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The Journal of Steroid Biochemistry and... Sep 2024The mineralocorticoid receptor (MR/NR3C2) is a member of the family of steroid receptors (SR) which also includes the estrogen receptor (ER), progesterone receptor (PR),... (Review)
Review
The mineralocorticoid receptor (MR/NR3C2) is a member of the family of steroid receptors (SR) which also includes the estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR) and glucocorticoid receptor (GR). They function primarily as nuclear receptors to regulate gene expression. While the other steroid hormone receptors are known to play important roles in the pathogenesis and progression of many cancers, relatively little is understood about the role of MR in cancer biology. This review focuses on examining new insights into the potential roles and mechanisms of action of MR in cancers.
Topics: Humans; Receptors, Mineralocorticoid; Neoplasms; Animals; Gene Expression Regulation, Neoplastic
PubMed: 38714226
DOI: 10.1016/j.jsbmb.2024.106541 -
JACC. Heart Failure Apr 2024Three medications are now guideline-recommended treatments for heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF), however, the...
BACKGROUND
Three medications are now guideline-recommended treatments for heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF), however, the cost-effectiveness of these agents in combination has yet to be established.
OBJECTIVES
The purpose of this study was to determine the cost-effectiveness of mineralocorticoid receptor antagonists (MRA), angiotensin receptor-neprilysin inhibitors (ARNIs), and sodium glucose co-transporter 2 inhibitors (SGLT2is) in individuals with HFmrEF/HFpEF.
METHODS
Using a 3-state Markov model, we performed a cost-effectiveness study using simulated cohorts of 1,000 patients with HFmrEF and HFpEF. Treatment with 1-, 2-, and 3-drug combinations was modeled. Based on a United States health care sector perspective, outcome data was used to calculate incremental cost-effectiveness ratios (ICERs) in 2023 United States dollars based on a 30-year time horizon.
RESULTS
Treatment with MRA, MRA+SGLT2i, and MRA+SGLT2i+ARNI therapy resulted in an increase in life years of 1.04, 1.58, and 1.80 in the HFmrEF subgroup, respectively, and 0.99, 1.54, and 1.77 in the HFpEF subgroup, respectively, compared with placebo. At a yearly cost of $18, MRA therapy resulted in ICERs of $10,000 per quality-adjusted life year (QALY) in both subgroups. The ICER for the addition of SGLT2i therapy ($4,962 per year) was $113,000 per QALY in the HFmrEF subgroup and $141,000 in the HFpEF subgroup. The addition of ARNI therapy ($5,504 per year) resulted in ICERs >$250,000 per QALY in both subgroups. If SGLT2i and ARNI were available at generic pricing the ICERs become <$10,000 per QALY in both EF subgroups. Outcomes were highly sensitive to assumed benefit in cardiovascular death.
CONCLUSIONS
For patients with heart failure, MRA was of high value, SGLT2i was of intermediate value, and ARNI was of low value in both HFmrEF and HFpEF subgroups. For patients with HFmrEF/HFpEF increased use of MRA and SGLT2i therapies should be encouraged and be accompanied with efforts to lower the cost of SGLT2i and ARNI therapies.
PubMed: 38703159
DOI: 10.1016/j.jchf.2024.03.006 -
Journal of Veterinary Internal Medicine May 2024This report describes the diagnosis and treatment of aldosterone resistance (AR) and acquired hyperkalemic type IV renal tubular acidosis (RTA) in 2 cats comparable to...
This report describes the diagnosis and treatment of aldosterone resistance (AR) and acquired hyperkalemic type IV renal tubular acidosis (RTA) in 2 cats comparable to acquired pseudohypoaldosteronism in people. One cat developed AR from chronic kidney disease after an acute kidney injury and was treated with furosemide per os, which resolved the hyperkalemic RTA. The second cat developed transient AR secondary to a bacterial urinary tract infection associated with urethral catheterization, and treatment with antibiotics resolved the hyperkalemic RTA.
PubMed: 38695414
DOI: 10.1111/jvim.17098 -
International Journal of Heart Failure Apr 2024Heart failure with mid-range ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF) represent over half of heart failure cases but lack proven effective... (Review)
Review
Heart failure with mid-range ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF) represent over half of heart failure cases but lack proven effective therapies beyond sodium-glucose cotransporter 2 inhibitor and diuretics. HFmrEF and HFpEF are heterogeneous conditions requiring precision phenotyping to enable tailored therapies. This review covers concepts on precision medicine approaches for HFmrEF and HFpEF. Areas discussed include HFmrEF mechanisms, anti-inflammatory and antifibrotic treatments for obesity-related HFpEF, If inhibition for HFpEF with atrial fibrillation, and mineralocorticoid receptor antagonism for chronic kidney disease-HFpEF. Incorporating precision phenotyping and matched interventions in HFmrEF and HFpEF trials will further advance therapy compared to blanket approaches.
PubMed: 38694928
DOI: 10.36628/ijhf.2023.0058 -
Scientific Reports May 2024Inflammation and fibrosis often occur in the kidney after acute injury, resulting in chronic kidney disease and consequent renal failure. Recent studies have indicated...
Inflammation and fibrosis often occur in the kidney after acute injury, resulting in chronic kidney disease and consequent renal failure. Recent studies have indicated that lymphangiogenesis can drive renal inflammation and fibrosis in injured kidneys. However, whether and how this pathogenesis affects the contralateral kidney remain largely unknown. In our study, we uncovered a mechanism by which the contralateral kidney responded to injury. We found that the activation of mineralocorticoid receptors and the increase in vascular endothelial growth factor C in the contralateral kidney after unilateral ureteral obstruction could promote lymphangiogenesis. Furthermore, mineralocorticoid receptor activation in lymphatic endothelial cells resulted in the secretion of myofibroblast markers, thereby contributing to renal fibrosis. We observed that this process could be attenuated by administering the mineralocorticoid receptor blocker eplerenone, which, prevented the development of fibrotic injury in the contralateral kidneys of rats with unilateral ureteral obstruction. These findings offer valuable insights into the intricate mechanisms underlying kidney injury and may have implications for the development of therapeutic strategies to mitigate renal fibrosis in the context of kidney disease.
Topics: Animals; Eplerenone; Lymphangiogenesis; Rats; Fibrosis; Kidney; Ureteral Obstruction; Mineralocorticoid Receptor Antagonists; Male; Receptors, Mineralocorticoid; Spironolactone; Vascular Endothelial Growth Factor C; Disease Models, Animal; Endothelial Cells; Rats, Sprague-Dawley; Myofibroblasts
PubMed: 38693148
DOI: 10.1038/s41598-024-60636-z -
Cureus Apr 2024Pseudohypoaldosteronism type 1 is a rare genetic disorder characterized by salt wasting and resistance to mineralocorticoids due to mutations in the gene which codes...
Pseudohypoaldosteronism type 1 is a rare genetic disorder characterized by salt wasting and resistance to mineralocorticoids due to mutations in the gene which codes for the aldosterone receptor proteins in the kidneys. This case study involves an infant who presented with poor growth and significant hyponatremia. There was improvement in growth and correction of hyponatremia with sodium supplementation, later found to carry a new genetic variant causing autosomal dominant pseudohypoaldosteronism type 1. A 14-day-old newborn presented with failure to thrive, severe hyponatremia, mild hyperkalemia, and metabolic acidosis. The electrolyte abnormalities were corrected with intravenous fluid and sodium supplementation. Continued oral sodium supplementation led to improved weight gain. Clinical suspicion and subsequent diagnostic testing led to a diagnosis of the autosomal dominant renal form of pseudohypoaldosteronism type 1. Genetic testing revealed a novel mutation on the gene, c.556_557del (p.Met186Valfs*3). The baby was discharged home on supplemental sodium and high-calorie formula for catch-up growth. Outpatient follow-up is ongoing.
PubMed: 38689677
DOI: 10.7759/cureus.59356 -
Toxicology and Applied Pharmacology May 2024Cytochrome P450 enzymes (CYPs) play a crucial role in the metabolism and synthesis of various compound classes. While drug-metabolizing CYP enzymes are frequently...
Cytochrome P450 enzymes (CYPs) play a crucial role in the metabolism and synthesis of various compound classes. While drug-metabolizing CYP enzymes are frequently investigated as anti-targets, the inhibition of CYP enzymes involved in adrenal steroidogenesis is not well studied. The steroidogenic enzyme CYP17A1 is a dual-function enzyme catalyzing hydroxylase and lyase reactions relevant for the biosynthesis of adrenal glucocorticoids and androgens. Inhibition of CYP17A1-hydroxylase leads to pseudohyperaldosteronism with subsequent excessive mineralocorticoid receptor activation, hypertension and hypokalemia. In contrast, specific inhibition of the lyase function might be beneficial for the treatment of prostate cancer by decreasing adrenal androgen levels. This study combined in silico and in vitro methods to identify drugs inhibiting CYP17A1. The most potent CYP17A1 inhibitors identified are serdemetan, mocetinostat, nolatrexed, liarozole, and talarozole. While some of these drugs are currently under investigation for the treatment of various cancers, their potential for the treatment of prostate cancer is yet to be explored. The DrugBank database was screened for CYP17A1 inhibitors, to increase the awareness for the risk of drug-induced pseudohyperaldosteronism and to highlight drugs so far unknown for their potential to cause side effects resulting from CYP17A1 inhibition.
Topics: Steroid 17-alpha-Hydroxylase; Humans; Computer Simulation; Male; Molecular Docking Simulation
PubMed: 38688424
DOI: 10.1016/j.taap.2024.116945 -
Journal of the American Heart... May 2024Among those with heart failure (HF), women are more likely to develop depression than men. Few studies have focused on the outcomes of female patients with HF with...
Prognostic Value of Depressive Symptoms for Cardiovascular Events in Female Patients With Heart Failure With Reduced Ejection Fraction and Heart Failure With Preserved Ejection Fraction.
BACKGROUND
Among those with heart failure (HF), women are more likely to develop depression than men. Few studies have focused on the outcomes of female patients with HF with depressive symptoms.
METHODS AND RESULTS
A total of 506 female patients with HF with preserved ejection fraction were included in this secondary analysis from the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) cohort, and 439 female patients with HF with reduced ejection fraction were included from the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) cohort. Depressive symptoms were measured using the Patient Health Questionnaire-9 and Beck Depression Inventory-II. The depression class was categorized by severity, and the change in clinical depression class was defined as aggravated (1-grade increase) or improved (1-grade decrease). The prognostic value of depressive symptoms was determined by using multivariable Cox proportional hazards models. Female patients with improved depressive symptoms had worse depressive status at baseline and lower baseline Kansas City Cardiomyopathy Questionnaire scores. Depression class at the 12-month visit and depression class change were the dominant prognostic factors for cardiovascular death in female patients with HF with preserved ejection fraction (hazard ratio [HR], 1.43 [95% CI, 1.02-2.01], =0.036; HR, 1.71 [95% CI, 1.14-2.55], =0.009). Among the patients with HF with reduced ejection fraction, both the depression class at baseline and depression class change had significant prognostic effects on cardiovascular death (HR, 3.30 [95% CI, 1.70-6.39], <0.001; HR, 2.21 [95% CI, 1.28-3.80], =0.004). However, the prognostic value of depressive assessments for hospitalization in patients with HF is unclear.
CONCLUSIONS
In female patients with HF with reduced ejection fraction, the depression class at baseline was most strongly associated with cardiovascular death, whereas in female patients with HF with preserved ejection fraction, the change in depression class exhibited a more significant prognostic trend.
Topics: Humans; Female; Heart Failure; Stroke Volume; Depression; Aged; Middle Aged; Prognosis; Ventricular Function, Left; Risk Factors; Sex Factors; Mineralocorticoid Receptor Antagonists; Proportional Hazards Models; Time Factors
PubMed: 38686893
DOI: 10.1161/JAHA.123.032961 -
Pharmaceuticals (Basel, Switzerland) Mar 2024Diabetic kidney disease is a frequent microvascular complication of diabetes and is currently the leading cause of chronic kidney disease and end-stage kidney disease... (Review)
Review
Diabetic kidney disease is a frequent microvascular complication of diabetes and is currently the leading cause of chronic kidney disease and end-stage kidney disease worldwide. Although the prevalence of other complications of diabetes is falling, the number of diabetic patients with end-stage kidney disease in need of kidney replacement therapy is rising. In addition, these patients have extremely high cardiovascular risk. It is more than evident that there is a high unmet treatment need in patients with diabetic kidney disease. Finerenone is a novel nonsteroidal mineralocorticoid receptor antagonist used for treating diabetic kidney disease. It has predominant anti-fibrotic and anti-inflammatory effects and exhibits several renal and cardiac protective effects. This review article summarizes the current knowledge and future prospects of finerenone in treating patients with kidney disease.
PubMed: 38675379
DOI: 10.3390/ph17040418 -
Toxics Mar 2024The safety of drinking water is a significant environmental issue of great concern for human health since numerous contaminants are often detected in drinking water and...
An Integrated Approach of Bioassays and Non-Target Screening for the Assessment of Endocrine-Disrupting Activities in Tap Water and Identification of Novel Endocrine-Disrupting Chemicals.
The safety of drinking water is a significant environmental issue of great concern for human health since numerous contaminants are often detected in drinking water and its sources. Boiling is a common household method used to produce relatively high-quality drinking water in some countries and regions. In this study, with the aid of an integrated approach of in vitro bioassays and non-target analysis based on high-resolution mass spectrometry coupled with liquid chromatography, alterations in endocrine-disrupting activities in tap water samples without and with boiling were revealed, as well as the potential endocrine-disrupting chemicals (EDCs) contributing to these alterations were identified. The organic extracts of tap water had no significant (ant)agonistic activities against an estrogen receptor (ER), progesterone receptor (PR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR) at enrichment concentrations of ≤10 times, posing no immediate or acute health risk to humans. However, the presence of agonistic activities against PR and MR and antagonistic activities against ER, PR, GR, and MR in OEs of tap water at relatively higher enrichment concentrations still raise potential health concerns. Boiling effectively reduced antagonistic activities against these steroid hormone receptors (SHRs) but increased estrogenic and glucocorticoid activities in drinking water. Four novel potential EDCs, including one UV filter (phenylbenzimidazole sulfonic acid, PBSA) and three natural metabolites of organisms (beta-hydroxymyristic acid, 12-hydroxyoctadecanoic acid, and isorosmanol) were identified in drinking water samples, each of which showed (ant)agonistic activities against different SHRs. Given the widespread use of UV filters in sunscreens to prevent skin cancer, the health risks posed by PBSA as an identified novel EDC are of concern. Although boiling has been thought to reduce the health risk of drinking water contamination, our findings suggest that boiling may have a more complex effect on the endocrine-disrupting activities of drinking water and, therefore, a more comprehensive assessment is needed.
PubMed: 38668470
DOI: 10.3390/toxics12040247