Dysregulation of the renin-angiotensin system in vascular dementia.

The renin-angiotensin system (RAS) regulates systemic and cerebral blood flow and is dysregulated in dementia. The major aim of this study was to determine if RAS signalling is dysregulated in vascular dementia. We measured markers of RAS signalling in white matter underlying the frontal and occipital cortex in neuropathologically confirmed cases of vascular dementia (n = 42), Alzheimer's disease (n = 50), mixed AD/VaD (n = 50) and age-matched controls (n = 50).

sPDGFRβ and neuroinflammation are associated with AD biomarkers and differ by race: The ASCEND Study.

Introduction: There remains an urgent need to identify preclinical pathophysiological mechanisms of Alzheimer's disease (AD) development in high-risk, racially diverse populations. We explored the relationship between cerebrospinal fluid (CSF) markers of vascular injury and neuroinflammation with AD biomarkers in middle-aged Black/African American (B/AA) and non-Hispanic White (NHW) participants.

Methods: Adults (45-65 years) with a parental history of AD were enrolled (n = 82).

The molecular basis of dapsone activation of CYP2C9-catalyzed nonsteroidal anti-inflammatory drug oxidation.

Positive heterotropic cooperativity, or "activation," results in an instantaneous increase in enzyme activity in the absence of an increase in protein expression. Thus, cytochrome P450 (CYP) enzyme activation presents as a potential drug-drug interaction mechanism. It has been demonstrated previously that dapsone activates the CYP2C9-catalyzed oxidation of a number of nonsteroidal anti-inflammatory drugs in vitro.

Altered Gene Expression Within the Renin-Angiotensin System in Normal Aging and Dementia.

The renin-angiotensin system (RAS) is dysregulated in Alzheimer's disease (AD). In this study, we have explored the hypothesis that an -age--related imbalance in brain RAS is a trigger for RAS dysregulation in AD. We characterized RAS gene expression in the frontal cortex from (i) a cohort of normal aging (n = 99, age range = 19-96 years) and (ii) a case-control cohort (n = 209) including AD (n = 66), mixed dementia (VaD + AD; n = 50), pure vascular dementia (VaD; n = 42), and age-matched controls (n = 51).

Drug-drug interactions that alter the exposure of glucuronidated drugs: Scope, UDP-glucuronosyltransferase (UGT) enzyme selectivity, mechanisms (inhibition and induction), and clinical significance.

Drug-drug interactions (DDIs) arising from the perturbation of drug metabolising enzyme activities represent both a clinical problem and a potential economic loss for the pharmaceutical industry. DDIs involving glucuronidated drugs have historically attracted little attention and there is a perception that interactions are of minor clinical relevance. This review critically examines the scope and aetiology of DDIs that result in altered exposure of glucuronidated drugs.

Elevated CSF angiopoietin-2 correlates with blood-brain barrier leakiness and markers of neuronal injury in early Alzheimer's disease.

Breakdown of the neurovascular unit in early Alzheimer's disease (AD) leads to leakiness of the blood-brain barrier (BBB), contributing to cognitive decline and disease pathology. Vascular stability depends on angiopoietin-1 (ANGPT1) signalling, antagonised by angiopoietin-2 (ANGPT2) upon endothelial injury. We have examined the relationship between CSF ANGPT2 and CSF markers of BBB leakiness and disease pathology, across three independent cohorts: (i) 31 AD patients and 33 healthy controls grouped according to their biomarker profile (i.

Elevated late-life blood pressure may maintain brain oxygenation and slow amyloid-β accumulation at the expense of cerebral vascular damage.

Hypertension in midlife contributes to cognitive decline and is a modifiable risk factor for dementia. The relationship between late-life hypertension and dementia is less clear. We have investigated the relationship of blood pressure and hypertensive status during late life (after 65 years) to post-mortem markers of Alzheimer's disease (amyloid-β and tau loads); arteriolosclerosis and cerebral amyloid angiopathy; and to biochemical measures of ante-mortem cerebral oxygenation (the myelin-associated glycoprotein:proteolipid protein-1 ratio, which is reduced in chronically hypoperfused brain tissue, and the level of vascular endothelial growth factor-A, which is upregulated by tissue hypoxia); blood-brain barrier damage (indicated by an increase in parenchymal fibrinogen); and pericyte content (platelet-derived growth factor receptor β, which declines with pericyte loss), in Alzheimer's disease ( = 75), vascular ( = 20) and mixed dementia ( = 31) cohorts.

Age-related reduction in brain ACE-2 is not exacerbated by Alzheimer's disease pathology in mouse models of Alzheimer's disease.

An imbalance in the circulatory and organ-specific renin-angiotensin system (RAS) pathways is associated with age-related dysfunction and disease including cardiovascular burden and more recently Alzheimer's disease (AD). It is currently unclear whether an age-associated imbalance in components of the RAS within the brain precedes the onset of AD or whether a RAS imbalance is associated with the onset of disease pathology and cognitive decline. Angiotensin-converting enzyme-1 (ACE-1) and -2 (ACE-2) protein (ELISA) and enzyme activity (FRET assay), markers of the classical and counter-regulatory RAS axis respectively, and Ang-II and Ang-(1-7) peptide levels (ELISA), were measured in the left cortex across four transgenic AD mouse models of amyloid pathology (5xFAD - 2, 6, and 12 months of age; Apd9 - 3-4, 12, and 18 months of age; Tg2576 - 3-4 and 24 months of age; and PDAPP - 3-4, 7, 11, 15, and 18 months of age) and littermate wild-type (WT) controls.

Understanding the Risk of Drug Interactions Between Ritonavir-Containing COVID-19 Therapies and Small-Molecule Kinase Inhibitors in Patients With Cancer.

Purpose: The introduction of COVID-19 therapies containing ritonavir has markedly expanded the scope of use for this medicine. As a strong cytochrome P450 3A4 inhibitor, the use of ritonavir is associated with a high drug interaction risk. There are currently no data to inform clinician regarding the likely magnitude and duration of interaction between ritonavir-containing COVID-19 therapies and small-molecule kinase inhibitors (KIs) in patients with cancer.

Dysregulation of ACE-1 in Normal Aging and the Early Stages of Alzheimer's Disease.

An imbalance in the renin-angiotensin system (RAS) is associated with cognitive decline and disease pathology in Alzheimer's disease (AD). In this study, we have investigated changes in the brain angiotensin-converting enzyme-1 (ACE-1) and angiotensin-II (Ang-II), and the counter-regulatory angiotensin-converting enzyme-2 (ACE-2), in the frontal and temporal cortex during normal aging and in the early stages of AD. We studied a cohort of normal aging (n = 121; 19-95 years age-at-death) from the Sudden Death Brain Bank, University of Edinburgh, United Kingdom, and AD and age-matched controls (n = 60) from the South West Dementia Brain Bank, University of Bristol, United Kingdom, stratified according to Braak tangle stage (BS): 0-II, III-IV (intermediate disease), and V-VI (end-stage disease).

Pathological changes within the cerebral vasculature in Alzheimer's disease: New perspectives.

Cerebrovascular disease underpins vascular dementia (VaD), but structural and functional changes to the cerebral vasculature contribute to disease pathology and cognitive decline in Alzheimer's disease (AD). In this review, we discuss the contribution of cerebral amyloid angiopathy and non-amyloid small vessel disease in AD, and the accompanying changes to the density, maintenance and remodelling of vessels (including alterations to the composition and function of the cerebrovascular basement membrane). We consider how abnormalities of the constituent cells of the neurovascular unit - particularly of endothelial cells and pericytes - and impairment of the blood-brain barrier (BBB) impact on the pathogenesis of AD.

Inhibitory effects of non-steroidal anti-inflammatory drugs on human liver microsomal morphine glucuronidation: Implications for drug-drug interaction liability.

The inhibitory effects of fifteen NSAIDs from six structurally distinct classes on human liver microsomal morphine glucuronidation were investigated. K values of selected NSAIDs were generated and employed to assess DDI liability in vivo. Potent inhibition was observed for mefenamic acid and tolfenamic acid; respective IC values for morphine 3- and 6-glucuronidation were 9.

Pericyte Contractile Responses to Endothelin-1 and Aβ Peptides: Assessment by Electrical Impedance Assay.

Pericytes are vascular mural cells that contract and relax in response to vasoactive stimuli to regulate neurovascular coupling and cerebral blood flow. Pericytes are damaged and degenerate in Alzheimer's disease (AD). We previously showed that the level of the regulatory vasoconstrictor, endothelin-1 (EDN1), is elevated in AD cerebral cortex and upregulated by amyloid-beta (Aβ).

Binding of SEP-363856 within TAAR1 and the 5HT receptor: implications for the design of novel antipsychotic drugs.

Current medications for schizophrenia typically modulate dopaminergic neurotransmission. While affecting positive symptoms, antipsychotic drugs have little clinical effect on negative symptoms and cognitive impairment. Moreover, newer 'atypical' antipsychotic drugs also have significant metabolic adverse-effects.

Enzyme Kinetics of Uridine Diphosphate Glucuronosyltransferases (UGTs).

Glucuronidation, catalyzed by uridine diphosphate glucuronosyltransferases (UGTs), is an important process for the metabolism and clearance of many lipophilic chemicals, including drugs, environmental chemicals, and endogenous compounds. Glucuronidation is a bisubstrate reaction that requires the aglycone and the cofactor, UDP-GlcUA. Accumulating evidence suggests that the bisubstrate reaction follows a compulsory-order ternary mechanism.

Effect of concomitant use of antihypertensives and immune check point inhibitors on cancer outcomes.

Objectives: Antihypertensives and cancer have a complex relationship. Among the antihypertensives, renin--angiotensin system inhibitors have strong immune modulatory activities that may affect immune check point inhibitors-related outcomes in cancer patients. We evaluated the association between concomitant use of renin--angiotensin system inhibitors and other antihypertensive agents with survival/toxicity outcomes from atezolizumab.

Proton Pump Inhibitors and Survival in Patients With Colorectal Cancer Receiving Fluoropyrimidine-Based Chemotherapy.

Background: Concomitant use of proton pump inhibitors (PPIs) may negatively affect the efficacy of anticancer drugs such as fluoropyrimidines in patients with colorectal cancer (CRC). The primary objective of this study was to assess whether there is an association between concomitant PPI use and survival outcomes in patients with CRC treated with a fluoropyrimidine-based chemotherapy.

Patients And Methods: A secondary analysis of 6 randomized controlled clinical trials in patients with advanced CRC was conducted using individual patient data through data-sharing platforms.

Systemic infection exacerbates cerebrovascular dysfunction in Alzheimer's disease.

We studied the effects of systemic infection on brain cytokine level and cerebral vascular function in Alzheimer's disease and vascular dementia, in superior temporal cortex (Brodmann area 22) from Alzheimer's disease patients (n = 75), vascular dementia patients (n = 22) and age-matched control subjects (n = 46), stratified according to the presence or absence of terminal systemic infection. Brain cytokine levels were measured using Mesoscale Discovery Multiplex Assays and markers of cerebrovascular function were assessed by ELISA. Multiple brain cytokines were elevated in Alzheimer's disease and vascular dementia: IL-15 and IL-17A were maximally elevated in end-stage Alzheimer's disease (Braak tangle stage V-VI) whereas IL-2, IL-5, IL12p40 and IL-16 were highest in intermediate Braak tangle stage III-IV disease.

Mediators of cerebral hypoperfusion and blood-brain barrier leakiness in Alzheimer's disease, vascular dementia and mixed dementia.

In vascular dementia (VaD) and Alzheimer's disease (AD), cerebral hypoperfusion and blood-brain barrier (BBB) leakiness contribute to brain damage. In this study, we have measured biochemical markers and mediators of cerebral hypoperfusion and BBB in the frontal (BA6) and parietal (BA7) cortex and underlying white matter, to investigate the pathophysiology of vascular dysfunction in AD, VaD and mixed dementia. The ratio of myelin-associated glycoprotein to proteolipid protein-1 (MAG:PLP1), a post-mortem biochemical indicator of the adequacy of ante-mortem cerebral perfusion; the concentration of fibrinogen adjusted for haemoglobin level, a marker of blood-brain barrier (BBB) leakiness; the level of vascular endothelial growth factor-A (VEGF), a marker of tissue hypoxia; and endothelin-1 (EDN1), a potent vasoconstrictor, were measured by ELISA in the frontal and parietal cortex and underlying white matter in 94 AD, 20 VaD, 33 mixed dementia cases and 58 age-matched controls.

Application of Model Informed Precision Dosing to Address the Impact of Pregnancy Stage and CYP2D6 Phenotype on Foetal Morphine Exposure.

Guidance regarding the effect of codeine and its metabolites on foetal development is limited by small studies and inconsistent findings. The primary objective was to use physiologically based pharmacokinetic modelling to investigate the impact of gestational stage and maternal CYP2D6 phenotype on foetal morphine exposure following codeine administration. Full body physiologically based pharmacokinetic models were developed and verified for codeine and morphine using Simcyp (version 19.

Arginine-259 of UGT2B7 Confers UDP-Sugar Selectivity.

Enzymes of the human UDP-glycosyltransferase (UGT) superfamily typically catalyze the covalent addition of the sugar moiety from a UDP-sugar cofactor to relatively low-molecular weight lipophilic compounds. Although UDP-glucuronic acid (UDP-GlcUA) is most commonly employed as the cofactor by UGT1 and UGT2 family enzymes, UGT2B7 and several other enzymes can use both UDP-GlcUA and UDP-glucose (UDP-Glc), leading to the formation of glucuronide and glucoside conjugates. An investigation of UGT2B7-catalyzed morphine glycosidation indicated that glucuronidation is the principal route of metabolism because the binding affinity of UDP-GlcUA is higher than that of UDP-Glc.

Correction to: ACE2 activation protects against cognitive decline and reduces amyloid pathology in the Tg2576 mouse model of Alzheimer's disease.

Unfortunately, the acknowledgement section was not included in the original publication.

Evidence-based strategies for the characterisation of human drug and chemical glucuronidation in vitro and UDP-glucuronosyltransferase reaction phenotyping.

Enzymes of the UDP-glucuronosyltransferase (UGT) superfamily contribute to the elimination of drugs from almost all therapeutic classes. Awareness of the importance of glucuronidation as a drug clearance mechanism along with increased knowledge of the enzymology of drug and chemical metabolism has stimulated interest in the development and application of approaches for the characterisation of human drug glucuronidation in vitro, in particular reaction phenotyping (the fractional contribution of the individual UGT enzymes responsible for the glucuronidation of a given drug), assessment of metabolic stability, and UGT enzyme inhibition by drugs and other xenobiotics. In turn, this has permitted the implementation of in vitro - in vivo extrapolation approaches for the prediction of drug metabolic clearance, intestinal availability, and drug-drug interaction liability, all of which are of considerable importance in pre-clinical drug development.