Inflammation and Acinar Cell Dual-Targeting Nanomedicines for Synergistic Treatment of Acute Pancreatitis via Ca2+ Homeostasis Regulation and Pancreas Autodigestion Inhibition.

Severe acute pancreatitis (AP) is a life-threatening pancreatic inflammatory disease with a high mortality rate (∼40%). Existing pharmaceutical therapies in development or in clinical trials showed insufficient treatment efficacy due to their single molecular therapeutic target, poor water solubility, short half-life, limited pancreas-targeting specificity, etc. Herein, acid-responsive hollow mesoporous Prussian blue nanoparticles wrapped with neutrophil membranes and surface modified with the N,N-dimethyl-1,3-propanediamine moiety were developed for codelivering membrane-permeable calcium chelator BAPTA-AM (BA) and trypsin activity inhibitor gabexate mesylate (Ga). In the AP mouse model, the formulation exhibited efficient recruitment at the inflammatory endothelium, trans-endothelial migration, and precise acinar cell targeting, resulting in rapid pancreatic localization and higher accumulation. A single low dose of the formulation (BA: 200 µg kg-1, Ga: 0.75 mg kg-1) significantly reduced pancreas function indicators to close to normal levels at 24 h, effectively restored the cell redox status, reduced apoptotic cell proportion, and blocked the systemic inflammatory amplified cascade, resulting in a dramatic increase in the survival rate from 58.3 to even 100%. Mechanistically, the formulation inhibited endoplasmic reticulum stress (IRE1/XBP1 and ATF4/CHOP axis) and restored impaired autophagy (Beclin-1/p62/LC3 axis), thereby preserving dying acinar cells and restoring the cellular "health status". This formulation provides an upstream therapeutic strategy with clinical translation prospects for AP management through synergistic ion homeostasis regulation and pancreatic autodigestion inhibition.

Iron deficiency at birth and risk of hidden hearing loss in infants modification by socioeconomic status: mother-newborn cohort in Shenyang, China.

OBJECTIVE: The diagnosis of hidden hearing loss (HHL) in calm state has not yet been determined, while the nutritional status is not involved in its pathogenic risk factors. In utero iron deficiency (ID) may delay auditory neural maturation in infants. We evaluated the association between ID and HHL as well as the modification effect of socioeconomic status (SES) on this association in newborns. STUDY DESIGN: We included 859 mother-newborns from the baseline of this observational northeast cohort. Data on exposure assessment included iron status [maternal hemoglobin (Hb) and neonatal heel prick serum ferritin (SF)] and SES (occupation, education and income). Auditory neural maturation was reflected by auditory brainstem response (ABR) testing and electrocochleography (ECochG). RESULTS: Iron status and SES were independently and jointly associated with the prediction of neonatal HHL by logistic and linear regression model. The mediation effects were performed by Process. ID increased absolute latency wave V, interpeak latency (IPL) III-V, and summting potentials (SP) /action potentials (AP), which were combined as HHL. Low SES showed the highest risk of HHL and the highest levels of related parameters in ID newborns. Moreover, after Corona Virus Disease 2019 (COVID-19) were positive, preschool children who experience ID in neonatal period were more likely to suffer from otitis media with effusion (OME). High SES also showed similar risk effects. CONCLUSION: Both low and high SES may strengthen the risk of ID on neonatal HHL in Northeast China.

Novel water-soluble and pH-responsive anticancer drug nanocarriers: doxorubicin-PAMAM dendrimer conjugates attached to superparamagnetic iron oxide nanoparticles (IONPs).

PH-responsive drug release system based on the conjugates of PAMAM dendrimers-doxorubicin (PAMAM-DOX) and superparamagnetic iron oxide (Fe(3)O(4)) nanoparticles (IONPs) has been constructed and characterized. The IONPs were stabilized by mPEG-G2.5 PAMAM dendrimers. The anticancer drug DOX was conjugated to the dendrimer segments of amino-stabilized IONPs using hydrazine as the linker via hydrazone bonds, which is acid cleavable and can be used as an ideal pH-responsive drug release system. The drug release profiles of DOX-PAMAM dendrimer conjugates were studied at pH 5.0 and 7.4. The results showed that the hydrolytic release profile can be obtained only at the condition of lysosomal pH (pH=5.0), and IONPs participated in carrying DOX to the tumor by the Enhanced Permeability and Retention (EPR) effect. These novel DOX-conjugated IONPs have the potential to enhance the effect of MRI contrast and cancer therapy in the course of delivering anticancer drugs to their target sites. Although the dendrimer-DOX-coated IONPs do not have any targeting ligands attached on their surface, they are potentially useful for cancer diagnosis in vivo.