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Some RNAs such as 28S rRNA, U1 small nuclear RNA (snRNA), and Y RNAs are known to be cleaved during apoptosis. The underlying mechanism, functions, and biological significance of RNA degradation in apoptosis remain elusive. Y RNAs are non-coding RNAs widely conserved from bacteria to mammals, and are major components of Ro ribonucleoprotein (RNP) complexes which contain the 60 kDa Ro protein (SS-A) and the 50 kDa La protein (SS-B). The autoantigenic Ro and La proteins were identified by autoantibodies present in the sera from patients with Systemic lupus erythematosus (SLE) and Sjögren's syndrome (SjS). We previously identified novel, functional small RNAs named AGO-taxis small RNAs (ASRs) that are specifically bound to Argonaute protein 1 (AGO1), which are processed from Y RNAs. Cell-free analysis combined with fractionation methods revealed that the apoptosis-specific biogenesis of ASRs or cleavage of Y RNA was induced by truncation of polypyrimidine tract-binding protein 1 (PTBP1), which is an endoribonuclease inhibitor of Y RNAs by caspase 3. Caspase 3-resistant PTBP1 mutant protected cleavage of Y RNAs in apoptosis induced by staurosporine. Furthermore, caspase 3-resistant PTBP1 mutant knock-in mice showed elevated cytokines, dysregulation of the germinal center formation compared to the wild-type mice at LPS stimulation, and high positivity of antinuclear antibody. Those results suggest that cleavage of Y RNAs or biogenesis of ASR during apoptosis has critical biological functions and their deregulation result in immune dysregulation and the formation of autoantibody, possibly leading to the development of autoimmune diseases.
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Lipid-mediated inflammation is involved in the development and malignancy of cancer. We previously demonstrated the existence of a novel oncogenic mechanism utilizing membrane lipids of extracellular vesicles in Epstein-Barr virus (EBV)-positive lymphomas and found that the lipid composition of lymphoma cells is skewed toward ω-3 fatty acids, which are anti-inflammatory lipids, suggesting an alteration in systemic lipid composition. The results showed that arachidonic acid (AA), an inflammatory lipid, was significantly reduced in the infected cells but detected at high levels in the sera of EBV-positive patients lead to the finding of the blockade of extracellular AA influx by downregulating FATP2, a long-chain fatty acid transporter that mainly transports AA in EBV-infected lymphoma cells. Low AA levels in tumor cells induced by downregulation of FATP2 expression confer resistance to ferroptosis and support tumor growth. TCGA data analysis and xenograft models have demonstrated that the axis plays a critical role in several types of cancers, especially poor prognostic cancers, such as glioblastoma and melanoma. Overall, our in vitro, in vivo, in silico, and clinical data suggest that several cancers exert oncogenic activity by maintaining their special lipid composition via extracellular blockade.
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INTRODUCTION: Cutaneous T-cell lymphoma (CTCL) is a chronic condition with low malignancy. The combined use of therapeutic agents and photo(chemo)therapy is widely applied for the treatment of CTCL. The efficacy and safety of bexarotene and photo(chemo)therapy combination therapy were previously confirmed in Japanese patients with CTCL. The efficacy and safety of the bexarotene and photo(chemo)therapy combination therapy was compared with bexarotene monotherapy in Japanese patients with CTCL. METHODS: This was a randomized, open-label, two-parallel-group, active-control specified clinical study in Japanese patients diagnosed with CTCL carried out over 8 weeks with a study extension conducted at two institutions. This study was registered in Japan Registry of Clinical Trials (jRCTs041180094). RESULTS: In the combination therapy group, 22 subjects received oral bexarotene (300 mg/m2 body surface area) once daily, followed by bath-psoralen and ultraviolet (UV) A or narrowband UVB. In the monotherapy group, 24 subjects received oral bexarotene (300 mg/m2) once daily. The efficacy analysis using the modified Severity-Weighted Assessment Tool, which included 39 patients, showed a response rate of 81.0% (17/21) in the combination therapy group and 83.3% (15/18) in the monotherapy group. No statistically significant difference was detected between groups. In the combination therapy group, four subjects showed a complete clinical response or complete response, and subjects with a partial response exhibited a high rate of skin lesion resolution, significantly better than in the monotherapy group. In the safety analysis, which included 46 treated subjects (22 in the combination therapy group and 24 in the monotherapy group), no adverse events or adverse drug reactions were reported in either group. CONCLUSION: Both bexarotene and photo(chemo)therapy combination therapy and bexarotene monotherapy were therapeutically effective in Japanese patients with CTCL and well tolerated. Combination therapy led to a higher skin lesion resolution rate and greater therapeutic effects compared with monotherapy. TRIAL REGISTRATION: jRCTs041180094.
This study evaluated the efficacy and safety of bexarotene monotherapy compared with bexarotene and photo(chemo)therapy combination therapy in Japanese patients with cutaneous T-cell lymphoma (CTCL). The study was a randomized, open-label, two-parallel-group, active-control specified clinical study in patients diagnosed with CTCL performed over an 8-week period with a study extension conducted in two institutions. In the combination therapy group, bexarotene (300 mg/m2 body surface area) was administered orally once daily to 22 subjects, followed by treatment with bath-psoralen and ultraviolet A (bath-PUVA) or narrowband UVB. In the bexarotene monotherapy group, bexarotene (300 mg/m2) was administered orally once daily to 24 subjects. Efficacy was assessed using the modified Severity-Weighted Assessment Tool. Among the 39 subjects analyzed for treatment efficacy, the response rate of the combination therapy group was 81.0% (17/21) and that of the monotherapy group was 83.3% (15/18). Differences between the two treatment groups were not statistically significant. Of the 21 subjects in the combination therapy group, 4 had a complete clinical response or complete response, and those with a partial response showed a higher skin lesion resolution rate than in the monotherapy group. The safety analysis revealed no reports of adverse events or adverse drug reactions among the 46 treated subjects (combination therapy group = 22; monotherapy group = 24). Thus, both bexarotene and photo(chemo)therapy combination therapy and bexarotene monotherapy were therapeutically effective and well tolerated in Japanese patients with CTCL. Patients receiving the combined therapy, however, showed a higher rate of skin lesion resolution.
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Resistência à Insulina , Inibidores da Fosfodiesterase 4 , Psoríase , Anti-Inflamatórios não Esteroides/uso terapêutico , Humanos , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/uso terapêutico , Psoríase/tratamento farmacológico , Índice de Gravidade de Doença , Talidomida/análogos & derivados , Talidomida/farmacologia , Talidomida/uso terapêutico , Resultado do TratamentoRESUMO
Psoriasis is a chronic inflammatory proliferative skin disease involving various types of chemokines regulating immune cell migration, localization, and activation. Bath psoralen plus UVA (PUVA) treatment is an established phototherapy for psoriasis, but its effects on chemokine levels remain unknown. We investigated the levels of 22 serum chemokines in 20 patients with psoriasis first treated with bath PUVA therapy between 2007 and 2011 in a single center and analyzed the associations between the chemokines and disease severity (PASI) before and after therapy to investigate the mechanisms of action of bath PUVA therapy. Before bath PUVA therapy, the PASI scores correlated with the serum levels of CCL17 (r = 0.581), CCL18 (r = 0.462), CCL19 (r = 0.477), and CXCL16 (r = 0.524). After bath PUVA, the serum levels of CCL17, CCL22, CXCL1, and CXCL9 were significantly decreased. Heatmap clustering and network analysis based on statistically significant Spearman correlations among the chemokines showed distinctive changes in the chemokine signature. Our findings revealed that the levels of several chemokines correlated with the disease state of psoriasis. Furthermore, bath PUVA therapy reduced the secretion of keratinocyte-derived chemokines that induce the migration of immune cells important for psoriasis pathogenesis, partly revealing the mechanism of the therapeutic activity.
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Detailed analysis of the cells that infiltrate lesional skin cannot be performed in skin biopsy specimens using immunohistochemistry or cell separation techniques because enzyme treatments applied during the isolation step can destroy small amounts of protein and minor cell populations in the biopsy specimen. Here, we describe a method for isolating T cells from drops of whole blood obtained from lesions during skin biopsy in patients with cutaneous T-cell lymphoma. Lesional blood is assumed to contain lesional resident cells, cells from capillary vessels, and blood overflowing from capillary vessels into the lesion area. The lesional blood showed substantial increases in distinct cell populations, chemokines, and the expression of various genes. The proportion of CD8+CD45RO+ T cells in the lesional blood negatively correlated with the modified severity-weighted assessment tool scores. CD4+CD45RO+ T cells in the lesional blood expressed genes associated with the development of cancer and progression of cutaneous T-cell lymphoma. In addition, CD8+CD45RO+ T cells in lesional blood had unique T-cell receptor repertoires in lesions of each stage. Assessment of lesional blood drops might provide new insight into the pathogenesis of mycosis fungoides and facilitate evaluation of the treatment efficacy for mycosis fungoides as well as other skin inflammatory diseases.
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Biomarcadores Tumorais , Linfoma Cutâneo de Células T/sangue , Linfoma Cutâneo de Células T/etiologia , Microambiente Tumoral/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Gerenciamento Clínico , Suscetibilidade a Doenças , Feminino , Humanos , Imuno-Histoquímica , Imunofenotipagem , Contagem de Linfócitos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Linfoma Cutâneo de Células T/diagnóstico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologiaRESUMO
BACKGROUND: Maximum cyclobutane pyrimidine dimer (CPD) formation in the skin induced by ultraviolet B (UVB) irradiation is thought to occur within a few minutes and is immediately decreased by the DNA repair system. OBJECTIVE: We evaluated the time course and differential effects of narrowband (NB-UVB) and broadband (BB-UVB) UVB on CPD formation. METHODS: We investigated CPD formation at various time-points in vivo, from 3 min to 72 h, after UVB irradiation using 2 mouse strains, C57BL/6 J and BALB/c. The backs of the mice were shaved and irradiated with NB-UVB or BB-UVB. Skin specimens were obtained and stained with anti-CPD antibody. Positive signals in the epidermis were measured using ImageJ. DNA was extracted from the isolated epidermis and subjected to quantitative CPD analysis by enzyme-linked immunosorbent assay (ELISA). RESULTS: CPDs induced by UVB irradiation (1 minimum erythemal dose) in epidermal skin were detected in the nucleus. Although the CPD levels increased immediately after irradiation (3 min), the highest level was detected at 1 h and the increase lasted 24-48 h after irradiation. BB-UVB tended to induce greater CPD levels than NB-UVB in both mouse strains. The ELISA showed similar results. CONCLUSIONS: CPDs were induced immediately after UV irradiation, with the maximum level observed 1 h after irradiation. BB-UVB irradiation tended to induce greater levels of CPD formation. In addition to the direct effects of UVB, the presence of CPDs in hair follicles, which were not irradiated by UVB, suggests that reactive oxygen species are also involved in CPD formation in the skin.
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Dano ao DNA/efeitos da radiação , Epiderme/efeitos da radiação , Dímeros de Pirimidina/análise , Raios Ultravioleta/efeitos adversos , Animais , Reparo do DNA , Epiderme/química , Epiderme/metabolismo , Folículo Piloso/química , Folículo Piloso/metabolismo , Camundongos , Modelos Animais , Dímeros de Pirimidina/efeitos da radiação , Espécies Reativas de Oxigênio/metabolismo , Fatores de TempoAssuntos
Fármacos Dermatológicos/farmacologia , Resistência a Medicamentos/genética , Infliximab/farmacologia , Subunidade p40 da Interleucina-12/genética , Psoríase/tratamento farmacológico , Adulto , Fármacos Dermatológicos/uso terapêutico , Feminino , Predisposição Genética para Doença , Técnicas de Genotipagem , Humanos , Infliximab/uso terapêutico , Subunidade p40 da Interleucina-12/imunologia , Japão , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Psoríase/diagnóstico , Psoríase/genética , Psoríase/imunologia , Falha de TratamentoRESUMO
Ultraviolet (UV)A1 phototherapy is effective for T-cell-mediated skin diseases such as atopic dermatitis and mast cell-mediated skin diseases such as mastocytoma. UVA1 phototherapy is also effective against the sclerotic lesions of systemic sclerosis and morphea. Currently, in Japan, access to UVA1 phototherapy is limited because the UVA1 phototherapy device has not yet been approved. On the basis of our experience, we report three patients with localized scleroderma who responded successfully to UVA1 phototherapy. Efficacy was assessed by histological analysis and elastography. UVA1 successfully ameliorated sclerotic lesions, including morphea, linear scleroderma and morphea lesions in a patient with limited cutaneous systemic sclerosis. No side-effects were observed during UVA1 phototherapy.
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Esclerodermia Localizada , Dermatopatias , Terapia Ultravioleta , Humanos , Japão , Fototerapia , Esclerodermia Localizada/radioterapia , Resultado do TratamentoRESUMO
PURPOSE: Topical active vitamin D3 application alone or in combination with topical steroid application is widely used to treat psoriasis. In Japan, combined calcipotriol hydrate/betamethasone dipropionate ointment has been used for patients with psoriasis vulgaris since September 2014. Current evidence regarding the incidence of hypercalcemia due to the use of this combination product, however, is insufficient. We evaluated the incidence of hypercalcemia following combined calcipotriol hydrate/betamethasone dipropionate ointment in patients with severe psoriasis vulgaris. METHODS: Japanese patients (n = 22) with extensive plaque psoriasis (body surface area: 20-30%) applied the combined calcipotriol hydrate/betamethasone dipropionate ointment once daily for 8 weeks, and their serum Ca concentrations were measured periodically. RESULTS: The mean serum Ca concentration changed only marginally, from 9.04 ± 0.34 mg/dL before treatment to 9.08 ± 0.39 mg/dL after 8 weeks of treatment. None of the patients had an elevated serum Ca concentration throughout the study. No cases of hypercalcemia were reported as an adverse event. No correlation was detected between the amount of the combined calcipotriol hydrate/betamethasone dipropionate ointment applied and changes in the serum Ca concentration. CONCLUSION: The incidence of hypercalcemia due to topical application of a combined calcipotriol hydrate/betamethasone dipropionate ointment is low in Japanese patients with severe psoriasis vulgaris.
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Betametasona/análogos & derivados , Calcitriol/análogos & derivados , Hipercalcemia/epidemiologia , Pomadas/química , Psoríase/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Betametasona/efeitos adversos , Betametasona/química , Betametasona/uso terapêutico , Calcitriol/efeitos adversos , Calcitriol/química , Calcitriol/uso terapêutico , Cálcio/sangue , Quimioterapia Combinada , Feminino , Humanos , Hipercalcemia/etiologia , Incidência , Japão , Masculino , Pessoa de Meia-Idade , Psoríase/patologia , Índice de Gravidade de Doença , Resultado do TratamentoAssuntos
Regulação da Expressão Gênica/efeitos da radiação , Imageamento Tridimensional , Proteínas de Filamentos Intermediários/metabolismo , Modelos Anatômicos , Pele/metabolismo , Raios Ultravioleta , Diferenciação Celular , Membrana Celular/patologia , Células Cultivadas , Relação Dose-Resposta à Radiação , Proteínas Filagrinas , Humanos , Queratinócitos/patologia , Pele/patologia , Pele/efeitos da radiação , Ácido Urocânico/metabolismoRESUMO
Findings from large epidemiologic studies indicate that there is a link between smoking and extrinsic skin ageing. We previously reported that matrix metalloproteinases (MMPs) mediate connective tissue damage in skin exposed to tobacco smoke extracts. Tobacco smoke contains more than 3800 constituents, including numerous water-insoluble polycyclic aromatic hydrocarbons (PAHs) that trigger aryl hydrocarbon receptor (AhR) signalling pathways. To analyse the molecular mechanisms involved in tobacco smoke-induced skin ageing, we exposed primary human fibroblasts and keratinocytes to tobacco smoke extracts. Hexane- and water-soluble tobacco smoke extracts significantly induced MMP-1 mRNA in both human cultured fibroblasts and keratinocytes in a dose-dependent manner. To clarify the involvement of the AhR pathway, we used a stable AhR-knockdown HaCaT cell line. AhR knockdown abolished the increased transcription of the AhR-dependent genes CYP1A1/CYP1B1 and MMP-1 induced by either of the tobacco smoke extracts. Furthermore, the tobacco smoke extracts induced 7-ethoxyresorufin-O-deethylase activity, which was almost completely abolished by AhR knockdown. Likewise, treating fibroblasts with AhR pathway inhibitors, that is, the flavonoids 3-methoxy-4-nitroflavone and α-naphthoflavone, blocked the expression of CYP1B1 and MMP-1. These findings suggest that the tobacco smoke extracts induce MMP-1 expression in human fibroblasts and keratinocytes via activation of the AhR pathway. Thus, the AhR pathway may be pathogenetically involved in extrinsic skin ageing.
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Queratinócitos/efeitos dos fármacos , Queratinócitos/fisiologia , Metaloproteinase 1 da Matriz/genética , Receptores de Hidrocarboneto Arílico/genética , Envelhecimento da Pele/fisiologia , Poluição por Fumaça de Tabaco/efeitos adversos , Hidrocarboneto de Aril Hidroxilases/genética , Linhagem Celular , Células Cultivadas , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1B1 , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/fisiologia , Hexanos/farmacologia , Humanos , Queratinócitos/citologia , Metaloproteinase 1 da Matriz/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Envelhecimento da Pele/efeitos dos fármacos , SolubilidadeRESUMO
BACKGROUND: Photo(chemo)therapy is widely used to treat psoriasis, the pathogenesis of which might be caused by an imbalance of Th17 cells/regulatory T cells (Treg). In the present study, we evaluated the effects of photo(chemo)therapy on the Th17/Treg balance and Treg function. METHODS: Peripheral blood was obtained from psoriasis patients treated with bath-psoralen ultraviolet A (UVA, n = 50) or narrowband ultraviolet B (UVB, n = 18), and age-matched healthy volunteers (n = 20). CD3(+)CD4(+)IL-17A(+) or CD4(+)CD25(+)Foxp3(+)cells were analyzed to estimate Th17 or Treg number by fluorescence-activated cell sorting. Moreover, CD4(+) CD25(-) T cells from patients treated with PUVA(n = 14) were incubated in CFSE and activated with or without CD4(+) CD25(+)T cells, and the suppressive function of CD4(+) CD25(+)T cells were analyzed. RESULTS: Photo(chemo)therapy significantly reduced Th17 levels from 5.66 ± 3.15% to 2.96 ± 2.89% in patients with increased Th17 (Th17/CD4>3.01% [mean+SD of controls]). In contrast, photo(chemo)therapy significantly increased Treg levels from 2.77 ± 0.75 to 3.40 ± 1.88% in patients with less than 4.07% Treg level, defined as the mean of controls. Furthermore, while Treg suppressed the CD4(+)CD25(-) T cell proliferation to a greater extent in controls (Treg Functional Ratio 94.4 ± 4.28%) than in patients (70.3±25.1%), PUVA significantly increased Treg Functional Ratio to 88.1 ± 6.47%. Th17 levels in severe patients (>30 PASI) were significantly higher as compared to controls. Th17 levels that were left after treatment in the patients not achieving PASI 50 (3.78 ± 4.18%) were significantly higher than those in the patients achieving PASI 75 (1.83±1.87%). Treg levels in patients achieving PASI 90 (4.89 ± 1.70%) were significantly higher than those in the patients not achieving PASI 90 (3.90 ± 1.66%). Treg levels prior to treatment with Th17 high decreased group (5.16 ± 2.20%) was significantly higher than that with Th17 high increased group (3.33 ± 1.39%). CONCLUSION: These findings indicate that Treg is dysfunctional in psoriasis patients, and photochemotherapy restores those dysfunctional Treg. Photo(chemo)therapy resolved the Th17/Treg imbalance in patients with psoriasis.
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Ficusina/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Psoríase/tratamento farmacológico , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/imunologia , Banhos , Estudos de Casos e Controles , Proliferação de Células , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Psoríase/imunologia , Psoríase/patologia , Índice de Gravidade de Doença , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Células Th17/imunologia , Células Th17/patologia , Raios UltravioletaAssuntos
Alopecia em Áreas/fisiopatologia , Antígenos CD4/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/fisiologia , Adulto , Idoso , Alopecia em Áreas/imunologia , Alopecia em Áreas/patologia , Biomarcadores/metabolismo , Estudos de Casos e Controles , Contagem de Células , Proliferação de Células , Criança , Suscetibilidade a Doenças , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
In this open-label study, we investigated the efficacy of excimer light (308 nm) with a filter to cut off wavelengths below 297 nm for the treatment of palmoplantar pustulosis (PPP). Twenty patients with PPP were recruited and treated once a week for a total of 30 sessions. Patient response was assessed every 10 sessions based on the Palmoplantar Pustulosis Area and Severity Index (PPPASI) score. Levels of Th17 cells and regulatory T cells (Treg) in the peripheral blood in patients with PPP were also evaluated. Mean PPPASI score was 19.5 at baseline, 13.2 at 10 treatments, 10.9 at 20 treatments and 9.5 at 30 treatments. Th17 levels after excimer therapy were not significantly different from those at baseline. In contrast, Treg levels after excimer therapy were significantly higher than those at baseline.