Initial and ongoing tobacco smoking elicits vascular damage and distinct inflammatory response linked to neurodegeneration

Garza, Alejandra P.; Morton, Lorena; Pállinger, Éva; Buzás, Edit I.; Schreiber, Stefanie; Schott, Björn H.; Dunay, Ildikò Rita

doi:10.1016/j.bbih.2023.100597

Cited by 15 publications

(5 citation statements)

References 101 publications

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“…In particular, a significant increase in KDM6B mRNA levels, along with downregulation of both PPARα and PPARγ gene expression, has been detected in the VTA of nicotine-exposed rats. Consistent with previous studies showing that KDM enzymes inhibit the expression and activity of the nuclear receptors PPARs [17,21], these findings support the hypothesis that the inflammatory process triggered by nicotine inhaled via HnB mainstream smoke [22] could be epigenetically influenced by KDMs and could entail PPAR regulation. Although both KDM6A and KDM6B have been reported to promote inflammatory processes through the removal of trimethyl marks at lysine 27 residues of H3 in gene promoter regions, our data seem to suggest the major involvement of the KDM6B isoform in modulating the inflammatory response within this specific brain region.…”

Section: Discussionsupporting

confidence: 91%

Unburned Tobacco Smoke Affects Neuroinflammation-Related Pathways in the Rat Mesolimbic System

Morosini,

Vivarelli,

Rullo

et al. 2024

IJMS

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Tobacco use disorder represents a significant public health challenge due to its association with various diseases. Despite awareness efforts, smoking rates remain high, partly due to ineffective cessation methods and the spread of new electronic devices. This study investigated the impact of prolonged nicotine exposure via a heat-not-burn (HnB) device on selected genes and signaling proteins involved in inflammatory processes in the rat ventral tegmental area (VTA) and nucleus accumbens (NAc), two brain regions associated with addiction to different drugs, including nicotine. The results showed a reduction in mRNA levels for PPARα and PPARγ, two nuclear receptors and anti-inflammatory transcription factors, along with the dysregulation of gene expression of the epigenetic modulator KDM6s, in both investigated brain areas. Moreover, decreased PTEN mRNA levels and higher AKT phosphorylation were detected in the VTA of HnB-exposed rats with respect to their control counterparts. Finally, significant alterations in ERK 1/2 phosphorylation were observed in both mesolimbic areas, with VTA decrease and NAc increase, respectively. Overall, the results suggest that HnB aerosol exposure disrupts intracellular pathways potentially involved in the development and maintenance of the neuroinflammatory state. Moreover, these data highlight that, similar to conventional cigarettes, HnB devices use affects specific signaling pathways shaping neuroinflammatory process in the VTA and NAc, thus triggering mechanisms that are currently considered as potentially relevant for the development of addictive behavior.

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Section: Discussionsupporting

confidence: 91%

Unburned Tobacco Smoke Affects Neuroinflammation-Related Pathways in the Rat Mesolimbic System

Morosini,

Vivarelli,

Rullo

et al. 2024

IJMS

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“…Flow cytometric analysis of pdEVs 48 , with size gating and tetraspanin marker expression selection (CD9, CD63, and CD81), confirmed the presence of isolated pdEVs, revealing no difference in abundance of circulating pdEVs between early chronic HTN and age-matched Ctrl (Fig. 6a, b).…”

Section: Impact Of Hypertensive Evs On Pericyte Mitochondrial Functionmentioning

confidence: 75%

“…Peripheral blood was collected from the portal vein of anesthetized animals using a 21G butterfly needle, immediately mixed with acid citrate dextrose (ACD), and subjected to two inversions for agent incorporation. Samples were processed within 1 h, as previously described 48 . Briefly, plasma separation was initially achieved by centrifugation at 1500 × g for 10 min, which was then transferred to sterile 1.5 ml Eppendorf tubes.…”

Section: Methodsmentioning

confidence: 99%

Pericytes mediate neurovascular remodeling in chronic arterial hypertension

Morton,

Garza,

Debska-Vielhaber

et al. 2024

Preprint

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Chronic arterial hypertension restructures the vascular architecture of the brain, leading to a series of pathological responses that culminate in cerebral small vessel disease. Pericytes respond dynamically to vascular challenges; however, how they manifest under the continuous strain of hypertension has not been elucidated. Therefore, in this study, we characterized pericyte behavior alongside hypertensive states in the spontaneously hypertensive stroke-prone rat (SHRSP) model, emphasizing their phenotypic and metabolic transformation. Our results reveal an early transition in PDGFRβ+ pericytes toward increased NG2 and CD13 co-expressing subtypes, signaling enhanced pericyte reactivity in an effort to stabilize vascular structures and an inflammatory engagement within the vascular niche in response to hypertensive stress. Gene expression profiling of microvessels revealed altered expression within crucial pathways i.e., angiogenesis, blood-brain barrier integrity, hypoxia and inflammation. Furthermore, we detected that circulating extracellular vesicles from SHRSP alter pericyte mitochondrial membrane potential, highlighting their ability to transmit pathogenic signals that exacerbate vascular remodeling. Detailed metabolic analysis revealed a significant shift toward glycolytic metabolism in pericytes already in initial hypertension, alongside a dysregulation of ATP production pathways. These findings emphasize the transformative influence of hypertension on cerebral pericytes and the extensive consequences on cerebral vascular health.

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“…To validate our approach, we included a second cohort (Magdeburg cohort) containing 55 ALS patients and 30 HC. For this cohort, blood was collected in tubes containing Ethylenediaminetetraacetic acid (EDTA) (BD Vacutainer) and further processed as previously described ( 5 ). Briefly, blood was lysed with 1X red blood cell lysing buffer (BioLegend, 10X) and washed before surface immunostaining.…”

Section: Methodsmentioning

confidence: 99%

Classifying flow cytometry data using Bayesian analysis helps to distinguish ALS patients from healthy controls

et al. 2023

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IntroductionGiven its wide availability and cost-effectiveness, multidimensional flow cytometry (mFC) became a core method in the field of immunology allowing for the analysis of a broad range of individual cells providing insights into cell subset composition, cellular behavior, and cell-to-cell interactions. Formerly, the analysis of mFC data solely relied on manual gating strategies. With the advent of novel computational approaches, (semi-)automated gating strategies and analysis tools complemented manual approaches.MethodsUsing Bayesian network analysis, we developed a mathematical model for the dependencies of different obtained mFC markers. The algorithm creates a Bayesian network that is a HC tree when including raw, ungated mFC data of a randomly selected healthy control cohort (HC). The HC tree is used to classify whether the observed marker distribution (either patients with amyotrophic lateral sclerosis (ALS) or HC) is predicted. The relative number of cells where the probability q is equal to zero is calculated reflecting the similarity in the marker distribution between a randomly chosen mFC file (ALS or HC) and the HC tree.ResultsIncluding peripheral blood mFC data from 68 ALS and 35 HC, the algorithm could correctly identify 64/68 ALS cases. Tuning of parameters revealed that the combination of 7 markers, 200 bins, and 20 patients achieved the highest AUC on a significance level of p < 0.0001. The markers CD4 and CD38 showed the highest zero probability. We successfully validated our approach by including a second, independent ALS and HC cohort (55 ALS and 30 HC). In this case, all ALS were correctly identified and side scatter and CD20 yielded the highest zero probability. Finally, both datasets were analyzed by the commercially available algorithm ‘Citrus’, which indicated superior ability of Bayesian network analysis when including raw, ungated mFC data.DiscussionBayesian network analysis might present a novel approach for classifying mFC data, which does not rely on reduction techniques, thus, allowing to retain information on the entire dataset. Future studies will have to assess the performance when discriminating clinically relevant differential diagnoses to evaluate the complementary diagnostic benefit of Bayesian network analysis to the clinical routine workup.

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Initial and ongoing tobacco smoking elicits vascular damage and distinct inflammatory response linked to neurodegeneration

Cited by 15 publications

References 101 publications

Unburned Tobacco Smoke Affects Neuroinflammation-Related Pathways in the Rat Mesolimbic System

Unburned Tobacco Smoke Affects Neuroinflammation-Related Pathways in the Rat Mesolimbic System

Pericytes mediate neurovascular remodeling in chronic arterial hypertension

Classifying flow cytometry data using Bayesian analysis helps to distinguish ALS patients from healthy controls

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