RESUMEN
Kinases, a class of enzymes controlling various substrates phosphorylation, are pivotal in both physiological and pathological processes. Although their conserved ATP binding pockets pose challenges for achieving selectivity, this feature offers opportunities for drug repositioning of kinase inhibitors (KIs). This study presents a cost-effective in silico prediction of KIs drug repositioning via analyzing cross-docking results. We established the KIs database (278 unique KIs, 1834 bioactivity data points) and kinases database (357 kinase structures categorized by the DFG motif) for carrying out cross-docking. Comparative analysis of the docking scores and reported experimental bioactivity revealed that the Atypical, TK, and TKL superfamilies are suitable for drug repositioning. Among these kinase superfamilies, Olverematinib, Lapatinib, and Abemaciclib displayed enzymatic activity in our focused AKT-PI3K-mTOR pathway with IC50 values of 3.3, 3.2 and 5.8â µM. Further cell assays showed IC50 values of 0.2, 1.2 and 0.6â µM in tumor cells. The consistent result between prediction and validation demonstrated that repositioning KIs via in silico method is feasible.
RESUMEN
Multiple myeloma (MM), a cancer of plasma cells, is the second most common hematological malignancy which is characterized by aberrant plasma cells infiltration in the bone marrow and complex heterogeneous cytogenetic abnormalities. Over the past two decades, novel treatment strategies such as proteasome inhibitors, immunomodulators, and monoclonal antibodies have significantly improved the relative survival rate of MM patients. However, the development of drug resistance results in the majority of MM patients suffering from relapse, limited treatment options and uncontrolled disease progression after relapse. There are urgent needs to develop and explore novel MM treatment strategies to overcome drug resistance and improve efficacy. Here, we review the recent small molecule therapeutic strategies for MM, and introduce potential new targets and corresponding modulators in detail. In addition, this paper also summarizes the progress of multi-target inhibitor therapy and protein degradation technology in the treatment of MM.
Asunto(s)
Antineoplásicos , Resistencia a Antineoplásicos , Mieloma Múltiple , Bibliotecas de Moléculas Pequeñas , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Humanos , Resistencia a Antineoplásicos/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Inhibidores de Proteasoma/farmacología , Inhibidores de Proteasoma/química , Inhibidores de Proteasoma/uso terapéutico , Estructura MolecularRESUMEN
Retinoic acid receptor-related orphan receptor γ (RORγ) acts as a crucial transcription factor in Th17 cells and is involved in diverse autoimmune disorders. RORγ allosteric inhibitors have gained significant research focus as a novel strategy to inhibit RORγ transcriptional activity. Leveraging the high affinity and selectivity of RORγ allosteric inhibitor MRL-871 (1), this study presents the design, synthesis, and characterization of 11 allosteric fluorescent probes. Utilizing the preferred probe 12h, we established an efficient and cost-effective fluorescence polarization-based affinity assay for screening RORγ allosteric binders. By employing virtual screening in conjunction with this assay, 10 novel RORγ allosteric inhibitors were identified. The initial SAR studies focusing on the hit compound G381-0087 are also presented. The encouraging outcomes indicate that probe 12h possesses the potential to function as a powerful tool in facilitating the exploration of RORγ allosteric inhibitors and furthering understanding of RORγ function.
Asunto(s)
Colorantes Fluorescentes , Células Th17 , Colorantes Fluorescentes/farmacología , Factores de Transcripción , Regulación de la Expresión Génica , Polarización de Fluorescencia , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismoRESUMEN
Over the past decades, the role of rearranged during transfection (RET) alterations in tumorigenesis has been firmly established. RET kinase inhibition is an essential therapeutic target in patients with RET-altered cancers. In clinical practice, initial efficacy can be achieved in patients through the utilization of multikinase inhibitors (MKIs) with RET inhibitory activity. However, the effectiveness of these MKIs is impeded by the adverse events associated with off-target effects. Recently, many RET-selective inhibitors, characterized by heightened specificity and potency, have been developed, representing a substantial breakthrough in the field of RET precision oncology. This Perspective focuses on the contemporary understanding of RET mutations, recent advancements in next-generation RET inhibitors, and the challenges associated with resistance to RET inhibitors. It provides valuable insights for the development of next-generation MKIs and selective RET inhibitors.
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Neoplasias Pulmonares , Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Proteínas Proto-Oncogénicas c-ret/genética , Medicina de Precisión , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Mutación , Neoplasias Pulmonares/tratamiento farmacológicoRESUMEN
Acute myeloid leukemia (AML) is the most common type of blood cancer and has been strongly correlated with the overexpression of Fms-like tyrosine kinase 3 (FLT3), a member of the class III receptor tyrosine kinase family. With the emergence of FLT3 internal tandem duplication alteration (ITD) and tyrosine kinase domain (TKD) mutations, the development of FLT3 small molecule inhibitors has become an effective medicinal chemistry strategy for AML. Herein, we have designed and synthesized two series of 1H-pyrrolo[2,3-b]pyridine derivatives CM1-CM24, as FLT3 inhibitors based on F14, which we previously reported, that can target the hydrophobic FLT3 back pocket. Among these derivates, CM5 showed significant inhibition of FLT3 and FLT3-ITD, with inhibitory percentages of 57.72 % and 53.77 % respectively at the concentration of 1 µΜ. Furthermore, CM5 demonstrated potent inhibition against FLT3-dependent human AML cell lines MOLM-13 and MV4-11 (both harboring FLT3-ITD mutant), with IC50 values of 0.75 µM and 0.64 µM respectively. In our cellular mechanistic studies, CM5 also effectively induces apoptosis by arresting cell cycle progression in the G0/G1 phase. In addition, the amide and urea linker function were discussed in detail based on computational simulations studies. CM5 will serve as a novel lead compound for further structural modification and development of FLT3 inhibitors specifically targeting AML with FLT3-ITD mutations.
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Leucemia Mieloide Aguda , Tirosina Quinasa 3 Similar a fms , Humanos , Apoptosis , Línea Celular Tumoral , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Piridinas/farmacologíaRESUMEN
The therapeutic benefits of available FLT3 inhibitors for AML are limited by drug resistance, which is related to mutations, as well toxicity caused by off-target effects. In this study, we introduce a new small molecule FLT3 inhibitor called danatinib, which was designed to overcome the limitations of currently approved agents. Danatinib demonstrated greater potency and selectivity, resulting in cytotoxic activity specific to FLT3-ITD and/or FLT3-TKD mutated models. It also showed a superior kinome inhibition profile compared to several currently approved FLT3 inhibitors. In diverse FLT3-TKD models, danatinib exhibited substantially improved activity at clinically relevant doses, outperforming approved FLT3 inhibitors. In vivo safety evaluations performed on the granulopoiesis of transgenic myeloperoxidase (MPO) zebrafish and mice models proved danatinib to have an acceptable safety profile. Danatinib holds promise as a new and improved FLT3 inhibitor for the treatment of AML, offering long-lasting remissions and improved overall survival rates.
Asunto(s)
Antineoplásicos , Leucemia Mieloide Aguda , Animales , Ratones , Pez Cebra , Resistencia a Antineoplásicos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , MutaciónRESUMEN
Virus infection has been one of the main causes of human death since the ancient times. Even though more and more antiviral drugs have been approved in clinic, long-term use can easily lead to the emergence of drug resistance and side effects. Fortunately, there are many kinds of metabolites which were produced by plants, marine organisms and microorganisms in nature with rich structural skeletons, and they are natural treasure house for people to find antiviral active substances. Aiming at many types of viruses that had caused serious harm to human health in recent years, this review summarizes the natural products with antiviral activity that had been reported for the first time in the past ten years, we also sort out the source, chemical structure and safety indicators in order to provide potential lead compounds for the research and development of new antiviral drugs.
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Productos Biológicos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Antivirales/farmacología , Productos Biológicos/farmacología , Movimiento CelularRESUMEN
Glioma is one of the most common types of brain tumors, and its high recurrence and mortality rates threaten human health. In 2008, the frequent isocitrate dehydrogenase 1 (IDH1) mutations in glioma were reported, which brought a new strategy in the treatment of this challenging disease. In this perspective, we first discuss the possible gliomagenesis after IDH1 mutations (mIDH1). Subsequently, we systematically investigate the reported mIDH1 inhibitors and present a comparative analysis of the ligand-binding pocket in mIDH1. Additionally, we also discuss the binding features and physicochemical properties of different mIDH1 inhibitors to facilitate the future development of mIDH1 inhibitors. Finally, we discuss the possible selectivity features of mIDH1 inhibitors against WT-IDH1 and IDH2 by combining protein-based and ligand-based information. We hope that this perspective can inspire the development of mIDH1 inhibitors and bring potent mIDH1 inhibitors for the treatment of glioma.
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Neoplasias Encefálicas , Glioma , Humanos , Isocitratos , Ligandos , Isocitrato Deshidrogenasa/metabolismo , Glioma/tratamiento farmacológico , Glioma/metabolismo , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , MutaciónRESUMEN
Aim: The clinical benefits of FLT3 inhibitors against acute myeloid leukemia (AML) have been limited by selectivity and resistance mutations. Thus, to identify FLT3 inhibitors possessing high selectivity and potency is of necessity. Methods & results: The authors used computational methods to systematically compare pocket similarity with 269 kinases. Subsequently, based on these investigations and beginning with in-house compound 10, they synthesized a series of 6-methyl-isoxazol[3,4-b]pyridine-3-amino derivatives and identified that compound 45 (IC50: 103 nM) displayed gratifying potency in human AML cell lines with FLT3-internal tandem duplications mutation as well as FLT3-internal tandem duplications-tyrosine kinase domain-transformed BaF3 cells. Conclusion: The integrated biological activity results indicated that compound 45 deserves further development for therapeutic remedies for AML.
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Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Inhibidores de Proteínas Quinasas , Mutación , Línea Celular , Apoptosis , Tirosina Quinasa 3 Similar a fms/genética , Línea Celular TumoralRESUMEN
Small molecule covalent drugs have proved to be desirable therapies especially on drug resistance related to point mutations. Secondary mutations of FLT3 have become the main mechanism of FLT3 inhibitors resistance which further causes the failure of treatment. Herein, a series of 4-(4-aminophenyl)-6-phenylisoxazolo[3,4-b]pyridine-3-amine covalent derivatives were synthesized and optimized to overcome the common secondary resistance mutations of FLT3. Among these derivatives, compound F15 displayed potent inhibition activities against FLT3 (IC50 = 123 nM) and FLT3-internal tandem duplication (ITD) by 80% and 26.06%, respectively, at the concentration of 1 µM. Besides, F15 exhibited potent activity against FLT3-dependent human acute myeloid leukemia (AML) cell lines MOLM-13 (IC50 = 253 nM) and MV4-11 (IC50 = 91 nM), as well as BaF3 cells with variety of secondary mutations. Furthermore, cellular mechanism assays indicated that F15 inhibited phosphorylation of FLT3 and its downstream signaling factors. Notably, F15 could be considered for further development as potential drug candidate to treat AML.
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Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/farmacología , Aminas/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/farmacología , Tirosina Quinasa 3 Similar a fms/uso terapéutico , Apoptosis , Proliferación CelularRESUMEN
Fms-like tyrosine kinase 3 (FLT3) mutation has been strongly associated with increased risk of relapse, and the irreversible covalent FLT3 inhibitors had the potential to overcome the drug-resistance. In this study, a series of simplified 4-(4-aminophenyl)-6-methylisoxazolo[3,4-b] pyridin-3-amine derivatives containing two types of Michael acceptors (vinyl sulfonamide, acrylamide) were conveniently synthesized to target FLT3 and its internal tandem duplications (ITD) mutants irreversibly. The kinase inhibitory activities showed that compound C14 displayed potent inhibition activities against FLT3 (IC50 = 256 nM) and FLT3-ITD by 73 % and 25.34 % respectively, at the concentration of 1 µM. The antitumor activities indicated that C14 had strong inhibitory activity against the human acute myeloid leukemia (AML) cell lines MOLM-13 (IC50 = 507 nM) harboring FLT3-ITD mutant, as well as MV4-11 (IC50 = 325 nM) bearing FLT3-ITD mutation. The biochemical analyses showed that these effects were related to the ability of C14 to inhibit FLT3 signal pathways, and C14 could induce apoptosis in MV4-11 cell as demonstrated by flow cytometry. Fortunately, C14 showed very weak potency against FLT3-independent human cervical cancer cell line HL-60 (IC50 > 10 µM), indicating that it might have no off-target toxic effects. In light of these data, compound C14 represents a novel covalent FLT3 kinase inhibitor for targeted therapy of AML.
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Antineoplásicos , Leucemia Mieloide Aguda , Aminas/farmacología , Antineoplásicos/química , Apoptosis , Línea Celular Tumoral , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Mutación , Inhibidores de Proteínas Quinasas/química , Tirosina Quinasa 3 Similar a fmsRESUMEN
OBJECTIVES: To explore the inter- and intra-observer reliability of Sonography-based Volume Computer Aided Diagnosis (SonoVCAD) in the display of 8 diagnostic planes of fetal echocardiography and to evaluate its efficiency. METHODS: Three-dimensional volume data sets of the 56 normal singleton fetuses were acquired from a 4-chamber view by using a volume probe. After processing the data sets by using SonoVCAD, 8 cardiac diagnostic planes were displayed automatically. Three doctors with different experiences of performing fetal echocardiography evaluated each diagnostic plane and the success rates of 8 diagnostic planes were calculated. Inter-observer and intra-observer reliabilities were estimated by Cohen's kappa statistics. RESULTS: A total of 276 volume data sets acquired from the 56 normal fetuses were used for SonoVCAD analysis and display. The success rate of each diagnostic section was more than 90%, ranging from 90.6% to 99.6%. Among 276 volumes, 81.5% (225/276) of volumes were able to generate all 8 diagnostic views successfully. Moderate to substantial agreement (kappa, 0.509-0.794) was found between 2 less experienced operators. Moderate to near-perfect agreement (kappa, 0.439-0.933) was found between an expert and 2 less experienced sonographers. Intra-observer reliability was substantial to near-perfect (kappa, 0.602-0.903). The efficiency of SonoVCAD was assessed. The expert spent less time than 2 less experienced examiners (P < 0.001) but no significant difference was found between 2 less experienced examiners (P = 0.176). Besides, SonoVCAD consumed significantly less time than 2-dimensional ultrasound (P < 0.001). CONCLUSIONS: SonoVCAD can significantly improve the success rates of 8 diagnostic planes in fetal echocardiography with low operator dependency, good reproducibility and high efficiency.
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Cardiopatías Congénitas , Ultrasonografía Prenatal , Computadores , Ecocardiografía Tetradimensional , Femenino , Corazón Fetal/diagnóstico por imagen , Cardiopatías Congénitas/diagnóstico por imagen , Humanos , Embarazo , Reproducibilidad de los Resultados , UltrasonografíaRESUMEN
A serial of naphthalenebenzimidizole-Pt complexes 1-6 were designed and synthesized as antitumor agents. In vitro antitumor assay results showed that complexes 1-6 exhibited moderate to high antiproliferative activity against Hela, HepG2, SKOV-3, NCI-H460, BEL-7404 and A549 cancer cell lines, while they displayed obvious sensitivity and selectivity against SMMC-7721 and U251 cell lines and low toxicity against normal HL-7702 cells, in comparison with cisplatin. In vivo antitumor assay results indicated that complex 1 and 5 exhibited important in vivo antiproliferative activity in the NCI-460 and SMMC-7721 models, in comparison with cisplatin, respectively. Complexes 1 and 5 exhibited better antiproliferative activity against A549CDDP and SKOV3CDDP cell lines than cisplatin, with IC50 values of 6.98 ± 0.47 µM, 5.62 ± 0.88 µM and 13.13 ± 2.11 µM, 5.30 ± 0.33 µM, respectively, while they displayed potential antiproliferation against A549 and SKOV3 cell lines, with IC50 values of 7.32 ± 0.51 µM, 5.19 ± 0.49 µM and 14.92 ± 0.11 µM, 12.19 ± 0.92 µM, indicating the introduction of naphthalenebenzimidizole into platinum-metal system may overcome the resistance. Mechanistic studies showed that the representative complexes 1 and 5 exerted the antitumor effect mainly by the obvious covalent binding with DNA and the upregulation of the expression level of intracellular topo I, showing different action mechanism from cisplatin.
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Antineoplásicos/farmacología , Bencimidazoles/farmacología , Diseño de Fármacos , Naftalenos/farmacología , Compuestos Organoplatinos/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Bencimidazoles/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Ratones , Ratones Desnudos , Estructura Molecular , Naftalenos/química , Neoplasias Experimentales , Compuestos Organoplatinos/síntesis química , Compuestos Organoplatinos/química , Relación Estructura-ActividadRESUMEN
Three new oxoaporphine Co(II), Ni(II) and Zn(II) complexes 1-3 have been synthesized and fully characterized. 1-3 have similar mononuclear structures with the metal and ligand ratio of 1:2. 1-3 exhibited higher cytotoxicity than the OD ligand and cisplatin against HepG2, T-24, BEL-7404, MGC80-3 and SK-OV-3/DDP cells, with IC50 value of 0.23-4.31 µM. Interestingly, 0.5 µM 1-3 significantly caused HepG2 arrest at S-phase, which was associated with the up-regulation of p53, p21, p27, Chk1 and Chk2 proteins, and decrease in cyclin A, CDK2, Cdc25A, PCNA proteins. In addition, 1-3 induced HepG2 apoptosis via a caspase-dependent mitochondrion pathway as evidenced by p53 activation, ROS production, Bax up-regulation and Bcl-2 down-regulation, mitochondrial dysfunction, cytochrome c release, caspase activation and PARP cleavage. Furthermore, 3 inhibited tumor growth in HepG2 xenograft model, and displayed more safety profile in vivo than cisplatin.
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Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Aporfinas/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Complejos de Coordinación/farmacología , Metales/farmacología , Mitocondrias/metabolismo , Fase S/efectos de los fármacos , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Aporfinas/síntesis química , Aporfinas/química , Calcio/metabolismo , Caspasas/metabolismo , Forma de la Célula/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Citocromos c/metabolismo , Daño del ADN , ADN-Topoisomerasas de Tipo II/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Células Hep G2 , Humanos , Ligandos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Mitocondrias/efectos de los fármacos , Modelos Biológicos , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Carga Tumoral/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A series of novel 2-oxo-quinoline derivatives containing α-aminophosphonates were designed and synthesized as antitumor agents. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay results demonstrated that some compounds exhibited moderate to high inhibitory activity against HepG2, SK-OV-3 and NCI-H460 tumor cell lines, and most compounds showed much lower cytotoxicity against HL-7702 normal cells than 5-FU and cisplatin. The action mechanism of representative compound 5b was investigated by fluorescence staining assay, flow cytometric analysis and western blot (WB) assay, which indicated that this compound induced apoptosis and G2/M phase arrest accompanied by an increase in the production of intracellular Ca2+ and reactive oxygen species (ROS) and affecting associated enzymes and genes.
RESUMEN
[Pd(L)(DMSO)Cl2] (1) and [Pt(L)(DMSO)Cl2] (2) with 9-amino-oxoisoaporphine (L), were synthesized and characterized. 1 and 2 are more selectively cytotoxic to Hep-G2 cells versus normal liver cells (HL-7702). Various experiments showed that 2 acted as telomerase inhibitors targeting G4-DNA and triggered cell apoptosis by interacting with c-myc G4-DNA. Furthermore, 2 significantly induced cell cycle arrest at both G2/M and S phase, which leading to the down-regulation of cdc25 A, cyclin D, cyclin B, cyclin A and CDK2 and the up-regulation of p53, p27, p21,chk1 and chk2. In addition, 2 also caused mitochondrial dysfunction. Taken together, we found that 2 exerted its cytotoxic activity mainly via inhibiting telomerase by interaction with c-myc G4-DNA and disruption of mitochondrial function.
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Apoptosis/efectos de los fármacos , ADN/química , G-Cuádruplex/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Compuestos Organometálicos/farmacología , Proteínas Proto-Oncogénicas c-myc/genética , Telomerasa/antagonistas & inhibidores , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Aporfinas/química , Transporte Biológico , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , ADN/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/patología , Compuestos Organometálicos/química , Compuestos Organometálicos/metabolismo , Platino (Metal)/química , Especies Reactivas de Oxígeno/metabolismo , Solubilidad , Relación Estructura-Actividad , Transcripción Genética/efectos de los fármacosRESUMEN
OBJECTIVE: To investigate the role of interleukin-17A (IL-17A) and Th17 cell in the pathogenesis of systemic lupus erythematosus (SLE), we studied the plasma IL-17A and the expression of Th17 cell transcription factor RORgammat in Chinese new-onset SLE patients. METHODS: Sixty SLE patients aged between 18 and 40 years and 56 age-matched healthy volunteers were involved in the study. Enzyme-linked immunosorbent assay was used to measure plasma IL-17A level, and rea1-time fluorescent quantitative polymerase chain reaction was used to measure RORgammat mRNA. RESULTS: The results showed that both IL-17A level and RORgammat mRNA in SLE patients were higher than that of controls. Correlation analysis indicated that plasma IL-17A level was positively correlated with Systemic Lupus Erythematosus Disease Activity Index, not with RORgammat mRNA. CONCLUSION: We concluded that IL-17A might play a role in the pathogenesis of SLE and associated with disease activity. RORgammat-determined Th17 cell might be involved with increased IL-17A in SLE but not exclusively the unique source.