HFD-exacerbated Metabolic Side Effects of Olanzapine Are Suppressed by ER Stress Inhibitor.

OBJECTIVE: Numerous schizophrenic patients are suffering from obesity primarily attributed to antipsychotic medication and poor dietary habits. This study investigated the progressive deterioration of olanzapine-induced metabolic disorders in the presence of a high-fat diet (HFD) and explored the involvement of endoplasmic reticulum (ER) stress. METHODS: Female Sprague-Dawley rats fed on a standard chow diet or HFD were treated with olanzapine (3 mg/kg/day) and the ER stress inhibitor 4-phenylbutyric acid (4-PBA, 1 and 0.5 g/kg/day) for 8 days. Changes in body weight, food intake, and plasma lipids were assessed. Hepatic fat accumulation was evaluated using oil red O staining. Western blotting and immunofluorescence assays were employed to examine the expression of ER stress markers, NOD-like receptor pyrin domain-containing protein 3 (NLRP3), and proopiomelanocortin (POMC) in the hypothalamus or liver. RESULTS: Compared to olanzapine alone, olanzapine+HFD induced greater weight gain, increased hyperlipidemia, and enhanced hepatic fat accumulation (P<0.05). Co-treatment with 4-PBA exhibited a dose-dependent inhibition of these effects (P<0.05). Further mechanistic investigations revealed that olanzapine alone activated ER stress, upregulated NLRP3 expression in the hypothalamus and liver, and downregulated hypothalamic POMC expression. The HFD exacerbated these effects by 50%-100%. Moreover, co-administration of 4-PBA dose-dependently attenuated the olanzapine+HFD-induced alterations in ER stress, NLRP3, and POMC expression in the hypothalamus and liver (P<0.05). CONCLUSION: HFD worsened olanzapine-induced weight gain and lipid metabolic disorders, possibly through ER stress-POMC and ER stress-NLRP3 signaling. ER stress inhibitors could be effective in preventing olanzapine+HFD-induced metabolic disorders.

Olanzapine Induces Inflammation and Immune Response via Activating ER Stress in the Rat Prefrontal Cortex.

OBJECTIVE: Antipsychotics, in particular olanzapine, are first-line medications for schizophrenia. The prefrontal cortex (PFC) is an important region for antipsychotics' therapeutic effects. The PFC inflammatory and immune pathways are associated with schizophrenia pathogenesis. However, the effect of antipsychotics on the inflammatory and immune pathways in the PFC remains unclear. We aimed to examined the time-dependent effect of olanzapine on inflammatory and immune markers in the PFC of rats. Since the inflammatory and immune pathways are related to endoplasmic reticulum (ER) stress, we further investigated whether or not olanzapine-induced inflammation and immune responses were related to ER stress. METHODS: Expression of pro-inflammatory markers including IkappaB kinase ß (IKKß), nuclear factor kappa B (NFκB), tumor necrosis factor α (TNF-α), interleukin-6 (IL-6) and IL-1ß, and immune-related proteins including inducible nitric oxide synthase (iNOS), toll-like receptor 2 (TLR2) and cluster of differentiation 14 (CD14) were examined by Western blotting. RESULTS: Olanzapine treatments for 1, 8 and 36 days significantly activated the inflammatory IKKß/NFκB signaling, and increased the expression of TNF-α, IL-6, IL-1ß and immune-related proteins such as iNOS, TLR4 and CD14. Olanzapine treatment for 1 day, 8 and 36 days also induced ER stress in the PFC. Co-treatment with an ER stress inhibitor, 4-phenylbutyrate, inhibited olanzapine-induced inflammation and the immune response in the PFC. CONCLUSION: These results suggested olanzapine exposure could be a factor that induces central inflammation and immunological abnormities in schizophrenia subjects. Olanzapine induces PFC inflammation and immune response, possibly via activating ER stress signaling.

Incorporating spin-orbit effects into surface hopping dynamics using the diagonal representation: a linear-response time-dependent density functional theory implementation with applications to 2-thiouracil.

In this study, we present a trajectory surface hopping (TSH) method that incorporates spin-orbit (SO) effects using the "diagonal representation" within the Linear-Response Time-Dependent Density Functional Theory (LR-TDDFT) framework. In this approach, the evaluation of spin-orbit coupling (SOC) matrix elements between singlet and triplet states employs the Casida's wave functions and the Breit-Pauli (BP) spin-orbit Hamiltonian with effective charge approximation. The new TSH approach is then used to investigate the excited-state relaxation of 2-thiouracil (2TU) in vacuum and water. On the basis of the simulation results, relaxation of the initially populated bright state is found to be dominated by the route S2 → S1 → T. The intersystem crossing (ISC) can occur at either the C2-puckered structure or the C2-pyramidalized S1 minimum, and is promoted by a three-state near-degeneracy (S1/T2/T1 in vacuum or S1/T3/T2 in water) as well as sizable SOCs. Our simulations achieve a good agreement with the available experimental measurements in terms of the internal conversion (IC) and ISC time scales, and complement the picture of the relaxation mechanisms of 2TU after photo-excitation to the first bright state.

"Self-repairing" nanoshell for cell protection.

Self-repair is nature's way of protecting living organisms. However, most single cells are inherently less capable of self-repairing, which greatly limits their wide applications. Here, we present a self-assembly approach to create a nanoshell around the cell surface using nanoporous biohybrid aggregates. The biohybrid shells present self-repairing behaviour, resulting in high activity and extended viability of the encapsulated cells (eukaryotic and prokaryotic cells) in harsh micro-environments, such as under UV radiation, natural toxin invasion, high-light radiation and abrupt pH-value changes. Furthermore, an interaction mechanism is proposed and studied, which is successful to guide design and synthesis of self-repairing biohybrid shells using different bioactive molecules.