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Background@#Recent studies suggest that MEK1/2 inhibitors, including binimetinib, significantly improve malignant melanoma (MM) patient survival. Growing evidence suggests that phytochemicals, especially curcumin, can overcome drug resistance in cancer cells through a variety of mechanisms. @*Objective@#This study aims to examine curcumin’s efficacy in vitro combined with binimetinib in human MM cells. @*Methods@#We used 2D monolayer and 3D spheroid human epidermal melanocyte culture models, HEMn-MP (human epidermal melanocytes, neonatal, moderately pigmented), and two human MM cell lines, G361 and SK-MEL-2, to evaluate cell viability, proliferation, migration, death, and reactive oxygen species (ROS) production following single therapy treatment, with either curcumin or binimetinib, or a combination of both. @*Results@#Compared to MM cells treated with single therapy, those with combination therapy showed significantly decreased cell viability and increased ROS production. We observed apoptosis following both single and combination therapies. However only those who had had combination therapy had necroptosis. @*Conclusion@#Collectively, our data demonstrates that curcumin exerts significant synergistic anticancer effects on MM cells by inducing ROS and necroptosis when combined with binimetinib. Therefore, a strategy of adding curcumin to conventional anticancer agents holds promise for treating MM.
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Background@#Pityriasis rosea is a self-limiting, acute, or subacute inflammatory skin disease that usually starts with a herald patch on the trunk and progresses to a generalized rash over the trunk and limbs. Some clinical trials have suggested that antibiotic macrolides help shorten the duration of skin manifestations in pityriasis rosea; however, the extent of the benefits is unclear. @*Objective@#To evaluate the effectiveness of antibiotic macrolides compared to placebo in pityriasis rosea. @*Methods@#A computerized search was performed using different databases, including Cochrane, Embase, and PubMed. Five randomized controlled trials were included. Then, statistical analyses of the outcome data extracted from the studies were performed using Rex Software (version 3.0.1). @*Results@#Total 160 records were identified by searching databases including Cochrane, Embase, and PubMed. The results of the meta-analysis demonstrated statistical differences between the use of antibiotic macrolides and placebo in the complete and partial resolution of pityriasis rosea (effectiveness) (RR: 1.84, 95% CI: 1.21∼2.78, p=0.004).However, in subgroup analyses, there were no statistical differences compared to placebo in the skin manifestation effectiveness group for azithromycin and clarithromycin, whereas erythromycin showed statistical differences. @*Conclusion@#Erythromycin was superior to placebo in the treatment of pityriasis rosea. However, this study had some limitations, including insufficient articles and data. Therefore, further investigation is required.
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Background@#Pityriasis rosea is a self-limiting, acute, or subacute inflammatory skin disease that usually starts with a herald patch on the trunk and progresses to a generalized rash over the trunk and limbs. Some clinical trials have suggested that antibiotic macrolides help shorten the duration of skin manifestations in pityriasis rosea; however, the extent of the benefits is unclear. @*Objective@#To evaluate the effectiveness of antibiotic macrolides compared to placebo in pityriasis rosea. @*Methods@#A computerized search was performed using different databases, including Cochrane, Embase, and PubMed. Five randomized controlled trials were included. Then, statistical analyses of the outcome data extracted from the studies were performed using Rex Software (version 3.0.1). @*Results@#Total 160 records were identified by searching databases including Cochrane, Embase, and PubMed. The results of the meta-analysis demonstrated statistical differences between the use of antibiotic macrolides and placebo in the complete and partial resolution of pityriasis rosea (effectiveness) (RR: 1.84, 95% CI: 1.21∼2.78, p=0.004).However, in subgroup analyses, there were no statistical differences compared to placebo in the skin manifestation effectiveness group for azithromycin and clarithromycin, whereas erythromycin showed statistical differences. @*Conclusion@#Erythromycin was superior to placebo in the treatment of pityriasis rosea. However, this study had some limitations, including insufficient articles and data. Therefore, further investigation is required.
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Background@#Inflammatory bowel disease (IBD) is a chronic, relapsing, inflammatory disease of the gastrointestinal tract. IBD tends to coincide with several cutaneous symptoms and signs; previous studies have suggested a link between IBD and immune-mediated skin diseases (ISDs) such as psoriasis, rosacea, and atopic dermatitis. However, there is a paucity of reports on extraintestinal cutaneous manifestations in patients with IBD from Asia and Korea. @*Objective@#We examined the prevalence of cutaneous manifestations in IBD patients and investigated the possible association between IBD and various dermatoses in a Korean tertiary care hospital. @*Methods@#Detailed questionnaires were administered to 120 patients diagnosed with IBD treated at the gastrointestinal center of our hospital. We also extracted their medical records retrospectively to obtain additional information about both their cutaneous manifestations and IBD, including disease duration and treatment course. A literature review on the prevalence of psoriasis in IBD patients was performed to clarify the association between those diseases. @*Results@#Crohn’s disease and ulcerative colitis were noted in 58 and 62 cases, respectively. Reactive skin lesions including aphthous stomatitis, erythema nodosum, and pyoderma gangrenosum were found in 12 cases (10%). ISDs such as psoriasis, rosacea, and atopic dermatitis were present in 3.3%, 21.7%, and 12.5% of cases, respectively. Other dermatoses including herpes zoster, xerosis, and skin fungal infection were also detected. @*Conclusion@#The prevalence of cutaneous manifestations in IBD is similar to that reported previously in Asian patients. Future investigations on the associations between skin diseases and IBD are needed to understand the pathogenesis and immunologic background of their comorbidities.
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Background@#Fractional carbon dioxide laser (FCL) has been used to treat keloid and hypertrophic scars as monotherapy or combination therapy, including intralesional triamcinolone acetonide (ITAC). However, whether the combination of FCL and ITAC is really effective compared with other treatments, such as ITAC monotherapy in treating keloid and hypertrophic scars, remains unclear.Objective To evaluate the effectiveness of FCL plus ITAC compared with ITAC monotherapy in treating keloid and hypertrophic scars. @*Methods@#A computerized search was performed in different databases, including Cochrane, Embase, and PubMed.One randomized controlled trial and two controlled clinical trials were included. Statistical analyses of the extracted outcome data from the studies were then calculated using the Rex Software (version 3.0.1). @*Results@#A total of 203 records were identified by searching databases, including Cochrane, Embase, and PubMed.The meta-analysis results, including three studies, demonstrated that although FCL combined with ITAC showed a slightly pronounced improvement in keloid and hypertrophic scars than ITAC monotherapy, there was no statistical difference (SMD: 0.26, 95% confidence interval [CI]: −0.10∼0.61, p=0.1541). @*Conclusion@#FCL combined with ITAC may not be a cost-effective treatment for the treatment of keloid and hypertrophic scars due to similar effectiveness compared with ITAC monotherapy. However, this study had limitations, including insufficiency of published articles and data. Therefore, further investigations are needed.
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Purpose@#We investigated the expression of Nrf2 in colorectal cancer and its correlation with clinicopathological characteristics as well as mechanisms and roles of Nrf2 expression including cell signaling pathway, survival, proliferation, and migration. @*Methods@#Nrf2 expression was measured in 12 and 30 different colorectal cancer (CRC) tissues by western blot (WB) and immunohistochemistry (IHC), respectively. SW480 cells were used for cell proliferation and cell migration tests. The correlation between the expression of Nrf2 and clinicopathologic parameters were evaluated using the chi-square or Fisher exact test. Data are expressed as the mean ± standard deviation for 3 independent experiments. P < 0.05 was considered statistically significant. @*Results@#Analysis of WB demonstrated that Nrf2 proteins were increased in CRC tissues, and decreased in normal tissues. IHC staining showed that the Nrf2 expression was elevated in CRC tissues, compared to matched normal tissues. When SW480 cells were suppressed with small interfering RNA of Nrf2, cell viability was inhibited, and cell apoptosis was increased. These results were found along with suppression of the phosphorylated form of extracellular signal-regulated kinase 1/2 and AKT. @*Conclusion@#This study suggests that overexpression of Nrf2 may be related to carcinogenesis and progression of CRC.
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Apigenin, a naturally occurring flavonoid, is known to exhibit significant anticancer activity. This study was designed to determine the effects of apigenin on two malignant mesothelioma cell lines, MSTO-211H and H2452, and to explore the underlying mechanism(s). Apigenin significantly inhibited cell viability with a concomitant increase in intracellular reactive oxygen species (ROS) and caused the loss of mitochondrial membrane potential (ΔΨm), and ATP depletion, resulting in apoptosis and necroptosis in monolayer cell culture. Apigenin upregulated DNA damage response proteins, including the DNA double strand break marker phospho (p)-histone H2A.X. and caused a transition delay at the G2 /M phase of cell cycle. Western blot analysis showed that apigenin treatment upregulated protein levels of cleaved caspase-3, cleaved PARP, p-MLKL, and p-RIP3 along with an increased Bax/Bcl-2 ratio.ATP supplementation restored cell viability and levels of DNA damage-, apoptosisand necroptosis-related proteins that apigenin caused. In addition, N-acetylcysteine reduced ROS production and improved ΔΨm loss and cell death that were caused by apigenin. In a 3D spheroid culture model, ROS-dependent necroptosis was found to be a mechanism involved in the anti-cancer activity of apigenin against malignant mesothelioma cells. Taken together, our findings suggest that apigenin can induce ROS-dependent necroptotic cell death due to ATP depletion through mitochondrial dysfunction. This study provides us a possible mechanism underlying why apigenin could be used as a therapeutic candidate for treating malignant mesothelioma.
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Apigenin, a naturally occurring flavonoid, is known to exhibit significant anticancer activity. This study was designed to determine the effects of apigenin on two malignant mesothelioma cell lines, MSTO-211H and H2452, and to explore the underlying mechanism(s). Apigenin significantly inhibited cell viability with a concomitant increase in intracellular reactive oxygen species (ROS) and caused the loss of mitochondrial membrane potential (ΔΨm), and ATP depletion, resulting in apoptosis and necroptosis in monolayer cell culture. Apigenin upregulated DNA damage response proteins, including the DNA double strand break marker phospho (p)-histone H2A.X. and caused a transition delay at the G2 /M phase of cell cycle. Western blot analysis showed that apigenin treatment upregulated protein levels of cleaved caspase-3, cleaved PARP, p-MLKL, and p-RIP3 along with an increased Bax/Bcl-2 ratio.ATP supplementation restored cell viability and levels of DNA damage-, apoptosisand necroptosis-related proteins that apigenin caused. In addition, N-acetylcysteine reduced ROS production and improved ΔΨm loss and cell death that were caused by apigenin. In a 3D spheroid culture model, ROS-dependent necroptosis was found to be a mechanism involved in the anti-cancer activity of apigenin against malignant mesothelioma cells. Taken together, our findings suggest that apigenin can induce ROS-dependent necroptotic cell death due to ATP depletion through mitochondrial dysfunction. This study provides us a possible mechanism underlying why apigenin could be used as a therapeutic candidate for treating malignant mesothelioma.
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Juvenile pemphigus vulgaris (JPV) is a rare variant of pemphigus vulgaris (PV) occurring in childhood and adolescence that has similar symptoms and the same histological and immunopathological features as classic adult PV. Although rare, advanced cases of JPV can be fatal due to secondary sepsis. Many patients with JPV are misdiagnosed and therefore not properly treated in the early stages of the disease. Although systemic corticosteroids are the therapeutic mainstay, long-term corticosteroid use has various adverse effects. Intravenous immunoglobulin (IVIG) was recently reported to reduce the side effects of corticosteroids. Here, we report a case of JPV in a 14-year-old boy treated with IVIG.
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Adolescente , Adulto , Humanos , Masculino , Corticoesteroides , Inmunoglobulinas , Inmunoglobulinas Intravenosas , Pénfigo , SepsisRESUMEN
Grover disease (also known as transient or persistent acantholytic dermatosis) is a pruritic polymorphic papulovesicular eruption that is histologically characterized by the presence of epidermal acantholysis. It primarily occurs in middle-aged individuals and manifests as scattered erythematous or brown papules as well as papulovesicles on the sun-exposed skin of the trunk. A 52-year-old man had erythematous papules and patches linearly arranged on the left thigh and leg with mild pruritus. The skin lesions were successfully treated with a topical corticosteroid. However, 2 months later, the lesions recurred. The histological examination of a punch biopsy revealed focal acantholytic clefts with dyskeratotic cells, hyperkeratosis, and the infiltration of perivascular lymphocytes and eosinophils. Taken together with the late onset and lack of family history, we diagnosed this condition as Grover disease distributed along the Blaschko line, a condition presented here for the first time.
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Humanos , Persona de Mediana Edad , Acantólisis , Biopsia , Eosinófilos , Pierna , Linfocitos , Prurito , Piel , MusloRESUMEN
Stromal cells provide a crucial microenvironment for overlying epithelium. Here we investigated the expression and function of a stromal cell-specific protein, stromal cell-derived factor-1 (SDF-1), in normal human skin and in the tissues of diseased skin. Immunohistology and laser capture microdissection (LCM)-coupled quantitative real-time RT-PCR revealed that SDF-1 is constitutively and predominantly expressed in dermal stromal cells in normal human skin in vivo. To our surprise, an extremely high level of SDF-1 transcription was observed in the dermis of normal human skin in vivo, evidenced by much higher mRNA expression level than type I collagen, the most abundant and highly expressed protein in human skin. SDF-1 was also upregulated in the tissues of many human skin disorders including psoriasis, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). Double immunostaining for SDF-1 and HSP47 (heat shock protein 47), a marker of fibroblasts, revealed that fibroblasts were the major source of stroma-cell-derived SDF-1 in both normal and diseased skin. Functionally, SDF-1 activates the ERK (extracellular-signal-regulated kinases) pathway and functions as a mitogen to stimulate epidermal keratinocyte proliferation. Both overexpression of SDF-1 in dermal fibroblasts and treatment with rhSDF-1 to the skin equivalent cultures significantly increased the number of keratinocyte layers and epidermal thickness. Conversely, the stimulative function of SDF-1 on keratinocyte proliferation was nearly completely eliminated by interfering with CXCR4, a specific receptor of SDF-1, or by knock-down of SDF-1 in fibroblasts. Our data reveal that extremely high levels of SDF-1 provide a crucial microenvironment for epidermal keratinocyte proliferation in both physiologic and pathologic skin conditions.
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Adulto , Humanos , Proliferación Celular , Quimiocina CXCL12 , Genética , Células Epidérmicas , Epidermis , Patología , Quinasas MAP Reguladas por Señal Extracelular , Metabolismo , Fibroblastos , Metabolismo , Regulación de la Expresión Génica , Queratinocitos , Biología Celular , Patología , Transducción de Señal , Enfermedades de la Piel , Genética , PatologíaRESUMEN
BACKGROUND: Generalized granuloma annulare (GGA) is a benign granulomatous disease of an unknown etiology. Although numerous studies about GGA have been reported, publications that describe the general clinical features of the disease are very sparse. OBJECTIVE: This study aimed to identify the clinical characteristics of Korean GGA cases. METHODS: We reviewed and analyzed the clinical data derived from four patients diagnosed with GGA at our hospital and the clinical data from 58 patients diagnosed with GGA at other Korean hospitals between 1995 and 2011. RESULTS: The cutaneous lesions could be divided into the annular (n=30, 48%) and nonannular (n=32, 52%) types, and the lesions were more common in males than in females, with 33 males and 29 females affected. The GGA incidence showed a bimodal distribution with respect to age at disease onset. Twenty-six cases (42%) presented within the first decade of life and 29 cases (47%) presented when they were in the fifth decade of life or older. Twelve patients (19%) had systemic diseases. Of note, diabetes mellitus (DM) occurred only in adult GGA patients who were aged over 40 years. CONCLUSION: In contrast to previously reported studies, this study shows that the age at GGA onset has a bimodal distribution, and that GGA occurs more often in males. The prevalence of DM among GGA-affected individuals was higher than that found in the general Korean population. Therefore, a DM workup should be undertaken for GGA-affected patients who are over 40 years of age.
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Adulto , Femenino , Humanos , Masculino , Diabetes Mellitus , Granuloma Anular , Incidencia , Corea (Geográfico) , PrevalenciaRESUMEN
Focal acral hyperkeratosis is a rare skin disorder, initially described by Dowd et al., which is sporadic or inherited in an autosomal dominant way. Clinically, the condition presents with small yellowish to white papules located on lateral aspects of the hands and feet. Histopathological alterations are limited to the epidermis and there are no changes in the elastic fibers of the dermis. In this case report, a 14-year-old girl had a two-year history of persistent, asymptomatic, multiple papules along the border of the hands and feet. A histologic section of papules from the left hand and foot showed marked hyperkeratosis and hypergranulosis of epidermis.
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Adolescente , Femenino , Humanos , Dermis , Tejido Elástico , Epidermis , Pie , Mano , PielRESUMEN
No abstract available.
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BACKGROUND: Reactive oxygen species (ROS) play an important role in the induction of apoptosis under pathological conditions. Recently, a significant increase in ROS production and disrupted apoptosis mechanisms in keloids have been reported. Nuclear factor erythroid 2-related factor 2 (Nrf2) represents one of the most important cellular defense mechanisms against oxidative stress and is implicated in the regulation of apoptosis. Recently, it has been reported that Nrf2 upregulates Bcl-2, an anti-apoptotic protein. OBJECTIVE: To compare Nrf2 protein expression in normal skin tissues to keloid tissues. METHODS: ROS generation in keloid tissues was evaluated with OxyBlot analysis. Western blotting and/or immunohistochemical staining approaches were used to study expression of Nrf2 or Bcl-2 in keloid and normal skin tissues. Cellular fractionation was performed to examine subcellular distribution of Nrf2. Transfection of fibroblasts with Nrf2-specific small interfering RNA (siRNA) was conducted to understand the relationship between Nrf2 expression and apoptosis induction. RESULTS: Protein oxidation, a marker of oxidative stress, is increased in keloid tissues. Western blot analysis clearly showed that Nrf2 and Bcl-2 are downregulated in keloid tissues. Immunohistochemical staining of Nrf2 confirmed the results of the western blot analysis. Transfection of fibroblasts with the Nrf2-specific siRNA results in increased apoptosis and decreased cell viability. CONCLUSION: Collectively, our data indicate that Nrf2 expression is downregulated in keloid tissues, and that Nrf2 is involved in the development of apoptosis in Nrf2 siRNA-transfected fibroblasts. We propose that a defective antioxidant system and apoptotic dysregulation may participate in keloid pathogenesis.
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Apoptosis , Western Blotting , Supervivencia Celular , Mecanismos de Defensa , Fibroblastos , Queloide , Factor 2 Relacionado con NF-E2 , Estrés Oxidativo , Especies Reactivas de Oxígeno , ARN Interferente Pequeño , Piel , TransfecciónRESUMEN
BACKGROUND: Reactive oxygen species (ROS) play an important role in the induction of apoptosis under pathological conditions. Recently, a significant increase in ROS production and disrupted apoptosis mechanisms in keloids have been reported. Nuclear factor erythroid 2-related factor 2 (Nrf2) represents one of the most important cellular defense mechanisms against oxidative stress and is implicated in the regulation of apoptosis. Recently, it has been reported that Nrf2 upregulates Bcl-2, an anti-apoptotic protein. OBJECTIVE: To compare Nrf2 protein expression in normal skin tissues to keloid tissues. METHODS: ROS generation in keloid tissues was evaluated with OxyBlot analysis. Western blotting and/or immunohistochemical staining approaches were used to study expression of Nrf2 or Bcl-2 in keloid and normal skin tissues. Cellular fractionation was performed to examine subcellular distribution of Nrf2. Transfection of fibroblasts with Nrf2-specific small interfering RNA (siRNA) was conducted to understand the relationship between Nrf2 expression and apoptosis induction. RESULTS: Protein oxidation, a marker of oxidative stress, is increased in keloid tissues. Western blot analysis clearly showed that Nrf2 and Bcl-2 are downregulated in keloid tissues. Immunohistochemical staining of Nrf2 confirmed the results of the western blot analysis. Transfection of fibroblasts with the Nrf2-specific siRNA results in increased apoptosis and decreased cell viability. CONCLUSION: Collectively, our data indicate that Nrf2 expression is downregulated in keloid tissues, and that Nrf2 is involved in the development of apoptosis in Nrf2 siRNA-transfected fibroblasts. We propose that a defective antioxidant system and apoptotic dysregulation may participate in keloid pathogenesis.
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Apoptosis , Western Blotting , Supervivencia Celular , Mecanismos de Defensa , Fibroblastos , Queloide , Factor 2 Relacionado con NF-E2 , Estrés Oxidativo , Especies Reactivas de Oxígeno , ARN Interferente Pequeño , Piel , TransfecciónRESUMEN
BACKGROUND: Reactive oxygen species (ROS) damages cell molecules, and modifies cell signaling. The nuclear factor E2-related factor (Nrf2) is a critical transcription regulator, which protects cells against oxidative damage. Nrf2 expression is increased in a large number of cancers. However, little information has been reported regarding the expression of Nrf2 in skin cancers. Hence, we explored the expression of Nrf2 protein in skin cancers. METHODS: The Nrf2 protein expression in 24 specimens, including 6 malignant melanomas (MM), 6 squamous cell carcinomas (SCC), 6 basal cell carcinomas (BCC), and 6 normal skin tissues, was evaluated by western blotting. Immunohistochemical staining was performed. The expression of Kelch-like ECH-associated protein 1 (Keap1), the key regulator of Nrf2, was also analyzed by western blotting. RESULTS: Small interfering RNA transfection to the melanoma cell line G361 confirmed that an approximately 66 kDa band was the true Nrf2 band. The western blot revealed that the Nrf2 protein was definitely expressed in normal skin tissues, but the Nrf2 expression was decreased in MM, SCC, and BCC. Immunohistochemical examination showed that expression of Nrf2 was decreased in all skin cancer tissues compared to the normal skin tissues. Keap1 was not expressed in all malignant skin tumors and normal skin tissues by western blot. CONCLUSIONS: ROS was increased in various types of cancers which proteins were highly expressed or underexpressed. This study demonstrated that the expression of Nrf2 protein was down-regulated in human malignant skin tumors. We suggest that decreased expression of Nrf2 is related to skin cancers.
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Humanos , Western Blotting , Carcinoma Basocelular , Carcinoma de Células Escamosas , Línea Celular , Melanoma , Factor 2 Relacionado con NF-E2 , Especies Reactivas de Oxígeno , ARN Interferente Pequeño , Piel , Neoplasias Cutáneas , TransfecciónRESUMEN
BACKGROUND: Aurora kinase A (Aurora-A) plays an important role in the regulation of mitosis and cytokinesis. Dysregulated Aurora-A leads to mitotic faults and results in pathological conditions. No studies on Aurora-A expression in human diabetic skin tissue have been reported. In light of this, we explored the expression of Aurora-A in human diabetic skin tissue. METHODS: Aurora-A protein was evaluated by western blotting in 6 human diabetic skin tissue and 6 normal skin specimens. RESULTS: Increased expression of Aurora-A protein was detected in all diabetic skin tissue samples in both western blot analysis and immunohistochemical staining. However, in the case of the normal skin tissue, no bands of Aurora-A protein were detected in either the western blotting analysis or the immunohistochemical staining. CONCLUSIONS: Thus far, there have been no studies on the expression of Aurora-A in diabetic skin tissue. However, we believe that oxidative DNA damage related to the expression of Aurora-A protein and Aurora-A could be involved inhuman diabetic skin tissue.