Tumor Necrosis Factor Research Articles

RAD001-mediated mTOR targeting in human monocyte-derived dendritic cells shifts them toward an immunogenic phenotype.

Dendritic cells (DCs) are essential for promoting T lymphocyte responses since they are specialist antigen-presenting cells. In order to maintain tolerance or initiate immune responses, DCs must be activated in a balanced and regulated manner via diverse signaling pathways. By using a variety of pharmacological components, we can interfere with their different signaling pathways such as the mammalian target of rapamycin (mTOR) to appropriately modulate DC activity. In the current study, we administered RAD001 to DCs to examine the impact of mTOR inhibition on both the maturation stage and the expression of inflammatory and anti-inflammatory molecules in DCs. Pure monocytes were cultivated and stimulated with GM-CSF and IL-4 to generate immature DCs, which were then treated with RAD001. The phenotype of the DCs was determined by labeling surface markers and analyzing them using flow cytometry. Afterward, real-time PCR was carried out to evaluate the expression of inflammatory and anti-inflammatory genes. The administration of RAD001 to DCs led to a significant upregulation in the gene expression of inflammatory molecules such as IL-12, IL-1β, tumor necrosis factor (TNF)-α, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-KB). Conversely, RAD001 treatment resulted in a decrease in the gene expression of anti-inflammatory factors IL-10 and indoleamine 2,3-dioxygenase (IDO). However, the expression of differentiation and antigen presentation-related markers CD11c and human leukocyte antigens (HLA)-DR in RAD001-treated DCs was lower and higher compared to the control group that did not receive the treatment, respectively. Taken together, our findings indicated that RAD001 treatment of DCs can be a promising therapeutic approach for the generation of immunogenic DCs in order to barricade tumor growth. However, there is a need for further investigation to evaluate the impacts of mTOR inhibition by RAD001 in DCs on cellular immune responses in vitro and in vivo.

Updated genetic background of generalized pustular psoriasis as an autoinflammatory keratinization disease.

Generalized pustular psoriasis (GPP) is a severe autoinflammatory keratinization disease (AiKD) characterized by acute flares of widespread sterile pustules and high fever. GPP is potentially life-threatening. Recently clarified genetic predisposing factors for GPP suggest that the excessive activation of innate immune pathways in the skin, including of interleukin (IL)-1 and IL-36 signaling, plays a significant role in the GPP pathogenesis. IL36RN, CARD14, AP1S3, MPO, SERPINA3, BTN3A3, and MEFV have been identified as GPP-related genes. The pathogenesis of GPP provoked by variants in these seven genes is tightly associated with the excessive activation of innate immune pathways and the resulting autoinflammation in the skin. Various biologics, including inhibitors for the tumor necrosis factor, IL-17, and IL-23 pathways, are used as treatments for GPP. The new understanding of the genetic background of GPP, mentioned above, indicates that the genetic predisposing factors are predominantly related to the excessive activation of innate immunity and autoinflammation. In this context, inhibitors of inflammatory signaling, including of the IL-1 and IL-36 pathways, have been used in clinical practice and investigated as potential future therapies.

Disruption of the gut microbiota-inflammation-brain axis in unmedicated bipolar disorder II depression

The relationships of the gut microbiota-inflammation-brain axis in depressive bipolar disorder (BD) remains under-elaborated. Sixty-five unmedicated depressive patients with BD II and 58 controls (HCs) were prospectively enrolled. Resting-state functional MRI data of static and dynamic amplitude of low-frequency fluctuation (ALFF) was measured, and abnormal ALFF masks were subsequently set as regions of interest to calculate whole-brain static functional connectivity (sFC) and dynamic functional connectivity (dFC). Fecal samples were collected to assess gut diversity and enterotypes using 16S amplicon sequencing. Blood samples were also collected, serum was assayed for levels of cytokines (interleukin [IL]-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor [TNF]-α). Patients with BD II exhibited decreased static ALFF values in the left cerebellum Crus II, and decreased cerebellar sFC and dFC to the right inferior parietal lobule and right superior frontal gyrus, respectively. Moreover, higher pro-inflammatory and anti-inflammatory cytokines levels, and increased proinflammatory bacteria and glutamate and gamma-aminobutyric acid metabolism related bacteria were identified in BD II. The interaction of Parabacteroides levels × IL-8 levels was an independent contributor to static ALFF in the left cerebellar Crus II. The findings bridged a gap in the underlying pathophysiological mechanism of the gut microbiota-inflammation-brain axis in BD II depression.

Pulmonary toxicity assessment of tumor necrosis factor α inhibitors in the treatment of IBD: a real world study based on US food and drug administration adverse events reporting system (FAERS).

Tumor necrosis factor α (TNF-α) inhibitors are widely used in the treatment of inflammatory bowel disease (IBD), but there is still a lack of systematic risk assessment for pulmonary toxicity. We calculated the pulmonary-related risk signals for four TNF-α inhibitors using the disproportionality analysis and also compared them with the pulmonary-related signals of seven other therapies. There were 8736 reports of pulmonary-related adverse events (AEs) to TNF-α inhibitors as the 'primary suspect (PS)' therapies. The median time to incident for pulmonary-related AEs was 148 (interquartile range [IQR] 21-721) days. TNF-α inhibitors exhibited the strongest signal of pulmonary toxicity compared to Interleukin 12/23 (IL-12/23) inhibitors, Integrin blockers, Jak inhibitors, and S1P receptor modulator. Golimumab exhibited the strongest signal compared to infliximab, certolizumab pegol, and adalimumab. The strongest signal corresponding to pneumonia, pulmonary tuberculosis, asthma, chronic obstructive pulmonary disease (COPD), pulmonary thrombosis, and pulmonary fibrosis is golimumab, infliximab, infliximab, natalizumab, upadacitinib, and adalimumab. TNF-α inhibitors had the strongest signal of pulmonary toxicity relative to other control therapies. Golimumab had the strongest signal of pulmonary toxicity relative to other TNF-α inhibitors. When TNF-α inhibitors are used in the treatment of IBD, pulmonary-related AEs should be vigilant.

Expanded tumor-associated polymorphonuclear myeloid-derived suppressor cells in Waldenstrom macroglobulinemia display immune suppressive activity

The role of the bone marrow (BM) microenvironment in regulating the antitumor immune response in Waldenstrom macroglobulinemia (WM) remains poorly understood. Here we transcriptionally and phenotypically profiled non-malignant (CD19- CD138-) BM cells from WM patients with a focus on myeloid derived suppressive cells (MDSCs) to provide a deeper understanding of their role in WM. We found that HLA-DRlowCD11b+CD33+ MDSCs were significantly increased in WM patients as compared to normal controls, with an expansion of predominantly polymorphonuclear (PMN)-MDSCs. Single-cell immunogenomic profiling of WM MDSCs identified an immune-suppressive gene signature with upregulated inflammatory pathways associated with interferon and tumor necrosis factor (TNF) signaling. Gene signatures associated with an inflammatory and immune suppressive environment were predominately expressed in PMN-MDSCs. In vitro, WM PMN-MDSCs demonstrated robust T-cell suppression and their viability and expansion was notably enhanced by granulocyte colony stimulating factor (G-CSF) and TNFα. Furthermore, BM malignant B-cells attracted PMN-MDSCs to a greater degree than monocytic MDSCs. Collectively, these data suggest that malignant WM B cells actively recruit PMN-MDSCs which promote an immunosuppressive BM microenvironment through a direct T cell inhibition, while release of G-CSF/TNFα in the microenvironment further promotes PMN-MDSC expansion and in turn immune suppression. Targeting PMN-MDSCs may therefore represent a potential therapeutic strategy in patients with WM.

Exploring Beta-sitosterol’s Role in Breast Cancer Treatment via Integrated Network Pharmacological Analysis and In Vitro Validation

Background Beta-sitosterol, a phytosterol similar to cholesterol, is found in various plants and is recognized for its potential anticancer properties; still, the mechanism of breast cancer (BC) remains elusive. Purpose This study investigates the potential targets of beta-sitosterol in BC using network pharmacological analysis and in vitro validation. Methods Targets of beta-sitosterol and BC were identified from online databases, including Swiss Target Prediction, SuperPred, GeneCards, and DisGeNET. Protein–protein interactions of common targets were analyzed using STRING version 11.0, and network construction and core target screening were performed with Cytoscape 3.8.0. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and gene ontology (GO) annotation were conducted using the ShinyGO web tool. Molecular docking analysis was done with AutoDock Vina and the in vitro validation, including cell viability, apoptosis, and gene expression analysis was done using MTT assay, acridine orange/ethidium bromide staining, and polymerase chain reaction (PCR), respectively. Results Sixty-eight common targets for beta-sitosterol and BC were identified from 209 beta-sitosterol targets and 1,350 BC-related genes. Five core targets (HIF1A, ESR1, STAT3, TNF, and MAPK3) were identified. GO analysis linked common targets to biological processes, cellular components, and molecular functions. KEGG pathway analysis showed enrichment in pathways such as central carbon metabolism in cancer, vascular endothelial growth factor signaling, and prolactin signaling. Beta-sitosterol’s impact on MCF7 cell viability was assessed via MTT assay, and its molecular effects were explored through PCR. Results demonstrated beta-sitosterol’s ability to hinder tumor progression by modulating genes involved in ESR1, mitogen-activated protein kinase, and tumor necrosis factor signaling pathways. Conclusion These findings highlight beta-sitosterol’s potential as an anticancer agent, offering new perspectives for clinical investigations through the modulation of key signaling pathways in BC.

The Plasma Proteome and Risk of Future Venous Thromboembolism-Results from the HUNT Study.

This study aimed to identify novel plasma proteins associated with first-lifetime venous thromboembolism (VTE) and molecular pathways involved in VTE pathogenesis. A case-cohort comprising incident VTE cases (n = 294) and a randomly sampled age- and sex-weighted subcohort (n = 1,066) was derived from the Trøndelag Health Study (HUNT3, n = 50,800). Blood samples were collected and stored at cohort inclusion (2006-2008), and participants were followed up to 5 years. Proteome-wide analyses was performed using the 7k SomaScan® proteomics platform, and weighted Cox-regression models adjusted for age, sex, and sample batch were conducted, with the Bonferroni method applied to account for multiple testing. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were applied on the top-ranked 200 proteins associated with VTE. Out of 7,288 human proteins, 7 proteins were significantly associated with higher VTE risk with p-value <6.9 × 10-6 (hazard ratios per 1 standard deviation increase in protein levels ranging from 1.39 to 1.86). Except for coagulation factor VIII and tumor necrosis factor soluble receptor II, these proteins were novel associations and included collagen alpha-3(VI):BPTI/Kunitz inhibitor, histo-blood group ABO system transferase, peroxidasin, human epididymis protein 4, and regulator of G protein signaling 3. KEGG analyses of the top-ranked 200 proteins revealed significant pathway enrichment of nine proteins in the complement (mainly lectin pathway) and coagulation (mainly intrinsic pathway) cascades. Our proteome-wide analysis led to discovery of five novel protein candidates associated with 5-year risk of future VTE. KEGG analyses supported an interplay between the complement and coagulation pathways in the pathogenesis of VTE.

Haloacetamides exacerbate non-alcoholic fatty liver disease induced by a high-fat diet in C57BL/6J mice.

Obesity, a significant global health issue, heightens the risk of non-alcoholic fatty liver disease (NAFLD). Its interaction with environmental pollutants might exacerbate NAFLD's severity. Haloacetamides (HAcAms), a group of emerging nitrogenous disinfection by-products (DBPs) and potent oxidative stressors, are found in chlorinated drinking water. Since oxidative stress is associated with HAcAms-DBPs cytotoxicity and a key factor in NAFLD pathogenesis, we hypothesize that HAcAms-DBPs could exacerbate liver injury and NAFLD, particularly with high-fat diets. This study examined HAcAms-DBPs' impact on liver lipid metabolism in mice treated with 1-100 times the background drinking water level (13.05 μg/L) for up to 16 weeks of oral administration. Compared to a high-fat-only group, mice co-exposed to a high-fat diet and HAcAms-DBPs for 16 weeks had elevated serum alanine transaminase, aspartate transaminase, triglyceride, hepatic lipid aggregation, and inflammation response. Under high-fat conditions, background drinking water levels of HAcAms significantly upregulated liver Acetyl-CoA carboxylase 1, fatty acid synthase, peroxisome proliferator-activated receptor γ (PPARγ), PPARγ coactivator-1α, glucose transporter 1 and 4 protein expression in C57BL/6J mice; 10 times background significantly increased expression of inflammatory marker tumor necrosis factor and liver fibrosis marker protein alpha-smooth muscle actin; 100 times further increased both liver damage and markers of early non-alcoholic steatohepatitis phenotypes like steatosis and lobular inflammation. HAcAms-DBPs plus high-fat conditions worsened liver damage. The possible health risks of NAFLD induced by HAcAms in obese individuals deserve further study.

Association of Therapies for Axial Spondyloarthritis on the Risk of Hip and Spine Fractures.

People with axial spondyloarthritis (axSpA) have increased fracture risk relative to the general population, possibly related to chronic inflammation. We assessed the impact of treatment with tumor necrosis factor inhibitors (TNFi) and non-biologic conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) on hip and spine fractures in axSpA, relative to nonsteroidal anti-inflammatory drugs (NSAIDs). We conducted a nested case-control study using 2006-2021 data from the MerativeTM MarketScan® Database. We included adults 18-65 years old with ≥1 inpatient or ≥2 outpatient axSpA ICD-9 or 10 diagnosis codes separated by ≥7 days. The primary outcome was hip and/or spine fracture, defined by ICD-9 or 10 diagnosis or procedure codes. For each fracture case, we selected up to 10 controls without fracture. We evaluated medication exposure (TNFi, csDMARDs, NSAIDs [referent], or none) hierarchically using pharmacy claims and procedure codes. We assessed the relation of medication exposure with hip and spine fracture risk using unconditional logistic regression with confounder adjustment. Our main analysis included 13,519 individuals with axSpA, comprising 1,229 cases and 12,290 controls. Individuals on TNFi had 29% lower odds of fracture compared to those on NSAIDs (OR 0.71, 95% CI 0.59-0.85), accounting for age, sex, and diagnosis year. Results were similar in the fully adjusted model (OR 0.75, 95% CI 0.62-0.91) and when stratified by sex. Using a large US insurance claims database, we found evidence for a protective effect of TNFi on fracture risk in axSpA underscoring a potential impact of TNFi in diminishing comorbidities linked with axSpA.

Real-world experience and long-term outcomes of a mandatory non-medical switch of adalimumab originator to biosimilars in inflammatory bowel disease.

Over the last decade, the treatment options for inflammatory bowel disease (IBD) have significantly progressed with the emergence of new medications designed to target various immune pathways and mitigate inflammation. Adalimumab (ADA) is a tumor necrosis factor alpha antagonist and stands as an effective treatment for IBD. In April 2021, the province of British Columbia implemented a mandatory non-medical switch policy of the ADA originator Humira® to ADA biosimilars. Biosimilars offer a potential cost-effective, safe, and efficacious alternative to the originator, yet there remains limited real-world evidence on long-term outcomes of ADA non-medical switching in IBD. To assess the long-term outcomes of non-medical switching from the ADA originator Humira® to an ADA biosimilar among IBD patients. A retrospective observational chart review study was conducted on IBD patients eligible for the provincially mandated non-medical switch to an ADA biosimilar. The primary outcome was treatment persistence at 30 months post-switch. Secondary outcomes included the proportion of and reasons for therapy alteration or ADA discontinuation, loss of response (LOR) rates, adverse events (AE), and clinical and biochemical remission status. Patients who remained on the originator throughout the switch period, through compassionate support or private pay, constituted the comparison group. Patients in the originator (n = 43) and biosimilar switch (n = 228) groups displayed similar demographics and baseline disease characteristics. By the study endpoint of 30 months, there was no difference in the rate of treatment persistence in either group (n = 36, 83.7% originator group vs n = 201, 88.2% biosimilar group, P = 0.451). Treatment persistence demonstrated similar rates of discontinuation between both study groups (log-rank P = 0.543). There was a numerical but not statistically significant difference in rates of adverse outcomes between either group (39.5% originator vs 28.9% biosimilars, P = 0.206). This included comparable rates of LOR (27.9% vs 17.5%) or AE (11.6% vs 11.4%) between the originator and biosimilar cohorts, respectively. C-reactive protein and fecal calprotectin levels were similar one year pre- and post-switch. These data support the long-term efficacy and safety of non-medical ADA switching in IBD and will help inform patients and physicians in jurisdictions currently undergoing biosimilar switching.

Effects of 3-day fasting on secretory IgA concentration in the saliva and lymphotoxin alpha expression in healthy volunteers: a proof of concept study.

animal studies have shown that enteral stimuli play an important role in modulating gut-associated lymphoid tissue. the main objectives of this study were 1) to evaluate the effect of 3-day fasting on secretory immunoglobulin A (S-IgA) in parotid saliva and 2) to determine the levels of lymphotoxin (LT) transcription in peripheral blood mononuclear cells (PBMNC) from healthy volunteers as a proxy for studying GALT health. these adult volunteers had fasted for three days as part of a cultural ritual. Eleven volunteers (seven men and four women) with a median age of 43 (40-56) were included. Parotid saliva and blood samples were collected on day 0 (no fasting) and three days after fasting. Parotid saliva was obtained using a modified on-Crittenden device, and S-IgA was quantified using ELISA. Total RNA was isolated from peripheral blood mononuclear cells, and the level of lymphotoxin (LT) mRNA expression was determined by RT-PCR. Lipopolysaccharide (LPS), IL-10 (interleukin), tumor necrosis factor (TNF)α, body composition and other metabolic indicators were measured. the median BMI was 27.3 kg/m2 (24.9-29.1). After 3 days of fasting, there were no significant differences in S-IgA concentrations (p = 0.657), LT expression (p = 0.063), LPS (p = 0.182), or IL-10 (p = 0.110). We found a statistical difference in TNFα levels (13.5 vs 11.3 pg/mL; p = 0.005) between the 0 and 3-day samples; TNFα decreased after fasting. further studies are needed to clarify the role of LT in the production of S-IgA and its relationship with nutritional status and inflammatory factors.

Natural small molecule hinokitone mitigates NASH fibrosis by targeting regulation of FXR-mediated hepatocyte apoptosis.

Liver fibrosis is the common fate of NASH and poses a major health threat with very limited pharmacological treatments. This study aims to investigate the preventive effect of hinokitone (HO), an isolated compound from Agathis dammara, on NASH fibrosis and its underlying mechanism. To investigate the effect of HO on NASH fibrosis, C57BL/6 mice were either fed a high-fat diet (HFD) in conjunction with intraperitoneal injection of CCl4 for 8 weeks or single CCl4 for 14 days to establish mouse liver fibrosis model, and HO was administered by gavage simultaneously. To elucidate the underlying mechanisms, HepG2 cells were stimulated by palmitic acid (PA) or tumor necrosis factor α plus actinomycin-D (Act-D + TNFα) to induce hepatocyte apoptosis model. Furthermore, hepatocyte Farnesoid-X-receptor (FXR) specifically knocked out mice were established by the albumin-Cre-loxP recombination enzyme system to ascertain the role of FXR in the anti-NASH fibrosis effects of HO. The results showed that HO presented dose-dependent anti-liver fibrosis efficacy in NASH mice induced by HFD + CCl4 and CCl4-induced mouse liver fibrosis. Cellularly, HO significantly inhibited PA-induced lipotoxic apoptosis and Act-D + TNFα-induced exogenous apoptosis in hepatocytes, which in turn prevented HSC activation. Mechanistically, bioinformatics analysis and surface plasmon resonance assay had identified hepatocyte FXR as a target of HO. Specifically, HO directly bound to FXR and upregulated its protein level by inhibiting proteasomal degradation. In turn, HO attenuated hepatocyte lipid deposition through upregulating the FXR's downstream target genes SHP and CES1, and reduced cleaved-CASP8 level, thereby inhibiting hepatocyte apoptosis. Furthermore, HO lost its function in the inhibition of hepatocyte apoptosis and liver fibrosis when knockout hepatocyte FXR. In conclusion, HO has an inhibitory effect on NASH fibrosis. This effect is mediated by targeting upregulation of hepatocyte FXR, which in turn attenuates hepatocyte apoptosis and thus indirectly inhibits the activation of HSCs.

Agaricus bisporus mannose-binding protein stimulates the innate immune cells

Purpose: A lectin-like protein from the mushroom Agaricus bisporus has been shown to slightly increase the proliferation of RAW 264.7 cells. Following its identification as a mannose-binding lectin, henceforth called A. bisporus mannose-binding protein (Abmb), the protein is hypothesized to stimulate the innate immune cells response. The present work was aimed to substantiate that hypothesis. Furthermore, this study complements Abmb exploration as a potential agent for anti-breast cancer, which its treatment is hampered with compromised immunity of patient receiving chemotherapy. Method: Abmb’s effect on the phagocytic activity of the macrophage was measured with FACS. Nitric oxide production was checked using Griess test while expression of the cytokines in the RAW 264.7 cells was analysed at gene and protein level using PCR and FACS, respectively. Abmb’s effect on the expression of surface markers of the human immune cells in the peripheral blood mononuclear cells was checked with specific antibodies for targeted cluster differentiation and analysed using FACS. Result: Abmb increased the phagocytic activity of the macrophage and NO production. Abmb increased the expression of cytokines i.e. tumour necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10. With the peripheral blood mononuclear cells, Abmb activated dendritic and Natural Killer cells, but not the B- or T-cells. Conclusion: Abmb increased the activity of the macrophage cells and activated the immune cells that are related to the innate immune system, particularly the cellular immunity.

Effects of Malondialdehyde on Growth Performance, Gastrointestinal Health, and Muscle Quality of Striped Catfish (Pangasianodon hypophthalmus)

Malondialdehyde (MDA) is a reactive carbonyl compound produced through lipid peroxidation during feed storage, which poses a significant threat to fish health. This study aimed to evaluate the effects of dietary MDA on the growth rate, gastrointestinal health, and muscle quality of striped catfish (Pangasianodon hypophthalmus). A basal diet (M0) containing 34% crude protein and 10.5% crude lipid was formulated. Each group was sprayed with malondialdehyde solution (0, 5, 10, 20, 40, and 80 mg/kg, on dietary crude lipid basis; 0, 0.53, 1.07, 2.13, 4.26, and 8.52 mg/kg, on dietary basis) before feeding, respectively. Each diet was randomly assigned to triplicates of 30 striped catfish (initial weight 31.38 g) per net cage. After 8 weeks, dietary inclusion of MDA regardless of level significantly depressed the growth rate and feed utilization. The extent of structural damage to the gastrointestinal tract increased progressively with increasing dietary MDA levels. The extent of damage to the intestinal biological barrier (intestinal microbial structure), chemical barrier (trypsin, lipase, amylase, and maltase activity), physical barrier (zonula occludent-2, occludin, claudin 7α, and claudin 12 relative expression), and immune barrier (contents of complement 4, complement 3, immunoglobulin M, and lysozyme activity) was dose-related to dietary MDA. Moreover, a linear decline in the activities of intestinal antioxidant enzymes (catalas, superoxide dismutase, et al.) and anti-inflammatory factor (transforming growth factor beta1, interleukin 10) relative expression was noted alongside an increase in dietary MDA content. In contrast, the relative expression levels of intestinal inflammatory factor (interleukin 8, transcription factor p65, tumor necrosis factor alpha) relative expression displayed an opposing trend. Additionally, dietary MDA exerted a linear influence on muscle color and texture characteristics. In conclusion, high doses of MDA (5–80 mg/kg) reduced the growth performance of striped catfish, attributed to linear damage to the gastrointestinal tract, a linear decrease in antioxidant function, and the occurrence of an inflammatory response. High doses of MDA (&gt;40 mg/kg) were observed to significantly increase dorsal muscle b-value and induce muscle yellowing.

Cannabis use in youth is associated with chronic inflammation.

Markers of inflammation and cannabis exposure are associated with an increased risk of mental disorders. In the current study, we investigated associations between cannabis use and biomarkers of inflammation. Utilizing a sample of 914 participants from the Avon Longitudinal Study of Parents and Children, we investigated whether interleukin-6 (IL-6), tumor necrosis factor α (TNFα), C-reactive protein (CRP), and soluble urokinase plasminogen activator receptor (suPAR) measured at age 24 were associated with past year daily cannabis use, less frequent cannabis use, and no past year cannabis use. We adjusted for a number of covariates including sociodemographic measures, body mass index, childhood trauma, and tobacco smoking. We found evidence of a strong association between daily or near daily cannabis use and suPAR. We did not find any associations between less frequent cannabis use and suPAR. We did not find evidence of an association between IL-6, TNFα or CRP, and cannabis use. Our finding that frequent cannabis use is strongly associated with suPAR, a biomarker of systemic chronic inflammation implicated in neurodevelopmental and neurodegenerative processes is novel. These findings may provide valuable insights into biological mechanisms by which cannabis affects the brain and impacts the risk of serious mental disorders.

Glucocorticoid sparing effect on Adalimumab for refractory Pyoderma gangrenosum in patients with Rheumatoid Arthritis: A Case series.

Pyoderma gangrenosum (PG) is a rare chronic skin disease characterized by painful skin ulcers. There are no treatment guidelines for PG; however, systemic treatment is often administered. Recently, adalimumab (ADA), a fully human monoclonal antibody against tumor necrosis factor, was approved for the treatment of refractory PG in Japan. However, data are limited, and it is not clear whether ADA has the same effect on the treatment of PG in patients with systemic rheumatic disease (SRD), including rheumatoid arthritis (RA). In addition, the glucocorticoid-sparing effect of ADA in SRD patients with PG has not yet been clarified. Herein, we present two successful cases of RA with glucocorticoid-refractory PG on ADA treatment. Our report suggests that ADA may have a glucocorticoid-sparing effect on refractory PG in patients with RA.

Osimertinib exacerbates immune checkpoint inhibitor-related severe adverse events by activating the IL-6/JAK/STAT3 pathway in macrophages.

The combination of epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and immune checkpoint inhibitors (ICIs) leads to an increased incidence of severe immune-related adverse events (irAEs). However, the mechanisms underlying macrophages in irAEs have not been elucidated. An osimertinib and ICI-induced irAE mouse model was constructed. Lung micro-CT scans were used to assess the degree of inflammatory infiltration. Hematoxylin-eosin staining was used to analyze the histopathologic inflammatory infiltration in mouse liver and lung tissues. Flow cytometry was used to detect the percentages of T cells, NK cells, and macrophages and the expression of EGFR. Enzyme-linked immunosorbent assay (ELISA) was used to detect the serum interleukin (IL)-6, alanine transaminase (ALT), ferritin, and tumor necrosis factor (TNF)-α levels. Total RNA extracted from mouse liver macrophages was analyzed by RNA-seq. Simple Western blot analysis was used to detect the IL-6/JAK/STAT3 pathway activation state. Osimertinib combined with ICIs upregulated EGFR expression on macrophages with increased serum IL-6, ALT, and ferritin levels. RNA-seq and simple Western blot analysis of mouse liver macrophages confirmed that that the IL-6/JAK/STAT3 pathway was activated in the combination treatment group. Ruxolitinib blocked the IL-6/JAK/STAT3 pathway and significantly decreased the serum IL-6, ALT, and ferritin levels in the combination treatment group. An osimertinib and ICI-induced irAE mouse model was constructed that showed osimertinib combined with ICIs inhibited EGFR phosphorylation and activated the IL-6/JAK/STAT3 signaling pathway in mouse liver macrophages, which led to the release of relevant cytokines.

Exploring the Efficacy of Joint Lavage in Knee Osteoarthritis: A Focus on Cytokines, Degrading Enzymes, and Oxidative Stress.

This study aimed to assess the effectiveness of joint lavage in managing knee osteoarthritis (OA) by evaluating its effect on pain relief, inflammatory markers, cartilage-degrading enzymes, and oxidative stress. Seventy patients with Kellgren-Lawrence grade 2 or 3 knee OA were selected for this single-center study. Joint lavage was performed, and pain and function were measured using the visual analog scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores at baseline and 24 weeks postintervention. Synovial fluid samples were collected at baseline, before lavage, and 24 weeks postintervention. Samples were stored at -80°C and analyzed in batches to minimize variability. At the time of analysis, the samples were thawed and evaluated for levels of proinflammatory cytokines, interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α), matrix metalloproteinase-3 (MMP-3), and total oxidant status (TOS), and oxidative stress index (OSI). Postintervention, VAS, and WOMAC scores significantly decreased (P < 0.001), with 100% achieving the minimal clinically important difference (MCID). Patient acceptable symptom state (PASS) rates varied: VAS (80%), WOMAC pain (50%), function (81.4%), and total (84.3%). Cytokine levels (IL-1β, IL-6, TNF-α) and MMP-3 significantly decreased (P < 0.001), along with TOS and OSI. Baseline TNF-α, IL-6, and IL-1β levels were significantly correlated with improvements in VAS and WOMAC scores. Moderate correlations were observed between reductions in IL-6/TNF-α and improvements in VAS/WOMAC. No significant associations were found between confounders and outcomes. Joint lavage resulted in marked pain relief and functional improvement while significantly reducing inflammatory markers, cartilage-degrading enzymes, and oxidative stress.

In vitro colonic fermentation of fermented Radix Astragali by Poria cocos and anti-hyperuricemia mechanism based on network pharmacology and experiment verification

AimThis research aimed to probe the effects of fecal microbiota and Lactobacillus acidophilus on the metabolism of Radix Astragali (RA) and Poria cocos solid fermenting Radix Astragali (FRA). It further explores pharmacological effects of RA, Poria cocos, and FRA on HUA mouse model and the mechanisms in HUA treatment.MethodsFecal microbiota and Lactobacillus acidophilus were used to ferment FRA and RA in vitro to probe the impacts of microbiota on the metabolism of active compound. A HUA mouse model was used to carry out pharmacodynamic experiment of anti-hyperuricemia. Network pharmacology and molecular docking was utilized to elucidate the underlying mechanisms of RA and Poria cocos in the treatment of HUA.ResultsThe results indicated that astragaloside IV (AG IV), total saponins, and flavonoids continuously decreased in FRA and RA during 48 h fecal microbiota colonic fermentation. During Lactobacillus acidophilus fermentation, in FRA, the content of AG IV peaked at 12 h with a value of 1.14 ± 0.20 mg/g; total saponins and flavonoids reached the highest values of 136.34 ± 6.15 mg/g at 12 h and 6.35 ± 0.06 mg/g at 6 h; AG IV and total saponins reached the highest values 0.63 ± 0.05 mg/g and 115.12 ± 4.12 mg/g at 12 h and 24 h in RA, respectively; and total flavonoids consecutively decreased. The counts of Lactobacillus acidophilus increased significantly in FRA compared with RA. Pharmacodynamic outcomes revealed that FRA effectively reduced blood levels of uric acid (UA), triglycerides (TG), xanthine oxidase (XOD), alanine aminotransferase (ALT), and aspartate transaminase (AST) in HUA mice, exerting protective effects on the liver and kidney. Network pharmacology showed that there were 93 common targets for RA, Poria cocos, and HUA with the top five core targets tumor necrosis factor (TNF), signal transducer and activator of transcription 3 (STAT3), cysteinyl aspartate specific proteinase 3 (CASP3), jun proto-oncogene (JUN), and estrogen receptor 1 (ESR1). Molecular docking analysis revealed that AG IV, calycosin and formononetin bond well to the core targets.ConclusionThis research revealed the interaction of RA and FRA with fecal microbiota and Lactobacillus acidophilus, RA and Poria cocos were featured with multiple components, target points, and signaling pathways in HUA treatment, which provided fresh insights for further HUA therapeutics.

The Potential of the Probiotic Isolate Lactobacillus plantarum SS18‐50 to Prevent Colitis in Mice

ABSTRACTThe objective of this study was to investigate the effect of the Lactobacillus plantarum (L. plantarum) SS18‐50 (an isolate with favorable probiotic properties following space traveling) on dextran sulfate sodium (DSS)‐induced colitis in mice. Male ICR mice were randomly assigned to one of six groups: a control group, a model group, and four intervention groups comprising the isolate (SS18‐50‐L and SS18‐50‐H) and the wild type (GS18‐L and GS18‐H) strains. The model group and the intervention groups were administered a 3.5% DSS (w/v) solution to induce acute enteritis. The four intervention groups were administered the corresponding bacterial suspensions, SS18‐50‐L (1.0 × 107 CFU/mL), SS18‐50‐H (1.0 × 109 CFU/mL), GS18‐L (1.0 × 107 CFU/mL), and GS18‐H (1.0 × 109 CFU/mL). The results demonstrated that the disease activity index (DAI) score of the SS18‐50‐H was markedly lower than that of the CON. Subsequently, the colon tissue of mice was analyzed to determine the levels of myeloperoxidase (MPO), superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA). The results demonstrated that all strains within the intervention groups exhibited good performance to prevent colitis. Particularly, the SS18‐50‐H strain exhibited a pronounced stimulative effect on GSH, an increase in SOD activity, and a decrease in MPO activity and MDA content. The SS18‐50‐H treatment resulted in a notable elevation in serum somatostatin (SS) levels and a concomitant reduction in endothelin (ET) and substance P (SP) levels, which approached normal ranges. The results of the RT‐qPCR analysis demonstrated that the mRNA expression levels of tumor necrosis factor (TNF‐α), cyclooxygenase (COX‐2), interleukin (IL‐10), and interleukin (IL‐6) in the SS18‐50‐H were significantly reduced to levels comparable to those observed in the CON. In conclusion, L. plantarum SS18‐50 has been demonstrated to inhibit the development of colitis in a dose‐dependent manner, thereby establishing it as a high‐quality lactic acid bacterium with a colitis inhibitory effect.