Glaucoma is a neurodegenerative eye disease characterized by progressive loss of retinal ganglion cells (RGCs), resulting in irreversible vision loss. Previous work demonstrated that irbesartan, an angiotensin II type I receptor blocker, promotes RGC survival in rat retinal explants. This study extends these findings to ex vivo mouse explants, in vivo optic nerve crush model, and transcriptomic analysis to identify associated pathways. Retinal explants from C57BL/6 mice were cultured for 4 days with irbesartan (10 μmol/L), vehicle, or angiotensin II (2 μmol/L). RGC survival was assessed by βIII-tubulin and RNA-binding protein with multiple splicing (RBPMS) immunostaining; superoxide and mitochondrial density were measured using dihydroethidium and MitoTracker Red CMXRos. Mice received vehicle or irbesartan (10 μmol/L) eye drops for 7 days after optic nerve crush to assess RGC survival. Irbesartan enhanced RGC survival in explants (1.5-fold and 4-fold; P = 0.0138 and 0.000129) and in vivo (1.7-fold; P = 0.0045). Irbesartan reduced dihydroethidium intensity (P < 0.0072) and preserved mitochondrial labeling at day 2 (P = 0.02). RNA sequencing revealed differential expression of electron transport chain genes (eg, Cox4i2 and Ndufa12), with gene set enrichment analysis showing enrichment of proinflammatory pathways in vehicle-treated explants and neuronal/metabolic pathways with irbesartan. In conclusion, irbesartan reduces oxidative stress and modulates mitochondrial and inflammatory pathways, potentially supporting RGC survival, thus providing insights relevant to glaucoma and optic neuropathies involving RGC degeneration.

Historically, IgA nephropathy (IgAN) was managed using supportive care, with a suggested 6 months of immunosuppressive therapy considered for patients at high risk of progressive kidney function decline (proteinuria, >0.75-1 g/d) despite ≥90 days of optimized supportive care. The evolving treatment landscape includes agents that target immunologic aspects of IgAN or better preserve kidney function, or both. Recent approvals include Nefecon, sparsentan, iptacopan, atrasentan, and sibeprenlimab. Nefecon, a targeted-release formulation of budesonide, is the only US Food and Drug Administration and European Medicines Agency fully approved agent that is designed to target the primary source of IgAN: galactose-deficient IgA1 production in the gut mucosa. Phase 3 data showed that Nefecon slowed estimated glomerular filtration rate decline and decreased proteinuria versus placebo, with an acceptable safety profile. Sparsentan, a fully US Food and Drug Administration- and European Medicines Agency-approved dual endothelin A/angiotensin II receptor antagonist, affects the generic responses to IgAN-induced nephron loss, potentially including glomerular inflammation and fibrosis. Sparsentan demonstrated a significant reduction in proteinuria and estimated glomerular filtration rate decline compared with irbesartan. Iptacopan inhibits complement factor B and has received accelerated US Food and Drug Administration approval. Interim phase 3 study data have shown that iptacopan significantly reduces proteinuria when compared with placebo. The endothelin A receptor antagonist atrasentan and A proliferation binding ligand inhibitor sibeprenlimab have also received accelerated US Food and Drug Administration approval, based on interim phase 3 results showing significant proteinuria reduction versus placebo in patients with IgAN. This expanded clinical armamentarium offers clinicians and patients greater choice and improved disease control in IgAN management.

Granular activated carbon (GAC) filtration is increasingly used for quaternary treatment of municipal wastewater to remove organic micropollutants, in line with the revised EU Urban Wastewater Treatment Directive (Directive (EU) 2024/3019). This review compiles and synthesises available, peer-reviewed, and long-term pilot- and full-scale studies and, in contrast to previous reviews, particularly addresses breakthrough of Urban Wastewater Treatment Directive (UWWTD) relevant indicator compounds in relation to operational lifespan and regulatory compliance. Most studies were conducted at pilot scale, with considerable variation in empty bed contact time, filtration rate, and GAC type. Breakthrough of indicator compounds varied widely, but citalopram, metoprolol, benzotriazole, and methylbenzotriazole generally showed relatively late breakthrough, indicating potential for longer filter lifespan, whereas candesartan and irbesartan more often showed early breakthrough. The available data further indicate that the selection of indicator compounds strongly affects the operational lifespan over which compliance with the UWWTD may be maintained. However, the limited number of long-term full-scale studies and the large variability in pre-treatment, filter design, carbon type, and operating conditions prevent robust quantitative assessment of these relationships. The findings highlight the need for more large-scale, long-term studies using a systematic evaluation framework to support the effective implementation of GAC filtration for UWWTD compliance.

Because no information is available on the use of irbesartan during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.

Focal segmental glomerulosclerosis (FSGS) represents a heterogeneous clinicopathological entity characterized by podocyte injury, progressive glomerular scarring, and a high risk of progression to end-stage renal disease. Despite advances in understanding its pathophysiology, therapeutic options have remained limited, largely centered on supportive care and immunosuppression, with inconsistent efficacy and significant adverse effects. The recent approval of sparsentan, a dual endothelin type A and angiotensin II type 1 receptor antagonist, marks a significant advancement in the management of FSGS by targeting key hemodynamic and molecular pathways implicated in disease progression. This article provides a comprehensive overview of the pathogenesis of FSGS, emphasizing the central role of podocyte injury and maladaptive responses to mechanical stress. It further reviews current treatment strategies and examines the clinical evidence underpinning the approval of sparsentan, particularly findings from the DUPLEX trial. Although sparsentan did not demonstrate a statistically significant benefit in preserving estimated glomerular filtration rate, it achieved a clinically meaningful reduction in proteinuria compared with irbesartan. The safety profile was generally acceptable, with manageable adverse effects, including hyperkalemia and hypotension. While sparsentan introduces a novel, non-immunosuppressive therapeutic option, its long-term impact on renal outcomes remains to be fully established. Ongoing research will be critical to defining its role within combination regimens and optimizing patient selection in this complex disease spectrum.

Intervertebral disc degeneration (IDD) is a primary cause of chronic low back pain, yet the specific cell subpopulations and metabolic mechanisms driving its progression remain incompletely understood. We performed an integrative analysis of single-cell RNA sequencing (scRNA-seq) and transcriptomic sequencing using public datasets (GSE230809, GSE186542) to characterise cellular heterogeneity in IDD. To elucidate the underlying pathological mechanisms, we employed senescence scoring, transcriptional entropy assessment, pseudotime trajectory inference, and hierarchical weighted gene co-expression network analysis (hdWGCNA). Metabolic pathway activity was evaluated with scMetabolism, and potential therapeutics were screened using the POINT platform. We identified a key fibrochondrocyte subpopulation, FC3, which exhibits high transcriptional entropy and plays a central role in IDD. The FC3 cluster was further resolved into three functional states: fibrotic, proliferative, and metabolic. Pseudotime trajectory inference indicated that FC3 (proliferative) cells potentially represent a progenitor-like state, partitioning toward fibrotic and metabolic lineages. Notably, the FC3 (metabolic) state displayed the lowest senescence score and the highest activity in the tricarboxylic acid (TCA) cycle. Through hdWGCNA and cross-dataset validation, malate dehydrogenase 2 (MDH2) was established as a central hub gene linking TCA cycle activation to the FC3 (metabolic) phenotype. Functional enrichment confirmed MDH2's role in oxidative phosphorylation, fatty acid metabolism, and cellular senescence. Drug screening identified several candidate compounds, including Platycodin D, Irbesartan, and Ergothioneine, whose corresponding targets exhibited specifically enhanced activity within the FC3 (metabolic) subpopulation of degenerated tissues. Our study reveals that metabolic dysregulation in the FC3 fibrochondrocyte subpopulation, driven by aberrant MDH2-mediated TCA cycle activation, is a critical mechanism promoting IDD. These findings highlight the therapeutic targeting value of the FC3 metabolic state and provide specific candidate compounds for the subsequent development of interventions against IDD.

Pharmaceutical transformation products (TPs) can pose greater environmental risks than parent compounds, yet their occurrence in surface waters remains inadequately characterized. This study employed retrospective analysis of non-target screening (NTS) data, literature mining, and molecular networking to characterize pharmaceutical TPs in the Pearl River Basin (PRB). Suspect screening against TP databases identified 74 TPs, while molecular networking revealed 62,387 feature pairs sharing common MS/MS fragments. Structural annotation suggested 51 TPs derived from 28 parent pharmaceuticals, including 26 previously unreported compounds. Hydroxylation, methylation, demethylation, and oxidation were the dominant transformation pathways, showing minimal sub-basin variation-indicating structural control over transformation processes. Predictive assessment revealed 65% of TPs exhibited enhanced mobility and 23% showed increased toxicity relative to parent compounds. Notably, the TP SR-49498 showed a significantly higher environmental risk quotient (RQ = 13.271) than its parent Irbesartan (RQ < 0.0001). Toxicological Priority Index (ToxPi) analysis prioritized 12 high-risk TPs. Overall, this study systematically characterized the occurrence and environmental risks of pharmaceutical TPs in the PRB, thereby advancing the understanding of their environmental fate and providing a scientific basis for future water pollution monitoring and risk management strategies.

Diabetic kidney disease is a frequent complication of diabetes and the predominant cause of end‑stage renal disease. However, the pathogenesis of diabetic kidney disease has not been fully elucidated. HK‑2 cells cultured in vitro were randomly divided into control, high glucose, high glucose + MCC950 and high glucose + irbesartan groups. The present study detected the mRNA and protein expression of NLRP3, caspase‑1, NF‑κB p65, α‑SMA, vimentin and N‑cadherin using reverse transcription‑quantitative PCR and western blotting. The present study also detected the protein expression of vimentin using immunocyte fluorescence. High glucose (40 mM) significantly increased the mRNA and protein levels of NLRP3, NF‑κB p65, caspase‑1 and epithelial‑mesenchymal transition (EMT) markers; these effects were attenuated by MCC950 and irbesartan administration. These results indicated that high glucose stimulation upregulated the expression of NLRP3 in HK‑2 cells and promoted the expression of EMT‑associated factors. Irbesartan inhibited the activation of the NLRP3 inflammasome and downregulated the expression of EMT‑related factors, which provided a basis for potential new strategies for the treatment of diabetic nephropathy.

Background/Objectives: Immunoglobulin A nephropathy (IgAN) is a type of chronic kidney disease (CKD) and the most common cause of kidney failure in patients <40 years of age. Previous economic models in CKD have generally defined health states solely by the progression of CKD. This manuscript presents an alternative method which also considers the level of proteinuria in a CKD patient. Methods: A cohort-level state transition model was developed, comparing the health benefits of sparsentan, a dual endothelin angiotensin receptor antagonist, to irbesartan, an angiotensin receptor blocker, in IgAN. Within four UP/C (proteinuria) states, patients are assigned to three sub-health states according to CKD stage. Patients with end-stage renal disease are grouped together, irrespective of UP/C, and are stratified instead by renal replacement therapy modality. Transition matrices are derived from a combination of data from PROTECT, a clinical trial comparing sparsentan to irbesartan, and the UK RaDaR registry. Health-related quality of life data from a general CKD population is used as a proxy. Results: Patients with IgAN who were modelled to receive treatment with sparsentan had an estimated total undiscounted life years of 25.5 years, a gain of 0.9 years in comparison with irbesartan. Patients were also more likely to spend more time in earlier CKD stages while in pre-ESRD. This translated to significant quality-adjusted life year gains for patients treated with sparsentan in comparison with irbesartan. Conclusions: This study presents a new structure for health economic models in IgAN that more comprehensively captures the effect of proteinuria in combination with CKD progression. This new approach ultimately allows for the more robust implementation of clinical trial data in IgAN and estimates of the cost-effectiveness of new treatments.

Nitrogen-bearing heterocycles have been fundamental scaffolds in drug discovery, contributing significantly to the design and development of therapeutic agents since the inception of modern medicinal chemistry. Among them, imidazolones have shown notable therapeutic relevance, particularly in oncology, antimicrobial resistance (AMR), and inflammation, yet they remain relatively underexplored. Nevertheless, the significant therapeutic and clinical efficacy of imidazolone-bearing drugs, such as Nilutamide, Irbesartan, and Leucettinib-21, in anticancer, antihypertensive, and neurotherapeutic applications has stimulated increasing interest in imidazolone chemistry and its medicinal potential. This review systematically discusses the major synthetic strategies, structure-activity relationships, and mechanistic principles governing the biological activity of imidazolones. Particular emphasis is placed on their rapidly expanding role as anticancer agents targeting enzymes and signaling proteins such as carbonic anhydrases, epidermal growth factor receptors (EGFR), Bcl-2 protein family, and checkpoint kinases, along with their potential applications in antimicrobial and anti-inflammatory therapies. Furthermore, the review highlights the complementary roles of computational modeling and biological evaluation in understanding the interactions of imidazolone-bearing compounds with various microbial and cancer-related receptors. These integrated studies reveal their ability to engage multiple biological targets and validate their observed pharmacological activities. The convergence of in silico predictions with experimental findings offers valuable guidance for the rational development of imidazolone-based therapeutics. Overall, this review emphasizes imidazolones as promising scaffolds with significant potential for future drug discovery and development.