TNF-α Inhibitors Research Articles

Involvement of Embryo-Derived and Monocyte-Derived Intestinal Macrophages in the Pathogenesis of Inflammatory Bowel Disease and Their Prospects as Therapeutic Targets.

Inflammatory bowel disease (IBD) is a group of intestinal inflammatory diseases characterized by chronic, recurrent, remitting, or progressive inflammation, which causes the disturbance of the homeostasis between immune cells, such as macrophages, epithelial cells, and microorganisms. Intestinal macrophages (IMs) are the largest population of macrophages in the body, and the abnormal function of IMs is an important cause of IBD. Most IMs come from the replenishment of blood monocytes, while a small part come from embryos and can self-renew. Stimulated by the intestinal inflammatory microenvironment, monocyte-derived IMs can interact with intestinal epithelial cells, intestinal fibroblasts, and intestinal flora, resulting in the increased differentiation of proinflammatory phenotypes and the decreased differentiation of anti-inflammatory phenotypes, releasing a large number of proinflammatory factors and aggravating intestinal inflammation. Based on this mechanism, inhibiting the secretion of IMs' proinflammatory factors and enhancing the differentiation of anti-inflammatory phenotypes can help alleviate intestinal inflammation and promote tissue repair. At present, the clinical medication of IBD mainly includes 5-aminosalicylic acids (5-ASAs), glucocorticoid, immunosuppressants, and TNF-α inhibitors. The general principle of treatment is to control acute attacks, alleviate the condition, reduce recurrence, and prevent complications. Most classical IBD therapies affecting IMs function in a variety of ways, such as inhibiting the inflammatory signaling pathways and inducing IM2-type macrophage differentiation. This review explores the current understanding of the involvement of IMs in the pathogenesis of IBD and their prospects as therapeutic targets.

Molecular mechanism of honeysuckle+forsythia in treatment of acute lung injury based on network pharmacology.

The pathogenesis of acute lung injury (ALI) is complex and it is a common critical illness in clinical practice, seriously threatening the lives of critically ill patients, for which no specific molecular marker exists and there is a lack of effective methods for the treatment of ALI. The present study aimed to investigate the mechanism of action of honeysuckle and forsythia in treatment of acute lung injury (ALI) based on network pharmacology and in vitro modeling. The active ingredients and targets of honeysuckle and forsythia were predicted using traditional Chinese medicine systems pharmacology, PubChem and Swiss Target Prediction databases, and the Cytoscape 3.7.2 software was used to construct a drug-component-potential target network. The potential targets were imported into the Search tool for recurring instances of neighboring genes) database to obtain protein-protein interactions and subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Targets analysis using Database for Annotation, Visualization, and Integrated Discovery. AutoDock Vina 1.1.2 software was used for docking between key active ingredients and the target proteins to analyze the binding ability of the active ingredients to the primary targets in honeysuckle and forsythia. A total of 64 male BALB/c mice were randomly divided into control, model, positive drug (Lianhua-Qingwen capsule), honeysuckle, forsythia, honeysuckle + forsythia high-, medium- and low-dose groups. Lipopolysaccharide (LPS) was used to induced an ALI model. The lung tissues of the mice were stained with hematoxylin-eosin and the serum levels of malondialdehyde (MDA) and the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were measured 4 h after the LPS administration. Reverse transcription-quantitative PCR and western blotting were used to detect NF-κB mRNA and protein expression, respectively. Active ingredients of honeysuckle and forsythia acted on 265 common targets in ALI, which regulated NF-κB, tumor necrosis factor-α (TNF-α) and PI3K-AKT signaling pathway, HIF-1 signalling pathway to slow the inflammatory response in treatment of ALI. In the positive drug group, honeysuckle, forsythia group, honeysuckle + forsythia high-, medium- and low-dose groups, lung tissue damage were significantly decrease compared with the model group, and inflammatory cell infiltration was reduced. Compared with the model group, honeysuckle + forsythia groups experienced decreased damage caused by the LPS and inflammation in the lung tissues and significantly decreased TNF-α and NF-κB and MDA concentration and significantly increased the SOD and GSH-Px activities. The mechanism of the effect of honeysuckle and forsythia on ALI may be mediated by inhibition of TNF-α and NF-κB expression and the activation of antioxidant mechanisms to decrease production of pro-inflammatory cytokines in lung tissue, thus treating ALI.

Cardiovascular Adverse Events Associated with Tumor Necrosis Factor-Alpha Inhibitors: A Real-World Pharmacovigilance Analysis.

Evidence regarding the association between various tumor necrosis factor-α (TNF-α) inhibitors and cardiovascular adverse events (AEs) is both limited and contradictory. A retrospective pharmacovigilance study was conducted using the FDA Adverse Event Reporting System (FAERS) database. Cardiovascular AEs associated with TNF-α inhibitors (adalimumab, infliximab, etanercept, golimumab, and certolizumab) were evaluated using a disproportionality analysis. To reduce potential confounders, adjusted ROR and subgroup analyses were performed. After excluding duplicates, 9,817 cardiovascular reports were associated with the five TNF-α inhibitors. Only adalimumab had positive signals for myocardial infarction (ROR=1.58, 95%CI=1.51-1.64) and arterial thrombosis (ROR=1.54, 95%CI=1.49-1.58). The remaining four TNF-α inhibitors did not show a risk association with any type of cardiovascular event. Further analyses of specific indication subgroups and after adjusting for any confounding factors demonstrated that adalimumab was still significantly associated with cardiovascular events, especially in patients with psoriasis (adjusted ROR=2.16, 95%CI=1.95-2.39). This study revealed that adalimumab was the only TNF-α inhibitor associated with an elevated risk of thrombotic cardiovascular AEs, whereas the other four TNF-α inhibitors did not show any risk effect. However, given the limitations of such pharmacovigilance studies, it is necessary to validate these findings in prospective studies in the future.

Increased neutrophil extracellular trap formation in oligoarticular, polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis: biomarkers for diagnosis and disease activity.

Neutrophil extracellular traps (NETs) are important factors in initiating and perpetuating inflammation. However, the role of NETs in different subtypes of juvenile idiopathic arthritis (JIA) has been rarely studied. Therefore, we aimed to explore the ability of JIA-derived neutrophils to release NETs and the effect of TNF-α (tumor necrosis factor-alpha) inhibitors on NET formation both in vitro and in vivo, and evaluate the associations of NET-derived products with clinical and immune-related parameters. The ability of neutrophils to release NETs and the effect of adalimumab on NET formation was assessed via in vitro stimulation and inhibition studies. Plasma NET-derived products were detected to assess the incidence of NET formation in vivo. Furthermore, flow cytometry and western blotting were used to detect NET-associated signaling components in neutrophils. Compared to those derived from HCs, neutrophils derived from patients with oligoarticular-JIA, polyarticular-JIA and enthesitis-related arthritis were more prone to generate NETs spontaneously and in response to TNF-α or PMA in vitro. Excessive NET formation existed in peripheral circulation of JIA patients, and elevated plasma levels of NET-derived products (cell-free DNA and MPO-DNA complexes) could accurately distinguish JIA patients from HCs and were positively correlated with disease activity. Multiple linear regression analysis showed that erythrocyte sedimentation rate and TNF-α levels were independent variables and were positively correlated with cell-free DNA concentration. Notably, TNF-α inhibitors could effectively prevent NET formation both in vitro and in vivo. Moreover, the phosphorylation levels of NET-associated kinases in JIA-derived neutrophils were markedly increased. Our data suggest that NETs might play pathogenic roles and may be involved in TNF-α-mediated inflammation in JIA. Circulating NET-derived products possess potential diagnostic and disease monitoring value. Furthermore, the preliminary results related to the molecular mechanisms of NET formation in JIA patients provide a theoretical basis for NET-targeted therapy.

TNF-α-positive patients with recurrent pregnancy loss: The etiology and management.

Elevated levels of tumor necrosis factor-alpha (TNF-α) have been associated with adverse pregnancy outcomes, specifically recurrent pregnancy loss (RPL). These elevated levels may be associated with the presence of autoantibodies. Although TNF-α inhibitors have shown promise in improving pregnancy rates, further research is needed to comprehend their impact and mechanisms in RPL patients. This study aims to investigate the association between elevated TNF-α levels and autoantibodies in RPL patients, as well as evaluate the effect of TNF-α inhibition on pregnancy outcomes. A total of 249 RPL patients were included in this study. Serum levels of TNF-α, autoantibodies, and complement were measured and monitored. Among these patients, 138 tested positive for TNF-α, while 111 tested negative. The medical records of these patients were retrospectively evaluated. Additionally, 102 patients with elevated TNF-α levels were treated with TNF-α inhibitors, and their pregnancy outcomes were assessed. TNF-α-positive RPL patients had higher levels of complement C1q, anti-cardiolipin (ACL)-IgA, ACL-IgM ,ACL-IgG, thyroglobulin antibody, and Anti-phosphatidylserine/prothrombin IgM antibody, as well as a higher positive rate of antinuclear antibodies compared to TNF-α-negative patients (23.19% vs. 12.6%, P< 0.05). Conversely, complement C3 were lower in TNF-α-positive patients (t test, P< 0.05). The use of TNF-α inhibitors led to a reduction in the early abortion rate (13.7% vs. 44.4%, P< 0.001) and an improvement in term delivery rate (52.0% vs. 27.8%, P= 0.012). Furthermore, patients who used TNF-α inhibitors before 5 weeks of pregnancy had a lower early abortion rate (7.7% vs. 24.3%, P= 0.033) and a higher term delivery rate (69.2% vs. 48.6%, P= 0.033). TNF-α plays a role in the occurrence and development of RPL, and its expression is closely associated with autoantibodies and complements. TNF-α inhibitors increase the term delivery rate in TNF-α-positive RPL patients, and their use before 5 weeks of pregnancy may more beneficial.

Screening with urine Histoplasma antigen test in asymptomatic patients starting TNF-alpha inhibitor therapy: a cohort study.

Histoplasmosis is the second most frequent granulomatous disease in patients treated with tumor necrosis factor (TNF)-α inhibitors, second only to tuberculosis. However, there is limited information about pre-therapy screening procedures and the need for preventive treatments for patients who will start immunobiologicals. This is a cohort study that evaluated the prevalence of histoplasmosis in asymptomatic HIV-negative patients before initiation of TNF-α inhibitors by testing for Histoplasma antigen in urine samples. The patients included completed a 180-day follow-up after the initiation of the biologics to assess the onset of symptoms suggestive of histoplasmosis. From January 2021 to December 2022, 54 patients who were prescribed a TNF-α inhibitor agent for treating autoimmune diseases in centers in southern Brazil were included. In the screening before therapy, the prevalence of a positive urinary Histoplasma antigen test was 14.8%. None of the 54 patients developed histoplasmosis after 6 months of immunobiological therapy, including the eight patients who tested positive. The prevalence of Histoplasma capsulatum infection in chronic patients may be higher than expected, but the impact of latent infection in asymptomatic patients is still uncertain, including those starting treatment with immunobiological drugs such as TNF-α inhibitors. Our study did not identify risk factors for the diagnosis of disseminated histoplasmosis in this group, including a positive result in an antigen test performed before immunobiological therapy. To date, there is no evidence to recommend routine antigen-based screening or preventive therapy for histoplasmosis before initiating a TNF-α inhibitor.

Evaluating the inhibition of IL-17A and TNFα in a cartilage explant model cultured with Th17-derived cytokines

IntroductionT-helper 17 (Th17) cells produce IL-17A playing a critical role in activating the pathogenic chain leading to joint tissue inflammation and destruction. Elevated levels of Th17 cells and IL-17A have been detected in skin lesions, blood, and synovial fluid from patients with psoriatic arthritis (PsA) and ankylosing spondylitis (AS). Moreover, IL-17A inhibitors suppress disease activity in psoriasis, PsA and AS, supporting the evidence of IL-17A contributing to the disease pathogenesis. Although, IL-17A inhibitors are widely approved, it remains unclear how the inhibitory effect of IL-17A alters the extracellular matrix (ECM) of the joint in a Th17-conditioned inflammatory milieu. Therefore, the aim of this study was to establish a cartilage model cultured with conditioned medium from Th17 cells and inhibitors to explore the effect of IL-17A inhibition on joint tissue remodeling. MethodsNaïve CD4+ T cells from healthy human buffy coat were differentiated into Th17 cells, followed by Th17 cell activation to secrete Th17-related cytokines and molecules into media. The activated Th17 cells were isolated from the conditioned media (CM) and analyzed using flow cytometry to verify Th17 cell differentiation. The CM were assessed with ELISA to quantify the concentrations of cytokines secreted into the media by the Th17 cells. Healthy bovine cartilage explants were cultured with the Th17-CM and treated with IL-17A and TNFα inhibitors for 21 days. In harvested supernatant from the cartilage cultures, MMP- and ADAMTS-mediated biomarker fragments of type II collagen, aggrecan, and fibronectin were measured by ELISA to investigate the ECM remodeling within the cartilage tissue. ResultsTh17-CM stimulated a catabolic response in the cartilage. Markers of type II collagen and aggrecan degradation were upregulated, while anabolic marker of type II collagen formation remained on similar levels as the untreated explants. The addition of IL-17A inhibitor to Th17-CM decreased the elevated type II collagen and aggrecan degradation, however, degenerative levels were still elevated compared to untreated group. The addition of TNFα inhibitor completely reduced both type II collagen and aggrecan degradation compared to untreated explants. Moreover, the TNFα inhibitor treatment did not alter the type II collagen formation compared to untreated group. ConclusionThis study suggests that inhibition of IL-17A in Th17-conditioned cartilage tissue only partially reduced the MMP-mediated type II collagen degradation and ADAMTS-mediated aggrecan degradation, while the TNFα inhibitor treatment fully reduced both MMP- and ADAMTS-mediated ECM degradation. This exploratory study where ECM biomarkers are combined with Th17-conditioned ex vivo model may hold great potential as output for describing joint disease mechanisms and predicting structural effects of treatment on joint tissue.

Tumor necrosis factor-α inhibitor for successful treatment of toxic epidermal necrolysis with severe infection: a case series.

Toxic epidermal necrolysis (TEN) is a rare severe cutaneous adverse reaction that involves more than 30% of the body surface area. TEN can be accompanied by a series of systemic symptoms and has a high risk of death. Tumor necrosis factor (TNF)-α inhibitors such as adalimumab and etanercept have been shown to be safe and effective for the treatment of TEN in some cases. However, clinical data on the use of TNF-α inhibitors to treat TEN with severe systemic infection are scarce. In the present study, three adult patients who developed TEN with serious active infection were successfully treated with etanercept. One of the three patients had active open pulmonary tuberculosis, and the other two had septicemia and/or fungal sepsis. All patients' skin lesions significantly improved after several days, and none of the patients developed emerging or re-emerging infectious diseases, adverse reactions, or a similar rash during follow-up. TNF-α inhibitors may be an effective treatment choice for TEN with severe systemic infection. However, further studies with large samples are still required for validation because clinical experience is limited.

Suppression by central adenosine A3 receptors of the cholinergic defense against cardiovascular aberrations of sepsis: role of PI3K/MAPKs/NFκB signaling.

Introduction: Despite the established role of peripheral adenosine receptors in sepsis-induced organ dysfunction, little or no data is available on the interaction of central adenosine receptors with sepsis. The current study tested the hypothesis that central adenosine A3 receptors (A3ARs) modulate the cardiovascular aberrations and neuroinflammation triggered by sepsis and their counteraction by the cholinergic antiinflammatory pathway. Methods: Sepsis was induced by cecal ligation and puncture (CLP) in rats pre-instrumented with femoral and intracisternal (i.c.) catheters for hemodynamic monitoring and central drug administration, respectively. Results: The CLP-induced hypotension, reduction in overall heart rate variability (HRV) and sympathovagal imbalance towards parasympathetic predominance were abolished by i.v. nicotine (100μg/kg) or i.c. VUF5574 (A3AR antagonist, 2µg/rat). In addition, the selective A3AR agonist, 3-iodobenzyl-5'-N-methylcarboxamidoadenosine IB-MECA, 4µg/rat, i.c.) exaggerated the hypotension and cardiac autonomic dysfunction induced by sepsis and opposed the favorable nicotine actions against these septic manifestations. Immunohistochemically, IB-MECA abolished the nicotine-mediated downregulation of NFκB and NOX2 expression in rostral ventrolateral medullary areas (RVLM) of brainstem of septic rats. The inhibitory actions of IB-MECA on nicotine responses disappeared after i.c. administration of PD98059 (MAPK-ERK inhibitor), SP600125 (MAPK-JNK inhibitor) or wortmannin (PI3K inhibitor). Moreover, infliximab (TNFα inhibitor) eliminated the IB-MECA-induced rises in RVLM-NFκB expression and falls in HRV, but not blood pressure. Conclusion: Central PI3K/MAPKs pathway mediates the A3AR counteraction of cholinergic defenses against cardiovascular and neuroinflammatory aberrations in sepsis.

The frequency of hepatitis B virus reactivation in patients receiving anti-TNF treatment: a single center, retrospective study

Objective : The equilibrium between the host immune response counter the hepatitis B virus (HBV) and the amount of viral replication is a crucial factor in the pathogenesis of HBV-associated liver disease. Tumor necrosis factor-alpha (TNF-α) is an considerable proinflammatory and immune regulatory cytokine in the pathogenesis of various inflammatory and autoimmune conditions. There is no consensus on using antiviral prophylaxis treatments in cases who have been exposed to hepatitis B but have not become chronically ill, and are thus planned to receive anti-TNF-α treatment.The aim of this study is to determine the frequency of reactivation after anti-TNF treatment in cases with isolated anti-HBc total positivity who have been exposed to hepatitis B virus. Matarail and Methods: Serological HBV infection markers (HBsAg, anti-HBc IgG and anti-HBs) of 1467 adult cases who received anti-TNF therapy for the indications of various rheumatological diseases in the rheumatology and physical therapy clinics between the years 2010-2021 were retrospectively screened using the hospital’s electronic information system. Results: 140 rheumatologic disease cases who took a TNF-α inhibitor (infliximab, adalimumab, etanercept, golimumab, certolizumab) treatment were included in this study. Before the cases were started on TNF-α treatment, all cases were anti-HBc total positive, 110 were anti-HBs positive, 30 were anti-HBs negative, and 4 were HbsAg positive and HBV-DNA negative. The median pre-treatment anti-HBc total and anti-HBs values of the cases were 5.6 IU/L and 79.29 IU/L, respectively. No HBV reactivation was observed in any of the 140 cases after a median follow-up duration of 71.5 (min. 8, max. 185) months. Conclusion: In conclusion, HBV reactivation was not detected in any of the anti-HBc positive cases included in this study, which suggest that anti-HBc positive cases can be followed up with close follow-up without starting them on anti-TNF therapies and antiviral prophylaxis.

Decreased risk of COVID-19 and long COVID in patients with psoriasis receiving IL-23 inhibitor: A cross-sectional cohort study from China

BackgroundAlthough clinical trials and real-world data suggest that the risk of COVID-19 and its complications is not exacerbated in patients with psoriasis treated by biological agents, the evidence for this is still limited. ObjectivesWe aimed to assess the outcomes of COVID-19 among Chinese patients with psoriasis treated by IL-23 inhibitor, and to compare these variables in patients receiving other therapies. MethodsA cross-sectional cohort study was conducted to compare psoriasis treatment with IL-23 inhibitor to other treatment methods. All the patients received a questionnaire that contained questions about their psoriasis treatment, COVID-19 symptoms, and related risk factors. The prevalence of COVID-19 was calculated, and logistic regression analyses were performed to determine the association between treatment method and COVID-19 risk. The symptoms of COVID-19 and long COVID were described for each treatment group. ResultsBetween December 2022 and February 2023, 732 patients with psoriasis were included in the final analysis. 549 patients had a SARS-CoV-2 infection during the study period. Our results showed that individuals who worked outdoors had a decreased risk of COVID-19, as did those who had other allergic disease. With regard to the effect of the treatment regimens, IL-23 inhibitor treatment was associated with a decreased risk of COVID-19 compared to almost all the other treatments except acitretin. Fever was the most common symptom, but the maximum temperature and duration of fever were comparable among the treatment groups. Patients treated with IL-23 inhibitor were more likely to be asymptomatic after recovery compared to patients treated with methotrexate, narrow-bound ultra violet B, or TNF-α inhibitor. ConclusionsIL-23 inhibitor treatment may lower the risk of COVID-19 and long COVID. Thus, IL-23 inhibitor treatment might be beneficial and positively considered for patients with psoriasis who require systemic treatment during periods when there is a surge in COVID-19 cases.

Does the effectiveness of biological medications in the treatment for psoriasis depend on the moment of starting therapy? A preliminary study.

It is well known that biological medications acting on selected elements of the immune response are highly effective in psoriasis treatment. It is a common perception that psoriasis is a seasonal disorder with improvement in warmer months, however it has not been unequivocally confirmed. It is not known whether the time of year of starting systematic therapy for psoriasis influences treatment outcomes. Changes in psoriasis severity scores during treatment with biologics were investigated. The scores were recorded for 62 patients with moderate to severe psoriasis at the beginning, after 1, 4 and 7 months of the therapy. Patients were divided into two groups: those beginning the treatment in the cold period of the year (November-March) and in the warm period (May-September). The seasonal groups were also divided into subgroups according to the type of biologics used: interleukin inhibitors and tumor necrosis factor α (TNF-α) inhibitors. Results of the treatment were analysed using standard statistical tests of differences between samples. After 1 and 4 months of the therapy, better efficacy of interleukin inhibitors was found in patients starting treatment in summer. The course of psoriasis improvement in patients taking TNF-α inhibitors resulted in consistent improvement regardless of the season. The outcome of the treatment after 7 months was similar for both seasonal groups and types of biologics used. Our understanding of the effectiveness of the treatments depending on the time of the year combined with the type of biologics used, may further improve results of the therapy.

Update on non-infectious uveitis treatment: anti-TNF-alpha and beyond.

Non-infectious uveitis (NIU) encompasses a range of conditions marked by inflammation within various layers of the eye. NIU is a significant contributor to irreversible vision loss among the working-age population in developed countries. The aim of treating uveitis is to manage inflammation, prevent its recurrences and to restore or salvage vision. Presently, the standard treatment protocol for NIU involves initiating corticosteroids as the primary therapeutic agents, although more aggressive approaches and steroid sparing agent may be necessary in certain cases. These advanced treatments option include synthetic immunosuppressants like antimetabolites, calcineurin inhibitors and alkylating agents. For patients who exhibit an intolerance or resistance to corticosteroids and conventional immunosuppressive therapies, biologic agents have emerged as a promising alternative. Notably, among the biologic treatments evaluated, TNF-α inhibitors, anti-CD20 therapy and alkylating agents have shown considerable efficacy. In this review, we delve into the latest evidence surrounding the effectiveness of biologic therapy and introduce novel therapeutic strategies targeting immune components as potential avenues for advancing treatment of NIU.

Neolignan Glycoside and Other Constituents From the Leaves of Ligustrum sinense and Their Anti-Inflammatory Activity

Objectives: The aim of the project was the isolation, structure elucidation, and anti-inflammatory evaluation of compounds from the leaves of Ligustrum sinense Lour. Methods: Chromatographic techniques were used to isolate anti-inflammatory compounds from the methanol extract of L sinense leaves. The structures of compounds were elucidated by analyses of mass spectra, nuclear magnetic resonance data, and Circular dichroism spectra. Compounds were evaluated using anti-inflammatory assays. Results: One new neolignane glucoside, neoligustrume A (1), along with eleven known compounds, ligujaponoside A (2), ligujaponoside B (3), ligustroside (4), oleuropein (5), ligustaloside A dimethyl acetal (6), ligustaloside B dimethyl acetal (7), olivil (8), (+)-cycloolivil (9), kaempferol 3- O-β-D-glucopyranoside-7- O-α-L-rhamnopyranoside (10), oleanoic acid (11), and hydroxytyrosol (12) were isolated from the methanol extract of L sinense leaves. Compounds 2, 3, and 12 showed significant inhibitory NO production with IC50 values of 16.3 ± 0.5, 18.2 ± 1.1, and 15.7 ± 1.9 μM, respectively. Compounds 4-7 and 11 showed moderate inhibitory NO production with IC50 values ranging from 21.4 to 45.0 µM. Moreover, compound 12 showed the most TNF-α inhibition with 58.1 ± 5.7% at a concentration of 50 μM. Conclusions: One new and 11 known compounds were isolated from L sinense. This is the first report of compounds 2-9 from L sinense. Compounds 2, 3, and 12 showed significant inhibitory NO production with IC50 values of 16.3 ± 0.5, 18.2 ± 1.1, and 15.7 ± 1.9 μM, respectively. Compound 12 could be the anti-inflammatory source.

Relationship between CCL25/CCR9 Levels in Follicular Fluid and High Ovarian Response in Patients with Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is one of the prevalent gynecological endocrine disorders encountered in clinical practice. Women diagnosed with PCOS demonstrate increased ovarian responsiveness, rendering them more prone to ovarian hyperstimulation syndrome (OHSS) during controlled ovarian stimulation (COS) procedures. The current study aimed at investigating whether CCL25/CCR9 plays a role in the pathological process of high ovarian response (HOR) during COS procedures. Single-center retrospective cohort study. Patients. A total of 200 PCOS patients who received a fixed regimen of gonadotropin-releasing hormone (GnRH) antagonist were enrolled in this study. The cohort comprised 118 patients exhibiting HOR and 82 patients demonstrating a normal ovarian response (NOR). The age and body mass index (BMI) variances across the two groups did not differ significantly. Similarly, the two groups observed no statistically significant differences in the baseline levels of luteinizing hormone (LH), progesterone (P), estradiol (E2), basal prolactin (PRL), and testosterone (T). Compared to the NOR group, HOR patients exhibit markedly elevated levels of anti-Müllerian hormone (AMH), antral follicle count (AFC), basal follicle-stimulating hormone (FSH), and HOMA-IR (all p < 0.05). Conversely, no statistically significant differences were observed between the two groups with respect to COS parameters, encompassing initial gonadotropin (Gn) dose, stimulation duration, and total Gn dose. During COS, the number of oocytes with diameter ≥14 mm, the levels of E2 on the HCG day, and the number of retrieved oocytes were significantly higher in the HOR group than in the NOR group (all p < 0.001). Additionally, the levels of CCL25/CCR9, matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinases (TIMPs), TNF-α, and IL-6 were significantly higher in the FF of the HOR group than in the NOR group (all p < 0. 001), while the variance in IL-1β levels between the two cohorts did not reach statistical significance. The relevance analysis results indicated that the levels of CCL25/CCR9 in the FF of the HOR group are positively correlated with the number of retrieved oocytes and oocytes with diameters ≥14 mm during COS, AMH levels, and AFC. Concurrently, the CCL25 levels in the FF of the HOR group were positively correlated with HOMA-IR. Multivariable linear regression analysis revealed that the elevated AFC and HOMA-IR independently increase the CCL25 levels. The CCL25/CCR9 levels in FF are positively correlated with the clinical indicators of HOR, suggesting that CCL25/CCR9 may play a role in the pathogenesis of HOR in patients with PCOS.

Riboflavin ameliorates intestinal inflammation via immune modulation and alterations of gut microbiota homeostasis in DSS-colitis C57BL/6 mice.

While there have been advancements in understanding the direct and indirect impact of riboflavin (B2) on intestinal inflammation, the precise mechanisms are still unknown. This study focuses on evaluating the effects of riboflavin (B2) supplementation on a colitis mouse model induced with 3% dextran sodium sulphate (DSS). We administered three different doses of oral B2 (VB2L, VB2M, and VB2H) and assessed its impact on various physiological and biochemical parameters associated with colitis. Mice given any of the three doses exhibited relative improvement in the symptoms and intestinal damage. This was evidenced by the inhibition of the pro-inflammatory cytokines TNF-α, IL-1β, and CALP, along with an increase in the anti-inflammatory cytokine IL-10. B2 supplementation also led to a restoration of oxidative homeostasis, as indicated by a decrease in myeloperoxidase (MPO) and malondialdehyde (MDA) levels and an increase in reduced glutathione (GSH) and catalase (CAT) activities. B2 intervention showed positive effects on intestinal barrier function, confirmed by increased expression of tight junction proteins (occludin and ZO-1). B2 was linked to an elevated relative abundance of Actinobacteriota, Desulfobacterota, and Verrucomicrobiota. Notably, Verrucomicrobiota showed a significant increase in the VB2H group, reaching 15.03% relative abundance. Akkermansia exhibited a negative correlation with colitis and might be linked to anti-inflammatory function. Additionally, a remarkable increase in n-butyric acid, i-butyric acid, and i-valeric acid was reported in the VB2H group. The ameliorating role of B2 in gut inflammation can be attributed to immune system modulation as well as alterations in the gut microbiota composition, along with elevated levels of fecal SCFAs.

Study of thyroid disorders in ankylosing spondylitis patients on anti-tumor necrosis factor treatment

Abstract: BACKGROUND: Ankylosing spondylitis (AS) is a systemic rheumatic disease characterized mainly by involvement of sacroiliac joints and axial skeleton. Tumor necrosis factor-alpha (TNF-α) inhibitors are biologic agents which are Food and Drug Administration approved to treat AS and also act as a key factor in the treatment of autoimmune thyroid disease. OBJECTIVE: This study aimed to evaluate the thyroid gland disorders (functions and thyroid autoantibodies) in AS patients on anti-TNF-α biologics and their relation to disease activity. PATIENTS AND METHODS: This comparative cross-sectional study included 75 AS patients classified into two groups: Group I: treated with NSAIDs (n = 30) and Group II: treated with anti-TNF-α biologics (n = 45). Thyroid function tests, thyroid autoantibodies, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and human leukocytic antigen B27 were measured. AS disease activity was assessed by Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), and Bath Ankylosing Spondylitis Metrology Index (BASMI) scores. Thyroid ultrasonography was used to detect any thyroid gland nodularity and echogenicity. RESULTS: There were significant differences between both groups regarding BASDAI (P = 0.005), CRP (P = 0.005), thyroid-stimulating hormone (TSH) (P = 0.001), and anti-thyroid peroxidase (anti-TPO) (P = 0.007). A significant difference was found regarding the thyroid status, with more normal thyroid and more hyperthyroid patients in the anti-TNF-treated group (P = 0.003). There were statistically significant positive correlations between BASDAI and CRP (P = 0.007), TSH (P = 0.004), and thyroid anti-TPO antibody (P = 0.008) in the anti-TNF-treated patients. By ultrasound examination of the thyroid gland, 75.6% of the anti-TNF group had normal thyroid gland compared to 56.6% of the other group, and the reported nodules were mostly of benign TIRADS classification. Comparing different subgroups of thyroid nodularity with different treatment regimens revealed significant differences in BASDAI and different laboratory investigations in favor of the anti-TNF-treated patients. CONCLUSION: From this cohort study, we can conclude that thyroid autoimmune disease and thyroid nodules in AS patients can be controlled by treatment with anti-TNF-α biologic drugs better than NSAIDs alone.

Golimumab and certolizumab pegol for the treatment of hidradenitis suppurativa: a literature review and future perspective.

Hidradenitis suppurativa (HS) is an inflammatory skin condition with an underlying inflammatory process. Due to the limited efficacy of available treatments, HS remains a therapeutic challenge. The safety and efficacy of tumor necrosis factor-α (TNF-α) inhibitors, adalimumab, infliximab, and etanercept, are well studied in this patient population, and in some cases, HS was unresponsive to them. In recent years, evidence has been growing regarding the application of other anti-TNFs, including certolizumab pegol (CPZ) and golimumab. We sought to evaluate the overall safety and efficacy of golimumab and CPZ in the management of HS. A comprehensive search was performed on the PubMed, Scopus, Web of Science, and Ovid Embase databases, as well as the Google Scholar search engine from initiation to 31 August 2023. A total of nine and four studies used CPZ and golimumab to treat HS, respectively. Individuals with concomitant inflammatory immune-mediated diseases, pregnant females, and patients who were refractory to previous treatments achieved a Hidradenitis Suppurativa Clinical Response following CPZ administration. Also, golimumab showed promise in treating recalcitrant HS after the failure of other treatments, such as adalimumab and anti-interleukin-1. CPZ and golimumab can be efficacious treatment options for moderate-to-severe HS, especially in patients who are unresponsive to other TNF inhibitors, such as adalimumab.

A Review on Drugs Used in the Management of Juvenile Idiopathic Arthritis

Juvenile idiopathic arthritis (JIA) is the most widespread rheumatic disease and main cause of disability in children. The disorder includes various classified forms depending on the affected joints’ location and number, as well as the presence or absence of various inflammatory markers. The specific cause is not known but is believed to involve a combination of genetic, humoral, and environmental factors. The aims of treating JIA are to reduce inflammation, reach remission, alleviate pain, sustain function, and do so with minimal side effects. Nonsteroidal anti-inflammatory drugs are still beneficial in mild cases, while intra-articular steroid injections remain the most common treatment for patients with oligoarticular juvenile idiopathic arthritis. Disease-modifying drugs like methotrexate and leflunomide have shown to be effective and safe, but in numerous patients, the disease continues to be active even with this therapy. These patients are given more specific medical care like tumour necrosis factor -alpha (TNF-α) inhibitors, interleukin-1 inhibitors, interleukin-6 inhibitors, selective costimulation modulators, and selective B-cell blockade. Treatment comes with risks, as several medications necessitate monitoring and patient education to manage potential complications. If left untreated, the disease can progress and become chronic, leading to significant illness and potentially having a devastating impact on the child’s quality of life. Despite the advancements in modern therapies improving patient outcomes, a significant portion of individuals still do not respond to treatment. This underscores the necessity for a deeper comprehension of disease development and recovery in order to properly categorize patients for appropriate treatment options.

Modulation of myocardial injury in polymicrobial sepsis: The dual role of interleukin-13 in cardiac inflammation and stress.

Polymicrobial sepsis is associated with a poor prognosis due to severe type-1 innate inflammation triggered by immune cells, such as dendritic cells and macrophages. This immune response frequently leads to damage in the heart. Although interleukin (IL)-13 is thought to play a protective role in organ inflammation, its function in polymicrobial sepsis remains unclear. We aimed to investigate the role of IL-13 in modulating myocardial injury during cecal ligation and puncture (CLP)-induced sepsis using a murine model. Cardiac troponin I (cTnI), a biomarker for myocardial damage, was measured in both IL-13-deficient (KO) and wild type (WT) mice subjected to CLP. Contrary to the conventional view of IL-13 as a protective cytokine, IL-13-competent mice exhibited significantly higher serum cTnI levels than IL-13-deficient mice, indicating exacerbated myocardial injury. Elevated cardiac tumor necrosis factor-alpha (TNF-α) levels and IL-1β in WT CLP mice corroborated this finding, suggesting IL-13's role in enhancing the inflammatory response. In vitro assays with bone marrow-derived dendritic cells (BMDCs) stimulated with lipopolysaccharide and Group A Streptococcus revealed a dose-dependent suppression of TNF-α and IL-6 production by recombinant IL-13. These findings indicate a complex role of IL-13 in sepsis, modulating inflammation but potentially increasing myocardial stress.