the importance of understanding and addressing immune imbalance related to sleep disturbances to improve disease outcomes.

The Impact of Remote Ischemic Preconditioning on Inflammation Markers in Patients Undergoing Coronary Artery Bypass Grafting.

Background: This study aimed to investigate if remote ischemic preconditioning reduces the inflammatory process on patients undergoing coronary artery bypass grafting (CABG). Methods: We conducted a case-control study involving 80 patients, half of whom underwent ischemic preconditioning for severe coronary artery disease (CAD) and subsequently underwent CABG. We assessed interleukin (IL)-1 and IL-6 levels using the enzyme-linked immunosorbent assay (ELISA) method, high-sensitivity troponin I (hsTnI) using chemiluminescent immunoassay (CLIA), and C-reactive protein (CRP) using the turbidimetric method at three key time points: before surgery (visit 1 or V1), immediately postoperatively (visit 2 or V2), and 1 week postoperatively (visit 3 or V3) in all subjects. Results: Ischemic preconditioned patients showed a significant decrease in proinflammatory markers (IL-1, IL-6) but not in CRP or hsTnI. Conclusions: This study demonstrated that remote ischemic preconditioning significantly reduced the levels of specific proinflammatory markers (IL-1 and IL-6), which may suggest general systemic protection. However, it did not demonstrate cardioprotection per se, as evidenced by the absence of a statistically significant decrease in hsTnI level.

Conservative management of spinal pathology with autologous conditioned serum: A systematic review of the literature.

BACKGROUND: Chronic inflammatory pain is associated with increased expression of interleukin (IL)-1, an inflammatory cytokine, and activity on its receptor (IL-1R). In response, the body produces IL-1R antagonist (IL-1Ra) to reduce this signaling. Autologous conditioned serum (ACS) is the only biologic therapy for spinal pathologies that enhances the action of endogenous IL-1Ra reserves to improve symptoms. This systematic review investigates the effectiveness of ACS in treating pain and disability caused by spinal pathologies. AIM: To evaluate the use of ACS as a conservative management option for spinal pathology. METHODS: A systematic review of PubMed/Medline was performed to identify studies investigating administration of ACS for treatment of any spinal pathology. RESULTS: Six articles were included, comprising 684 patients treated with epidural (n = 133) or transforaminal (n = 551) ACS injections. Patients had an average age of 54.0 years with slight female predominance (53.2%). The lumbar spine was most commonly treated, with 567 patients (82.9%) receiving injections for lumbar radiculopathy (n = 67), degenerative disc disease (DDD) (n = 372), or spinal stenosis (n = 128); cervical injections were performed in 109 patients (15.9%). Mean (SD) follow-up was 21.7 (4.8) weeks from first ACS injection. All studies investigating mechanical lumbar and lumbar or cervical radicular pain reported significant pain reduction at final follow-up compared to baseline. ACS achieved comparable or superior results to lumbar epidural steroid injections. Adverse events were reported in 21 patients (3.1%), with no serious adverse events. CONCLUSION: ACS injection is a safe and effective intervention for pain reduction in many spinal pathologies, including cervical and lumbar radiculopathies.

The role of inflammasomes as central inflammatory hubs in Mycobacterium tuberculosis infection.

Mycobacterium tuberculosis (Mtb) infection represents a global health problem and is characterized by formation of granuloma with a necrotic center and a systemic inflammatory response. Inflammasomes have a crucial role in the host immune response towards Mtb. These intracellular multi-protein complexes are assembled in response to pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Inflammasome platforms activate caspases, leading to the maturation of the proinflammatory cytokines interleukin (IL)-1 and 18 and the cleavage of gasdermin D (GSDMD), a pore-forming protein responsible for cytokine release and pyroptotic cell death. Recent in vitro and in vivo findings have highlighted the importance of inflammasome signaling and subsequent necrotic cell death in Mtb-infected innate immune cells. However, we are just beginning to understand how inflammasomes contribute to disease or to a protective immune response in tuberculosis (TB). A detailed molecular understanding of inflammasome-associated pathomechanisms may foster the development of novel host-directed therapeutics or vaccines with improved activity. In this mini-review, we discuss the regulatory and molecular aspects of inflammasome activation and the associated immunological consequences for Mtb pathogenesis.

Association of Serum Biomarkers With Neurocognitive Decline After PCI in Small Cell Lung Cancer: An Exploratory Study of the Phase III NCT01780675 Trial.

INTRODUCTION: Blood samples were collected to explore potential serum biomarkers associated with neurocognitive function in small-cell lung cancer (SCLC) patients who received prophylactic cranial irradiation (PCI). METHODS: This pre-specified study included patients with blood samples available, who participated in a phase III trial (NCT01780675). Blood samples were collected before PCI and 3-days post-initiating PCI. Neurocognitive decline was defined as a decrease of ≥ 5 points on total recall in the Hopkins Verbal Learning Test-Revised (HVLT-R) assessed from pre-PCI to 4-months post-PCI. Biomarkers were screened using univariate logistic regression analysis. P < .1 was considered statistically significant. RESULTS: Forty-eight enrolled patients who had blood samples at baseline were included and 27 were available for analysis as the other 21 did not assess neurocognitive function at 4-months. Lower levels of Tie-2 (OR = 0.999, 90% CI 0.998-1.000, P = .062), and higher levels of MIP-1b (OR = 1.022, 90% CI 1.000-1.044, P = .093), CCL-17 (OR = 1.004, 90% CI 1.001-1.006, P = .029), and IL-1α (OR = 1.597, 90% CI 1.077-2.367, P = .05) before PCI were correlated with neurocognitive decline at 4-months. Decrease of VEGF-C (OR = 0.972, 90% CI 0.949-0.996, P = .055), CCL-17 (OR = 0.993, 90% CI 0.988-0.999, P = .036), IL-1α (OR = 0.788, 90% CI 0.635-0.979, P = .071), and VEGF (OR = 0.981, 90% CI 0.965-0.997, P = .051) 3-days post-initiating PCI were also associated with neurocognitive decline at 4-months. CONCLUSIONS: Biomarker levels before PCI and changes in their levels 3-days post-initiating PCI may be linked to subsequent neurocognitive decline at 4-months. If validated, these biomarkers could be used to predict the risk of neurocognitive decline and act as a decision aid for personalized PCI in SCLC.

Clinical Utility of Rilonacept for the Treatment of Recurrent Pericarditis: Design, Development, and Place in Therapy.

Recurrent pericarditis (RP) has been traditionally regarded as a "nightmare" for both clinicians and patients. Until approximately a decade ago, available treatments were thin on the ground with non-steroidal anti-inflammatory medications, glucocorticoids, colchicine, and classical immunosuppressants being the only options. The first important step in the tale of RP was the advent of colchicine in clinical practice, which has been shown to halve the rate of first and subsequent pericarditis recurrences. The second major breakthrough advance in this setting was the introduction of interleukin-1 inhibitors based on the recently unveiled autoinflammatory nature of pericarditis. At present, anti-interleukin-1 inhibitors available for clinical use in patients with refractory RP include anakinra and rilonacept, with the latter having obtained FDA approval for this indication. Apart from the remarkable efficacy and good safety profile which is a common feature of all anti-interleukin-1 compounds, rilonacept has the advantage of weekly administration (instead of daily compared to anakinra) which is important in terms of adherence to treatment and improved quality of life albeit at the expense of a higher cost. This review aims to summarize the available evidence on the role of rilonacept in the treatment of RP and the reduction of the recurrences risk.

Majeed syndrome: first description in a patient of central-European ancestry.

OBJECTIVES: We present the first case of a Majeed syndrome in a girl of central-European ancestry. METHODS: : Patient's medical records were reviewed. A NGS panel for autoinflammatory diseases was performed and the mutation was confirmed by Sanger analysis. Freshly isolated monocytes were activated with LPS +/- ATP. The concentration of inflammatory cytokines was assessed in monocytes supernatants. RESULTS: A 2-year-old girl presented with pain in the lower limbs, increase of acute phase reactants and persistent microcytic anaemia. The MRI showed bilateral STIR hyper-intensity of the spongy osseous tissue of femur, tibia, radius, ulna, and astragalus. Bone marrow analysis revealed increased trilinear cellularity with signs of dyserythropoietic anaemia. NGS panel detected the presence of two novel compound heterozygous mutations in the LPIN2 gene, confirmed by Sanger analysis. Treatment with anakinra was started with a prompt resolution of the clinical picture. Increased kinetics and concentration of IL-1ß was observed in the patient's monocytes compared with healthy controls, with a marked drop following the start of therapy. About six months after the start of the therapy, resolution of MRI findings, microcytic anaemia and dyserythropoiesis at bone marrow aspirate was observed. CONCLUSION: We describe the first case of Majeed syndrome in a patient of central-European ancestry. The functional test on circulating monocytes before and after therapy with anakinra confirmed pathogenicity of the mutation and the role of LPIN2 in the NLRP3 inflammasome activation. Anti-IL1 agents were effective, leading not only to the resolution of bone lesion but also to an improvement of dyserythropoiesis.

Evidence on Hidradenitis Suppurativa as an Autoinflammatory Skin Disease.

Hidradenitis suppurativa (HS) is a chronic and debilitating inflammatory skin disease that often exhibits heterogeneity in its clinical presentation, especially in the context of its rare syndromic forms. The pathogenesis of HS results from a complex interplay of genetic predisposition, innate and adaptive immunity dysregulation, smoking, obesity and environmental factors. In the early phase of the disease, the innate immune system is hyperactivated, contributing to tissue damage and triggering the activation and amplification of the adaptive immune response, which plays a pivotal role in the chronic stages of the disease. Recent studies focused on elucidating the importance of innate immunity impairment and autoinflammation in HS and increasing evidence has emerged on the occurrence of the disease in the context of well-known monogenic and polygenic autoinflammatory syndromes (AIDs). This review provides a comprehensive examination of the current scientific background supporting the contribution of autoinflammation to HS etiology, including genetic data, molecular studies and clinical evidence, as well as the association between HS and AIDs. However, further research is needed to shed light on the pathogenic mechanism of this challenging condition and to identify potential perspectives for future therapeutic approaches.

Constitutive DAMPs in CNS injury: From preclinical insights to clinical perspectives.

Damage-associated molecular patterns (DAMPs) are endogenous molecules released in tissues upon cellular damage and necrosis, acting to initiate sterile inflammation. Constitutive DAMPs (cDAMPs) have the particularity to be present within the intracellular compartments of healthy cells, where they exert diverse functions such as regulation of gene expression and cellular homeostasis. However, after injury to the central nervous system (CNS), cDAMPs are rapidly released by stressed, damaged or dying neuronal, glial and endothelial cells, and can trigger inflammation without undergoing structural modifications. Several cDAMPs have been described in the injured CNS, such as interleukin (IL)-1α, IL-33, nucleotides (e.g. ATP), and high-mobility group box protein 1. Once in the extracellular milieu, these molecules are recognized by the remaining surviving cells through specific DAMP-sensing receptors, thereby inducing a cascade of molecular events leading to the production and release of proinflammatory cytokines and chemokines, as well as cell adhesion molecules. The ensuing immune response is necessary to eliminate cellular debris caused by the injury, allowing for damage containment. However, seeing as some molecules associated with the inflammatory response are toxic to surviving resident CNS cells, secondary damage occurs, aggravating injury and exacerbating neurological and behavioral deficits. Thus, a better understanding of these cDAMPs, as well as their receptors and downstream signaling pathways, could lead to identification of novel therapeutic targets for treating CNS injuries such as SCI, TBI, and stroke. In this review, we summarize the recent literature on cDAMPs, their specific functions, and the therapeutic potential of interfering with cDAMPs or their signaling pathways.

Effectiveness and safety of canakinumab in cryopyrin-associated periodic syndrome: a retrospective study in China.

OBJECTIVE: Cryopyrin-associated periodic syndrome (CAPS) is characterized by excessive IL-1ß release resulting in systemic and organ inflammation. As an anti-IL-1 agent, canakinumab has been approved with all CAPS phenotypes in USA and European countries. However, the use of canakinumab in CAPS in Chinese patients was rarely reported. In this study, we aimed to assess the effectiveness and safety of canakinumab in Chinese patients with CAPS. METHODS: Patients with CAPS treated with canakinumab were included. Clinical data were collected retrospectively from medical records. Treatment response was evaluated by CAPS disease activity score, C-reactive protein (CRP), and/or serum amyloid A (SAA) levels. Data was analyzed at canakinumab initiation, at months 1, 3, 6, 9, and 12, or the last follow-up. RESULTS: A total of 10 CAPS patients were included. 40% of patients were males, the median age at disease onset was 2.5 (2.5, 6) days and the median duration of follow-up while on canakinumab was 22.5 (8.5, 27.5) months. 80% (8/10) of CAPS patients presented with moderate-severe disease activity before the canakinumab treatment. 30% (3/10) of patients required canakinumab dose increase to control disease activity. After treatments, 60% (6/10) of CAPS patients achieved complete remission without relapse and the rest showed minimal disease activity. Clinical symptoms such as fever and rash were improved significantly in most patients (80%). Although abnormal imaging in brain MRI remained in over half of those patients, neurological manifestations were all relieved. 60% (6/10) of patients received prednisone before starting canakinumab therapy and five of them discontinued prednisone later. The most common adverse event was infection (40%). No serious adverse events occurred during the treatment of canakinumab. CONCLUSIONS: Canakinumab may be effective and tolerable for Chinese CAPS patients, helping to reduce the dosage of corticosteroids. However, additional trials on large samples are required to further evaluate its efficacy and safety in China.

MicroRNAs as Epigenetic Regulators of Obesity.

In obesity, the process of adipogenesis largely determines the number of adipocytes in body fat depots. Adipogenesis is regulated by several adipocyte-selective micro-ribonucleic acids (miRNAs) and transcription factors that modulate adipocyte proliferation and differentiation. However, some miRNAs block the expression of master regulators of adipogenesis. Since the specific miRNAs display different expressions during adipogenesis, in mature adipocytes and permanent obesity, their use as biomarkers or therapeutic targets is feasible. Upregulated miRNAs in persistent obesity are downregulated during adipogenesis. Moreover, some of the downregulated miRNAs in obese individuals are upregulated in mature adipocytes. Induction of adipocyte stress and hypertrophy leads to the release of adipocyte-derived exosomes (AdEXs) that contain the cargo molecules, miRNAs. miRNAs are important messengers for intercellular communication involved in metabolic responses and have very specific signatures that direct the metabolic activity of target cells. While each miRNA targets multiple messenger RNAs (mRNAs), which may coordinate or antagonize each other's functions, several miRNAs are dysregulated in other tissues during obesity-related comorbidities. Deletion of the miRNA-processing enzyme DICER in pro-opiomelanocortin-expressing cells results in obesity, which is characterized by hyperphagia, increased adiposity, hyperleptinemia, defective glucose metabolism, and alterations in the pituitary-adrenal axis. In recent years, RNA-based therapeutical approaches have entered clinical trials as novel therapies against overweight and its complications. Development of lipid droplets, macrophage accumulation, macrophage polarization, tumor necrosis factor receptor-associated factor 6 activity, lipolysis, lipotoxicity, and insulin resistance are effectively controlled by miRNAs. Thereby, miRNAs as epigenetic regulators are used to determine the new gene transcripts and therapeutic targets.