In situ forming an injectable hyaluronic acid hydrogel for drug delivery and synergistic tumor therapy.

Stimulus-responsive injectable hydrogel has the key characteristics of in situ drug-loading ability and the controlled drug release, enabling efficient delivery and precise release of chemotherapy drugs at the tumor site, thereby being used as a local drug delivery system for sustained tumor treatment. This article designed a smart responsive injectable hydrogel loaded with anti-tumor drugs and nanoparticles to achieve efficient and specific synergistic treatment of tumors. Hyaluronic acid (HA) hydrogel obtained by cross-linking HA-SH (HS) and HA-Tyr (HT) through horseradish peroxidase (HRP), and doxorubicin hydrochloride (DOX) and folic acid-polyethylene glycol-amine (FA-PEG-NH2) modified PDA (denoted as PPF) were encapsulated to construct the HS/HT@PPF/D hydrogel. The hydrogel had good biocompatibility, injectability, and could respond to multiple stimuli at the tumor site, thereby achieving controlled drug release. At the same time, PPF gave it excellent photothermal efficiency, photothermal stability and tumor targeting. In vitro and in vivo experimental results showed that the HS/HT@PPF/D hydrogel combined with near-infrared laser irradiation could significantly improve its anti-tumor effect and could almost eliminate the entire tumor mass without obvious adverse reactions. The HS/HT@PPF/D hydrogel could achieve multi-stimulus-responsive drug delivery and be used for precise chemo-photothermal synergistic tumor treatment, thus providing a new platform for local synergistic tumor treatment.

In vivo assembly enhanced binding effect augments tumor specific ferroptosis therapy.

Emerging evidence indicates that the activation of ferroptosis by glutathione peroxidase 4 (GPX4) inhibitors may be a prominent therapeutic strategy for tumor suppression. However, the wide application of GPX4 inhibitors in tumor therapy is hampered due to poor tumor delivery efficacy and the nonspecific activation of ferroptosis. Taking advantage of in vivo self-assembly, we develop a peptide-ferriporphyrin conjugate with tumor microenvironment specific activation to improve tumor penetration, endocytosis and GPX4 inhibition, ultimately enhancing its anticancer activity via ferroptosis. Briefly, a GPX4 inhibitory peptide is conjugated with an assembled peptide linker decorated with a pH-sensitive moiety and ferriporphyrin to produce the peptide-ferriporphyrin conjugate (Gi-F-CAA). Under the acidic microenvironment of the tumor, the Gi-F-CAA self-assembles into large nanoparticles (Gi-F) due to enhanced hydrophobic interaction after hydrolysis of CAA, improving tumor endocytosis efficiency. Importantly, Gi-F exhibits substantial inhibition of GPX4 activity by assembly enhanced binding (AEB) effect, augmenting the oxidative stress of ferriporphyrin-based Fenton reaction, ultimately enabling antitumor properties in multiple tumor models. Our findings suggest that this peptide-ferriporphyrin conjugate design with AEB effect can improve the therapeutic effect via induction of ferroptosis, providing an alternative strategy for overcoming chemoresistance.

Spatiotemporally controlled AuNPs@ZIF-8 based nanocarriers for synergistic photothermal/chemodynamic therapy.

High efficiency and spatio-temporal control remains a challenge for multi-modal synergistic cancer therapy. Herein, based on gold nanoparticles (AuNPs) and zeolite-like imidazole skeleton material (ZIF-8), a spatio-temporal controllable photothermal/ chemical dynamic/ chemotherapy three modal synergistic anti-tumor nano-carrier (HAZD) was developed. HAZD has a size of 128.75 ± 11.86 nm, a drug loading ratio of 21.5 ± 2.2 % and an encapsulation efficiency of 71.8 ± 1.7 %. Stability, acid responsive release character, outstanding catalytic ability to generate ROS, relatively high thermal conversion efficiency up to 62.38 % and spatio-temporal controllable abilities are also found within this nano-carrier. Furthermore, HAZD performed good antitumor ability in vivo with the comprehensive effects of photothermal/ chemical dynamic/ chemotherapy. The tumor growth inhibition value is 97.1 % within 12 days, indicating its great potential in multi-modal synergistic cancer therapy. STATEMENT OF SIGNIFICANCE: Cancer remains one of the major culprits that seriously harm human health currently. With the development of materials and nanotechnology, great improvements have been made in multimodal anti-tumor strategies. However, temporal- and spatial-controllable multi-modal synergistic nanocarriers are urgently awaited for efficient and low-toxicity tumor therapy. This article proposes a spatio-temporally controllable three-modal anti-tumor strategy and designs an anti-tumor drug delivery system based on gold nanoparticles (AuNPs) and zeolite-like imidazole skeleton material (ZIF-8), which shows acid-responsive release characteristics, catalytic ability to generate ROS, relatively high thermal conversion efficiency up to 62.38 %, as well as spatio-temporal controllable abilities. Moreover, it demonstrates outstanding anti-tumor ability, with a tumor growth inhibition value of 97.1 % within 12 days, revealing its significant potential for future personalized and precise anti-tumor treatments.

Development and challenges of antimicrobial peptide delivery strategies in bacterial therapy: A review.

The escalating global prevalence of antimicrobial resistance poses a critical threat, prompting concerns about its impact on public health. This predicament is exacerbated by the acute shortage of novel antimicrobial agents, a scarcity attributed to the rapid surge in bacterial resistance. This review delves into the realm of antimicrobial peptides, a diverse class of compounds ubiquitously present in plants and animals across various natural organisms. Renowned for their intrinsic antibacterial activity, these peptides provide a promising avenue to tackle the intricate challenge of bacterial resistance. However, the clinical utility of peptide-based drugs is hindered by limited bioavailability and susceptibility to rapid degradation, constraining efforts to enhance the efficacy of bacterial infection treatments. The emergence of nanocarriers marks a transformative approach poised to revolutionize peptide delivery strategies. This review elucidates a promising framework involving nanocarriers within the realm of antimicrobial peptides. This paradigm enables meticulous and controlled peptide release at infection sites by detecting dynamic shifts in microenvironmental factors, including pH, ROS, GSH, and reactive enzymes. Furthermore, a glimpse into the future reveals the potential of targeted delivery mechanisms, harnessing inflammatory responses and intricate signaling pathways, including adenosine triphosphate, macrophage receptors, and pathogenic nucleic acid entities. This approach holds promise in fortifying immunity, thereby amplifying the potency of peptide-based treatments. In summary, this review spotlights peptide nanosystems as prospective solutions for combating bacterial infections. By bridging antimicrobial peptides with advanced nanomedicine, a new therapeutic era emerges, poised to confront the formidable challenge of antimicrobial resistance head-on.

MicroRNA therapeutics and nucleic acid nano-delivery systems in bacterial infection: a review.

Bacteria that have worked with humans for thousands of years pose a major threat to human health even today, as drug resistance has become a prominent problem. Compared to conventional drug therapy, nucleic acid-based therapies are a promising and potential therapeutic strategy for diseases in which nucleic acids are delivered through a nucleic acid delivery system to regulate gene expression in specific cells, offering the possibility of curing intractable diseases that are difficult to treat at this stage. Among the many nucleic acid therapeutic ideas, microRNA, a class of small nucleic acids with special properties, has made great strides in biology and medicine in just over two decades, showing promise in preclinical drug development. In this review, we introduce recent advances in nucleic acid delivery systems and their clinical applications, highlighting the potential of nucleic acid therapies, especially miRNAs extracted from traditional herbs, in combination with the existing set of nucleic acid therapeutic systems, to potentially open up a new line of thought in the treatment of cancer, viruses, and especially bacterial infectious diseases.

Research progress of nanoparticle targeting delivery systems in bacterial infections.

Bacterial infection is a huge threat to the health of human beings and animals. The abuse of antibiotics have led to the occurrence of bacterial multidrug resistance, which have become a difficult problem in the treatment of clinical infections. Given the outstanding advantages of nanodrug delivery systems in cancer treatment, many scholars have begun to pay attention to their application in bacterial infections. However, due to the similarity of the microenvironment between bacterial infection lesions and cancer sites, the targeting and accuracy of traditional microenvironment-responsive nanocarriers are questionable. Therefore, finding new specific targets has become a new development direction of nanocarriers in bacterial prevention and treatment. This article reviews the infectious microenvironment induced by bacteria and a series of virulence factors of common pathogenic bacteria and their physiological functions, which may be used as potential targets to improve the targeting accuracy of nanocarriers in lesions.

Gold Nanoclusters Enhance the Efficacy of the Polymer-Based Chaperone in Restoring and Maintaining the Native Conformation of Human Islet Amyloid Polypeptide.

The misfolding and un-natural fibrillation of proteins/peptides are associated with many conformation diseases, such as human islet amyloid polypeptide (hIAPP) in type 2 diabetes (T2D). Inspired by molecular chaperones maintaining protein homeostasis in vivo, many polymer-based artificial chaperones were introduced to regulate protein/peptide folding and fibrillation. However, the pure polymer chaperones prefer to agglomerate into large-size micelles in the physiological environment and thus lose their chaperone functions, which greatly restricts the application of polymer-based chaperones. Here, we designed and prepared a core-shell artificial chaperone based on a dozen poly-(N-isopropylacrylamide-co-N-acryloyl-O-methylated-l-arginine) (PNAMR) anchored on a gold-nanocluster (AuNC) core. The introduction of the AuNC core significantly reduced the size and enhanced the efficacy and stability of polymer-based artificial chaperones. The PNAMR@AuNCs, with a diameter of 2.5 ± 0.5 nm, demonstrated exceptional ability in maintaining the natively unfolded conformation of protein away from the misfolding and the following fibrillation by directly binding to the natively unfolded monomolecular hIAPP and hence in preventing their conversion into toxic oligomers. More excitingly, the PNAMR@AuNCs were able to restore the natural unfolded conformation of hIAPP via dissolving the ß-sheet-rich hIAPP fibrils. Considering the uniform molecular mechanism of protein misfolding and fibrillation in conformation disorders, this finding provides a generic therapeutic strategy for neurodegenerative diseases and other conformation diseases by using PNAMR@AuNC artificial chaperones to restore and maintain the native conformation of amyloid proteins.

Nitric Oxide and Tumors: From Small-Molecule Donor to Combination Therapy.

As an important endogenous signaling molecule, nitric oxide (NO) is involved in various physiological and pathological activities in living organisms. It is proved that NO plays a critical role in tumor therapy, while the extremely short half-life and nonspecific distribution of NO greatly limit its further clinical applications. Thus, the past few decades have witnessed the progress made in conquering these shortcomings, including developing innovative NO donors, especially smart and multimodal nanoplatforms. These platforms can precisely control the spatiotemporal distribution of therapeutic agents in the organism, which make big differences in tumor treatment. Here current NO therapeutic mechanisms for cancer, NO donors from small molecules to smart-responsive nanodrug delivery platforms, and NO-based combination therapy are comprehensively reviewed, emphasizing outstanding breakthroughs in these fields and hoping to bring new insights into NO-based tumor treatments.

Recent advances in the intracellular delivery of macromolecule therapeutics.

Intracellular delivery of macromolecules is a critical procedure for biological research and drug discovery, including proteins, peptides, vaccines, antibodies and genes. The penetration of macromolecule therapeutics through the cell membrane to intracellular targets is a prerequisite for their biological activity, but most delivery systems rely on the endocytic pathway to enter the cell and confront an inability to escape from the lysosome. A profound understanding of the cellular internalization of transporting carriers can (i) optimize the design of drug delivery systems, (ii) maintain the biological activity of biomolecular drugs, (iii) improve the efficiency of intracellular macromolecule transport and release, (iv) bring new opportunities for the discovery of macromolecule therapeutics and treatment of refractory disease. This article summarizes the uptake pathway of intracellular delivery vehicles for macromolecule drugs, hoping to provide ideas and references for macromolecule therapeutics delivery systems.

Research progress on tumor hypoxia-associative nanomedicine.

Hypoxia at the solid tumor site is generally related to the unrestricted proliferation and metabolism of cancerous cells, which can cause tumor metastasis and aggravate tumor progression. Besides, hypoxia plays a substantial role in tumor treatment, and it is one of the main reasons that malignant tumors are difficult to cure and have a poor prognosis. On account of the tumor specific hypoxic environment, many hypoxia-associative nanomedicine have been proposed for tumor treatment. Considering the enhanced targeting effect, designing hypoxia-associative nanomedicine can not only minimize the adverse effects of drugs on normal tissues, but also achieve targeted therapy at the lesion site. Mostly, there can be three strategies for the treatment of hypoxic tumor, including improvement of hypoxic environment, hypoxia responsive drug release and hypoxia activated prodrug. The review describes the design principle and applications of tumor hypoxia-associative nanomedicine in recent years, and also explores its development trends in solid tumor treatment. Moreover, this review presents the current limitations of tumor hypoxia-associative nanomedicine in chemotherapy, radiotherapy, photodynamic therapy, sonodynamic therapy and immunotherapy, which may provide a reference for clinic translation of tumor hypoxia-associative nanomedicine.

Emerging single-atom iron catalysts for advanced catalytic systems.

Due to the elusive structure-function relationship, traditional nanocatalysts always yield limited catalytic activity and selectivity, making them practically difficult to replace natural enzymes in wide industrial and biomedical applications. Accordingly, single-atom catalysts (SACs), defined as catalysts containing atomically dispersed active sites on a support material, strikingly show the highest atomic utilization and drastically boosted catalytic performances to functionally mimic or even outperform natural enzymes. The molecular characteristics of SACs (e.g., unique metal-support interactions and precisely located metal sites), especially single-atom iron catalysts (Fe-SACs) that have a similar catalytic structure to the catalytically active center of metalloprotease, enable the accurate identification of active centers in catalytic reactions, which afford ample opportunity for unraveling the structure-function relationship of Fe-SACs. In this review, we present an overview of the recent advances of support materials for anchoring an atomic dispersion of Fe. Subsequently, we highlight the structural designability of support materials as two sides of the same coin. Moreover, the applications described herein illustrate the utility of Fe-SACs in a broad scope of industrially and biologically important reactions. Finally, we present an outlook of the major challenges and opportunities remaining for the successful combination of single Fe atoms and catalysts.

Applications of Gold Nanoparticles in Brain Diseases across the Blood-Brain Barrier.

Brain diseases, including Alzheimer's disease (AD), brain tumors and Parkinson's disease (PD), pose heavy pressure on the public healthcare system. The main obstacle to vanquish brain diseases is the blood-brain barrier (BBB), which is a selective barrier mainly formed by brain endothelial cells. BBB prevents almost all drugs from reaching the brain, thereby hindering drug delivery. Over the past few decades, considerable signs of progress have been made in crossing the BBB and treating brain diseases. Gold nanoparticles (AuNPs) demonstrate the characteristics of adjustable size, unique optical properties, flexible surface modification, and good biocompatibility, which all contribute AuNPs as a promising candidate in biomedical fields. This article reviews the structure and properties of BBB, and discusses main transport routes through the BBB. Besides, nanoparticles, specially AuNPs applied in brain diseases as main drug delivery platforms, are systematically summarized, emphasizing several methods to modify AuNPs, including tuning particle size and surface modification, which are aimed at promoting BBB penetration or prolonging circulation time of AuNPs. In addition, AuNPs utilized in brain diseases are introduced in detail from the aspects of brain imaging, AD, brain tumors, and PD. Prospects and challenges that need to be considered in further investigations and clinical transformation of AuNPs used in brain diseases are also included, hoping to bring new insights into the applications of AuNPs in brain diseases.

Enhanced delivery of theranostic liposomes through NO-mediated tumor microenvironment remodeling.

Highly efficient delivery of nanoagents to the tumor region remains the primary challenge for cancer nanomedicine. Herein, we propose a NO-mediated tumor microenvironment (TME) remodeling strategy for the high-efficient delivery of nanoagents into tumor. Quantum dots (QDs) with bright fluorescence in the near-infrared IIb (NIR-IIb, 1500-1700 nm) window and high photothermal conversion efficiency were encapsulated into liposomes for the imaging-guided photothermal therapy (PTT) of tumor. The fabrication of PEG and arginine-glycine-aspartate (RGD) peptide on liposomes ensured the prolonged circulation in vivo and active targeting to tumor. Moreover, the loading of a natural NO generator L-arginine in liposomes realized the continuous generation of NO in the acidic TME. By co-localization fluorescence imaging and western blot of tumor tissue, we confirmed that the release of NO activated the expression of metalloproteinases in TME and further degraded Collagen I in the peripheral region of the tumor, thus removing the barrier for the permeation of liposomes. Attributed to the enhanced accumulation of liposomes inside the tumor, NIR IIb imaging-guided PTT was achieved with remarkable therapeutic efficacy.

A Lysosome-Targeting Self-Condensation Prodrug-Nanoplatform System for Addressing Drug Resistance of Cancer.

Lysosome-targeting self-assembling prodrugs had emerged as an attractive approach to overcome the acquisition of resistance to chemotherapeutics by inhibiting lysosomal sequestration. Taking advantage of lysosomal acidification induced intracellular hydrolytic condensation, we developed a lysosomal-targeting self-condensation prodrug-nanoplatform (LTSPN) system for overcoming lysosome-mediated drug resistance. Briefly, the designed hydroxycamptothecine (HCPT)-silane conjugates self-assembled into silane-based nanoparticles, which were taken up into lysosomes by tumor cells. Subsequently, the integrity of the lysosomal membrane was destructed because of the acid-triggered release of alcohol, wherein the nanoparticles self-condensed into silicon particles outside the lysosome through intracellular hydrolytic condensation. Significantly, the LTSPN system reduced the half-maximal inhibitory concentration (IC50) of HCPT by approximately 4 times. Furthermore, the LTSPN system realized improved control of large established tumors and reduced regrowth of residual tumors in several drug-resistant tumor models. Our findings suggested that target destructing the integrity of the lysosomal membrane may improve the therapeutic effects of chemotherapeutics, providing a potent treatment strategy for malignancies.

Gold nanoclusters eliminate obesity induced by antipsychotics.

Obesity induced by antipsychotics have plagued more than 20 million people worldwide. However, no drug is available to eliminate the obesity induced by antipsychotics. Here we examined the effect and potential mechanisms of a gold nanoclusters (AuNCs) modified by N-isobutyryl-L-cysteine on the obesity induced by olanzapine, the most prescribed but obesogenic antipsychotics, in a rat model. Our results showed that AuNCs completely prevented and reversed the obesity induced by olanzapine and improved glucose metabolism profile in rats. Further mechanism investigations revealed that AuNCs exert its anti-obesity function through inhibition of olanzapine-induced dysfunction of histamine H1 receptor and proopiomelanocortin signaling therefore reducing hyperphagia, and reversing olanzapine-induced inhibition of uncoupling-protein-1 signaling which increases thermogenesis. Together with AuNCs' good biocompatibility, these findings not only provide AuNCs as a promising nanodrug candidate for treating obesity induced by antipsychotics, but also open an avenue for the potential application of AuNCs-based nanodrugs in treating general obesity.

Engineering Nanointerfaces of Au25 Clusters for Chaperone-Mediated Peptide Amyloidosis.

Synthetic nanomaterials possessing biomolecular-chaperone functions are good candidates for modulating physicochemical interactions in many bioapplications. Despite extensive research, no general principle to engineer nanomaterial surfaces is available to precisely manipulate biomolecular conformations and behaviors, greatly limiting attempts to develop high-performance nanochaperone materials. Here, we demonstrate that, by quantifying the length (-SCxR±, x = 3-11) and charges (R- = -COO-, R+ = -NH3+) of ligands on Au25 gold nanochaperones (AuNCs), simulating binding sites and affinities of amyloid-like peptides with AuNCs, and probing peptide folding and fibrillation in the presence of AuNCs, it is possible to precisely manipulate the peptides' conformations and, thus, their amyloidosis via customizing AuNCs nanointerfaces. We show that intermediate-length liganded AuNCs with a specific charge chaperone peptides' native conformations and thus inhibit their fibrillation, while other types of AuNCs destabilize peptides and promote their fibrillation. We offer a microscopic molecular insight into peptide identity on AuNCs and provide a guideline in customizing nanochaperones via manipulating their nanointerfaces.

Mechanisms of Pannexin 1 (PANX1) Channel Mechanosensitivity and Its Pathological Roles.

Pannexins (PANX) were cloned based on their sequence homology to innexins (Inx), invertebrate gap junction proteins. Although there is no sequence homology between PANX and connexins (Cx), these proteins exhibit similar configurations. The PANX family has three members, PANX1, PANX2 and PANX3. Among them, PANX1 has been the most extensively studied. The PANX1 channels are activated by many factors, including high extracellular K+ ([K+]e), high intracellular Ca2+ ([Ca2+]i), Src family kinase (SFK)-mediated phosphorylation, caspase cleavage and mechanical stimuli. However, the mechanisms mediating this mechanosensitivity of PANX1 remain unknown. Both force-from-lipids and force-from-filaments models are proposed to explain the gating mechanisms of PANX1 channel mechanosensitivity. Finally, both the physiological and pathological roles of mechanosensitive PANX1 are discussed.

Chemical compositions and pharmacological activities of natural musk (Moschus) and artificial musk: A review.

ETHNOPHARMACOLOGICAL RELEVANCE: Natural musk (Moschus), derived naturally from male musk deer (Moschus berezovskii Flerov, Moschus sifanicus Przewalski, or Moschus moschiferus Linnaeus), has long been an important component of traditional Chinese medicine (TCM), and was used as resuscitation, blood circulation, and collateral drainage. detumescence and pain relief. Artificial musk was researched and applied into TCM as natural musk being as unsustainable resources. AIM OF THE STUDY: We mainly summarized chemical compositions, pharmacological activities and mechanism of action of natural and artificial musk, and designed to serve as a foundation for further research into musk chemical compositions and pharmacological effect. MATERIALS AND METHODS: Those mainstream scientific databases including Google Scholar, ScienceDirect, SpringerLink, CNKI, Wiley Online Library, web of science, were used for searching with below "Keywords", as well as literature-tracking. Literatures spanned 1962 to 2021, and involved into Chinese, English, Janpanese, Korean. RESULTS: Natural musk contains some very desirable but scarce compounds, as well as their biological features, which led to the development of artificial musk. The chemical ingredients, pharmacological activities, and mechanisms of action of natural and artificial musk are summarized and compared in this paper. Polypeptide and protein, muscone, musclide, steroids, muscopyridine, and other chemical constituents of musk demonstrated important therapeutic properties against inflammation, immune system disorders, neurological disorders, cardiovascular system disorders, and so on. The mechanism of action contributed to effect on mediators, acceptors and relative signal pathways. CONCLUSIONS: Natural and artificial musk were revealed having some activated compounds, and showed excellent pharmacological effect. Meantime, above two sides of natural and artificial musk ought to get further research.

A phosphorescent probe for in vivo imaging in the second near-infrared window.

In the second near-infrared spectral window (NIR-II; with wavelengths of 1,000-1,700 nm), in vivo fluorescence imaging can take advantage of reduced tissue autofluorescence and lower light absorption and scattering by tissue. Here, we report the development and in vivo application of a NIR-II phosphorescent probe that has lifetimes of hundreds of microseconds and a Stokes shift of 430 nm. The probe is made of glutathione-capped copper-indium-selenium nanotubes, and in acidic environments (pH 5.5-6.5) switches from displaying fluorescence to phosphorescence. In xenograft models of osteosarcoma and breast cancer, intravenous or intratumoral injections of the probe enabled phosphorescence imaging at signal-to-background ratios, spatial resolutions and sensitivities higher than NIR-II fluorescence imaging with polymer-stabilized copper-indium-sulfide nanorods. Phosphorescence imaging may offer superior imaging performance for a range of biomedical uses.

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.