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ABSTRACT: BACKGROUND: Rituximab, a monoclonal antibody directed against B lymphocytes, has been found to be a therapeutic agent for severe, refractory autoimmune bullous diseases. However, a dosing schedule or treatment indication of rituximab has not yet been established. OBJECTIVES: We investigated the efficacy of rituximab and different dosing schedules for different disease severities, retrospectively. METHODS: A total of 23 patients with pemphigus who received rituximab were evaluated by a review of medical records. Group 1 patients (n = 10) with severe pemphigus were treated with three or four infusions of rituximab at a dose of 375 mg/m(2) at 1-week intervals. Group 2 (n = 13) patients with mild to moderate pemphigus were treated with two infusions of rituximab at the same dose. Late end points, occurrence of relapse and adverse events and numbers of B cells were evaluated. RESULTS: The mean follow-up period was 25.6 months in group 1 and 17.8 months in group 2. In group 1, six patients (60.0%) achieved complete remission (CR), including two patients off therapy (CR OFF) and four patients on therapy (CR ON). The other four patients (40.0%) achieved partial remission on therapy (PR ON). In group 2, nine patients (69.2%) achieved CR (4 CR OFF, 5 CR ON) and four patients (30.8%) achieved PR ON. During the follow-up period, relapse occurred in five patients of group 1 and three patients of group 2. No serious adverse events were observed in any patients. CONCLUSIONS: We concluded that rituximab is an effective and safe treatment method not only in severe, recalcitrant pemphigus but also in mild to moderate pemphigus. Low dose of rituximab seemed to be sufficient to treat mild to moderate pemphigus.
Journal of the European Academy of Dermatology and Venereology 01/2013; · 2.98 Impact Factor
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ABSTRACT: This is a pilot study analysing association of chemokine gene polymorphisms (CXCL1, rs3117604; CXCL2, rs3806792; CCL2, rs2857656 and rs3760396; CCL5, rs2107538) in Korean patients with ischemic stroke (IS) (n = 120) and age-matched controls (n = 267). The CXCL1 gene and particularly T allele of rs3117604 was associated with IS.
International Journal of Immunogenetics 11/2012; · 1.29 Impact Factor
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ABSTRACT: In spite of the growing popularity of herbal medicines and natural food supplements, their effects on cardiovascular homeostasis remain largely unknown, especially regarding pro-thrombotic risks.
In the present study, 21 herbal tea extracts were screened for the procoagulant activities on platelets, an important promoter of thrombosis to examine if herbal medicines or natural products may have prothrombotic risks. We discovered that Dipsacus asper (DA), known to have analgesic and anti-inflammatory effects, potently induced procoagulant activities in platelets. We tried to identify the active ingredient and elucidate the underlying mechanism.
Among 10 major ingredients of DA, dipsacus saponin C (DSC) was identified as a key active ingredient in DA-induced procoagulant activities. DSC-induced procoagulant activities were achieved by the exposure of phosphatidylserine (PS) and PS-bearing microparticle generation that were caused by the alteration in the activities of phospholipid translocases: scramblase and flippase. These events were initiated by increased intracellular calcium and ATP depletion. Notably, DSC induced a series of apoptotic events including the disruption of mitochondrial membrane potential, translocation of Bax and Bak, cytochrome c release and caspase-3 activation. The key roles of apoptotic pathway and caspase activation were demonstrated by the reversal of DSC-induced PS exposure and procoagulant activities with the pretreatment of caspase inhibitors. Interestingly, EGTA reversed DSC-induced procoagulant activities and apoptotic events suggesting that an intracellular calcium increase may play a central role. These results were also confirmed in vivo where platelets of the rats exposed to DSC or DA exhibited PS exposure. Most importantly, DSC or DA administration led to increased thrombus formation.
These results demonstrate that herbal medicines or natural products such as DA or DSC might have prothrombotic risks through procoagulant activation of platelets.
Journal of Thrombosis and Haemostasis 03/2012; 10(5):895-906. · 5.73 Impact Factor
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ABSTRACT: Seborrhoeic keratoses (SKs) are very common benign epidermal lesions without malignant potential. Ultraviolet radiation, old age and viruses are well-known risk factors for disease development. However, the pathomechanisms of SK are not fully understood.
To detect and characterize the genes that are involved in the pathogenesis of SK.
We performed a gene expression study using paired lesional and nonlesional skin samples from patients with SK.
We identified and validated 19 differentially expressed genes in SK. Of these 19 genes, we focused on p63 transcription factor, which plays a pivotal role in epidermal development by regulating its transcriptional programme. We found by immunofluorescence that the expression of ΔNp63α, the most abundantly expressed p63 isoform, was significantly increased in SK as compared with normal skin. Moreover, siRNA-mediated knockdown of ΔNp63 led to the downregulation of 11 genes, including a member of the tensin family TNS4. Chromatin immunoprecipitation assay revealed that TNS4 was a target gene of p63.
We identified upregulated genes in SK using genome-wide cDNA microarray and elucidated the functional contribution of p63 to the disease transcriptome by gene-silencing assay. Taken together, these data may provide a novel insight into the molecular basis of these benign skin lesions.
British Journal of Dermatology 10/2011; 166(2):337-42. · 3.67 Impact Factor
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ABSTRACT: Because inflammation is a factor promoting ageing, all-trans retinoic acid (RA)-induced irritation may have a negative influence on collagen accumulation in human skin despite its stimulation of collagen production.
To determine whether RA-induced irritation detrimentally affects RA efficacy as represented by new collagen synthesis.
Retinoic acid (0·01%, 0·025% or 0·05%) or vehicle was applied to the buttock skin of elderly male volunteers three times a week for 8 weeks under continuous occlusion. Every 2 weeks, biopsy specimens were obtained and immunohistochemical analysis was performed to determine levels of type I procollagen expression and inflammatory cell infiltration.
Topical RA regardless of concentration increased type I procollagen expression in human skin in vivo after 2 weeks. However, only 0·01% RA continuously increased type I procollagen expression up to 8 weeks. After 4 weeks, significant infiltrations of macrophages and neutrophils were observed in 0·025% and 0·05% RA-treated skin, and procollagen expression had returned to baseline.
Excessive RA-induced inflammation might prevent collagen accumulation in aged skin despite the positive effect of RA on collagen production.
British Journal of Dermatology 05/2011; 165(3):669-72. · 3.67 Impact Factor
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H J Park,
M J Kim,
S W Kang,
S K Kim,
J S Lee,
H K Park,
S D Yoo,
D H Kim,
D H Yun,
H S Kim,
J W Kim, J H Chung,
Y S Jeong
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ABSTRACT: Interleukin-4 (IL4) polymorphisms (rs2243250, rs2070874) were analysed in Korean patients with ischaemic stroke (IS) (n=119) and intracerebral haemorrhage (ICH) (n=79), and age-matched controls (n =267, IS; n=401, ICH) using direct sequencing. Both single nucleotide polymorphisms and their haplotypes were associated with ICH, but not IS.
International Journal of Immunogenetics 04/2011; 38(4):321-5. · 1.29 Impact Factor
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H. J. Park,
M. J. Kim,
S. W. Kang,
S. K. Kim,
J. S. Lee,
H. K. Park,
S. D. Yoo,
D. H. Kim,
D. H. Yun,
H. S. Kim,
J. W. Kim, J. H. Chung,
Y. S. Jeong
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ABSTRACT: Interleukin-4 (IL4) polymorphisms (rs2243250, rs2070874) were analysed in Korean patients with ischaemic stroke (IS) (n = 119) and intracerebral haemorrhage (ICH) (n = 79), and age-matched controls (n =267, IS; n = 401, ICH) using direct sequencing. Both single nucleotide polymorphisms and their haplotypes were associated with ICH, but not IS.
International Journal of Immunogenetics 04/2011; 38(4):321 - 325. · 1.29 Impact Factor
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ABSTRACT: Cigarette smoke is a complex mixture of more than 4700 chemical compounds including free radicals and oxidants and it is a world widely known problem to health. Nicotine is the major compound of tobacco and known as the cause of gingivitis and periodontitis. It induces intracellular oxidative stress recognized as the important agent in the damage of biological molecules. The aim of this study is to clarify the cytotoxic pathway of nicotine in human gingival fibroblasts (HGFs).
Human gingival fibroblasts stimulated by nicotine were used as an in vitro model. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to detect cell viability and reactive oxygen species (ROS) generation was assessed with 2,7-dichlorofluoroscein diacetate (DCF-DA). Morphological change was detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end labelling (TUNEL) assay, stained with 4,6-diamidino-2-phenylindole (DAPI). To delineate the roles of extracellular signal-regulated kinase (ERK), P38 and c-Jun N-terminal kinase (JNK), Western blot and caspase-3 (CASP3) activity assay were performed.
Exposure of the human gingival fibroblasts to nicotine reduced cell viability by time and dose dependent and increased the generation of ROS. It also showed morphological evidence of increased apoptosis, resulted in transient activation of JNK and ERK concomitant with activation of P38, and stimulated apoptosis as evidenced by CASP3 activation and Poly ADP ribose polymerase (PARP) cleavage.
These results suggest that nicotine induces apoptosis through the ROS generation and CASP3 dependent pathways in HGFs.
Archives of oral biology 04/2011; 56(10):1091-7. · 1.65 Impact Factor
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Journal of the European Academy of Dermatology and Venereology 04/2011; 25(4):492-3. · 2.98 Impact Factor
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ABSTRACT: The aim of this study was to determine whether the HLA-G gene was associated with susceptibility to rheumatoid arthritis (RA). Major histocompatibility complex, class I, G (HLA-G) is involved in immunoregulatory processes and particularly in pathogenesis of inflammatory disorders. To investigate possible association between HLA-G and RA, 296 RA patients and 468 healthy controls were enrolled in this study. Two-promoter single-nucleotide polymorphisms (SNPs) (rs1736936, -1202T/C and rs2735022, -586C/T) in HLA-G gene were analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). For analysis of data, Helixtree software, SNPAnalyzer, SNPStats, and Haploview version 4.2 were used. Multiple logistic regression models (codominant, dominant, and recessive) were performed for odds ratio (OR), 95% confidence interval (CI), and P value. There were no significant differences in distributions of genotypes and haplotypes between RA patients and control subjects. In clinical features of RA, we found differences between C-reactive protein levels (≥0.5 or <0.5 mg/dL) and two-promoter SNPs. Rs1736936 was significant in codominant (P = 0.028, OR = 0.66, 95% CI = 0.45-0.96) and dominant (P = 0.046, OR = 0.58, 95% CI = 0.34-0.99) models. Also, rs2735022 was significant in codominant (P = 0.038, OR = 0.67, 95% CI = 0.46-0.98) and dominant (P = 0.03, OR = 0.55, 95% CI = 0.33-0.94) models. However, these significant associations disappear after Bonferroni correction. Our results suggest that HLA-G promoter polymorphisms may be not associated with the development of RA in Korean population.
Rheumatology International 01/2011; 32(2):509-12. · 1.88 Impact Factor
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ABSTRACT: Atopic dermatitis (AD) is a chronic pruritic skin condition affecting as much as 15% of children in industrialized countries. While the underlying pathophysiology of AD is not entirely understood, several studies have suggested that AD may mediated by oxidative stress. Glutathione S-transferases (GSTs) are a class of polymorphic enzymes that function to protect against oxidative stress. To identify any possible associations between GSTs polymorphisms and AD susceptibility, the prevalence of two specific polymorphisms -GSTM1 and GSTT1 (homozygous deletion vs. undeleted) - were quantified by multiplex PCR in 145 patients with AD and 267 healthy controls. In individuals with AD, GSTM1/GSTT1 polymorphisms were compared with family history of AD, age of disease onset, disease severity [per SCORing Atopic Dermatitis (SCORAD)], serum IgE level and presence of other allergic diseases. While the GSTM1-null genotype was found to be significantly associated with AD (P = 0.033, OR = 1.579, 95% CI = 1.037-2.403), the correlation between the GSTT1-null genotype and AD did not reach statistical significance (P = 0.577, OR = 1.125, 95% CI = 0.744-1.702). The GSTM1-null genotype was also found to be significantly associated with a childhood onset of AD, the absence of other allergic diseases, and a family history of AD. In combination, these results suggest that GSTM1 is associated with AD susceptibility in Korean subjects.
International Journal of Immunogenetics 12/2010; 38(2):145-50. · 1.29 Impact Factor
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ABSTRACT: Toll-like receptors (TLRs) are innate immune mediators that stimulate nuclear factor kappa B and the inflammatory cytokines. TLR1 is expressed in renal tubular epithelial cells when the kidney is injured, but the role of TLR1 gene in glomerulonephritis has not been clearly elucidated. We aimed to investigate the association of TLR1 polymorphisms with immunoglobulin A nephropathy (IgAN) in children. One hundred and ninety pediatric patients with biopsy-proven IgAN and 283 healthy control subjects were enrolled. Two single nucleotide polymorphisms of TLR1 gene [rs4833095 (missense, Asn248Ser) and rs5743557 (promoter, -414C/T)] were selected and genotyped by direct sequencing. For rs4833095, the C/T genotype in the codominant model (vs. the T/T genotype) [odds ratio (OR) = 2.11, 95% confidence interval (CI): 1.21-3.69, P = 0.009] and the genotype containing C allele (C/T and C/C) in the dominant model (vs. the T/T genotype) (OR = 1.97, 95% CI: 1.16-3.34, P = 0.012) were associated with an increased risk of IgAN. For rs5743557, the T/T genotype in the codominant model (vs. the C/C genotype) (OR = 1.74, 95% CI: 1.02-2.96, P = 0.041) appeared to be associated with IgAN risk. In haplotype analysis, the CT haplotype revealed an association with IgAN (codominant model, OR = 1.38, 95% CI: 1.06-1.80, P = 0.017; dominant model, OR = 1.76, 95% CI: 1.16-2.67, P = 0.008). After Bonferroni correction, the association of the genotypes of rs4833095 and the CT haplotype with IgAN risk remained significant. These findings suggest that TLR1 gene polymorphisms may affect IgAN susceptibility in Korean children.
International Journal of Immunogenetics 11/2010; 38(2):133-8. · 1.29 Impact Factor
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ABSTRACT: The precise cause of vitiligo is unknown. However, autoimmunity is considered the most likely aetiology, especially in nonsegmental vitiligo (NSV). In this study we determined whether or not the transforming growth factor beta receptor II (TGFBR2) gene contributes to susceptibility for NSV in the Korean population. Blood samples were collected from 415 controls and 233 cases. We selected three single nucleotide polymorphisms (SNPs) in the TGFBR2 gene. The genotypes of the SNPs were determined using direct sequencing. All of the SNPs were significantly different between the vitiligo patients and controls (rs2005061, co-dominant, dominant, recessive, P < 0.05; rs3773645, co-dominant, dominant, recessive, P < 0.05; rs3773649, co-dominant, recessive, P < 0.05). In addition, haplotype 1 (CG) and haplotype 2 (GA) of the linkage disequilibrium (LD) block were also associated with a risk of NSV. The present study suggests that TGFBR2 might be related to NSV.
International Journal of Immunogenetics 08/2010; 37(4):289-91. · 1.29 Impact Factor
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British Journal of Dermatology 04/2010; 163(3):651-3. · 3.67 Impact Factor
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ABSTRACT: Metabolic syndrome (MetS) is rapidly growing into one of the major public health issues worldwide. Interleukin 1 receptor antagonist (IL1Ra) functions as a competitor of proinflammatory cytokines and has an important role in metabolic functions, including insulin secretion. To identify the relationship between the interleukin 1 receptor antagonist gene (IL1RN) and MetS, we genotyped nine single nucleotide polymorphisms (SNPs) in the gene using direct sequencing in 66 MetS patients and 346 normal subjects in the Korean population. Among the nine polymorphisms, after adjusting for age and sex, rs928940 (G>T) showed a significant association with MetS in the codominant ( P= 0.023) and recessive models ( P= 0.011). Also, rs315952 (C>T) exhibited a significant association with MetS in the codominant model ( P= 0.046). The results suggest that the IL1RN polymorphisms may be associated with MetS in the Korean population.
Experimental and Clinical Endocrinology & Diabetes 03/2010; 118(5):333-7. · 1.69 Impact Factor
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ABSTRACT: Vitiligo is a pigmentary skin disorder characterized by a chronic and progressive loss of melanocytes. Although the aetiology of vitiligo is currently unknown, several theories have been proposed to explain the pathogenesis of this disease, including autoimmune, neural, self-destruction, oxidative stress, and genetic theories. Thioredoxin domain containing 5 (TXNDC5) is a newly identified member of the thioredoxin family. TXNDC5 has a protein disulphide isomerase-like domain which plays an important role in protein folding and chaperone activity, against endoplasmic reticulum (ER) stress induced by oxidative stress within the ER.
To determine whether variation in the TXNDC5 gene contributes to the risk of developing nonsegmental vitiligo (NSV) in the Korean population.
We conducted a case-control association study of 230 patients with NSV and 417 matched, unaffected controls. Seven single nucleotide polymorphisms (SNPs) in the TXNDC5 gene were selected for study.
Of the selected SNPs, three exonic SNPs (rs1043784, rs7764128 and rs8643) were statistically associated with NSV. Among them, rs1043784 remained a statistically significant association following Bonferroni correction. These three SNPs were located within a block of linkage disequilibrium; the haplotypes AGG and GAA, consisting of rs1043784, rs7764128 and rs8643, demonstrated a significant association with NSV.
These results suggest that TXNDC5 gene polymorphisms are associated with the development of NSV in the Korean population.
British Journal of Dermatology 11/2009; 162(4):759-64. · 3.67 Impact Factor
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ABSTRACT: Evidence for beneficial effects of squalene on ultraviolet (UV)-induced photoageing of the skin is lacking.
To investigate whether squalene supplementation improves signs and molecular markers of photoageing in human skin in vivo.
In total, 40 female volunteers aged > 50 years received two different doses [13.5 g/day (low-dose group) and 27 g/day (high-dose group)] of squalene for 90 days. At baseline and at the completion of the study, facial wrinkles were measured using skin replicas. Skin samples were taken to compare type I procollagen and matrix metalloproteinase 1 mRNA levels by real-time reverse-transcriptase PCR, and for type I procollagen immunostaining. Skin samples were also taken 24 h after 2 x minimal erythema dose (MED) of UV irradiation before and after squalene intake to assess UV-induced thymine dimer formation and keratinocytic apoptosis.
In total, 37 subjects completed the trial. Transient loose stool was experienced by 35% of volunteers in the low-dose group and 55% in the high-dose group. Facial wrinkles decreased significantly (P < 0.05) in the high-dose group, while procollagen type I mRNA levels and MED increased significantly in the low-dose group. Procollagen immunostaining tended to increase in both groups. Facial erythema decreased and pigmentation increased significantly in both groups. UV-induced keratinocytic apoptosis and thymine dimer staining were substantially reduced in both groups.
Daily ingestion of 13.5 or 27 g of squalene per day resulted in antiageing effects in photoaged skin. However, in view of the frequent incidence of loose stool experienced by the subjects, the risk-benefit ratio of high-dose squalene supplementation is too high to recommend it for treating skin ageing.
Clinical and Experimental Dermatology 07/2009; 34(4):500-8. · 1.20 Impact Factor
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ABSTRACT: Doxorubicin (DOX) is a widely used anticancer drug for solid tumors and hematologic malignancy, but its active use is hampered by serious adverse effects, including thrombocytopenia. Although bone marrow toxicity of DOX has been suggested to be the sole mechanism underlying the reduced platelet counts, the direct effects of DOX on platelets have never been examined.
Here, we investigated the DOX-induced platelet cytotoxicity and its underlying mechanism in an effort to elucidate the contribution of platelet cytotoxicity to DOX-induced thrombocytopenia.
In freshly isolated human platelets, DOX induced platelet cytotoxicity in a time-dependent and concentration-dependent manner. Reactive oxygen species (ROS) generation, decreased glutathione levels and subsequent protein thiol depletion were shown to underlie the DOX-induced platelet cytotoxicity. Conspicuously, DOX-treated platelets displayed apoptotic features such as caspase-3 activation, reduced mitochondrial transmembrane potential, and phosphatidylserine exposure. Decreased glutathiolation of procaspase-3 was shown to be a link between protein thiol depletion and caspase-3 activation. It is of note that DOX-mediated platelet cytotoxicity was significantly enhanced by shear stress, a common complicating factor in cancer patients. These in vitro results were further confirmed by an in vivo animal model, where administration of DOX induced a platelet count decrease, ROS generation, caspase-3 activation, protein thiol depletion, and damaged platelet integrity.
We demonstrated that DOX can directly induce platelet cytotoxicity through ROS generation, decreased glutathione levels, and protein thiol depletion. We believe that this study provides important evidence for the role of DOX-induced platelet cytotoxicity in the development of thrombocytopenia in DOX-treated patients.
Journal of Thrombosis and Haemostasis 06/2009; 7(7):1172-83. · 5.73 Impact Factor
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ABSTRACT: Mast cells are key effector cells in diverse immunological and pathological processes. It is still unclear why there are more mast cells at peripheral and sun-exposed skin sites than at sun-protected sites.
To investigate changes in mast cell numbers associated with natural ageing and photoageing, and to observe the effects of ultraviolet (UV) and infrared (IR) radiation and heat on the prevalence of mast cells and tryptase expression in human skin in vivo.
Sun-exposed and sun-protected skin samples were taken from individuals in four different age groups. UV, IR or heat-treated buttock skin of young volunteers was also obtained. Mast cells were quantified by immunohistochemical staining of mast cell-specific tryptase and chymase. The expression of tryptase was determined by Western blotting.
Both sun-exposed and sun-protected skin showed a gradual decrease in total mast cells (MC(Total)) number with ageing. The number of mast cells in sun-exposed skin was significantly higher than that in sun-protected skin. After UV irradiation (2 minimal erythema doses), MC(Total) and mast cells expressing tryptase and chymase were significantly increased at 24 and 48 h postirradiation. After IR irradiation (3 minimal heating doses) and heat treatment (43 degrees C for 90 min), MC(Total) reached peak induction at 8 and 48 h after stimulation, respectively. Tryptase expression was also clearly upregulated by UV, IR and heat.
Our data demonstrate that mast cell numbers decreased with ageing in human skin. Also, mast cells may be activated and recruited by UV, IR and heat. These findings should further our understanding of the reason for the high prevalence of mast cells at peripheral sun-exposed skin sites.
British Journal of Dermatology 10/2008; 160(2):393-402. · 3.67 Impact Factor
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ABSTRACT: Hesperidin, a known flavonoid constituent of citrus, reduces the proliferation of many cancer cells. The apoptotic effects of hesperidin on human colon cancer cells, SNU-C4, were determined at concentrations of 1-100 microM. At 100 microM, hesperidin reduced cell viability to 65.00+/-0.05% of control values in a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell death induced by hesperidin showed apoptotic features in 4,6-diamidino-2-phenylindole (DAPI) staining and in terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays. Examination of the expression of apoptosis-regulating genes indicated that hesperidin treatment decreased the expression of B-cell CLL/lymphoma 2 (BCL2) mRNA, and increased the expression of BCL2-associated X protein (BAX). The expression and activity of the major apoptotic factor caspase3 (CASP3) was increased significantly with hesperidin treatment. Hesperidin down-regulated the protein expression of pro-CASP3, and up-regulated the level of active CASP3. Thus, these results suggest that hesperidin could induce apoptosis in human colon cancer cells through CASP3 activation.
Phytomedicine 02/2008; 15(1-2):147-51. · 3.27 Impact Factor
