The aggregation of human islet amyloid polypeptide (hIAPP or amylin) is associated with the pathogenesis of type 2 diabetes mellitus. Increasing evidence suggests that the interaction of hIAPP with β-cell membranes plays a crucial role in cytotoxicity. However, the hIAPP-lipid interaction and subsequent membrane perturbation is not well understood at atomic level. In this study, as a first step to gain insight into the mechanism of hIAPP-induced cytotoxicity, we have investigated the detailed interactions of hIAPP monomer and dimer with anionic palmitoyloleolyophosphatidylglycerol (POPG) bilayer using all-atom molecular dynamics (MD) simulations. Multiple MD simulations have been performed by employing the initial configurations where the N-terminal region of hIAPP is pre-inserted in POPG bilayer. Our simulations show that electrostatic interaction between hIAPP and POPG bilayer plays a major role in peptide-lipid interaction. In particular, the N-terminal positively-charged residues Lys1 and Arg11 make a dominant contribution to the interaction. During peptide-lipid interaction process, peptide dimerization occurs mostly through the C-terminal 20–37 region containing the amyloidogenic 20–29-residue segment. Membrane-bound hIAPP dimers display a pronounced ability of membrane perturbation than monomers. The higher bilayer perturbation propensity of hIAPP dimer likely results from the cooperativity of the peptide-peptide interaction (or peptide aggregation). This study provides insight into the hIAPP-membrane interaction and the molecular mechanism of membrane disruption by hIAPP oligomers.

Recent experiments in function mechanism study reported that a pH low-insertion peptide (pHLIP) can insert into a zwitterionic palmitoyloleoylphosphatidylcholine (POPC) lipid bilayer at acidic pH while binding to the bilayer surface at basic pH. However, the atomic details of the pH-dependent interaction of pHLIP with a POPC bilayer are not well understood. In this study, we investigate the detailed interactions of pHLIP with a POPC bilayer at acidic and basic pH conditions as those used in function mechanism study, using all-atom molecular dynamics (MD) simulations. Simulations have been performed by employing the initial configurations, where pHLIP is placed in aqueous solution, parallel to bilayer surface (system S), partially-inserted (system P), or fully-inserted (system F) in POPC bilayers. On the basis of multiple 200-ns MD simulations, we found (1) pHLIP in system S can spontaneously insert into a POPC bilayer at acidic pH, while binding to the membrane surface at basic pH; (2) pHLIP in system P can insert deep into a POPC bilayer at acidic pH, while it has a tendency to exit, and stays at bilayer surface at basic pH; (3) pHLIP in system F keeps in an α-helical structure at acidic pH while partially unfolding at basic pH. This study provides at atomic-level the pH-induced insertion of pHLIP into POPC bilayer.

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IntroductionThe geriatric nutritional risk index (GNRI), a nutritional screening tool specifically for the aging population, has been proven to be associated with worse outcomes in chronic kidney disease patients, especially in the hemodialysis population. However, the predictive validity of GNRI in critically ill elderly patients with acute kidney injury (AKI) is yet to be determined. This analysis sought to examine the prognostic effects of GNRI on elderly AKI patients in intensive care units (ICUs).MethodsWe collected elderly AKI patient-relevant data from the Medical Information Mart for Intensive Care III database. AKI was diagnosed and staged according to the “Kidney Disease Improving Global Outcomes” criteria. In the study, 1-year mortality was considered the primary outcome, whereas in-hospital, ICU, 28-day and 90-day mortality, and prolonged length of stay in ICU and hospital were selected as the secondary outcomes.ResultsIn all, 3,501 elderly patients with AKI were selected for this study, with a 1-year mortality rate of 36.4%. We classified the study population into low (≤98) and high (>98) GNRI groups based on the best cutoff value. The incidence of endpoints was remarkably lower in patients with elevated GNRI (p < 0.001). When stratified by the AKI stage, patients with high GNRI at AKI stages 1, 2, and 3 had markedly lower 1-year mortality than those with low GNRI (all p < 0.05). The multivariable regression analysis identified the independent prognostic ability of GNRI on the research outcomes (all p < 0.05). Restricted cubic spline exhibited a linear correlation between GNRI and 1-year death (p for non-linearity = 0.434). The prognostic implication of GNRI on 1-year mortality was still significant in patients with the most subgroups.ConclusionIn critically ill elderly patients with AKI, elevated GNRI upon admission was strongly correlated with a lower risk of unfavorable outcomes.

Background No studies have been published on the correlation between lactic dehydrogenase-to-albumin ratio (LAR) and poor prognosis of acute kidney injury (AKI) patients, warranting further research. This analysis sought to investigate the prognostic implication of LAR in critically ill patients with AKI. Methods The present study enrolled 11,046 and 5180 adults with AKI from the Medical Information Mart for Intensive Care III (MIMIC III) and MIMIC IV, respectively. Data from MIMIC IV were identified as the training cohort, and those from MIMIC III were identified as the validation cohort. We applied multivariate regression analysis to identify the link between LAR and all-cause mortality. Restricted cubic spline (RCS) was conducted to figure out the correlation between LAR and in-hospital mortality. Furthermore, we carried out stratification analyses to examine if the effects of LAR on in-hospital mortality were consistent across various subclasses. Results The level of LAR was remarkably higher in the in-hospital non-survivor group ( p < 0.001). Furthermore, the increased LAR group presented a remarkably higher rate of in-hospital mortality at AKI stages 1, 2, and 3 compared with the decreased LAR group (all p < 0.001). Multivariate regression analyses exhibited the independent prognostic significance of LAR for all-cause mortality (all p < 0.001). MIMIC III observed concordant results. RCS indicated a non-linear correlation between LAR and in-hospital death ( P for non-linearity < 0.001). The relationship between LAR and in-hospital mortality was still significant in patients with various subclasses. Conclusions Elevated LAR at admission is a prognostic risk factor for critically ill patients with AKI. Supplementary Information The online version contains supplementary material available at 10.1007/s10157-023-02321-5.