Dataset Information

Novel Elongator Protein 2 Inhibitors Mitigating Tumor Necrosis Factor-α Induced Osteogenic Differentiation Inhibition.

ABSTRACT: Tumor necrosis factor-α is a common cytokine that increases in inflammatory processes, slows the differentiation of bone formation, and induces osteodystrophy in the long-term inflammatory microenvironment. Our previous study confirmed that the Elongation protein 2 (ELP2) plays a significant role in osteogenesis and osteogenic differentiation, which is considered a drug discovery target in diseases related to bone formation and differentiation. In this study, we applied an in silico virtual screening method to select molecules that bind to the ELP2 protein from a chemical drug molecule library and obtained 95 candidates. Then, we included 11 candidates by observing the docking patterns and the noncovalent bonds. The binding affinity of the ELP2 protein with the candidate compounds was examined by SPR analysis, and 5 out of 11 compounds performed good binding affinity to the mouse ELP2 protein. After in vitro cell differentiation assay, candidates 2# and 5# were shown to reduce differentiation inhibition after tumor necrosis factor-α stimulation, allowing further optimization and development for potential clinical treatment of inflammation-mediated orthopedic diseases.

SUBMITTER: Wu WJ

PROVIDER: S-EPMC8629650 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Novel Elongator Protein 2 Inhibitors Mitigating Tumor Necrosis Factor-<i>α</i> Induced Osteogenic Differentiation Inhibition.

Wu Wen-Jiao WJ Xia Chang-Liang CL Ou Shuan-Ji SJ Yang Yang Y Ma Yun-Fei YF Hou Yi-Long YL Yang Qing-Po QP Zhang Jun J Li Jian-Wei JW Qi Yong Y Xu Chang-Peng CP

BioMed research international 20211122

Tumor necrosis factor-<i>α</i> is a common cytokine that increases in inflammatory processes, slows the differentiation of bone formation, and induces osteodystrophy in the long-term inflammatory microenvironment. Our previous study confirmed that the Elongation protein 2 (ELP2) plays a significant role in osteogenesis and osteogenic differentiation, which is considered a drug discovery target in diseases related to bone formation and differentiation. In this study, we applied an in silico virtu ...[more]

PMID: 34853789

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Project description:ImportanceTumor necrosis factor α (TNF) inhibitor-induced psoriasiform eruption is well recognized in adults, but few reports document this paradoxical effect in children.ObjectiveTo characterize the clinical features and the clinical time course of TNF inhibitor-induced psoriasiform eruptions in children.Design, setting, and participantsA multicenter retrospective case series of children younger than 18 years seen between January 1, 2000, and December 31, 2016, who developed a new-onset psoriasiform eruption while taking a TNF inhibitor for a nondermatologic disorder. Participating sites were members of the Pediatric Dermatology Research Alliance. Data were entered into a Research Electronic Data Capture database at the Mayo Clinic (ie, the coordinating center).ResultsPsoriasiform eruptions were identified in 103 TNF inhibitor-treated patients (median age, 13.8 years [IQR, 11.7-16.4 years]; 52 female patients [50%]; 57 White patients [55%]), with 67 patients (65%) treated with infliximab, 35 (34%) with adalimumab, and 1 (1%) with certolizumab pegol. Most patients had no personal history (101 [98%]) or family history of psoriasis (60 patients [58%]). Inflammatory bowel disease was the most common indication for treatment with TNF inhibitor (94 patients [91%]). The primary extracutaneous disease was under control in 95 patients (92%) who developed the eruption. Most patients (n = 85 [83%]) developed psoriasiform eruptions at multiple anatomic sites, with scalp involvement being most common (65 patients [63%]). Skin disease developed at a median of 14.5 months (IQR, 9-24 months) after TNF inhibitor initiation. To treat the psoriasiform eruption, topical steroidal and nonsteroidal medication was prescribed for all patients. Systemic therapy was added for 30 patients (29%): methotrexate for 24 patients (23%), oral corticosteroids for 8 patients (8%), and azathioprine for 1 patient (1%). For 26 patients (25%), suboptimal effectiveness with topical medications alone prompted discontinuation of the initial TNF inhibitor and a change to a second-line TNF inhibitor with cutaneous improvement in 23 patients (88%) by a median of 3 months (IQR, 2-4 months). Eight patients (31%) who started a second-line TNF inhibitor developed a subsequent TNF inhibitor-induced psoriasiform eruption at a median of 6 months (IQR, 4-8 months). Persistent skin disease in 18 patients (17%) prompted discontinuation of all TNF inhibitors; 11 patients changed to a non-TNF inhibitor systemic therapy, and 7 discontinued all systemic therapy.Conclusions and relevanceIn this case series, paradoxical TNF inhibitor-induced psoriasiform eruptions were seen in children treated with TNF inhibitors for any indication, and there appears to be a class effect among the varying TNF inhibitors. The majority of these children were able to continue TNF inhibitor therapy with adequate skin-directed and other adjuvant therapies.

Project description:ImportanceTumor necrosis factor inhibitors (TNFis) can induce antidrug antibody (ADA) formation and loss of therapeutic response. However, the utility of ADA testing and the association between ADAs and treatment response in patients with noninfectious uveitis (NIU) is not well understood.ObjectiveTo assess the frequency of ADAs and their association with drug levels and clinical response in patients with NIU treated with adalimumab or infliximab.Design, setting, and participantsThis retrospective cross-sectional study included patients diagnosed with NIU who received adalimumab or infliximab and underwent testing for serum drug level and ADAs at the National Eye Institute from September 2017 to July 2021.ExposuresSerum drug level testing with reflex testing for ADA levels was performed.Main outcomes and measuresThe main outcome was the association between drug levels and ADAs, clinical response, and concurrent antimetabolite use in patients treated with TNFis for NIU.ResultsOf 54 patients included in the study, 42 received adalimumab (mean [SD] age, 43.6 [19.6] years; 25 [59.5%] female) and 12 received infliximab (mean [SD] age, 42.7 [20.4] years; 7 [58.3%] male). In the adalimumab group, mean (SD) drug level was 9.72 (6.82) μg/mL, mean (SD) ADA level was 84.2 (172.9) arbitrary units/mL, and ADA frequency was 35.7% (15 of 42 patients). Mean drug level was lower in those with ADAs compared with those without ADAs (mean [SD], 2.8 [2.6] μg/mL vs 13.6 [5.2] μg/mL; difference: 10.8 μg/mL; 95% CI, 8.3-13.2 μg/mL; P < .001). There was a higher mean drug level with concurrent antimetabolite use compared with monotherapy (mean [SD], 11.0 [7.3] μg/mL vs 6.8 [4.5] μg/mL; difference: -4.2 μg/mL; 95% CI, -8.7 to 0.2 μg/mL; P = .06). Multivariable modeling showed that a 1-arbitrary unit increase in ADAs was associated with a -0.02 μg/mL (95% CI, -0.01 to -0.34 μg/mL) difference in mean drug level (P < .001). Favorable clinical response was associated with a threshold drug level above 2.7 μg/mL or an antibody level below 15.2 μg/mL. The mean (SD) drug level in the infliximab group was 27.02 (18.15) μg/mL, and no ADAs were detected.Conclusions and relevanceIn this study, 35.7% of adalimumab-treated patients with NIU had ADAs. The presence of ADAs was associated with lower drug levels, and higher ADA levels were associated with increased risk of TNFi treatment failure. Although limited by the retrospective design, our results suggest that therapeutic drug monitoring may be considered among patients experiencing therapy failure to help exclude ADAs as a potential cause of treatment failure.

Project description:ObjectiveTo study the effect of tumor necrosis factor α (TNFα) inhibitors on progressive spinal damage in patients with ankylosing spondylitis (AS).MethodsAll AS patients meeting the modified New York criteria who had been monitored prospectively and had at least 2 sets of spinal radiographs a minimum of 1.5 years apart were included in the study (n=334). The patients received standard therapy, which included nonsteroidal antiinflammatory drugs and TNFα inhibitors. Radiographic severity was assessed by the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Patients with a rate of AS progression that was ≥1 mSASSS unit/year were considered progressors. Univariable and multivariable regression analyses were done. Propensity score matching and sensitivity analysis were performed. A zero-inflated negative binomial (ZINB) model was used to analyze the effect of TNFα inhibitors on the change in the mSASSS with varying followup periods. Potential confounders, such as disease activity (as assessed by the Bath Ankylosing Spondylitis Disease Activity Index), the erythrocyte sedimentation rate, C-reactive protein level, HLA-B27 positivity, sex, age at onset, smoking burden (number of pack-years), and baseline damage, were included in the model.ResultsTNFα inhibitor treatment was associated with a 50% reduction in the odds of progression, with an odds ratio (OR) of 0.52 (95% confidence interval [95% CI] 0.30-0.88, P=0.02). Patients with a delay of >10 years in starting therapy were more likely to experience progression as compared to those who started earlier (OR 2.4 [95% CI 1.09-5.3], P=0.03). In the ZINB model, the use of TNFα inhibitors significantly reduced disease progression when the gap between radiographs was >3.9 years. The protective effect of TNFα inhibitors was stronger after propensity score matching.ConclusionTreatment with TNFα inhibitors appears to reduce radiographic progression in AS patients, especially with early initiation and with longer duration of followup.

Project description:Background:Listeria monocytogenes is historically a central nervous system pathogen of consideration in the very young, very old, and immune suppressed. Diagnosis of Listeria is based on positive bodily fluid culture or PCR testing. Cerebral edema is nonspecific and can be a manifestation of vasculitis, trauma, anoxia, ischemia, infarction, malignancy, or an infectious process. A main mechanism of immune protection against Listeria is tumor necrosis factor (TNF). Lenalidomide, an immunosuppressant, inhibits TNF. Case Presentation. A 61-year-old female with diabetes mellitus 2 and multiple myeloma treated with stem cell transplant and immunosuppressant (lenalidomide) was found to have cerebral edema after presenting with headache for 3?weeks and new focal neurologic deficits. Vitals signs were stable, with no meningeal exam findings and unremarkable initial serum testing. Blood cultures on days 0 and 2 of hospitalization as well as cerebral spinal fluid cultures were negative for infectious organisms. PCR testing of CSF was also negative for microorganisms. Brain biopsy was scheduled but postponed due to outstanding prion testing. The patient's focal neurologic deficits worsened prompting administration of dexamethasone after extensive negative infectious disease workup. By day 6, gross neurologic function deteriorated prompting transfer to higher level of care where the patient spiked a fever and one set of blood cultures revealed Gram-positive bacillus. Aggressive antimicrobial therapy was initiated, excluding ampicillin; however, this was later added. Blood culture further identified Listeria monocytogenes. By day 17, the patient suffered demise. Autopsy revealed brain microabscess lesions consistent with Listeria. Conclusion:Clinicians should employ prophylactic antimicrobial treatment for Listeria when caring for those patients presenting with cerebral edema who are immune suppressed with TNF inhibition no matter the initial exam findings, serum testing, and/or radiologic interpretation. If initial workup is negative and brain biopsy is needed to determine the next course of action in the patient with cerebral edema, transfer the patient to a higher level of care if unable to complete biopsy at your facility in an expedient fashion.

Dataset Information

Novel Elongator Protein 2 Inhibitors Mitigating Tumor Necrosis Factor-α Induced Osteogenic Differentiation Inhibition.

Publications

Novel Elongator Protein 2 Inhibitors Mitigating Tumor Necrosis Factor-<i>α</i> Induced Osteogenic Differentiation Inhibition.

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