Pagano, G. | Search bioRxiv

bioRxiv2025

Ablation of Prdm16 and beige fat causes vascular remodeling and elevated blood pressure

While excess adiposity is a major risk factor for hypertension and cardiovascular disease, brown fat is associated with protection from these pathologies. Whether brown fat has a causal role in this process and the underlying molecular mechanisms remain unknown. Here we investigate the role of murine beige fat, as a model of inducible brown fat in humans, in adipocyte-vascular crosstalk. Using mice with an adipocyte-specific deletion of PRDM16, resulting in a loss of beige adipocyte identity, we discover a dramatic remodeling of perivascular adipose tissue, increased vascular reactivity and elevated blood pressure. We further show that the circulating enzyme Qsox1 is de-repressed in Prdm16-deficient adipocytes, and deletion of Qsox1 in PRDM16cKO mice rescues vascular fibrosis and reactivity. These results demonstrate a key new role for beige adipocytes in blood pressure regulation and identify Qsox1 as an important mediator of adipocyte-vascular crosstalk.

physiology↗

bioRxiv2022

T cell landscape definition by multi-omics identifies Galectin-9 as novel immunotherapy target in chronic lymphocytic leukemia

Failure of cancer immunotherapy is linked to T cell exhaustion. To decipher the underlying mechanisms, we explored the T cell landscape in blood, bone marrow and lymph node samples of patients with chronic lymphocytic leukemia (CLL), and spleen samples of a CLL mouse model. By single-cell RNA-sequencing, mass cytometry (CyTOF), and multiplex image analysis of tissue microarrays, we identified a disease-specific accumulation of distinct regulatory T cell subsets and T cell exhaustion stages and their trajectories in CLL lymph nodes. Integration of T cell receptor sequencing data revealed a clonal expansion of CD8+ precursor exhausted T cells (TPEX), suggesting their CLL reactivity. Interactome analyses identified the TIM3 ligand Galectin-9 as a novel immunoregulatory molecule in CLL. Blocking of Galectin-9 in CLL-bearing mice slowed down disease development and reduced the number of TIM3-expressing T cells. Galectin-9 expression correlated with shorter survival of patients with CLL, renal cell carcinoma or glioma. Statement of significanceOur findings for the first time define the T cell landscape in CLL lymph nodes and reshape the current understanding of T cell exhaustion in this malignancy. They further introduce Galectin-9 as novel immune checkpoint with a high potential to overcome resistance to PD1 targeting drugs in CLL and beyond.

cancer biology↗

bioRxiv2019

Swallowing and chewing difficulties are associated with presynaptic dopaminergic dysfunction and greater non-motor symptom burden in early drug-naïve Parkinson’s patients

BackgroundThe underlying pathophysiology of swallowing and chewing difficulties is multifactorial and evidence clarifying the precise mechanisms are scarce. Dysfunction in dopamine-related and non-dopamine-related pathways, changes in cortical networks related with swallowing and peripheral mechanisms have been implicated in the pathogenesis of swallowing difficulties. We aimed at investigating whether swallowing and chewing difficulties are associated with presynaptic dopaminergic deficits, faster motor symptom progression and cognitive decline in a population of early drug-naive patients with Parkinsons disease.\n\nMethodsBy exploring the database of Parkinsons Progression Markers Initiative we identified forty-nine early drug-naive Parkinsons disease patients with swallowing difficulties. Swallowing and chewing impairment was identified with SCOPA-AUT question 1 (answer regularly) and was assessed with MDS-UPDRS Part-II, Item 2.3 (Chewing and Swallowing). We compared Parkinsons disease patients with swallowing and chewing difficulties to Parkinsons disease patients without difficulties, and investigated differences in striatal [123I]FP-CIT single photon emission computed tomography levels. Using Cox proportional hazards analyses, we also evaluated whether swallowing impairment can predict motor deterioration and cognitive dysfunction.\n\nResultsPatients with Parkinsons disease, harbored a greater deterioration regarding motor and non-motor symptoms and decreased [123I]FP-CIT binding when compared with patients without swallowing and chewing impairment. Higher burden of swallowing and chewing dysfunction (MDS-UPDRS-II, item 2.3) was correlated with lower [123I]FP-CIT uptakes within the striatum (rs=-0.157; P=0.002) and the caudate (rs=-0.156; P=0.002). The presence of swallowing and chewing difficulties was not a predictor of motor progression (Hazard ratio [HR]: 1.143, 95% confidence interval [CI]: 0.848-1.541; P=0.379) or cognitive decline (HR: 1.294, 95% CI: 0.616-2.719; P=0.496).\n\nConclusionsSwallowing and chewing impairment is associated with decreased presynaptic dopaminergic integrity within caudate and greater motor and non-motor symptoms burden in early drug-naive PD.\n\nAuthor contributionsS.P. and M.P. conceived the study, conceptualized the experimental design. M.P., S.P., G.D. and G.P. gave input to experimental design. S.P. wrote the first draft and prepared the manuscript. G.P. and S.P. performed the statistical analysis. G.P., G.D., T.Y. and S.P. generated the figures. F.N., M.P., S.P., G.P., G.D. interpreted the data. All authors revised and gave input to the manuscript.\n\nFinancial Disclosure StatementData used in the preparation of this article were obtained from the Parkinsons Progression Markers Initiative (PPMI) database (www.ppmi-info.org/data). For up-to-date information on the study, visit www.ppmi-info.org. PPMI - a public-private partnership - is sponsored by the Michael J. Fox Foundation for Parkinsons Research (MJFF) and is co-funded by MJFF, Abbvie, Avid Radiopharmaceuticals, Biogen Idec, Bristol-Myers Squibb, Covance, Eli Lilly & Co., F. Hoffman-La Roche, Ltd., GE Healthcare, Genentech, GlaxoSmithKline, Lundbeck, Merck, MesoScale, Piramal, Pfizer and UCB.PPMI. Industry partners are contributing to PPMI through financial and in-kind donations and are playing a lead role in providing feedback on study parameters through the Industry Scientific Advisory Board (ISAB). Through close interaction with the study, the ISAB is positioned to inform the selection and review of potential progression markers that could be used in clinical testing.\n\nMr. Polychronis, Dr. Dervenoulas, Ms Yousaf, Dr. Niccolini, Dr. Pagano and Prof. Politis report no disclosures.\n\nPotential Conflicts of InterestNo potential conflict of interest relevant to this article was reported.

neuroscience↗