Search Results (297)

Indoleamine 2,3-dioxygenase 1 (IDO-1) and interferon-gamma (IFN-γ) are proteins that play a significant role in inflammatory conditions and tumor development. The detection of IDO1 and IFN-γ is crucial for understanding their interplay in immune responses. This study introduced a novel method for the simultaneous quantitative determination of IDO-1 and IFN-γ in different biological samples/materials. The method is based on an optical biosensor, with surface plasmon resonance detection carried out by the imaging version of the sensor (SPRi). Biotinylated antibodies immobilized on the surfaces of the linker and carboxymethylated dextran served as the recognition elements for the developed biosensor. Relevant studies were conducted to optimize the activities of the biosensor by employing appropriate reagent concentrations. Validation was performed for each protein separately; low detection and quantification limits were obtained (for IDO-1 LOD = 0.27 ng/mL, LOQ = 0.81 ng/mL; for IFN-γ LOD = 1.76 pg/mL and LOQ = 5.29 pg/mL). The sensor operating ranges were 0.001–10 ng/mL for IDO-1 and 0.1–1000 pg/mL for IFN-γ. The constructed biosensor demonstrated its sensitivity and precision when the appropriate analytical parameters were determined, based on the proposed method. It can also selectively capture IDO-1 and IFN-γ from a large sample matrix. The biosensor efficiency was confirmed by the determination of IDO-1 and IFN-γ in simultaneous measurements of the plasma and urine samples of patients diagnosed with bladder cancer and the control group. The outcomes were compared to those obtained using a certified ELISA test, demonstrating convergence between the two methodologies. The preliminary findings demonstrate the biosensor’s efficacy and suitability for comprehensive analyses of the examined biological samples. Full article

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immune cells that play a central role in regulating host immune responses during fungal infections. Their recruitment is mediated by pathogen recognition receptors, particularly Dectin-1 and CARD9 signaling, which promote the production of reactive oxygen species (ROS) and IL-1β. Once activated, MDSCs suppress T-cell and natural killer cell functions through immunosuppressive cytokines like IL-10 and TGF-β, as well as enzymes such as arginase-1 and indoleamine 2,3-dioxygenase 1 (IDO-1). This review explores the role of MDSCs in fungal infections caused by Candida spp., Paracoccidioides brasiliensis, Aspergillus spp., and Cryptococcus neoformans, emphasizing their impact on immune modulation and disease progression. The emerging evidence suggests that fungal bioactive compounds, such as polysaccharides, can influence MDSC activity and restore immune balance. Notably, therapies targeting MDSCs have demonstrated promise in both fungal infections. In particular, infections with P. brasiliensis and C. neoformans show improved T-cell responses following MDSC-targeted interventions. Additionally, polysaccharides from Grifola frondosa and exposure to Aspergillus sydowii affect MDSC behavior, supporting the potential of modulating these cells therapeutically. Together, these findings highlight the relevance of MDSCs in fungal pathogenesis and underscore their potential as targets for immunotherapeutic strategies in infectious diseases. Full article

Machine learning (ML) algorithms hold the potential to outperform the selection of patients for immunotherapy (ICIs) compared to previous biomarker studies. We analyzed the predictive performance of ML models and compared them to traditional clinical biomarkers (TCBs) in the field of gastrointestinal (GI) cancers. The study has been registered in PROSPERO (number: CRD42023465917). A systematic search of PubMed was conducted to identify studies applying different ML algorithms to GI cancer patients treated with ICIs using tumor RNA gene expression profiles. The outcomes included were response to immunotherapy (ITR) or survival. Additionally, we compared the ML methodology details and predictive power inherent in the published gene sets using 5-fold cross-validation and logistic regression (LR), on an available well-defined ICI-treated metastatic gastric cancer (GC) cohort (n = 45). A set of standard clinical ICI biomarkers (MLH, MSH, and CD8 genes, plus PMS2 and PD-L1)) and de-novo calculated principal components (PCs) of the original datasets were also included as additional points of comparison. Nine articles were identified as eligible to meet the inclusion criteria. Three were pan-cancer studies, five assessed GC, and one studied colorectal cancer (CRC). Classification and regression models were used to predict ICI efficacy. Next, using LR, we validated the predictive power of applied ML algorithms on RNA signatures, using their reported receiver operating characteristics (ROC) analysis area under the curve (AUC) values on a well-defined ICI-treated gastric cancer (GC) dataset (n = 45). In two cases our method has outperformed the published results (reported/LR comparison: 0.74/0.831, 0.67/0.735). Besides the published studies, we have included two benchmarks: a set of TCBs and using principal components based on the whole dataset (PCA, 99% explained variance, 40 components). Interestingly, a study using a selected gene set (immuno-oncology panel) with AUC = 0.83 was the only one that outperformed the TCB (AUC = 0.8) and the PCA (AUC =0.81) results. Cross-validation of the predictive performance of these genes on the same GC dataset and an investigation of their prognostic role on a collated multi-cohort GC dataset of n = 375 resected, or chemotherapy-treated patients revealed that genes mannose-6-phosphate receptor (M6PR), Indoleamine 2,3-Dioxygenase 1 (IDO1), Neuropilin-1 (NRP1), and MAGEA3 performed similarly, or better than established biomarkers like PD-L1 and MSI. We found an immuno-oncology panel with an AUC = 0.83 that outperformed the clinical benchmark or the PC results. We recommend further investigation and experimental validation in the case of M6PR, IDO1, NRP1, and MAGEA3 expressions based on their strong predictive power in GC ITR. Well-designed studies with larger sample sizes and nonlinear ML models might help improve biomarker selections. Full article

Chitosan is increasingly utilized in combination with melatonin in novel formulations for a wide range of therapeutic applications. As a biocompatible and biodegradable polymer, chitosan exhibits notable properties, including antioxidant, antimicrobial, moisturizing, and absorption capabilities, in addition to a high potential for chemical modification due to its functional groups. These characteristics make it a valuable material in biomedical, pharmaceutical, cosmetic, food packaging, and environmental applications. Melatonin, an indoleamine primarily synthesized in the pineal gland but also found in various peripheral organs and in diverse organisms—including plants, bacteria, and fungi—has been extensively investigated for its antioxidant, anti-apoptotic, and anti-inflammatory activities, as well as its roles in immunomodulation, mitochondrial function, and melanin biosynthesis. This review summarizes recent advances in the combined use of chitosan and melatonin, with emphasis on their synergistic effects in wound healing, anti-cancer therapies, tissue engineering (i.e., skin and bone regeneration), and drug delivery systems. Additional potential applications are discussed in the context of cosmetology, aesthetic medicine, and veterinary practice. Full article

To clarify the physiological importance of the tryptophan catabolizing enzyme, indoleamine 2,3-dioxygenase, in human pregnancy, we have studied how the expression of this enzyme controls extravillous cytotrophoblast invasion into the decidua. We have generated an Ishikawa cell line stably transfected with a plasmid encoding indoleamine 2,3-dioxygenase under the control of a tetracycline inducible promoter. Using this Ishikawa cell line and extravillous cytotrophoblast cell line, HTR-8/SVneo, we developed a quantitative in vitro trophoblast invasion assay. When trophoblast cells were cultured on a layer of Ishikawa cells expressing indoleamine 2,3-dioxygenase, tryptophan degradation was enhanced and trophoblast cell invasion was suppressed. These findings suggest that indoleamine 2,3-dioxygenase expressed in the decidua may play a role in regulating trophoblast invasion. Full article

In order to take advantage of both immunotherapeutic and epigenetic antitumor agents, a series of imidazothiazole-based hydroxamic acid derivatives were designed based on the pharmacophore fusion strategy and evaluated as potent IDO1 and HDAC6 dual inhibitors. Among these inhibitors, the most potent compound 3-(4-Bromophenyl)-N-{4-[(7-(hydroxyamino)-7-oxoheptyl)amino]phenyl}imidazo[2,1-b]thiazole-5-carboxamide (10e) showed considerable IDO1 inhibitory activity and a good selectivity profile for HDAC6 over the other HDAC isoforms. The intracellular inhibition of HDAC6 by 10e was validated by Western blot analysis. Docking studies illustrated that the possible binding modes of compound 10e interacted with IDO1 and HDAC6. Moreover, compound 10e was found to arrest the cell cycle at the G2/M phase in HCT-116 cells. In particular, compound 10e also exhibited potent in vivo antitumor efficacy in CT26 tumor-bearing BALB/c mice models, with no significant toxicity. Collectively, this work provides a promising lead compound that serves as IDO1/HDAC6 dual inhibitor for the development of novel antitumor agents. Full article

Background and Objectives: Acute ulcerative colitis is characterized by excessive mucosal inflammation and epithelial disruption, often driven by dysregulated cytokine and immune signaling. Indoximod (1-methyl-DL-tryptophan), although not a direct enzymatic inhibitor, modulates the indoleamine 2,3-dioxygenase (IDO) pathway and has been reported to exert immunoregulatory effects in various models of inflammation. This study aimed to evaluate the protective effects of Indoximod in an acetic acid-induced colitis model in rats, focusing on histopathological changes and inflammatory mediators. Materials and Methods: Thirty male Wistar albino rats were randomly assigned to three groups (n = 10 per group): Group 1 (Control) received 0.9% saline oral gavage; Group 2 (Colitis) received intrarectal 4% acetic acid to induce colitis and were then treated with saline; Group 3 (Colitis + Indoximod) received 4% acetic acid followed by oral gavage administration of Indoximod (30 mg/kg) for 15 consecutive days. Histopathological evaluation of colonic tissues was performed using hematoxylin and eosin (H&E) staining. Colonic expression of Toll-like receptor 4 (TLR4) and plasma levels of tumor necrosis factor-alpha (TNF-α), pentraxin-3 (PTX-3), and platelet-activating factor (PAF) were quantified using enzyme-linked immunosorbent assay (ELISA). Results: Acetic acid-induced colitis significantly increased mucosal damage, TLR4 expression, and circulating levels of TNF-α, PTX-3, and PAF compared with controls (p < 0.001). Indoximod treatment markedly reduced histological injury and significantly suppressed TLR4 and TNF-α levels (p < 0.01), along with partial reductions in PTX-3 (p < 0.05). However, PAF levels remained elevated despite treatment, indicating limited efficacy in PAF-associated pathways. Conclusions: Indoximod exhibited anti-inflammatory effects in this acute colitis model, likely by downregulating key proinflammatory mediators. Full article

Background: Glaucoma is a leading cause of irreversible visual loss worldwide, characterized by progressive retinal ganglion cell (RGC) degeneration and optic nerve damage. Current therapies mainly focus on lowering intraocular pressure (IOP), yet fail to address pressure-independent neurodegenerative mechanisms. Melatonin, an endogenously produced indoleamine, has gained attention for its potential in modulating both IOP and neurodegeneration through diverse cellular pathways. This review evaluates the therapeutic relevance of melatonin in glaucoma by examining its mechanistic actions and emerging delivery approaches. Methods: A comprehensive literature search was conducted via PubMed and Medline to identify studies published between 2000 and 2025 on melatonin’s roles in glaucoma. Included articles discussed its effects on IOP regulation, RGC survival, oxidative stress, mitochondrial integrity, and inflammation. Results: Evidence supports melatonin’s involvement in IOP reduction via MT receptor activation and its synergism with adrenergic and enzymatic regulators. Moreover, it protects RGCs by mitigating oxidative stress, preventing mitochondrial dysfunction, and inhibiting apoptotic and inflammatory cascades. Recent advances in ocular drug delivery systems enhance its bioavailability and therapeutic potential. Conclusions: Melatonin represents a multi-target candidate for glaucoma treatment. Further clinical studies are necessary to establish optimal dosing strategies, delivery methods, and long-term safety in patients. Full article

Immunotherapy has become one of the primary forms of cancer treatment. The inhibition of immune checkpoint molecules, including indoleamine 2,3-dioxygenase (IDO), is a promising approach for immunotherapy. Phosphatase and tensin homolog (PTEN) is well known as a tumor suppressor that antagonizes oncogenic signaling molecules/pathways and plays a key role in the prognosis and (immuno)therapy of the disease. In this study, twenty healthy and tumorous renal tissue pairs were investigated, and the mRNA (RT-qPCR) and protein (Western blot) expression of IDO and PTEN were analyzed. In two cancer cell lines (CAKI-2; A-498), the protein of IDO and PTEN was measured followed by IDO induction with interferon alpha-2 (IFN-α2). According to our results, a significantly higher mRNA expression of IDO and PTEN was found in tumorous tissues compared to the adjacent healthy kidney specimens. The mRNA expression of IDO and PTEN showed a positive correlation in 80% of the sample pairs. Western blot results confirmed the protein expression of both IDO and PTEN. In the cell lines, immunocytochemistry showed that IDO is inducible with IFN-α2. In summary, our results suggest that IDO expression may play a role in the development of renal cancer, and IDO as well as PTEN might be potential biomarkers for patients with RCC. Full article

Lead (Pb) is a toxic heavy metal that severely impairs plant growth and crop quality. Melatonin, a widely present indoleamine compound, enhances plant stress tolerance, yet its role in tea plant resistance to lead stress remains unclear. This study examined two tea genotypes with distinct anthocyanin levels, Longjing43 (LJ43) and Zijuan (ZJ), comparing their phenotype, antioxidant capacity, secondary metabolite synthesis, and lead transport gene expression under lead stress. Excessive Pb exposure caused severe oxidative stress, reducing PSII efficiency, increasing ROS accumulation, and intensifying lipid peroxidation. ZJ, with higher anthocyanin concentration, exhibited stronger lead stress resistance than LJ43. Under lead stress, melatonin promoted phenylalanine accumulation in ZJ, facilitating its conversion into anthocyanins and catechins via key gene regulation (CsC4H, CsLAR, and CsANS). Moreover, exogenous melatonin significantly reduced Pb concentrations in roots, stems, and leaves, with a more pronounced effect in ZJ (reductions of 20.46%, 53.30%, and 38.17%, respectively), which might be associated with the downregulation of Pb transport genes like CsZIP1 (notably showing a 29-fold decrease). While these results suggest that melatonin might enhance Pb stress tolerance by modulating flavonoid metabolism and restricting Pb uptake, the specific roles of anthocyanins and catechins in this process remains to be fully elucidated. Further studies are necessary to clarify the primary bioactive compounds and mechanisms involved in melatonin-mediated heavy metal stress mitigation. Full article

Melatonin (N-acetyl-5-methoxytryptamine) is a hormone associated with the regulation of biological rhythms. The indoleamine is secreted by the pineal gland during the night, following a circadian rhythm. The highest plasmatic levels are reached during the night, whereas the lowest levels are achieved during the day. In addition to the pineal gland, other organs and tissues also produce melatonin, like, for example, the retina, Harderian glands, gut, ovaries, testes, skin, leukocytes, or bone marrow. The list of organs is extensive, including the cerebellum, airway epithelium, liver, kidney, adrenals, thymus, thyroid, pancreas, carotid body, placenta, and endometrium. At all these locations, the availability of melatonin is intended for local use. Interestingly, a decline of the circadian amplitude of the melatonin secretion occurs in old subjects in comparison to that found in younger subjects. Moreover, genetic and environmental factors are the primary causes of diseases, and oxidative stress is a key contributor to most pathologies. Numerous studies exist that show interesting effects of melatonin in different models of disease. Impairment in its secretion might have deleterious consequences for cellular physiology. In this regard, melatonin is a natural compound that is a carrier of a not yet completely known potential that deserves consideration. Thus, melatonin has emerged as a helpful ally that could be considered as a guard with powerful tools to orchestrate homeostasis in the body, majorly based on its antioxidant effects. In this review, we provide an overview of the widespread actions of melatonin against diseases preferentially affecting the elderly. Full article

Psoriasis is a systemic disease affecting 2–3% of the general population. Tryptophan (TRP) is an amino acid metabolized in the kynurenine pathway (KP). The aim of this study was to assess the kynurenine pathway’s metabolites in serum and urine of psoriatic patients and explore the possible interplay with the disease’s pathogenesis and its comorbidities. The study involved 60 patients with plaque psoriasis and 30 healthy volunteers matched for gender, age, and BMI. Serum and urine samples were taken from the participants and tested for TRP, indoleamine 2,3-dioxygenase (IDO), 2,3-tryptophan dioxygenase (TDO), kynurenine (KYN), kynurenic acid (KYNA), quinolinic acid (QUIN), and numerous laboratory parameters. Correlations between the metabolites’ levels and clinical, laboratory parameters and depression occurrence were statistically evaluated. Concentrations of tryptophan, kynurenic acid, and quinolinic acid in serum and urine were significantly higher among patients with psoriasis (p < 0.05 and p < 0.001, p < 0.05 and p < 0.05 and p < 0.001 and p < 0.001, respectively). A significant stimulation of the kynurenine pathway in serum and urine of patients with psoriasis suggests its role in its pathogenesis and interplay between chronic inflammation or comorbidities. Further research is needed to discover whether the increase in KP metabolites is an indicator of inflammation or a compensatory mechanism in psoriasis. Full article

Mesenchymal stromal cells (MSCs) influence tumor biology and immunology by releasing cytokines, chemokines and growth factors. Currently, cisplatin is an integral part of drug-based tumor therapy, for example, in head and neck squamous cell carcinoma (HNSCC). Cisplatin treatment induces apoptosis as a primary mechanism of action; however, additional immunomodulatory effects of cisplatin are gaining interest. The aim of this study is to evaluate the possible immunomodulatory effects of cisplatin in human MSCs (hMSCs). The MSCs, obtained from human bone marrow, were characterized by analyzing plastic adherence, typical surface features, and ability to differentiate. Toxicity analysis of cisplatin’s effects on primary MSCs, including the determination of a subtoxic concentration, was performed using the MTT assay. Enzyme-linked immunosorbent assays (ELISA) and a quantitative real-time polymerase chain reaction (qRT-PCR) were used to identify potentially immunomodulatory factors. Additionally, a scratch assay was performed to evaluate cell migration. First, subtoxic cisplatin concentrations were determined. A significantly reduced protein expression of indoleamine 2,3-dioxygenase 1 (IDO1) in MSCs under the influence of subtoxic cisplatin concentrations was demonstrated. Similarly, IL-6 protein expression was qualitatively reduced at subtoxic concentrations, although without statistical significance. At the mRNA level, qRT-PCR showed a non-significant, cisplatin concentration-dependent reduction in the expression of both IL-6 and IDO1. The scratch assay showed no statistically significant influence on migration after cisplatin treatment. In MSCs, there is tendency to a decrease in IL-6 and IDO1 at both protein and mRNA level after cisplatin exposure. These effects are congruent with each other and dose-dependent. This indicates that cisplatin not only acts via the known cytotoxic effect, but may induce a reduction in tumor-supporting proteins, like IL-6 and IDO1, by MSCs in the tumor microenvironment at subtoxic concentrations. Traditional cytostatic compounds, which can favorably modulate the immune system in the tumor microenvironment, may open new avenues to explore treatment strategies specifically targeting immunomodulation. Overall, the results indicate beneficial immunomodulation by cisplatin. Full article

Background/Objectives: Blast-induced traumatic ocular injuries (bTOI) pose a significant risk to military and civilian populations, often leading to visual impairment or blindness. Retina, the innermost layer of ocular tissue consisting of photoreceptor and glial cells, is highly susceptible to blast injuries. Despite its prevalence, the molecular mechanisms underlying retinal damage following bTOI remain poorly understood, hindering the development of targeted therapies. Melatonin, a neuroprotective indoleamine with antioxidant, anti-inflammatory, and circadian regulatory properties, is synthesized in the retina and plays a crucial role in retinal health. Similarly, retina-specific genes, such as Rhodopsin, Melanopsin, and RPE65, are essential for photoreceptor function, visual signaling, and the visual cycle. However, their responses to blast exposure have not been thoroughly investigated. Methods: In this study, we utilized a ferret model of bTOI to evaluate the temporal expression of melatonin-synthesizing enzymes, such as tryptophan hydroxylase 1 and 2 (TPH1 and TPH2), Aralkylamine N-acetyltransferase (AANAT), and Acetylserotonin-O-methyltransferase (ASMT), and retina-specific genes (Rhodopsin, Melanopsin) and retinal pigment epithelium-specific 65 kDa protein (RPE65) at 4 h, 24 h, 7 days, and 28 days post-blast. Ferrets were exposed to tightly coupled blast overpressure waves using an advanced blast simulator, and retinal tissues were collected for quantitative polymerase chain reaction (qPCR) analysis. Results: The results revealed dynamic and multiphasic transcriptional responses. TPH1 and TPH2 exhibited significant upregulation at 24 h, followed by downregulation at 28 days, indicating blast-induced dysregulation of tryptophan metabolism, including melatonin synthesis. Similarly, AANAT and ASMT showed acute downregulation post-blast, with late-phase disruptions. Rhodopsin expression increased at 24 h but declined at 28 days, while Melanopsin and RPE65 demonstrated early upregulation followed by downregulation, reflecting potential disruptions in circadian regulation and the visual cycle. Conclusions: These findings highlight the complex regulatory mechanisms underlying retinal responses to bTOI, involving neuroinflammation, oxidative stress, and disruptions in melatonin synthesis and photoreceptor cell functions. The results emphasize the therapeutic potential of melatonin in mitigating retinal damage and preserving visual function. Full article

Objectives: The aim was to simultaneously investigate inflammatory biomarkers, neopterin, the kynurenine/tryptophan (Kyn/Trp) pathway, vitamin D (VitD), vitamin D binding protein (VDBP), and erythrocyte folate, in cerebral palsy (CP). Methods: A case–control study was conducted at Mersin University Hospital. Three- to ten-year-old patients with spastic CP (n = 50) and age- and gender-matched healthy controls (n = 55) were included. Serum levels of neopterin, Trp, Kyn and 25OHD, plasma VDBP, and erythrocyte folate concentrations were measured. Indoleamine-2,3-dioxygenase 1 (IDO-1) enzyme activity was evaluated according to the Kyn/Trp ratio. Comparison and correlation analyses were performed. Results: The levels of neopterin, Trp, and Kyn were lower in children with CP than in healthy controls (p = 0.037, p < 0.001, and p = 0.003, respectively). IDO1 was not significantly different between the CP and control groups (p = 0.214). The levels of VitD and VDBP were higher in children with CP (p < 0.001 and p = 0.001, respectively). The level of erythrocyte folate was also higher in children with CP (p < 0.001). No significant correlation was found between age and inflammatory biomarkers in the CP group. Neopterin was correlated with the level of Gross Motor Function Classification System (GMFCS) level (r = 0.292, p = 0.044), while there was no significant correlation between the other biomarkers and the level of GMFCS in the CP group. Conclusions: Inflammatory biomarkers of neopterin and Kyn are lower, inflammatory biomarkers of VDBP and erythrocyte folate are higher, and anti-inflammatory VitD is higher in children with spastic CP compared to healthy children. More knowledge is needed to demonstrate inflammatory and anti-inflammatory status in children with CP. Full article