Evaluation of the Chetomin effect on histopathological features in a murine acute spinal cord injury model.

Background: Several research studies have been focused on improving the treatment and prognosis of acute spinal cord injury, as part of this initiative we investigated the use of Chetomin to reduce the inflammatory response in this pathology. Methods: An experimental, prospective, cross-sectional study was performed using 42 Wistar rats where we analyzed the effect of Chetomin compared to methylprednisolone administered 1 and 8 h after the spinal cord injury in a murine model. Results: Chetomin administration 8h post-injury decreased IL-6 and VEGF expression; and, and its administration 1h post-injury decreased NF-kB expression. Conclusions: Chetomin has anti-inflammatory effects in acute spinal cord injury, whether these effects are observable with other proinflammatory markers should be investigated.

The implications of the TNFα-TNFR2 immune checkpoint signaling pathway in cancer treatment: From immunoregulation to angiogenesis.

Despite the tremendous advances that have been made in biomedical research, cancer remains one of the leading causes of death worldwide. Several therapeutic approaches have been suggested and applied to treat cancer with impressive results. Immunotherapy based on targeting immune checkpoint signaling pathways proved to be one of the most efficient. In this review article, we will focus on the recently discovered TNFα-TNFR2 signaling pathway, which controls the immunological and pro-angiogenic properties of many immunoregulatory and pro-angiogenic cells such as endothelial progenitor cells (EPCs), mesenchymal stem cells (MSCs), and regulatory T cells (Tregs). Due to their biological properties, these cells can play a major role in cancer progression and metastasis. Therefore, we will discuss the advantages and disadvantages of an anti-TNFR2 treatment that could carry two faces under one hood. It interrupts the immunosuppressive and pro-angiogenic behaviors of the above-mentioned cells and interferes with tumor growth and survival.

Facial Hyperpigmentation Following Adalimumab.

BACKGROUND: Tumor necrosis factor alpha (TNF-α) inhibitors, such as adalimumab, have significantly advanced the treatment of inflammatory diseases. However, these therapies are associated with various cutaneous adverse reactions. CASE PRESENTATION: We describe two rare instances of isolated facial hyperpigmentation induced by adalimumab. Both patients presented with asymptomatic, isolated brown macules on the cheeks following adalimumab treatment for ankylosing spondylitis. The hyperpigmentation appeared shortly after starting the medication in both cases. In one case, the hyperpigmentation persisted despite stopping the medication, while in the second case, it completely resolved within one month after discontinuation. However, in the second patient, the hyperpigmentation recurred after switching to certolizumab, another TNF-α inhibitor. No skin biopsies were performed, and both patients were otherwise healthy, with normal laboratory evaluations. CONCLUSION: Hyperpigmentation is an uncommon adverse reaction of this class of drugs, with only a few reported cases in the literature. The recurrence of hyperpigmentation after switching to another TNF-α agent, certolizumab, further suggests that this reaction may be a class effect, adding new insights into the spectrum of cutaneous side effects associated with TNF-α inhibitors. Clinicians should consider this potential side effect in patients presenting with hyperpigmentation, and sun protection should be recommended as a preventive measure.

VE-cadherin shedding in vitro and in patients with aortic aneurysm and dissection.

VE-cadherin (VEC) is a major endothelial adhesion protein, which controls vascular homeostasis. During vascular diseases, VEC can be shed from the endothelial surface by proteases like ADAM10/17, which cleave the extracellular domain of VEC in response to inflammatory cytokines like TNF-α. The resulting, soluble fragments (sVEC) are discussed as a potential marker for endothelial barrier breakdown. However, its pathologic role or its potential as a specific biomarker for aortic diseases is yet unknown. Here we investigated the specificity and linkage of sVEC production with ADAM10/17 and TNF-α, both in vitro and in patients with aortic aneurysms and dissections, comparing the findings with those from patients with carotid stenosis and varicosis. Thereby, the baseline levels of sVEC, TNF-α, ADAM10 and Albumin was measured in clinical plasma samples and cell culture supernatants of human aortic endothelial cells (HAOEC) treated with TNF-α or ADAM10/17 inhibitors. The integrity of HAOEC monolayers was tested by permeability assays using Alexa488-conjugated dextran (10 kDa). Peripheral EDTA plasma samples taken preoperatively from patients ≥ 18 years of age that were diagnosed for aortic dissection (n = 29), aortic aneurysm (n = 76), carotid stenosis (n = 29) and varicose veins (n = 24) were included. In vitro shedding of VEC was induced by TNF-α and depends on ADAM10/17, which led to altered endothelial permeability. Absolute plasma sVEC levels in patients with aortic dissection (3016 ± 1008 ng/mL) and aneurysm (3288 ± 1376 ng/mL) were not statistically significantly different from patients with carotid stenosis (3013 ± 687.6 ng/mL) and varicose veins (3313 ± 1337 ng/mL). Plasma sVEC levels correlated positively with plasma TNF-α (r = 0.5586, p < 0.0001) and ADAM10 (r = 0.7003, p < 0.0001) levels with the highest degree of correlation between ADAM10 and sVEC for chronic aortic dissection (r = 0.7890, p = 0.0013), reflecting TNF-α and ADAM10 dependency of VEC shedding. In summary, VEC shedding and (plasma) sVEC levels are influenced by TNF-α and ADAM10/17 and could play a relevant role in the specific pathophysiological context of aortic diseases.

Jiajiejian gel ameliorates thyroid nodules through regulation of thyroid hormones and suppression of the (IL-6, TNF-α, IL-1ß)/JAK2/STAT3/VEGF pathway.

Background: The high incidence of thyroid nodules and their rapid growth in recent years have become an important issue affecting public health. Traditional Chinese medicine (TCM) external treatments have unique advantages in treating this disease, but the currently available external preparations are relatively few and the therapeutic mechanism is unclear. Jiajiejian gel (JJJG) is a TCM external preparation developed by our team for the thyroid nodule treatment, which has been preliminarily proven to be safe and effective in clinical practice. Objective: The current study was aimed to elucidate the therapeutic effects and the underlying mechanisms of JJJG on thyroid nodules in rats. Methods: The contents of paeonol and forsythoside A in JJJG were determined by HPLC. The thyroid nodules rat model was established through oral gavage of 0.1% propylthiouracil (PTU) for 6 weeks and meanwhile the rats were treated with external JJJG (0.26, 0.52, 1.04 g/kg). Subsequently, the therapeutic effect of JJJG was observed by means of ultrasonic examination, morphology observation, organ coefficients determination and histopathological analysis. Mechanismlly, the levels of FT3, FT4 and TSH in serum were measured and transcriptomics methods were used to analyse and screen the key targets and pathways of alleviating thyroid nodules by JJJG. Further, gene and protein expression levels of key factors in the pathways were measured and validated using quantitative real-time PCR, ELISA, western blotting and immunofluorescence, so as to clarify the therapeutic mechanism. Results: The contents of the paeonol and forsythoside A were 1.160 and 0.608 mg/g, respectively. JJJG reduced thyroid swelling, improved nodular lesions, decreased thyroid coefficients, and inhibited abnormal nodular hyperplasia of follicular epithelial cells. In terms of mechanism, JJJG significantly increased the levels of FT3 and FT4 and decreased TSH level in serum (P < 0.05). Transcriptomics suggested that the (IL-6, TNF-α, IL-1ß)/JAK2/STAT3/VEGF pathway may be one of the key mechanisms in the treatment of thyroid nodules by JJJG. Further validation experiments demonstrated that JJJG significantly reduced the mRNA expression and protein content of IL-1ß, IL-6 and TNF-α in thyroid tissue, as well as the mRNA expression of JAK2, STAT3 and VEGF and the protein expression of p-JAK2/JAK2, p-STAT3/STAT3 and VEGF (P < 0.05). Conclusion: This study indicates that JJJG efficiently ameliorates thyroid nodules by regulating the levels of FT3, FT4 and TSH in serum and suppressing (IL-6, TNF-α, IL-1ß)/JAK2/STAT3/VEGF pathway in thyroid tissue, providing a potential therapeutic approach for thyroid nodules.

TNFα has differential effects on the transcriptome profile of selected populations in murine cartilage.

Objective: To further our understanding of the role of tumor necrosis factor (TNF)α on the inflammatory response in chondrocytes. Design: We explored the effects of TNFα on the transcriptome of epiphyseal chondrocytes from newborn C57BL/6 mice at the total and single cell (sc) resolution. Results: Gene set enrichment analysis of total RNA-Seq from TNFα-treated chondrocytes revealed enhanced response to biotic stimulus, defense and immune response and cytokine signaling and suppressed cartilage and skeletal morphogenesis and development. scRNA-Seq analyzed 14,239 â€‹cells and 24,320 genes and distinguished 16 â€‹cell clusters. The more prevalent ones were constituted by limb bud and chondrogenic cells and fibroblasts comprising ∼73 â€‹% of the cell population. Genes expressed by joint fibroblasts were detected in 5 clusters comprising ∼45 â€‹% of the cells isolated. Pseudotime trajectory finding revealed an association between fibroblast and chondrogenic clusters which was not modified by TNFα. TNFα decreased the total cells recovered by 18.5 â€‹% and the chondrogenic, limb bud and mesenchymal clusters by 32 â€‹%, 27 â€‹% and 7 â€‹%, respectively. TNFα had profound effects on the insulin-like growth factor (IGF) axis decreasing Igf1, Igf2 and Igfbp4 and inducing Igfbp3 and Igfbp5, explaining an inhibition of collagen biosynthesis, cartilage and skeletal morphogenesis. Ingenuity Pathway Analysis of scRNA-Seq data revealed that TNFα enhanced the osteoarthritis, rheumatoid arthritis, pathogen induced cytokine storm and interleukin 6 signaling pathways and suppressed fibroblast growth factor signaling. Conclusions: Epiphyseal chondrocytes are constituted by diverse cell populations distinctly regulated by TNFα to promote inflammation and suppression of matrix biosynthesis and growth.

Effect of galectin-3, IL-1, IL-6 and TNF-alpha on disease prognosis and mortality in COVID-19 patients.

INTRODUCTION: COVID-19 is a significant cause of morbidity and mortality. It is crucial to identify biomarkers that can aid in predicting patients' prognosis and mortality. This study evaluated the relationship between galectin-3 (Gal-3), interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) levels and the prognosis and mortality of COVID-19 patients. METHODOLOGY: The study included 69 COVID-19 patients (32 outpatients, 37 inpatients) and 19 healthy controls. Gal-3, IL-1, IL-6, and TNF-α levels in serum samples were measured using an ELISA test. RESULTS: In a comparison between the patient and healthy control groups, it was observed that the patient group had significantly higher levels of Gal-3, IL-6, and TNF-α. Comparison between the outpatient and inpatient groups revealed that the hospitalized patient group had significantly higher levels of IL-6 and TNF-α, while the Gal-3 levels were lower in this group. In the analysis of subgroups to assess disease severity, critical COVID-19 patients exhibited elevated levels of Gal-3 and IL-6 compared to those with severe COVID-19. Moreover, Gal-3 and IL-6 were identified as having predictive value for mortality in hospitalized patients, while both IL-6 and TNF-α demonstrated diagnostic accuracy across all patient groups. CONCLUSIONS: The study results indicate that the levels of IL-6 TNF-α play a crucial role in determining the hospitalization and mortality of COVID-19 patients. Additionally, it was observed that Gal-3 and IL-6 levels can be utilized to assess the severity of the disease and predict mortality in patients who require hospitalization.

Noninvasive, Multimodal Inflammatory Biomarker Discovery for Systemic Inflammation (NOVA Study): Protocol for a Cross-Sectional Study.

BACKGROUND: Prolonged systemic inflammation is recognized as a major contributor to the development of various chronic inflammatory diseases. Daily measurements of inflammatory biomarkers can significantly improve disease monitoring of systemic inflammation, thus contributing to reducing the burden on patients and the health care system. There exists, however, no scalable, cost-efficient, and noninvasive biomarker for remote assessment of systemic inflammation. To this end, we propose a novel, multimodal, and noninvasive approach for measuring inflammatory biomarkers. OBJECTIVE: This study aimed to evaluate the relationship between the levels of inflammatory biomarkers in serum (gold standard) and those measured noninvasively in urine, sweat, saliva, exhaled breath, stool, and core body temperature in patients with systemic inflammation. METHODS: This study is a single-center, cross-sectional study and includes a total of 20 participants (10 patients with systemic inflammation and 10 control patients). Eligible participants provide serum, urine, sweat, saliva, exhaled breath, and stool samples for biomarker analyses. Core body temperature is measured using a sensor. The primary end point is the level of C-reactive protein (CRP). The secondary end points are interleukin (IL)-1ß, IL-6, IL-8, IL-10, and tumor necrosis factor-α levels. The tertiary end points are fractional exhaled nitric oxide, calprotectin, and core body temperature. Samples will be collected in 2 batches, enabling preliminary analysis of the first batch (patients 1-5 from each group). The full analysis will include both batches. CRP and cytokine levels will be measured using enzyme-linked immunosorbent assay and electrochemiluminescence immunoassay. For statistical analysis, the Shapiro-Wilk test will be used to evaluate the normality of the distribution in each variable. We will perform the 2-tailed t test or Wilcoxon rank sum test to compare the levels of inflammatory biomarkers between patients with systemic inflammations and control patients. Pearson and Spearman correlation coefficients will assess the relationship between inflammatory biomarkers from noninvasive methods and serum biomarkers. Using all-subset regression analysis, we will determine the combination of noninvasive methods yielding the highest predictive accuracy for serum CRP levels. Participants' preferences for sampling methods will be assessed through a questionnaire. RESULTS: The study received ethics approval from the independent research ethics committee of Canton Zurich on October 28, 2022. A total of 20 participants participated in the study measurements. Data collection started on February 22, 2023, and was completed on September 22, 2023. Participants were on average 52.8 (SD 14.4; range 24-82) years of age, and 70% (14/20) of them were women. The analysis results reporting findings are expected to be published in 2025. CONCLUSIONS: This study aims to evaluate the feasibility of noninvasive, multimodal assessment of inflammatory biomarkers in patients with systemic inflammation. Promising results could lead to the creation of noninvasive and potentially digital biomarkers for systemic inflammation, enabling continuous monitoring and early diagnosis of inflammatory activity in a remote setting. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/62877.

Causal correlations between inflammatory proteins and heart failure: A two-sample Mendelian randomization analysis.

AIMS: Inflammation plays a critical role in both the development and progression of heart failure (HF), which is a leading cause of morbidity and mortality worldwide. However, the causality between specific inflammation-related proteins and HF risk remains unclear. This study aims to investigate the genetically supported causality between inflammatory proteins and HF using a two-sample Mendelian randomization (MR) analysis. METHODS AND RESULTS: We utilized genome-wide association study (GWAS) data of 91 inflammation-related proteins as exposures from the SCALLOP Consortium (14,824 participants), alongside outcome GWAS summary statistics from FinnGen (29,218 cases/381,838 controls) and HERMES (47,309 cases/930,014 controls) for HF, to conduct a two-sample MR analysis. For each inflammatory protein, instrumental variables (IVs) were chosen following the three foundational assumptions of the MR analysis, requiring a minimum of three qualifying single nucleotide polymorphisms (SNPs) each with a P < 5e-8. Associations between inflammatory proteins and HF were assessed through inverse-variance weighted (IVW), MR-Egger regression, weighted median and weighted mode analysis. The reliability and validity of the results were evaluated by examining heterogeneity, horizontal pleiotropy, leave-one-out analysis, meta-analysis and reverse MR analysis. Heterogeneity refers to the variation in results across different genetic variants. Horizontal pleiotropy occurs when a genetic variant influences multiple traits through different biological pathways. Addressing both heterogeneity and horizontal pleiotropy is crucial for ensuring the reliability and interpretability of MR results. Our analysis identified associations between three inflammatory proteins and HF risk. Matrix metalloproteinase-1 (MMP-1) (OR, 1.09; 95% CI, 1.00-1.18; P = 0.04) and TNF-beta (OR, 1.05; 95% CI, 1.01-1.09; P = 0.01) were positively associated with HF risk in FinnGen. In contrast, urokinase-type plasminogen activator (uPA) was inversely associated with HF risk in both FinnGen (OR, 0.85; 95% CI, 0.78-0.92; P = 3.27e-5) and HERMES (OR, 0.93; 95% CI, 0.87-0.99; P = 0.03). No evidence of heterogeneity and horizontal pleiotropy was observed in the MR analysis, indicating the robustness of our findings. A meta-analysis further supported this association, indicating a reduced risk (OR, 0.89; 95% CI, 0.81-0.98; P = 0.02). No reverse causality was found between HF and these three inflammatory proteins (P > 0.05 for all). CONCLUSIONS: This study provides genetically supported evidence of the causal association of specific inflammatory proteins with HF risk. The positive association of MMP-1 and TNF-beta with HF suggests their roles in disease pathogenesis, whereas the inverse association of the uPA indicates its potential protective effect. Our findings highlight the potential of targeting specific inflammatory pathways as a therapeutic strategy for HF.

Disseminated Tuberculosis in a Patient on Tumor Necrosis Factor (TNF)-α Inhibitor Treatment for Ankylosing Spondylitis: A Case Report.

Tumour necrosis factor-alpha (TNF-α) inhibitors are commonly used in the treatment of ankylosing spondylitis (AS) due to their effectiveness in reducing inflammation and slowing disease progression. However, their use is associated with an increased risk of opportunistic infections, particularly tuberculosis (TB). This case report presents a young male patient in the United Kingdom (UK) with AS, who had been on long-term biological therapy with adalimumab, a TNF-α inhibitor. The patient developed disseminated TB, which rapidly progressed and unfortunately resulted in the patient's death. This case underscores the importance of comprehensive screening for latent TB before initiating TNF-α inhibitor therapy, as well as ongoing monitoring throughout treatment. Given the multicultural nature of the UK, where individuals may be exposed to TB without traveling to endemic areas, careful attention to TB risk across all ethnicities is critical. This case highlights the need for heightened vigilance and tailored preventive strategies to mitigate the risks of TNF-α therapy.

Long-term follow-up of children with Crohn's disease and small bowel mucosal lesions detected through video capsule endoscopy.

OBJECTIVES: We report disease outcomes of pediatric Crohn's disease (CD) affecting the proximal small bowel (SB) and detected through video capsule endoscopy (VCE). METHODS: We undertook a retrospective review of CD patients with VCE performed under age 18 between 2003 and 2017 and having received any biologics. We identified patients from our institutional registry. RESULTS: Eligible patients (n = 118) had their first VCE performed after a median of 0.1 years after diagnostic endoscopies at a median age of 12.2 years. The proximal SB disease group (Paris classification L4b inclusive) comprised 70 patients with extensive SB lesions in 81% and deep ulcers in 79%. Patients with Paris L1-3 disease with no findings in VCE or disease restricted to the terminal ileum comprised the control group. At first VCE, levels of albumin (34 g/L vs. 37 g/L) and hemoglobin (117 g/L vs. 127 g/L) were lower in SB patients (p < 0.02). After the first VCE, 68% were introduced to biologics, while 10% already received them. Follow-up VCE was performed after a median of 2.4 years (SB group n = 42; controls n = 21). Proximal SB findings had disappeared in 40% of SB patients, and extensive lesions and deep ulcers had decreased to 26% and 29%, respectively (p = 0.001). In the control group, one had progressed to proximal disease. During the clinical follow-up of a median of 4.7 years, one patient with SB underwent surgery for a jejunal stricture. CONCLUSIONS: Proximal SB disease detected through capsule endoscopy abated in most patients with biological medication.

Unveiling the interaction and combined effects of multiple metals/metalloids exposure to TNF-α and kidney function in adults using bayesian kernel machine regression and quantile-based G-computation.

BACKGROUND: Exposure to multiple metals may cause adverse effects, particularly in the kidneys. However, studies on the combined and interaction effects of metal mixtures on human health remain limited. OBJECTIVE: The study aims to evaluate the interaction between metals and assess the combined effects of exposure to metal mixtures on tumor necrosis factor-alpha (TNF-α) levels and kidney function METHODS: Particular emphasis has been placed on the impact of various metals, including arsenic (As), cadmium (Cd), lead (Pb), as well as essential trace elements, such as cobalt (Co), copper (Cu), selenium (Se), and zinc (Zn), on human health and their potential collective influence on both TNF-α and kidney function. This cross-sectional study analyzed the data of 421 adults who underwent a health examination. Generalized linear model (GLM), Bayesian kernel machine regression (BKMR), and quantile-based G-computation (qgcomp) were used to evaluate the association and joint effects between the metals and TNF-α, as well as kidney function. RESULTS: Increased concentrations of As (ß = 0.11, 95 % CI = 0.05, 0.17) and Pb (ß = 0.30, 95 % CI = 0.23, 0.37) in the blood were associated with elevated levels of TNF-α, while elevated Cu (ß = -0.42, 95 % CI = -0.77, -0.07) levels were linked to a significant reduction in TNF-α. The overall effect of metals mixture showed a significant association with a decline in eGFR and an increase TNF-α in the BKMR model. Qgcomp analysis of the metals mixture (ß = -0.06, 95 % CI = -0.07, -0.05) indicated that As, Pb, and Zn were the primary contributors to the reduction in eGFR, while As and Pb were the major contributors in metals mixture (ß = 0.12, 95 % CI = 0.08, 0.15) to the elevation of TNF-α levels. CONCLUSION: Exposure to multiple metals could have joint association with the TNF-α levels and kidney function. Furthermore, TNF-α could act as a mediator between metal mixtures and eGFR.

Therapeutic effects of Mudan Granules on diabetic retinopathy: mitigating fibrogenesis caused by FBN2 deficiency and inflammation associated with TNF-α elevation.

ETHNOPHARMACOLOGICAL RELEVANCE: Mudan granules (MuD), a time-honored traditional Chinese patent medicine (TCPM), are widely utilized in the clinical treatment of diabetic peripheral neuropathy (DPN). In the field of biomedical diagnostics, both diabetic retinopathy (DR) and DPN are recognized as critical microvascular complications associated with diabetes. According to the principles of traditional Chinese medicine (TCM), these conditions are primarily attributed to a deficiency in Qi and the obstruction of collaterals. Despite this, the protective effects of MuD on DR and the underlying mechanisms remain to be comprehensively elucidated. AIMS OF THE STUDY: The purpose of this study was to investigate the effect of MuD on DR and to further explore the promising therapeutic targets. METHODS: A diabetic mouse model was established by administering 60 mg/kg of streptozotocin (STZ) via intraperitoneal injection for five consecutive days. The therapeutic efficacy of MuD was evaluated using a comprehensive approach, which included electroretinogram (ERG) analysis, histopathological examination, and assessment of serum biochemical markers. Then, the pharmacodynamic mechanisms of MuD were systematically analyzed using Tandem Mass Tags-based proteomics. Meanwhile, the candidate compounds of MuD were analyzed by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) and molecular docking was applied to estimate the affinity of the active ingredient to their potential key targets. In addition, the functional mechanisms identified through bioinformatics analysis were confirmed by molecular biological methods. RESULTS: We demonstrated that MuD provided significant protection to retinal function and effectively mitigated the reduction in retinal thickness observed in the animal model. Through proteomic analysis, we identified a substantial regulation by MuD of 70 biomarkers associated with diabetic retinal damage. These proteins were notably enriched in the tumor necrosis factor (TNF) signaling pathway, a critical mediator in inflammatory processes. A particularly intriguing finding was the significant downregulation of fibrillin-2 (FBN2) in the diabetic retina compared to the control group (0.36 times the level), and its most pronounced upregulation (3.26 times) in the MuD treatment group. This suggests that FBN2 may play a pivotal role in the protective effects of MuD. Molecular docking analyses have unveiled a robust interplay between the components of MuD and TNF-α. Further corroboration was provided by molecular biological methods, which confirmed that MuD could suppress TNF-mediated inflammation and prevent retinal neovascularization and fibrogenesis. CONCLUSION: MuD have the potential to alleviate diabetic retinal dysfunction by effectively curbing the fibrogenesis-associated neoangiogenesis and mitigating the inflammatory response, thereby restoring retinal health and function.

Network Pharmacological Analysis of Hydroxychloroquine Intervention in the Treatment of Iga Nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis globally and has a high propensity to develop into end-stage renal disease (ESRD). Hydroxychloroquine has been proven to reduce proteinuria in IgAN patients, but the precise mechanism remains unclear. Therefore, network pharmacology was used to investigate the mechanism. METHODS: PubChem and SwissADME databases were utilized to acquire the structure of hydroxychloroquine. The SwissTargetPrediction, PharmMapper, DrugBank, TargetNet, and BATMAN-TCM databases were then utilized to obtain the targets. The target genes related to IgAN were then gathered from the databases, which included GeneCards, PHARMGKB, DrugBank, OMIM, and DisGeNET. Common targets were obtained by UniProt. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to define the main molecular mechanisms and pathways. Furthermore, a protein-protein interaction (PPI) network was constructed using the STRING tool, and the core targets were obtained by Cytoscape. Finally, molecular docking between the core targets and hydroxychloroquine was performed. RESULTS: 167 common target genes were acquired by overlapping. The core targets were TNF, ALB, IL1B, JUN, FOS, SRC, and MMP9. The GO and KEGG results showed the targets to be related to the production of inflammatory cytokines and chemokines and were engaged in the toll-like receptor (TLR) signaling pathway. At the same time, the molecular docking results showed that the core targets all combined with hydroxychloroquine closely. CONCLUSION: This study proved that hydroxychloroquine may treat IgAN through the TLR signaling pathway, and the restraint of TNF, TLR, IL1B, and JUN may be essential for the treatment.

Brain MRI White Matter Abnormalities in Pediatric Non-Infectious Uveitis.

BACKGROUND: Childhood chronic non-infectious uveitis (cNIU) is a challenging disease whose differential diagnosis may include demyelinating diseases. We aim to describe the white matter abnormalities (WMA) in brain MRI in childhood cNIU. METHODS: This is a multicentric retrospective study involving children with cNIU followed at the Pediatric rheumatology units of Florence and the ophthalmology department of the UMC Utrecht who underwent a Brain MRI. Demographic, clinical, laboratory and imaging information was collected. The presence of WMA was considered as the main outcome. RESULTS: Data of 123 children was collected (66 from Utrecht and 57 from Florence), of whom 51 were males, with a median uveitis onset at age 9 years (range 3-16) for the UMC Utrecht and 8.75 years (range 1.6-15.1) for Florence. We evaluated 39 children with anterior uveitis, 35 with intermediate uveitis, 1 with posterior uveitis and 48 with panuveitis. Uveitis was idiopathic in 105. On brain MRI, 33 patients (26.8%) showed WMA, and most of them had non-anterior uveitis (72.8%). WMA were more frequent in males (χ2 5.25, p = 0.02). No difference in underlying systemic disease was seen between patients with and without WMA, but 40% of patients with TINU and 27.3% of patients with idiopathic uveitis showed WMA. None of the patients received a diagnosis of demyelinating disease during follow-up. CONCLUSION: As WMA were found in 26.8% of patients who were screened in our cohort, brain MRI might be useful in cNIU. However, the clinical significance of these WMA could not be determined in this study. An interdisciplinary evaluation is necessary to assess the appropriate management, and a longer follow up is necessary to determine the prognosis of some of these WMA.

TNF-α, and TNFRs in gastrointestinal cancers.

Tumor necrosis factor-alpha (TNF-α) is a multifunctional cytokine that plays a role in the hemostasis of the immune system, inflammation, and cell proliferation. However, it can also have a dark side as it is involved in pro-inflammatory cytokines and pathological processes such as cell growth and death, autoimmunity, and inflammation, leading to a wide range of chronic inflammatory diseases, including digestive cancer. TNF-alpha binds to two distinct receptors, TNFRI and TNFRII. Upon binding of the ligand to these receptors, TNF receptor-associated factors (TRAFs) are recruited to the cytoplasmic receptor, triggering the activation of transcription factors such as NF-kB and Activator protein 1 (AP_1). In contrast, binding of cytokines to certain family members, such as TNF RI and Fas Ligand (Fas L), leads to the secretion and initiation of apoptosis. Gastrointestinal malignancies are among the most common types of cancer globally. Despite extensive research, the exact cause of these tumors remains a mystery. Unfortunately, they often have a poor prognosis and are often detected at a late stage. The global incidence of gastrointestinal cancers, including those of the stomach, esophagus, colon, liver, and pancreas, is on the rise, leading to a surge in both incidence and mortality. Growth factors and cytokines, which are signaling molecules found in the tumor microenvironment, are thought to be major contributors to the development and metastasis of these cancers. In this review, we explored the role of TNF-α, and its receptors in the development of digestive cancers, including its signaling pathways and functions.

The Effect of Boric Acid and Calcium Fructoborate on T Helper Cell Differentiation by Influencing Foxp3 and Ror-γt in Rheumatoid Arthritis and Systemic Lupus Erythematosus.

Many animal and human studies indicate that boric acid and calcium fructoborate have effects on helper T cells in immunity. The aim of our study is to evaluate the effects of boric acid and calcium fructoborate on Treg (CD4+Foxp3+) and Th17 (CD4+Ror-γt+) cell populations and related cytokine levels in mononuclear cells isolated from peripheral blood samples of rheumatoid arthritis and systemic lupus erythematosus patients. Newly diagnosed rheumatoid arthritis (n = 10) patients, systemic lupus erythematosus (n = 5) patients, and healthy individuals (n = 9) were included in this study. Consent forms were obtained from all individuals participating the study, blood samples were taken, and peripheral blood mononuclear cells were isolated. Isolated cells were exposed to low-dose and high-dose boric acid and calcium fructoborate in cell culture. Treg and Th17 cell populations were analyzed by flow cytometry after 48 h of exposure. IL-2, IL-6, IL-17, IL-23, TNF-α, and TGF-ß levels in the culture medium were tested by ELISA method. At the end of the study, in healthy controls, high-dose BA improved the Treg/Th17 population but could not display similar effects on RA and SLE group. However, both boric acid and calcium fructoborate at different doses showed an increasing effect on Ror-γt in RA and SLE group. Different doses of BA and CaF treatment found to have a variable effect on cytokine. Both BA and CaF in low doses decreased TNF-α levels in RA group which shows that these boron compounds could contribute positively to the treatment of autoimmune diseases.

Microglia regulate cortical remyelination via TNFR1-dependent phenotypic polarization.

Microglia are strongly implicated in demyelinating neurodegenerative diseases with increasing evidence for roles in protection and healing, but the mechanisms that control CNS remyelination are poorly understood. Here, we show that microglia-specific deletion of tumor necrosis factor receptor 1 (TNFR1) and pharmacological inhibition of soluble TNF (solTNF) or downstream interleukin-1 receptor (IL-1R) allow maturation of highly activated disease-associated microglia with increased size and myelin phagocytosis capacity that accelerate cortical remyelination and motor recovery. Single-cell transcriptomic analysis of cortex at disease onset reveals that solTNF inhibition enhances reparative IL-10-responsive while preventing damaging IL-1-related signatures of disease-associated microglia. Longitudinal brain transcriptome analysis through disease reveals earlier recovery upon therapeutic loss of microglia TNFR1. The functional relevance of microglia inflammatory polarization pathways for disease is validated in vivo. Furthermore, disease-state microglia producing downstream IL-1/IL-18/caspase-11 targets are identified in human demyelinating lesions. Overall, redirecting disease microglia polarization by targeting cytokines is a potential approach for improving CNS repair in demyelinating disorders.

A systematic approach to identify gaps in neuroimmunology: TNF-α and fear learning deficits, a worked example.

BACKGROUND: The pathophysiology of several neurodegenerative and neuropsychiatric disorders is linked to an altered immune system. However, it is often unclear how the immune system specifically affects these disorders since neuroimmune interactions are very complex. In this paper, we introduce an adjusted version of the adverse outcome pathway (AOP) approach from toxicology to the field of neuroimmunology. A review of the effect of TNF-α on fear learning deficits is used as a worked example to demonstrate how an AOP approach can help identify gaps of knowledge and crucial steps in the pathophysiology of neuroimmunological disorders. METHODS: The AOP was constructed in five steps. First, the adverse outcome was formulated clearly and specifically. Second, the link between the molecular initiating event and the adverse outcome was established with a preliminary literature search in the Medline database. Third, a systematic literature search was performed in which we identified 95 relevant articles. Fourth, the main biological processes and relevant key events were identified. Fifth, the links between key events were determined and an AOP network was constructed. RESULTS: We identified three pathways through which TNF-α may affect fear learning. First, TNF-α receptor activation increases NF-κB levels which increases oxidative stress levels and reduces the activity of glutamate transporters. This alters the synaptic plasticity which is associated with impaired fear acquisition, consolidation, and fear extinction. Second, activation of TNF-α receptors increases the expression and capacity of the serotonin transporter which is linked to impaired fear acquisition, expression, and extinction. Third, TNF-α receptor 1 activation can induce necroptosis, leading to neuroinflammation which is linked to fear learning deficits. CONCLUSION: To successfully apply the AOP approach in neuroimmunology we recommend defining adverse outcomes more precisely, establishing stronger connections between key events from various biological processes, incorporating feedforward and feedback loops, and identifying more mechanistic knowledge in later key events. These adjustments are needed to map the complex processes within the field of neuroimmunology and to identify gaps of knowledge.