Search Results (122)

The therapeutic landscape for heart failure (HF), particularly in patients with mildly reduced (HFmrEF) and preserved ejection fraction (HFpEF), has historically been characterized by limited effective disease-modifying options. The recent approval of nonsteroidal mineralocorticoid receptor antagonists (nsMRAs), specifically finerenone, represents a major paradigm shift. This review synthesizes contemporary evidence, including the landmark FINEARTS-HF trial, which demonstrated significant reductions in cardiovascular death and heart failure hospitalizations in patients with left ventricular ejection fraction (LVEF) ≥ 40%. These findings contrast with the neutral overall results and subgroup limitations observed with steroidal MRAs such as spironolactone in the TOPCAT trial. Mechanistic distinctions, cardiorenal benefits, and emerging metabolic effects of finerenone are explored alongside its complementary role with sodium–glucose cotransporter-2 (SGLT2) inhibitors. Practical considerations for implementation, including patient selection, dosing, monitoring, and combination therapy strategies, are discussed. Overall, nsMRAs establish a new foundation for the management of HFmrEF and HFpEF and represent a critical advancement in contemporary heart failure therapeutics. Full article

Myocardial fibrosis is a common pathological feature of multiple cardiovascular diseases, including heart failure, hypertension, and myocardial infarction, and is associated with poor prognosis. Despite extensive research, clinically validated molecular biomarkers for early diagnosis and reliable therapeutic targets for myocardial fibrosis remain limited. Post-translational modifications (PTMs), including phosphorylation, acetylation, ubiquitination, SUMOylation, and glycosylation, are critical regulators of fibrosis-related signaling pathways, yet a systematic bioinformatics-driven identification of PTM-related hub genes has not been performed. Three publicly available GEO datasets (GSE57345, GSE133054, GSE76314) comprising cardiac tissue from heart failure and control patients were integrated. Differentially expressed genes (DEGs) were identified using the limma package, then intersected with a curated PTM gene set derived from PhosphoSitePlus and UniProt databases. Weighted gene co-expression network analysis (WGCNA) identified fibrosis-associated modules, and protein–protein interaction (PPI) network analysis via STRING and CytoHubba pinpointed hub genes. Diagnostic performance was assessed by receiver operating characteristic (ROC) analysis across independent validation cohorts. Immune cell infiltration was estimated using CIBERSORT.Molecular docking with AutoDock Vina (version 1.2.3) was performed to evaluate binding affinity of FDA-approved cardiovascular drugs against identified hub protein targets. A total of 863 DEGs were identified in the training cohort (|log₂FC| > 1.0, adjusted p < 0.05), of which 138 overlapped with the PTM gene set. WGCNA revealed a turquoise module (r = 0.79, p < 0.001) most significantly correlated with fibrosis severity. PPI analysis identified five hub genes: SIRT3, SMAD3, NEDD4L, UBC9, and CAMK2D. ROC analysis demonstrated strong diagnostic performance (AUC range: 0.82–0.92) validated in independent cohorts. Hub genes showed significant correlations with M2 macrophage infiltration. Molecular docking identified spironolactone and finerenone as top-ranked ligands with binding energies of −8.7 and −8.4 kcal/mol against SMAD3 and SIRT3, respectively. This study, which is entirely in silico and based on publicly available transcriptomic datasets, systematically identifies five PTM-related hub genes as candidate diagnostic biomarkers and prioritised drug-repurposing targets in myocardial fibrosis. These findings are hypothesis-generating and require experimental validation (protein-level confirmation, cell- and animal-based functional assays, and biophysical binding studies) before any diagnostic or therapeutic claim can be made. Full article

Mineralocorticoid receptor antagonists (MRAs) are the cornerstone of the management of heart failure and chronic kidney disease. A well-known adverse event, hyperkalemia, is associated with fatal arrhythmia and discontinuation of MRA. Our narrative review discusses the personalized treatment of MRAs, focusing on the pharmacological profile and drug–drug interactions to address safety concerns related to hyperkalemia. Clinicians should scrupulously monitor potassium levels, especially during dose titration, and review each patient’s medication list. Cytochrome P450 3A4 (CYP3A4) inhibitors are pharmacokinetic precipitators that interact with most MRAs, except spironolactone, and adversely affect the risk of hyperkalemia, although suggestive evidence is scarce. Potassium-elevating drugs synergistically increase serum potassium levels when co-administered with an MRA (e.g., renin-angiotensin aldosterone inhibitors, co-trimoxazole, non-steroidal anti-inflammatory drugs, calcineurin inhibitors, and β blockers). Additional approaches include correction of metabolic acidosis using sodium bicarbonate, potassium-lowering therapy using loop and thiazide diuretics, and sodium-glucose cotransporter 2 inhibitors. Novel potassium binders enable patients to receive the maximum-tolerated MRA with fewer gastrointestinal side effects. Individualized interventions for hyperkalemia risk are important in treatment using MRA. Full article

Background/Objectives: Diuretics are recommended for hemodynamically stable patients with COVID-19-associated acute respiratory distress syndrome (ARDS) who have a positive fluid balance. However, furosemide use may be limited by hypokalemia in this population. We aimed to evaluate the clinical and biochemical effects of spironolactone in critically ill patients with COVID-19-associated ARDS. Methods: In this retrospective cohort study, 60 patients with COVID-19-associated ARDS admitted to the intensive care unit (ICU) between March and May 2020 were grouped according to diuretic therapy (furosemide vs. spironolactone). Patients were followed for five days (T0–T4). Demographic characteristics and clinical/laboratory parameters were recorded. A two-sided p value < 0.05 was considered statistically significant. Results: Thirty-one patients received furosemide (F group) and 29 received spironolactone (S group). On day 5, in the F group, cumulative fluid balance and serum sodium increased significantly over time (p < 0.05). Lactate increased significantly over time in both groups (p < 0.05). N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels increased significantly from T0 to T4 in the F group (p < 0.05). Conclusions: Spironolactone use was associated with a more favorable trajectory of organ dysfunction and improved volume, electrolyte, and cardiac stress marker dynamics compared with furosemide in patients with COVID-19-associated ARDS. Although confirmation in larger prospective studies is needed, spironolactone may be considered a reasonable diuretic alternative in selected patients, particularly when potassium preservation and avoidance of hypernatremia are clinical priorities. Full article

Background/Objectives: For patients diagnosed with chronic kidney disease (CKD), it is important to follow guidelines addressing dose-adjustments for renally eliminated drugs to avoid complications related to toxicity and subtherapeutic effects. In Saudi Arabia, limited data are available regarding appropriate medication doses for CKD. In this study, we investigated the prevalence of inappropriately administered drugs in patients with CKD and examined factors associated with unadjusted renal dosing. Methods: A retrospective, cross-sectional, observational analysis (2023–2025) was conducted via a systematic electronic medical record review of hospitalized patients diagnosed with CKD and cardiovascular diseases (CVDs) in the Al-Baha region, Saudi Arabia. Medications were selected and evaluated for appropriate dosing based on creatinine clearance (CrCl). Medications were categorized as appropriately adjusted, inappropriately adjusted, unadjusted, or contraindicated. Results: A total of 440 patients (787 prescriptions) were included. At the patient level, 85% had at least one appropriately adjusted medication, 13% had at least one inappropriately adjusted medication, 30% had at least one medication that was not adjusted despite indication, 34% had at least one medication requiring no adjustment, and 17% had at least one contraindicated medication (categories are not mutually exclusive). At the prescription level, which was the primary analytic unit (N = 787), 48% of prescriptions were appropriately adjusted, 7% were inappropriately adjusted, 17% were not adjusted despite indication, 19% required no adjustment, and 10% were contraindicated. Antibiotics accounted for the largest share of inappropriate adjustments, representing 77% (43/56) of all inappropriate dose-adjustment events. In exploratory bivariate analyses, age was not statistically significantly associated with dosing outcomes (Holm-adjusted p = 0.145). Polypharmacy was highly prevalent (91% of patients) but was not significantly associated with any dosing outcome in these exploratory analyses, likely due to limited statistical power. Conclusions: Our results showed that several regularly prescribed drugs, including metformin, sitagliptin, ceftazidime, ciprofloxacin, and spironolactone, were inappropriately prescribed to patients with CKD. These dosing errors can be avoided by increasing clinicians’ and pharmacists’ awareness of appropriate dosage modifications essential for patients with CKD. Full article

Xeroderma pigmentosum group B (XPB/ERCC3) and group D (XPD/ERCC2) helicases are integral components of the transcription factor IIH (TFIIH) complex, coordinating DNA unwinding during transcription initiation and nucleotide excision repair (NER). XPB functions as an ATP-driven translocase that generates torsional strain to promote promoter melting and DNA opening at lesion sites, whereas XPD acts as a 5′ to 3′ helicase responsible for lesion verification and extension of the repair bubble. Structural and biochemical studies have clarified how TFIIH subunits regulate these helicases—p52 and p8 modulate XPB’s translocation activity, while p44, p62, and MAT1 control XPD’s helicase function through conformational and compositional transitions within the complex. Beyond their canonical roles, XPB and XPD participate in diverse cellular pathways, including cell-cycle regulation and oxidative stress response, highlighting their involvement in maintaining genome integrity beyond repair and transcription. Mutations in either helicase lead to xeroderma pigmentosum (XP), trichothiodystrophy (TTD), or combined XP/Cockayne syndrome (XP/CS) phenotypes, emphasizing the essential role of TFIIH integrity for human health. Recent biochemical and pharmacological advances have further revealed the therapeutic relevance of these helicases—XPB as a target of small-molecule inhibitors such as triptolide, Minnelide, and spironolactone, and XPD as a potential modulator of cancer sensitivity to DNA-damaging treatments. Collectively, XPB and XPD exemplify the structural and functional versatility of TFIIH helicases across repair, transcription, and genome maintenance. Full article

Objectives: Diuretics are frequently used in bronchopulmonary dysplasia (BPD), yet evidence describing their short-term physiological effects remains limited. This study aimed to describe early changes in respiratory support parameters and safety outcomes following combined oral spironolactone and hydrochlorothiazide (SP/HCTZ) therapy in preterm infants with BPD. Methods: A retrospective, single-center before–after observational study was conducted. Preterm infants diagnosed with BPD who initiated SP/HCTZ therapy were included. Respiratory parameters (FiO₂, PEEP, and flow rate) and serum electrolytes were compared between Day 1 (initiation) and Day 3 of treatment. A predefined clinical response was defined as either a ≥10% reduction in FiO₂ or a step-down in respiratory support modality. Results: Fifty-six infants (mean gestational age 27.7 ± 2.3 weeks) were analyzed. After 72 h of SP/HCTZ therapy, mean FiO₂ decreased from 26.2 ± 6.3% to 22.4 ± 3.4% (p < 0.001). Significant reductions were also observed in PEEP and cannula flow rates (p = 0.004 and p = 0.003, respectively). Overall, 39 infants (69.6%) met the predefined clinical response criteria. The prevalence of hyponatremia (Na < 133 mmol/L) increased from 7.1% at baseline to 25.0% on Day 3 (p = 0.039). Conclusions: Initiation of SP/HCTZ was temporally associated with short-term reductions in respiratory support parameters; however, these findings should be interpreted as associations rather than treatment effects. Given the increased frequency of hyponatremia by Day 3, close electrolyte monitoring appears warranted during the early phase of therapy. Full article

Residual congestion (RC) at discharge predicts adverse outcomes in heart failure with reduced ejection fraction (HFrEF). Its impact on the implementation of guideline-directed medical therapies (GDMT) remains unclear. N-terminal pro-B-type natriuretic peptide (NT-proBNP) trajectory during hospitalisation reflects RC and may be associated with GDMT implementation. The aim was to assess whether discharge NT-proBNP and a fall in NT-proBNP < 30% during hospitalisation (ΔNT-proBNP < 30%) predict GDMT underuse in acute HFrEF. In this prospective observational study, NT-proBNP was measured at hospital admission and 48–72 h before discharge. Provision of individual GDMT drug classes was assessed and GDMT underuse was defined as prescription of <3 key GDMT drug classes at discharge. 391 HFrEF patients (mean age, 69.9 ± 13.1years, 67.3% male) were included. ΔNT-proBNP < 30% was identified in 108 (27.6%). Higher discharge NT-proBNP was independently associated with lower likelihood of prescribing ACE-inhibitors, sacubitril/valsartan, eplerenone/spironolactone, or empagliflozin/dapagliflozin. ΔNT-proBNP < 30% was associated with 17% higher odds of GDMT underuse (95% confidence interval, 1.10–1.31, p < 0.001), regardless of clinical characteristics or in-hospital management. Patients with ΔNT-proBNP < 30% were discharged on lower doses of titratable GDMT medications. In-hospital NT-proBNP burden and trajectory, as markers of RC, are associated with GDMT underutilisation at discharge in acute HFrEF. Addressing RC may impact treatment quality in acute HFrEF. Full article

Background: Cardiovascular polypharmacy inherently amplifies the risk of drug–drug interactions (DDIs), yet most studies remain limited to isolated drug pairs or predefined high-risk classes, without mapping the systemic architecture through which interactions accumulate. Objectives: To characterize the burden, severity, and network structure of potential DDIs in a real-world cohort of hospitalized cardiovascular patients using interaction profiling combined with graph-theoretic network analysis. Methods: This retrospective observational study included 250 hospitalized cardiovascular patients. All home medications at admission were analyzed using the Drugs.com interaction database, and a drug interaction network was constructed to compute topological metrics (i.e., degree, betweenness, and eigenvector centrality). Results: Polypharmacy was highly prevalent, with a mean of 7.7 drugs per patient, and 98.4% of patients exhibited at least one potential DDI. A total of 4353 interactions were identified, of which 12.1% were classified as major, and 35.2% of patients presented high-risk profiles with ≥3 major interactions. Interaction burden showed a strong correlation with medication count (r = 0.929). Network analysis revealed a limited cluster of hub medications, particularly pantoprazole, furosemide, spironolactone, amiodarone, and perindopril, that disproportionately governed both interaction density and high-severity risk. Conclusions: These findings move beyond conventional pairwise screening by demonstrating how interaction risk propagates through interconnected therapeutic networks. The study supports the integration of hub-focused deprescribing, targeted monitoring strategies, and network-informed clinical decision support to mitigate DDI risk in cardiovascular polypharmacy. Future studies should link potential DDIs to clinical outcomes and validate network-based prediction models in prospective settings. Full article

Intestinal impairment plays a pivotal role in many chronic conditions, including chronic kidney disease (CKD), a progressive disorder affecting over 800 million people worldwide. CKD does not only affect the kidney, but it is recognized as a systemic condition characterized by chronic low-grade inflammation, that contributes to disease progression and associated complications. The intestine is one of the major sources of CKD-associated inflammation, also due to the production and accumulation of some uremic toxins, normally excreted by healthy kidneys, such as indoxyl sulfate (IS). IS is a pro-inflammatory and pro-oxidant protein-bound uremic toxin that increases intestinal epithelial permeability, promotes microbial translocation, and enhances inflammatory and oxidative responses. Although IS-induced intestinal damage has been documented, the underlying molecular mechanisms and effective therapeutic strategies to counteract its effects remain to be elucidated. Against this backdrop in the present study, we investigated the impact of plumericin, an iridoid spironolactone, on IS-induced intestinal impairment using IEC-6, an intestinal epithelial cells model. In IS-treated IEC-6, plumericin reduces apoptosis, inhibits inflammation and oxidative stress, and restores epithelial wound repair. In these conditions plumericin also promotes Nrf-2 and inhibits NF-kB and AhR activation induced by IS. Moreover, the same inhibitory effect of plumericin on inflammation and oxidative stress and in promoting wound repair is also observed in the presence of IS and pro-inflammatory stimuli, as occurs in CKD considering the associated systemic low-grade inflammation. These findings suggest that plumericin may represent a promising therapeutic candidate for intestinal impairment in CKD acting with an integrated mechanism. Full article

Background: Two natural steroids derived from cholesterol pathways are testosterone and progesterone, androgen and antiandrogen receptor binding. Steroid androgen antagonists can be prescribed to treat an array of diseases and disorders such as gender dysphoria. In men, androgen antagonists are frequently used to treat prostate cancer and hyperplasia. Sex hormones regulate the expression of the viral receptors in COVID-19 progression, and these hormones may act as a metabolic signal-mediating response to changes in glucose and Reactive Oxygen Species (ROS). The objective of the present study is to use artificial intelligence (AI) applications in healthcare to predict the targets and to assess biological assays of novel steroid derivatives prepared in house from the commercially available 16-dehydropregnenolone acetate (DPA^®) aimed at achieving the metabolic stability of glucose and steroid brain homeostasis. This suggests the introduction of aromatic or aliphatic structures in the steroid B-ring and D-ring. This is important since the roles of 5α-reductase and ROS in brain control of glucose and novel steroids homeostasis remain unclear. Methods: A tool prediction was used as a tuned algorithm, with the novel steroid derivatives data in web interface to carry out their pharmacological evaluation. The new steroidal derivatives were determined with neuroprotection effect using the select biomarkers of oxidative stress on induced hypoglycemic male rat brain and liver. The enzyme kinetics was established by the inhibition of the 5α-reductase enzyme on the brain myelin. Results: We used novel chemical structures to order the information of a Swiss data bank that allow target predictions. Biological assays suggest that steroid derivatives with an electrophilic center can interact more efficiently with the 5α-reductase enzyme, and by this way, induce neuroprotection in hypoglycemia model. All compounds were synthesized with a yield of 30–80% and evaluated with tool target prediction to understand the molecular mechanisms underlying a given phenotype or bioactivity and to rationalize possible favorable or unfavorable side effects, as well as to predict off-targets of known molecules and to clear the way for drug repurposing. Apart, they turned out to be good inhibitors for the 5α-reductase enzyme. Conclusions: The probed efficacy of these novel steroids with respect to spironolactone control appears to be a promising compound for future hormonal therapy with neuroprotection activity in glucose disorder status. However, further research with clinically meaningful endpoints is needed to optimize the use of androgen antagonists in these hormonal therapies in COVID-19 progression. Full article

Background: Sudden cardiac death (SCD) remains a major cause of cardiovascular mortality. Implantable cardioverter-defibrillators (ICDs) reduce arrhythmic mortality, but current selection based largely on left ventricular ejection fraction (LVEF) lacks precision. Many patients undergo device implantation without ever receiving therapy, while others at risk remain unprotected. Interpretable machine learning (ML) can integrate diverse clinical variables and refine patient selection while maintaining transparency in clinical reasoning. Methods: We retrospectively analyzed 607 patients who underwent ICD or CRT-D implantation at a Croatian tertiary care center. Baseline demographic, clinical, echocardiographic, laboratory, and device-related variables were collected. Patients were followed through routine device interrogations, with appropriate ICD activation serving as a surrogate for SCD prevention. A logistic regression (LR) model was trained to predict appropriate device activation. Results: LR model demonstrated strong predictive ability (AUC-ROC 0.74, sensitivity 86.50%). Significant predictors included ventricular tachycardia (VT) burden, sustained VT, longer follow-up, and secondary prevention. The combination of furosemide and spironolactone therapy was linked to lower predicted SCD risk. Conclusions: ML applied to routinely collected data can support risk stratification in SCD and complement existing guideline criteria by reinforcing known predictors and uncovering novel associations. Full article

Through the mineralocorticoid receptor, aldosterone controls extracellular volume and arterial blood pressure by stimulating Na⁺ absorption and K⁺ secretion in epithelial cells of the kidney, colon, and several glands. Hyperaldosteronism promotes fibrosis and inflammation in epithelial and non-epithelial tissues, thereby favoring loss of kidney and heart function. Mineralocorticoid receptor blockade therefore gains relevance especially in renal and cardiac disease. Kidney-derived Klotho is a powerful anti-aging protein with anti-fibrosis and anti-inflammatory effects providing cardio- and nephroprotection. We wondered whether Klotho expression and production is influenced by mineralocorticoid receptor agonists and antagonists. Using four renal cell lines, Madin-Darby canine kidney (MDCK), normal rat kidney, subtype 52E (NRK-52E), human kidney 2 (HK2) cells, and primary renal proximal tubule epithelial cells (RPTECs), and the four most frequently prescribed mineralocorticoid receptor blockers, spironolactone, eplerenone, finerenone, and esaxerenone, we assessed Klotho gene expression by qRT-PCR and Klotho protein by Western blotting. Aldosterone and eplerenone did not significantly affect Klotho expression in either cell line. Spironolactone enhanced Klotho expression in MDCK and NRK-52E cells and downregulated Klotho in HK2 cells and RPTECs. Novel non-steroidal mineralocorticoid receptor antagonist finerenone downregulated Klotho expression in MDCK, NRK-52E, and low-dose finerenone in HK2 cells. To conclude, common mineralocorticoid receptor antagonists are characterized by highly diverse effects on Klotho in four renal cell lines. Further studies are needed to define the role of mineralocorticoid receptor blockade for Klotho production. Full article

Background/Objectives: Acne vulgaris is a prevalent dermatological condition, yet clear, region-specific management guidelines, particularly for India’s diverse population, remain limited. Effective acne management extends beyond pharmacologic therapy, emphasizing proper skincare, patient education, and adherence strategies. This consensus aims to provide tailored, evidence-based recommendations for optimizing acne treatment in the Indian context. Methods: A panel of 14 dermatology experts with ≥15 years of experience reviewed literature, real-world clinical practices, and patient-centric factors relevant to acne management in India. Using a modified Delphi process with two virtual voting rounds, 61 statements across seven clinical domains were evaluated. Consensus was defined as ≥75% agreement. Results: Topical retinoids remain the first-line therapy, with combination regimens (benzoyl peroxide or topical antibiotics) preferred to enhance efficacy and minimize antibiotic resistance. Hormonal therapies, including combined oral contraceptives and spironolactone, are recommended for females with resistant acne. Guidance includes individualized treatment plans, baseline investigations, and selection of appropriate topical and systemic agents. Special considerations for pregnancy and lactation prioritize maternal and fetal safety. Conclusions: This expert consensus provides practical, evidence-based recommendations for acne management in India, integrating pharmacological and non-pharmacological approaches. The tailored guidance supports individualized care, antibiotic stewardship, and improved treatment adherence, aiming to enhance patient outcomes nationwide. Full article

Skeletal muscle aging, or sarcopenia, involves progressive muscle mass and function loss, which limits mobility and independence in elderly populations. This decline is driven by chronic inflammation, oxidative stress, and insulin resistance, all of which impair muscle regeneration and accelerate protein breakdown. Mineralocorticoid receptors (MRs), known for their roles in electrolyte balance, have emerged as key regulators of these processes in skeletal muscle. MR activation promotes inflammatory signaling, increases oxidative stress, and worsens insulin resistance, accelerating sarcopenia progression. This review examines the impact of MRs on muscle health and highlights the therapeutic potential of targeting these receptors to counteract age-related muscle loss. MR antagonists, such as spironolactone, show promise in reducing inflammation and oxidative damage, potentially slowing sarcopenia. Physical exercise, an established intervention for muscle health, may enhance MR antagonism effects by improving insulin sensitivity and reducing inflammation. However, more research is needed to determine the efficacy and safety of combined MR antagonists and exercise protocols for preventing sarcopenia in older adults. Full article