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关键词： NLRP3   IL- beta 1   Oral squamous cell carcinoma   Potentially malignant oral disorder   Inflammasome  

摘要： BackgroundNucleotide-binding domain-like receptor protein 3 (NLRP3), an inflammasome, is reported to be dysregulated or aberrantly expressed in chronic inflammation, leading to a myriad of inflammatory disorders, autoimmune diseases, and cancer. This study aimed to explore the expression and role of NLRP3 protein and the secreted cytokine IL-beta 1 in oral squamous cell carcinoma (OSCC) and potentially malignant oral disorders (PMOD).Material & MethodsTissue NLRP3 expression was quantified using sandwich ELISA in 30 cases each of OSCC, PMOD, and normal oral mucosa. Serum IL-beta 1 level was also measured by ELISA to determine their correlation. In surgically treated OSCC cases, pathological parameters such as tumor size, depth of invasion (DOI), pTNM stage, and perineural & lymphovascular invasion were assessed and correlated with NLRP3 & IL-beta 1 levels to investigate their roles in tumor progression, invasion, and *** NLRP3 expression was markedly elevated in OSCC, with significant IL-beta 1 levels observed in the serum of both OSCC and PMOD cases. Both markers showed a pronounced increase with the severity of dysplasia, indicating a strong association (p = 0.003%). The expression levels of tissue NLRP3 and serum IL-beta 1 were positively correlated with DOI and tumor size. Furthermore, their elevated levels, alongside higher histological grades, indicate roles in the dedifferentiation and progression of tumor *** findings indicated that increased expression of NLRP3 and IL-beta 1 in PMOD correlates with higher transformation rates, along with tumor progression and dedifferentiation in OSCC. Consequently, these markers hold promise as valuable targets for prognostic assessment, diagnostics, and therapeutic strategies in OSCC.

关键词： Preeclampsia   circ_0003314   miR-26b-5p   IL1RAP  

摘要： Preeclampsia (PE) is a pregnancy-related syndrome that can lead to a variety of pathophysiological processes, such as impaired implantation. The pathogenesis of PE involves circular RNA (circRNA). The study aims to determine the role of a novel circRNA, circ_0003314, in trophoblast cell phenotypes. Circ_0003314, microRNA-26b-5p (miR-26b-5p) and IL-1 receptor accessory protein (IL1RAP) expression were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation was investigated by MTT assay and 5-Ethynyl-2'-deoxyuridine assay. Cell migration and invasion were investigated by transwell assay. Cell apoptotic rate and angiogenesis were investigated by flow cytometry analysis and tube formation assay, respectively. Protein expression was detected by western blotting. The binding relationship between miR-26b-5p and circ_0003314 or IL1RAP was identified using dual-luciferase reporter assay and RNA pull-down assay. Circ_0003314 and IL1RAP expression were significantly increased, while miR-26b-5p was decreased in placental tissues of PE patients. Circ_0003314 overexpression inhibited trophoblast cell proliferation, migration, invasion and angiogenesis and induced cell apoptosis. Additionally, circ_0003314 acted as a sponge for miR-26b-5p, and miR-26b-5p bound to IL1RAP. Introduction of miR-26b-5p or silencing of IL1RAP attenuated the effects of circ_0003314 overexpression on trophoblast cell phenotypes. Further, circ_0003314 induced IL1RAP expression through miR-26b-5p in trophoblast cells. Circ_0003314 regulated trophoblast cell phenotypes by increasing IL1RAP expression through binding to miR-26b-5p.

关键词： IL-37   gastrointestinal   inflammation   cancer   colorectal cancer  

摘要： Gastrointestinal mucosal surface is frequently under challenge due to it's the large surface area and most common entry of microbes. IL-37, an anti-inflammatory cytokine, regulates local and systemic host immunity. H. pylori infection leads to the inhibition of IL-37 in the gastric mucosa, contributing to heightened mucosal inflammation and destruction, thereby facilitating increased proliferation of H. pylori. Food allergy, due to immune dysregulation, also contribute to GI injury. On the other hand, elevated levels of IL-37 observed in gastric cancer patients align with reduced host immunity at the cellular and humoral levels, indicating that IL-37 may contribute to the development of gastric cancer via suppressing pro-inflammatory responses. While IL-37 provides protection in an IBD animal model, the detection of highly produced IL-37 in IBD patients suggests a stage-dependent role, being protective in acute inflammation but potentially exacerbates the development of IBD in chronic conditions. Moreover, elevated colonic IL-37 in CRC correlates with overall survival time and disease time, indicating a protective role for IL-37 in CRC. The differential regulation and expression of IL-37 between upper- and lower-GI organs may be attributed to variations in the microbial flora. This information suggests that IL-37 could be a potential therapeutic agent, depending on the stage and location.

关键词： adverse reaction   vertigo   headache   sars-cov-2 vaccination   recoverin antibodies  

摘要： Retinopathy, small fiber neuropathy (SFN), and encephalopathy associated with recoverin antibodies have not been previously reported as side effects of BNT162b2 vaccination in a patient with HLA-B27-associated spondylarthritis. The patient is a 47-year-old male with a 10-year history of HLA-B27-associated spondylarthritis without recurrence, who developed acute and post-acute COVID vaccination syndrome (ACVS/PACVS) after the first dose of the BNT162b2 vaccine. The PACVS manifested as cerebral disease, eye disease, and SFN. Two years after the onset of the adverse effects, recurrent elevated recoverin antibodies were detected. Despite the administration of various treatments, most symptoms persisted for more than three years, and only a few interventions such as glucocorticoids, hyperbaric oxygen therapy, botulinum toxin, inuspheresis, and HELP (heparin-induced extracorporeal LDL precipitation) apheresis showed a transient beneficial effect. In conclusion, this case offers an example of a collection of symptoms following SARS-CoV-2 vaccination (SC2V) in a patient with a specific autoimmune disorder and positivity for anti-recoverin antibodies. These clinical manifestations may be triggered by an exaggerated immune response known as multisystemic inflammatory syndrome in adults to SC2V. Clinicians should report other similar cases to determine if a pattern exists.

关键词： Intensity estimation   Felt percentage   Macroseismology   Diagnostic effects   Macroseismic scale   Earthquake  

摘要： The lower degrees of the macroseismic scales are estimated mainly using the diagnostic related to the percentage of people who felt the earthquake ("felt" percentage). However, estimating this percentage by examining only a sub-sample of people may be biased, as those who complete the questionnaires are predominantly those who have felt the earthquake. One way to solve this problem is to send a specific request to them when an earthquake occurs. The 'Hai Sentito il Terremoto' (HSIT) site began implementing this strategy in December 2008 by allowing users to register on the website. Thanks to contributions from registered users, the HSIT database has been populated with "not felt" reports, which since 2009 have outnumbered the "felt" ones. The diagnostics of registered and unregistered users were analyzed separately in a sample of municipalities, showing no difference between the two types of users with the exception of "not felt" reports number. Despite the availability of the "not felt" reports, the experimental "felt" percentage is still overestimated when compared to those indicated in the Mercalli-Cancani-Sieberg scale. To refine the intensity calculation, the number of 'not felt' reports was multiplied by a correction factor, estimated at 6, to correctly use the 'felt' percentage. The macroseismic intensity and event magnitude do not affect this correction factor. By using both on-request reports and a correction factor it is possible to overcome the problem of underreporting "not felt" reports, more accurately estimate low intensities, and better define the "felt"-"not felt" boundary.

摘要： Hybrid-based design has gained significant interest in the development of novel active substances with anti-inflammatory properties. In this study, two series of new pyrazole-pyridazine-based hybrids, 5a-f and 6a-f, were designed and synthesized. Molecules containing pyrazole and pyridazine pharmacophores in a single molecule, each with a unique mechanism of action and different pharmacological characteristics, are believed to exert higher biological activity. The cell viability of all compounds was evaluated using MTT assay in LPS-induced RAW264.7 macrophages. In vitro COX-1 and COX-2 inhibition assays were performed for the investigation of the anti-inflammatory activity of target compounds. Trimethoxy derivatives 5f and 6f were the most active candidates, demonstrating higher COX-2 inhibitory action than celecoxib, with IC50 values of 1.50 and 1.15 mu M, respectively. Bromo derivative 6e demonstrated a COX-2 inhibitory activity comparable to celecoxib. Further, the ability of compounds 5f, 6e, and 6f to inhibit the generation of specific pro-inflammatory cytokines and mediators, including nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and prostaglandin-E2 (PGE-2), in RAW264.7 macrophages stimulated by LPS was also estimated. Compounds 5f and 6f demonstrated the most potent activity. Morover, according to the investigation using molecular modeling studies, derivatives 5f and 6f showed respectable binding affinity towards the COX-2 active site compared to the reference ligand. Moreover, the ADME parameters, physicochemical characteristics, pharmacokinetic characteristics, and l of the most potent compounds were also computed.

关键词： osteomyelitis   etanercept   tumor necrosis factor inhibitors   adalimumab   acquired hyperostosis syndrome  

摘要： Objectives Primary chronic non-bacterial osteomyelitis of the mandible (CNOM) is a rare auto-inflammatory disease of unknown aetiology that bears pathophysiological resemblance to both SAPHO syndrome in adults and chronic recurrent multifocal osteomyelitis (CRMO) in children. Both SAPHO and CRMO respond to TNF-alpha blockade. Previously reported treatment regimens in CNOM including NSAIDs, corticosteroids, antibiotics, anti-resorptive therapy and surgery all bear disappointing results. TNF-alpha blockade is suggested as a treatment option by some experts but this is not backed by any clinical data. We sought to retrospectively and exhaustively report our experience of anti-TNF-alpha therapy in refractory *** Fifteen patients with refractory CNOM and high disease burden were referred to our centre. TNF-alpha blockade was attempted in 10 cases, given its efficacy in neighbouring diseases, its good tolerance profile and failure of previous treatment strategies. We herein retrospectively report detailed outcomes for all patients having received anti-TNF-alpha therapy for this indication in our *** TNF-alpha-targeting therapy resulted in a rapid and sustained remission in a majority of patients with CNOM, without serious adverse events. Treatment was tapered and stopped without relapse in some patients despite a refractory course of several years. Male sex seems to be associated with a poorer *** Our results suggest that blocking TNF-alpha is efficient and safe in CNOM.

关键词： Rheumatoid Arthritis   JAK3   Molecular docking   DFT calculations   Molecular dynamics simulations  

摘要： Rheumatoid Arthritis (RA) is a persistent autoimmune disease affecting approximately 0.5-1 percent of the world population. RA prevalence is higher in woman aged between 35 and 50 years than in age matched men, though this difference is less evident among elderly patients. The profound immune specific effects of disrupted JAK 3 (Janus kinase 3) signaling highlight the possibility of therapeutic targeting of JAK3 as a highly specific mode of immune system suppression. To address the above problem which is unendurable to patients and in the hope to cater some respite to such suffering we have targeted JAK 3 protein and JAK/STAT signaling pathway with compounds downloaded from FDA database, and performed screening of all available compounds docked against JAK3 protein. The difference between the target protein and other proteins of the same family was studied using cross docking and the compounds having higher binding affinity to JAK3 protein also showed more selectivity towards the particular protein. Density functional theory and molecular dynamics simulation study was done to study the compounds at their atomic level to know more about their drug likeliness. At the end of the study and based on our analysis we have come up with three FDA approved drugs that can be proposed as a treatment option for Rheumatoid Arthritis.

关键词： IL1RAP   T cell engager   Acute myeloid leukemia   Leukemic stem cells   Immunotherapy  

摘要： Background The interleukin-1 receptor accessory protein (IL1RAP) is highly expressed on acute myeloid leukemia (AML) bulk blasts and leukemic stem cells (LSCs), but not on normal hematopoietic stem cells (HSCs), providing an opportunity to target and eliminate the disease, while sparing normal hematopoiesis. Herein, we report the activity of BIF002, a novel anti-IL1RAP/CD3 T cell engager (TCE) in AML. Methods Antibodies to IL1RAP were isolated from CD138+ B cells collected from the immunized mice by optoelectric positioning and single cell sequencing. Individual mouse monoclonal antibodies (mAbs) were produced and characterized, from which we generated BIF002, an anti-human IL1RAP/CD3 TCE using Fab arm exchange. Mutations in human IgG1 Fc were introduced to reduce Fc gamma R binding. The antileukemic activity of BIF002 was characterized in vitro and in vivo using multiple cell lines and patient derived AML samples. Results IL1RAP was found to be highly expressed on most human AML cell lines and primary blasts, including CD34+ LSC-enriched subpopulation from patients with both de novo and relapsed/refractory (R/R) leukemia, but not on normal HSCs. In co-culture of T cells from healthy donors and IL1RAP(high) AML cell lines and primary blasts, BIF002 induced dose- and effector-to-target (E:T) ratio-dependent T cell activation and leukemic cell lysis at subnanomolar concentrations. BIF002 administered intravenously along with human T cells led to depletion of leukemic cells, and significantly prolonged survival of IL1RAP(high) MOLM13 or AML patient-derived xenografts with no off-target side effects, compared to controls. Of note, BiF002 effectively redirects T cells to eliminate LSCs, as evidenced by the absence of disease initiation in secondary recipients of bone marrow (BM) from BIF002+T cells-treated donors (median survival not reached;all survived > 200 days) compared with recipients of BM from vehicle- (median survival: 26 days;p = 0.0004) or isotype control anti

关键词： Nutrition  

摘要： Skeletal muscle has gained recognition as an endocrine organ releasing myokines upon contraction during physical exercise. These myokines exert both local and pleiotropic health benefits, underscoring the crucial role of muscle function in countering obesity and contributing to the overall positive effects of exercise on health. Here, we found that exercise activates muscle p38 gamma, increasing locomotor activity through the secretion of interleukin-15 (IL-15). IL-15 signals in the motor cortex, stimulating locomotor activity. This activation of muscle p38 gamma, leading to an increase locomotor activity, plays a crucial role in reducing the risk of diabetes and liver steatosis, unveiling a vital muscle-brain communication pathway with profound clinical implications. The correlation between p38 gamma activation in human muscle during acute exercise and increased blood IL-15 levels highlights the potential therapeutic relevance of this pathway in treating obesity and metabolic diseases. These findings provide valuable insights into the molecular basis of exercise-induced myokine responses promoting physical activity.