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Frontiers in Endocrinology 2023X-linked adrenoleukodystrophy (X-ALD; OMIM:300100) is a progressive neurodegenerative disorder caused by a congenital defect in the ATP-binding cassette transporters... (Review)
Review
X-linked adrenoleukodystrophy (X-ALD; OMIM:300100) is a progressive neurodegenerative disorder caused by a congenital defect in the ATP-binding cassette transporters sub-family D member 1 gene (ABCD1) producing adrenoleukodystrophy protein (ALDP). According to population studies, X-ALD has an estimated birth prevalence of 1 in 17.000 subjects (considering both hemizygous males and heterozygous females), and there is no evidence that this prevalence varies among regions or ethnic groups. ALDP deficiency results in a defective peroxisomal β-oxidation of very long chain fatty acids (VLCFA). As a consequence of this metabolic abnormality, VLCFAs accumulate in nervous system (brain white matter and spinal cord), testis and adrenal cortex. All X-ALD affected patients carry a mutation on the ABCD1 gene. Nevertheless, patients with a defect on the ABCD1 gene can have a dramatic difference in the clinical presentation of the disease. In fact, X-ALD can vary from the most severe cerebral paediatric form (CerALD), to adult adrenomyeloneuropathy (AMN), Addison-only and asymptomatic forms. Primary adrenal insufficiency (PAI) is one of the main features of X-ALD, with a prevalence of 70% in ALD/AMN patients and 5% in female carriers. The pathogenesis of X-ALD related PAI is still unclear, even if a few published data suggests a defective adrenal response to ACTH, related to VLCFA accumulation with progressive disruption of adrenal cell membrane function and ACTH receptor activity. The reason why PAI develops only in a proportion of ALD/AMN patients remains incompletely understood. A growing consensus supports VLCFA assessment in all male children presenting with PAI, as early diagnosis and start of therapy may be essential for X-ALD patients. Children and adults with PAI require individualized glucocorticoid replacement therapy, while mineralocorticoid therapy is needed only in a few cases after consideration of hormonal and electrolytes status. Novel approaches, such as prolonged release glucocorticoids, offer potential benefit in optimizing hormonal replacement for X-ALD-related PAI. Although the association between PAI and X-ALD has been observed in clinical practice, the underlying mechanisms remain poorly understood. This paper aims to explore the multifaceted relationship between PAI and X-ALD, shedding light on shared pathophysiology, clinical manifestations, and potential therapeutic interventions.
Topics: Adult; Humans; Male; Female; Child; Adrenoleukodystrophy; ATP-Binding Cassette Transporters; Addison Disease; Fatty Acids; Adrenal Cortex; Glucocorticoids
PubMed: 38034003
DOI: 10.3389/fendo.2023.1309053 -
Cardiovascular Research Oct 2023Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction, microvascular dysfunction, and myocardial fibrosis with recent evidence...
AIMS
Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction, microvascular dysfunction, and myocardial fibrosis with recent evidence implicating the immune system in orchestrating cardiac remodelling.
METHODS AND RESULTS
Here, we show the mouse model of deoxycorticosterone acetate (DOCA)-salt hypertension induces key elements of HFpEF, including diastolic dysfunction, exercise intolerance, and pulmonary congestion in the setting of preserved ejection fraction. A modified single-cell sequencing approach, cellular indexing of transcriptomes and epitopes by sequencing, of cardiac immune cells reveals an altered abundance and transcriptional signature in multiple cell types, most notably cardiac macrophages. The DOCA-salt model results in differential expression of several known and novel genes in cardiac macrophages, including up-regulation of Trem2, which has been recently implicated in obesity and atherosclerosis. The role of Trem2 in hypertensive heart failure, however, is unknown. We found that mice with genetic deletion of Trem2 exhibit increased cardiac hypertrophy, diastolic dysfunction, renal injury, and decreased cardiac capillary density after DOCA-salt treatment compared to wild-type controls. Moreover, Trem2-deficient macrophages have impaired expression of pro-angiogenic gene programmes and increased expression of pro-inflammatory cytokines. Furthermore, we found that plasma levels of soluble TREM2 are elevated in DOCA-salt treated mice and humans with heart failure.
CONCLUSIONS
Together, our data provide an atlas of immunological alterations that can lead to improved diagnostic and therapeutic strategies for HFpEF. We provide our dataset in an easy to explore and freely accessible web application making it a useful resource for the community. Finally, our results suggest a novel cardioprotective role for Trem2 in hypertensive heart failure.
Topics: Humans; Mice; Animals; Heart Failure; Desoxycorticosterone Acetate; Stroke Volume; Hypertension; Cardiomyopathies; Myeloid Cells; Leukocytes; Membrane Glycoproteins; Receptors, Immunologic
PubMed: 37314125
DOI: 10.1093/cvr/cvad093 -
Endocrinology Sep 2023Stress induces changes in nervous system function on different signaling levels, from molecular signaling to synaptic transmission to neural circuits to behavior-and on... (Review)
Review
Stress induces changes in nervous system function on different signaling levels, from molecular signaling to synaptic transmission to neural circuits to behavior-and on different time scales, from rapid onset and transient to delayed and long-lasting. The principal effectors of stress plasticity are glucocorticoids, steroid hormones that act with a broad range of signaling competency due to the expression of multiple nuclear and membrane receptor subtypes in virtually every tissue of the organism. Glucocorticoid and mineralocorticoid receptors are localized to each of the cellular compartments of the receptor-expressing cells-the membrane, cytosol, and nucleus. In this review, we cover the neuroendocrine effects of stress, focusing mainly on the rapid actions of acute stress-induced glucocorticoids that effect changes in synaptic transmission and neuronal excitability by modulating synaptic and intrinsic neuronal properties via activation of presumed membrane glucocorticoid and mineralocorticoid receptors. We describe the synaptic plasticity that occurs in 4 stress-associated brain structures, the hypothalamus, hippocampus, amygdala, and prefrontal cortex, in response to single or short-term stress exposure. The rapid transformative impact of glucocorticoids makes this stress signal a particularly potent effector of acute neuronal plasticity.
Topics: Glucocorticoids; Receptors, Mineralocorticoid; Neuronal Plasticity; Brain; Synaptic Transmission; Receptors, Glucocorticoid; Stress, Psychological
PubMed: 37788632
DOI: 10.1210/endocr/bqad149 -
Blood Oct 2023Historically, the majority of patients with complement-mediated atypical hemolytic uremic syndrome (CaHUS) progress to end-stage kidney disease (ESKD). Single-arm trials... (Observational Study)
Observational Study
Historically, the majority of patients with complement-mediated atypical hemolytic uremic syndrome (CaHUS) progress to end-stage kidney disease (ESKD). Single-arm trials of eculizumab with a short follow-up suggested efficacy. We prove, for the first time to our knowledge, in a genotype matched CaHUS cohort that the 5-year cumulative estimate of ESKD-free survival improved from 39.5% in a control cohort to 85.5% in the eculizumab-treated cohort (hazard ratio, 4.95; 95% confidence interval [CI], 2.75-8.90; P = .000; number needed to treat, 2.17 [95% CI, 1.81-2.73]). The outcome of eculizumab treatment is associated with the underlying genotype. Lower serum creatinine, lower platelet count, lower blood pressure, and younger age at presentation as well as shorter time between presentation and the first dose of eculizumab were associated with estimated glomerular filtration rate >60 ml/min at 6 months in multivariate analysis. The rate of meningococcal infection in the treated cohort was 550 times greater than the background rate in the general population. The relapse rate upon eculizumab withdrawal was 1 per 9.5 person years for patients with a pathogenic mutation and 1 per 10.8 person years for those with a variant of uncertain significance. No relapses were recorded in 67.3 person years off eculizumab in those with no rare genetic variants. Eculizumab was restarted in 6 individuals with functioning kidneys in whom it had been stopped, with no individual progressing to ESKD. We demonstrated that biallelic pathogenic mutations in RNA-processing genes, including EXOSC3, encoding an essential part of the RNA exosome, cause eculizumab nonresponsive aHUS. Recessive HSD11B2 mutations causing apparent mineralocorticoid excess may also present with thrombotic microangiopathy.
Topics: Humans; Child, Preschool; Atypical Hemolytic Uremic Syndrome; Platelet Count; Complement System Proteins; Thrombotic Microangiopathies; Cohort Studies; Kidney Failure, Chronic
PubMed: 37369098
DOI: 10.1182/blood.2022018833 -
Frontiers in Medicine 2023Diabetic kidney disease (DKD) is a complication of diabetes that can lead to kidney failure. Over the years, several drugs have been developed to combat this disease. In... (Review)
Review
Diabetic kidney disease (DKD) is a complication of diabetes that can lead to kidney failure. Over the years, several drugs have been developed to combat this disease. In the early 90s, angiotensin blockade (ACEi and ARBs) was introduced, which revolutionized the treatment of DKD. In recent years, newer drugs such as sodium-glucose co-transporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, endothelin antagonists, and mineralocorticoid receptor antagonists (MRA) have shown great promise in reducing albuminuria and protecting the kidneys. These drugs are being used in combination with lifestyle modifications, patient education, and risk factor modification to effectively manage DKD. In this review, we will explore the latest pharmacological options, their efficacy, and their potential to revolutionize the management of this debilitating disease.
PubMed: 38105902
DOI: 10.3389/fmed.2023.1264497 -
Clinical Pharmacokinetics Dec 2023Finerenone, a selective and nonsteroidal antagonist of the mineralocorticoid receptor, has received regulatory approval with the indication of cardiorenal protection in... (Review)
Review
Finerenone, a selective and nonsteroidal antagonist of the mineralocorticoid receptor, has received regulatory approval with the indication of cardiorenal protection in patients with chronic kidney disease associated with type 2 diabetes. It is rapidly and completely absorbed and undergoes first-pass metabolism in the gut wall and liver resulting in a bioavailability of 43.5%. Finerenone can be taken with or without food. The pharmacokinetics of finerenone are linear and its half-life is 2 to 3 h in the dose range of up to 20 mg. Cytochrome P450 (CYP) 3A4 (90%) and CYP2C8 (10%) are involved in the extensive biotransformation of finerenone to pharmacologically inactive metabolites, which are excreted via both renal (80%) and biliary (20%) routes. Moderate or severe renal impairment, or moderate hepatic impairment result in area-under-the-curve increases of finerenone (< 40%), which do not require a dose adjustment per se, as the starting dose is based on estimated glomerular filtration rate (eGFR) and titrated according to serum potassium levels and eGFR decline. No relevant effects of age, sex, body size or ethnicity on systemic finerenone exposure were identified. Modulators of CYP3A4 activity were found to affect finerenone exposure, consistent with its classification as a sensitive CYP3A4 substrate. Serum potassium should be monitored during drug initiation or dosage adjustment of either a moderate or weak CYP3A4 inhibitor or finerenone, and the dose of finerenone should be adjusted as appropriate. Its use with strong inhibitors is contraindicated and strong or moderate inducers of CYP3A4 should be avoided. Finerenone has no potential to affect relevant CYP enzymes and drug transporters.
Topics: Humans; Cytochrome P-450 CYP3A; Mineralocorticoid Receptor Antagonists; Diabetes Mellitus, Type 2; Potassium; Renal Insufficiency, Chronic
PubMed: 37875671
DOI: 10.1007/s40262-023-01312-9