[Aims] Flavonoid apigenin (API) has a wide range of biological functions, particularly anti-inflammation. Indoleamine 2,3-dioxygenase (IDO) and 2-Amino-3-carboxymuconate-6-semialdehyde decarboxylase (ACMSD) are important tryptophan metabolic enzymes that play pivotal roles in the production of toxic metabolite quinolinic acid. However, the relationship between inflammation and ACMSD remains unclear. The present study investigated the relationship between inflammation and tryptophan metabolic key enzymes. Similarly, the anti-inflammatory effect of API on important tryptophan metabolic enzymes was examined in lipopolysaccharide (LPS)-treated microglial cells. [Main methods] MG6 cells were exposed to LPS with or without API treatment for 24-48 h. IDO and ACMSD mRNA expression and production of inflammatory mediators were analyzed. Activation of inflammatory signaling pathways, such as mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB), was also examined to study the mechanism of API in the inflammatory state. [Key findings] LPS suppressed ACMSD expression and enhanced IDO expression. However, API elevated ACMSD mRNA expression and suppressed IDO mRNA expression in LPS-treated MG6 cells. Furthermore, API suppressed interleukin-6 and nitric oxide production, whereas overproduction of inflammatory mediators enhanced IDO expression and assisted tryptophan degradation. API also inhibited activation of extracellular signal-regulated kinase (Erk) and jun N-terminal kinase (JNK) MAPK, and degradation of IκBα. [Significance] These results indicate alteration of ACMSD expression under inflammatory conditions. Moreover, API recovers expression of tryptophan metabolic key enzymes, which may be mediated by inhibition of proinflammatory mediator production via inactivation of Erk, JNK MAPK, and NF-κB pathways in LPS-stimulated microglial cells.

Over the past decade, our understanding of human diseases has rapidly grown from the rise of single-cell spatial biology. While conventional tissue imaging has focused on visualizing morphological features, the development of multiplex tissue imaging from fluorescence-based methods to DNA- and mass cytometry-based methods has allowed visualization of over 60 markers on a single tissue section. The advancement of spatial biology with a single-cell resolution has enabled the visualization of cell-cell interactions and the tissue microenvironment, a crucial part to understanding the mechanisms underlying pathogenesis. Alongside the development of extensive marker panels which can distinguish distinct cell phenotypes, multiplex tissue imaging has facilitated the analysis of high dimensional data to identify novel biomarkers and therapeutic targets, while considering the spatial context of the cellular environment. This mini-review provides an overview of the recent advancements in multiplex imaging technologies and examines how these methods have been used in exploring pathogenesis and biomarker discovery in cancer, autoimmune and infectious diseases.

Asthma is a complicated lung disease, which has increased morbidity and mortality rates in worldwide. There is an overlap between asthma pathophysiology and mitochondrial dysfunction and MSCs may have regulatory effect on mitochondrial dysfunction and treats asthma. Therefore, immune-modulatory effect of MSCs and mitochondrial signaling pathways in asthma was studied. After culturing of MSCs and producing asthma animal model, the mice were treated with MSCs via IV via IT. BALf\'s eosinophil Counting, The levels of IL-4, -5, -13, -25, -33, INF-γ, Cys-LT, LTB4, LTC4, mitochondria genes expression of COX-1, COX-2, ND1, Nrf2, Cytb were measured and lung histopathological study were done. BALf\'s eosinophils, the levels of IL-4, -5, -13, -25, -33, LTB4, LTC4, Cys-LT, the mitochondria genes expression (COX-1, COX-2, Cytb and ND-1), perivascular and peribronchial inflammation, mucus hyper-production and hyperplasia of the goblet cell in pathological study were significantly decreased in MSCs-treated asthma mice and reverse trend was found about Nrf-2 gene expression, IFN-γ level and ratio of the INF-γ/IL-4. MSC therapy can control inflammation, immune-inflammatory factors in asthma and mitochondrial related genes, and prevent asthma immune-pathology.

New strategies for immune modulation have shown real promise in regenerative medicine as well as the fight against autoimmune diseases, allergies, and cancer. Dendritic cells (DCs) are gatekeepers of the immune system and their ability in shaping the adaptive immune responses makes DCs ideal targets for immune modulation. Carbohydrates are abundant in different biological systems and are known to modulate DC phenotype and function. However, how simple monosaccharides instruct DC function is less well understood. In this study, we used a combinatorial array of immobilized monosaccharides to investigate how they modulate DC phenotype and function and crucially the impact of such changes on downstream adaptive immune responses. Our data show that a selection of monosaccharides significantly suppress lipopolysaccharide-induced DC activation as evidenced by a reduction in CD40 expression, IL-12 production, and indoleamine 2,3-dioxygenase activity, while inducing a significant increase in IL-10 production. These changes are indicative of the induction of an anti-inflammatory or regulatory phenotype in DCs, which was further confirmed in DC-T cell co-cultures where DCs cultured on the \'regulatory\' monosaccharide-coated surfaces were shown to induce naïve T cell polarization toward regulatory phenotype. Our data also highlighted a selection of monosaccharides that are able to promote mixed Treg and Th17 cell differentiation, a T cell phenotype expected to be highly immune suppressive. These data show the potential immunomodulatory effects of immobilized monosaccharides in priming DCs and skewing T cell differentiation toward an immune-regulatory phenotype. The ability to fine-tune immune responses using these simple carbohydrate combinations (e.g. as coatings for existing materials) can be utilized as novel tools for immune modulation with potential applications in regenerative medicine, implantable medical devices, and wound healing where reduction of inflammatory responses and maintaining immune homeostasis are desirable.

Immunotherapy strategies targeting the programmed cell death ligand 1 (PD-L1)/programmed cell death 1 (PD-1) pathway in clinical treatments have achieved remarkable success in treating multiple types of cancer. However, owing to the heterogeneity of tumors and individual immune systems, PD-L1/PD-1 blockade still shows slow response rates in controlling malignancies in many patients. Accumulating evidence has shown that an effective response to anti-PD-L1/anti-PD-1 therapy requires establishing an integrated immune cycle. Damage in any step of the immune cycle is one of the most important causes of immunotherapy failure. Impairments in the immune cycle can be restored by epigenetic modification, including reprogramming the environment of tumor-associated immunity, eliciting an immune response by increasing the presentation of tumor antigens, and by regulating T cell trafficking and reactivation. Thus, a rational combination of PD-L1/PD-1 blockade and epigenetic agents may offer great potential to retrain the immune system and to improve clinical outcomes of checkpoint blockade therapy.

Over the past few decades, there has been growing interest in understanding the molecular mechanisms of cancer pathogenesis and progression, as it is still associated with high morbidity and mortality. Current management of large bone sarcomas typically includes the complex therapeutic approach of limb salvage or sacrifice combined with pre- and postoperative multidrug chemotherapy and/or radiotherapy, and is still associated with high recurrence rates. The development of cellular strategies against specific characteristics of tumour cells appears to be promising, as they can target cancer cells selectively. Recently, Mesenchymal Stromal Cells (MSCs) have been the subject of significant research in orthopaedic clinical practice through their use in regenerative medicine. Further research has been directed at the use of MSCs for more personalized bone sarcoma treatments, taking advantage of their wide range of potential biological functions, which can be augmented by using tissue engineering approaches to promote healing of large defects. In this review, we explore the use of MSCs in bone sarcoma treatment, by analyzing MSCs and tumour cell interactions, transduction of MSCs to target sarcoma, and their clinical applications on humans concerning bone regeneration after bone sarcoma extraction.

Breast milk is the only source of the essential amino acid tryptophan (TRP) in breast-fed infants. Low levels of TRP could have implications for infant neurodevelopment. The objectives of the present study were to compare the relationship of TRP and its neuroactive pathway metabolites kynurenine (Kyn) and kynurenic acid (KynA) in preterm and term expressed breast milk (EBM) in the first 14 d following birth, and the relationship of TRP metabolism to maternal stress and immune status. A total of twenty-four mothers were recruited from Cork University Maternity Hospital: twelve term (>38 weeks) and twelve preterm (<35 weeks). EBM samples were collected on days 7 and 14. Free TRP, Kyn and KynA were measured using HPLC, total TRP using MS, cytokines using the Meso Scale Discovery (MSD) assay system, and cortisol using a cortisol ELISA kit. Although total TRP was higher in preterm EBM in comparison with term EBM (P < 0·05), free TRP levels were lower (P < 0·05). Kyn, KynA and the Kyn:TRP ratio increased significantly in term EBM from day 7 to day 14 (P < 0·05), but not in preterm EBM. TNF-α, IL-6 and IL-8 were higher in day 7 preterm and term EBM in comparison with day 14. There were no significant differences between term and preterm EBM cortisol levels. Increased availability of total TRP, lower levels of free TRP and alterations in the temporal dynamics of TRP metabolism in preterm compared with term EBM, coupled with higher EBM inflammatory markers on day 7, may have implications for the neurological development of exclusively breast-fed preterm infants.

Mesenchymal stem cells (MSCs) inhibit the proliferation or activation of lymphocytes, and their inhibitory effects do not require human leukocyte antigen (HLA)-matching because MSCs express low levels of HLA molecules. Therefore, MSCs may be able to regulate immune responses. In this study, we determined whether MSCs could inhibit psoriasis-like skin inflammation in mice. After induction of psoriasis-like skin inflammation using intradermal injection of IL-23 or topical application of imiquimod with or without treatment with MSC, mouse skins were collected, and H&E staining and real-time PCR were performed. IL-23-induced skin inflammation was inhibited when MSCs were injected on day -1 and day 7. The expression of proinflammatory cytokines such as IL-6, IL-17, and TNF-α was inhibited by MSC injection, and the expression of chemokines such as CCL17, CCL20, and CCL27 was also decreased in mouse skin. We also determined whether MSCs could not only prevent but also treat psoriasis-like skin inflammation in mice. Furthermore, in vitro experiments also showed anti-inflammatory effects of MSCs. Dendritic cells which are co-cultured with MSCs suppressed CD4+ T cell activation and differentiation, which are important for the pathogenesis of psoriasis. These results suggest that MSCs could be useful for treating psoriasis.

Indoleamine 2,3-dioxygenase (IDO) is an immunoregulatory enzyme. Remarkably, we discovered IDO-specific T cells that can influence adaptive immune reactions in patients with cancer. Further, a recent phase I clinical trial demonstrated long-lasting disease stabilization without toxicity in patients with non-small-cell lung cancer (NSCLC) who were vaccinated with an IDO-derived HLA-A2-restricted epitope.

The accumulation of tumor infiltrating lymphocytes (TILs) in ovarian cancer is prognostic for increased survival while increases in immunosuppressive regulatory T-cells (Tregs) are associated with poor outcomes. Approaches that bolster tumor-reactive TILs may limit tumor progression. However, identifying tumor-reactive TILs in ovarian cancer has been challenging, though adoptive TIL therapy in patients has been encouraging. Other forms of TIL immunomodulation remain under investigation including Treg depletion, antibody-based checkpoint modification, activation and amplification using dendritic cells, antigen presenting cells or IL-2 cytokine culture, adjuvant cytokine injections, and gene-engineered T-cells. Many approaches to TIL manipulation inhibit ovarian cancer progression in preclinical or clinical studies as monotherapy. Here, we review the impact of TILs in ovarian cancer and attempts to mobilize TILs to halt tumor progression. We conclude that effective TIL therapy for ovarian cancer is at the brink of translation and optimal TIL activity may require combined methodologies to deliver clinically-relevant treatment.