Effects Of Immune Activation Research Articles

Investigation of age and sex-specific effects of maternal immune activation on insulin signalling and cognitive functions

Investigation of age and sex-specific effects of maternal immune activation on insulin signalling and cognitive functions

Comprehensive evaluation of biopolymer immune implants for peritoneal metastasis carcinoma therapy.

Immunotherapy has been widely used in the treatment of advanced stage cancers with spreading metastases, while the fully activation of immune system often requires sustained and long-acting immune stimulation by immunotherapeutic agents. In previous studies, we designed a biopolymer immune implant by dynamic covalent bonds and achieved sustained release of loaded immunotherapeutic agents, thus stimulated systemic immune activation and elicited immune memory effects. Herein, we further optimized the implants and carried out a comprehensive evaluation of the implants on peritoneal metastasis carcinoma (PMC) therapy. Our results showed that the implants fabricated with 8-arm polyethylene glycol amine (8-arm PEG-NH2) and 40% oxidation degree dextran (ODEX) exhibited a satisfactory degradation time for activating the antitumor immunity. The drug combination of oxaliplatin (OxP) and resiquimod (R848) could be sustainably released from the implants for 18days. The implants cured 75% of mice with PMC and elicited immune memory effects to resist tumor re-challenge without obvious side effects observed. Mechanism analysis revealed that the implants could serve as an in-situ vaccine to enhance the infiltration of activated dendritic cells (DCs), T cells and natural killer (NK) cells inside the tumor, as well as increase the serum tumor necrosis factor α (TNF-α), interferon-γ (IFN-γ) and interleukin 12 (IL-12) levels. These results strongly support the clinical translation potential of this sustained released biopolymer immune implants for PMC therapy.

Gadolinium-Bisphosphonate Nanoparticle-Based Low-Dose Radioimmunotherapy for Osteosarcoma.

Osteosarcoma is a malignant osteogenic tumor with a high metastatic rate commonly occurring in adolescents. Although radiotherapy is applied to treat unresectable osteosarcoma with radiation resistance, a high dose of radiotherapy is required, which may weaken the immune microenvironment. Therefore, there is an urgent need to develop novel agents to maximize the radiotherapeutic effects by eliciting immune activation effects. In this study, we synthesized therapeutic gadolinium-based metal-bisphosphonate nanoparticles (NPs) for osteosarcoma treatment that can be combined with radiotherapy. The gadolinium ion (Gd) was chelated with zoledronic acid (Zol), a commonly used drug to prevent/treat osteoporosis or bone metastases from advanced cancers, and stabilized by ovalbumin (OVA) to produce OVA-GdZol NPs. OVA-GdZol NPs were internalized into K7M2 osteosarcoma cells, showing a high sensitization effect under X-ray irradiation. Cell pretreatment of OVA-GdZol NPs significantly enhanced the radiation therapeutic effect in vitro by reducing the cell colonies and increased the signal of γH2AX-positive cells. More importantly, OVA-GdZol NPs promoted the maturation of bone marrow-derived dendritic cells (BMDCs) and M1 polarization of macrophages. The inhibitory effect on K7M2 osteosarcoma of OVA-GdZol NPs and X-ray radiation was evident, indicated by a significantly reduced tumor volume, high survival rate, and decreased lung metastasis. Meanwhile, both innate and adaptive immune systems were activated to exert a strong antitumor effect. The above results highly suggest that OVA-GdZol NPs serve as both radiosensitizers and immune adjuvants, suitable for the sequential combination of vaccination and radiotherapy.

IMMU-27. SIMULTANEOUS TARGETING OF THE PD-L1 AND THE TGF-Β PATHWAYS WITH BINTRAFUSP ALFA IN EXPERIMENTAL GLIOMAS

Abstract Currently, immunotherapy is one of the most promising research areas in oncology, but immunotherapeutic strategies do not have proven clinical activity against glioblastoma so far. The immunosuppressive microenvironment of gliomas limits an appropriate anti-tumor immune response and represents a major challenge in the context of immunotherapy. Therefore, novel therapeutic strategies that reactivate the immune system and allow for potent anti-glioma immune responses are needed. Bintrafusp alfa is a bifunctional fusion protein that is composed of the extracellular domain of human transforming growth factor-beta receptor type II (TGF-βRII) and a human IgG1 monoclonal antibody blocking programmed death-ligand 1 (PD-L1). It is designed to target the TGF-β and the PDL-1 pathways simultaneously by specifically localizing to the tumor via the anti-PD-L1 moiety and sequestering TGF-β within the tumor microenvironment. We analyzed interrelations between the immunosuppressive factors TGF-β and PD-L1 in glioblastoma samples from patients and observed a significant correlation that points towards a co-regulation of both targets as part of a gene expression network. Next, we assessed the activity of bintrafusp alfa in human and murine glioma cell lines in vitro and observed interference with TGF-β-induced Smad2 phosphorylation as a bona fide response marker of TGF-β pathway activation and an increase in immune cell-mediated glioma cell killing. In vivo, bintrafusp alfa prolonged the survival of glioma-bearing immunocompetent mice, whereas the survival benefit was absent in immunodeficient Rag1-/- mice lacking T and B cell populations. Characterization of the tumor microenvironment by immunohistochemistry and high-dimensional flow cytometry confirmed the immune-activating effects of bintrafusp alfa. In summary, these encouraging results demonstrate that novel treatment options such as bintrafusp alfa may have the potential to overcome the lack of immunogenicity and reinvigorate anti-tumor immune responses to efficiently combat glioblastoma.

Small interfering RNA: Discovery, pharmacology and clinical development-An introductory review.

Post-transcriptional gene silencing targets and degrades mRNA transcripts, silencing the expression of specific genes. RNA interference technology, using synthetic structurally well-defined short double-stranded RNA (small interfering RNA [siRNA]), has advanced rapidly in recent years. This introductory review describes the utility of siRNA, by exploring the underpinning biology, pharmacology, recent advances and clinical developments, alongside potential limitations and ongoing challenges. Mediated by the RNA-induced silencing complex, siRNAs bind to specific complementary mRNAs, which are subsequently degraded. siRNA therapy offers advantages over other therapeutic approaches, including ability of specifically designed siRNAs to potentially target any mRNA and improved patient adherence through infrequent administration associated with a very long duration of action. Key pharmacokinetic and pharmacodynamic challenges include targeted administration, poor tissue penetration, nuclease inactivation, rapid renal elimination, immune activation and off-target effects. These have been overcome by chemical modification of siRNA and/or by utilising a range of delivery systems, increasing bioavailability and stability toallow successful clinical translation. Patisiran (hereditary transthyretin-mediated amyloidosis) was the first licensed siRNA, followed by givosiran (acute hepatic porphyria), lumasiran (primary hyperoxaluria type 1) and inclisiran (familial hypercholesterolaemia), which all use N-acetylgalactosamine (GalNAc) linkage for effective liver-directed delivery. Others are currently under development for indications varying from rare genetic diseases to common chronic non-communicable diseases (hypertension, cancer). Technological advances are paving the way for broader clinical use. Ongoing challenges remain in targeting organs beyond the liver and reaching special sites (e.g., brain). By overcoming these barriers, siRNA therapy has the potential to substantially widen its therapeutic impact.

Integrative analyses of immune-related biomarkers and associated mechanisms in coronary heart disease

Various studies showed that the effect of immune activation is pro-atherogenic and coronary heart disease (CHD) should therefore be considered an autoimmune disease. This study aimed to identify potential immune-related biomarkers, pathways, and the potential regulatory networks underlying CHD. Differentially expressed genes (DEGs) between CHD and control samples were determined by analyzing GSE71226 and GSE9128. The overlapping differential expression immune-related genes (DE-IRGs) for CHD were identified by analyzing the ImmPort database and two GEO databases. A total of 384 DE-IRGs were identified. Subsequently, comprehensive enrichment analyses suggested that DE-IRGs were enriched in immune-related pathways, including autoimmune thyroid disease, the intestinal immune network for IGA production, and downstream signaling events of B cell receptors. The signature of DE-IRGs was validated using an external independent dataset GSE20681 (AUC = 0.875). Furthermore, we conducted protein–protein interaction network analysis and identified eight hub genes, which were most enriched in regulation of defense response, NF-κB signaling pathway, regulation of JNK cascade, and regulation of cytokine production. Moreover, networks of miRNAs-mRNAs and transcription factors (TFs)-mRNA underlying the integrated data were established, involving eight miRNAs and 76 TF-targeting hub genes. Ultimately, 17 SNPs in miRNA-mediated gene networks were identified. We screened potential immune-related genes in CHD and constructed miRNA-mRNA-TF and SNP-miRNA networks, which not only provide inspired insights into the occurrence and the molecular mechanisms of CHD but also lay a foundation for targeting potential biomarkers using immunotherapy and for understanding the molecular mechanisms of CHD.

Delayed effects of neonatal immune activation on brain neurochemistry and hypothalamic-pituitary-adrenal axis functioning.

During the postnatal period, the brain is highly sensitive to stress and inflammation, which are hazardous to normal growth and development. There is increasing evidence that inflammatory processes in the early postnatal period increase the risk of psychopathologies and cognitive impairment later in life. On the other hand, there are few studies on the ability of infectious agents to cause long-term neuroinflammation, leading to changes in the hypothalamic-pituitary-adrenal axis functioning and an imbalance in the neurotransmitter system. In this review, we examine short- and long-term effects of neonatal-induced inflammation in rodents on glutamatergic, GABAergic and monoaminergic systems and on hypothalamic-pituitary-adrenal axis activity.

A homodimeric IL-15 superagonist F4RLI with easy preparation, improved half-life, and potent antitumor activities.

Interleukin-15 (IL-15) is a promising candidate for cancer immunotherapy due to its potent immune-activating effects. There are several IL-15 molecules currently in clinical trials but facing shortages of poor half-life, circulation instability, or complicated production and quality control processes. The aim of this study is to design a novel IL-15 superagonist to set out the above difficulties, and we constructed F4RLI consisting of the GS-linker spaced IgG4 Fc fragment, soluble IL-15 Rα (sIL-15Rα), and IL-15(N72D). Using a single plasmid transient transfection in HEK293E cells, the matured F4RLI was secreted in the form of homodimer and got purified by an easy step of protein A affinity chromatography. The F4RLI product can significantly stimulate the proliferation of human CD3+CD8+ T cells and NK cells in vitro. Meanwhile, F4RLI greatly extended the half-life and prolonged the exposure of IL-15 in mice nearly by 28- and 200-fold, respectively, in comparison with that of the IL-15 monomer. In vivo, F4RLI vastly expanded mouse splenic CD8+ T lymphocytes, illustrating its potential in tumor immunotherapy. Further studies showed that the combination of F4RLI with the immune checkpoint blocker atezolizumab played a synergistic effect in treating MC38 mouse tumor by increasing the percentage of CD8+ T cells in tumor tissue. Moreover, the combination therapy of F4RLI with the angiogenesis inhibitor bevacizumab resulted in significant tumor growth suppression in a xenograft human HT-29 mouse model. Overall, our results demonstrate a homodimeric IL-15 superagonist F4RLI with advances in manufacturing processes and biopharmaceutical applications for cancer immunotherapy. KEY POINTS: • The homodimeric structure of F4RLI facilitates its easy production processes and quality control. • The fusion with Fc and sIL-15Rα extends the plasma half-life of IL-15 by about 28-fold. • F4RLI can play synergistic antitumor activity with the PD-1/PD-L1 checkpoint inhibitor or angiogenesis inhibitor.

Investigating the “two-hit hypothesis”: Effects of prenatal maternal immune activation and adolescent cannabis use on neurodevelopment in mice

Prenatal exposure to maternal immune activation (MIA) and chronic adolescent cannabis use are both risk factors for neuropsychiatric disorders. However, exposure to a single risk factor may not result in major mental illness, indicating that multiple exposures may be required for illness onset. Here, we examine whether combined exposure to prenatal MIA and adolescent delta-9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis, lead to enduring neuroanatomical and behavioural changes in adulthood.Mice were prenatally exposed to viral mimetic, poly I:C (5 mg/kg), or vehicle at gestational day (GD) 9, and postnatally exposed to chronic THC (5 mg/kg, intraperitoneal) or vehicle during adolescence (postnatal day [PND]28–45). Longitudinal magnetic resonance imaging (MRI) was performed pre-treatment, PND 25, post-treatment, PND 50, and in adulthood, PND85, followed by behavioural tests for anxiety-like, social, and sensorimotor gating. Post-mortem assessment of cannabinoid (CB)1 and 2 receptor expressing cells was performed in altered regions identified by MRI (anterior cingulate and somatosensory cortices, striatum, and hippocampus).Subtle deviations in neurodevelopmental trajectory and subthreshold anxiety-like behaviours were observed in mice exposed to both risk factors. Sex-dependent effects were observed in patterns of shared brain-behaviour covariation, indicative of potential sex differences in response to MIA and THC. Density of CB1 and CB2 receptor positive cells was significantly decreased in all mice exposed to MIA, THC, or both.These findings suggest that there may be a cumulative effect of risk factor exposure on gross neuroanatomical development, and that the endocannabinoid system may be sensitive to both prenatal MIA, adolescent THC, or the combination.

Regulatory Effects of Maternal Immune Activation and Environmental Enrichment on Glucocorticoid Receptor and FKBP5 Expression in Stress-sensitive Regions of the Offspring Brain

A mother’s exposure to immune challenge during pregnancy is well known to be a detrimental factor to the development of the offspring’s brain and an impetus for neuropsychiatric disorders. Previous studies have shown that these adverse events can dysregulate the stress response machinery. Two crucial components of the stress axis considered to be affected have been targets in these studies: the glucocorticoid receptor (GR), and FKBP5 which regulates GR activity. The implementation of interventions such as Environmental Enrichment (EE) have shown positive results in protecting the brain against the consequences associated with gestational insults. In light of this, we investigated the transcriptional regulation of GR and FKBP5 from six stress-sensitive brain regions of the offspring using a rat model of maternal immune activation (MIA). Furthermore, we analyzed the effect of an enriched environment on their expression. We found an increase in FKBP5 in MIA rats in five brain regions. RT-qPCR analysis of MIA’s effect on GR yielded insignificant results. However, we found that EE increased GR expression in the medial preoptic area which could be indicative of a positive regulation by EE. This study provides evidence of the impact of both gestational insult and EE on the regulation of stress responsive genes in the developing brain.

Abstract A029: SQ3370: CAPAC platform enables tumor-localized therapy and minimizes systemic toxicities

Abstract Conventional chemotherapies lack specificity for tumor tissue, have a low therapeutic index, and induce systemic toxicities including cardiomyopathy. SQ3370 utilizes the Click Activated Protodrugs Against Cancer (CAPAC) platform to localize doxorubicin (Dox) to tumor tissue while minimizing systemic exposure. SQ3370 consists of an intratumoral injection of a biopolymer followed by 5 daily intravenous doses of an attenuated protodrug of Dox. The tumor-localized activation of Dox is enabled by mutually reactive click chemistry groups on the biopolymer and protodrug, and is therefore agnostic to tumor characteristics that can vary from patient to patient. This allows the CAPAC platform to be readily applicable to diverse tumor types, including heterogeneous sarcoma subtypes. The lead candidate, SQ3370 is currently being evaluated in a Phase I study in patients with advanced solid tumors (NCT04106492). In preclinical studies, SQ3370 treatment showed reduced toxicity, enabling doses of 19.1-fold and 8.9-fold the maximum tolerated dose of conventional Dox in mice and dogs, respectively. Further, there was no evidence of cardiotoxicity in dogs at this dose. In syngeneic dual-tumor mouse models of MCA205 fibrosarcoma, MC38 colon carcinoma, and B16-F10 melanoma, only one tumor was injected with the biopolymer. Following 5 daily intravenous doses of the protodrug, dose-dependent antitumor responses were seen in the injected and non-injected lesions across all syngeneic models. Furthermore, T-cell infiltration was observed in both lesions of the MC38 dual-tumor model, suggesting activation of an antitumor immune response by SQ3370. The combination of SQ3370 with an immune adjuvant (TLR9 agonist) further prolonged overall survival, improved the antitumor response, and increased the number of complete responses compared to the monotherapy, likely by enhancing the immune activation effects of SQ3370. Conventional Dox can induce cardiomyopathy at incidences of 1-20% for cumulative doses from 300-500 mg/m2 in humans. In the Phase I trial, SQ3370 was well tolerated in patients receiving more than 1000 mg/m2 Dox in cumulative doses. Treated tumors included sarcoma (73%), breast cancer (7.7%), gyne (7.7%), and others (11.5%). Dose escalation is ongoing. Most frequent adverse events (AEs), included nausea, fatigue, and anemia. Ejection fraction (LVEF), indicative of cardiac function, remained normal during the study period. No AEs that led to discontinuation or death were related to SQ3370 by investigator assessment.In summary, SQ3370 facilitates localization of Dox at the tumor with minimal systemic toxicity and demonstrates the first proof of concept of the click chemistry-based CAPAC platform. The CAPAC Platform represents a new therapeutic modality to treat solid tumors by using a drug with known efficacy, such as Dox, and expanding its pharmacological capabilities. Citation Format: Jose M. Mejia Oneto, Sangeetha Srinivasan, Jesse M. McFarland, Matthew Tso, Masa Aleckovic. SQ3370: CAPAC platform enables tumor-localized therapy and minimizes systemic toxicities [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A029.

A Triple Therapeutic Strategy with Antiexosomal Iron Efflux for Enhanced Ferroptosis Therapy and Immunotherapy.

Ferroptosis is a form of regulated cell death which can not only kill tumor cells but also enhance immunogenicity of tumor cells, and it is evidenced to be involved in a variety of tumor treatments, especially in cancer immunotherapy. Tumor cell-derived exosomes are reported to influence the progression and metastasis process of tumors. In the process of ferroptosis, exosomes are also demonstrated as mediators to export iron under high intracellular iron concentration and resist ferroptosis. Under this regard, the combined application of ferroptosis inducer and the inhibitor of iron-containing exosomes may enhance the ferroptosis. Herein, biocompatible hybrid nanoparticles composed of the iron oxide nanoparticles, polymers with oxaliplatin attached, and siProminin2 are constructed. The siProminin2 mediated exosomal inhibition can restore the intracellular iron concentration, which can also inhibit the secretion of tumor cell-derived exosomes. The combination of immunotherapy with oxaliplatin, ferroptosis-based cancer therapy and inhibition of tumor cell-derived exosomes can enhance the immune activation effects. The nanoparticles represent an excellent triple therapeutic strategy for enhancing ferroptosis-based cancer therapy and immunotherapy.

ORAL LICHEN PLANUS AND HEPATITIS C: A CASE REPORT

A 65-year-old woman sought treatment for pain in the buccal mucosa, with lesions that appeared and disappeared spontaneously. The patient reported having controlled hypertension and being a social drinker and former smoker. No cervical lymphadenopathy or mucocutaneous alterations were present, and icterus eyes were noted. On intraoral examination, painful nonremovable bilateral white striated and reticulated lesions were observed in the buccal mucosa. Therefore, the diagnosis was oral lichen planus (OLP). Blood count, blood glucose, Serum glutamic-oxalacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT) and hepatite C virus anti-(HCV) exams were requested. Anti-HCV was positive for hepatitis C. Oral lesions were treated with clobetasol propionate mouthwash, with total remission of the lesions. The patient was referred for medical treatment and follow-up. Because OLP is usually observed in patients with hepatitis C infection, considering the effect of persistent systemic inflammation and immune activation, it is important to diagnose correctly to establish treatment and improve the patient's quality of life. A 65-year-old woman sought treatment for pain in the buccal mucosa, with lesions that appeared and disappeared spontaneously. The patient reported having controlled hypertension and being a social drinker and former smoker. No cervical lymphadenopathy or mucocutaneous alterations were present, and icterus eyes were noted. On intraoral examination, painful nonremovable bilateral white striated and reticulated lesions were observed in the buccal mucosa. Therefore, the diagnosis was oral lichen planus (OLP). Blood count, blood glucose, Serum glutamic-oxalacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT) and hepatite C virus anti-(HCV) exams were requested. Anti-HCV was positive for hepatitis C. Oral lesions were treated with clobetasol propionate mouthwash, with total remission of the lesions. The patient was referred for medical treatment and follow-up. Because OLP is usually observed in patients with hepatitis C infection, considering the effect of persistent systemic inflammation and immune activation, it is important to diagnose correctly to establish treatment and improve the patient's quality of life.

Biomineralized hydrogel DC vaccine for cancer immunotherapy: A boosting strategy via improving immunogenicity and reversing immune-inhibitory microenvironment

The postoperative recurrence and metastasis of triple negative breast cancer (TNBC) remain one fatal reason for the failure of clinical treatments. Although the rise of immunotherapy has brought hopes for reducing postoperative recurrence and potential metastasis, the low immune response and immunosuppression of tumor microenvironment (TME) still restrain its extensive application. Herein, we reported a boosting strategy by improving immunogenicity and reversing suppressive TME to realize efficient immunotherapy of TNBC. In this work, a CaCO3 biomineralized hydrogel DC vaccine was synthesized by fixing the membrane proteins of 4T1 cells-DCs fusion cells (FP) into biomineralized silk fibroin hydrogel. On one side, the FP-containing biomineralized hydrogel vaccine (SH@FP@CaCO3) has increased immunogenicity by providing a wide variety of tumor-associated antigens (TAAs) and realizing long-term protein release for DCs maturation and T cell activation. On the other side, the introduction of CaCO3 would increase the pH of TME and promote the polarization of M2-type macrophages to M1-type macrophages, thus reversing the immune-inhibitory microenvironment and relieving the immunosuppressive effect on T cells. The results indicate that the biomineralized hydrogel vaccine shows excellent immune activation effects by simultaneously enhancing the immunogenicity and reversing the immunosuppression TME, which provides a promising strategy for cancer immunotherapy.

Comprehensive characterization of glucomannans from different sources to trigger moderate macrophages immune activation

Macrophage activation is involved in the outcome of many diseases and is recognized as one of the best targets for disease intervention. Glucomannans had shown promising immunomodulatory potential. Herein, the activation performance of macrophages by glucomannans from different sources was thoroughly investigated. Glucomannans triggered the immune activation of macrophages, which was mainly manifested in increasing the secretion of immune effector molecules, enhancing the endocytosis and phagocytosis of macrophages, and selectively facilitating the expression of M1 phenotype. The participation of NF-κB and MAPK signaling pathways further validated the immune activation of macrophages by glucomannans. Correlation analysis indicated acetyl might be a feasible target for glucomannans to induce immune activation and the molecular weight (Mw) of glucomannans was also inseparable from the performance of immune activation. In conclusion, glucomannans showed a moderate immune activation effect on macrophages, and their difference in immune activation was closely related to the acetyl content and Mw.

Synthesis, Antibacterial Activity, and Action Mechanism of Novel Sulfonamides Containing Oxyacetal and Pyrimidine.

Bacterial leaf blight (BLB) and bacterial leaf streak (BLS) are two serious bacterial diseases caused by Xanthomonas oryzae pv. oryzae (Xoo) and Xanthomonas oryzae pv. oryzicola (Xoc), respectively. However, the control of these diseases by conventional pesticides remains challenging due to development of resistances. We aimed to address this pending problem and developed a series of novel pyrimidine sulfonamide derivatives. Structurally, title compounds bear a unique oxyacetal group, which has a proven immune-activating effect. Compound E35 designed based on the 3D-QSAR model was demonstrated as the optimal in vitro activity against Xoo and Xoc, with EC50 values of 26.7 and 30.8 mg/L, respectively, which were higher than the positive controls bismerthiazol (29.9 and 32.7 mg/L) and thiodiazole copper (30.5 and 36.4 mg/L). On the prevention level, the biological activity test showed compound E35 had superior protective activity (43.7%) on BLS to thiodiazole copper (32.1%). The defense enzymes and proteomics results suggested that compound E35 could be a versatile candidate as it improved plant's resistance to disease.

Biodegradable hydrogen peroxide nanogenerator for controllable cancer immunotherapy via modulating cell death pathway from apoptosis to pyroptosis

Damage-associated molecular patterns (DAMPs) generated by dying tumor cells can react with host immune systems to activate autonomous immune responses. However, there are still huge challenges in achieving precise release of DAMPs for controllable cancer immunotherapy. As we all know, apoptosis is a process by which cells automatically end their lives determined by genes, and generally does not cause the strong release of DAMPs and immune responses. However, pyroptosis, as an emerging unique pathway of programmed cell death, can trigger a strong inflammatory response by generating large amount of DAMPs. Based on this, we prepared ZnO2 as the donator of H2O2 to trigger pyroptosis and apoptosis by using high concentration of ZnO2 (HZnO2) and low concentration of ZnO2 (LZnO2) respectively, and further compared the different immune activation effects between these two cell death pathways. For the first time, we found HZnO2 can induce pyroptosis effectively and its immune activation effect is better than that of apoptosis induced by LZnO2. Therefore, this nanoplatform provides a new pyroptosis inducer and a new insight for understanding the relationship between cell death pathway and immune responses.

Interactions Among Brain-Derived Neurotrophic Factor and Neuroimmune Pathways Are Key Components of the Major Psychiatric Disorders.

The purpose of this review is to summarize the current knowledge regarding the reciprocal associations between brain-derived neurotrophic factor (BDNF) and immune-inflammatory pathways and how these links may explain the involvement of this neurotrophin in the immune pathophysiology of mood disorders and schizophrenia. Toward this end, we delineated the protein-protein interaction (PPI) network centered around BDNF and searched PubMed, Scopus, Google Scholar, and Science Direct for papers dealing with the involvement of BDNF in the major psychosis, neurodevelopment, neuronal functions, and immune-inflammatory and related pathways. The PPI network was built based on the significant interactions of BDNF with neurotrophic (NTRK2, NTF4, and NGFR), immune (cytokines, STAT3, TRAF6), and cell-cell junction (CTNNB, CDH1) DEPs (differentially expressed proteins). Enrichment analysis shows that the most significant terms associated with this PPI network are the tyrosine kinase receptor (TRKR) and Src homology region two domain-containing phosphatase-2 (SHP2) pathways, tyrosine kinase receptor signaling pathways, positive regulation of kinase and transferase activity, cytokine signaling, and negative regulation of the immune response. The participation of BDNF in the immune response and its interactions with neuroprotective and cell-cell adhesion DEPs is probably a conserved regulatory process which protects against the many detrimental effects of immune activation and hyperinflammation including neurotoxicity. Lowered BDNF levels in mood disorders and schizophrenia (a) are associated with disruptions in neurotrophic signaling and activated immune-inflammatory pathways leading to neurotoxicity and (b) may interact with the reduced expression of other DEPs (CTNNB1, CDH1, or DISC1) leading to multiple aberrations in synapse and axonal functions.

Icaritin-loaded PLGA nanoparticles activate immunogenic cell death and facilitate tumor recruitment in mice with gastric cancer

This study aimed to explore the anti-tumor effect of icaritin loading poly (lactic-co-glycolic acid) nanoparticles (refer to PLGA@Icaritin NPs) on gastric cancer (GC) cells. Transmission Electron Microscope (TEM), size distribution, zeta potential, drug-loading capability, and other physicochemical characteristics of PLGA@Icaritin NPs were carried out. Furthermore, flow cytometry, confocal laser scanning microscope (CLSM), Cell Counting Kit-8 (CCK-8), Transwell, Elisa assay and Balb/c mice were applied to explore the cellular uptake, anti-proliferation, anti-metastasis, immune response activation effects, and related anti-tumor mechanism of PLGA@Icaritin NPs in vitro and in vivo. PLGA@Icaritin NPs showed spherical shape, with appropriate particle sizes and well drug loading and releasing capacities. Flow cytometry and CLSM results indicated that PLGA@Icaritin could efficiently enter into GC cells. CCK-8 proved that PLGA@Icaritin NPs dramatically suppressed cell growth, induced Lactic dehydrogenase (LDH) leakage, arrested more GC cells at G2 phase, and inhibited the invasion and metastasis of GC cells, compared to free icaritin. In addition, PLGA@Icaritin could help generate dozens of reactive oxygen species (ROS) within GC cells, following by significant mitochondrial membrane potentials (MMPs) loss and excessive production of oxidative-mitochondrial DNA (Ox-mitoDNA). Since that, Ox-mitoDNA further activated the releasing of damage associated molecular pattern molecules (DAMPs), and finally led to immunogenic cell death (ICD). Our in vivo data also elaborated that PLGA@Icaritin exerted a powerful inhibitory effect (∼80%), compared to free icaritin (∼60%). Most importantly, our results demonstrated that PLGA@Icaritin could activate the anti-tumor immunity via recruitment of infiltrating CD4+ cells, CD8+ T cells and increased secretion of cytokine immune factors, including interferon-γ (IFN-γ) tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1).++ Our findings validate that the successful design of PLGA@Icaritin, which can effectively active ICD and facilitate tumor recruitment in GC through inducing mitoDNA oxidative damage.

Dual hit mouse model to examine the long-term effects of maternal immune activation and post-weaning social isolation on schizophrenia endophenotypes

Evidence suggests that early life adversity, such as maternal immune activation (MIA), can alter brain development in the offspring and confer increased risk for psychopathology and psychiatric illness in later life. In this study, the long-term effects of MIA, post-weaning social isolation, and the combination were assessed on behavioural and immunological profiles in adult male and female offspring.On gestation day 12.5, pregnant mice were weighed and injected with either polyinosinic:polycytidylic acid (5 mg/kg) or saline and cytokines levels were assayed 3 hrs later to confirm immune activation. The behaviour and immunological profiles of male and female offspring were examined in adolescence (P34–36), and adulthood (P55–80).MIA induced an increase in the pro-inflammatory cytokine IL-6 in pregnant dams three hours after administration (p < 0.001) that correlated with a decrease in body temperature (p < 0.05). The effect of MIA on the immunological phenotype of the offspring was evident in adolescence, but not in adulthood. MIA selectively induced hypoactivity in adolescent males, a phenotype that persisted until adulthood, but had no effect on cognition in males or females. In contrast, social isolation stress from adolescence resulted in impaired sociability (p < 0.05) and increased anxiety (p < 0.05) particularly in adult females. There was no synergistic effect of the dual-hit on immune parameters, sociability, anxiety or cognitive behaviours.Given the negative impact and sex-dependent effects of SI stress on locomotor and anxiety-like behaviour, future investigations should examine whether the health risks of social isolation, such as that experience during the COVID-19 pandemic, are mediated through increased anxiety.