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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 |

REPOSITORIES: biostudies-literature

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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.

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

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