Reduction-Assisted Calcination Enhances the Photocatalytic Activity of ZnO and WO3 Nanoparticles in Biomass Conversion.

Rising energy needs and environmental issues have prompted the creation of effective and affordable photocatalysts for converting biomass. Utilizing abundant biomass, oxidation of 5-hydroxymethylfurfural (HMF) emerges as a method for generating high-value chemicals from biomass, offering an alternative to fossil fuels. We synthesized defect-engineered metal oxides (ZnO and WO3) by calcination with NaBH4 as a reducing agent. Atomic-level analyses identified oxygen vacancy defects induced by the reduction of metal ions within the metal oxide nanoparticles. Further analysis showed an unchanged band gap but an up to 4-fold increase in current density. This enhancement is attributed to the trapping of electrons in defect sites created during the calcination process. The formation of new electron donor states hindered photogenerated electron-hole recombination, enhancing the photocatalytic efficiency of the metal oxide. The photocatalytic degradation yield of HMF was over 95%, and the selective organic products 2,5-diformylfuran (DFF) and 2,5-furandicarboxylic acid (FDCA) were obtained without byproducts. Kinetic studies demonstrated that the photocatalytic conversion reaction rates were accelerated by up to 3.5-fold. Improved photocatalytic activity for HMF oxidation was achieved by introducing oxygen vacancy defects upon the reduction of metal ions within the metal oxides. Our results provide a promising approach for designing efficient photocatalysts.

The Immune Suppressor IGSF1 as a Potential Target for Cancer Immunotherapy.

The development of first-generation immune-checkpoint inhibitors targeting PD-1/PD-L1 and CTLA-4 ushered in a new era in anticancer therapy. Although immune-checkpoint blockade therapies have shown clinical success, a substantial number of patients yet fail to benefit. Many studies are under way to discover next-generation immunotherapeutic targets. Immunoglobulin superfamily member 1 (IGSF1) is a membrane glycoprotein proposed to regulate thyroid function. Despite containing 12 immunoglobin domains, a possible role for IGSF1, in immune response, remains unknown. Here, our studies revealed that IGSF1 is predominantly expressed in tumors but not normal tissues, and increased expression is observed in PD-L1low non-small cell lung cancer (NSCLC) cells as compared with PD-L1high cells. Subsequently, we developed and characterized an IGSF1-specific human monoclonal antibody, WM-A1, that effectively promoted antitumor immunity and overcame the limitations of first-generation immune-checkpoint inhibitors, likely via a distinct mechanism of action. We further demonstrated high WM-A1 efficacy in humanized peripheral blood mononuclear cells (PBMC), and syngeneic mouse models, finding additive efficacy in combination with an anti-PD-1 (a well-characterized checkpoint inhibitor). These findings support IGSF1 as an immune target that might complement existing cancer immunotherapeutics.

Optical Coherence Tomographic Optic Nerve Head Morphology in Myopia III: The Exposed Neural Canal Region in Healthy Eyes-Implications for High Myopia.

PURPOSE: To determine the prevalence and magnitude of optical coherence tomography (OCT) exposed neural canal (ENC), externally oblique choroidal border tissue (EOCBT), and exposed scleral flange (ESF) regions in 362 non-highly myopic (spherical equivalent -6.00 to 5.75 diopters) eyes of 362 healthy subjects. DESIGN: Cross-sectional study. METHODS: After OCT optic nerve head (ONH) imaging, Bruch membrane opening (BMO), the anterior scleral canal opening (ASCO), and the scleral flange opening (SFO) were manually segmented. BMO, ASCO, and SFO points were projected to the BMO reference plane. The direction and magnitude of BMO/ASCO offset as well as the magnitude of ENC, EOCBT, and ESF was calculated within 30° sectors relative to the foveal-BMO axis. Hi-ESF eyes demonstrated an ESF ≥100 µm in at least 1 sector. Sectoral peri-neural canal choroidal thickness (pNC-CT) was measured and correlations between the magnitude of sectoral ESF and proportional pNC-CT were assessed. RESULTS: Seventy-three Hi-ESF (20.2%) and 289 non-Hi-ESF eyes (79.8%) were identified. BMO/ASCO offset as well as ENC, EOCBT, and ESF prevalence and magnitude were greatest inferior temporally where the pNC-CT was thinnest. Among Hi-ESF eyes, the magnitude of each ENC region correlated with the BMO/ASCO offset magnitude, and the sectors with the longest ESF correlated with the sectors with proportionally thinnest pNC-CT. CONCLUSIONS: ONH BMO/ASCO offset, either as a cause or result of ONH neural canal remodeling, corresponds with the sectoral location of maximum ESF and minimum pNC-CT in non-highly myopic eyes. Longitudinal studies to characterize the development and clinical implications of ENC Hi-ESF regions in non-highly myopic and highly myopic eyes are indicated.

Targeting isoforms of RON kinase (MST1R) drives antitumor efficacy.

Recepteur d'origine nantais (RON, MST1R) is a single-span transmembrane receptor tyrosine kinase (RTK) aberrantly expressed in numerous cancers, including various solid tumors. How naturally occurring splicing isoforms of RON, especially those which are constitutively activated, affect tumorigenesis and therapeutic response, is largely unknown. Here, we identified that presence of activated RON could be a possible factor for the development of resistance against anti-EGFR (cetuximab) therapy in colorectal cancer patient tissues. Also, we elucidated the roles of three splicing variants of RON, RON Δ155, Δ160, and Δ165 as tumor drivers in cancer cell lines. Subsequently, we designed an inhibitor of RON, WM-S1-030, to suppress phosphorylation thereby inhibiting the activation of the three RON variants as well as the wild type. Specifically, WM-S1-030 treatment led to potent regression of tumor growth in solid tumors expressing the RON variants Δ155, Δ160, and Δ165. Two mechanisms for the RON oncogenic activity depending on KRAS genotype was evaluated in our study which include activation of EGFR and Src, in a trimeric complex, and stabilization of the beta-catenin. In terms of the immunotherapy, WM-S1-030 elicited notable antitumor immunity in anti-PD-1 resistant cell derived mouse model, likely via repression of M1/M2 polarization of macrophages. These findings suggest that WM-S1-030 could be developed as a new treatment option for cancer patients expressing these three RON variants.

Mutant PIK3CA as a negative predictive biomarker for treatment with a highly selective PIM1 inhibitor in human colon cancer.

Significant improvement in targeted therapy for colorectal cancer (CRC) has occurred over the past few decades since the approval of the EGFR inhibitor cetuximab. However, cetuximab is used only for patients possessing the wild-type oncogene KRAS, NRAS, and BRAF, and even most of these eventually acquire therapeutic resistance, via activation of parallel oncogenic pathways such as RAS-MAPK or PI3K/Akt/mTOR. The two aforementioned pathways also contribute to the development of therapeutic resistance in CRC patients, due to compensatory and feedback mechanisms. Therefore, combination drug therapies (versus monotherapy) targeting these multiple pathways may be necessary for further efficacy against CRC. In this study, we identified PIK3CA mutant (PIK3CA MT) as a determinant of resistance to SMI-4a, a highly selective PIM1 kinase inhibitor, in CRC cell lines. In CRC cell lines, SMI-4a showed its effect only in PIK3CA wild type (PIK3CA WT) cell lines, while PIK3CA MT cells did not respond to SMI-4a in cell death assays. In vivo xenograft and PDX experiments confirmed that PIK3CA MT is responsible for the resistance to SMI-4a. Inhibition of PIK3CA MT by PI3K inhibitors restored SMI-4a sensitivity in PIK3CA MT CRC cell lines. Taken together, these results demonstrate that sensitivity to SMI-4a is determined by the PIK3CA genotype and that co-targeting of PI3K and PIM1 in PIK3CA MT CRC patients could be a promising and novel therapeutic approach for refractory CRC patients.

Amyloid Fibers Increase Free Radicals of Synthetic Melanin.

Functional amyloid fibers are crucial in melanogenesis, but their roles are incompletely understood. In particular, their relationship with intrinsic spin characters of melanin remains unexplored. Here, we show that adding an amyloid scaffold greatly augments the spin density in synthetic melanin. It also brings about concurrent alterations in water dispersibility, bandgaps, and radical scavenging properties of the synthetic melanin, which facilitates its applications in solar water remediation and protection of human keratinocytes from UV irradiation. This work provides implications in the unrevealed role of functional amyloid in melanogenesis and in the origin of the superiority of natural melanin toward its synthetic variants in terms of the spin-related properties.

Hint from an Enzymatic Reaction: Superoxide Dismutase Models Efficiently Suppress Colorectal Cancer Cell Proliferation.

Superoxide dismutases (SODs) are essential antioxidant enzymes that prevent massive superoxide radical production and thus protect cells from damage induced by free radicals. However, this concept has rarely been applied to directly impede the function of driver oncogenes, thus far. Here, leveraging efforts from SOD model complexes, we report the novel finding of biomimetic copper complexes that efficiently scavenge intracellularly generated free radicals and, thereby, directly access the core consequence of colorectal cancer suppression. We conceived four structurally different SOD-mimicking copper complexes that showed distinct disproportionation reaction rates of intracellular superoxide radical anions. By replenishing SOD models, we observed a dramatic reduction of intracellular reactive oxygen species (ROS) and adenine 5'-triphosphate (ATP) concentrations that led to cell cycle arrest at the G2/M stage and induced apoptosis in vitro and in vivo. Our results showcase how nature-mimicking models can be designed and fine-tuned to serve as a viable chemotherapeutic strategy for cancer treatment.

Association of overexpressed carboxyl-terminal amyloid precursor protein in brains with altered glucose metabolism and liver toxicity.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease. The deposition of amyloid plaques mainly composed of amyloid beta (Aß) is observed in brain regions in AD patients. AD presents with similar pathophysiology to that of metabolic syndrome, including glucose and insulin resistance. In addition, epidemiological studies indicate diabetes, impaired glucose metabolism, and obesity increase the prevalence of AD. The liver is considered a key organ in the reciprocal relationship between AD and metabolic syndrome and is the major organ for the clearance of Aß in the periphery. Furthermore, liver dysfunction aggravates Aß-induced pathophysiology. Aß is produced in the brain and peripheral tissues and penetrates the blood-brain barrier. However, in vivo evidence showing the effect of Aß on the crosstalk between the brain and liver has not been reported yet. In the present study, we investigated the toxicity of brain-derived Aß on glucose metabolism and the liver using transgenic mice overexpressing the carboxyl-terminal of amyloid precursor protein in the brain. The transgenic mice were overweight, which was associated with impaired glucose metabolism and insulin resistance, but not due to increased food intake. In addition, transgenic mice had enlarged livers and reduced gene expressions associated with glucose and lipid metabolism. Thus, overexpressed amyloid precursor protein in the brain may promote being overweight and glucose resistance, possibly through liver toxicity.

Polypropylene microplastics promote metastatic features in human breast cancer.

Microplastics (MPs) are now a global issue due to increased plastic production and use. Recently, various studies have been performed in response to the human health risk assessment. However, these studies have focused on spherical MPs, which have smooth edges and a spherical shape and account for less than 1% of MPs in nature. Unfortunately, studies on fragment-type MPs are very limited and remain in the initial stages. In this study, we studied the effect that 16.4 µm fragment type polypropylene (PP) MPs, which have an irregular shape and sharp edges and form naturally in the environment, had on breast cancer. The detrimental effects of PPMPs on breast cancer metastasis were examined. Here, 1.6 mg/ml of PPMP, which does not induce cytotoxicity in MDA-MB-231, was used, and at this concentration, PPMP did not induce morphological changes or cellular migrating in the MDA-MB-231 and MCF-7 cells. However, PPMP incubation for 24 hours in the MDA-MB-231 cells significantly altered the level of cell cycle-related transcripts in an RNA-seq analysis. When confirmed by qRT-PCR, the gene expression of TMBIM6, AP2M1, and PTP4A2 was increased, while the transcript level of FTH1 was decreased. Further, secretion of the pro-inflammatory cytokine IL-6 from cancer cells was elevated with the incubation of PPMP for 12 hours. These results suggest that PPMP enhances metastasis-related gene expression and cytokines in breast cancer cells, exacerbating breast cancer metastasis.

OCT Optic Nerve Head Morphology in Myopia II: Peri-Neural Canal Scleral Bowing and Choroidal Thickness in High Myopia-An American Ophthalmological Society Thesis.

PURPOSE: To use optical coherence tomography (OCT) to characterize optic nerve head (ONH) peri-neural canal (pNC) scleral bowing (pNC-SB) and pNC choroidal thickness (pNC-CT) in 69 highly myopic and 138 healthy, age-matched, control eyes. DESIGN: Cross-sectional, case control study. METHODS: Within ONH radial B-scans, Bruch membrane (BM), BM opening (BMO), anterior scleral canal opening (ASCO), and pNC scleral surface were segmented. BMO and ASCO planes and centroids were determined. pNC-SB was characterized within 30° foveal-BMO (FoBMO) sectors by 2 parameters: pNC-SB-scleral slope (pNC-SB-SS), measured within 3 pNC segments (0-300, 300-700, and 700-1000 µm from the ASCO centroid); and pNC-SB-ASCO depth relative to a pNC scleral reference plane (pNC-SB-ASCOD). pNC-CT was calculated as the minimum distance between the scleral surface and BM at 3 pNC locations (300, 700, and 1100 µm from the ASCO). RESULTS: pNC-SB increased and pNC-CT decreased with axial length (P < .0133; P < .0001) and age (P < .0211; P < .0004) among all study eyes. pNC-SB was increased (P < .001) and pNC-CT was decreased (P < .0279) in the highly myopic compared to control eyes, and these differences were greatest in the inferior quadrant sectors (P < .0002). Sectoral pNC-SB was not related to sectoral pNC-CT in control eyes, but was inversely related to sectoral pNC-CT (P < .0001) in the highly myopic eyes. CONCLUSIONS: Our data suggest that pNC-SB is increased and pNC-CT is decreased in highly myopic eyes and that these phenomena are greatest in the inferior sectors. They support the hypothesis that sectors of maximum pNC-SB may predict sectors of greatest susceptibility to aging and glaucoma in future longitudinal studies of highly myopic eyes. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

DGG-300273, a novel WNT/ß-catenin inhibitor, induces apoptotic cell death by activating ROS-BIM signaling in a Wnt-dependent manner in colon cancer cells.

Dysregulated Wnt signaling is associated with malignant oncogenic transformation, especially in colon cancer. Recently, numerous drugs have been developed based on tumorigenesis biomarkers, thus having high potential as drug targets. Likewise, WNT/ß-catenin pathway members are attractive therapeutic targets for colon cancer and are currently in various stages of development. However, although inhibitors of proteins regulating the WNT/ß-catenin signaling pathway have been extensively studied, they have yet to be clinically approved, and the underlying molecular mechanism(s) of their anticancer effects remain poorly understood. Herein, we show that a novel WNT/ß-catenin inhibitor, DGG-300273, inhibits colon cancer cell growth in a Wnt-dependent manner due to upregulation of the BCL2-family protein Bim and caspase-dependent apoptotic cell death. Additionally, DGG-300273-mediated cell death occurs by increased reactive oxygen species (ROS), as shown by abrogation of apoptotic cell death and ROS production following pretreatment with the antioxidant N-acetylcysteine. These results suggest that DGG-300273 represents a promising investigational drug for the treatment of Wnt-associated cancer, thus warranting further characterization and study.

Agile and versatile climbing on ferromagnetic surfaces with a quadrupedal robot.

A climbing robot that can rapidly move on diverse surfaces such as floors, walls, and ceilings will have an enlarged operational workspace compared with other terrestrial robots. However, the climbing skill of robots in such environments has been limited to low speeds or simple locomotion tasks. Here, we present an untethered quadrupedal climbing robot called MARVEL (magnetically adhesive robot for versatile and expeditious locomotion), capable of agile and versatile climbing locomotion in ferromagnetic environments. MARVEL excels over prior climbing robots in terms of climbing speed and ability to execute various motions. It demonstrates the fastest vertical and inverted walking speed, whereas its versatile locomotion ability enables the highest number of gaits and locomotion tasks. The key innovations are an integrated foot design using electropermanent magnets and magnetorheological elastomers that provide large adhesion and traction forces, torque control actuators, and a model predictive control framework adapted for stable climbing. In experiments, the robot achieved locomotion on ceilings and vertical walls up to 0.5 meter (1.51 body lengths) per second and 0.7 meter (2.12 body lengths) per second, respectively. Furthermore, the robot exhibited complex behaviors such as stepping over 10-centimeter-wide gaps; overcoming 5-centimeter-high obstacles; and making transitions between floors, walls, and ceilings. We also show that MARVEL could climb on a curved surface of a storage tank covered with up to 0.3-millimeter-thick paint with rust and dust.

Selective Oxidation of Biomass Molecules via ZnO Nanoparticles Modified Using Charge Mismatch of the Doped Co ions.

A charge mismatch between transition-metal-ion dopants and metal oxide nanoparticles (MO NPs) within an engineered complex engenders a significant number of oxygen vacancies (VO) on the surface of the MO NP construct. To elucidate in-depth the mechanism of this tendency, Co ions with different charge states (Co3+ and Co2+) were doped into ZnO NPs, and their atomic structural changes were correlated with their photocatalytic efficiency. We ascertained that the increase of the Zn-O bond distances was distinctly affected by Co3+-ion doping, and, subsequently, the number of VO was noticeably increased. We further investigated the mechanistic pathways of the photocatalytic oxidation of 2,5-hydroxymethylfurfural (HMF), which have been widely investigated as biomass derivatives because of their potential use as precursors for the synthesis of sustainable alternatives to petrochemical substances. To identify the reaction products in each oxidation step, selective oxidation products obtained from HMF in the presence of pristine ZnO NPs, Co3+- and Co2+-ion-doped ZnO NPs were evaluated. We confirmed that Co3+-ion-doped ZnO NPs can efficiently and selectively oxidize HMF with a good conversion rate (∼40%) by converting HMF to 2,5-furandicarboxylic acid (FDCA). The present study demonstrates the feasibility of improving the production efficiency of FDCA (an alternative energy material) by using enhanced photocatalytic MO NPs with the help of the charge mismatch between MO and metal-ion dopants.

Designed Amyloid Fibers with Emergent Melanosomal Functions.

Short peptides designed to self-associate into amyloid fibers with metal ion-binding ability have been used to catalyze various types of chemical reactions. This manuscript demonstrates that one of these short-peptide fibers coordinated with CuII can exhibit melanosomal functions. The coordinated CuII and the amyloid structure itself are differentially functional in accelerating oxidative self-association of dopamine into melanin-like species and in regulating their material properties (e.g., water dispersion, morphology, and the density of unpaired electrons). The results have implications for the role of functional amyloids in melanin biosynthesis and for designing peptide-based supramolecular structures with various emergent functions.

CJ14939, a Novel JAK Inhibitor, Increases Oxaliplatin-induced Cell Death Through JAK/STAT Pathway in Colorectal Cancer.

BACKGROUND/AIM: Colorectal cancer is reported to have the highest mortality rate among human malignancies. Although many research results for the treatment of colorectal cancer have been reported, there is no suitable treatment when resistance has developed. Therefore, it is necessary to develop new therapeutic agents. Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling plays an essential role in cell differentiation, proliferation, and survival. Abnormal activation of the JAK/STAT signaling pathway, by gene mutation or amplification, may induce cancer development, and sustained JAK/STAT activation is involved in chemoresistance. While many therapeutic agents have been developed to treat colon cancer, there remains no drug to overcome resistance to chemotherapies. The purpose of this study was to determine the potential of CJ14939 as a novel JAK inhibitor for the treatment of colorectal cancer. MATERIALS AND METHODS: In this study, cell culture, cell death assay, 3- (4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay, colony formation assay, immunoblot analysis and tumor xenograft were applied. RESULTS: CJ14939 induced cell death, and inhibited phosphorylation of JAK1 and STAT3 in colorectal cancer cells. Furthermore, CJ14939 also promoted oxaliplatin-induced cell death, up-regulated expression of cleaved caspase-3, and down-regulated expression of phospho-JAK1 and phospho-STAT3. In vivo, co-treatment with CJ14939 and oxaliplatin notably reduced tumor growth when compared with CJ14939 or oxaliplatin treatment alone. CONCLUSION: This study identifies the important potential of CJ14939 in colorectal cancer treatment and suggests that combining CJ14939 with oxaliplatin might be a novel therapeutic strategy for patients with colorectal cancer.

An end-on bis(µ-hydroxido) dimanganese(II,III) azide complex for C-H bond and O-H bond activation reactions.

We report the synthesis of an end-on dinuclear Mn(II) azide complex with two bridging azide ligands that served as a precursor for the formation of an end-on bis(µ-hydroxido) dinuclear Mn(II,III) azide complex upon oxidation by organic peroxide or peracids. Combined experimental and theoretical studies on the reactivity of the end-on bis(µ-hydroxido) dinuclear Mn(II,III) azide complex suggest that the reaction with substrates having weak C-H bond and O-H bond dissociation energy occurred via a H-atom abstraction reaction in a concerted manner.

Bioinspired nonheme iron complex that triggers mitochondrial apoptotic signalling pathway specifically for colorectal cancer cells.

The activation of dioxygen is the keystone of all forms of aerobic life. Many biological functions rely on the redox versatility of metal ions to perform reductive activation-mediated processes entailing dioxygen and its partially reduced species including superoxide, hydrogen peroxide, and hydroxyl radicals, also known as reactive oxygen species (ROS). In biomimetic chemistry, a number of synthetic approaches have sought to design, synthesize and characterize reactive intermediates such as the metal-superoxo, -peroxo, and -oxo species, which are commonly found as key intermediates in the enzymatic catalytic cycle. However, the use of these designed complexes and their corresponding intermediates as potential candidates for cancer therapeutics has scarcely been endeavored. In this context, a series of biomimetic first-row transition metal complexes bearing a picolylamine-based water-soluble ligand, [M(HN3O2)]2+ (M = Mn2+, Fe2+, Co2+, Cu2+; HN3O2 = 2-(2-(bis(pyridin-2-ylmethyl)amino)ethoxy)ethanol) were synthesized and characterized by various spectroscopic methods including X-ray crystallography and their dioxygen and ROS activation reactivity were evaluated in situ and in vitro. It turned out that among these metal complexes, the iron complex, [Fe(HN3O2)(H2O)]2+, was capable of activating dioxygen and hydrogen peroxide and produced the ROS species (e.g., hydroxyl radical). Upon the incubation of these complexes with different cancer cells, such as cervical, breast, and colorectal cancer cells (MDA-MB-231, AU565, SK-BR-3, HeLa S3, HT-29, and HCT116 cells), only the iron complex triggered cellular apoptosis specifically for colorectal cancer cells; the other metal complexes show negligible anti-proliferative activity. More importantly, the biomimetic complexes were harmless to normal cells and produced less ROS therein. The use of immunocytochemistry combined with western blot analysis strongly supported that apoptosis occurred via the intrinsic mitochondrial pathway; in the intracellular network, [Fe(HN3O2)(H2O)]2+ resulted in (i) the activation and/or production of ROS species, (ii) the induction of intracellular impaired redox balance, and (iii) the promotion of the mitochondrial apoptotic signaling pathway in colorectal cancer cells. The results have implications for developing novel biomimetic complexes in cancer treatments and for designing potent candidates with cancer-specific antitumor activity.

Mono- and dinuclear zinc complexes bearing identical bis(thiosemicarbazone) ligand that exhibit alkaline phosphatase-like catalytic reactivity.

Mono- and dinuclear zinc(II) complexes bearing bis(thiosemicarbazone) (bTSC) ligand were employed in the cleavage of phosphoester bonds. Comparative kinetic studies combined with theory suggested that the P-O bond cleavage is much accelerated by dinuclear zinc(II) complex in the presence of base. Based on the DFT-optimized structures of the proposed intermediates, it is plausible that (1) the removal of sulfur atoms of bTSC ligand from the zinc center provides two vacant sites for the binding of water (or hydroxide ion) and phosphoester and (2) the H-bonding between water (or hydroxide ion) and phosphoester, through several water molecules, may also assist the P-O bond cleavage and facilitate the nucleophilic attack. The kinetic and catalytic studies on the hydrolysis of phosphoester by dinuclear zinc complex showed a much-enhanced reactivity under basic reaction conditions, reaching over 95% conversion yield within 4 h. The currently presented compounds are arguably one of the faster synthetic Zn-based model performing phosphatase-like activity presented so far.

Mutation SVCT2 promotes cell proliferation, invasion and migration in colorectal cancer.

The sodium-dependent vitamin C transporter 2 (SVCT2) surface glycoprotein regulates ascorbate accumulation in the plasma, often resulting in the induction of cancer cell death. Therefore, high expression of this gene associates with increased overall survival in several cancers. However, in colorectal cancer (CRC), high (likely mutated) SVCT2 expression relates to poor overall survival, and its functional significance has not been studied. Thus, we hypothesize that mutant SVCT2 expression could affect CRC patient survival. According to biological databases, SVCT2 has been found to be mutated frequently, and SVCT2 E264K has a particularly high pathogenic score (0.98), compared to other SVCT2 mutant sites, in CRC patients. Interestingly, our results reveal expression of SVCT2 E264K in many CRC tissues and cells. Also, we found wild-type SVCT2 expression to be largely localized to the cytoplasm and membrane, while SVCT2 E264K was restricted to the cytoplasm. We further found that SVCT2 E264K overexpression increases cell growth. By contrast, SVCT2 E264K knockdown significantly reduced cell proliferation and promoted cell apoptosis, resulting in inhibition of cell invasion and migration. Taken together, SVCT2 E264K plays a critical role in proliferation in CRC. Our results suggest that SVCT2 E264K could be a promising novel therapeutic target in CRC.

Synthesis, characterization and catalytic activity of a mononuclear nonheme copper(II)-iodosylbenzene adduct.

Iodosylbenzene (PhIO) and its derivatives have attracted significant attention due to their various applications in organic synthesis and biomimetic studies. For example, PhIO has been extensively used for generating high-valent metal-oxo species that have been regarded as key intermediates in diverse oxidative reactions in biological system. However, recent studies have shown that metal-iodosylbenzene adduct, known as a precursor of metal-oxo species, plays an important role in transition metal-catalyzed oxidation reactions. During last few decades, extensive investigations have been conducted on the synthesis and reactivity studies of metal-iodosylbenzene adducts with early and middle transition metals including manganese, iron, cobalt. Nevertheless, metal-iodosylbenzene adducts with late transition metals such as nickel, copper and zinc, still remains elusive. Herein, we report a novel copper(II)-iodosylbenzene adduct bearing a linear ligand composed of two pyridine rings and an ethoxyethanol side-chain, [Cu(OIPh)(HN3O2)]2+ (1). The copper(II)-iodosylbenzene adduct was characterized by several spectroscopic methods including UV-vis spectroscopy, electrospray ionization mass spectrometer (ESI MS), and electron paramagnetic resonance (EPR) combined with theoretical calculations. Interestingly, 1 can carry out the catalytic sulfoxidation reaction. In sulfoxidation reaction with thioanisole under catalytic reaction condition, not only two-electron but also four-electron oxidized products such sulfoxide and sulfone were yielded, respectively. However, 1 was not an efficient oxidant towards CH bond activation and epoxidation reactions due to the steric hindrance created by the intramolecular H-bonding interaction between HN3O2 ligand and iodosylbenzene moiety.