Background Serum albumin and alkaline phosphatase (ALP) are established biomarkers of adverse outcomes. The albumin-to-alkaline phosphatase ratio (AAPR) has demonstrated prognostic value in various chronic diseases, but its relevance to mortality in older end-stage kidney disease (ESKD) patients remains unclear. Methods We analyzed ESKD patients aged ≥ 70 years who initiated hemodialysis at 16 university hospitals in South Korea. Patients were stratified into AAPR tertiles (low ≤ 0.224; moderate 0.225–0.440; high > 0.440), and associations with all-cause mortality were assessed using Kaplan–Meier survival and Cox proportional hazards models adjusted for demographic, clinical, and laboratory factors. Results The study included 1,990 patients with a mean age of 77.4 ± 5.3 years, of whom 55.7% were male. During a median follow-up of 5.9 years, 1,197 patients (60.1%) died. Mortality was highest in the lowest AAPR tertile (66.6%) and lowest in the highest tertile (53.3%; P = 0.012). In fully adjusted Cox proportional hazards models, patients in the lowest AAPR tertile had a significantly higher risk of all-cause mortality compared with those in the highest tertile (HR 1.28, 95% CI 1.08–1.51, P = 0.004). Furthermore, lower AAPR levels as a continuous variable were independently associated with increased mortality risk (HR 1.08, 95% CI 1.02–1.13; P = 0.008), with a non-linear association observed in restricted spline analysis. Subgroup analyses demonstrated a consistent prognostic trend of AAPR across all clinical subgroups, without significant interaction effects. Conclusion Lower AAPR independently predicts higher all-cause mortality in older ESKD patients initiating hemodialysis.
Ferroptosis, an iron-dependent form of regulated cell death, has been increasingly linked to neurodegeneration in Parkinson’s disease (PD). The lipid-peroxidizing enzyme 5-lipoxygenase (5-LOX) contributes to ferroptotic stress, while montelukast, a leukotriene receptor antagonist widely used for asthma, indirectly interferes with this pathway. Here, we investigated whether montelukast protects against dopaminergic injury in a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Mice were evaluated for behavioral deficits and underwent histological and biochemical analyses to assess iron burden, oxidative stress, ferroptosis markers, and neuroinflammation. Montelukast administration alleviated MPTP-induced motor dysfunction, preserved tyrosine hydroxylase–positive neurons, and reduced α-synuclein accumulation. Treatment also decreased iron deposition and malondialdehyde production while restoring glutathione and superoxide dismutase activity. At the molecular level, montelukast upregulated xCT/GPX4 while downregulating ACSL4/5-LOX, indicating suppression of ferroptosis. Moreover, montelukast attenuated microglial activation and pro-inflammatory cytokine expression. Collectively, our results suggest that prophylactic administration of montelukast mitigates dopaminergic neurodegeneration by modulating markers of ferroptosis and inflammatory signaling. These findings indicate the GPX4/ACSL4/5-LOX axis as a potential neuroprotective target for PD.
Investigate the cellular response of human nucleus pulposus (HNP) cells to serum deprivation, focusing on the role of high mobility group box1(HMGB1) in regulating autophagy and apoptosis, and elucidate the time-dependent activation of autophagy shifting toward apoptosis under nutrient stress. Additionally, the study evaluated the impact of autophagy inhibition by chloroquine (CQ) on apoptosis progression. HNP samples were obtained from the human biobank with exemption from IRB screening (IRB number DC25SASI0012) to evaluate the impact of nutritional deprivation. Comprehensive analyses encompassed detailed evaluations of cellular morphology, viability, DNA integrity, and metabolic function, providing an integrated view of cellular status. Western blotting (WB), fluorescence-activated cell sorting (FACS), and immunofluorescence (IF) were used to detect LC3, P62, HMGB1, and cleaved caspase-3. Real-time quantitative polymerase chain reaction (RT-qPCR) further revealed changes in gene expression related to autophagy (LC3, P62) and apoptosis (caspase-3), highlighting cellular stress responses. Serum deprivation markedly reduced HNP cell viability, altered morphology, and suppressed metabolic activity, while inducing a time-dependent increase in autophagy, peaking at 48 h. Furthermore, elevated LC3-II, decreased P62, and increased cytoplasmic translocation of HMGB1 indicate activation of HMGB1-mediated autophagy. Simultaneously, cleaved caspase-3 levels rose, suggesting HMGB1’s involvement in shifting the balance toward apoptosis. IF and RT-qPCR confirmed enhanced LC3 and cleaved caspase-3 expression, while FACS analysis revealed increased apoptotic cell populations with declining serum levels. These findings highlight a crucial interplay between autophagy and apoptosis regulated by HMGB1 under nutrient-deprived conditions. Eventually, CQ treatment inhibited autophagic flux by blocking LC3-II degradation, thereby amplifying apoptosis. Serum deprivation potently induced HMGB1-mediated autophagy-apoptosis interplay in HNP cells, with CQ enhancing apoptosis by inhibiting autophagy.
BACKGROUND AND OBJECTIVES:Substantial efforts have been made to categorize the diverse and broad population of individuals with primary hypertension into more defined, homogeneous subgroups according to their hormonal responses to biological stimuli, such as low-renin hypertension. This study aimed to explore the phenotype and prognosis of patients with untreated primary hypertension with high renin and aldosterone levels. METHODS:In this study, we explored hypertensive phenotypes related to renin and aldosterone levels in untreated patients with primary hypertension (n=747). Patients were stratified into 4 groups on the basis of plasma renin activity (≥1.0 ng/mL/hr or <1.0 ng/mL/hr) and the plasma aldosterone concentration (≥15 ng/dL or <15 ng/dL).: high renin and aldosterone (n=172), low renin and high aldosterone (n=70), high renin and low aldosterone (n=308), and low renin and aldosterone (n=196). RESULTS:Multinomial logistic regression analysis revealed that younger age (p<0.001), higher pulse rates (p=0.002), and greater nighttime systolic blood pressure (p=0.046) were independent predictors of high renin and aldosterone levels. Microalbuminuria (25.5%, p<0.001) and elevated uric acid levels (5.5±1.4 mg/dL, p=0.006) were also more prevalent in this group. CONCLUSIONS:These findings highlight the importance of stratifying hypertensive phenotypes to enable personalized treatment for primary hypertensives with elevated renin and aldosterone levels.
