Engineering Central Substitutions in Heptamethine Dyes for Improved Fluorophore Performance.

As a major family of red-shifted fluorophores that operate beyond visible light, polymethine dyes are pivotal in light-based biological techniques. However, methods for tuning this kind of fluorophores by structural modification remain restricted to bottom-up synthesis and modification using coupling or nucleophilic substitutions. In this study, we introduce a two-step, late-stage functionalization process for heptamethine dyes. This process enables the substitution of the central chlorine atom in the commonly used 4'-chloro heptamethine scaffold with various aryl groups using aryllithium reagents. This method borrows the building block and designs from the xanthene dye community and offers a mild and convenient way for the diversification of heptamethine fluorophores. Notably, this efficient conversion allows for the synthesis of heptamethine-X, the heptamethine scaffold with two ortho-substituents on the 4'-aryl modification, which brings enhanced stability and reduced aggregation to the fluorophore. We showcase the utility of this method by a facile synthesis of a fluorogenic, membrane-localizing fluorophore that outperforms its commercial counterparts with a significantly higher brightness and contrast. Overall, this method establishes the synthetic similarities between polymethine and xanthene fluorophores and provides a versatile and feasible toolbox for future optimizing heptamethine fluorophores for their biological applications.

ATPase Copper Transporting Beta (ATP7B) Is a Novel Target for Improving the Therapeutic Efficacy of Docetaxel by Disulfiram/Copper in Human Prostate Cancer.

Docetaxel has been the standard first-line chemotherapy for lethal metastatic prostate cancer (mPCa) since 2004, but resistance to docetaxel treatment is common. The molecular mechanisms of docetaxel resistance remain largely unknown and could be amenable to interventions that mitigate resistance. We have recently discovered that several docetaxel-resistant mPCa cell lines exhibit lower uptake of cellular copper and uniquely express higher levels of a copper exporter protein ATP7B. Knockdown of ATP7B by silencing RNAs (siRNA) sensitized docetaxel-resistant mPCa cells to the growth-inhibitory and apoptotic effects of docetaxel. Importantly, deletions of ATP7B in human mPCa tissues predict significantly better survival of patients after their first chemotherapy than those with wild-type ATP7B (P = 0.0006). In addition, disulfiram (DSF), an FDA-approved drug for the treatment of alcohol dependence, in combination with copper, significantly enhanced the in vivo antitumor effects of docetaxel in a docetaxel-resistant xenograft tumor model. Our analyses also revealed that DSF and copper engaged with ATP7B to decrease protein levels of COMM domain-containing protein 1 (COMMD1), S-phase kinase-associated protein 2 (Skp2), and clusterin and markedly increase protein expression of cyclin-dependent kinase inhibitor 1 (p21/WAF1). Taken together, our results indicate a copper-dependent nutrient vulnerability through ATP7B exporter in docetaxel-resistant prostate cancer for improving the therapeutic efficacy of docetaxel.

Cranial suture lineage and contributions to repair of the mouse skull.

The cranial sutures are proposed to be a stem cell niche, harbouring skeletal stem cells that are directly involved in development, homeostasis and healing. Like the craniofacial bones, the sutures are formed from both mesoderm and neural crest. During cranial bone repair, neural crest cells have been proposed to be key players; however, neural crest contributions to adult sutures are not well defined, and the relative importance of suture proximity is unclear. Here, we use genetic approaches to re-examine the neural crest-mesoderm boundaries in the adult mouse skull. These are combined with calvarial wounding experiments suggesting that suture proximity improves the efficiency of cranial repair. Furthermore, we demonstrate that Gli1+ and Axin2+ skeletal stem cells are present in all calvarial sutures examined. We propose that the position of the defect determines the availability of neural crest-derived progenitors, which appear to be a key element in the repair of calvarial defects.

Comparative Analysis of Pharmacokinetics and Metabolites of Three Main Terpenoids before and after Compatibility of Frankincense and Myrrh in Rats by UHPLC-MS.

BACKGROUND: 3-acetyl-11-keto-beta-boswellic acid (AKBA) and 11-keto-boswellic acid (KBA) are the main active components of frankincense as pentacyclic triterpenoids, which are designated by the European Pharmacopoeia 8.0 as the quality standard for the evaluation of Indian frankincense, 2-methoxy-8,12-epoxygermacra- 1(10),7,11-trien-6-one (MCS134) is a non-volatile sesquiterpene compound in myrrh. OBJECTIVE: In this paper, the absorption pharmacokinetics and metabolites of AKBA, KBA and MCS134 after frankincense, myrrh and their compatibility were analyzed, elaborated their absorption and metabolism mechanism and provided the ideas for the research on the bioactive components of frankincense and myrrh compatibility in vivo. METHODS: The area under the blood concentration time curve (AUC), half-life (t_1/2) and drug clearance (CL) of AKBA, KBA and MCS134 in rats were analyzed by LC-TQ / MS. The metabolites of AKBA, KBA and MCS134 in rats were analyzed by ultra-high pressure liquid chromatography with a linear ion trap-high resolution Orbitrap mass spectrometry system (UHPLC-LTQ-Orbitrap-MS). RESULTS: The results showed that AKBA, KBA and MCS134 reached the maximum plasma concentration at about 2 h, 2 h and 15 min, respectively. AUC_0-t and t_1/2 of the three components increased in varying degrees after compatibility, and the clearance/ bioavailability (CL/F) decreased. AKBA, KBA and MCS134 were metabolized in phase I and phase II in rats, and there represented differences before and after compatibility. CONCLUSION: After the compatibility of frankincense and myrrh, the absorption of effective components was improved to some extent, and there were some differences in the metabolites in rats. The results provide ideas for elucidating the in vivo effect mechanism of frankincense and myrrh.

A Fluorescent Unnatural Mannosamine Derivative with Enhanced Emission Upon Complexation with Cucurbit[7]uril.

Metabolic incorporation of unnatural functionality on glycans has allowed chemical biologists to observe and affect cellular processes. Recent work has resulted in glycan-fluorophore structures that allow for direct visualization of glycan-mediated processes, shining light on their role in living systems. This work describes the serendipitous discovery of a small chemical reporter-fluorophore. Investigations into the mechanism of fluorescence arising from (trimethylsilyl)methylglycine appended on mannosamine suggest rigidity and restriction of lone pair geometry contribute to the fluorescent behaviour. In fact, in situ cyclization and encapsulation in cucurbit[7]uril enhance fluorescence to levels that can be observed in live cells. While the reported unnatural mannosamine does not traverse the sialic acid biosynthetic pathway, this discovery may lead to small, "turn-on" chemical reporters for incorporation in living systems.

Shortwave Infrared Fluorofluorophores for Multicolor In Vivo Imaging.

Developing chemical tools to detect and influence biological processes is a cornerstone of chemical biology. Here we combine two tools which rely on orthogonality- perfluorocarbons and multiplexed shortwave infrared (SWIR) fluorescence imaging- to visualize nanoemulsions in real time in living mice. Drawing inspiration from fluorous and SWIR fluorophore development, we prepared two SWIR-emissive, fluorous-soluble chromenylium polymethine dyes. These are the most red-shifted fluorous fluorophores- "fluorofluorophores"-to date. After characterizing the dyes, their utility was demonstrated by tracking perfluorocarbon nanoemulsion biodistribution in vivo. Using an excitation-multiplexed approach to image two variables simultaneously, we gained insight into the importance of size and surfactant identity on biodistribution.

Water-soluble chromenylium dyes for shortwave infrared imaging in mice.

In vivo imaging using shortwave infrared light (SWIR, 1000-2000 nm) benefits from deeper penetration and higher resolution compared to using visible and near-infrared wavelengths. However, the development of biocompatible SWIR contrast agents remains challenging. Despite recent advancements, small molecule SWIR fluorophores are often hindered by their significant hydrophobicity. We report a platform for generating a panel of soluble and functional dyes for SWIR imaging by late-stage functionalization of a versatile fluorophore intermediate, affording water-soluble dyes with bright SWIR fluorescence in serum. Specifically, a tetra-sulfonate derivative enables clear video-rate imaging of vasculature with only 0.05 nmol dye, and a tetra-ammonium dye shows strong cellular retention for tracking of tumor growth. Additionally, incorporation of phosphonate functionality enables imaging of bone in awake mice. This modular design provides insights for facile derivatization of existing SWIR fluorophores to introduce both solubility and bioactivity towards in vivo bioimaging.

[Combination characteristics of frankincense and myrrh and progress and prospect of their combination efficacy and mechanism].

Herbal pair is formed based on the experience summary of doctors' deep understanding and perception of the medicinal nature in long-term clinical practice. It gradually becomes the exquisite structural unit for preparing traditional Chinese medicine(TCM) prescriptions, and often plays a core bridge role in the prescription combination. Frankincense and myrrh are raw resin materials of incense abroad, which are subsequently included as Chinese medicinal herbs and endowed with rich medicinal connotation. With the functions of relaxing Zang-fu organs, activating blood and relieving pain, they have definite clinical efficacy. From the perspective of herbal description and clinical application, this study systematically analyzed the combination of frankincense and myrrh as well as their combination proportion, efficacy characterization, diseases and syndromes, effective components and action mechanism. On this basis, the focus of in-depth research of frankincense-myrrh and the application prospects were proposed, in order to further reveal the potential meditation law of this herbal pair, thus contributing to clinical practice and drug innovation of traditional Chinese medicine, and providing reference for understanding of TCM medicinal nature and research of herbal pairs.

Potential roles of gut microbiota and microbial metabolites in chronic inflammatory pain and the mechanisms of therapy drugs.

Observational findings achieved that gut microbes mediate human metabolic health and disease risk. The types of intestinal microorganisms depend on the intake of food and drugs and are also related to their metabolic level and genetic factors. Recent studies have shown that chronic inflammatory pain is closely related to intestinal microbial homeostasis. Compared with the normal intestinal flora, the composition of intestinal flora in patients with chronic inflammatory pain had significant changes in Actinomycetes, Firmicutes, Bacteroidetes, etc. At the same time, short-chain fatty acids and amino acids, the metabolites of intestinal microorganisms, can regulate neural signal molecules and signaling pathways, thus affecting the development trend of chronic inflammatory pain. Glucocorticoids and non-steroidal anti-inflammatory drugs in the treatment of chronic inflammatory pain, the main mechanism is to affect the secretion of inflammatory factors and the abundance of intestinal bacteria. This article reviews the relationship between intestinal microorganisms and their metabolites on chronic inflammatory pain and the possible mechanism.

Mulberry leaves ameliorate diabetes via regulating metabolic profiling and AGEs/RAGE and p38 MAPK/NF-κB pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Mulberry leaves have been used as traditional hypoglycemic medicine-food plant for thousand years in China. According to traditional Chinese medicine theory, type 2 diabetes mellitus (T2DM) belongs to the category of XiaoKe. Presently, the research of mulberry leaf hypoglycemic and lipid-lowering direction is mature, but the curative effects of alkaloids, flavonoids, polysaccharides, and other bioactive ingredients and the related mechanism is still unclear. AIM OF THE STUDY: This paper aims to study the efficacy and mechanism of alkaloids, flavonoids, polysaccharides, and other bioactive components in mulberry leaves in the treatment of T2DM individually. MATERIALS AND METHODS: The determination of levels of fasting blood glucose (FBG), triglyceride (TG) and total cholesterol (T-Cho), and pyruvate kinase (PK), hexokinase (HK), and alanine aminotransferase (ALT/GPT) of in plasma of diabetic mice. Urine metabolomics was analyzed by UPLC-QTOF/MS to evaluate differential metabolites from multiple metabolic pathways. The glucose uptake of HepG2 cells and 3T3-L1 cells. Expression of Caspase-3 and caspase-9, inflammatory injury and p38MAPK/NF-κB signaling pathway in GLUTag cells. RESULTS: Our study revealed alkaloids, flavonoids, and polysaccharides in mulberry leaf could increase the levels of PK, HK, and ALT/GPT, and decrease the levels of TG and T-Cho significantly, and regulate glucose, amino acid, and lipid metabolism. Furthermore, 1-deoxynojirimycin (DNJ) and isoquercitrin (QG) both could increase glucose uptake and promote differentiation of HepG2 cells, increase PPARγ, C/EBPα and SREBP-l expression in 3T3-L1 cells, and inhibit AGEs-induced injury and apoptosis in GLUTag cells, reduce the expression of proteins related to AGEs/RAGE and p38MAPK/NF-κB pathway. Notably, isoquercitrin exhibited more pronounced anti-diabetic efficacy. CONCLUSIONS: The alkaloids, flavonoids, and polysaccharides from mulberry leaf exhibited hypoglycemic activity through the regulation of glucose, amino acid, and lipid metabolism. 1-DNJ and QG increased glucose uptake and promoted differentiation of HepG2 cells, increased PPARγ, C/EBPα and SREBP-l expression in 3T3-L1 cells, and inhibited AGEs-induced injury and apoptosis in GLUTag cells via the AGEs/RAGE and p38 MAPK/NF-κB pathway.

The ionophore thiomaltol induces rapid lysosomal accumulation of copper and apoptosis in melanoma.

In this report, we investigate the toxicity of the ionophore thiomaltol (Htma) and Cu salts to melanoma. Divalent metal complexes of thiomaltol display toxicity against A375 melanoma cell culture resulting in a distinct apoptotic response at submicromolar concentrations, with toxicity of Cu(tma)2 > Zn(tma)2 >> Ni(tma)2. In metal-chelated media, Htma treatment shows little toxicity, but the combination with supplemental CuCl2, termed Cu/Htma treatment, results in toxicity that increases with suprastoichiometric concentrations of CuCl2 and correlates with the accumulation of intracellular copper. Electron microscopy and confocal laser scanning microscopy of Cu/Htma treated cells shows a rapid accumulation of copper within lysosomes over the course of hours, concurrent with the onset of apoptosis. A buildup of ubiquitinated proteins due to proteasome inhibition is seen on the same timescale and correlates with increases of copper without additional Htma.

Spatiotemporal Control of Biology: Synthetic Photochemistry Toolbox with Far-Red and Near-Infrared Light.

The complex network of naturally occurring biological pathways motivates the development of new synthetic molecules to perturb and/or detect these processes for fundamental research and clinical applications. In this context, photochemical tools have emerged as an approach to control the activity of drug or probe molecules at high temporal and spatial resolutions. Traditional photochemical tools, particularly photolabile protecting groups (photocages) and photoswitches, rely on high-energy UV light that is only applicable to cells or transparent model animals. More recently, such designs have evolved into the visible and near-infrared regions with deeper tissue penetration, enabling photocontrol to study biology in tissue and model animal contexts. This Review highlights recent developments in synthetic far-red and near-infrared photocages and photoswitches and their current and potential applications at the interface of chemistry and biology.

[Ant i-inflammatory mechanism of active components in Olibanum and Myrrha based on network pharmacology and cell experiments].

Two terpenes, 3-keto-tirucalla-8,24-dien-21-oic acid(KTDA) and 2-methoxy-5-acetoxy-furanogermacr-1(10)-en-6-one(FSA), are isolated from Olibanum and Myrrha respectively, which are characterized by high yield and easy crystallization during the preparation. The present study explored the regulatory targets and anti-inflammatory mechanism of KTDA and FSA based on network pharmacology and cell viability assay. First, the drug-likeness of KTDA and FSA was predicted by Swiss ADME. The target prediction of active components was carried out by Swiss Target Prediction and Pharmmapper. TTD, Drug Bank, and Gene Cards were searched for inflammation-related target genes of KTDA and FSA. Protein-protein interaction(PPI) analysis was performed on the inflammatory targets of KTDA and FSA by STRING, and Cytoscape was used to conduct topological analysis of the interaction results and construct the PPI network. GO function and KEGG pathway enrichment analyses of inflammatory targets of KTDA and FSA were carried out by DAVID, and a " component-target-pathway" network was constructed. Finally, lipopolysaccharide(LPS)-induced RAW264. 7 cells were treated with KTDA and FSA at different concentrations, and nitric oxide(NO) concentration and protein and m RNA expression levels were detected. The results showed that both KTDA and FSA showed good drug-likeness. A total of 157 and 142 inflammation-related targets of KTDA and FSA were screened out. PPI network analysis showed that MAPK1, AKT1, MAPK8, PIK3 CA,PIK3 R1, EGFR, etc. might be the key proteins for the anti-inflammatory effect. PI3 K/AKT and MAPK signaling pathways were obtained by KEGG and GO-BP enrichment. Cell experiment results showed that KTDA and FSA could exert anti-inflammatory effects by inhibiting NO production, reducing the phosphorylation levels of JNK, p38, and AKT proteins, and down-regulating the m RNA expression of interleukin(IL)-1ß and IL-6. Meanwhile, FSA could also inhibit ERK phosphorylation. The results indicated that KTDA and FSA had significant anti-inflammatory activity, which provided a scientific basis and important support for the further research,development, and utilization of Olibanum and Myrrha.

Establishing design principles for emissive organic SWIR chromophores from energy gap laws.

Rational design of bright near and shortwave infrared (NIR: 700-1000 SWIR: 1000- 2000 nm) emitters remains an open question with applications spanning imaging and photonics. Combining experiment and theory, we derive an energy gap quantum yield master equation (EQME), describing the fundamental limits in SWIR quantum yields (ϕ F ) for organic chromophores. Evaluating the photophysics of 21 polymethine NIR/SWIR chromophores to parameterize the EQME, we explain the precipitous decline of ϕ F past 900 nm through decreasing radiative rates and increasing nonradiative losses via high frequency vibrations relating to the energy gap. Using the EQME we develop an energy gap independent ϕ F NIR/SWIR chromophore comparison metric. We show electron donating character on polymethine heterocycles results in relative increases in radiative efficiency obscured by a simultaneous redshift. Finally, the EQME yields rational chromophore design insights shown by how deuteration (backed by our experimental results) or molecular aggregation increases SWIR ϕ F .

A microtubule-localizing activity-based sensing fluorescent probe for imaging hydrogen peroxide in living cells.

Hydrogen peroxide (H2O2) is a major reactive oxygen species (ROS) in living systems with broad roles spanning both oxidative stress and redox signaling. Indeed, owing to its potent redox activity, regulating local sites of H2O2 generation and trafficking is critical to determining downstream physiological and/or pathological consequences. We now report the design, synthesis, and biological evaluation of Microtubule Peroxy Yellow 1 (MT-PY1), an activity-based sensing fluorescent probe bearing a microtubule-targeting moiety for detection of H2O2 in living cells. MT-PY1 utilizes a boronate trigger to show a selective and robust turn-on response to H2O2 in aqueous solution and in living cells. Live-cell microscopy experiments establish that the probe co-localizes with microtubules and retains its localization after responding to changes in levels of H2O2, including detection of endogenous H2O2 fluxes produced upon growth factor stimulation. This work adds to the arsenal of activity-based sensing probes for biological analytes that enable selective molecular imaging with subcellular resolution.

[Mechanism of Olibanum-Myrrha in treatment of rheumatoid arthritis based on network pharmacology and molecular docking].

In this paper, network pharmacology method and molecular docking technique were used to investigate the target genes of Olibanum and Myrrha compatibility and the possible mechanism of action in the treatment of rheumatoid arthritis(RA). Our team obtained the main active components of Olibanum-Myrrha based on literatures study, relevant traditional Chinese medicine systematic pharmacological databases and literature retrieval, and made target prediction of the active components through SwissTargetPrediction database. At the same time, RA-related targets were collected through DrugBank, GeneCards and Therapeutic Target Database(TDD) databases; and VENNY 2.1 was use to collect intersection targets to map common targets of drug and disease of Venn diagram online. The team used STRING database to construct PPI protein interaction network diagram, and screen out core targets according to the size of the interaction, and Cytoscape 3.6.0 software was used to construct network models of "traditional Chinese medicine-component-target" "traditional Chinese medicine-component-target-disease" and core target interaction network model. The intersection target was analyzed by using DAVID 6.8 online database for GO function analysis and KEGG pathway enrichment analysis, and Pathon was used to visualization. AutoDock Vina and Pymol were used to connect the core active components with the core targets. Sixteen active components of Olibanum-Myrrha pairs were found and collected in the laboratory, and 320 relevant potential targets, 468 RA-related targets and 62 intersection targets were obtained through the Venn diagram. It mainly acted on multiple targets, such as IL6, TNF, IL1 B and MAPK1, involving TNF signaling pathway and Toll-like receptor signaling pathway in RA treatment. Finally, in this study, possible targets and signaling pathways of Olibanum-Myrrha compatibility therapy for RA were discussed, and molecular docking between core targets and core active components was conducted, which could provide scientific basis for the study on the mechanism of Olibanum-Myrrha compatibility.

Lysosomal SLC46A3 modulates hepatic cytosolic copper homeostasis.

The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes hepatic toxicity associated with prominent lipid accumulation in humans. Here, the authors report that the lysosomal copper transporter SLC46A3 is induced by TCDD and underlies the hepatic lipid accumulation in mice, potentially via effects on mitochondrial function. SLC46A3 was localized to the lysosome where it modulated intracellular copper levels. Forced expression of hepatic SLC46A3 resulted in decreased mitochondrial membrane potential and abnormal mitochondria morphology consistent with lower copper levels. SLC46A3 expression increased hepatic lipid accumulation similar to the known effects of TCDD exposure in mice and humans. The TCDD-induced hepatic triglyceride accumulation was significantly decreased in Slc46a3-/- mice and was more pronounced when these mice were fed a high-fat diet, as compared to wild-type mice. These data are consistent with a model where lysosomal SLC46A3 induction by TCDD leads to cytosolic copper deficiency resulting in mitochondrial dysfunction leading to lower lipid catabolism, thus linking copper status to mitochondrial function, lipid metabolism and TCDD-induced liver toxicity.

Quantitative tooth wear analysis of index teeth compared to complete dentition.

OBJECTIVES: Recent software advancements have facilitated quantification of erosive tooth wear progression using intraoral scans. This paper investigated if wear on commonly affected surfaces (central incisors and first molars) was representative of wear on the full arch. METHODS: Bimaxillary digital intraoral scans (True Definition, 3 M, USA) of patients (n = 30) from the monitoring arm of the Radboud Tooth Wear Project, were taken at baseline and at 3 years (+/-10months). The occlusal/incisal surface of each tooth (excluding 3rd molars) was analysed for volume change and volume change per mm of analysed surface area in WearCompare (www.leedsdigitaldentistry.com/Wearcompare) following previously published protocols. Data were normal, descriptives and multi-level linear regression analysis was performed in Stata v15.1 taking patient level and surface type data into account. RESULTS: Data from 556 surfaces in 29 patients were included in analysis. Per patient, mean volume loss (95 % CI) was -0.91mm3(-1.28,-0.53) on all surfaces, -1.85mm3(-2.83,-0.86) on index surfaces, -2.53mm3(-3.91,-1.15) on molar surfaces and -0.83 mm3(-1.34,-0.31) on upper central incisal surfaces. Statistical differences were observed between analysing all surfaces and index teeth(p = 0.002) in addition to molar surfaces(p < 0.0001). Mean volume loss per mm2 of surface analysed was -0.024 mm3 (-0.031,-0.017), -0.028mm3 (-0.041,-0.014), -0.030mm3 (-0.046,-0.013) and -0.025mm3 (-0.041,-0.010) for all surfaces, index surfaces, first molar surfaces and central incisor surfaces respectively with no statistical differences between groups. CONCLUSIONS: Wear on upper central incisors was not statistically different to full arch wear analysis. If the surface area is standardised, wear on both index surfaces are statistically similar to wear on the full arch. CLINICAL SIGNIFICANCE: These results suggest that analysing rates of wear on index teeth can be a resource-saving substitute for analysing rates of wear on the entire dentition, provided the surface area is standardised. If whole surfaces are analysed, the molar surfaces will show greater rates of wear.

Single cell analysis reveals multiple requirements for zinc in the mammalian cell cycle.

Zinc is widely recognized as essential for growth and proliferation, yet the mechanisms of how zinc deficiency arrests these processes remain enigmatic. Here we induce subtle zinc perturbations and track asynchronously cycling cells throughout division using fluorescent reporters, high throughput microscopy, and quantitative analysis. Zinc deficiency induces quiescence and resupply stimulates synchronized cell-cycle reentry. Monitoring cells before and after zinc deprivation we found the position of cells within the cell cycle determined whether they either went quiescent or entered another cell cycle but stalled in S-phase. Stalled cells exhibited prolonged S-phase, were defective in DNA synthesis and had increased DNA damage levels, suggesting a role for zinc in maintaining genome integrity. Finally, we demonstrate zinc deficiency-induced quiescence occurs independently of DNA-damage response pathways, and is distinct from mitogen removal and spontaneous quiescence. This suggests a novel pathway to quiescence and reveals essential micronutrients play a role in cell cycle regulation.

Inflammation mobilizes copper metabolism to promote colon tumorigenesis via an IL-17-STEAP4-XIAP axis.

Copper levels are known to be elevated in inflamed and malignant tissues. But the mechanism underlying this selective enrichment has been elusive. In this study, we report a axis by which inflammatory cytokines, such as IL-17, drive cellular copper uptake via the induction of a metalloreductase, STEAP4. IL-17-induced elevated intracellular copper level leads to the activation of an E3-ligase, XIAP, which potentiates IL-17-induced NFκB activation and suppresses the caspase 3 activity. Importantly, this IL-17-induced STEAP4-dependent cellular copper uptake is critical for colon tumor formation in a murine model of colitis-associated tumorigenesis and STEAP4 expression correlates with IL-17 level and XIAP activation in human colon cancer. In summary, this study reveals a IL-17-STEAP4-XIAP axis through which the inflammatory response induces copper uptake, promoting colon tumorigenesis.