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BACKGROUND: This study aimed to investigate the contralateral breast cancer (CBC) recurrence rate in Korean breast cancer patients according to their BRCA1/2 germline mutation status, focusing particularly on the CBC recurrence risk in BRCA1/2 negative (BRCAx) patients. METHODS: We conducted a retrospective study on 13,107 primary breast cancer patients. The patients were divided into high-risk and low-risk groups for hereditary breast cancer based on the Korean National Health Insurance Service's eligibility criteria for BRCA1/2 germline mutation testing. The high-risk group was further categorized into the BRCA mutation group, the BRCAx group, and the not tested group. We evaluated the overall survival and cumulative risk of developing CBC in these patients. RESULTS: Among 4494 high-risk patients, 973 (21.7%) underwent genetic testing for BRCA1/2 germline mutation, revealing mutations in 158 patients (16.2%). We observed significant overall survival differences across all four groups, with the high-risk, not-tested group demonstrating notably worse overall survival (p < 0.001). However, when adjusted for other prognostic factors, there was no significant differences in hazard ratio of death between the four groups. The cumulative risk of CBC also varied among the groups. Patients with BRCA1/2 mutations showed a 7.3-fold increased risk of CBC compared to the low-risk group (95% CI 4.11-13.0, p < 0.001). Interestingly, BRCAx patients also demonstrated a significantly higher risk of CBC (HR 2.77, 95% CI 1.76-4.35, p < 0.001). The prognostic importance of the BRCAx for CBC recurrence persisted after adjusting for the age and subtype, but became insignificant when the family history of breast cancer was adjusted. CONCLUSION: Breast cancer patients who are at high risk of hereditary breast cancer but with wild-type BRCA 1/2 genes (BRCAx) have increased risk of developing contralateral breast cancer when compared to the low-risk patients. More careful surveillance and follow-up can be offered to these patients especially when they have family history of breast cancer.
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Proteína BRCA1 , Neoplasias de la Mama , Humanos , Femenino , Proteína BRCA1/genética , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Estudios Retrospectivos , Proteína BRCA2/genética , República de Corea/epidemiologíaRESUMEN
This study aimed to elucidate the structural congeners of natural izenamides A, B, and C (1-3) responsible for cathepsin D (CTSD) inhibition. Structurally modified izenamides were synthesized and biologically evaluated, and their biologically important core structures were identified. We confirmed that the natural statine (Sta) unit (3S,4S)-γ-amino-ß-hydroxy acid is a requisite core structure of izenamides for inhibition of CTSD, which is closely related to the pathophysiological roles in numerous human diseases. Interestingly, the statine-incorporated izenamide C variant (7) and 18-epi-izenamide B variant (8) exhibited more potent CTSD-inhibitory activities than natural izenamides.
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Catepsina D , Inhibidores de Proteasas , Humanos , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasas/químicaRESUMEN
The discovery of small molecules that regulate specific neuronal phenotypes is important for the development of new therapeutic candidates for neurological diseases. Estrogen-related receptor γ (ERRγ), an orphan nuclear receptor widely expressed in the central nervous system (CNS), is closely related to the regulation of neuronal metabolism and differentiation. We previously reported that upregulation of ERRγ could enhance dopaminergic neuronal phenotypes in the neuroblastoma cell line, SH-SY5Y. In this study, we designed and synthesized a series of new ERRγ agonists using the X-ray crystal structure of the GSK4716-bound ERRγ complex and known synthetic ligands. Our new ERRγ agonists exhibited increased transcriptional activities of ERRγ. In addition, our molecular docking results supported the experimental findings for ERRγ agonistic activity of the potent analogue, 5d. Importantly, 5d not only enhanced the expression of dopaminergic neuronal-specific molecules, TH and DAT but also activated the relevant signaling events, such as the CREB-mediated signaling pathway. The results of the present study may provide useful clues for the development of novel ERRγ agonists for neurological diseases related to the dopaminergic nervous system.
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Neuronas Dopaminérgicas , Receptores de Estrógenos , Neuronas Dopaminérgicas/metabolismo , Simulación del Acoplamiento Molecular , Fenotipo , Receptores de Estrógenos/metabolismo , Regulación hacia ArribaRESUMEN
The first total syntheses of isocorniculatolide B, corniculatolide B, and corniculatolide C, consisting of isomeric corniculatolide skeletons, have been accomplished in a divergent manner. The key features of the synthesis involve the construction of diaryl ether linkages by nucleophilic aromatic substitution, installation of a C14-substituted alkyl side chain via a sequence of Baeyer-Villiger reaction and Claisen rearrangement, and efficient construction of corniculatolide and isocorniculatolide frameworks, including 17-membered (exterior) macrolactone skeletons from a versatile diaryl ether intermediate by Mitsunobu macrolactonization. Moreover, we prepared the structural congeners of isomeric corniculatolides via diverted total synthesis approach including desmethyl analogues and related dimeric macrolides. The anti-inflammatory activities of the synthesized natural products, analogues and synthetic intermediates were also investigated. In particular, corniculatolide B significantly inhibited the protein expression of COX-2 and the mRNA expressions of TNF-α, IL-1ß and IL-6 by inhibiting of NF-κB signaling in intestinal epithelial cells induced by lipopolysaccharide treatment. It also significantly inhibited the promoter activity and the phosphorylation of subunits p50 and p65 of NF-κB to the same extent as Bay 11-7082, a potent IκB kinase inhibitor. These results suggest that corniculatolide B might have therapeutic potential in inflammatory bowel disease via NF-κB signaling pathway.
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Antiinflamatorios no Esteroideos/farmacología , Lactonas/farmacología , Macrólidos/farmacología , FN-kappa B/antagonistas & inhibidores , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Línea Celular , Relación Dosis-Respuesta a Droga , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Lactonas/síntesis química , Macrólidos/síntesis química , Estructura Molecular , FN-kappa B/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
A collective synthetic route for tricyclic guaiane sesquiterpenes and total syntheses of (+)-dysodensiol F, (+)-10ß,14-dihydroxy-allo-aromadendrane, and (-)-dendroside C aglycon starting from a versatile hydroazulene intermediate were accomplished. The key features of these syntheses involve late-stage carbene-mediated diastereoselective cyclopropanation, construction of an unusual cis-fused-hydroazulene skeleton via intramolecular Dieckmann condensation, and highly stereoselective tandem conjugate addition/intramolecular allylic alkylation to afford a 5/7/3 tricyclic skeleton of guaiane natural products. The synthesis of (-)-dendroside C aglycon and the first total synthesis of (+)-dysodensiol F and (+)-10ß,14-dihydroxy-allo-aromadendrane are described in detail. Activation of the Nrf2/ARE signaling pathway by (-)-dendroside C aglycon is also disclosed via our synthesis.
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A concise and scalable synthetic route for optically pure (4S) and (4R)-5-(3',4'-dihydroxyphenyl)-γ-valerolactones (DHPVs), catechin metabolites, has been developed via the efficient construction of a γ-valerolactone moiety from hexenol. Noticeably, the different skin wrinkle-reducing activities of each metabolite were revealed via our unique syntheses of DHPVs in an enantiomerically pure form.
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Catequina/síntesis química , Catequina/farmacología , Lactonas/síntesis química , Lactonas/farmacología , Piel/efectos de los fármacos , Humanos , Estructura Molecular , Oxidación-Reducción , Envejecimiento de la Piel/efectos de los fármacosRESUMEN
Despite numerous reports on the beneficial effects of catechin or epicatechin contained in tea and cacao extract on human health, a conclusive and precise molecular mechanism has not been elucidated. Metabolism of chemical compounds in gut microbiota recently gained significant attention, and extensive studies have been devoted in this field. In conjunction with these results, our group focused on the anti-inflammatory effects of both enantiomers of DHPV (5-(3',4'-dihydroxyphenyl)-γ-valerolactone), produced in the intestine by microbiota metabolism, on IEC-6 cells. Divergent and efficient enantioselective synthesis of (S)- and (R)-DHPV was efficiently achieved by cross-metathesis and Sharpless asymmetric dihydroxylation as a key reaction for four steps in 16% and 14% overall yields, respectively. The anti-inflammatory effects of two enantiomers were tested on IEC-6 cells, and we found that (S)-DHPV was more active than (R)-DHPV. This result implicates that the metabolite produced in the gut has beneficial effects on IEC-6 cells of rat intestines, and the chirality of the metabolite is important for its anti-inflammatory activity. This also provided information for the future discovery of novel small molecular therapeutics for the treatment of inflammatory bowel disease.
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Antiinflamatorios , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Mucosa Intestinal/metabolismo , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/química , Antiinflamatorios/farmacología , Línea Celular , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patología , Mucosa Intestinal/patología , Lactonas/síntesis química , Lactonas/química , Lactonas/farmacología , RatasRESUMEN
The first total syntheses of izenamides A, B, and C, which are depsipeptides inhibitor of cathepsin D, were accomplished. In addition, the stereochemistry of izenamide B was confirmed by our syntheses. The key features of our synthetic route involve the avoidance of critical 2,5-diketopiperazine (DKP) formation and the minimization of epimerization during the coupling of amino acids for the target peptides.
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Catepsina D/antagonistas & inhibidores , Depsipéptidos/síntesis química , Depsipéptidos/farmacología , Depsipéptidos/química , Dicetopiperazinas/químicaRESUMEN
The identification and three step synthesis of 3-O-protocatechuoylceanothic acid, a novel and natural GPR120 agonist, is described. This ceanothane-type triterpenoid was identified from the components of Ziziphus jujuba roots and was found to be a new GPR120 agonist with a novel structure. We synthetically converted ceanothic acid, which does not have GPR120 agonist activity, into 3-O-protocatechuoylceanothic acid in three steps. In addition, we present the corrected NMR spectrum of 3-O-protocatechuoylceanothic acid based on our synthesis.
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Receptores Acoplados a Proteínas G/química , Triterpenos/síntesis química , Triterpenos/farmacología , Animales , Células CHO , Técnicas de Química Sintética , Cricetulus , Humanos , Ligandos , Estructura Molecular , Receptores Acoplados a Proteínas G/agonistas , Proteínas Recombinantes , Relación Estructura-ActividadRESUMEN
Ionic liquids (ILs) have gained much attention as alternative solvents to volatile organic solvents due to their attractive properties. This study aimed to develop an efficient method for the selective separation of decursin (D) and decursinol angelate (DA) from Angelica gigas Nakai (A. gigas) using ILs and crystallization. The IL 1-butyl-3-methylimidazolium tetrafluoroborate ((BMIm)BF4) was the most efficient at extracting D and DA. Parameters including solid-to-liquid ratio, time, and temperature were optimized by response surface methodology (RSM). Under optimal extraction conditions (1 g/6.5 mL solid-to-liquid ratio, 60 °C temperature, and 120 min time), the extraction yields of D and DA were 43.32 mg/g (97.06%) and 17.87 mg/g (97.12%), respectively. Moreover, drowning out crystallization using deionized water (DW) as an anti-solvent offered an excellent ability to recover D and DA from the A. gigas-(BMIm)BF4 extraction solution. The rates of recovery and the total purity of D and DA were found to be greater than 97%. Therefore, a rapid and efficient method of combining ILs with crystallization was effectively achieved for the selective separation of D and DA. This approach is assumed to be beneficial in the pharmaceutical industry for the effective obtention of D- and DA-enriched products.
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Angelica/química , Benzopiranos/aislamiento & purificación , Imidazoles/química , Benzopiranos/química , Butiratos , Cristalización , Líquidos Iónicos/química , Estructura Molecular , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificaciónRESUMEN
The asymmetric total synthesis of the marine natural product (+)-(3E)-pinnatifidenyne was accomplished. The key features of the synthesis involve the construction of an eight-membered cyclic ether by the abnormally regioselective Pd(0)-catalyzed cyclization, the installation of a double bond in the oxocene skeleton by sequential in situ deconjugative isomerization, and the efficient introduction of the crucial chloride mediated by the substrate-controlled diastereoselective reduction.
RESUMEN
We propose an Ag reflector layer with an AgCu alloy layer as a thermally reliable reflector for high power flip-chip and vertical light emitting diodes (LEDs). By annealing the deposited Ag and Cu layers, intermixed grains and grain boundaries from the alloyed AgCu layer were formed on the LEDs, and CuO nano dots precipitated at the grain boundaries. A thick AgCu layer was deposited to cover the AgCu alloy layer. The precipitation of the CuO nano dots at the grain boundaries suppressed Ag agglomeration, leading to enhanced light reflectance after the annealing process. Consequently, the alloyed AgCu/Ag reflector produced by annealing at a high temperature of 500 °C demonstrated a higher reflectance of 78% and a lower contact resistance of 7.0 × 10-5 Ω · cm2.
RESUMEN
BACKGROUND: Agastache rugosa (Fisch. & C.A.Mey.) Kuntze (Korean mint) is used to treat diverse types of human disorders in traditional medicine. In recent years, its non-fermented leaf extract (ARE) has been shown to possess protective properties against ultraviolet-B (UV-B) radiation-induced photooxidative stress. The present work aimed to examine whether probiotic bacterial fermentation would potentiate the skin anti-photoaging activity of ARE or not, by comparing the protective properties of ARE and corresponding fermented extract (ARE-F) against UV-B radiation-induced photooxidative stress in HaCaT keratinocytes. METHODS: ARE-F was produced from ARE by the fermentation with Lactobacillus rhamnosus HK-9, a type of Gram-positive probiotic bacterial strain. Anti-photoaging activities were evaluated by analyzing reactive oxygen species (ROS), promatrix metalloproteinases (proMMPs), total glutathione (GSH) and total superoxide dismutase (SOD) in UV-B-irradiated HaCaT keratinocytes. Antiradical activity was determined using 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging assay. RESULTS: ARE-F contained higher attenuating activity on the UV-B-induced ROS generation than ARE. Similarly, ARE-F was able to diminish the UV-B-induced proMMP-9 and -2 more effectively than ARE. ARE-F displayed higher tendencies to augment the UV-B-reduced total GSH content and SOD activity than ARE. However, there were no significant difference between ARE and ARE-F in ABTS radical scavenging activities. CONCLUSIONS: The findings suggest that the UV-B radiation-protective activity of ARE is enhanced by probiotic bacterial fermentation, which might improve the therapeutic and cosmetic values of A. rugosa leaves.
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Agastache/química , Antioxidantes/farmacología , Extractos Vegetales/farmacología , Probióticos/farmacología , Línea Celular Tumoral , Fermentación , Glutatión/metabolismo , Humanos , Lacticaseibacillus rhamnosus , Metaloproteinasa 9 de la Matriz/metabolismo , Modelos Biológicos , Hojas de la Planta/química , Probióticos/química , Especies Reactivas de Oxígeno/metabolismo , Envejecimiento de la Piel , Superóxido Dismutasa/metabolismo , Rayos Ultravioleta , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Obesity, characterized by excess lipid accumulation, has emerged as a leading public health problem. Excessive, adipocyte-induced lipid accumulation raises the risk of metabolic disorders. Adipose-derived stem cells (ASCs) are mesenchymal stem cells (MSCs) that can be obtained from abundant adipose tissue. High fat mass could be caused by an increase in the size (hypertrophy) and number (hyperplasia) of adipocytes. Reactive oxygen species (ROS) are involved in the adipogenic differentiation of human adipose-derived stem cells (hASCs). Lowering the level of ROS is important to blocking or retarding the adipogenic differentiation of hASCs. Nuclear factor erythroid 2-related factor-2 (Nrf2) is a transcription factor that mediates various antioxidant enzymes and regulates cellular ROS levels. Neohesperidin dihydrochalcone (NHDC), widely used as artificial sweetener, has been shown to have significant free radical scavenging activity. In the present study, (E)-3-(4-chlorophenyl)-1-(2,4,6-trimethoxyphenyl)prop-2-en-1-one (CTP), a novel NHDC analogue, was synthesized and examined to determine whether it could inhibit adipogenic differentiation. The inhibition of adipogenic differentiation in hASCs was tested using NHDC and CTP. In the CTP group, reduced Oil Red O staining was observed compared with the differentiation group. CTP treatment also downregulated the expression of PPAR-γ and C/EBP-α, adipogenic differentiation markers in hASCs, compared to the adipogenic differentiation group. The expression of FAS and SREBP-1 decreased in the CTP group, along with the fluorescent intensity (amount) of ROS. Expression of the Nrf2 protein was slightly decreased in the differentiation group. Meanwhile, in both the NHDC and CTP groups, Nrf2 expression was restored to the level of the control group. Moreover, the expression of HO-1 and NQO-1 increased significantly in the CTP group. Taken together, these results suggest that CTP treatment suppresses the adipogenic differentiation of hASCs by decreasing intracellular ROS, possibly through activation of the Nrf2 cytoprotective pathway. Thus, the use of bioactive substances such as CTP, which activates Nrf2 to reduce the cellular level of ROS and inhibit the adipogenic differentiation of hASCs, could be a new strategy for overcoming obesity.
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Adipogénesis/efectos de los fármacos , Tejido Adiposo/citología , Chalconas/química , Chalconas/farmacología , Hesperidina/análogos & derivados , Factor 2 Relacionado con NF-E2/metabolismo , Células Madre/efectos de los fármacos , Línea Celular , Células Cultivadas , Hesperidina/química , Hesperidina/farmacología , Humanos , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Células Madre/citologíaRESUMEN
The versatile synthesis of (-)-6-desmethyl-fluvirucinine A1 was accomplished at a 24% overall yield through a thirteen-step process from a known vinylpiperidine. The key part involved the elaboration of the distal stereocenters and a macrolactam skeleton via conformationally-induced diastereocontrol and the iterative aza-Claisen rearrangements of lactam precursors.
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Lactamas/síntesis química , Catálisis , Cristalografía por Rayos X , Lactamas/química , Conformación Molecular , Estructura Molecular , EstereoisomerismoRESUMEN
α-Vinyl or α-acetylenyl azacycles were easily synthesized from 7- to 9-membered lactams and 6- to 9-membered lactams via N,O-acetal trimethylsilyl (TMS) ethers. Organocopper and organostannane reagents afforded reasonable yields for the respective N-acyliminium ion vinylation and acetylenylation intermediates generated from N,O-acetal TMS ethers in the presence of a Lewis acid.
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Acetales/química , Éteres/química , Lactamas/química , Cobre/química , Compuestos Organometálicos/química , Compuestos de Estaño/químicaRESUMEN
CONTEXT: Geniposide (genipin-1-O-ß-d-glucoside) is a major bioactive ingredient in the fruits of gardenia [Gardenia jasminoides J. Ellis (Rubiaceae)], a traditional herbal medicine in Asian countries. OBJECTIVE: This work assesses the skin anti-photoaging potential of geniposide in human dermal fibroblasts under UV-B irradiation. MATERIALS AND METHODS: The anti-photoaging property of geniposide, at varying concentrations (5, 12 and 30 µM) treated for 30 min prior to UV-B irradiation, was evaluated by analysing reactive oxygen species (ROS), promatrix metalloproteinase-2 (proMMP-2), glutathione (GSH), superoxide dismutase (SOD), nuclear factor erythroid 2-related factor 2 (Nrf2) and cellular viability. RESULTS: Geniposide suppressed the ROS elevation under UV-B irradiation, which was revealed using three ROS-sensitive fluorescent dyes. The use of 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA), dihydroethidium (DHE) and dihydrorhodamine 123 (DHR-123) elicited the IC50 values of 10.5, 9.8 and 21.0 µM, respectively. Geniposide attenuated proMMP-2 at activity and protein levels that were elevated under UV-B-irradiation. Geniposide at 5, 12 and 30 µM augmented the UV-B-reduced total GSH content to 1.9 ± 0.1-, 2.2 ± 0.2- and 4.1 ± 0.2-fold, respectively. Geniposide at 5, 12 and 30 µM upregulated total SOD activity to 2.3 ± 0.1-, 2.5 ± 0.3- and 3.3 ± 0.3-fold, respectively, under UV-B irradiation. The UV-B-reduced Nrf2 levels were also upregulated by geniposide treatment. Geniposide, at the concentrations used, was unable to interfere with cellular viabilities under UV-B irradiation. DISCUSSION AND CONCLUSIONS: After the skin anti-photoaging potential of geniposide may be further verified, it can be utilized as a safer resource in the manufacture of effective anti-aging cosmetics.
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Dermis/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Iridoides/farmacología , Estrés Oxidativo/efectos de los fármacos , Envejecimiento de la Piel/efectos de los fármacos , Rayos Ultravioleta/efectos adversos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Dermis/patología , Dermis/efectos de la radiación , Relación Dosis-Respuesta a Droga , Fibroblastos/patología , Fibroblastos/efectos de la radiación , Humanos , Estrés Oxidativo/fisiología , Estrés Oxidativo/efectos de la radiación , Especies Reactivas de Oxígeno/metabolismo , Envejecimiento de la Piel/patología , Envejecimiento de la Piel/efectos de la radiaciónRESUMEN
The first total syntheses of the bioactive cyclodepsipeptides ohmyungsamycinâ A and B are described. Key features of our synthesis include the concise preparation of a linear cyclization precursor that consists of N-methyl amides and non-proteinogenic amino acids, and its macrolactamization from a bent conformation. The proposed structure of ohmyungsamycinâ B was revised based on its synthesis. The cyclic core of the ohmyungsamycins was shown to be responsible for the excellent antituberculosis activity, and ohmyungsamycin variants with truncated chains were evaluated for their biological activity.
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Péptidos Cíclicos/síntesis química , Modelos Moleculares , Conformación Molecular , Péptidos Cíclicos/químicaRESUMEN
A divergent synthetic methodology for a tabernaemontanine-related alkaloid was developed. The synthetic route features practical improvements in the Pictet-Spengler cyclization for the tetrahydro-ß-carboline intermediate and an unprecedented tandem Reformatsky-aza-Claisen rearrangement to create the core carbon skeleton and stereochemistries of tabernaemontanine-related alkaloids.
RESUMEN
Ginsenoside Re (Re), a major ginsenoside of ginseng, enhanced the cornified cell envelope (CE) formation in HaCaT keratinocytes under normal conditions. In HaCaT keratinocytes, Re was also able to upregulate filaggrin protein and caspase-14 activity in a concentration-dependent manner. These findings reasonably imply that Re possesses a desirable property of improving skin barrier function.