ABSTRACT Gasdermin E (GSDME) is a unique member of the gasdermin family linked to deafness, cancer, and neurodegenerative diseases, and mediates chemotherapy‐induced pyroptosis; however, its pore‐forming mechanism remains poorly understood. Here, we present cryo‐EM structures of GSDME pores with oligomeric stoichiometries ranging from 23 to 29 protomers. Using mutagenesis, liposome leakage assays, and analysis of cancer‐associated mutations, we identified key residues responsible for membrane binding, shallow membrane insertion, and oligomerization through three distinct structural interfaces. Molecular dynamics simulations reveal dynamic lipid recruitment and specificity: Anionic TMCL2 is selectively recruited by basic residues to facilitate shallow membrane penetration, while zwitterionic DPhPC solvates polar protein regions. Within the assembled 25‐mer pore, specific lipids act as structural stabilizers to reinforce the intermolecular hydrogen bond network. Our findings support a stepwise, time‐dependent mechanism underlying GSDME pore assembly. This study provides critical mechanistic insights into GSDME function and may guide the development of targeted therapeutics for cancers and neurodegenerative diseases.
ABSTRACT National‐level data regarding population disparities and Type 2 Diabetes Mellitus (T2DM)‐specific mortality trends, using ICD‐10 E11 and comparing pancreatic cancer deaths with versus without T2DM, remain incompletely characterized. This study aimed to analyze temporal trends and demographic/geographic disparities in United States pancreatic cancer (PC) + T2DM mortality (1999–2020) to identify high‐risk populations and generate hypotheses for future targeted interventions. We analyzed death records with PC and T2DM from Wide‐ranging Online Data for Epidemiologic Research (CDC WONDER), calculating age‐adjusted mortality rates (AAMRs) and annual percent changes (APCs) across demographic and geographic strata. Concurrently, National Health and Nutrition Examination Survey (NHANES) 2007–2016 data were utilized to estimate the weighted prevalences of key behavioral risk factors (smoking, alcohol, high‐saturated‐fat diet). Among 17 744 deaths, the age‐adjusted mortality rate (AAMR) for deaths with co‐listed PC and T2DM increased from 0.16 to 0.53 per 100 000 population between 1999 and 2020, while mortality from PC without T2DM remained relatively stable. Adults aged 75–84 bore the highest absolute burden, whereas 45–54‐year‐olds showed the fastest recent increase. Hispanics had the fastest overall increase, Non‐Hispanic (NH) Whites experienced sharp recent acceleration, and NH Blacks maintained a heavy baseline burden. Geographically, the AAMR in 2020 was higher in nonmetropolitan than metropolitan areas, although the full‐period average annual percent change (AAPC) was higher in metropolitan areas. Among the four United States Census regions, the West had the highest AAMR in 2020 and the highest full‐period AAPC, whereas the South exhibited the fastest recent increase after 2014. Complementary NHANES data show distinct demographic patterns in behavioral risk factors (smoking, alcohol, high‐saturated‐fat diet) at the population level, providing contextual background for the observed mortality disparities. However, these general‐population estimates are not linked to the mortality cohort and serve only as descriptive context. Deaths with both pancreatic cancer and Type 2 diabetes mellitus recorded on death certificates increased substantially in the United States from 1999 to 2020, while mortality from PC without T2DM remained relatively stable. The coexisting burden is characterized by marked demographic and geographic disparities. While behavioral risk factors may contribute to these patterns, ecological comparisons cannot establish causation, and prospective studies are needed to evaluate targeted interventions such as smoking and dietary management, telehealth expansion, and policy‐level efforts to reduce financial barriers.
ABSTRACT Nonvisual arrestins , also known as Beta‐arrestins, are known for their diverse role in GPCR signal transduction. Here, we present evidence that Beta‐Arrestin‐2, a protein whose nuclear concentration is actively kept low, binds to Nucleolar Organizing Regions (NORs) on the metaphase chromosomes at the onset of cell division, after the disappearance of the nuclear membrane and stays bound therein in the daughter cells. After reformation of the nucleoli, it stays bound to the nucleoli until actively transported out of the reformed nucleus during interphase. This binding is unique for Beta‐Arrestin‐2, as the closely associated Beta‐Arrestin‐1 does not show this behavior at all. We also observed an intranuclear accumulation of Beta‐Arrestin‐2 after P2X7 receptor stimulation, similar to what has been described for Beta‐Arrestin‐2 after TRPV receptor stimulation. Present data identify a cyclic and well‐organized shuttling between NORs and the cytoplasm of Beta‐Arrestin‐2 during cell division, indicating a novel and unknown role for Beta‐Arrestin‐2 in cell physiology. Our data may also indicate a common intracellular signaling mechanism for a diverse group of receptors currently believed to function only as ligand‐gated channels (P2X7 and TRPV).
ABSTRACT Diabetic peripheral neuropathy (DPN) is a common and disabling complication of diabetes and a major cause of sensory dysfunction. In established disease, nerve injury may continue despite partial metabolic improvement, suggesting that local nerve microenvironmental mechanisms sustain damage. The mediators linking macrophage activation to Schwann‐cell dysfunction and sensory abnormalities remain unclear. We studied matrix metalloproteinase‐12 (MMP12) in 20‐week‐old male C57BLKS/J db/db mice and normoglycemic m/m controls. Sciatic nerves were assessed by histology, Luxol fast blue staining, and transmission electron microscopy. Functional studies included motor and sensory nerve conduction, von Frey testing, and Hargreaves testing. RNA sequencing, tissue validation, primary macrophages cultured under high‐glucose or mannitol osmotic‐control conditions, macrophage‐conditioned medium, and the MMP12 inhibitor MMP408 were used to define mechanism and intervention effects. Recombinant fibronectin 1 (FN1), recombinant MMP12, and the TLR4 inhibitor TAK‐242 were used to assess the involvement of TLR4 signaling in Schwann cells. Db/db mice showed demyelination, impaired nerve conduction, and abnormal sensory responses. RNA sequencing highlighted extracellular matrix and cell‐adhesion pathways and identified Mmp12 as a hub gene. Diabetic sciatic nerves showed increased MMP12, reduced FN1, and substantial MMP12 colocalization with F4/80‐positive macrophages. Compared with the mannitol osmotic‐control condition, high glucose increased macrophage MMP12 expression, while conditioned medium from these cells activated TLR4/NF‐κB signaling, increased c‐Jun expression and apoptosis, and impaired Schwann‐cell migration. MMP408 partly reversed these changes in vitro. Recombinant FN1 and MMP12 cotreatment activated TLR4/NF‐κB/c‐Jun signaling in Schwann cells, and these changes were attenuated by TAK‐242. In vivo, MMP408 preserved FN1 expression and improved myelin structure, myelin‐related protein expression, nerve conduction, and sensory abnormalities. MMP408 reduced serum total cholesterol and triglyceride levels but had no significant effects on body weight, blood glucose, or serum insulin levels. A macrophage‐associated MMP12–Fn1 axis may contribute to establish DPN through Schwann‐cell dysfunction and represents a potential therapeutic target for diabetic neuropathic sensory dysfunction.
ABSTRACT Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by the loss of nigral dopaminergic neurons, often linked to oxidative stress and impaired cellular resilience. Selenoprotein W (SELENOW), known for its high selenium sensitivity and redox‐regulatory functions, has an unclear role in the PD‐related nigrostriatal pathway. In this study, we first observed that whole‐brain SELENOW knockout mice displayed increased vulnerability to 6‐hydroxydopamine (6‐OHDA)‐induced PD modeling. To investigate this further, we generated mice with dopaminergic neuron‐specific SELENOW knockout. While SELENOW deficiency in these neurons did not influence overall growth or baseline motor behaviors, it led to worsened motor dysfunction and increased loss of nigrostriatal dopaminergic neurons following unilateral intrastriatal 6‐OHDA injection. Moreover, we observed that SELENOW expression was downregulated under PD conditions. Mechanistically, this heightened susceptibility appeared linked to increased nigral oxidative stress, a weakened response of the antioxidant regulator NRF2, and diminished activation of the striatal AKT signaling pathway. In conclusion, the present study identifies SELENOW as an important modulator of dopaminergic neuron vulnerability to PD, likely through NRF2‐mediated redox and stress‐responsive signaling. These findings offer new insights into the role of selenoproteins in PD and suggest potential clues for therapeutic strategies.
