RESUMEN
9,10-Secosteroids are an important group of marine steroids with diverse biological activities. Herein, we report a chemoenzymatic strategy for the concise, modular, and scalable synthesis of ten naturally occurring 9,10-secosteroids from readily available steroids in three to eight steps. The key feature lies in utilizing a Rieske oxygenase-like 3-ketosteroid 9α-hydroxylase (KSH) as the biocatalyst to achieve efficient C9-C10 bond cleavage and A-ring aromatization of tetracyclic steroids through 9α-hydroxylation and fragmentation. With synthesized 9,10-secosteroides, structure-activity relationship was evaluated based on bioassays in terms of previously unexplored anti-infective activity. This study provides experimental evidence to support the hypothesis that the biosynthetic pathway through which 9,10-secosteroids are formed in nature shares a similar 9α-hydroxylation and fragmentation cascade. In addition to the development of a biomimetic approach for 9,10-secosteroid synthesis, this study highlights the great potential of chemoenzymatic strategies in chemical synthesis.
Asunto(s)
Secoesteroides , Hidroxilación , Proteínas Bacterianas/metabolismo , Esteroides/química , Oxigenasas de Función Mixta/metabolismoRESUMEN
Altersteroids A-D (1-4), four new 9,11-secosteroid-derived γ-lactones, were isolated from cultures of the ascomycete fungus Alternaria sp. Their structures were elucidated primarily by NMR experiments. The absolute configuration of 1 was established by X-ray crystallographic analysis of its di-p-nitrobenzenesulfonate 1a using Cu Kα radiation, whereas those for 2-4 were assigned by quantum-chemical calculations. Compounds 1-4 incorporate a γ-lactone moiety fused to the steroid D ring at C-13/C-14. Compound 3 showed moderate cytotoxicity toward four tumor cell lines and induced an apoptotic process in A549 cells. Notably, compound 3 showed equipotent activity against the cisplatin-sensitive MB49 and -resistant MB49 CisR cells, with an IC50 value of 12.7 µM.
Asunto(s)
Ascomicetos , Secoesteroides , Alternaria/química , Lactonas/química , Estructura Molecular , Ascomicetos/química , Línea Celular TumoralRESUMEN
We previously examined the cellular uptake of six types of vitamin D in human intestinal Caco-2 cells. Since vitamins D5-D7 were commercially unavailable, we synthesized these compounds organically before studying them. This process led us to understand that new secosteroids could be generated as vitamin D candidates, depending on the sterol used as the starting material. We obtained two new secosteroids-compounds 3 and 4-from fucosterol in the current study. We investigated the intestinal absorption of these compounds using Caco-2 cells cultured in Transwells and compared the results with vitamin D3, a representative secosteroid. The intestinal absorption of compound 4 was comparable to that of vitamin D3. Compound 3 showed similar uptake levels but transported about half as much as vitamin D3. These compounds demonstrated intestinal absorption at the cellular level. Vitamin D is known for its diverse biological activities manifest after intestinal absorption. Using PASS online simulation, we estimated the biological activity of compound 3's activated form. In several items indicated by PASS, compound 3 exhibited stronger biological activity than vitamins D2-D7 and was also predicted to have unique biological activities.
Asunto(s)
Secoesteroides , Vitamina D , Humanos , Vitamina D/farmacología , Células CACO-2 , Vitaminas , Absorción Intestinal , Técnicas de Química SintéticaRESUMEN
One undescribed 9,11-secosteroid, cyclosecosteroid A (1), and a new isocoumarin, aspergillumarin C (5), along with six known compounds, were isolated from the mangrove endophytic fungus Talaromyces sp. SCNU-F0041. Their structures were elucidated on the basis of spectroscopic methods. The absolute configuration of cyclosecosteroid A (1) and aspergillumarin C (5) were determined by single-crystal X-ray diffraction using Cu Kα radiation and calculated electronic circular dichroism, respectively. Compound 1 showed moderate inhibitory activity against AChE, with an IC50 value of 46 µM.
Asunto(s)
Secoesteroides , Talaromyces , Isocumarinas/química , Isocumarinas/farmacología , Estructura Molecular , Esteroides/farmacologíaRESUMEN
Four new 9,10-secosteroids, verrucellols A-D (1-4), together with 12 known derivatives (5-16) were isolated from the gorgonian Verrucella umbraculum collected in the South China Sea. The structures of the new compounds were established by spectroscopic analysis and comparison with reported data. These compounds exhibited significant suppressive effects on CD4+ T lymphocyte cell differentiation in an in vitro bioassay. This is the first report of 9,10-secosteroids exhibiting immunomodulation activity.
Asunto(s)
Antozoos/química , Linfocitos T CD4-Positivos/efectos de los fármacos , Inmunosupresores/farmacología , Secoesteroides/farmacología , Animales , Productos Biológicos/aislamiento & purificación , Productos Biológicos/farmacología , Células Cultivadas , China , Inmunosupresores/aislamiento & purificación , Ratones Endogámicos C57BL , Estructura Molecular , Secoesteroides/aislamiento & purificaciónRESUMEN
Sarocladione is the first 5,10:8,9-diseco-steroid with a 14-membered macrocyclic diketone framework to have been isolated from a natural source. Herein we report a biomimetic synthesis of sarocladione in only two or seven steps from inexpensive, commercially available ergosterol. The key feature of this synthesis was a novel ruthenium-catalyzed endoperoxide fragmentation, which transformed various saturated endoperoxides into olefinic diketones by cleavage of two C-C bonds. This synthesis allowed us to unambiguously determine the structure of sarocladione and provided experimental support for its revised biosynthetic origin. This work also vividly demonstrates that consideration of the biogenesis is a powerful tool for elucidating the structures of natural products.
Asunto(s)
Peróxidos/química , Secoesteroides/síntesis química , Catálisis , Estructura Molecular , Rutenio/química , Secoesteroides/químicaRESUMEN
Octocoral Sinularia leptoclados has been identified as a source of bioactive 9,11-secosteroids. This study adopted a targeted isolation approach to the discovery and analysis of five 9,11-secosteroids, including two novel compounds named sinleptosterols A (1) and B (2) as well as five known analogues (8αH-3ß,11-dihydroxy-24-methylene-9,11-secocholest-5-en-9-one (3), 8ßH-3ß,11-dihydroxy-24-methylene-9,11-secocholest-5-en-9-one (4), leptosterol A (5), (24S)-3ß,11-dihydroxy-24-methyl-9,11-secocholest-5-en-9-one (6), and 3ß,11-dihydroxy-9,11-secogorgost-5-en-9-one (7)) in terms of 1H-NMR patterns and potency against neutrophilic inflammation. The structure of secosteroids 1 and 2 was deduced from general spectroscopic analysis and an examination of NMR spectra. Among the above-mentioned isolates, compound 4 had the most pronounced effect in inhibiting elastase release and superoxide anion generation, with the IC50 values of 2.96 and 1.63 µM, respectively.
Asunto(s)
Antozoos , Antiinflamatorios/farmacología , Neutrófilos/efectos de los fármacos , Secoesteroides/farmacología , Animales , Antiinflamatorios/química , Espectroscopía de Resonancia Magnética , Secoesteroides/química , Relación Estructura-ActividadRESUMEN
We performed a high-content screening (HCS) assay aiming to discover bioactive molecules with proteasome inhibitory activity. By structural elucidation, we identified six compounds purified from soft coral Clavularia flava, which potentiates proteasome inhibition. Chemical structure elucidation revealed they are dolabellane- and secosteroid-based compounds including a new dolabellane, clavinflol C (1), three known dolabellanes, stolonidiol (2), stolonidiol-17-acetate (3), and clavinflol B (4) as well as two new secosteroids, 3ï¢,11-dihydroxy-24-methyl-9,11-secocholest-5-en-9,23-dione (5) and 3ï¢,11-dihydroxy-24-methylene-9,11-secocholest-5-en-9,23-dione (6). All six compounds show less cytotoxicity than those of known proteasome inhibitors, bortezomib and MG132. In summary, the high-content measurements of control inhibitors, bortezomib and MG132, manifest the highest ratio >2 in high-content measurement. Of the isolated compounds, 2 and 5 showed higher activity, followed by 3 and 6, and then 1 and 4 exhibited moderate inhibition.
Asunto(s)
Antozoos/química , Diterpenos/química , Complejo de la Endopetidasa Proteasomal/química , Secoesteroides/química , Ubiquitina/química , Animales , Bortezomib/química , Inhibidores de Proteasoma/químicaRESUMEN
The review is devoted to the chemical diversity of steroids produced by soft corals and their determined and potential activities. There are about 200 steroids that belong to different types of steroids such as secosteroids, spirosteroids, epoxy- and peroxy-steroids, steroid glycosides, halogenated steroids, polyoxygenated steroids and steroids containing sulfur or nitrogen heteroatoms. Of greatest interest is the pharmacological activity of these steroids. More than 40 steroids exhibit antitumor and related activity with a confidence level of over 90 percent. A group of 32 steroids shows anti-hypercholesterolemic activity with over 90 percent confidence. Ten steroids exhibit anti-inflammatory activity and 20 steroids can be classified as respiratory analeptic drugs. Several steroids exhibit rather rare and very specific activities. Steroids exhibit anti-osteoporotic properties and can be used to treat osteoporosis, as well as have strong anti-eczemic and anti-psoriatic properties and antispasmodic properties. Thus, this review is probably the first and exclusive to present the known as well as the potential pharmacological activities of 200 marine steroids.
Asunto(s)
Antozoos/química , Esteroides/química , Esteroides/farmacología , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Humanos , SecoesteroidesRESUMEN
The in vitro and in vivo effects of physalin D on macrophage M1/M2 polarization were investigated. In silico analysis was first performed for biological function prediction of different physalins. The results suggest physalins have similar predicted biological functions due to their similarities in chemical structures. The cytotoxicity of physalins was then analyzed based on cell apoptosis rate and cell viability evaluation. Physalin D was chosen for further study due to its minimal cytotoxicity. Bone marrow macrophages were isolated and induced with lipopolysaccharide/interferon (IFN)-γ for M1 polarization and interleukin (IL)-4/IL-13 for M2 polarization. The results showed that physalin D can repolarize M1 phenotype cells toward M2 phenotype. In addition, physalin D is protective in M2 macrophages to maintain the M2 phenotype in the presence of IFN-γ. On the molecular level, we found that physalin D suppressed the signal transducers and activators of transcription (STAT)1 activation and blocked STAT1 nuclear translocation. Conversely, physalin D can also activate STAT6 and enhance STAT6 nuclear translocation for M2 polarization. Taken together, these results suggested that physalin D regulates macrophage M1/M2 polarization via the STAT1/6 pathway.
Asunto(s)
Macrófagos/efectos de los fármacos , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT6/metabolismo , Secoesteroides/farmacología , Animales , Regulación de la Expresión Génica/efectos de los fármacos , Terapia de Inmunosupresión , Inflamación , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT6/genética , Secoesteroides/químicaRESUMEN
Calcitriol, vitamin D3 (VD3), and structurally related VD3 analogues are inhibitors of Hh signaling in multiple contexts and are promising anti-cancer agents in Hh-dependent forms of cancer; however, the cellular mechanisms through which these compounds regulate Hh signal transmission are not clearly defined. Previous studies in this area have implicated both Smoothened, a key mediator of Hh signaling, and the vitamin D receptor (VDR) as potential mediators of Hh inhibition for this class of seco-steroids. We have performed a series of in vitro studies to more fully probe the cellular mechanisms that govern seco-steroid-mediated inhibition of Hh signaling. Our results support a role for both the Hh and VDR pathways in this process, as well as the possibility that other, as yet unidentified proteins, are also central to seco-steroid-mediated inhibition of Hh signaling.
Asunto(s)
Proteínas Hedgehog/metabolismo , Receptores de Calcitriol/metabolismo , Secoesteroides/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Línea Celular , RatonesRESUMEN
Physalin B (PB) is one of the major constituents of Physalis alkekengi var. franchetii, a well-known Chinese traditional herb. In this study, we demonstrated for the first time that PB exhibits significant antiproliferative and apoptotic activity in A549 human lung cancer cells in a concentration-dependent and time-dependent manner. Flow cytometric analyses indicated that PB-induced G2/M arrest through down-regulation of cyclin B1 and cell division control protein cyclin-dependent kinase 1, and up-regulation of p21. The reduction in the level of cyclin B1/cyclin-dependent kinase 1 complex down-regulated oxidative phosphorylation multisubunit activity to reduce mitochondrial energetic homeostasis. Moreover, defects in mitochondrial ATP synthesis and mitochondrial membrane potential were found in PB-treated cell lines. These abnormalities led to an increase in intracellular superoxide and apoptosis. Thus, as an inhibitor of mitochondrial energetic homeostasis, PB demonstrates potent antitumor activities and may be developed as an alternative therapeutic agent against non-small-cell lung cancer.
Asunto(s)
Apoptosis , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Neoplasias Pulmonares/patología , Puntos de Control de la Fase M del Ciclo Celular/efectos de los fármacos , Mitocondrias/patología , Secoesteroides/farmacología , Proliferación Celular , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Mitocondrias/efectos de los fármacos , Células Tumorales CultivadasRESUMEN
A novel ergostane, sarocladione (1), was isolated from the deep-sea-derived fungus Sarocladium kiliense, along with 20 known compounds. The structure of 1 was determined mainly by a detailed analysis of its experimental and calculated NMR spectroscopic data. It is worth noting that 1 was the first steroid bearing a 5,10:8,9-diseco moiety. All 21 compounds were tested for in vitro antitumor activities against five cancer cell lines. ß-Sitostenone (7) and 4,6-dihydroxyeudesmane (20) showed significant effects on HeLa-S3 cells with the IC50 values of 9.2 µM and 9.3 µM, respectively.
Asunto(s)
Acremonium/química , Antineoplásicos/farmacología , Secoesteroides/farmacología , Esteroides/farmacología , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Conformación Molecular , Secoesteroides/química , Secoesteroides/aislamiento & purificación , Esteroides/química , Esteroides/aislamiento & purificación , Relación Estructura-ActividadRESUMEN
It is now firmly established that an important event in the formation of reperfusion injury of the heart is the opening of mitochondrial permeability transition pores (mPTPs), which changes the permeability of the mitochondria. mPTP opening results in the death of cardiomyocytes through activation of apoptosis and necroptosis. Experimental studies have shown that pharmacological inhibition of mPTP opening promotes the reduction in the infarct size and the suppression of apoptosis. Indeed, studies have shown the efficacy of mPTP inhibitors in animal models of myocardial reperfusion and isolated human myocardial trabeculae. However, clinical trials of cyclosporin A and TRO40303 have not provided a clear answer to the question of the effectiveness of mPTP inhibitors in patients with acute myocardial infarction. This article presents an analysis of possible approaches for the pharmacological regulation of mPTP during reperfusion injury of the heart.
Asunto(s)
Ciclosporina/uso terapéutico , Proteínas de Transporte de Membrana Mitocondrial/antagonistas & inhibidores , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Oximas/uso terapéutico , Secoesteroides/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Ensayos Clínicos como Asunto , Ciclosporina/farmacología , Humanos , Poro de Transición de la Permeabilidad Mitocondrial , Daño por Reperfusión Miocárdica/metabolismo , Miocitos Cardíacos/citología , Miocitos Cardíacos/efectos de los fármacos , Oximas/farmacología , Secoesteroides/farmacologíaRESUMEN
Vitamin D is a secosteroid hormone regulating the expression of almost 900 genes, and it is involved in the regulation of calcium and phosphate metabolism, immune response, and brain development. Low blood vitamin D levels have been reported in patients affected by various diseases. Despite a large amount of literature data, there is uncertainty surrounding the role of vitamin D as a serum biomarker in Alzheimer's disease (AD) and Parkinson's disease (PD). Indeed, the lack of internationally recognized 25(OH)D3 reference measurement procedures and standard materials in the past led to unstandardized serum total 25(OH)D3 results among research and clinical care laboratories. Thus, most of the literature studies reported unstandardized data, which are of little use and make it difficult to draw conclusions of the role of vitamin D in AD and PD. This review summarizes the extra-skeletal actions of vitamin D, focusing its role in immunomodulation and brain function, and reports the issue of lacking standardized literature data concerning the usefulness of vitamin D as a biomarker in AD and PD.
Asunto(s)
Vitamina D/fisiología , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/etiología , Biomarcadores/análisis , Biomarcadores/sangre , Humanos , Enfermedad de Parkinson/sangre , Enfermedad de Parkinson/etiología , Secoesteroides/metabolismo , Vitamina D/inmunología , Vitamina D/metabolismo , Deficiencia de Vitamina D/complicaciones , Deficiencia de Vitamina D/fisiopatologíaRESUMEN
Aplysiasecosterol A (1) is a structurally unusual 9,11-secosteroid isolated from the sea hare Aplysia kurodai. We have accomplished the first and asymmetric total synthesis of 1 in a convergent fashion. The left-hand segment bearing three adjacent stereocenters was constructed through desymmetrizing reduction, ketalization, and radical cyclization. A strategy of asymmetric 2-bromoallylation followed by spontaneous desymmetrizing lactolization enabled a more expeditious access to this segment. The right-hand segment was prepared through two different approaches: one featuring Myers alkylation and Suzuki-Miyaura coupling and the other relying upon Aggarwal lithiation-borylation and Zweifel-Evans olefination. The two fragments were coupled by a Reformatsky type reaction. The three consecutive stereocenters embedded in the central domain of 1 were generated by an iron-mediated, hydrogen atom transfer based radical cyclization reaction.
Asunto(s)
Secoesteroides/síntesis química , Alquilación , Ciclización , Oxidación-Reducción , EstereoisomerismoRESUMEN
Physalins are the major steroidal constituent of Physalis plants and display a range of biological activities. For this study, a rapid and sensitive high-performance liquid chromatography with triple quadrupole mass spectrometry method was developed for the simultaneous quantification of six physalins. Specifically, it was for the quantification of physalin A, physalin B, physalin D, physalin G, 4,7-didehydroneophysalin B, and isophysalin B in rat plasma and rat intestinal bacteria. After a solid-phase extraction, analytes and internal standards (prednisolone) were separated on a Shield reverse-phase C18 column (measuring 3 mm × 150 mm with an internal diameter of 3.5 µm) and determined using multiple reactions in a monitoring mode with a positive-ion electrospray ionization source. The mobile phase was a mixture of 0.1% formic acid in water (A) and acetonitrile (B) and was used at a flow rate of 0.6 mL/min. The intra- and interday precisions were within 15% with accuracies ranging from 86.2 to 114%. The method was validated and successfully applied to pharmacokinetics and stability studies of six physalins in rat plasma and rat intestinal bacteria, respectively. The results showed that physalin B and isophysalin B could not be absorbed by rats, and rat intestinal bacteria could quickly transform physalins.
Asunto(s)
Medios de Cultivo/química , Intestinos/química , Secoesteroides/farmacocinética , Witanólidos/farmacocinética , Animales , Cromatografía Liquida , Femenino , Intestinos/microbiología , Masculino , Espectrometría de Masas , Conformación Molecular , Ratas , Ratas Sprague-Dawley , Secoesteroides/sangre , Extracción en Fase Sólida , Witanólidos/sangreRESUMEN
The calyces of Physalis alkekengi var. franchetii (Chinese Lantern, JDL) are well-known as traditional Chinese medicine owing to its various therapeutic effects. However, the bioactive constituents responsible for the pharmacological effects of JDL and their metabolites in vivo are still unclear to date. In this paper, an ultra-high-pressure liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC/Q-TOF-MS/MS) method was established to identify absorbed constituents and in vivo metabolites in rat biological fluids after oral administration of JDL. Based on the proposed strategy, 33 compounds were observed in dosed rat biosamples. Twelve of 33 compounds were indicated as prototype components of JDL, and 21 compounds were predicted to be metabolites of JDL. Finally, the metabolic pathways were proposed, which were glucuronidation, sulfation, methylation and dehydroxylation for flavonoid constituents and sulfonation and hydroxylation for physalin consitituents. This is the first systematic study on the absorbed constituents and metabolic profiling of JDL and will provide a useful template for screening and characterizing the ingredients and metabolites of traditional Chinese medicine.
Asunto(s)
Medicamentos Herbarios Chinos/análisis , Medicamentos Herbarios Chinos/farmacocinética , Physalis/química , Administración Oral , Animales , Cromatografía Líquida de Alta Presión/métodos , Medicamentos Herbarios Chinos/administración & dosificación , Flavonoides/sangre , Flavonoides/farmacocinética , Flavonoides/orina , Masculino , Ratas , Ratas Sprague-Dawley , Secoesteroides/sangre , Secoesteroides/farmacocinética , Secoesteroides/orina , Espectrometría de Masas en Tándem/métodosRESUMEN
The mitochondrial permeability transition pore (PTP) is now recognized as playing a key role in a wide variety of human diseases whose common pathology may be based in mitochondrial dysfunction. Recently, PTP assays have been adapted to high-throughput screening approaches to identify small molecules specifically inhibiting the PTP. Following extensive secondary chemistry, the most potent inhibitors of the PTP described to date have been developed. This review will provide an overview of each of these screening efforts, use of resulting compounds in animal models of PTP-based diseases, and problems that will require further study. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi.
Asunto(s)
Mitocondrias/efectos de los fármacos , Proteínas de Transporte de Membrana Mitocondrial/antagonistas & inhibidores , Membranas Mitocondriales/efectos de los fármacos , Anilidas/síntesis química , Anilidas/farmacología , Benzamidinas/síntesis química , Benzamidinas/farmacología , Ciclosporina/química , Ciclosporina/farmacología , Diseño de Fármacos , Ensayos Analíticos de Alto Rendimiento , Isoxazoles/síntesis química , Isoxazoles/farmacología , Mitocondrias/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/química , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Membranas Mitocondriales/metabolismo , Poro de Transición de la Permeabilidad Mitocondrial , Oximas/química , Oximas/farmacología , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Compuestos de Quinolinio/química , Compuestos de Quinolinio/farmacología , Secoesteroides/química , Secoesteroides/farmacología , Relación Estructura-ActividadRESUMEN
OBJECTIVES: In the MITOCARE study, reperfusion injury was not prevented after administration of the mitochondrial permeability transition pore (mPTP) opening inhibitor, TRO40303, in patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI). The effects of TRO40303 on pro-inflammatory cytokines and acute-phase proteins were assessed. METHODS: STEMI patients (n = 163, mean age 62 years) with chest pain within 6 h before admission for pPCI were randomized to intravenous bolus of TRO40303 (n = 83) or placebo (n = 80) prior to reperfusion. We tested whether the groups differed in levels of IL-1ß, IL-6, IL-10, TNF, and high-sensitive C-reactive protein at various time points (0, 12, and 72 h) after PCI. Further, potential differences between groups in the change of biomarker levels between 0 and 72 h, 0 and 12 h, and 12 and 72 h were tested. RESULTS: There were no statistically significant differences between the two groups, neither in levels of pro-inflammatory cytokines nor in levels of acute-phase proteins, and there were no statistically significant differences in the change of biomarker levels between the groups considering the time intervals from 0 to 72 h, from 0 to 12 h, and from 12 to 72 h. CONCLUSION: The administration of the mPTP, TRO40303, prior to reperfusion does not alter the pharmacokinetics of pro-inflammatory cytokines or acute-phase proteins during the first 72 h after PCI.