BACKGROUND: The combination of a photosensitizer and indoleamine-2,3 dioxygenase (IDO) inhibitor provides a promising photoimmunotherapy (PIT) strategy for melanoma treatment. A dual drug delivery system offers a potential approach for optimizing the inhibitory effects of PIT on melanoma proliferation and metastasis.
OBJECTIVE: To develop a dual drug delivery system based on PIT and to study its efficacy in inhibiting melanoma proliferation and metastasis.
METHODS: We constructed a multifunctional nano-porphyrin material (P18-APBA-HA) using the photosensitizer-purpurin 18 (P18), hyaluronic acid (HA), and 4-(aminomethyl) phenylboronic acid (APBA). The resulting P18-APBA-HA was inserted into a phospholipid membrane and the IDO inhibitor epacadostat (EPA) was loaded into the internal phase to prepare a dual drug delivery system (Lip\\EPA\\P18-APBA-HA). Moreover, we also investigated its physicochemical properties, targeting, anti-tumor immunity, and anti-tumor proliferation and metastasis effects.
RESULTS: The designed system utilized the pH sensitivity of borate ester to realize an enhanced-targeting strategy to facilitate the drug distribution in tumor lesions and efficient receptor-mediated cellular endocytosis. The intracellular release of EPA from Lip\\EPA\\P18-APBA-HA was triggered by thermal radiation, thereby inhibiting IDO activity in the tumor microenvironment, and promoting activation of the immune response. Intravenous administration of Lip\\EPA\\P18-APBA-HA effectively induced anti-tumor immunity by promoting dendritic cell maturation, cytotoxic T cell activation, and regulatory T cell suppression, and regulating cytokine secretion, to inhibit the proliferation of melanoma and lung metastasis.
CONCLUSIONS: The proposed nano-drug delivery system holds promise as offers a promising strategy to enhance the inhibitory effects of the combination of EPA and P18 on melanoma proliferation and metastasis.

Indoleamine-2,3-dioxygenase 1 (IDO1) is an immunomodulatory enzyme known to catalyse the initial and rate limiting step of kynurenine pathway of l-tryptophan metabolism. IDO1 enzyme over expression plays a crucial role in progression of cancer, malaria, multiple sclerosis and other life-threatening diseases. Several efforts over the last two decades have been invested by the researchers for the discovery of different IDO1 inhibitors and the plasticity of the IDO1 enzyme ligand binding pocket provide ample opportunities to develop new heterocyclic scaffolds targeting this enzyme. In the present work, based on the X-ray crystal structure of human IDO1 coordinated with few ligands, we designed and synthesized new fused heterocyclic compounds and evaluated their potential human IDO1 inhibitory activity (compound 30 and 41 showed IC50 values of 23 and 13 µM, respectively). The identified HITs were observed to be non-toxic to HEK293 cells at 100 µM concentration. The observed activity of the synthesized compounds was correlated with the specific interactions of their structures at the enzyme pocket using docking studies. A detailed analysis of docking results of the synthesized analogues as well as selected known IDO1 inhibitors revealed that most of the inhibitors have some reasonable docking scores in at least two crystal structures and have similar orientation as that of co-crystal ligands.

Itching is an unpleasant sensation on the skin that could negatively impact the quality of life. Over the years, many non-pharmacological and pharmacological approaches have been introduced to mitigate this burdensome condition; However, the effectiveness of these methods remains questioned. Bromhexine, derived from the Adhatoda vasica plant, is a safe drug with minimal side effects. It has been widely used in managing respiratory symptoms over the years. The results of our study revealed that bromhexine has the potential to alleviate acute itch induced by Compound 48/80, a known mast cell destabilizer. According to our findings, bromhexine exerts its antipruritic effects primarily by inhibiting the Transmembrane Protein Serine Protease 2 (TMPRSS2) and, to a lesser extent, by decreasing the activation of the Kynurenine Pathway (KP). We further investigated the KP involvement by administrating 1-Methyl Tryptophan (1-MT), a known indoleamine-2,3-dioxygenase (IDO) inhibitor. 1-MT was found to be effective in reducing the itch itself. Moreover, co-administration of bromhexine and 1-MT resulted in synergistic antipruritic effects, suggesting that KP plays a role in acute itch. To conclude, we have presented for the first time a repositioning of bromhexine as a treatment for acute itch. In addition, we addressed the involvement of TMPRSS2 and KP in this process.

Astragaloside IV (AS-IV) is a chemical found in traditional Chinese medicine called Astragalus membranaceus (Fisch.) Bunge that has antitumor properties. However, the roles and mechanisms of AS-IV in uterine leiomyomas (ULMs) are unclear. The immunosuppressive enzyme indoleamine-2,3-dioxygenase-1 (IDO1) is involved in tumor formation. IDO1 is a new and reliable prognostic indicator for several cancers. In this work, AS-IV was applied to ULM cells in various concentrations. CCK-8, immunofluorescence, and flow cytometry were used to examine the proliferation and apoptosis of ULM cells caused by AS-IV. After lentiviral vector transduction with IDO1 short hairpin RNA (shRNA), the knockdown and overexpression of IDO1 were stable in ULM cells. To verify the antitumor effect of AS-IV in vivo, we established a rat model of uterine leiomyoma. HE staining, Masson staining, and transmission electron microscopy were used to observe pathological changes in the uterus, and the levels of serum sex hormones were measured by radio immune assay (RIA). The levels of CD3+T, CD4+T, and CD25+ Foxp3+Treg in rat peripheral blood were detected by flow cytometry. Western blotting and immunohistochemistry were used to examine protein expression. We found that AS-IV dramatically increased the apoptotic rate of ULM cells and reduced viability in a time- and dosage-dependent manner. After sh-IDO1 lentiviral transfection, we discovered that knocking down IDO1 reversed the effects of AS-IV on ULM cell proliferation and autophagy. We also found that AS-IV can effectively inhibit the growth of ULMs in vivo. AS-IV may promote apoptosis and autophagy in ULMs by activating PTEN/PI3K/AKT signaling through inhibition of IDO1. These findings imply that AS-IV exerts antifibroid effects, and the underlying mechanism may be IDO1, which is involved in proliferation, apoptosis, and autophagy.

Indoleamine-2,3-dioxygenase (IDO) is the \"rate-limiting\" enzyme in the kynurenine (Kyn) pathway of the tryptophan (Trp) catabolism. By its immune-modulatory effect, IDO initiates changes to the physiologically balanced immune state and plays a key role in the pathogenesis of various diseases, as well as in the perioperative setting during surgery. In autoimmune processes, highly malignant cancers such as glioblastoma or organ transplantation, IDO\'s involvement has been studied extensively. However, in severe systemic infections, as present in sepsis, it is not yet completely understood. Hereafter, in this narrative review, we present the current knowledge of IDO\'s implication on such complex immune-related processes. Moreover, we address the role of IDO as a predictive biomarker as well as a therapeutic target for immune-mediated diseases. Finally, we discuss IDO in the setting of surgical trauma-induced stress and highlight its promising use as a biomarker in the pre-operative setting for all disciplines involved in the decision-making process and treatment of patients undergoing surgery.

Indoleamine 2,3 dioxygenase (IDO), first discovered in the 1960s, is an enzyme that has become a highly investigated metabolic target in cancer research. IDO is the rate-limiting step in tryptophan metabolism catabolism into its byproducts - kynurenines. Both IDO and kynurenines have been implicated in altering the tumor microenvironment, allowing for a tolerogenesis by affecting T-cell maturation and proliferation, and more specifically by inducing differentiation into T regulatory cells. Two mechanisms have been suspected in creating this environment: tryptophan starvation and metabolite toxicity. IDO has been shown to be expressed not only in cancer cells but also in antigen-presenting cells. The exact mechanisms underlying the two different sites of expression have not been fully elucidated. To date, most literature has focused on the role of IDO in solid tumors; we provide a review of IDO and its impact on hematological malignancies - more specifically, acute myeloid leukemia. The pathophysiology of IDO will be discussed, including a summarization of the literature to date on how IDO expression effects prognosis and disease progression in acute myeloid leukemia, along with current IDO-specific therapeutics with future considerations.

Dendritic cell (DC)-based vaccine has been established in tumor immunotherapy. Importantly, the efficiency of anti-tumor T-cells in draining lymph nodes is dependent on the status of DCs surrounding in tumors. It has been shown that Indoleamine 2,3-dioxygenase (IDO) plays a key role to induce tolerogenic DCs in tumor microenvironment, and tyrosine kinase inhibitors (TKIs) can suppress the function of IDO in DCs. However, the stimulatory effect of TKI-modified DCs on T cells remains unclear. In this report, we found that one type of TKI-dasatinib can modify DCs to increasing the activation of allogenic T cells. These TKI-modified DCs delayed the onset of B16 melanoma progression in mice. In mechanistic studies, TKIs did not increase the maturation but reduce the expression and phosphorylation levels of IDO and IDO mediated tryptophan metabolism in DCs. In addition, the suppressive effect of TKIs on tryptophan metabolism may be caused by blocking c-Kit pathway in DCs. Furthermore, the increased phosphorylation of general control nonderepressible (GCN2) and decreased expression of aryl hydrocarbon receptor (AhR)/aryl hydrocarbon receptor nuclear translocator (ARNT) were observed in the T cells activated by TKI-modified DCs, suggesting the enhancement of effector function of T cells. These results indicate that TKI could be used to modulate DC immunogenic activity and may potentially be applied in DC-based cancer immunotherapy.

Mesenchymal stem cells (MSCs) are multipotent adult stem cells which have become popular research targets for their use in cellular therapy for tissue repair. While recent advancements in research have shown the MSCs have immunomodulatory functions which are altered in response to host inflammatory molecules, how these stimuli produce different functional outcomes is not understood. Here, we evaluate research examining how the proinflammatory cytokine interferon-γ (IFN-γ) affects the immunomodulatory functions of MSCs by altering their metabolism. This study indicates that IFN-γ causes an increase in glycolytic activity and uncoupling of glycolysis to tricarboxylic acid cycle and hence, the glycolytic metabolites and intermediates can be funneled toward the production of anti-inflammatory modulators indoleamine-2,3-dioxygenase and PGE2. A complete understanding of how MSCs\' cellular metabolism affects their function is necessary for their employment in cellular therapy, as MSCs have been demonstrated to have pro- and anti-inflammatory functions. These findings are a large step forward in the understanding of the regulation of MSCs and toward their eventual use in cellular therapy, specifically for stroke recovery, in which MSCs have been shown to have powerful neuroprotective and neurogenerative effects.

Cancer metastases is still a hurdle for good prognosis and live quality of breast cancer patients. Treatment strategies that can inhibit metastatic cancer while treating primary cancer are needed to improve the therapeutic effect of breast cancer. Methods: In this study, a dual functional drug conjugate comprised of protoporphyrin IX and NLG919, a potent indoleamine-2,3-dioxygenase (IDO) inhibitor, is designed to combine photodynamic therapy and immune checkpoint blockade to achieve both primary tumor and distant metastases inhibition. Liposomal delivery is applied to improve the biocompatibility and tumor accumulation of the drug conjugate (PpIX-NLG@Lipo). A series of in vitro and in vivo experiments were carried out to examine the PDT effect and IDO inhibition activity of PpIX-NLG@Lipo, and subsequently evaluate its anti-tumor capability in the bilateral 4T1 tumor-bearing mice. Results: The in vitro and in vivo experiments demonstrated that PpIX-NLG@Lipo possess strong ability of ROS generation to damage cancer cells directly through PDT. Meanwhile, PpIX-NLG@ Lipo can induce immunogenic cell death to elicit the host immune system. Furthermore, PpIX-NLG@Lipo interferes the activity of IDO, which can amplify PDT-induced immune responses, leading to an increasing amount of CD8+ T lymphocytes infiltrated into tumor site, finally achieve both primary and distant tumor inhibition. Conclusion: This work presents a novel conjugate approach to synergize photodynamic therapy and IDO blockade for enhanced cancer therapy through simultaneously inhibiting both primary and distant metastatic tumor.

A novel library of C2-substituted tryptamines (based on diverse C2-aroyl/arylimino indoles and indole-diketopiperazine hybrids) possessing antimitotic properties were designed, synthesized and screened for their inhibitory activity against tubulin polymerization, and against proliferation of A549 lung cancer, HeLa cervical cancer, MCF7 breast cancer and HePG2 liver cancer cell lines. The design of molecules were inspired from known antimitotic compounds and natural products. The molecular docking of the designed compounds indicated that they bind to the colchicin binding site of tubulin. They were synthesized by a unique iodine catalysed oxidative ring opening reaction of 1-aryltetrahydro-β-carbolines. Among the compounds synthesized quite a few compounds induced cytotoxicity on the cancer cells by disrupting the tubulin polymerization. They were found to be non-toxic for healthy cells. Immuno Fluorescence study for the most active molecules (between ~6 μM concentration) against A549 and HeLa cells demonstrated complete disruption and shrinkage of the microtubule structures. These compounds also inhibited indoleamine-2, 3-dioxygenase with low micromolar IC50.