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Serrano, P.

Publications and source records attributed to Serrano, P..

3 recordsLinked to original sources
bioRxiv2024

BT-11 repurposing potential for Alzheimer's disease and insights into its mode of actions

Neuroinflammation is a key pathological hallmark of Alzheimers disease (AD). Investigational and FDA approved drugs targeting inflammation already exist, thus drug repurposing for AD is a suitable approach. BT-11 is an investigational drug that reduces inflammation in the gut and improves cognitive function. BT-11 is orally active and binds to lanthionine synthetase C-like 2 (LANCL2), a glutathione-s-transferase, thus potentially reducing oxidative stress. We investigated the effects of BT-11 long-term treatment on the TgF344-AD rat model. BT-11 reduced hippocampal-dependent spatial memory deficits, A{beta} plaque load and neuronal loss in males, and mitigated microglia numbers in females. BT-11 treatment led to hippocampal transcriptomic changes in signaling receptor, including G-protein coupled receptor pathways. We detected LANCL2 in hippocampal nuclear and cytoplasmic fractions with potential different post-translational modifications, suggesting distinct functions based on its subcellular localization. LANCL2 was present in oligodendrocytes, showing a role in oligodendrocyte function. To our knowledge, these last two findings have not been reported. Overall, our data suggest that targeting LANCL2 with BT-11 improves cognition and reduces AD-like pathology by potentially modulating G-protein signaling and oligodendrocyte function. Our studies contribute to the field of novel immunomodulatory AD therapeutics, and merit further research on the role of LANCL2 in this disease.

neuroscience↗
bioRxiv2024

L-Phenylalanine is a metabolic checkpoint of human Th2 cells

After the primary response, circulating memory CD4+T effector and T regulatory cells (Treg) regulate recall responses, which are impaired in allergy. Using mass spectrometry, we discovered distinct metabolomes of these cells in humans and their unique enrichment in amino acids. By assessing energy metabolism in in vitro and ex vivo single-cell analyses, we determined that increased intracellular L-phenylalanine boosts glycolysis while limiting OXPHOS in CD4+T, memory CD4+T and Th2, but not in Treg cells. L-phenylalanine also restrains memory CD4+T proliferation in an IL4I1-dependent manner and inhibits Th2 cell proliferation and differentiation. RNA-sequencing, metabolomics, flow cytometry and proteomics, validated in vitro and across patients cohorts, revealed an impairment in LAT1-dependent transport of L-phenylalanine into Th2 cells in allergy with an increase in its intracellular processing, accompanied by an expansion of pathogenic Th2 cells. Thus, our study identifies L-phenylalanine as a checkpoint in the development, energy metabolism and function of Th2 cells.

immunology↗
bioRxiv2023

Diazoxide/dibenozylmethane treatment mitigates spatial memory deficits and pathology and up regulates protective genes in an Alzheimer's transgenic rat model

INTRODUCTIONAlzheimers disease (AD) is a multifactorial disease for which therapeutic efficacy should benefit from a multi-target approach. Thus, we evaluated a combined chronic treatment with diazoxide (DZ) and dibenzoylmethane (DIB). DZ is a potassium channel activator. DIB counteract eIF2-P-driven stress responses. The individual therapeutic benefits of each drug on attenuating neurodegeneration and apoptosis were previously examined, but not as a combined treatment. METHODSWe evaluated the efficacy of chronic DZ/DIB treatment on TgF344-AD rats (Tg-AD) at 4- and 11-months of age and wild-type littermates. Spatial working memory was assessed with the radial 8-arm maze, and AD pathology by immunohistochemistry. We used RNA sequencing for transcriptome analysis. RESULTSDZ/DIB-treatment mitigated the spatial memory deficits as well as the buildup of hippocampal A{beta} plaques and tau PHF exhibited by 11-month Tg-AD rats. The DZ/DIB-treatment had no effect on wild-type littermates. We did not detect AD-related deficits in untreated 4-month Tg-AD rats, but DZ/DIB-treatment altered their transcriptome. DZ/DIB-treatment of 4-month Tg-AD rats upregulated several genes normally downregulated in AD and/or aging. Expression of two potential early biomarkers for AD, EGR2 (early growth response 2) and HISIT1H2AA (histone H2AA), were also altered by the DZ/DIB treatment in 4-month Tg-AD rats. The treatment reduced levels of eIF2, a protein involved in abnormal translational repression and a contributing factor to neuronal loss. DISCUSSIONThis preclinical study represents the first report on the combined DZ/DIB-treatment. Besides the benefits of this treatment on spatial memory and AD pathology, we identified two potential early AD biomarkers. Furthermore, the DZ/DIB-treatment prevented downregulation of genes associated with AD and/or aging. Overall, our results strongly support that the combination DZ/DIB-treatment mitigates AD pathology. Evaluations across multiple AD-related models are warranted to further corroborate that the DZ/DIB combination is a candidate treatment for AD. HighlightsO_LIDZ/DIB treatment improves cognitive deficits and AD pathology in TgF344-AD rats C_LIO_LIEGR2 and HISIT1H2AA genes are potential early AD biomarkers in TgF344-AD rats C_LIO_LIDZ/DIB treatment of 4-month TgF344-AD rats blocks downregulation of AD/aging genes C_LI RESEARCH IN CONTEXT1. Systematic Review: We reviewed the literature using traditional sources (e.g., PubMed) to assess the status of DZ and DIB treatment individually in preclinical studies in animal models. To our knowledge there is no data with this chronic combined treatment. 2. Interpretation: Treatment takes advantage of a polypharmacological approach to AD therapeutics, considering the multifactorial nature of AD. DZ and DIB individually have been successful in mitigating hippocampal AD pathology but their combined effects were unknown, particularly in a rodent model that shows a more complete disease progression that incorporates aging as a risk factor. The effects of the treatment go beyond previous data in individual DZ and DIB treatment, supporting the need for combination drug treatments to treat a multifactorial disorder. 3. Future Directions: Investigate the potential of DZ/DIB treatment to stop the progression or ameliorate AD pathology when administered at a later age, when pathology is first detected. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=138 HEIGHT=200 SRC="FIGDIR/small/555966v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@7cc6a0org.highwire.dtl.DTLVardef@1d468feorg.highwire.dtl.DTLVardef@390f19org.highwire.dtl.DTLVardef@e40c8_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗