RESUMEN
Kaempferia parviflora (Krachaidum (KD)) is a traditional herbal medicine and has properties that are beneficial for human health. In the current study, we sought to investigate the anti-inflammatory properties of KD extract (KPE). In mouse skin tissue, UV light representing solar wavelengths (sUV) increased COX-2 expression, while treatment with KPE reduced this effect. The anti-inflammatory activity of KPE was confirmed in in vitro models. MAPK signaling pathways were activated by sUV irradiation, and this was also repressed in the presence of KPE treatment. It is assumed that the anti-inflammatory activity of KPE is caused by the antioxidative effect. Furthermore, we confirmed the critical role of oxidative stress in sUV-induced COX-2 expression. We analyzed the polyphenol composition of KPE. Of the polyphenols identified, gallic acid, apigenin, and tangeretin were identified as the major polyphenols (at 9.31 ± 1.27, 2.37 ± 0.14, and 2.15 ± 0.19 µg/mg dry weight, resp.). Collectively, these findings show that in the presence of sUV irradiation, KD has anti-inflammatory properties and antioxidative effects in the skin.
Asunto(s)
Antioxidantes/uso terapéutico , Medicina de Hierbas/métodos , Zingiber officinale/química , Animales , Antioxidantes/farmacología , Humanos , RatonesRESUMEN
The soy isoflavone daidzein is bioconverted to 7,8,4'-trihydroxyisoflavone (7,8,4'-THIF) by microorganisms. Here, we investigated the matrix metalloproteinase (MMP)-1 inhibitory properties of 7,8,4'-THIF that arise through the suppression of UVB-induced MMP-1 expression. 7,8,4'-THIF reduced UVB-induced MMP-1 expression at the transcriptional level in primary human dermal fibroblasts and inhibited UVB-induced transcriptional activity of AP-1, a major activator of MMP-1 expression. Additionally, it was observed that the mitogen-activated protein kinase (MAPK) pathway, a crucial signalling cascade for MMP-1 expression, was suppressed by 7,8,4'-THIF. Protein kinase C iota (PKCι) was suspected to be a direct target of 7,8,4'-THIF. The direct interaction between 7,8,4'-THIF and PKCι was confirmed using pull-down assays and immobilized metal ion affinity-based fluorescence polarization assays. Finally, we observed that 7,8,4'-THIF inhibited UVB-induced MMP-1 expression in a human skin equivalent model. Taken together, these results suggest that 7,8,4'-THIF, a bioconversion product of daidzein, suppresses UVB-induced MMP-1 expression.
Asunto(s)
Isoenzimas/antagonistas & inhibidores , Isoflavonas/farmacología , Metaloproteinasa 1 de la Matriz/metabolismo , Proteína Quinasa C/antagonistas & inhibidores , Evaluación Preclínica de Medicamentos , Humanos , Envejecimiento de la Piel/efectos de los fármacos , Rayos UltravioletaRESUMEN
BACKGROUND: CT-P6 is a proposed biosimilar to reference trastuzumab. In this study, we aimed to establish equivalence of CT-P6 to reference trastuzumab in neoadjuvant treatment of HER2-positive early-stage breast cancer. METHODS: In this randomised, double-blind, active-controlled, phase 3 equivalence trial, we recruited women aged 18 years or older with stage I-IIIa operable HER2-positive breast cancer from 112 centres in 23 countries. Inclusion criteria were an Eastern Cooperative Oncology Group performance status score of 0 or 1; a normal left ventricular ejection fraction of at least 55%; adequate bone marrow, hepatic, and renal function; at least one measureable lesion; and known oestrogen and progesterone receptor status. Exclusion criteria included bilateral breast cancer, previous breast cancer treatment, previous anthracycline treatment, and pregnancy or lactation. We randomly allocated patients 1:1 to receive neoadjuvant CT-P6 or reference trastuzumab intravenously (eight cycles, each lasting 3 weeks, for 24 weeks; 8 mg/kg on day 1 of cycle 1 and 6 mg/kg on day 1 of cycles 2-8) in conjunction with neoadjuvant docetaxel (75 mg/m2 on day 1 of cycles 1-4) and FEC (fluorouracil [500 mg/m2], epirubicin [75 mg/m2], and cyclophosphamide [500 mg/m2]; day 1 of cycles 5-8) therapy. We stratified randomisation by clinical stage, receptor status, and country and used permuted blocks. We did surgery within 3-6 weeks of the final neoadjuvant study drug dose, followed by an adjuvant treatment period of up to 1 year. We monitored long-term safety and efficacy for 3 years after the last patient was enrolled. Participants and investigators were masked to treatment until study completion. The primary efficacy endpoint, analysed in the per-protocol population, was pathological complete response, assessed via specimens obtained during surgery, analysed by masked central review of local histopathology reports. The equivalence margin was -0·15 to 0·15. This trial is registered with ClinicalTrials.gov, number NCT02162667, and is ongoing, but no longer recruiting. FINDINGS: Between Aug 7, 2014, and May 6, 2016, we randomly allocated 549 patients (271 [49%] to CT-P6 vs 278 [51%] to reference trastuzumab). A similar proportion of patients achieved pathological complete response with CT-P6 (116 [46·8%; 95% CI 40·4-53·2] of 248 patients) and reference trastuzumab (129 [50·4%; 44·1-56·7] of 256 patients). The 95% CI of the estimated treatment outcome difference (-0·04% [95% CI -0·12 to 0·05]) was within the equivalence margin. 19 (7%) of 271 patients in the CT-P6 group reported serious treatment-emergent adverse events versus 22 (8%) of 278 in the reference trastuzumab group; frequent (occurring in more than one patient) serious adverse events were febrile neutropenia (four [1%] vs one [<1%]) and neutropenia (one [<1%] vs two [1%]). Grade 3 or worse treatment-related adverse events occurred in 17 (6%) of 271 patients in the CT-P6 group versus 23 (8%) of 278 in the reference trastuzumab group; the most frequently reported adverse event was neutropenia in ten (4%) versus 14 (5%). INTERPRETATION: CT-P6 showed equivalent efficacy to reference trastuzumab and adverse events were similar. Availability of trastuzumab biosimilars could increase access to this targeted therapy for HER2-positive early-stage cancer. FUNDING: Celltrion Inc.