Tryptophan deficiency induced by indoleamine 2,3-dioxygenase 1 results in glucose transporter 1-dependent promotion of aerobic glycolysis in pancreatic cancer.

Indoleamine 2,3-dioxygenase 1 (IDO1), the key enzyme in the catabolism of the essential amino acid tryptophan (Trp) through kynurenine pathway, induces immune tolerance and is considered as a critical immune checkpoint, but its impacts as a metabolism enzyme on glucose and lipid metabolism are overlooked. We aim to clarify the potential role of IDO1 in aerobic glycolysis in pancreatic cancer (PC). Analysis of database revealed the positive correlation in PC between the expressions of IDO1 and genes encoding important glycolytic enzyme hexokinase 2 (HK2), pyruvate kinase (PK), lactate dehydrogenase A (LDHA) and glucose transporter 1 (GLUT1). It was found that IDO1 could modulate glycolysis and glucose uptake in PC cells, Trp deficiency caused by IDO1 overexpression enhanced glucose uptake by stimulating GLUT1 translocation to the plasma membrane of PC cells. Besides, Trp deficiency caused by IDO1 overexpression suppressed the apoptosis of PC cells via promoting glycolysis, which reveals the presence of IDO1-glycolysis-apoptosis axis in PC. IDO1 inhibitors could inhibit glycolysis, promote apoptosis, and exhibit robust therapeutic efficacy when combined with GLUT1 inhibitor in PC mice. Our study reveals the function of IDO1 in the glucose metabolism of PC and provides new insights into the therapeutic strategy for PC.

The relationship among amyloid-ß deposition, sphingomyelin level, and the expression and function of P-glycoprotein in Alzheimer's disease pathological process.

In Alzheimer's disease, the transporter P-glycoprotein is responsible for the clearance of amyloid-ß in the brain. Amyloid-ß correlates with the sphingomyelin metabolism, and sphingomyelin participates in the regulation of P-glycoprotein. The amyloid cascade hypothesis describes amyloid-ß as the central cause of Alzheimer's disease neuropathology. Better understanding of the change of P-glycoprotein and sphingomyelin along with amyloid-ß and their potential association in the pathological process of Alzheimer's disease is critical. Herein, we found that the expression of P-glycoprotein in APP/PS1 mice tended to increase with age and was significantly higher at 9 and 12 months of age than that in wild-type mice at comparable age. The functionality of P-glycoprotein of APP/PS1 mice did not change with age but was significantly lower than that of wild-type mice at 12 months of age. Decreased sphingomyelin levels, increased ceramide levels, and the increased expression and activity of neutral sphingomyelinase 1 were observed in APP/PS1 mice at 9 and 12 months of age compared with the levels in wild-type mice. Similar results were observed in the Alzheimer's disease mouse model induced by intracerebroventricular injection of amyloid-ß1-42 and human cerebral microvascular endothelial cells treated with amyloid-ß1-42. In human cerebral microvascular endothelial cells, neutral sphingomyelinase 1 inhibitor interfered with the changes of sphingomyelin metabolism and P-glycoprotein expression and functionality caused by amyloid-ß1-42 treatment. Neutral sphingomyelinase 1 regulated the expression and functionality of P-glycoprotein and the levels of sphingomyelin and ceramide. Together, these findings indicate that neutral sphingomyelinase 1 regulates the expression and function of P-glycoprotein via the sphingomyelin/ceramide pathway. These studies may serve as new pursuits for the development of anti-Alzheimer's disease drugs.

IDO1 can impair NK cells function against non-small cell lung cancer by downregulation of NKG2D Ligand via ADAM10.

Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the rate-limiting step in tryptophan catabolism along the kynurenine (Kyn) pathway and exerts immunosuppressive properties mainly via activation of transcription factor aryl hydrocarbon receptor (AhR) pathway. IDO1 induces NK cells dysfunction via downregulation of the activating receptor NKG2D on NK cells, but whether and how it affects the expression of NKG2D Ligand (NKG2DL) on tumor cells remains unclear. Since a disintegrin and metalloprotease 10 (ADAM10) plays a potential role in the shedding of NKG2DL and the releasing of soluble NKG2DL (sNKG2DL), we investigated how IDO1 modulates the expression of NKG2DL via ADAM10 in non-small cell lung cancer (NSCLC). We found that IDO1 expression was negatively correlated with NKG2DL expression while positively correlated with ADAM10 expression with human lung cancer brain metastasis tissue, NSCLC cells and LLC tumor-bearing mice. IDO1 could regulate ADAM10 expression via IDO1-Kyn-AhR signaling pathway and subsequently regulate NKG2DL expression. IDO1 deficiency led to retarded tumor growth and improved NK cells function in NSCLC mice. IDO1 inhibitors improved NK cells function in vitro and in vivo. The combo of IDO1 inhibitor and NK cells exhibited more therapeutic efficacy than either of the single IDO1 inhibitor or NK cells treatment.

IDO1/TDO dual inhibitor RY103 targets Kyn-AhR pathway and exhibits preclinical efficacy on pancreatic cancer.

Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzing the conversion of tryptophan (Trp) to kynurenine (Kyn) in kynurenine pathway (KP) is involved in the immunosuppression in pancreatic cancer (PC), but the value of IDO1 as an independent prognostic marker for PC is uncertain. Moreover, the correlation between tryptophan 2,3-dioxygenase (TDO), an isozyme of IDO1, and PC is largely unknown. Using TCGA database, the correlation between IDO1 and/or TDO expression and PC patients' survival was analyzed. The expressions of IDO1 and TDO in PC cells and PC mice were examined. The effects of IDO1, TDO or dual inhibition on IDO1 and TDO effector pathway (Aryl hydrocarbon receptor, AhR) and on migration and invasion of PC cells were investigated. The block effect of IDO1/TDO dual inhibitor RY103 on KP was evaluated. The preclinical efficacy of RY103 and its immunomodulatory effect on KPIC orthotopic PC mice and Pan02 tumor-bearing mice were explored. Results showed that IDO1/TDO co-expression is an independent prognostic marker for PC. RY103 can significantly block KP and target Kyn-AhR pathway to blunt the migration and invasion of PC cells, exhibit preclinical efficacy and ameliorate IDO1/TDO-mediated immunosuppression in PC mice.

A 6.78-MHz distance-insensitive wireless power transfer system with a dual-coupled L-type matching network.

A 6.78-MHz wireless power transfer (WPT) system can achieve a long transmission distance, which is based on magnetically coupled resonant technology. Due to its high quality factor coils, the system performance is greatly affected by position displacement. In this paper, a weakly coupled and distance-insensitive WPT system with a dual-coupled L-type matching network was proposed. To improve displacement tolerance, the proposed system used a dual mutual inductance matching network, which did not require feedback to change capacitance or inductance dynamically. To remain lightweight, printed multi-coils without ferrites were used. To obtain a higher efficiency over a weakly coupled distance, a series of parameters were optimized, i.e., the optimal dimension, the matching distance, and the real center. To verify the output performance in X/Y/Z-axis displacements, a prototype with a maximum output power of 50 W was created, and a DC-DC efficiency of 75%-81% was achieved in a Z-axis displacement of ±15 mm and in an X/Y-axis displacement of ±20 mm.

What is the prospect of indoleamine 2,3-dioxygenase 1 inhibition in cancer? Extrapolation from the past.

Indoleamine 2,3-dioxygenase 1 (IDO1), a monomeric heme-containing enzyme, catalyzes the first and rate-limiting step in the kynurenine pathway of tryptophan metabolism, which plays an important role in immunity and neuronal function. Its implication in different pathophysiologic processes including cancer and neurodegenerative diseases has inspired the development of IDO1 inhibitors in the past decades. However, the negative results of the phase III clinical trial of the would-be first-in-class IDO1 inhibitor (epacadostat) in combination with an anti-PD1 antibody (pembrolizumab) in patients with advanced malignant melanoma call for a better understanding of the role of IDO1 inhibition. In this review, the current status of the clinical development of IDO1 inhibitors will be introduced and the key pre-clinical and clinical data of epacadostat will be summarized. Moreover, based on the cautionary notes obtained from the clinical readout of epacadostat, strategies for the identification of reliable predictive biomarkers and pharmacodynamic markers as well as for the selection of the tumor types to be treated with IDO1inhibitors will be discussed.

Evaluation and comparison of the commonly used bioassays of human indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO).

Inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are potential drugs for the treatment of tumor and neurological diseases. A variety of bioassays have been developed to evaluate IDO1/TDO (IDO1 and/or TDO) inhibitors, with uncertainty regarding how the differences in the assay methods or protocols may influence the assay outcomes. The enzymatic assays of IDO1/TDO are usually performed with NFK assay and Kyn adduct assay while the cellular assays of IDO1 are carried out with Hela assay and HEK293 assay. The present study focused on the comparison of the most common bioassays of IDO1/TDO. In addition, the effects of major factors of bioassays such as reaction time and culture medium on the assay outcomes were evaluated. The study will provide reference for the researchers to select IDO1/TDO inhibitors with bioassays, and promote the development of IDO1/TDO inhibitors.

Optimization and analysis of a grounded type dynamic vibration absorber with lever component.

Dynamic vibration absorber (DVA) with large auxiliary mass has better control performance, but it is also more bulky. Therefore, the mass ratio (the ratio of auxiliary mass of DVA to mass of controlled object) is usually limited to make the DVA easy to install and suitable for engineering practice. In this paper a grounded type DVA with lever component is proposed, which aims to increase the effective mass and reduce unnecessary mass to improve control performance of the DVA. Firstly, the motion differential equations of the DVA are established and solved. Secondly, the optimum parameters are obtained based on H∞ and H2 optimization criterion. Then, the performances of the grounded type DVA equipped with and without the lever are investigated. Finally, the control performance of the DVA is compared with other three typical DVAs under H∞ and H2 criterion. In this type DVA there are no global optimum parameters, and larger frequency ratio will get better control performance. If the amplification ratio (the ratio of lever power arm to lever resistance arm) is greater than 1, the introduced lever will contribute to control performance of the DVA. Its control performance is better than those of other three typical DVAs. The use of the lever can increase the effective mass of the DVA, thereby improving the control performance of the DVA. The DVA can achieve good performance at small mass ratio by adjusting amplification ratio, which may provide theoretical basis for the design of new kinds of DVAs.

Both IDO1 and TDO contribute to the malignancy of gliomas via the Kyn-AhR-AQP4 signaling pathway.

Indoleamine 2,3-dioxygenase 1 (IDO1), indoleamine 2,3-dioxygenase 2 (IDO2), and tryptophan 2,3-dioxygenase (TDO) initiate the first step of the kynurenine pathway (KP), leading to the transformation of L-tryptophan (Trp) into L-kynurenine (Kyn) and other downstream metabolites. Kyn is known as an endogenous ligand of the aryl hydrocarbon receptor (AhR). Activation of AhR through TDO-derived Kyn is a novel mechanism to support tumor growth in gliomas. However, the role of IDO1 and IDO2 in this mechanism is still unknown. Herein, by using clinical samples, we found that the expression and activity of IDO1 and/or TDO (IDO1/TDO) rather than IDO2 were positively correlated with the pathologic grades of gliomas. The expression of IDO1/TDO rather than IDO2 was positively correlated with the Ki67 index and overall survival. The expression of IDO1/TDO was positively correlated with the expression of aquaporin 4 (AQP4), implying the potential involvement of IDO1/TDO in glioma cell motility. Mechanistically, we found that IDO1/TDO accounted for the release of Kyn, which activated AhR to promote cell motility via the Kyn-AhR-AQP4 signaling pathway in U87MG glioma cells. RY103, an IDO1/TDO dual inhibitor, could block the IDO1/TDO-Kyn-AhR-AQP4 signaling pathway and exert anti-glioma effects in GL261 orthotopic glioma mice. Together, our results showed that the IDO1/TDO-Kyn-AhR-AQP4 signaling pathway is a new mechanism underlying the malignancy of gliomas, and suggest that both IDO1 and TDO might be valuable therapeutic targets for gliomas.

H2S suppresses indoleamine 2, 3-dioxygenase 1 and exhibits immunotherapeutic efficacy in murine hepatocellular carcinoma.

BACKGROUND: Over-expression and over-activation of immunosuppressive enzyme indoleamine 2, 3 -dioxygenase 1 (IDO1) is a key mechanism of cancer immune escape. However, the regulation of IDO1 has not been fully studied. The relation between hydrogen sulfide (H2S) and IDO1 is unclear. METHODS: The influences of endogenous and exogenous H2S on the expression of IDO1, iNOS and NF-κB and STAT3 signaling proteins were investigated using qPCR or western blot, and the production of nitric oxide (NO) was analyzed by nitrate/nitrite assay in Cse-/- mice and MCF-7 and SGC-7901 cells. The effect of H2S on IDO1 activity was investigated by HPLC and in-vitro enzymatic assay. The effect of H2S on tryptophan metabolism was tested by luciferase reporter assay in MCF-7 and SGC-7901 cells. The correlation between H2S-generating enzyme CSE and IDO1 was investigated by immunostaining and heatmaps analysis in clinical specimens and tissue arrays of hepatocellular carcinoma (HCC) patients. The immunotherapeutic effects of H2S on H22 HCC-bearing mice were investigated. RESULTS: Using Cse-/- mice, we found that H2S deficiency increased IDO1 expression and activity, stimulated NF-κB and STAT3 pathways and decreased the expression of NO-generating enzyme Inos. Using IDO1-expressing MCF-7 and SGC-7901 cells, we found that exogenous H2S inhibited IDO1 expression by blocking STAT3 and NF-κB pathways, and decreased IDO1 activity via H2S/NO crosstalk, and combinedly decreased the tryptophan metabolism. The negative correlation between H2S-generating enzyme CSE and IDO1 was further validated in clinical specimens and tissue arrays of HCC patients. Additionally, H2S donors effectively restricted the tumor development in H22 HCC-bearing mice via downregulating IDO1 expression, inducing T-effector cells and inhibiting MDSCs. CONCLUSIONS: Thus, H2S, as a novel negative regulator of IDO1, shows encouraging antitumor immunotherapeutic effects and represents a novel therapeutic target in cancer therapy.