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In some tumors, a small number of cancer cells are scattered in a large fibrotic stroma. Here, we demonstrate a novel mechanism for expansion of pro‐tumor fibroblasts via cancer‐associated fibroblast (CAF)‐mediated education of normal fibroblasts (NFs). When NFs were incubated with conditioned medium from CAFs, the resulting CAF‐educated fibroblasts (CEFs) generated reactive oxygen species, which induced NF‐κB‐mediated expression of inflammatory cytokines and the extracellular matrix protein asporin (ASPN), while expression of a common CAF marker gene, α‐SMA, was not increased. ASPN further increased CEF expression of downstream molecules, including indoleamine 2,3‐dioxygenase 1 (IDO‐1), kynureninase (KYNU), and pregnancy‐associated plasma protein‐A (PAPP‐A). These CEFs induce cytocidal effects against CD8+ T cells and IGF‐I activation in cancer cells. CEFs were generated without cancer cells by the direct mixture of NFs and CAFs in mouse xenografts, and once CEFs were generated, they sequentially educated NFs, leading to continuous generation of CEFs. In diffuse‐type gastric cancers, ASPNhigh/IDO‐1high/KYNUhigh/α‐SMA− CEFs were located at the distal invading front. These CEFs expanded in the fibrotic stroma and caused dissemination of cancer cells. ASPN may therefore be a key molecule in facilitating tumor spreading and T‐cell suppression., Cancer‐associated fibroblast (CAF)‐educated fibroblasts (CEFs), a newly identified source of pro‐tumor fibroblasts, were generated from normal fibroblast (NFs) by CAF‐mediated education. CAFs activated reactive oxygen species production in NFs, reprogramming them to secrete inflammatory cytokines and ASPN. ASPN further induced expression of IDO‐1, KYNU, and PAPP‐A in CEFs, leading to cancer cell dissemination, CD8+ T‐cell cytotoxicity, and activation of IGF‐I signaling in cancer cells.

Earth-abundant metal-catalyzed oxidative conversion of ammonia into dinitrogen is a promising process to utilize ammonia as a transportation fuel. Herein, we report the manganese-catalyzed ammonia oxidation under chemical or electrochemical conditions using a manganese complex bearing (1S,2S)-N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine. Under chemical conditions using oxidant, up to 17.1 equivalents of N2 per catalyst are generated. Also, mechanistic studies by stoichiometric reactions reveal that a nucleophilic attack of ammonia on manganese nitrogenous species occurs to form a nitrogen-nitrogen bond leading to dinitrogen. Moreover, we conduct density functional theory (DFT) calculations to confirm the plausible reaction mechanism. In addition, this reaction system is applicable under electrochemical conditions. The catalytic reaction proceeds with 96 % faradaic efficiency (FE) in bulk electrolysis to give up to 6.56 equivalents of N2 per catalyst.

Ceiling culture-derived preadipocytes (ccdPAs) and adipose-derived stem cells (ASCs) can be harvested from human subcutaneous fat tissue using the specific gravity method. Both cell types possess a similar spindle shape without lipid droplets. We previously reported that ccdPAs have a higher adipogenic potential than ASCs, even after a 7-wk culture. We performed a genome-wide epigenetic analysis to examine the mechanisms contributing to the adipogenic potential differences between ccdPAs and ASCs. Methylation analysis of cytosines followed by guanine (CpG) using a 450-K BeadChip was performed on human ccdPAs and ASCs isolated from three metabolically healthy females. Chromatin immunoprecipitation sequencing was performed to evaluate trimethylation at lysine 4 of histone 3 (H3K4me3). Unsupervised machine learning using t-distributed stochastic neighbor embedding to interpret 450,000-dimensional methylation assay data showed that the cells were divided into ASC and ccdPA groups. In Kyoto Encyclopedia of Genes and Genomes pathway analysis of 1,543 genes with differential promoter CpG methylation, the peroxisome proliferator-activated receptor (PPAR) and adipocytokine signaling pathways ranked in the top 10 pathways. In the PPARγ gene, H3K4me3 peak levels were higher in ccdPAs than in ASCs, whereas promoter CpG methylation levels were significantly lower in ccdPAs than in ASCs. Similar differences in promoter CpG methylation were also seen in the fatty acid-binding protein 4 and leptin genes. In conclusion, we analyzed the epigenetic status of adipogenesis-related genes as a potential mechanism underlying the differences in adipogenic differentiation capability between ASCs and ccdPAs.

An electrophotochemical ring-opening bromination of unstrained tert-cycloalkanols has been developed. This electrophotochemical method enables the oxidative transformation of cycloalkanols with 5- to 7-membered rings into synthetically useful ω-bromoketones without the use of chemical oxidants or transition-metal catalysts. Alkoxy radical species would be key intermediates in the present transformation, which generate through homolysis of the O-Br bond in hypobromite intermediates under visible light irradiation.

Pancreatic gastrinoma is a rare pancreatic neuroendocrine tumor with an incidence of about 0.5–21.5 cases per million people worldwide. The most common sites are the duodenum (75%), pancreas (20%), and other organs (5%). Gastrinomas are malignant in about 60–90% of cases (1-5). Malignant gastrinomas originating beneath the duodenal mucosa often metastasize to the liver, even if the tumor diameter is ≤1 cm. Therefore, in patients with gastrinoma and Zollinger–Ellison syndrome, it is important to determine the number and site(s) of gastrinoma(s), as well as the presence or absence of liver metastases. However, the detection sensitivity of computed tomography (CT) and magnetic resonance imaging is about 10–50%, that of angiography is 20–50%, and that of somatostatin receptor scintigraphy is 30–70%. Tumor size is strongly correlated with the detection sensitivity of any examination modality, and tumors of

Cooperative photoredox- and nickel-catalyzed alkylative cyclization reactions of iodoalkynes with 4-alkyl-1,4-dihydropyridines as alkylation reagents under visible light irradiation have been achieved to afford the corresponding alkylated cyclopentylidenes in good to high yields. Introduction of substituents at the propargylic position of iodoalkynes has led to the stereoselective formation of E-isomers. The present reaction system provides a novel synthetic method for alkylative cyclization reactions of both terminal and internal alkynes with cooperative photoredox and nickel catalysis.

Background/aim This study clarified the predictive impact of serum biomarkers on therapeutic sensitivity to nivolumab in patients with gastric cancer (GC). Patients and methods The outcomes of 27 patients who received nivolumab to treat postoperative recurrent or unresectable advanced GC were reviewed. Blood testing was performed immediately before and after two courses of nivolumab. We also focused on the rate of change of each blood variable. Results The decrease in albumin (Alb) levels (p=0.035) and increase in lactate dehydrogenase (LDH) levels (p=0.012) after two courses of nivolumab were significantly larger in patients with disease progression. Furthermore, therapeutic resistance was significantly associated with an elevated LDH-to-Alb ratio (LAR) after two courses of nivolumab. Conclusion Decreased Alb or increased LDH levels after two courses of nivolumab predicted nivolumab sensitivity in patients with GC. An increased LAR was a meaningful predictor of nivolumab resistance.

Background Insulin-like growth factor-1 (IGF-1) acts on glucose and protein metabolism and human growth and also influences blood pressure and renal function. This study investigated whether the single-nucleotide polymorphism of IGF-1, rs35767, plays a role in metabolic syndrome indicators, including blood pressure, glucose metabolism, uric acid levels, and renal function. Methods In this retrospective longitudinal cohort study, blood samples from 1506 Japanese individuals were collected and used for genotyping for variant rs35767: T > C in the IGF-1 upstream promoter. Data were analyzed to identify associations between IGF-1 genotypes and patient biochemical parameters, including the components of metabolic syndrome and the long-term change in renal function. Results The cohort rs35767 genotypes included 650 CC carriers (43.2%), 687 TC carriers (45.6%), and 169 TT carriers (11.2%). Multiple regression analysis revealed no association between IGF-1 genotype and blood pressure, glycated hemoglobin level, and serum uric acid level. However, in females, blood pressure was negatively correlated with the TT genotype. Longitudinal observation revealed that the decline in eGFR over 10 years was greater in TT (− 18.51 ± 1.04 mL/min/1.73m2) than in CC carriers (− 16.38 ± 0.52 mL/min/1.73m2; P Conclusion The present study suggests that renal function declines faster in individuals with the TT genotype at the IGF-1 rs35767 locus than in those with the CC genotype, suggesting that the TT genotype is associated with the long-term chronological decline in renal function.

A series of rhenium complexes bearing a pyridine-based PNP-type pincer ligand are synthesized from rhenium phosphine complexes as precursors. A dinitrogen-bridged dirhenium complex bearing the PNP-type pincer ligands catalytically converts dinitrogen into ammonia during the reaction with KC8 as a reductant and [HPCy3 ]BArF 4 (Cy=cyclohexyl, ArF =3,5-(CF3 )2 C6 H3 ) as a proton source at -78 °C to afford 8.4 equiv of ammonia based on the rhenium atom of the catalyst. The rhenium-dinitrogen complex also catalyzes silylation of dinitrogen in the reaction with KC8 as a reductant and Me3 SiCl as a silylating reagent under ambient reaction conditions to afford 11.7 equiv of tris(trimethylsilyl)amine based on the rhenium atom of the catalyst. These results demonstrate the first successful example of catalytic nitrogen fixation under mild reaction conditions using rhenium-dinitrogen complexes as catalysts.

Macropinocytosis is among ubiquitous cellular uptake mechanisms of peptide-based intracellular delivery. Due to its capability of engulfing large macromolecules, macropinocytosis shows promise as a route for the intracellular uptake of biomacromolecules and nanoparticles. We previously reported SN21, a peptide derived from the N-terminus of stromal cell-derived growth factor 1α (SDF-1α), as a potent macropinocytosis inducer. In this work, we obtained the 8-residue analog P4A bearing higher macropinocytosis induction ability. P4A contains vital cysteine residues in its sequence, which immediately reacts with cystine in culture medium to convert into its oxidized forms, including the intramolecularly oxidized form (oxP4A) as the dominant and active species. The conjugate of oxP4A with membrane lytic peptide LK15 delivered bioactive proteins into cells; notably, this peptide delivered functional proteins fused with a negatively charged protein tag at a significantly reduced amount (up to nanomolar range) without compromising the delivery efficiency and the cellular activities of delivered proteins.

The development of transition metal-catalyzed enantioselective propargylic substitution reactions has gained much progress in recent years, however, no successful example with phosphorus-centered nucleophiles has yet been reported until now. Herein, we report the first successful example of ruthenium-catalyzed enantioselective propargylic substitution reactions of propargylic alcohols with diarylphosphine oxides as phosphorus-centered nucleophiles. This synthetic approach provides a new method to prepare chiral phosphorus-containing organic compounds.

The shallow coastal water zone of the tide-less southern Baltic Sea is dominated by exposed sandy sediments which are typically inhabited by microphytobenthic communities, but their primary production is poorly studied, and hence four stations between 3.0 and 6.2 m depth were investigated. Sediment cores were carefully taken to keep the natural layering and exposed in a controlled self-constructed incubator. Respiratory oxygen consumption and photosynthetic oxygen production were recorded applying planar oxygen optode sensors. We hypothesized that with increasing water depths the effects of wind- and wave-induced erosion and mixing of the upper sediment layer are dampened and expected higher microphytobenthic biomass and primary production in the incubated cores. Our data partly confirm this hypothesis, as cores sampled at the most exposed stations contained only 50% chlorophyll a m−2 compared to the deeper stations. However, primary production was highly variable, probably due to fluctuating sediment-disturbing conditions before the cores were taken. Due to these physical forces sand grains were highly mobile and rounded, and small epipsamic benthic diatoms dominated, which preferentially occurred in some cracks and crevices as visualized by scanning electron microscopy. The data fill an important gap in reliable production data for sandy sediments of the southern Baltic Sea, and point to the ecological importance and relevant contribution of microphytobenthic communities to the total primary production of this marine ecosystem. Oxygen planar optode sensor spots proved to be a reliable, sensitive and fast detection system for ex situ oxygen exchange measurements in the overlying water of intact sediment cores.

The development of facile synthetic methods for stereodefined aliphatic cyclic amines is an important research field in synthetic organic chemistry since such scaffolds constitute a variety of natural products and biologically active compounds. N-Acyl cyclic N,O-acetals which prepared by electrochemical oxidation of the corresponding cyclic amines have proven to be useful and versatile precursors for the synthesis of such skeletons. In this Personal Account, we introduce our efforts toward the development of synthetic strategies for the diastereo- and/or enantioselective synthesis of cyclic amines by using electrochemically prepared cyclic N,O-acetals. In addition, the investigation of the "memory of chirality" in the electrooxidative methoxylation of N-acyl amino acid derivatives, the strategy for the synthesis of chiral azabicyclic compounds by utilizing electrochemical oxidation, and halogen cation-mediated synthesis of nitrogen-containing heterocycles are also described.

Asporin (ASPN), a small leucine‐rich proteoglycan expressed predominantly by cancer associated fibroblasts (CAFs), plays a pivotal role in tumor progression. ASPN is also expressed by some cancer cells, but its biological significance is unclear. Here, we investigated the effects of ASPN expression in gastric cancer cells. Overexpression of ASPN in 2 gastric cancer cell lines, HSC‐43 and 44As3, led to increased migration and invasion capacity, accompanied by induction of CD44 expression and activation of Rac1 and MMP9. ASPN expression increased resistance of HSC‐43 cells to oxidative stress by reducing the amount of mitochondrial reactive oxygen species. ASPN induced expression of the transcription factor HIF1α and upregulated lactate dehydrogenase A (LDHA) and PDH‐E1α, suggesting that ASPN reprograms HSC‐43 cells to undergo anaerobic glycolysis and suppresses ROS generation in mitochondria, which has been observed in another cell line HSC‐44PE. By contrast, 44As3 cells expressed high levels of HIF1α in response to oxidant stress and escaped apoptosis regardless of ASPN expression. Examination of xenografts in the gastric wall of ASPN–/– mice revealed that growth of HSC‐43 tumors with increased micro blood vessel density was significantly accelerated by ASPN; however, ASPN increased the invasion depth of both HSC‐43 and 44As3 tumors. These results suggest that ASPN has 2 distinct effects on cancer cells: HIF1α‐mediated resistance to oxidative stress via reprogramming of glucose metabolism, and activation of CD44‐Rac1 and MMP9 to promote cell migration and invasion. Therefore, ASPN may be a new therapeutic target in tumor fibroblasts and cancer cells in some gastric carcinomas., We demonstrate the importance of ASPN‐mediated resistance of tumor cells to oxidative stress. ASPN expression increased the levels of HIF1a, which shifted glucose metabolism to anaerobic glycolysis and reduced the amount of mitochondrial reactive oxygen species (mtROS), thereby attenuating ROS‐induced apoptosis.

Highly regioselective intramolecular aminolysis of 3,4-epoxy amines has been achieved. Key features of this reaction are (1) chemoselective activation of epoxides in the presence of unprotected aliphatic amines in the same molecules by a La(OTf)3 catalyst and (2) excellent regioselectivity for anti-Baldwin 5-endo-tet cyclization. This reaction affords 3-hydroxy-2-alkylpyrrolidines stereospecifically in high yields. DFT calculations revealed that the regioselectivity might be attributed to distortion energies of epoxy amine substrates. The use of this reaction was demonstrated by the first enantioselective synthesis of an antispasmodic agent prifinium bromide.

Methyl-CpG binding domain protein 3 (MBD3) belongs to the methyl-CpG binding protein family. MBD3 facilitates the initiation of neural stem cell reprogramming. Melanoma originates in melanocytes derived from neural crest stem cells; therefore, we investigated the role of MBD3 in melanoma. MBD3 was overexpressed in melanoma compared with pigmented nevi. MBD3 knockdown had no effect on the proliferation of melanoma cells (A375 and A2058 cells). Contrarily, it significantly reduced the migration and invasion of A375 cells, but had no significant effect on A2058 cells. Furthermore, MBD3 knockdown reduced N-cadherin protein levels and matrix metalloproteinase-2 (MMP-2) activity in A375 cells, but had no significant effect on A2058 cells. Based on these results, the MBD3 expression level may be a useful biomarker for the diagnosis of melanoma. Thus, MBD3 has potential as a novel therapeutic target for some melanoma patients.

There are few studies examining the association between homocysteine (Hcy) level and the risk of hypertension with consideration for folate and vitamin B12 as related to Hcy level. We simultaneously examined the associations of plasma levels of Hcy, folate, and vitamin B12, and dietary folate intake with the prevalence of hypertension. Participants included 1046 men and 1033 women (mean age ± standard deviation: 56.0 ± 8.9 years) in the Japan Multi-Institutional Collaborative Cohort Study. Dietary folate intake was estimated using a validated food frequency questionnaire. Hypertension was defined based on measured blood pressure and use of antihypertensive medication. A total of 734 participants (35.3%) had hypertension. Multivariate-adjusted odds ratios of hypertension for the highest quartile group of Hcy were 2.36 (95% CI 1.41–3.96) in men and 1.86 (95% CI 1.11–3.11) in women, as compared with the lowest group (P for trend = 0.014 and 0.005, respectively). Dietary folate intake was not correlated with hypertension in both men and women (P for trend = 0.099 and 0.703, respectively). Plasma vitamin B12 was positively associated with hypertension only in women (P for trend = 0.027). Plasma Hcy level was positively linked with hypertension after controlling for covariates, including folate and vitamin B12.

BACKGROUND The physical activity (PA) of patients may change after microsurgical treatment for lower extremity lymphedema (LEL). We investigated whether PA changes perioperatively and whether it influences the treatment result. PATIENTS AND METHODS Sixty patients with unilateral LEL (56 secondary and 4 primary) underwent lymphatic microsurgeries. Patients were divided into two groups based on improvement in International Physical Activity Questionnaire Short Form (IPAQ-SF) categories; the outcomes were compared. RESULTS Fifty-three patients in whom linear pattern could be partially observed in indocyanine green lymphography or lymphoscintigraphy underwent lymphaticovenular anastomosis (LVA); seven patients in whom no linear pattern was observed underwent simultaneous LVA and vascularized lymph node transfer. No surgical complication was observed. The median IPAQ-SF score significantly improved from 990 (interquartile range: 231-2,376) to 1,386 (interquartile range: 940.5-4,158; p

Patients who undergo renal replacement therapy often exhibit a high plasma linezolid concentration. Linezolid is metabolized via oxidation. Nafamostat mesilate has antioxidant effects and is frequently used as an anticoagulant during renal replacement therapy. We aimed to investigate the effect of nafamostat mesilate on plasma linezolid concentration. We examined whether the co-administration of linezolid and nafamostat had any effect on plasma linezolid concentration. Mice were randomly allocated to two groups (n = 18/group): linezolid (100 mg kg-1 , subcutaneous injection) + nafamostat (30 mg kg-1 , intraperitoneal injection) and linezolid + saline. At 5 hours, the linezolid concentration was significantly higher in the linezolid + nafamostat co-administration group than that in the linezolid + saline group (20.6 ± 9.8 vs 3.6 ± 1.2 μg/mL, respectively P < .001). The antioxidant effects of nafamostat may inhibit linezolid metabolism, resulting in the adverse event of high linezolid concentration if both are administered concurrently during renal replacement therapy.

We have found that an iridium-dinitrogen complex bearing an anionic benzene-based PCP-type pincer ligand works as an effective catalyst for the reduction of dinitrogen into tris(trimethylsilyl)amin...

Metal-free N- and O-arylation reactions of pyridin-2-ones as ambident nucleophiles have been achieved with diaryliodonium salts on the basis of base-dependent chemoselectivity. In the presence of N,N-diethylaniline in fluorobenzene, pyridin-2-ones were very selectively converted to N-arylated products in high yields. On the other hand, the O-arylation reactions smoothly proceeded with the use of quinoline in chlorobenzene, leading to high yields and selectivities. In these methods, a variety of pyridin-2-ones in addition to pyridin-4-one and a set of diaryliodonium salts were accepted as suitable reaction partners., Chemical Science, 11(31), pp.8295-8300; 2020

Objective Inflammatory bowel disease (IBD) is an intractable condition. Existing models of experimental IBD are limited by their inability to create consistent ulcers between animals. The aim of this study was to develop a novel model of experimental colitis with ulcers of reproducible size. Design We used a 3D printer to fabricate a novel device containing a small window (10 × 10 mm) that could be inserted rectally to facilitate the creation of a localized ulcer in the rat intestinal mucosa. The mucosa within the window of the device was exposed to 2,4,6-trinitrobenzene sulfonic acid (TNBS) to generate ulceration. We evaluated the effects of conventional drug therapies (mesalazine and prednisolone) and local transplantation of allogeneic adipose-derived mesenchymal stem cells (ASCs) on ulcer size (measured from photographic images using image analysis software) and degree of inflammation (assessed histologically). Results The novel method produced localized, circular or elliptical ulcers that were highly reproducible in terms of size and depth. The pathological characteristics of the lesions were similar to those reported previously for conventional models of TNBS-induced colitis that show greater variation in ulcer size. Ulcer area was significantly reduced by the administration of mesalazine or prednisolone as an enema or localized injection of ASCs. Conclusion The new model of TNBS-induced colitis, made with the aid of a device fabricated by 3D printing, generated ulcers that were reproducible in size. We anticipate that our new model of colitis will provide more reliable measures of treatment effects and prove useful in future studies of IBD therapies., Highlights • Adipose-derived stem cells (ASCs) are being explored as a new treatment for IBD because they can downregulate inflammation and improve tissue repair. • A new model of TNBS-induced colitis was developed using a custom-designed device fabricated by a 3D printer. • The novel model of colitis generated ulcers that were highly reproducible in size. • The size of the ulcer was reduced by mesalazine or prednisolone (administered as an enema) or by localized injection of ASCs.

Ruthenium-catalyzed propargylic reduction of propargylic alcohols bearing a terminal alkyne moiety is accomplished by using Hantzsch ester as a nucleophilic hydride source. A variety of secondary a...

Neurofibrillary tangles, one of the pathological hallmarks of Alzheimer's disease, consist of highly phosphorylated tau proteins. Tau protein binds to microtubules and is best known for its role in regulating microtubule dynamics. However, if tau protein is phosphorylated by activated major tau kinases, including glycogen synthase kinase 3β or cyclin-dependent kinase 5, or inactivated tau phosphatase, including protein phosphatase 2A, its affinity for microtubules is reduced, and the free tau is believed to aggregate, thereby forming neurofibrillary tangles. We previously reported that pitavastatin decreases the total and phosphorylated tau protein using a cellular model of tauopathy. The reduction of tau was considered to be due to Rho-associated coiled-coil protein kinase (ROCK) inhibition by pitavastatin. ROCK plays important roles to organize the actin cytoskeleton, an expected therapeutic target of human disorders. Several ROCK inhibitors are clinically applied to prevent vasospasm postsubarachnoid hemorrhage (fasudil) and for the treatment of glaucoma (ripasudil). We have examined the effects of ROCK inhibitors (H1152, Y-27632, and fasudil [HA-1077]) on tau protein phosphorylation in detail. A human neuroblastoma cell line (M1C cells) that expresses wild-type tau protein (4R0N) by tetracycline-off (TetOff) induction, primary cultured mouse neurons, and a mouse model of tauopathy (rTG4510 line) were used. The levels of phosphorylated tau and caspase-cleaved tau were reduced by the ROCK inhibitors. Oligomeric tau levels were also reduced by ROCK inhibitors. After ROCK inhibitor treatment, glycogen synthase kinase 3β, cyclin-dependent kinase 5, and caspase were inactivated, protein phosphatase 2A was activated, and the levels of IFN-γ were reduced. ROCK inhibitors activated autophagy and proteasome pathways, which are considered important for the degradation of tau protein. Collectively, these results suggest that ROCK inhibitors represent a viable therapeutic route to reduce the pathogenic forms of tau protein in tauopathies, including Alzheimer's disease.

In this study, an efficient numerical model for predicting ship waves was developed using Green’s functions. Avoiding detailed description of the complex boundary conditions around a ship, this mod...

Ruthenium- and copper-catalyzed propargylic substitution reactions of propargylic alcohol derivatives with N-monosubstituted hydrazones as ambident nucleophiles are achieved in which N-monosubstituted hydrazones exhibit impressive different reactivities depending on different catalytic systems, behaving as carbon-centered nucleophiles to give the corresponding propargylic alkylated products in ruthenium catalysis, or as nitrogen-centered nucleophiles to afford the corresponding propargylic aminated products in copper catalysis. DFT calculations were carried out to investigate the detailed reaction pathways of these two systems. Further transformation of propargylic substituted products affords the corresponding multisubstituted pyrazoles as cyclization products in good to high yields.

Among synthetic models of nitrogenases, iron–dinitrogen complexes with a Fe–C bond have attracted increasing attention in recent years. Here we report the synthesis of square-planar iron(I)–dinitrogen complexes supported by anionic benzene-based PCP- and POCOP-type pincer ligands as carbon donors. These complexes catalyze the formation of ammonia and hydrazine from the reaction of dinitrogen (1 atm) with a reductant and a proton source at -78 °C, producing up to 252 equiv of ammonia and 68 equiv of hydrazine (388 equiv of fixed N atom) based on the iron atom of the catalyst. Anionic iron(0)–dinitrogen complexes, considered an essential reactive species in the catalytic reaction, are newly isolated from the reduction of the corresponding iron(I)–dinitrogen complexes. This study examines their reactivity using experiments and DFT calculations.

Summary Turning non-inflamed (cold) tumors into inflamed (hot) tumors is important for maximizing the effect of immune checkpoint inhibitors (ICIs) against malignancies. We showed that lactate, a product of the Warburg effect, inhibited the efficacy of ICIs and suppressed IL-12 p40 expression in dendritic cells (DCs) through reducing NF-κB p65, p50, and c-Rel DNA-binding activity to the IL-12 p40 promoter. Additionally, lactate promoted the expression of early growth response protein 1 (EGR1), whose expression was increased in human invasive melanoma compared with non-invasive melanoma. We also found that EGR1 interacts with serum response factor (SRF) and represses the expression of CD80 in DCs. These findings suggest that lactate and its induced EGR1 are key factors that turn hot tumors into cold tumors and may represent targets in cancer treatment with ICIs., Graphical abstract, Highlights • Lactate suppressed IL-12 p40 expression in dendritic cells • Lactate promoted the expression of early growth response protein 1 (EGR1) • EGR1 interacts with serum response factor (SRF) and represses the expression of CD80 • Lactate and EGR1 switch inflamed (hot) tumors to non-inflamed (cold) tumors, Immunology; Immune response; Cancer

A copper-catalyzed enantioselective transformation of tris(hydroxymethyl)aminomethane-derived aminotriols was developed to provide multisubstituted oxazolines with a tetrasubstituted carbon center. The present transformation consisted of sequential reactions involving mono-sulfonylation of aminotriols, subsequent intramolecular cyclization to afford prochiral oxazoline diols, and sulfonylative asymmetric desymmetrization of resultant oxazoline diols. In addition, the kinetic resolution process would be involved in the sulfonylative asymmetric desymmetrization step, which would amplify the enantiopurities of the desired products. Various aminotriols were tolerated in the present reaction, affording the desired oxazolines in good to high yields with excellent enantioselectivities. The synthetic utility of the present reaction was demonstrated by the transformation of the optically active oxazoline into a chiral α-tertiary amine motif.

Background Coagulation disturbances in several liver diseases lead to thrombin generation, which triggers intracellular injury via activation of protease-activated receptor-1 (PAR-1). Little is known about the thrombin/PAR-1 pathway in hepatic ischemia-reperfusion injury (IRI). The present study aimed to clarify whether a newly selective PAR-1 antagonist, vorapaxar, can attenuate liver damage caused by hepatic IRI, with a focus on apoptosis and the survival-signaling pathway. Methods A 60-min hepatic partial-warm IRI model was used to evaluate PAR-1 expression in vivo. Subsequently, IRI mice were treated with or without vorapaxar (with vehicle). In addition, hepatic sinusoidal endothelial cells (SECs) pretreated with or without vorapaxar (with vehicle) were incubated during hypoxia-reoxygenation in vitro. Results In naive livers, PAR-1 was confirmed by immunohistochemistry and immunofluorescence analysis to be located on hepatic SECs, and IRI strongly enhanced PAR-1 expression. In IRI mice models, vorapaxar treatment significantly decreased serum transaminase levels, improved liver histological damage, reduced the number of apoptotic cells as evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling staining (median: 135 versus 25, P = 0.004), and induced extracellular signal-regulated kinase 1/2 (ERK 1/2) cell survival signaling (phospho-ERK/total ERK 1/2: 0.96 versus 5.34, P = 0.004). Pretreatment of SECs with vorapaxar significantly attenuated apoptosis and induced phosphorylation of ERK 1/2 in vitro (phospho-ERK/total ERK 1/2: 0.66 versus 3.04, P = 0.009). These changes were abolished by the addition of PD98059, the ERK 1/2 pathway inhibitor, before treatment with vorapaxar. Conclusions The results of the present study revealed that hepatic IRI induces significant enhancement of PAR-1 expression on SECs, which may be associated with suppression of survival signaling pathways such as ERK 1/2, resulting in severe apoptosis-induced hepatic damage. Thus, the selective PAR-1 antagonist attenuates hepatic IRI through an antiapoptotic effect by the activation of survival-signaling pathways.

Introduction: Renal replacement therapy (RRT) is widely used in the treatment of septic acute kidney injury. However, little is known about how the adsorption properties of hemofilters used in RRT affect antibiotic concentration. Because a cytokine-adsorption membrane is frequently used in RRT, it is important to determine the antibiotic adsorption capacity of this membrane. Objective: The present study aimed to investigate the antibiotic adsorption capacity of different hemofilter membranes by in vitro experiments using 2 antibacterial agents (linezolid and doripenem). Methods: We performed experimental hemofiltration in vitro using polyacrylonitrile (AN69ST), polymethylmethacrylate (PMMA), and polysulfone (PS) hemofilters for 1,440 min. The test solution was a 1,000-mL substitution fluid containing 30 µg/mL linezolid and 120 µg/mL doripenem. We measured drug concentrations at the inlet, outlet, and filtrate ports of the hemofilters for 1,440 min and calculated the sieving coefficient (SC) and adsorption rate (Ra) of the drugs onto the hemofilters. Results: The amount of linezolid adsorbed onto AN69ST, PMMA, and PS membranes was decreased relative to that in the control group at 15 min (p < 0.05). However, no SC for linezolid was obtained thereafter. The Ra of linezolid onto AN69ST, PMMA, and PS membranes was higher than that in the control group (p < 0.05). In contrast, no significant differences were observed in the concentrations and Ra values of doripenem adsorbed onto AN69ST, PMMA, and PS membranes compared with those in the control group. Conclusions: Doripenem was not adsorbed onto PMMA, PS, and AN69ST membranes. Linezolid was adsorbed onto PMMA, PS, and AN69ST membranes, but only temporarily, and this did not affect drug bioavailability.

Boron-doped diamond (BDD) electrodes have a wide potential window and can produce ozone by water electrolysis at high voltage. Though ozone has strong oxidative power (standard oxidation potential: 2.07 V vs. NHE), it cannot decompose certain types of recalcitrant organic matter completely. We developed an advanced oxidation process (AOP), in which hydroxy radicals with stronger oxidative power (standard oxidation potential: 2.85 V vs. NHE) are formed using a combination of ozone, photocatalyst, and UV. In this study, we fabricated a mesoporous TiO2/BDD hybrid electrode and examined its potential for AOPs. A synergetic effect between electrochemical water treatment and photocatalytic water treatment was observed with the hybrid electrode that did not occur with the BDD electrode.

Few studies have investigated the interactions between HDL-C-related SNPs identified by genome-wide association (GWA) study and physical activity (PA) on HDL-C. First, we conducted a sex-stratified GWA study in a discovery sample (2,231 men and 2,431 women) and replication sample (2,599 men and 3,109 women) to identify SNPs influencing log-transformed HDL-C in Japanese participants in the baseline survey of the Japan Multi-Institutional Collaborative Cohort Study. We also replicated previously reported HDL-C-related SNPs in a combined (discovery plus replication) sample (4,830 men and 5,540 women). We then analyzed the interactions of the HDL-C-related SNPs with PA on HDL-C. The sex-stratified GWA analyses identified 11 and 10 HDL-C-related SNPs in men and women as targets for an interaction analysis. Among these, only one interaction of ABCA1 rs1883025 with PA was statistically significant in men, after Bonferroni correction [P-interaction = 0.001 (α = 0.05/21 = 0.002)]. The per-major-allele (C allele) increase in log-transformed HDL-C was lost in men with low PA (β = 0.008) compared with those with medium (β = 0.032) or high PA (β = 0.034). These findings suggest that the benefit of carrying a C allele of ABCA1 rs1883025 on enhancing HDL-C may be attenuated in inactive men.

Gout is a chronic inflammatory disease caused by precipitation of urate crystals in the joints, kidneys, and urinary tract. Independent of urate deposition disorders, recent studies have shown a positive association between circulating uric acid (UA) levels and cardiovascular (CV) diseases. These results indicate that UA is a precipitating factor of both gout and the progression of CV diseases, including hypertension and/or chronic kidney disease (CKD). A large body of evidence has shown that UA-lowering therapies are effective in preventing the progression of hypertension/CKD and that a causal relationship exists between serum UA level and CV diseases. Despite the urgent need for effective UA-lowering drugs that can be used to obtain better therapeutic outcomes and prognosis, only few drugs have been developed in the past decades. Recently, febuxostat and topiroxostat, which are xanthine oxidoreductase inhibitors, were developed and used in clinical practice. Of note, after the approval of lesinurad, which is a urate transporter-1 (URAT-1) inhibitor, in the United States in 2015, dotinurad (Fig. 1), a novel promising drug with selective UA reabsorption inhibitory property, was recently developed in Japan in 2018. Dotinurad is indicated for patients with hyperuricemia/gout as most patients with hyperuricemia are classified into “underexcretion type”, which requires the inhibition of URAT-1 to excrete excess UA via the kidney. Focusing on dotinurad, the present study highlighted the multifaceted preliminary new trials that assessed for drug efficacy and safety, pharmacokinetics (PK) according to age and gender, the presence or absence of liver and kidney disorders, drug interactions with NSAID, and non-inferiority of dotinurad to either febuxostat or benzbromarone. A series of studies included in this supplemental review indicate that dotinurad reduces serum UA levels, and its efficacy and safety are similar to those of other UA-lowering agents currently used even in hyperuricemic patients with various clinical conditions. Moreover, two exploratory studies with a small sample size were conducted to compare PK parameters between patients with overproduction- and underexcretion-type hyperuricemia, and results showed that the effects of UA-lowering agents were comparable between the two subtype groups.

The palladium-catalyzed deuterodechlorination of alkenyl chlorides has been developed, and a variety of deuterated alkenes were synthesized with precise control of the deuterium incorporation. This...

We investigated the conditions of sample preparation for obtaining low contact resistance to Al/Ti electrode on n-GaN fabricated by Si implantation and analyzed its interface structure. In conditions of sample preparation showing the lowest resistance, we found that there is an AlN layer and not the generally believed TiN layer on the interface between the electrode and the GaN substrate. Silicon was implanted into GaN followed by annealing at 1200 °C to investigate the effects of surface carrier concentration on ohmic contact. Layers of Ti and Al were then deposited and annealed at 550–800 °C. In the sample annealed at 600 °C with a relatively high fluence of 5 × 1014 atoms/cm2, the sample displayed the lowest contact resistance of 1.2 × 10−7 Ωcm2. This indicates that the formation of a high concentration of impurities on the GaN surface, resulting from Si implantation effectively reduced the contact resistance of the Al/Ti electrode. Ti and Al were also deposited on un-implanted GaN substrates, and the resulting multilayer electrodes with different Al/Ti ratios were annealed at 550–900 °C to investigate the electrode structure and the detail structure of metal/semiconductor interface. The film compositions and the interfacial microstructures of the samples were analyzed by the Rutherford backscattering spectroscopy method, optical microscopy, high-resolution scanning electron microscopy (STEM), energy-dispersive X-ray spectroscopy (EDX), and electron energy loss spectroscopy (EELS). For samples with Al/Ti ratios of ∼4.2, the under part of electrode became rich in Al at annealing temperatures of 550–600 °C. On the basis of the STEM and EELS analysis, Ti was not present at immediately above the GaN substrate interface, whereas AlN (thickness = 1–2 nm) was present. The RBS-determined total amount of Ga was 5 × 1015 atoms/cm2, which corresponds to the amount of Ga in 1.1 nm of the GaN layer that is probably replaced by the AlN layer.

Immune-mediated processes are considered important in the pathogenesis of bone marrow failure syndromes (BFS). We previously reported that natural killer group 2D (NKG2D) ligands were expressed on pathological blood cells of patients with BFS and that NKG2D immunity may be involved in bone marrow failure. In addition to membranous NKG2D ligands on the cell surface, soluble NKG2D ligands can exist in plasma. We therefore examined the relationship between soluble NKG2D ligands and blood cell counts in 86 patients with BFS, including aplastic anemia, myelodysplastic syndrome with single lineage dysplasia, and paroxysmal nocturnal hemoglobinuria. Approximately half of the BFS patients were positive for soluble NKG2D ligands in the plasma by enzyme-linked immunosorbent assay, and soluble NKG2D ligand-positive BFS patients exhibited severe cytopenia regardless of membranous NKG2D ligand expression. In vitroanalyses demonstrated that soluble ULBP1, an NKG2D ligand, down-regulated NKG2D receptors on CD2-positive cells in peripheral blood. Moreover, soluble ULBP1 attenuated the cytotoxic effects of peripheral blood mononuclear cells on K562, which express membranous ULBP1. Our results suggest that soluble NKG2D ligands can be easy-to-measure biomarkers for the prediction of activity of immune-meditated bone marrow injury in BFS and that soluble NKG2D ligands suppress redundant immune-mediated bone marrow injury.

A new activation annealing technology that can efficiently and uniformly heat the ion implanted transparent GaN substrates was developed. Annealing temperature was reduced by 80–50 °C using the GaN substrates coated with the carbon film on the backside. The performance of ion implanted GaN MISFETs using the newly developed low temperature annealing method were also demonstrated.

Catalytic C-H borylation has been reported using newly designed iron complexes bearing a 4,5,6,7-tetrahydroisoindol-2-ide-based PNP pincer ligand. The reaction tolerated various five-membered heteroarenes, such as pyrrole derivatives, as well as six-membered aromatic compounds, such as toluene. Successful examples of the iron-catalyzed sp3 C-H borylation of anisole derivatives were also presented.

A diastereodivergent synthesis of N-substituted iminolactones by bromoiminolactonization of α-substituted α-allylmalonamides is reported. Whereas bromocyclization under conventional chemical conditions provided cis-bromoiminolactones, electrochemical conditions exhibited complementary diastereoselectivity to afford the trans-products. A variety of substituents on the nitrogen atoms and an α-position of the malonamide were tolerated under both sets of conditions to afford the corresponding iminolactones in excellent yields and high diastereoselectivities.

3-[3-Amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)-phenyl]-propionic acid (AK106-001616) is a novel, potent, and selective inhibitor of the cytosolic phospholipase A2 (cPLA2) enzyme. Unlike traditional nonsteroidal anti-inflammatory drugs and selective cyclooxygenase-2 inhibitors, AK106-001616 reduced prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) production by stimulated cells. The suppression of PGE2 and LTB4 production was also confirmed using an air pouch model in rats administered a single oral dose of AK106-001616. AK106-001616 alleviated paw swelling in a rat adjuvant-induced arthritis (AIA) model. The maximum effect of the inhibitory effect of AK106-001616 was comparable with that of naproxen on paw swelling in a rat AIA model. Meanwhile, the inhibitory effect of AK106-001616 was more effective than that of naproxen in the mouse collagen antibody-induced arthritis model with leukotrienes contributing to the pathogenesis. AK106-001616 dose dependently reversed the decrease in paw withdrawal threshold not only in rat carrageenan-induced hyperalgesia, but also in a rat neuropathic pain model induced by sciatic nerve chronic constriction injury (CCI). However, naproxen and celecoxib did not reverse the decrease in the paw withdrawal threshold in the CCI model. Furthermore, AK106-001616 reduced the disease score of bleomycin-induced lung fibrosis in rats. In addition, AK106-001616 did not enhance aspirin-induced gastric damage in fasted rats, increase blood pressure, or increase the thromboxane A2/ prostaglandin I2 ratio that is thought to be an underlying mechanism of thrombotic cardiovascular events increased by selective cyclooxygenase-2 inhibitors. Taken together, these data demonstrate that oral AK106-001616 may provide valuable effects for wide indications without attendant gastrointestinal and cardiovascular risks.

We have designed and synthesized divalent initiators that contain a fluorescent terquinoxaline unit with two palladium groups for the living polymerization of 1,2-diisocyanobenzenes. Using these divalent initiators, the bidirectional living polymerization of a monomer bearing (

The enantioselective copper-catalyzed oxidative desymmetrization for the synthesis of chiral α-substituted serine derivatives is reported. The combination of Cu(OTf)2/(R,R)-PhBOX catalyst system, N...