Cheminformatics analysis of indoleamine and tryptophan 2,3-dioxygenase inhibitors: A descriptor and fingerprint based machine learning approach to disclose selectivity measures.

Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) are attractive drug targets for cancer immunotherapy. After disappointing results of the epacadostat as a selective IDO inhibitor in phase III clinical trials, there is much interest in the development of the TDO selective inhibitors. In the current study, several data analysis methods and machine learning approaches including logistic regression, Random Forest, XGBoost and Support Vector Machines were used to model a data set of compounds retrieved from ChEMBL. Models based on the Morgan fingerprints revealed notable fragments for the selective inhibition of the IDO, TDO or both. Multiple fragment docking was performed to find the best set of bound fragments and their orientation in the space for efficient linking. Linking the fragments and optimization of the final molecules were accomplished by means of an artificial intelligence generative framework. Finally, selectivity of the optimized molecules was assessed and the top 4 lead molecules were filtered through PAINS, Brenk and NIH filters. Results indicated that phenyloxalamide, fluoroquinoline, and 3-bromo-4-fluroaniline confer selectivity towards the IDO inhibition. Correspondingly, 1-benzyl-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione was found to be an integral fragment for the selective inhibition of the TDO by constituting a coordination bond with the Fe atom of heme. In addition, furo[2,3-c]pyridine-2,3-diamine was found as a common fragment for inhibition of the both targets and can be used in the design of the dual target inhibitors of the IDO and TDO. The new fragments introduced here can be a useful building blocks for incorporation into the selective TDO or dual IDO/TDO inhibitors.

Evaluation of real-time fluorescence sensors and benchtop fluorescence for tracking and predicting sewage contamination in the Tijuana River Estuary at the US-Mexico border.

Cross-border flow of untreated sewage from Mexico into the USA via the Tijuana River is public health issue with negative consequences for coastal communities. Here we evaluate the potential application of fluorescence-based, submersible tryptophan-like (TRP) and humic-like (CDOM) fluorescence sensors for real-time tracking of wastewater pollution in an estuarine environment. Sonde fluorescence measurements were compared with benchtop fluorescence, fecal indicator bacteria (FIB) concentrations, and real-time specific conductivity measurements in the Tijuana River Estuary during dry and wet weather conditions, and with and without cross-border flow. TRP and CDOM fluorescence concentrations were low during times without cross-border flow and two-three orders of magnitude higher during storm events and after cross-border sewage flow events. Major deterioration in water quality, including hypoxic conditions, was observed after consistent, long-term cross-border sewage flow. Real-time TRP and CDOM fluorescence concentrations had a significant linear relationship with fecal indicator bacteria (FIB) concentrations during dry weather periods with cross-border flow (p < 0.001) but were poorly correlated during stormflow and during less polluted periods with no cross-border flow. TRP and CDOM fluorescence acquired on discrete samples using a benchtop fluorometer correlated significantly (p < 0.001) with FIB concentrations under all cross-border flow conditions. Based on these relationships, the greatest amount of untreated wastewater in the estuary's surface layer during cross-border flow events was estimated at >80 % and occurred during neap tides, when concentrated, sewage-laden freshwater flowed over dense saline seawater due to stratification and lack of mixing in the estuary. These results are important because exposure to untreated sewage poses severe health risks for residents and visitors to adjacent coastal areas. While benchtop fluorescence was more effective for estimating the degree of wastewater pollution, submersible TRP and CDOM sensors provided a real-time alert of sewage contamination, which can be utilized in other sewage impacted estuarine environments.

Revolutionizing our understanding of Parkinson's disease: Dr. Heinz Reichmann's pioneering research and future research direction.

Millions of individuals around the world are afflicted with Parkinson's disease (PD), a prevalent and incapacitating neurodegenerative disorder. Dr. Reichmann, a distinguished professor and neurologist, has made substantial advancements in the domain of PD research, encompassing both fundamental scientific investigations and practical applications. His research has illuminated the etiology and treatment of PD, as well as the function of energy metabolism and premotor symptoms. As a precursor to a number of neurotransmitters and neuromodulators that are implicated in the pathophysiology of PD, he has also investigated the application of tryptophan (Trp) derivatives in the disease. His principal findings and insights are summarized and synthesized in this narrative review article, which also emphasizes the challenges and implications for future PD research. This narrative review aims to identify and analyze the key contributions of Reichmann to the field of PD research, with the ultimate goal of informing future research directions in the domain. By examining Reichmann's work, the study seeks to provide a comprehensive understanding of his major contributions and how they can be applied to advance the diagnosis and treatment of PD. This paper also explores the potential intersection of Reichmann's findings with emerging avenues, such as the investigation of Trp and its metabolites, particularly kynurenines, which could lead to new insights and potential therapeutic strategies for managing neurodegenerative disorders like PD.

Identification of technological/metabolic/environmental profiles associated with cheeses accumulating the neuroactive compound tryptamine.

Tryptamine is a neuromodulator of the central nervous system. It is also a biogenic amine, formed by the microbial decarboxylation of L-tryptophan. Tryptamine accumulation in cheese has been scarcely examined. No studies are available regarding the factors that could influence its accumulation. Determining the tryptamine content and identifying the factors that influence its accumulation could help in the design of functional tryptamine-enriched cheeses without potentially toxic concentrations being reached. We report the tryptamine concentration of 300 cheese samples representing 201 varieties. 16% of the samples accumulated tryptamine, at between 3.20 mg kg-1 and 3012.14 mg kg-1 (mean of 29.21 mg kg-1). 4.7% of cheeses accumulated tryptamine at higher levels than those described as potentially toxic. Moreover, three technological/metabolic/environmental profiles associated with tryptamine-containing cheese were identified, as well as the hallmark varieties reflecting each. Such knowledge could be useful for the dairy industry to control the tryptamine content of their products.

2-Aminoacetophenone formation through UV-C induced degradation of tryptophan in the presence of riboflavin in model wine: Role of oxygen and transition metals.

2-Aminoacetophenone is an off-flavor that can result from tryptophan degradation via riboflavin-photosensitized reaction. This study investigates the impact of light exposure, provided by a UV-C source, oxygen concentrations and transition metals on the formation of 2-aminoacetophenone in model wine containing tryptophan and riboflavin. Irrespective of oxygen and transition metals, >85% of tryptophan were degraded via first-order kinetics to unknown product(s). However, longer light exposure and more oxygen caused 2-aminoacetophenone concentrations to increase. Transition metals decelerated the 2-aminoacetophenone formation and acetaldehyde was formed suggesting photo-Fenton reaction occurred as a competitive reaction. The degradation rate of riboflavin inclined with less oxygen and in the presence of transition metals due to the depletion of oxygen by photo-Fenton reaction. Oxygen plays an important role in the regeneration of riboflavin and therefore must be seen as an intensifier for light-induced 2-aminoacetophenone formation. This paper provides new insights into riboflavin-photosensitized reactions.

Investigations Towards Tryptophan Uptake and Transport Across an In Vitro Model of the Oral Mucosa Epithelium.

Tryptophan is an essential amino acid and plays an important role in several metabolic processes relevant for the human health. As the main metabolic pathway for tryptophan along the kynurenine axis is involved in inflammatory responses, changed metabolite levels can be used to monitor inflammatory diseases such as ulcerative colitis. As a progenitor of serotonin, altered tryptophan levels have been related to several neurogenerative diseases as well as depression or anxiety. While tryptophan concentrations are commonly evaluated in serum, a non-invasive detection approach using saliva might offer significant advantages, especially during long-term treatments of patients or elderly. In order to estimate whether active transport processes for tryptophan might contribute to a potential correlation between blood and saliva tryptophan concentrations, we investigated tryptophan's transport across an established oral mucosa in vitro model. Interestingly, treatment with tryptophan revealed a concentration dependent secretion of tryptophan and the presence of a saturable transporter while transport studies with deuterated tryptophan displayed increased permeability from the saliva to the blood compartment. Protein analysis demonstrated a distinct expression of L-type amino acid transporter 1 (LAT1), the major transporter for tryptophan, and exposure to inhibitors (2 -amino-2-norbornanecarboxylic acid (BCH), L-leucine) led to increased tryptophan levels on the saliva side. Additionally, exposure to tryptophan in equilibrium studies resulted in a regulation of LAT1 at the mRNA level. The data collected in this study suggest the participation of active transport mechanisms for tryptophan across the oral mucosa epithelium. Future studies should investigate the transport of tryptophan across salivary gland epithelia in order to enable a comprehensive understanding of tryptophan exchange at the blood-saliva barrier.

Understanding the Kynurenine Pathway: A Narrative Review on its Impact across Chronic Pain Conditions.

Chronic pain is a debilitating symptom with a significant negative impact on the quality of life and socioeconomic status, particularly among adults and the elderly. Major Depressive Disorder (MDD) stands out as one of the most important comorbid disorders accompanying chronic pain. The kynurenine pathway serves as the primary route for tryptophan degradation and holds critical significance in various biological processes, including the regulation of neurotransmitters, immune responses, cancer development, metabolism, and inflammation. This review encompasses key research studies related to the kynurenine pathway in the context of headache, neuropathic pain, gastrointestinal disorders, fibromyalgia, chronic fatigue syndrome, and MDD. Various metabolites produced in the kynurenine pathway, such as kynurenic acid and quinolinic acid, exhibit neuroprotective and neurotoxic effects, respectively. Recent studies have highlighted the significant involvement of kynurenine and its metabolites in the pathophysiology of pain. Moreover, pharmacological interventions targeting the regulation of the kynurenine pathway have shown therapeutic promise in pain management. Understanding the underlying mechanisms of this pathway presents an opportunity for developing personalized, innovative, and non-opioid approaches to pain treatment. Therefore, this narrative review explores the role of the kynurenine pathway in various chronic pain disorders and its association with depression and chronic pain.

ß-CD@AgNPs with peroxisase-like activity for colorimetric determination of chiral tryptophan.

Different enantiomer forms of amino acids play different roles in multifarious fields, and improper use will cause irreversible effects. Therefore, the identification of chiral amino acids is a vital issue in the field of pharmaceutical analysis. Herein, a chiral sensing system of ß-cyclodextrin coated silver nanoparticle (ß-CD@AgNPs) with peroxidase-like activity was designed for the fast and efficient colorimetric identification of tryptophan (Trp) enantiomers based on the difference in binding capacity between D/L-Trp and ß-CD. The results showed the satisfactory linearity for detecting D/L-Trp over the concentration range from 0.2 to 4 mM with a LOD of 0.16 and 0.18 mM, respectively. Moreover, the absorbance increased linearly with the rise of D-Trp concentration percentage in the Trp enantiomer mixture. The proposed method avoided the use of natural enzymes and improved the stability due to the protective effect of cyclodextrin, which provided a new idea for selective colorimetric recognition and detection of D/L-Trp based on cyclodextrin.

Integrated bioinformatics analysis and experimental validation to understand tryptophan metabolism-related genes in hepatocellular carcinoma.

Background: Tryptophan (Trp) metabolism is closely related to tumor immunity, and its disorder can cause an immunosuppressive microenvironment, promoting the occurrence and development of hepatocellular carcinoma (HCC). The aim of this study is to explore and validate the independent prognostic genes in patients suffered from HCC. Methods: The transcriptome data of GSE87630 from GEO database were downloaded to analyze differentially expressed genes (DECs) which were intersected with the gene sets of Trp metabolism from MsigDB database. Univariate/multivariate COX regression was performed to identify the genes with independent prognostic significance. TCGA, GTEx, UALCAN, and GEPIA2 databases were applied to analyze DEGs for prognosis. RNA seq data of HCC from TCGA database were collected for Lasso regression analysis. The ssGSEA algorithm was used to perform the analysis of TCGA data. The effects of the candidate differential gene on HCC cells proliferation and migration were evaluated using EdU immunofluorescence and transwell assays. Results: Trp metabolism-related DECs for HCCs were obtained, including MAOB, CYP1A2, KYNU, CYP2E1, ALDH2, CYP2C18, TDO2, AOX1, CYP3A4 and INMT. Moreover, multivariate COX regression results showed that ALDH2 can serve as an independent prognostic molecule and its transcriptional and translational levels were significantly reduced in the tumor tissues. The low expression of ALDH2 was associated with poor prognosis. Overexpression of ALDH2 dramatically reduced the HCC cells proliferation and migration. Conclusion: ALDH2 is associated with Trp metabolism and its downregulation in HCC has a potential value on prognosis. Overexpression of ALDH2 can reduce the proliferation and migration of HCC cells.

Emerging chemophysiological diversity of gut microbiota metabolites.

Human physiology is profoundly influenced by the gut microbiota, which generates a wide array of metabolites. These microbiota-derived compounds serve as signaling molecules, interacting with various cellular targets in the gastrointestinal tract and distant organs, thereby impacting our immune, metabolic, and neurobehavioral systems. Recent advancements have unveiled unique physiological functions of diverse metabolites derived from tryptophan (Trp) and bile acids (BAs). This review highlights the emerging chemophysiological diversity of these metabolites and discusses the role of chemical and biological tools in analyzing and therapeutically manipulating microbial metabolism and host targets, with the aim of bridging the chemical diversity with physiological complexity in host-microbe molecular interactions.

Signals from intestinal microbiota mediate the crosstalk between the lung-gut axis in an influenza infection mouse model.

Introduction: Introduction: The influenza virus primarily targets the respiratory tract, yet both the respiratory and intestinal systems suffer damage during infection. The connection between lung and intestinal damage remains unclear. Methods: Our experiment employs 16S rRNA technology and Liquid Chromatography-Mass Spectrometry (LC-MS) to detect the impact of influenza virus infection on the fecal content and metabolites in mice. Additionally, it investigates the effect of influenza virus infection on intestinal damage and its underlying mechanisms through HE staining, Western blot, Q-PCR, and flow cytometry. Results: Our study found that influenza virus infection caused significant damage to both the lungs and intestines, with the virus detected exclusively in the lungs. Antibiotic treatment worsened the severity of lung and intestinal damage. Moreover, mRNA levels of Toll-like receptor 7 (TLR7) and Interferon-b (IFN-b) significantly increased in the lungs post-infection. Analysis of intestinal microbiota revealed notable shifts in composition after influenza infection, including increased Enterobacteriaceae and decreased Lactobacillaceae. Conversely, antibiotic treatment reduced microbial diversity, notably affecting Firmicutes, Proteobacteria, and Bacteroidetes. Metabolomics showed altered amino acid metabolism pathways due to influenza infection and antibiotics. Abnormal expression of indoleamine 2,3-dioxygenase 1 (IDO1) in the colon disrupted the balance between helper T17 cells (Th17) and regulatory T cells (Treg cells) in the intestine. Mice infected with the influenza virus and supplemented with tryptophan and Lactobacillus showed reduced lung and intestinal damage, decreased Enterobacteriaceae levels in the intestine, and decreased IDO1 activity. Discussion: Overall, influenza infection caused damage to lung and intestinal tissues, disrupted intestinal microbiota and metabolites, and affected Th17/Treg balance. Antibiotic treatment exacerbated these effects. Supplementation with tryptophan and Lactobacillus improved lung and intestinal health, highlighting a new understanding of the lung-intestine connection in influenza-induced intestinal disease.

Game of microbes: the battle within - gut microbiota and multiple sclerosis.

Multiple sclerosis (MS) is a chronic and progressive autoimmune disease of the central nervous system (CNS), with both genetic and environmental factors contributing to the pathobiology of the disease. While human leukocyte antigen (HLA) genes have emerged as the strongest genetic factor, consensus on environmental risk factors are lacking. Recently, trillions of microbes residing in our gut (microbiome) have emerged as a potential environmental factor linked with the pathobiology of MS as PwMS show gut microbial dysbiosis (altered gut microbiome). Thus, there has been a strong emphasis on understanding the factors (host and environmental) regulating the composition of the gut microbiota and the mechanism(s) through which gut microbes contribute to MS disease, especially through immune system modulation. A better understanding of these interactions will help harness the enormous potential of the gut microbiota as a therapeutic approach to treating MS.

GFR decline predicts total mortality and mediates the effect of tryptophan metabolism on death risk in type 2 diabetes.

CONTEXT: The independent role of glomerular filtration rate (GFR) decline in shaping the risk of mortality in people with type 2 diabetes has only been partially addressed. OBJECTIVE: The objective of the study was twofold: i) to investigate the association between all-cause mortality and eGFR changes over time; ii) to understand whether renal dysfunction mediates the effect of tryptophan metabolism on death risk. DESIGN: Prospective study with an average follow-up of 14.8 years. SETTING: Research Hospital. PATIENTS: The aggregate Gargano Mortality Study included 962 patients with type 2 diabetes who had at least three eGFR recordings and at least 1.5 years of follow-up. INTERVENTIONS: This was an observational study, with no intervention. MAIN OUTCOME MEASURES: Rate of all-cause mortality. RESULTS: Age and sex adjusted annual incident rate of mortality was 2.75 events per 100 person-years. The median annual rate of decline of eGFR was 1.3 ml/min per 1.73 m2 per year (range -3.7; 7.8). The decline of kidney function was strongly and independently associated with the risk of death. Serum kynurenine-to-tryptophan ratio (KTR) was associated with both eGFR decline and all-cause mortality. Causal mediation analysis showed that 24.3% of the association between KTR and mortality was mediated by eGFR decline. CONCLUSIONS: In patients with type 2 diabetes, eGFR decline is independently associated with the risk of all-cause mortality and mediates a significant proportion of the association between tryptophan metabolism and death.

4-Vinylpyridine copolymers for improved LC-MS tryptophan and kynurenine determination in human serum.

Tryptophan (an essential amino acid) and its clinically important metabolite-kynurenine contribute to several fundamental biological processes and methods that allow their determination in biological samples are in demand. The novelty of the work was a demonstration of the utility of two polymers: 4-vinylpyridine crosslinked with trimethylolpropane trimethacrylate (poly(4VP-co-TRIM)) or 1,4-dimethacryloyloxybenzene (poly(4VP-co-14DMB))-in terms of human serum clean-up for simultaneous LC-MS determination of tryptophan and kynurenine. The goal was to achieve a reduction of the matrix effect, which is responsible for signal suppression, with minimal capture of analytes. The adsorption properties of the polymeric beads were studied by evaluating the adsorption kinetics and isotherms in model matrices. Therefore, the adsorption capacities of both molecules were not efficient, the tested 4-vinylpyridine-based copolymers have shown great promise (especially poly(4VP-co-TRIM)) as sorbents for serum clean-up. In the model human serum matrix, poly(4VP-co-TRIM) provided good recoveries of tryptophan and kynurenine (76% and 87%, respectively) and allowed for the reduction of the matrix effect. Performances of both copolymers were compared to those of commercially available sorbents (octadecylsilane, activated charcoal, and primary secondary amine).

Kynurenines as a Novel Target for the Treatment of Inflammatory Disorders.

This review discusses the potential of targeting the kynurenine pathway (KP) in the treatment of inflammatory diseases. The KP, responsible for the catabolism of the amino acid tryptophan (TRP), produces metabolites that regulate various physiological processes, including inflammation, cell cycle, and neurotransmission. These metabolites, although necessary to maintain immune balance, may accumulate excessively during inflammation, leading to systemic disorders. Key KP enzymes such as indoleamine 2,3-dioxygenase 1 (IDO1), indoleamine 2,3-dioxygenase 2 (IDO2), tryptophan 2,3-dioxygenase (TDO), and kynurenine 3-monooxygenase (KMO) have been considered promising therapeutic targets. It was highlighted that both inhibition and activation of these enzymes may be beneficial, depending on the specific inflammatory disorder. Several inflammatory conditions, including autoimmune diseases, for which modulation of KP activity holds therapeutic promise, have been described in detail. Preclinical studies suggest that this modulation may be an effective treatment strategy for diseases for which treatment options are currently limited. Taken together, this review highlights the importance of further research on the clinical application of KP enzyme modulation in the development of new therapeutic strategies for inflammatory diseases.

Tyrosine and tryptophan in urine as biomarkers for prostate cancer: A validation study.

Prostate cancer (PCa) is a common male malignancy and early diagnosis is crucial for successful treatment. The current study aims to validate results from a pilot study that demonstrated an inverse association between urine tyrosine and tryptophan levels and the severity of PCa. This study comprised a cohort of 97 patients with benign prostatic hyperplasia, 93 patients diagnosed with localized PCa, 75 patients diagnosed with locally advanced PCa, and 68 patients diagnosed with metastatic PCa. The tyrosine and tryptophan levels in the samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and electrochemical sensors in accordance with the pilot to maintain uniformity for accurately evaluating the data. One-way ANOVA with post Tukey test as well as the Wilcoxon Rank Sum Test were performed. Analyzing 333 patients across PCa stages with consistent methods, we observed no significant differences in tyrosine and tryptophan levels between PCa patients and controls, finally rejecting the use of tyrosine and tryptophan as PCa biomarkers. We did, however, verify the strong correlation between the urinary concentrations of tyrosine and tryptophan found in the pilot study.

Disturbances of the gut microbiota-derived tryptophan metabolites as key actors in vagotomy-induced mastitis in mice.

Previous studies have demonstrated that gut microbiota dysbiosis promotes the development of mastitis. The interaction of the vagus nerve and gut microbiota endows host homeostasis and regulates disease development, but whether the vagus nerve participates in the pathogenesis of mastitis is unclear. Here, vagotomized mice exhibit disruption of the blood-milk barrier and mammary gland inflammation. Notably, mastitis and barrier damage caused by vagotomy are dependent on the gut microbiota, as evidenced by antibiotic treatment and fecal microbiota transplantation. Vagotomy significantly alters the gut microbial composition and tryptophan metabolism and reduces the 5-hydroxyindole acetic acid (5-HIAA) level. Supplementation with 5-HIAA alleviates vagotomy-induced mastitis, which is associated with the activation of the aryl hydrocarbon receptor (AhR) and subsequent inhibition of the NF-κB pathway. Collectively, our findings indicate the important role of the vagus-mediated gut-mammary axis in the pathogenesis of mastitis and imply a potential strategy for the treatment of mastitis by targeting the vagus-gut microbiota interaction.

Association of Non-Suicidal Self-Injury with Tryptophan Hydroxylase 2 Gene Polymorphism and Negative Life Events Among Adolescents with Depression in Northern China.

Objective: To investigate the association between single nucleotide polymorphisms (SNPs) of tryptophan hydroxylase 2 (TPH2) (rs11178997, rs11178998, and rs120074175) and negative life events in adolescent depression with Non-suicidal self-injury (NSSI). Methods: Genomic DNA was extracted from 197 adolescents with depression (participants group, including NSSI group and non-NSSI group), as well as from 100 healthy controls (control group), in northern China. PCR technology was utilized to amplify DNA fragments and detect genotypes in both groups. The Adolescent Life Event Scale (ASLEC) was employed to conduct a questionnaire survey among the participants and control groups. Differences in allele and genotype frequency distribution between the two groups were analyzed using the X^2 test, while generalized multifactor dimensionality reduction (GMDR) was used to analyze gene-environment interactions. Results: Significant differences were observed in ASLEC scores between the control group and both the NSSI group and non-NSSI group (P<0.05). Additionally, significant differences were found in the interpersonal relationship factor and punishment factor between the NSSI group and non-NSSI group (P < 0.05). Moreover, a significant difference was identified in SNP genotype of rs11178997 between the depression group (NSSI group + non-NSSI group) and control group (P<0.05). GMDR analysis revealed an interaction among rs11178997, rs11178998, and ASLEC. Conclusion: Adolescents with depression, particularly females, may exhibit a tendency to employ NSSI as an emotional coping mechanism when confronted with greater family and interpersonal challenges. The AT genotype of TPH2 gene locus rs11178997 is more prevalent among adolescents with depression. Furthermore, the occurrence of NSSI may be associated with an interaction involving polymorphic sites rs11178997 and rs11178998 along with life events.

Gut microbiota and healthy longevity.

Recent progress on the underlying biological mechanisms of healthy longevity has propelled the field from elucidating genetic modification of healthy longevity hallmarks to defining mechanisms of gut microbiota influencing it. Importantly, the role of gut microbiota in the healthy longevity of the host may provide unprecedented opportunities to decipher the plasticity of lifespan on a natural evolutionary scale and shed light on using microbiota-targeted strategies to promote healthy aging and combat age-related diseases. This review investigates how gut microbiota affects healthy longevity, focusing on the mechanisms through which gut microbiota modulates it. Specifically, we focused on the ability of gut microbiota to enhance the intestinal barrier integrity, provide protection from inflammaging, ameliorate nutrientsensing pathways, optimize mitochondrial function, and improve defense against age-related diseases, thus participating in enhancing longevity and healthspan.

YWHAB is regulated by IRX5 and inhibits the migration and invasion of breast cancer cells.

Highly metastatic and heterogeneous breast cancer affects the health of women worldwide. Abnormal expression of tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein ß (YWHAB), also known as 14-3-3ß, is associated with the tumorigenesis and progression of bladder cancer, lung cancer and hepatocellular carcinoma; however, to the best of our knowledge, the role of YWHAB in breast cancer remains unknown. In the present study, a dual luciferase assay demonstrated that the transcription factor iroquois homeobox 5 may regulate YWHAB expression by affecting the promoter sequence upstream of its transcription start site. Subsequently, it was demonstrated that overexpression of YWHAB did not affect proliferation, but did reduce the migration and invasion of MDA-MB-231 cells. Furthermore, knockdown of YWHAB promoted the migration and invasion of MCF7 cells. Transcriptomics analysis demonstrated that when YWHAB was overexpressed, 61 genes were differentially expressed, of which 43 genes were upregulated and 18 genes were downregulated. These differentially expressed genes (DEGs) were enriched in cancer-related pathways, such as 'TNF signaling pathway' [Kyoto Encyclopedia of Genes and Genomes (KEGG): map04688]. The pathway with the largest number of DEGs was 'Rheumatoid arthritis' (KEGG: map05323). Notably, YWHAB downregulated vimentin, which is a mesenchymal marker, thus suggesting that it may weaken the mesenchymal properties of cells. These findings indicate that YWHAB may be a potential therapeutic target in breast cancer and further work should be performed to assess its actions as a potential tumor suppressor.