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  • Despite extensive studies on the

    2024-06-14

    Despite extensive studies on the expression of T. pallidum-induced pro-inflammatory cytokines, very little is known about T. pallidum-mediated intracellular signaling pathway activation, that leads to cytokine expression in macrophages. A network of signaling molecules, transcription factors, epigenetic mechanisms, and posttranscriptional regulators underlie macrophage polarization [18]. A previous study reported that PI3K/Akt pathway activation is an important element in M1 differentiation [9,19]. Similar to this study, we found that the phosphorylated forms of Akt, mTOR, S6, p65, and IκBα were higher in macrophages treated with T. pallidum than in those treated with PBS. Further Akt or NFκB inhibition confirmed that T. pallidum-induced M1 macrophage differentiation was associated with Akt-mTOR-NFκB signaling. Unexpectedly, the mTOR inhibitor rapamycin significantly decreased p-mTOR expression but increased IL-1β and TNF-α expression, consistent with the results that inhibiting mTOR by rapamycin increased M1 marker expression [20]. However, genes do not work in isolation, instead, complex molecular networks and cellular pathways are often involved in disease pathogenesis [21]. Apart from this signaling pathway, whether T. pallidum modulates other events, such as cytokine production, signaling pathway cross-talk, or CORM-3 remodeling, requires further investigation. In this study, we verified the role of T. pallidum-induced macrophage modulation in only the early stage in vitro. Further studies are required to understand the role of macrophage modulation in T. pallidum-infected animals. In addition, as the time of the T. pallidum macrophage treatment was extended to 24 or 48 h, cell growth gradually decreased. Our observation period was 12 h. Therefore, extending the time limit in further experiments using another cell line is necessary to address macrophage modulation in late syphilis.
    Conclusions In summary, we show that T. pallidum promotes macrophage switching to pro-inflammatory M1 macrophages in vitro. In addition, the present study provides evidence demonstrating that Akt, mTOR and NF-κB pathway activation in T. pallidum stimulates M1 macrophages.
    Introduction Intracerebral hemorrhage (ICH) is a stroke subtype that is associated with high mortality neurological impairments [1,2]. ICH accounts for 10–15% of all strokes in the USA, Europe and Australia and 20–30% of strokes in Asia, with about two million cases worldwide per year [3]. Despite its high fatality rate and disability rate, no efficient pharmacological preventions are available [4]. Glycine is the simplest non-essential amino acid which plays a fundamental role in cell metabolism. It is a major inhibitory neurotransmitter that binds to glycine receptor to inhibit postsynaptic neurons in the adult CNS. In the previous study, glycine has been shown to have neuroprotective effect in ischemia-reperfusion, anoxia, hypoxia and reactive oxygen species (ROS) [[5], [6], [7]]. A study of Gusev EI SV from Russia reports that glycine treatment shows significantly improved outcome and tended to decrease the 30 day mortality of ischemic stroke patients [8]. However, whether glycine has a neuroprotective property in hemorrhagic stroke is not known. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor with the important function that dephosphorylates both protein and lipid substrates [9,10]. PTEN regulates several basic cellular functions, such as cell cycle progression, cell migration, cell spreading and cell growth. It displays its lipid phosphatase activity by antagonizing Akt-dependent cell survival-promoting signaling via dephosphorylation of PIP3 (phosphatidylinositol (3,4,5)-trisphosphate) [9,11]. Akt is a multi-isoform serine/threonine kinase which plays a pivotal role in promoting cell survival and it is a direct downstream target of PI3K [10,12]. Our previous data CORM-3 indicate that PTEN inhibition by bpV(pis) enhancing Akt activation so as to confer neuroprotection in ischemia-reperfusion injury.