Mecanismos de disfunção da barreira hematoencefálica no paciente criticamente enfermo: ênfase no papel das metaloproteinases de matriz

Rojas, Hugo; Ritter, Cristiane

doi:10.1590/s0103-507x2011000200016

Cited by 15 publications

(7 citation statements)

References 53 publications

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“…However, for a drug lacking CNS activity, as investigated here, a low penetration value is desired, to minimize side effects. 47,48 For the structure 6 (log PBH* = 0.367), the values were higher than those presented by 7 (log PBH = -0.322) and N,N-DHL (log PBH = -0.292). The literature 49 suggests that PBH values less than 1 (brain/ /blood < 1) assign the molecule to the inactive status in the CNS.…”

Section: Pharmacokinetic and Toxicity Predictions Studiesmentioning

confidence: 79%

Ligand- and structure-based virtual screening from 16-((diisobutylamino)methyl)-6α-hydroxyivouacapane-7β,17β-lactone a compound with potential anti-prostate cancer activity

Silva

Poiani

Ramos

et al. 2019

JSCS

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Prostate cancer is one of the leading causes of disease and death on the planet. The probable bioactive pose of 16-((diisobutylamino)methyl)-6α-hydroxyvouacapane-7β,17β-lactone (N,N-DHL), a pivot compound with prostatic anti-cancer activity, was investigated via a semi-empirical method (PM3) and refined with the base set 6-31+G(d,p) calculated in the DFT method at the B3LYP level of theory. This structure was used in ligand-based virtual screening for five commercial compound bases using the software ROCS and EON that selected 2000 per base and another that resulted in 100 per base, respectively. This set was used for pharmacokinetic and toxicological predictions. The molecular overlap index at 50 % steric/electrostatic provided 68 structures that were used for a molecular docking study. The results showed that of 238,922 structures, only eight, 7 (-10.9 kcal mol-1) as the best in the series and 1 (-8.1 kcal mol-1) as less favorable, with others in this range (±2.8 kcal mol-1) with their respective binding affinity: 8 (-8.2 kcal mol-1), 5 (-8.2 kcal mol-1), 4 (-8.3 kcal mol-1), 2 (-8.5 kcal mol-1), 3 (-8.6 kcal mol-1) and 6 (-8.8 kcal mol-1) remaining in the final selection. The predictions for 21 pharmacokinetic properties were within the recommended range, similar to 95 % of the drugs available on the market, with no toxicity warning. The structures showed similarity greater than 75 % to the pivot based on binding affinity and predictions but only the structures 6 and 7 were considered more promising for their potential anti-prostate cancer activity (PC-3).

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Section: Pharmacokinetic and Toxicity Predictions Studiesmentioning

confidence: 79%

Ligand- and structure-based virtual screening from 16-((diisobutylamino)methyl)-6α-hydroxyivouacapane-7β,17β-lactone a compound with potential anti-prostate cancer activity

Silva

Poiani

Ramos

et al. 2019

JSCS

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“…For example, Iqgap1 regulates the function of claudin (e.g., CLDN5), while LCK regulates the function of PECAM1 [34,35]. Timp 1 and Timp4 regulate Mmp2 [36,37].…”

Section: Resultsmentioning

confidence: 99%

Paracellular and Transcellular Leukocytes Diapedesis Are Divergent but Interconnected Evolutionary Events

Mickael

Kubick

Klimovich³

et al. 2021

Genes

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Infiltration of the endothelial layer of the blood-brain barrier by leukocytes plays a critical role in health and disease. When passing through the endothelial layer during the diapedesis process lymphocytes can either follow a paracellular route or a transcellular one. There is a debate whether these two processes constitute one mechanism, or they form two evolutionary distinct migration pathways. We used artificial intelligence, phylogenetic analysis, HH search, ancestor sequence reconstruction to investigate further this intriguing question. We found that the two systems share several ancient components, such as RhoA protein that plays a critical role in controlling actin movement in both mechanisms. However, some of the key components differ between these two transmigration processes. CAV1 genes emerged during Trichoplax adhaerens, and it was only reported in transcellular process. Paracellular process is dependent on PECAM1. PECAM1 emerged from FASL5 during Zebrafish divergence. Lastly, both systems employ late divergent genes such as ICAM1 and VECAM1. Taken together, our results suggest that these two systems constitute two different mechanical sensing mechanisms of immune cell infiltrations of the brain, yet these two systems are connected. We postulate that the mechanical properties of the cellular polarity is the main driving force determining the migration pathway. Our analysis indicates that both systems coevolved with immune cells, evolving to a higher level of complexity in association with the evolution of the immune system.

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“…Exposure to DEP deregulated the expression of several transporters and receptors that are critically involved in BBB functionality namely ABCB1, multidrug-resistance associated proteins (MRP)1, MRP2, MRP4, breast cancer resistance protein (BCRP), glucose transporter (GLUT)1, and the metabolizing enzyme glutathione S-transferase (GST)π (Hartz et al, 2008). Several reports have demonstrated an increased BBB permeability following exposure to a mixed vehicular emission, translated essentially by deregulation of the TJs (Rojas et al, 2011;Oppenheim et al, 2013;Bernardi et al, 2021). For instance, human brain microvascular endothelial cells in culture exposed to nanoparticles of aluminum oxide exhibit reduced cell viability, altered mitochondrial function, increased oxidative stress, and diminished expression of the TJs proteins claudin-5 and occludin (Chen et al, 2008;Block and Calderón-Garcidueñas, 2009).…”

Section: Impact On Endothelial Functionsmentioning

confidence: 99%

Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors

Lecordier

Manrique-Castano

Moghrabi

et al. 2021

Front. Aging Neurosci.

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Vascular dementia (VaD) constitutes the second most prevalent cause of dementia in the world after Alzheimer’s disease (AD). VaD regroups heterogeneous neurological conditions in which the decline of cognitive functions, including executive functions, is associated with structural and functional alterations in the cerebral vasculature. Among these cerebrovascular disorders, major stroke, and cerebral small vessel disease (cSVD) constitute the major risk factors for VaD. These conditions alter neurovascular functions leading to blood-brain barrier (BBB) deregulation, neurovascular coupling dysfunction, and inflammation. Accumulation of neurovascular impairments over time underlies the cognitive function decline associated with VaD. Furthermore, several vascular risk factors, such as hypertension, obesity, and diabetes have been shown to exacerbate neurovascular impairments and thus increase VaD prevalence. Importantly, air pollution constitutes an underestimated risk factor that triggers vascular dysfunction via inflammation and oxidative stress. The review summarizes the current knowledge related to the pathological mechanisms linking neurovascular impairments associated with stroke, cSVD, and vascular risk factors with a particular emphasis on air pollution, to VaD etiology and progression. Furthermore, the review discusses the major challenges to fully elucidate the pathobiology of VaD, as well as research directions to outline new therapeutic interventions.

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Mecanismos de disfunção da barreira hematoencefálica no paciente criticamente enfermo: ênfase no papel das metaloproteinases de matriz

Cited by 15 publications

References 53 publications

Ligand- and structure-based virtual screening from 16-((diisobutylamino)methyl)-6α-hydroxyivouacapane-7β,17β-lactone a compound with potential anti-prostate cancer activity

Ligand- and structure-based virtual screening from 16-((diisobutylamino)methyl)-6α-hydroxyivouacapane-7β,17β-lactone a compound with potential anti-prostate cancer activity

Paracellular and Transcellular Leukocytes Diapedesis Are Divergent but Interconnected Evolutionary Events

Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors

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