The neuroinflammation is a crucial component of virtually all neurodegenerative disorders, including Alzheimer's disease (AD). The bacterial lipopolysaccharide (LPS), a potent activator of the innate immune system, was suggested to influence or even trigger the neuropathological alterations in AD. LPS-induced neuroinflammation involves changes in transcription of several genes, thus controlling these molecular processes may be a potentially efficient strategy to attenuate the progression of AD. Since genome-wide association studies showed that the majority of AD-related genetic risk factors (AD-GRF) are connected to the immune system, our aim was to identify AD-GRF affected in the hippocampus by LPS-induced systemic inflammatory response (SIR). Moreover, we analysed the role of bromodomain and extraterminal domain (BET) proteins, the readers of the acetylation code, in controlling the transcription of selected AD-GRF in the brain during neuroinflammation. In our study, we used a mouse model of LPS-induced SIR and mouse microglial BV2 cells. JQ1 was used as an inhibitor of BET proteins. The level of mRNA was analysed using microarrays and qPCR. Our data demonstrated that among the established AD-GRF, only the expression of Cd33 was significantly upregulated in the hippocampus during SIR. In parallel, we observed an increase in the expression of Brd4, a BET family member. JQ1 prevented an LPS-evoked increase in Cd33 expression in the hippocampus of mice. Moreover, JQ1 reduced Cd33 expression in BV2 microglial cells stimulated with blood serum from LPS-treated mice. Our study suggests that LPS-evoked SIR may increase Cd33 gene expression in the brain, and inhibition of BET proteins through suppression of Cd33 expression could be a promising strategy in prevention or in slowing down the progression of neuroinflammation and may potentially affect the pathomechanism of AD.
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http://dx.doi.org/10.5114/fn.2024.138140 | DOI Listing |
Mol Cell
January 2025
Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia; Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Centre for Cancer Research, University of Melbourne, Melbourne, VIC, Australia. Electronic address:
Several transcription inhibitors have been developed as cancer therapies. However, they show modest clinical activity, highlighting that our understanding of the cellular response to transcriptional inhibition remains incomplete. Here we report that potent inhibitors of transcription not only impact mRNA output but also markedly impair mRNA transcript localization and nuclear export.
View Article and Find Full Text PDFXi Bao Yu Fen Zi Mian Yi Xue Za Zhi
December 2024
Department of Toxicology, School of Public Health, Shenyang Medical College, Shenyang 110034, China. *Corresponding author, E-mail:
Objective To investigate the protective effect of curcumin (Cur) against arsenic-induced neuroimmune toxicity and the underlying molecular mechanisms in vivo. Methods Eighty SPF female C57BL/6 mice were randomly assigned to four groups: a control group, an arsenic-treated group, a Cur-treated group and an arsenic+Cur group, with 20 mice in each group. The control group received distilled water; the arsenic-treated group was given 50 mg/L NaAsO in the drinking water; the Cur-treated group was gavaged with 200 mg/kg of curcumin for 45 days; and the arsenic+Cur group received distilled water and was gavaged with 200 mg/kg of curcumin.
View Article and Find Full Text PDFNat Commun
January 2025
Institute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
A balance between stem cell self-renewal and differentiation is required to maintain concurrent proliferation and cellular diversification in organoids; however, this has proven difficult in homogeneous cultures devoid of in vivo spatial niche gradients for adult stem cell-derived organoids. In this study, we leverage a combination of small molecule pathway modulators to enhance the stemness of organoid stem cells, thereby amplifying their differentiation potential and subsequently increasing cellular diversity within human intestinal organoids without the need for artificial spatial or temporal signaling gradients. Moreover, we demonstrate that this balance between self-renewal and differentiation can be effectively and reversibly shifted from secretory cell differentiation to the enterocyte lineage with enhanced proliferation using BET inhibitors, or unidirectional differentiation towards specific intestinal cell types by manipulating in vivo niche signals such as Wnt, Notch, and BMP.
View Article and Find Full Text PDFThe risk of severe outcomes of influenza increases during pregnancy. Whether vaccine-induced T cell memory-primed prepregnancy retains the ability to mediate protection during pregnancy, when systemic levels of several hormones with putative immunomodulatory functions are increased, is unknown. Here, using murine adoptive transfer systems and a translationally relevant model of cold-adapted live-attenuated influenza A virus vaccination, we show that preexisting virus-specific memory T cell responses are largely unaltered and highly protective against heterotypic viral challenges during pregnancy.
View Article and Find Full Text PDFSci Rep
December 2024
Department of Life Sciences, University of Siena, Siena, Italy.
The scaffold protein AMBRA1, which participates in the autophagy pathway, also promotes CD4 T cell differentiation to Tregs independent of autophagy through its interactor PP2A. Here we have investigated the role of AMBRA1 in CD8 T cell differentiation to cytotoxic T cells (CTL). AMBRA1 depletion in CD8 T cells was associated with impaired expression of the transcription factors RUNX3 and T-BET that drive CTL differentiation and resulted in impaired acquisition of cytotoxic potential.
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