Nickel-Catalyzed Double Deoxygenative C-N Coupling of Acyloxyamines.

A double deoxygenative C-N coupling protocol has been developed by employing acyloxyamines through N-O bond activation. The C-N bond formation under mild reaction conditions, employing NiCl2 as the catalyst and cataCXiumA as a ligand, results in the production of a diverse array of alkylated secondary or tertiary amines, including heterocyclic amines. This method introduces a novel catalytic strategy that emphasizes the versatility of nickel-catalyzed reactions, extending beyond traditional synthetic boundaries.

Dual Photoredox and Nickel Catalysis in Regioselective Diacylation: Exploring the Versatility of Nickel Oxidation States in Allene Activation.

We present a nickel-catalyzed regioselective radical diacylation of allenes with ketoacids to produce 1,4-dione products by dual photoredox and nickel catalysis. This integrated approach merges redox-active oxidative addition and reductive elimination steps with migratory insertion. The acyl radical generated in the photoredox cycle sequentially adds to Ni(I) and Ni(II) intermediates following a Ni(I)-Ni(II)-Ni(II)-Ni(III)-Ni(I) catalytic cycle. This methodology, supported by DFT calculations, demonstrates the potential of nickel catalysis in the creation of complex molecular architectures.

Value-Added Products from Coffee Waste: A Review.

Coffee waste is often viewed as a problem, but it can be converted into value-added products if managed with clean technologies and long-term waste management strategies. Several compounds, including lipids, lignin, cellulose and hemicelluloses, tannins, antioxidants, caffeine, polyphenols, carotenoids, flavonoids, and biofuel can be extracted or produced through recycling, recovery, or energy valorization. In this review, we will discuss the potential uses of by-products generated from the waste derived from coffee production, including coffee leaves and flowers from cultivation; coffee pulps, husks, and silverskin from coffee processing; and spent coffee grounds (SCGs) from post-consumption. The full utilization of these coffee by-products can be achieved by establishing suitable infrastructure and building networks between scientists, business organizations, and policymakers, thus reducing the economic and environmental burdens of coffee processing in a sustainable manner.

Converting textile waste into value-added chemicals: An integrated bio-refinery process.

The rate of textile waste generation worldwide has increased dramatically due to a rise in clothing consumption and production. Here, conversion of cotton-based, colored cotton-based, and blended cotton-polyethylene terephthalate (PET) textile waste materials into value-added chemicals (bioethanol, sorbitol, lactic acid, terephthalic acid (TPA), and ethylene glycol (EG)) via enzymatic hydrolysis and fermentation was investigated. In order to enhance the efficiency of enzymatic saccharification, effective pretreatment methods for each type of textile waste were developed, respectively. A high glucose yield of 99.1% was obtained from white cotton-based textile waste after NaOH pretreatment. Furthermore, the digestibility of the cellulose in colored cotton-based textile wastes was increased 1.38-1.75 times because of the removal of dye materials by HPAC-NaOH pretreatment. The blended cotton-PET samples showed good hydrolysis efficiency following PET removal via NaOH-ethanol pretreatment, with a glucose yield of 92.49%. The sugar content produced via enzymatic hydrolysis was then converted into key platform chemicals (bioethanol, sorbitol, and lactic acid) via fermentation or hydrogenation. The maximum ethanol yield was achieved with the white T-shirt sample (537 mL/kg substrate), which was 3.2, 2.1, and 2.6 times higher than those obtained with rice straw, pine wood, and oak wood, respectively. Glucose was selectively converted into sorbitol and LA at a yield of 70% and 83.67%, respectively. TPA and EG were produced from blended cotton-PET via NaOH-ethanol pretreatment. The integrated biorefinery process proposed here demonstrates significant potential for valorization of textile waste.

Construction of a Pentacyclic Framework Enabled by Nickel Catalysis.

We present a novel nickel-catalyzed reaction of indole-tethered 2-alkynylphenol esters with various (hetero)aryl boronic acids, resulting in the synthesis of diversely functionalized pentacyclic benzofurocyclohepta[b]indole derivatives. This unprecedented cascade reaction involves the arylative cyclization of alkynes, nucleophilic attack of the indole moiety on the oxonium ion intermediate, 1,2-alkyl group migration, and aromatization. The synthesized molecules exhibit exceptional cytotoxicity against multiple cancer cell lines while maintaining biocompatibility toward healthy cells.

Nickel-Catalyzed Enantioselective Synthesis of 2,3,4-Trisubstituted 3-Pyrrolines.

The development of synthetic methods to produce highly functionalized chiral 3-pyrrolines is of indisputable importance because of their prevalence in natural and synthetic bioactive molecules. Unfortunately, previous general cycloaddition approaches using allenoates, could not synthesize 3,4-disubstituted 3-pyrrolines. Herein, an original approach to yield 2,3,4-trisubstituted 3-pyrrolines with chirality at the 2-position is presented. A NiII /Fc-i-PrPHOX catalytic system facilitated a redox-neutral highly stereoselective process that exhibited an enantioselectivity of up to 99 %. Enantioenriched 3-pyrrolines can be converted to other valuable classes of N-heterocycles.

Nickel-Catalyzed trans-Carboamination across Internal Alkynes to Access Multifunctionalized Indoles.

A Ni-catalyzed reaction was developed for the synthesis of multifunctionalized indoles. The reaction proceeded through oxidative cyclization of the Ni(0)/P^N complex with an enyne system, 2-alkynyl anilinoacrylate, to provide a nickelacycle intermediate. The trans-carboamination around the internal alkyne was achieved by syn/anti-rotation of the Ni-carbenoid intermediate formed by C-N bond cleavage of the nickelacycle, and 3-alkenylated indoles were formed by C-N bond-forming reductive elimination. Notably, the synthesized indoles could be successfully transformed to functionalized carbazoles.

Enhanced Biomass Yield of and Saccharification in Transgenic Tobacco Over-Expressing ß-Glucosidase.

Here, we report an increase in biomass yield and saccharification in transgenic tobacco plants (Nicotiana tabacumL.) overexpressing thermostable ß-glucosidase from Thermotoga maritima, BglB, targeted to the chloroplasts and vacuoles. The transgenic tobacco plants showed phenotypic characteristics that were significantly different from those of the wild-type plants. The biomass yield and life cycle (from germination to flowering and harvest) of the transgenic tobacco plants overexpressing BglB were 52% higher and 36% shorter than those of the wild-type tobacco plants, respectively, indicating a change in the genome transcription levels in the transgenic tobacco plants. Saccharification in biomass samples from the transgenic tobacco plants was 92% higher than that in biomass samples from the wild-type tobacco plants. The transgenic tobacco plants required a total investment (US$/year) corresponding to 52.9% of that required for the wild-type tobacco plants, but the total biomass yield (kg/year) of the transgenic tobacco plants was 43% higher than that of the wild-type tobacco plants. This approach could be applied to other plants to increase biomass yields and overproduce ß-glucosidase for lignocellulose conversion.

Photo-induced reactions for disassembling of coloaded photosensitizer and drug molecules from upconversion-mesoporous silica nanoparticles: An effective synergistic cancer therapy.

Photodynamic therapy is an emerging noninvasive cancer treatment approach, which requires a photosensitizer (PS), light, and molecular oxygen. In this study, we have successfully fabricated a dual nature (pH- and reactive-oxygen-species-responsive) upconversion nanoparticles (UCNPs) to utilize coloaded doxorubicin (DOX) and chlorin e6 (Ce6) with high antitumor efficacy. The model anticancer drug (DOX) and PS (Ce6) were conjugated in a ratio of 1:1 (w:w), and then loaded on the surface of UCNPs@mesoporous silica (mSiO2) (85.63 ± 9.87 nm). Cellular uptake could be achieved by either increased permeability or ionic effect of UCNPs@mSiO2, where Ce6 controlled the DOX release under a near-infrared (NIR) laser irradiation at 980 nm. A cytotoxicity analysis revealed that the dual-responsive UCNPs@mSiO2 could successfully deliver DOX and Ce6 at the tumor site, causing cell death with a high efficiency. This study shows that the modified UCNPs@mSiO2 is a promising system to realize NIR-light-triggered PS and drug delivery approach to improve synergistic therapies in vitro and in vivo, in the future.

Total kidney and liver volume is a major risk factor for malnutrition in ambulatory patients with autosomal dominant polycystic kidney disease.

BACKGROUND: In patients with autosomal dominant polycystic kidney disease (ADPKD), malnutrition may develop as renal function declines and the abdominal organs become enlarged. We investigated the relationship of intra-abdominal mass with nutritional status. METHODS: This cross-sectional study was performed at a tertiary hospital outpatient clinic. Anthropometric and laboratory data including serum creatinine, albumin, and cholesterol were collected, and kidney and liver volumes were measured. Total kidney and liver volume was defined as the sum of the kidney and liver volumes and adjusted by height (htTKLV). Nutritional status was evaluated by using modified subjective global assessment (SGA). RESULTS: In a total of 288 patients (47.9% female), the mean age was 48.3 ± 12.2 years and the mean estimated glomerular filtration rate (eGFR) was 65.3 ± 25.3 mL/min/1.73 m2. Of these patients, 21 (7.3%) were mildly to moderately malnourished (SGA score of 4 and 5) and 63 (21.7%) were at risk of malnutrition (SGA score of 6). Overall, patients with or at risk of malnutrition were older, had a lower body mass index, lower hemoglobin levels, and poorer renal function compared to the well-nourished group. However, statistically significant differences in these parameters were not observed in female patients, except for eGFR. In contrast, a higher htTKLV correlated with a lower SGA score, even in subjects with an eGFR ≥45 mL/min/1.73 m2. Subjects with an htTKLV ≥2340 mL/m showed an 8.7-fold higher risk of malnutrition, after adjusting for age, hemoglobin, and eGFR. CONCLUSIONS: Nutritional risk was detected in 30% of ambulatory ADPKD patients with relatively good renal function. Intra-abdominal organomegaly was related to nutritional status independently from renal function deterioration.

Effects of stimulating interleukin -2/anti- interleukin -2 antibody complexes on renal cell carcinoma.

BACKGROUND: Current therapies for advanced renal cell carcinoma (RCC) have low cure rates or significant side effects. It has been reported that complexes composed of interleukin (IL)-2 and stimulating anti-IL-2 antibody (IL-2C) suppress malignant melanoma growth. We investigated whether it could have similar effects on RCC. METHODS: A syngeneic RCC model was established by subcutaneously injecting RENCA cells into BALB/c mice, which were administered IL-2C or phosphate-buffered saline every other day for 4 weeks. RCC size was measured serially, and its weight was assessed 4 weeks after RENCA injection. Immune cell infiltration into RCC lesions and spleen was assessed by flow cytometry and immunohistochemistry. RESULTS: IL-2C treatment increased the numbers of CD8(+) memory T and natural killer (NK) cells in healthy BALB/c mice (P < 0.01). In the spleen of RCC mice, IL-2C treatment also increased the number of CD8(+) memory T, NK cells, and macrophages as compared to PBS-treated controls (P < 0.01). The number of interferon-γ- and IL-10-producing splenocytes increased and decreased, respectively after 4 weeks in the IL-2C-treated mice (P < 0.01). Tumor-infiltrating immune cells including CD4(+) T, CD8(+) T, NK cells as well as macrophages were increased in IL-2C-treated mice than controls (P < 0.05). Pulmonary edema, the most serious side effect of IL-2 therapy, was not exacerbated by IL-2C treatment. However, IL-2C had insignificant inhibitory effect on RCC growth (P = 0.1756). CONCLUSIONS: IL-2C enhanced immune response without significant side effects; however, this activity was not sufficient to inhibit RCC growth in a syngeneic, murine model.

Herbacetin Is a Novel Allosteric Inhibitor of Ornithine Decarboxylase with Antitumor Activity.

Ornithine decarboxylase (ODC) is a rate-limiting enzyme in the first step of polyamine biosynthesis that is associated with cell growth and tumor formation. Existing catalytic inhibitors of ODC have lacked efficacy in clinical testing or displayed unacceptable toxicity. In this study, we report the identification of an effective and nontoxic allosteric inhibitor of ODC. Using computer docking simulation and an in vitro ODC enzyme assay, we identified herbacetin, a natural compound found in flax and other plants, as a novel ODC inhibitor. Mechanistic investigations defined aspartate 44 in ODC as critical for binding. Herbacetin exhibited potent anticancer activity in colon cancer cell lines expressing high levels of ODC. Intraperitoneal or oral administration of herbacetin effectively suppressed HCT116 xenograft tumor growth and also reduced the number and size of polyps in a mouse model of APC-driven colon cancer (ApcMin/+). Unlike the well-established ODC inhibitor DFMO, herbacetin treatment was not associated with hearing loss. Taken together, our findings defined the natural product herbacetin as an allosteric inhibitor of ODC with chemopreventive and antitumor activity in preclinical models of colon cancer, prompting its further investigation in clinical trials.

Lignocellulose conversion for biofuel: a new pretreatment greatly improves downstream biocatalytic hydrolysis of various lignocellulosic materials.

BACKGROUND: Lignocellulosic biomass is an attractive renewable resource for future liquid transport fuel. Efficient and cost-effective production of bioethanol from lignocellulosic biomass depends on the development of a suitable pretreatment system. The aim of this study is to investigate a new pretreatment method that is highly efficient and effective for downstream biocatalytic hydrolysis of various lignocellulosic biomass materials, which can accelerate bioethanol commercialization. RESULTS: The optimal conditions for the hydrogen peroxide-acetic acid (HPAC) pretreatment were 80 °C, 2 h, and an equal volume mixture of H2O2 and CH3COOH. Compared to organo-solvent pretreatment under the same conditions, the HPAC pretreatment was more effective at increasing enzymatic digestibility. After HPAC treatment, the composition of the recovered solid was 74.0 % cellulose, 20.0 % hemicelluloses, and 0.9 % lignin. Notably, 97.2 % of the lignin was removed with HPAC pretreatment. Fermentation of the hydrolyzates by S. cerevisiae resulted in 412 mL ethanol kg(-1) of biomass after 24 h, which was equivalent to 85.0 % of the maximum theoretical yield (based on the amount of glucose in the raw material). CONCLUSION: The newly developed HPAC pretreatment was highly effective for removing lignin from lignocellulosic cell walls, resulting in enhanced enzymatic accessibility of the substrate and more efficient cellulose hydrolysis. This pretreatment produced less amounts of fermentative inhibitory compounds. In addition, HPAC pretreatment enables year-round operations, maximizing utilization of lignocellulosic biomass from various plant sources.

Aptamer-conjugated magnetic nanoparticles enable efficient targeted detection of integrin αvß3 via magnetic resonance imaging.

An understanding of neovascularization and/or angiogenesis in cancer is acutely required for effective cancer therapy due to concerns about tumor growth and metastasis. In particular, integrin αvß3 is closely associated with cell migration and invasion during angiogenesis. Hence, we developed aptamer(αvß3)-conjugated magnetic nanoparticles (Apt(αvß3)-MNPs) to enable precise detection of integrin-expressing cancer cells using magnetic resonance imaging. Apt(αvß3)-MNPs exhibited not only cytocompatibility, but also an efficient targeting ability with high magnetic sensitivity through in vitro/in vivo studies. The results of this study demonstrate that Apt(αvß3)-MNPs have the potential to be used for accurate tumor diagnosis and therapy.

Autophagy and cellular senescence mediated by Sox2 suppress malignancy of cancer cells.

Autophagy is a critical cellular process required for maintaining cellular homeostasis in health and disease states, but the molecular mechanisms and impact of autophagy on cancer is not fully understood. Here, we found that Sox2, a key transcription factor in the regulation of the "stemness" of embryonic stem cells and induced-pluripotent stem cells, strongly induced autophagic phenomena, including intracellular vacuole formation and lysosomal activation in colon cancer cells. The activation occurred through Sox2-mediated ATG10 gene expression and resulted in the inhibition of cell proliferation and anchorage-independent colony growth ex vivo and tumor growth in vivo. Further, we found that Sox2-induced-autophagy enhanced cellular senescence by up-regulating tumor suppressors or senescence factors, including p16(INK4a), p21 and phosphorylated p53 (Ser15). Notably, knockdown of ATG10 in Sox2-expressing colon cancer cells restored cancer cell properties. Taken together, our results demonstrated that regulation of autophagy mediated by Sox2 is a mechanism-driven novel strategy to treat human colon cancers.

Crowding effects on the formation and maintenance of nuclear bodies: insights from molecular-dynamics simulations of simple spherical model particles.

The physics of structure formation and maintenance of nuclear bodies (NBs), such as nucleoli, Cajal bodies, promyelocytic leukemia bodies, and speckles, in a crowded nuclear environment remains largely unknown. We investigate the role of macromolecular crowding in the formation and maintenance of NBs using computer simulations of a simple spherical model, called Lennard-Jones (LJ) particles. LJ particles form a one-phase, dilute fluid when the intermolecular interaction is weaker than a critical value, above which they phase separate and form a condensed domain. We find that when volume-exclusive crowders exist in significant concentrations, domain formation is induced even for weaker intermolecular interactions, and the effect is more pronounced with increasing crowder concentration. Simulation results show that a previous experimental finding that promyelocytic leukemia bodies disappear in the less-crowded condition and reassemble in the normal crowded condition can be interpreted as a consequence of the increased intermolecular interactions between NB proteins due to crowding. Based on further analysis of the simulation results, we discuss the acceleration of macromolecular associations that occur within NBs, and the delay of diffusive transport of macromolecules within and out of NBs when the crowder concentration increases. This study suggests that in a polydisperse nuclear environment that is enriched with a variety of macromolecules, macromolecular crowding not only plays an important role in the formation and maintenance of NBs, but also may perform some regulatory functions in response to alterations in the crowding conditions.

Co-immobilization of three cellulases on Au-doped magnetic silica nanoparticles for the degradation of cellulose.

Three cystein-tagged cellulases co-immobilized on AuNP and Au-MSNP for the hydrolytic degradation of cellulose. The biochemical properties, stabilities, activities and reusability of these co-immobilized systems were compared to those of mixtures of free cellulases.

Embryonic stem-cell-preconditioned microenvironment induces loss of cancer cell properties in human melanoma cells.

The cancer microenvironment affects cancer cell proliferation and growth. Embryonic stem (ES)-preconditioned 3-dimensional (3-D) culture of cancer cells induces cancer cell reprogramming and results in a change in cancer cell properties such as differentiation and migration in skin melanoma. However, the mechanism has not yet been clarified. Using the ES-preconditioned 3-D microenvironment model, we provide evidence showing that the ES microenvironment inhibits proliferation and anchorage-independent growth of SK-MEL-28 melanoma cells. We also found that the ES microenvironment suppresses telomerase activity and thereby induces senescence in SK-MEL-28 cells. Furthermore, we observed that gremlin, an antagonist of BMP4, is secreted from ES cells and plays an important role in cellular senescence. Knocking down gremlin in the ES microenvironment increases proliferation and anchorage-independent growth of SK-MEL-28 melanoma cells. Taken together, these results demonstrated that gremlin is a crucial factor responsible for abrogating melanoma properties in the ES-preconditioned 3-D microenvironment.

Sensitive angiogenesis imaging of orthotopic bladder tumors in mice using a selective magnetic resonance imaging contrast agent containing VEGF121/rGel.

OBJECTIVES: To investigate the efficiency of magnetic resonance imaging (MRI) contrast agents employing vascular endothelial growth factor (VEGF121)/rGel conjugated MnFe2O4 nanocrystals for imaging of neovasculature using a bladder tumor model. MATERIALS AND METHODS: VEGF121/rGel was conjugated to MnFe2O4 nanoparticles (MNPs). The targeting efficiency and detection capability of the VEGF121/rGel-MNPs were investigated in both KDR-deficient (253JB-V) and KDR-overexpressing (PAE/KDR) cells using MRI. The internalization of VEGF121/rGel-MNPs into cells was confirmed by electron microscopy. Their phosphorylation ability and cytotoxicity were compared with unconjugated VEGF121/rGel. The orthotopic tumor mice were established by implanting low KDR-expressing 253JB-V cells into the bladder dome. After tail-vein injection of VEGF121/rGel-MNPs, the MR signal enhancement of intratumoral vessels by VEGF121/rGel-MNPs was observed and inhibition test using VEGF121 was also conducted. Ex vivo MR imaging of tumor tissue, and a fluorescence immunostaining study was also performed. RESULTS: The water-soluble VEGF121/rGel-MNPs (44.5 ± 1.2 nm) were stably suspended in the biologic media and exhibited a high relaxivity coefficient (423 mMs). They demonstrated sufficient targeting capability against KDR-overexpressing PAE/KDR cells, as confirmed by dose-dependent MR images and VEGF121 inhibition tests. The phosphorylation activity of KDR and cytotoxicity of VEGF121/rGel-MNPs were evaluated. VEGF121/rGel-MNPs successfully targeted the tumor and provided accurate anatomic details through (i) acquisition of clear neoangiogenic vascular distributions and (ii) obvious enhancement of the MR signal in T2*-weighted images. Immunostaining and blocking studies demonstrated the specific targeting ability of VEGF121/rGel-MNPs toward intratumoral angiogenesis. CONCLUSIONS: Synthesized VEGF121/rGel-MNPs as targeted MR imaging contrast agents can be specifically delivered to tumors and bind to KDR-expressing angiogenic tumor vessels.

Eriodictyol inhibits RSK2-ATF1 signaling and suppresses EGF-induced neoplastic cell transformation.

RSK2 is a widely expressed serine/threonine kinase, and its activation enhances cell proliferation. Here, we report that ATF1 is a novel substrate of RSK2 and that RSK2-ATF1 signaling plays an important role in EGF-induced neoplastic cell transformation. RSK2 phosphorylated ATF1 at Ser-63 and enhanced ATF1 transcriptional activity. Docking experiments using the crystal structure of the RSK2 N-terminal kinase domain combined with in vitro pulldown assays demonstrated that eriodictyol, a flavanone found in fruits, bound with the N-terminal kinase domain of RSK2 to inhibit RSK2 N-terminal kinase activity. In cells, eriodictyol inhibited phosphorylation of ATF1 but had no effect on the phosphorylation of RSK, MEK1/2, ERK1/2, p38 or JNKs, indicating that eriodictyol specifically suppresses RSK2 signaling. Furthermore, eriodictyol inhibited RSK2-mediated ATF1 transactivation and tumor promoter-induced transformation of JB6 Cl41 cells. Eriodictyol or knockdown of RSK2 or ATF1 also suppressed Ras-mediated focus formation. Overall, these results indicate that RSK2-ATF1 signaling plays an important role in neoplastic cell transformation and that eriodictyol is a novel natural compound for suppressing RSK2 kinase activity.