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Given the prevalence of pyridine motifs in FDA-approved drugs, selective fluoroalkylation of pyridines and quinolines is essential for preparing diverse bioisosteres. However, conventional Minisci reactions often face challenges in achieving precise regioselectivity due to competing reaction sites of pyridine and the limited availability of fluoroalkyl radical sources. Herein, we present a light-driven, C4-selective fluoroalkylation of azines utilizing N-aminopyridinium salts and readily available sulfinates. Our approach employs electron donor-acceptor complexes, achieving highly C4-selective fluoroalkylation under mild conditions without an external photocatalyst. This practical method not only enables the installation of CF2H groups but also allows for the incorporation of CF2-alkyl groups with diverse functional entities, surpassing the limitations of previous methods. The versatility of the radical pathway is further demonstrated through straightforward three-component reactions involving alkenes and [1.1.1]propellane. Detailed experimental and computational studies have elucidated the origins of regioselectivity, providing profound insights into the mechanistic aspects.
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Mesoscopic-scale stacking reconfigurations are investigated when van der Waals (vdW) films are stacked. A method to visualize complicated stacking structures and mechanical distortions simultaneously in stacked atom-thick films using Raman spectroscopy is developed. In the rigid limit, it is found that the distortions originate from the transfer process, which can be understood through thin film mechanics with a large elastic property mismatch. In contrast, with atomic corrugations, the in-plane strain fields are more closely correlated with the stacking configuration, highlighting the impact of atomic reconstructions on the mesoscopic scale. It is discovered that the grain boundaries do not have a significant effect while the cracks are causing inhomogeneous strain in stacked polycrystalline films. This result contributes to understanding the local variation of emerging properties from moiré structures and advancing the reliability of stacked vdW material fabrication.
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This research explores the enantioselective hydrosulfonylation of various α,ß-unsaturated carbonyl compounds via the use of visible light and redox-active chiral Ni-catalysis, facilitating the synthesis of enantioenriched α-chiral sulfones with remarkable enantioselectivity (exceeding 99 % ee). A significant challenge entails enhancing the reactivity between chiral metal-coordinated carbonyl compounds and moderate electrophilic sulfonyl radicals, aiming to minimize the background reactions. The success of our approach stems from two distinctive attributes: 1) the Cl-atom abstraction employed for sulfonyl radical generation from sulfonyl chlorides, and 2) the single-electron reduction to produce a key enolate radical Ni-complex. The latter process appears to enhance the feasibility of the sulfonyl radical's addition to the electron-rich enolate radical. An in-depth investigation into the reaction mechanism, supported by both experimental observations and theoretical analysis, offers insight into the intricate reaction process. Moreover, the versatility of our methodology is highlighted through its successful application in the late-stage functionalization of complex bioactive molecules, demonstrating its practicality as a strategy for producing α-chiral sulfones.
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A high-throughput, accurate screening is crucial for the prevention and control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Current methods, which involve sampling from the nasopharyngeal (NP) area by medical staffs, constitute a fundamental bottleneck in expanding the testing capacity. To meet the scales required for population-level surveillance, self-collectable specimens can be used; however, its low viral load has hindered its clinical adoption. Here, we describe a magnetic nanoparticle functionalized with synthetic apolipoprotein H (ApoH) peptides to capture, concentrate, and purify viruses. The ApoH assay demonstrates a viral enrichment efficiency of >90% for both SARS-CoV-2 and its variants, leading to an order of magnitude improvement in analytical sensitivity. For validation, we apply the assay to a total of 84 clinical specimens including nasal, oral, and mouth gargles obtained from COVID-19 patients. As a result, a 100% positivity rate is achieved from the patient-collected nasal and gargle samples, which exceeds that of the traditional NP swab method. The simple 12 min pre-enrichment assay enabling the use of self-collectable samples will be a practical solution to overcome the overwhelming diagnostic capacity. Furthermore, the methodology can easily be built on various clinical protocols, allowing its broad applicability to various disease diagnoses.
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COVID-19 , Humanos , COVID-19/diagnóstico , SARS-CoV-2 , beta 2-Glicoproteína I , Teste para COVID-19 , Nasofaringe , Manejo de Espécimes/métodos , PeptídeosRESUMO
Transition metal dichalcogenides (TMDs) have been considered as promising materials for oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) electrocatalysis. While there have been numerous studies focusing on layered TMDs, the ORR and OER catalytic activity trends of various cubic pyrite TMDs have not been systematically explored yet. Herein, we investigated 12 earth abundant element-based pyrite TMDs (MX2, where M = Mn, Fe, Co, Ni and X = S, Se, Te) using density functional theory (DFT) calculations. We initially constructed surface Pourbaix diagrams to determine the most stable surface coverages under the reaction conditions and found that the oxidized surfaces are most energetically preferred in all cases. We then calculated the binding free energies of reaction intermediates (O*, OH* and OOH*) and established their scaling relations. The electrochemical ORR and OER performances were then displayed on two-dimensional volcano plots, which suggest MnS2, FeS2, NiTe2 and CoSe2 to be ORR active, and CoTe2 and CoSe2 to be OER active. In addition, we built multivariate linear regression models to predict ΔGO* and ΔGOH* using only atomic and bulk properties to readily estimate the catalytic activities of pyrite TMDs and to explore correlations between those properties. Particularly, we found that the electron affinity and bulk Bader charges of metal atoms are critical in determining the ORR and OER catalytic activities, which could be used as a guidance for future catalyst design.
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The human skin sebum suggests that it (along with other epidermal surface lipids) plays a role in skin barrier formation, the moderation of cutaneous inflammation, and antimicrobial defense. Various methods have been developed for collecting and measuring skin sebum. We tested methods of detection using "color intensity", by staining the skin casual sebum. This process was conducted in three steps; first, the selection of materials for sebum collection; second, staining the collected sebum; third, the development of a device that can measure the level of stained sebum. A plastic film was used to effectively collect sebum that increased with the replacement time of the sebum. In addition, the collected sebum was stained with Oil Red O (ORO) and checked with RGB; as a result, the R2 value was higher than 0.9. It was also confirmed that the correlation value was higher than 0.9 in the comparison result with Sebumeter®, which is a common standard technology. Finally, it was confirmed that the R2 value was higher than 0.9 in the detection value using the sensor. In conclusion, we have proven the proof of concept (PoC) for this method, and we would like to introduce an effective sebum measurement method that differs from the existing method.
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Sebo , Pele , Compostos Azo , Humanos , Coloração e RotulagemRESUMO
Site-selective C-H functionalization in chemical feedstocks is a challenging and useful reaction in the broad field of chemical research. Here, we report a modular photochemical platform for the site-selective C-H pyridylation of unactivated hydrocarbons via the unique synergistic effects of triplet excited anthraquinone and an amidyl radical-based reverse hydrogen atom transfer (RHAT) agent. The selective pyridylation of tertiary and secondary C(sp3)-H bonds in abundant chemical feedstocks was achieved by employing various N-aminopyridinium salts in a highly selective fashion, thus providing a new catalytic system for the direct construction of high-value-added compounds under ambient reaction conditions. Moreover, this operationally simple protocol is applicable to a variety of linear-, branched-, and cyclo-alkanes and more complex molecules with high degrees of site selectivity under visible-light conditions, which provides rapid and straightforward access to versatile synthons for upgrading feedstocks under mild, metal-free reaction conditions.
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By utilizing an underexplored reactivity mode of N-aminopyridinium ylides, we developed the visible-light-induced ortho-selective aminopyridylation of alkenes via radical-mediated 1,3-dipolar cycloaddition. The photocatalyzed single-electron oxidation of N-aminopyridinium ylides generates the corresponding radical cations that enable previously inaccessible 1,3-cycloaddition with a broader range of alkene substrates. The resulting cycloaddition adducts rapidly undergo subsequent homolytic cleavage of the N-N bond, conferring a substantial thermodynamic driving force to yield various ß-aminoethylpyridines. Remarkably, amino and pyridyl groups can be installed into both activated and unactivated alkenes with modular control of ortho-selectivity and 1,2-syn-diastereoselectivity under metal-free and mild conditions. Combined experimental and computational studies are conducted to clarify the detailed reaction mechanism and the origins of site selectivity and diastereoselectivity.
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Previous animal studies have reported that pyrethroids can cause dopamine system abnormalities and attention-deficit/hyperactivity disorder (ADHD) phenotypes. However, epidemiological studies investigating the associations between pyrethroid exposure and ADHD are limited. We aimed to investigate the association between pyrethroid exposure and ADHD-like symptoms among preschool-age children. We used data from 385 children at 4 years of age participating in the Environment and Development of Children (EDC) study. We evaluated pyrethroid exposure through questionnaires and urinary 3-phenoxybenzoic acid (3-PBA) concentrations. We assessed ADHD-like symptoms using the Korean ADHD rating scale (K-ARS). We conducted negative binomial regressions to evaluate the associations between pyrethroid exposure and ADHD-like symptoms. Residential use of insecticide adhesive (ß = 0.42, 95% CI: 0.11, 0.74) and insecticide spray (ß = 0.33, 95% CI: 0.08, 0.59) was associated with an increase in log-transformed creatinine-adjusted urinary 3-PBA concentrations. Residential insecticide adhesive use was associated with a 51.6% increase in K-ARS scores (95% confidence interval [CI]: 6.3, 116.1) among boys, when compared with non-users. When compared with creatinine-adjusted 3-PBA levels <0.50 µg/g creatinine, creatinine-adjusted 3-PBA levels ≥3.80 µg/g creatinine were associated with a 58% increase in K-ARS scores (95% CI: 0.1, 150.5) among boys. We found associations of residential pyrethroid insecticide use and urinary 3-PBA concentrations with K-ARS scores among preschool-age boys. Since the present study explored cross-sectional associations in preschool-age children, the possibility of reverse causality cannot be dismissed. Further studies implementing a cohort study design are warranted.
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Transtorno do Deficit de Atenção com Hiperatividade , Inseticidas , Piretrinas , Transtorno do Deficit de Atenção com Hiperatividade/induzido quimicamente , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Benzoatos , Criança , Pré-Escolar , Estudos de Coortes , Estudos Transversais , Humanos , Inseticidas/toxicidade , Masculino , Piretrinas/toxicidadeRESUMO
The medicinal mushroom Cordyceps militaris has been reported to possess anticancer and immunomodulatory effects. We investigated the immunostimulatory effects of culture supernatant of C. militaris (WIB-801CE) by examining its in vitro enhancing effects on cell proliferation and cytokine releases in splenocytes and its in vivo effects on cyclophosphamide-induced immunosuppressed mice. WIB-801CE enhanced normal and methotrexate-induced cell proliferation. WIB-801CE significantly ameliorated interleukin (IL)-2, interferon-γ, and tumor necrosis factor-α secretion in methotrexate-induced splenocytes. Oral administration of WIB-801CE effectively increased the cyclophosphamide-suppressed splenocyte proliferation and natural killer cytotoxic activity. WIB-801CE effectively recovered cyclophosphamide-induced decreases in IL-2, interferon-γ, tumor necrosis factor-α, and IL-10 level. The collective data implicate WIB-801CE as a therapeutic candidate in ameliorating the immunosuppression through immunostimulatory properties.
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Cordyceps/química , Ciclofosfamida/farmacologia , Desoxiadenosinas/química , Medicamentos de Ervas Chinesas/farmacologia , Fibrinolíticos/farmacologia , Extratos Vegetais/farmacologia , Animais , Proliferação de Células , Terapia de Imunossupressão , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Two chromone C-glucosides, biflorin (1) and isobiflorin (2), were isolated from the flower buds of Syzygium aromaticum L. (Myrtaceae). Here, inhibitory effects of 1 and 2 on lipopolysaccharide (LPS)-induced production of nitric oxide (NO) and prostaglandin E2 (PGE2) in RAW 264.7 macrophages were evaluated, and 1 (IC50 = 51.7 and 37.1 µM, respectively) was more potent than 2 (IC50 > 60 and 46.0 µM). The suppression of NO and PGE2 production by 1 correlated with inhibition of iNOS and COX-2 protein expression. Compound 1 reduced inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) mRNA expression via inhibition of their promoter activities. Compound 1 inhibited the LPS-induced production and mRNA expression of tumor necrosis factor-α (TNF-α) and interleukin (IL)-6. Furthermore, 1 reduced p-STAT1 and p-p38 expression but did not affect the activity of nuclear factor κ light-chain enhancer of activated B cells (NF-κB) or activator protein 1 (AP-1). In a mouse model of LPS-induced endotoxemia, 1 reduced the mRNA levels of iNOS, COX-2, and TNF-α, and the phosphorylation-mediated activation of the signal transducer and activator of transcription 1 (STAT1), consequently improving the survival rates of mice. Compound 1 showed a significant anti-inflammatory effect on carrageenan-induced paw edema and croton-oil-induced ear edema in rats. The collective data indicate that the suppression of pro-inflammatory gene expression via p38 mitogen-activated protein kinase and STAT1 inactivation may be a mechanism for the anti-inflammatory activity of 1.
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Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Naftoquinonas/isolamento & purificação , Naftoquinonas/farmacologia , Fator de Transcrição STAT1/efeitos dos fármacos , Syzygium/química , Animais , Anti-Inflamatórios/farmacologia , Carragenina/farmacologia , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/antagonistas & inibidores , Modelos Animais de Doenças , Edema/induzido quimicamente , Endotoxemia/tratamento farmacológico , Flores/química , Mediadores da Inflamação , Interleucina-6 , Masculino , Camundongos , Estrutura Molecular , NF-kappa B/antagonistas & inibidores , Naftoquinonas/química , Óxido Nítrico/biossíntese , Ratos , Fator de Transcrição AP-1 , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
We investigated the effect of chikusetsusaponin IVa (CS) and chikusetsusaponin IVa methyl ester (CS-ME) from the roots of Achyranthes japonica NAKAI on lipopolysaccharide (LPS)-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production in RAW264.7 macrophages. CS-ME more potently inhibited LPS-induced NO and PGE2 production than CS. CS-ME concentration-dependently inhibited LPS-induced tumor necrosis factor (TNF)-α and interleukin (IL)-6 and IL-1ß production in RAW264.7 macrophages and mouse peritoneal macrophages. Consistent with these findings, CS-ME suppressed LPS-induced expression of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 at protein level as well as iNOS, COX-2, TNF-α, IL-6, and IL-1ß at mRNA level. In addition, CS-ME suppressed LPS-induced transcriptional activity of nuclear factor (NF)-κB and activator protein (AP)-1. The anti-inflammatory properties of CS-ME might result from suppression of iNOS, COX-2, TNF-α, IL-6, and IL-1ß expression through downregulation of NF-κB and AP-1 in macrophages.
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Achyranthes , Anti-Inflamatórios/farmacologia , Ésteres/farmacologia , Ácido Oleanólico/análogos & derivados , Saponinas/farmacologia , Animais , Anti-Inflamatórios/isolamento & purificação , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Ésteres/isolamento & purificação , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Lipopolissacarídeos , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Ácido Oleanólico/isolamento & purificação , Ácido Oleanólico/farmacologia , Raízes de Plantas/química , Células RAW 264.7 , Saponinas/isolamento & purificação , Fator de Transcrição AP-1/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The synthesis of a new series of 21 fused coumarin derivatives is described, and the biological evaluation of their in vitro antiinflammatory effects as inhibitors of lipopolysaccharide (LPS)-induced nitric oxide (NO) and prostaglandin E2 (PGE2 ) production in RAW 264.7 macrophages. The target compounds 1a-u were first tested for cytotoxicity to determine a non-toxic concentration for antiinflammatory screening, so that the inhibitory effects against NO and PGE2 production would not be caused by cytotoxicity. Compounds 1f and 1p were the most active PGE2 inhibitors with IC50 values of 0.89 and 0.95 µM, respectively. Western blot and cell-free COX-2 screening showed that their effects were due to inhibition of both COX-2 protein expression and COX-2 enzyme activity. Their IC50 values against the COX-2 enzyme were 0.67 and 0.85 µM, respectively, which is more potent than etoricoxib. The selectivity indexes of compounds 1f and 1p against COX-2 compared to COX-1 were 41.1 and 42.5, respectively. Compound 1f showed strong inhibitory effects at 5 µM concentration on COX-2 mRNA expression in LPS-induced RAW 264.7 macrophages. Moreover, the tricyclic compounds 1l and 1n as well as the tetracyclic analog 1u were the most potent NO inhibitors, with one-digit micromolar IC50 values. They showed dose-dependent inhibition of inducible nitric oxide synthase (iNOS) protein expression. The tetracyclic derivative 1u was the most potent inhibitor of NO production. It also exhibited a strong inhibitory effect on iNOS mRNA expression in LPS-induced RAW 264.7 macrophages.
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Cumarínicos/síntese química , Cumarínicos/farmacologia , Dinoprostona/biossíntese , Regulação para Baixo/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Óxido Nítrico/biossíntese , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Células Cultivadas , Ciclo-Oxigenase 2/biossíntese , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Relação Dose-Resposta a Droga , Lipopolissacarídeos , Camundongos , Óxido Nítrico Sintase Tipo II/biossíntese , Relação Estrutura-AtividadeRESUMO
OBJECTIVE: There is increasing preclinical evidence indicating that metformin, a medication commonly used for type 2 diabetes mellitus, may protect against cancer. Motivated by this emerging evidence we asked 2 questions: (1) can metformin prevent ovarian cancer growth by altering metabolism and (2) will metformin increase sensitivity to chemotherapy. STUDY DESIGN: The effect of metformin in ovarian cancer was tested in vitro and with 2 different mouse models. In vitro, cell lines (n = 6) were treated with metformin (10-40 mmol/L) or phosphate-buffered saline solution and cellular proliferation and metabolic alterations (adenosine monophosphate-activated protein kinase activity, glycolysis, and lipid synthesis) were compared between the 2 groups. In mouse models, a prevention study was performed by treating mice with metformin (250 mg/kg/d intraperitoneally) or placebo for 2 weeks followed by intraperitoneal injection of the SKOV3ip1 human ovarian cancer cell line, and the mean number of tumor implants in each treatment group was compared. In a treatment study, the LSL-K-ras(G12D/+)/PTEN(floxP/floxP) genetic mouse model of ovarian cancer was used. Mice were treated with placebo, paclitaxel (3 mg/kg/wk intraperitoneally for 7 weeks), metformin (100 mg/kg/d in water for 7 weeks), or paclitaxel plus metformin, and tumor volume was compared among treatment groups. RESULTS: In vitro, metformin decreased proliferation of ovarian cancer cell lines and induced cell cycle arrest, but not apoptosis. Further analysis showed that metformin altered several aspects of metabolism including adenosine monophosphate-activated protein kinase activity, glycolysis, and lipid synthesis. In the prevention mouse model, mice that were pretreated with metformin had 60% fewer tumor implants compared with controls (P < .005). In the treatment study, mice that were treated with paclitaxel plus metformin had a 60% reduction in tumor weight compared with controls (P = .02), which is a level of tumor reduction greater than that resulting from either paclitaxel or metformin alone. CONCLUSION: Based on these results, we conclude that metformin alters metabolism in ovarian cancer cells, prevents tumor growth, and increases sensitivity to chemotherapy in vitro and in mouse models. These preclinical findings suggest that metformin warrants further investigation for use as an ovarian cancer therapeutic.
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Antineoplásicos/uso terapêutico , Metformina/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/prevenção & controle , Paclitaxel/uso terapêutico , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Humanos , Metformina/farmacologia , Camundongos , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Carga Tumoral/efeitos dos fármacosRESUMO
BACKGROUND: The skin microbiome is essential in guarding against harmful pathogens and responding to environmental changes by generating substances useful in the cosmetic and pharmaceutical industries. Among these microorganisms, Streptococcus is a bacterial species identified in various isolation sources. In 2021, a strain of Streptococcus infantis, CX-4, was identified from facial skin and found to be linked to skin structure and elasticity. As the skin-derived strain differs from other S. infantis strains, which are usually of oral origin, it emphasizes the significance of bacterial variation by the environment. OBJECTIVE: This study aims to explore the unique characteristics of the CX-4 compared to seven oral-derived Streptococcus strains based on the Whole-Genome Sequencing data, focusing on its potential role in skin health and its possible application in cosmetic strategies. METHODS: The genome of the CX-4 strain was constructed using PacBio Sequencing, with the assembly performed using the SMRT protocol. Comparative whole-genome analysis was then performed with seven closely related strains, utilizing web-based tools like PATRIC, OrthoVenn3, and EggNOG-mapper, for various analyses, including protein association analysis using STRING. RESULTS: Our analysis unveiled a substantial number of Clusters of Orthologous Groups in diverse functional categories in CX-4, among which sphingosine kinase (SphK) emerged as a unique product, exclusively present in the CX-4 strain. SphK is a critical enzyme in the sphingolipid metabolic pathway, generating sphingosine-1-phosphate. The study also brought potential associations with isoprene formation and retinoic acid synthesis, the latter being a metabolite of vitamin A, renowned for its crucial function in promoting skin cell growth, differentiation, and maintaining of skin barrier integrity. These findings collectively suggest the potential of the CX-4 strain in enhancing of skin barrier functionality. CONCLUSION: Our research underscores the potential of the skin-derived S. infantis CX-4 strain by revealing unique bacterial compounds and their potential roles on human skin.
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Genoma Bacteriano , Streptococcus , Humanos , Filogenia , Streptococcus/genética , Sequenciamento Completo do GenomaRESUMO
A polysaccharide fraction from Diospyros kaki (PLE0) leaves was previously reported to possess immunostimulatory, anti-osteoporotic, and TGF-ß1-induced epithelial-mesenchymal transition inhibitory activities. Although a few beneficial effects against colon cancer metastasis have been reported, we aimed to investigate the anti-metastatic activity of PLE0 and its underlying molecular mechanisms in HT-29 and HCT-116 human colon cancer cells. We conducted a wound-healing assay, invasion assay, qRT-PCR analysis, western blot analysis, gelatin zymography, luciferase assay, and small interfering RNA gene silencing in colon cancer cells. PLE0 concentration-dependently inhibited metastasis by suppressing cell migration and invasion. The suppression of N-cadherin and vimentin expression as well as upregulation of E-cadherin through the reduction of p-GSK3ß and ß-catenin levels resulted in the outcome of this effect. PLE0 also suppressed the expression and enzymatic activity of matrix metalloproteinases (MMP)-2 and MMP-9, while simultaneously increasing the protein and mRNA levels of the tissue inhibitor of metalloproteinases (TIMP-1). Furthermore, signaling data disclosed that PLE0 suppressed the transcriptional activity and phosphorylation of p65 (a subunit of NF-κB), as well as the phosphorylation of c-Jun and c-Fos (subunits of AP-1) pathway. PLE0 markedly suppressed JNK phosphorylation, and JNK knockdown significantly restored PLE0-regulated MMP-2/-9 and TIMP-1 expression. Collectively, our data indicate that PLE0 exerts an anti-metastatic effect in human colon cancer cells by inhibiting epithelial-mesenchymal transition and MMP-2/9 via downregulation of GSK3ß/ß-catenin and JNK signaling.
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A one-pot umpolung method for the ring-opening pyridylation of unstrained cyclic amines was developed using N-amidopyridinium salts. This process involves the formation of electron donor-acceptor complexes between bromide and N-amidopyridinium salts, ultimately leading to the functionalization of pyridines. This protocol is compatible with a range of 5- or 6-membered cyclic amines and pyridines, thereby providing a powerful synthon for preparing C4-functionalized pyridines under visible-light conditions in the absence of an external photocatalyst.
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Photocycloaddition is a powerful reaction to enable the conversion of alkenes into high-value synthetic materials that are normally difficult to obtain under thermal conditions. Lactams and pyridines, both prominent in pharmaceutical applications, currently lack effective synthetic strategies to combine them within a single molecular structure. Here we describe an efficient approach to diastereoselective pyridyl lactamization via a photoinduced [3+2] cycloaddition, based on the unique triplet-state reactivity of N-N pyridinium ylides in the presence of a photosensitizer. The corresponding triplet diradical intermediates allow the stepwise radical [3+2] cycloaddition with a broad range of activated and unactivated alkenes under mild conditions. This method exhibits excellent efficiency, diastereoselectivity and functional group tolerance, providing a useful synthon for ortho-pyridyl γ- and δ-lactam scaffolds with syn-configuration in a single step. Combined experimental and computational studies reveal that the energy transfer process leads to a triplet-state diradical of N-N pyridinium ylides, which promotes the stepwise cycloaddition.
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To compare total en bloc spondylectomy (TES) with stereotactic ablative radiotherapy (SABR) for single spinal metastasis, we undertook a single center retrospective study. We identified patients who had undergone TES or SABR for a single spinal metastasis between 2000 and 2019. Medical records and images were reviewed for patient and tumor characteristics, and oncologic outcomes. Patients who received TES were matched to those who received SABR to compare local control and survival. A total of 89 patients were identified, of whom 20 and 69 received TES and SABR, respectively. A total of 38 matched patients were analyzed (19 TES and 19 SABR). The median follow-up period was 54.4 (TES) and 26.1 months (SABR) for matched patients. Two-year progression-free survival (PFS) and overall survival (OS) rates were 66.7% and 72.2% in the TES and 38.9% and 50.7% in the SABR group, respectively. At the final follow-up of the matched cohorts, no significant differences were noted in OS (p = 0.554), PFS (p = 0.345) or local progression (p = 0.133). The rate of major complications was higher in the TES than in the SABR group (21.1% vs. 10.5%, p = 0.660). These findings suggest that SABR leads to fewer complications compared to TES, while TES exhibits better mid-term control of metastatic tumors.
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OBJECTIVE: To test if estrogen promotes carcinogenesis in vitro and in a genetic mouse model of ovarian cancer and whether its effects can be inhibited by a novel selective estrogen receptor modulator (SERM), bazedoxifene. METHODS: Bazedoxifene was synthesized and it was confirmed that the drug abrogated the uterine stimulatory effect of 17ß-estradiol in mice. To determine if hormones alter tumorigenesis in vivo LSL-K-ras(G12D/+)Pten(loxP/loxP) mice were treated with vehicle control, 17ß-estradiol or bazedoxifene. Hormone receptor status of a cell line established from LSL-K-ras(G12D/+)Pten(loxP/loxP) mouse ovarian tumors was characterized using Western blotting and immunohistochemistry. The cell line was treated with hormones and invasion assays were performed using Boyden chambers and proliferation was assessed using MTT assays. RESULTS: In vitro 17ß-estradiol increased both the invasion and proliferation of ovarian cancer cells and bazedoxifene reversed these effects. However, in the genetic mouse model neither treatment with 17ß-estradiol nor bazedoxifene changed mean tumor burden when compared to treatment with placebo. The mice in all treatment groups had similar tumor incidence, metastatic nodules and ascites. CONCLUSION: While 17ß-estradiol increases the invasion and proliferation of ovarian cancer cells, these effects do not translate into increased tumor burden in a genetic mouse model of endometrioid ovarian cancer. Likewise, while the SERM reversed the detrimental effects of estrogen in vitro, there was no change in tumor burden in mice treated with bazedoxifene. These findings demonstrate the complex interplay between hormones and ovarian carcinogenesis.