Dysregulation of cholesterol homeostasis is an early signal of ß-cell proteotoxicity characteristic of type 2 diabetes.

Type 2 diabetes (T2D) is a common metabolic disease due to insufficient insulin secretion by pancreatic ß-cells in the context of insulin resistance. Islet molecular pathology reveals a role for protein misfolding in ß-cell dysfunction and loss with islet amyloid derived from islet amyloid polypeptide (IAPP), a protein coexpressed and cosecreted with insulin. The most toxic form of misfolded IAPP is intracellular membrane disruptive toxic oligomers present in ß-cells in T2D and in ß-cells of mice transgenic for human IAPP (hIAPP). Prior work revealed a high degree of overlap of transcriptional changes in islets from T2D and prediabetic 9- to 10-wk-old mice transgenic for hIAPP with most changes being pro-survival adaptations and therefore of limited therapeutic guidance. Here, we investigated islets from hIAPP transgenic mice at an earlier age (6 wk) to screen for potential mediators of hIAPP toxicity that precede predominance of pro-survival signaling. We identified early suppression of cholesterol synthesis and trafficking along with aberrant intra-ß-cell cholesterol and lipid deposits and impaired cholesterol trafficking to cell membranes. These findings align with comparable lipid deposits present in ß-cells in T2D and increased vulnerability to develop T2D in individuals taking medications that suppress cholesterol synthesis.NEW & NOTEWORTHY ß-Cell failure in type 2 diabetes (T2D) is characterized by ß-cell misfolded protein stress due to the formation of toxic oligomers of islet amyloid polypeptide (IAPP). Most transcriptional changes in islets in T2D are pro-survival adaptations consistent with the slow progression of ß-cell loss. In the present study, investigation of the islet transcriptional signatures in a mouse model of T2D expressing human IAPP revealed decreased cholesterol synthesis and trafficking as a plausible early mediator of IAPP toxicity.

Simultaneous Enhancement of Magnetothermal and Photothermal Responses by Zn, Co Co-Doped Ferrite Nanoparticles.

Reducing nanoparticle (NP) dosage for hyperthermia therapy has remained a great challenge. In this work, efficiencies of alternating current (AC) magnetic field and near-infrared (NIR) heating are simultaneously enhanced by Zn and Co co-doping of magnetite NPs. The optimum magnetic anisotropy for maximized loss power under each magnetic field is achieved by tuning the doping concentration. The specific loss power of Zn0.3 Co0.08 Fe2.62 O4 @SiO2 NPs reaches 2428 W g-1 under an AC field of 27 kA m-1 at 430 kHz; 12 296 W g-1 under NIR laser irradiation at 808 nm and 2.5 W cm-2 ; and an unprecedented value of 14 724 W g-1 under dual mode. These values far exceed what has been achieved previously in iron oxide NPs. Ex vivo experiments on sacrificial mice show that while the NP dosage is substantially reduced to that used for magnetic resonance imaging, the surface body temperature of the mice reaches 50 °C after exposure to both AC field and laser irradiation under field parameters and laser intensity below safety limits. This nanoplatform is thus promising for multi-modal local hyperthermia therapy.

Bone Tumor Suppression in Rabbits by Hyperthermia below the Clinical Safety Limit Using Aligned Magnetic Bone Cement.

Demonstrating highly efficient alternating current (AC) magnetic field heating of nanoparticles in physiological environments under clinically safe field parameters has remained a great challenge, hindering clinical applications of magnetic hyperthermia. In this work, exceptionally high loss power of magnetic bone cement under the clinical safety limit of AC field parameters, incorporating direct current field-aligned soft magnetic Zn0.3 Fe2.7 O4 nanoparticles with low concentration, is reported. Under an AC field of 4 kA m-1 at 430 kHz, the aligned bone cement with 0.2 wt% nanoparticles achieves a temperature increase of 30 °C in 180 s. This amounts to a specific loss power value of 327 W gmetal-1 and an intrinsic loss power of 47 nHm2 kg-1 , which is enhanced by 50-fold compared to randomly oriented samples. The high-performance magnetic bone cement allows for the demonstration of effective hyperthermia suppression of tumor growth in the bone marrow cavity of New Zealand White Rabbits subjected to rapid cooling due to blood circulation, and significant enhancement of survival rate.