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1.
Dermatol Ther ; : e15303, 2022 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-34984792

RESUMO

Chronic spontaneous urticaria (CSU) is characterized by the spontaneous development of wheals, itching, and/or angioedema, for ≥6 weeks. In China, non-sedating H1-antihistamines (H1AH) are the recommended first-line treatment, with escalation up to 4× the standard dose in symptomatic patients to achieve control. Treatment options for Chinese patients who remain symptomatic on H1AH treatment are limited. This 20-week randomized, double blind, placebo-controlled, parallel-group study investigated the efficacy and safety of omalizumab as an add-on therapy for the treatment of patients with CSU who remained symptomatic despite H1AH treatment in China. Adult patients (N = 418) diagnosed with refractory CSU for ≥6 months were randomized (2:2:1) to receive omalizumab 300 mg (OMA300), omalizumab 150 mg (OMA150) or placebo, subcutaneously, every 4 weeks. Primary outcome was change from baseline to week 12 in weekly itch severity score (ISS7). Safety was assessed by rates of adverse events (AEs). Demographic and disease characteristics at baseline were comparable across treatment groups. At week 12, statistically significant greater decreases from baseline were observed in ISS7 with OMA300 (least square mean difference [LSM]: -4.23; 95% confidence interval [CI]: -5.70, -2.77; p < 0.001) and OMA150 (LSM: -3.79; 95% CI: -5.24, -2.33; p < 0.001) versus placebo. Incidence of treatment-emergent AEs over 20 weeks was slightly higher with OMA300 (71.3%) compared to OMA150 and placebo groups (64.7% and 63.9%, respectively). The incidences of serious AEs were balanced between groups. This study demonstrated the efficacy and safety of omalizumab in Chinese adult patients with CSU who remained symptomatic despite H1AH therapy.

2.
Stem Cells Dev ; 2022 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-35044224

RESUMO

Extrinsic injury can evoke intrinsic stimulation and subsequently initiate the physiological repair process. This study aims to investigate whether clinically acceptable micro-injury could be employed to create local stimuli to induce hair regeneration and vitiligo repigmentation. A novel device was designed and manufactured to precisely control the micro-injury parameters. Then the most appropriate extent of micro-injury without over-damaging the skin was evaluated. Finally, the effects of micro-injury on hair regeneration and vitiligo repigmentation were examined by macroscopical observation, histological staining, gene and protein expression analysis. We discover that proper micro-injury effectively induces hair regeneration by activating the hair follicle stem cell proliferation and migration downwards to the hair matrix, finally shifting the hair follicle stage from telogen into anagen. On vitiligo model mice, micro-injury also induces the hair follicle melanocyte stem cells to migrate upwards to the interfollicular epidermis, activating and giving rise to melanocytes to repopulate the vitiligo lesion. Mechanistic analysis indicates that the canonical Wnt/-catenin pathway plays a key role in the micro-injury-induced repair process. The present study demonstrates that micro-injury has great potential in inducing hair regeneration and vitiligo repigmentation, laid a foundation to develop a micro-injury-based treatment method in alopecia and vitiligo.

3.
J Am Acad Dermatol ; 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-35026342

RESUMO

BACKGROUND: Vunakizumab (SHR-1314) is a novel interleukin-17A monoclonal antibody that has shown preliminary efficacy and tolerability in phase I trials. OBJECTIVE: To evaluate the efficacy and safety of vunakizumab in moderate-to-severe plaque psoriasis. METHODS: In this 36-week, multi-center, double-blinded, phase II study (NCT03463187), 187 eligible patients with moderate-to-severe plaque psoriasis were randomized 1:1:1:1:1 to receive vunakizumab (40, 80, 160, or 240 mg) or placebo subcutaneously every four weeks until week 12 (2 more drug administrations for the vunakizumab groups on week 16/20). The primary endpoint was at least 75% improvement in the psoriasis area and severity index (PASI 75) at week 12. RESULTS: At week 12, there were significantly greater proportions of PASI 75 responders in all vunakizumab groups compared to placebo (40, 80, 160, 240 mg: 56.8%, 65.8%, 81.6%, 86.5% vs 5.4%; all P < .001); the proportions of patients achieving physician's global assessment response of 0 or 1 were also higher with vunakizumab (45.9%, 47.4%, 60.5%, 73.0% vs 8.1%). No unexpected adverse effects were observed. LIMITATIONS: The study was relatively short in duration and included no active control. CONCLUSION: Vunakizumab showed promising efficacy for moderate-to-severe plaque psoriasis, with good tolerability, warranting further investigation in larger and longer-term studies.

4.
Dermatol Ther ; : e15295, 2021 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-34967065

RESUMO

There are multiple treatment modalities for periungual warts (PWs), although most are destructive and painful, limiting their application. Radiotherapy is a non-invasive method suitable for treating PW patients with contraindications to invasive procedures. To investigate the efficacy and safety of topical Tretinoin combined with Superficial X-ray therapy (SXRT) in treating PWs. This study included patients with 65 PWs who underwent treatment and a 3-month follow-up. Twenty four PWs were subjected to SXRT alone (group A). The remaining 41 PWs were subjected to SXRT combined with the application of the Tretinoin cream from the first day (group B). The overall clinical response rate, recurrence rates, cosmetic outcomes, and adverse events were observed during the follow-up period. The complete clearance rate (75% vs. 92.7% in groups A and B, respectively) and healing times (19.9 vs. 16.0 days in groups A and B, respectively) between the two groups were significantly different (p < 0.046 and 0.04), indicating the combination treatment is more effective. Notably, there was no damaging or permanent deformation on the nail, and the other adverse effects were mild and bearable. Topical Tretinoin combined with SXRT therapy is an effective strategy for treating PWs, with minor side effects. It is painless and with excellent cosmetic outcomes.

5.
J Photochem Photobiol B ; 226: 112350, 2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34785489

RESUMO

Solar UVA irradiation-generated reactive oxygen species (ROS) induces the expression of matrix metalloproteinase 1 (MMP-1), leading to photoaging, however the molecular mechanism remains unclear. In the present study, we found that eriodictyol remarkably reduces UVA-mediated ROS generation and protects the skin cells from oxidative damage and the ensuing cell death. Moreover eriodictyol pretreatment significantly down-regulates the UVA-induced MMP-1 expression, and lowers the inflammatory responses within the skin cells. Pretreatment with eriodictyol upregulates the expression of tissue inhibitory metalloproteinase 1 (TIMP-1) and collagen-I (COL-1) at the transcriptional level in a dose-dependent manner. UVA-induced phosphorylation levels of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and p38 leading to increased MMP-1 expression are significantly reduced in eriodictyol-treated skin cells. In addition, eriodictyol pretreatment significantly suppresses inflammatory cytokines and inhibits the activation of MAPK signaling cascades in skin cells. Taken together, our results demonstrate that eriodictyol has both potent anti-inflammatory and anti-photoaging effects.

6.
Am J Transl Res ; 13(1): 420-433, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33527034

RESUMO

Although the abnormal expression of members of the E2F family has been reported to participate in carcinogenesis in many human types of cancer, the bioinformatics role of the E2F family in melanoma is unknown. This research was designed to detect the expression, methylation, prognostic value and potential effects of the E2F family in melanoma. We investigated E2F family mRNA expression from the Oncomine and GEPIA databases and their methylation status in the MethHC database. Meanwhile, we detected the relative E2F family expression levels by qPCR and immunohistochemistry. Kaplan-Meier Plotter was used to draw survival analysis charts, and gene functional enrichment analyses were applied through cBioPortal database analysis. E2F1/2/3/4/5/6 mRNA and proteins were clearly upregulated in cutaneous melanoma patients, and high expression levels of E2F1/2/3/6 were statistically related to high methylation levels. Increased mRNA expression of E2F1/2/3/6 was related to lower overall survival rates (OS) and disease-free survival (DFS) in cutaneous melanoma cases. Meanwhile, E2F1/2/3/6 carried out these effects through regulating multiple signaling pathways, including the MAPK, PI3K-Akt and p53 signaling pathways. Taking together, our findings suggest that E2F1/2/3/6 could act as potential targets for precision therapy in cutaneous melanoma patients.

7.
Dermatology ; 237(4): 603-610, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33352561

RESUMO

BACKGROUND: Topical agents are still the mainstay for the treatment of mild-to-moderate plaque psoriasis, in which fixed combinations play an important role. Tazarotene/betamethasone dipropionate (Taz/BD) cream is a novel fixed combination approved for treating plaque psoriasis in China, but its efficacy and safety have not been verified in a real-world environment. OBJECTIVES: The primary objective was to investigate the efficacy and safety of Taz/BD cream in treating plaque psoriasis. The secondary objectives were to assess its relapse after discontinuation and the efficacy and safety profiles during retreatment. METHODS: A prospective, multicenter, large-scale observational study was conducted. Adult patients with chronic plaque psoriasis involving <20% of the body surface area were enrolled. Taz/BD cream was applied once daily for 4 weeks. Patients who achieved ≥90% improvement in the Psoriasis Area and Severity Index (PASI) from baseline to week 4 were followed up to investigate relapse after drug withdrawal. Relapsed patients underwent another 4-week treatment. RESULTS: In total, 2,299 eligible patients were enrolled, and 2,095 patients (91.1%) completed the 4-week study. The mean PASI improvement at week 4 was 53.7%, and the PASI 50/75 response rates were 62.5 and 26.8%, respectively. The mean PASI reduction in plaque induration, desquamation and erythema were 58.3, 61.0 and 40.0%, respectively (p < 0.001). Adverse reactions occurred in 445 patients (20.8%) at week 4. The most frequently reported adverse reactions were local skin irritation, including pruritus (10%), pain (6.7%), erythema (6.1%) and desquamation (1.8%). During the post-treatment period, 47 patients (24.0%) relapsed within 8 weeks after drug discontinuation. Forty-five patients were retreated for another 4 weeks, and the PASI 50/75 response rates were 72.7 and 40.9%, respectively. There were no unexpected safety signals during retreatment. CONCLUSION: Taz/BD cream is effective and well tolerated in treating mild-to-moderate plaque psoriasis under near real-world conditions and demonstrates efficacy and safety during retreatment.

8.
Biomed Pharmacother ; 131: 110663, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32858501

RESUMO

The glyoxalase system is a ubiquitous enzymatic network which plays important roles in biological life. It consists of glyoxalase 1 (GLO1), glyoxalase 2 (GLO2), and reduced glutathione (GSH), which perform an essential metabolic function in cells by detoxifying methylglyoxal (MG) and other endogenous harmful metabolites into non-toxic d-lactate. MG and MG-derived advanced glycation endproducts (AGEs) are associated with various diseases, such as diabetes, cardiovascular disease, neurodegenerative disorders and cancer, and GLO1 is a key rate-limiting enzyme in the anti-glycation defense. The abnormal activity and expression of GLO1 in various diseases make this enzyme a promising target for drug design and development. This review focuses on the regulatory mechanism of GLO1 in diverse pathogenic conditions with a thorough discussion of GLO1 regulators since their discovery, including GLO1 activators and inhibitors. The different classes, chemical structure and structure-activity relationship are embraced. Moreover, assays for the discovery of small molecule regulators of the glyoxalase system are also introduced in this article. Compared with spectrophotometer-based assay, microplate-based assay is a more simple, rapid and quantitative high-throughput method. This review will be useful to design novel and potent GLO1 regulators and hopefully provide a convenient reference for researchers.


Assuntos
Produtos Biológicos/metabolismo , Produtos Biológicos/uso terapêutico , Lactoilglutationa Liase/metabolismo , Aldeído Pirúvico/metabolismo , Animais , Produtos Biológicos/farmacologia , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Glicosilação/efeitos dos fármacos , Humanos , Lactoilglutationa Liase/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Aldeído Pirúvico/antagonistas & inibidores
9.
Fitoterapia ; 141: 104484, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31954180

RESUMO

The Src-homology 2 domain-containing phosphatase 2 (SHP2), encoded by PTPN11, has been reported oncogenic tyrosine phosphatase associated with various tumors and played critical roles in many cell signaling events. Targeting SHP2 by small molecules may be a promising way for cancer therapy. Herein, a new abietane diterpenoid, named 3-acetoxylteuvincenone G (3-AG), was isolated from the whole plants of Ajuga ovalifolia var. calantha. The structure of the new compound was elucidated by means of extensive spectroscopic analyses. Using recombinant enzyme activity assay and cellular thermal shift assay, we found that 3-AG was a selective inhibitor of SHP2. Molecular docking suggested 3-AG displayed an orientation favorable to nucleophilic attack in the catalytic domain of SHP2. 3-AG suppressed A549 cell proliferation (IC50 = 10.79 ± 0.14 µM), invasion and induced cell apoptosis through SHP2/ERK1/2 and SHP2/AKT pathways. In summary, 3-AG, a potent, selective, and efficacious SHP2 inhibitor, may be a promising small molecule to treat human lung epithelial cancer.


Assuntos
Abietanos/farmacologia , Apoptose/efeitos dos fármacos , Diterpenos/química , Diterpenos/farmacologia , Lamiaceae/química , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Células A549 , Abietanos/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética
10.
Arch Dermatol Res ; 312(1): 41-49, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31538224

RESUMO

To investigate the protective effect of ethanol extract of Gynura bicolor (GB) against UVB-induced photodamage of skin and the possible mechanisms. DPPH (1,1-diphenyl-2-pico radical) test was used to detect the antioxidant capacity of ethanol extract of Gynura bicolor (GB). The protective effects of GB against UVB irritation were detected both in Hacat cells and photodamage rat models. UVB irradiation could inhibit viability and induce apoptosis of Hacat cells in a dose-dependent manner. The pretreatment of Hacat cells by GB could obviously reverse the effects in a dose-dependent manner. The mRNA and protein expressions of p53, Bax, caspase-3 were increased, while anti-apoptotic protein Bcl-2 was decreased and this effect could be reversed by GB pretreatment in a dose-dependent manner. In vivo, the application of GB could alleviate the skin damage of SD rats and improve the superficial inflammation of the dermis as well as inhibit the expressions of P53 and Caspase-3 induced by UVB irradiation. Ethanol extract of Gynura bicolor could protect the photodamage of human Hacat keratinocytes and SD rats against UVB irradiation by inhibiting P53-mediated Bcl-2/ BAX/Casaspe-3 apoptosis pathway.


Assuntos
Asteraceae/química , Etanol/química , Extratos Vegetais/farmacologia , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Proteína Supressora de Tumor p53/metabolismo , Raios Ultravioleta/efeitos adversos , Animais , Apoptose , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/efeitos da radiação , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Proteína Supressora de Tumor p53/genética , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
11.
Mater Sci Eng C Mater Biol Appl ; 107: 110254, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31761216

RESUMO

Polymorphous light eruption (PLE) is one of the acquired idiopathic photodermatosis mainly induced by immoderate UV radiation. In order to realize UV protection and medicine administration simultaneously for polymorphous light eruption protection and therapy, Acetyl-11-keto-ß-boswellic acid (AKBA) loaded Zinc Oxide (ZnO) nanoparticles of which drug release behavior is UV-controlled has been successfully synthesized. Such nanoparticles can not only reflect UV but also transfer the energy to release AKBA which presents an excellent antioxidant and anti-inflammatory effects. In addition, they are biocompatible to HaCaT cells. As a result, they have a great potential in combining UV protection and medicine administration simultaneously for PLE protection and therapy.


Assuntos
Nanopartículas/química , Triterpenos/química , Raios Ultravioleta , Óxido de Zinco/química , Anti-Inflamatórios/química , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Antioxidantes/química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/metabolismo , Materiais Biocompatíveis/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Liberação Controlada de Fármacos , Humanos , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Nanopartículas/toxicidade , Transtornos de Fotossensibilidade/patologia , Transtornos de Fotossensibilidade/prevenção & controle , Espécies Reativas de Oxigênio , Triterpenos/metabolismo , Triterpenos/farmacologia
12.
Oncol Lett ; 18(3): 2917-2922, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31452772

RESUMO

The development of melanoma may involve long non-coding RNAs (lncRNAs); however, the functions of the majority of lncRNAs in melanoma are unknown. The present study investigated the role of long intergenic non-protein coding RNA p53 induced transcript (LINC-PINT) in melanoma. In the present study, quantitative PCR was used to detect gene expression, overexpression experiments were performed to analyze gene interactions and CCK-8 assays were used to analyze cell proliferation. LINC-PINT was downregulated, while BRAF-activated non-coding RNA (BANCR) was upregulated in melanoma tissues compared with normal adjacent tissues. Expression levels of LINC-PINT decreased, while expression levels of BANCR increased with increasing tumor thickness. The expression levels of LINC-PINT and BANCR were inversely associated in melanoma tissues but not in healthy adjacent tissue. LINC-PINT overexpression downregulated BANCR expression in melanoma cells, while BANCR overexpression did not significantly affect LINC-PINT expression. LINC-PINT overexpression inhibited melanoma cell proliferation in vitro compared to controls. BANCR overexpression attenuated the effects of LINC-PINT overexpression. The present study revealed that lncRNA LINC-PINT is downregulated in melanoma and may regulate melanoma cell proliferation by downregulating lncRNA BANCR.

13.
Cell Commun Signal ; 17(1): 3, 2019 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-30634993

RESUMO

BACKGROUND: Despite therapeutic advancements (e.g. B-RAF inhibitors) targeting cutaneous melanoma, many cellular processes, including inducible heme oxygenase 1 (HO-1), counteract treatments for malignancies. So there is an urgent need to find biological treatment targets, develop new therapeutic approaches and achieve longer responses. This study aimed to explore the relationship of HO-1 and B-Raf via mediating ERK1/2 signaling on cell cycle in melanoma. METHODS: Immunohistochemistry was applied to evaluate the levels of HO-1 and B-Raf expression in melanoma tissues and adjacent healthy tissues. Co-immunoprecipitation (Co-IP) assessed the interaction of HO-1 with B-Raf. Further study overexpression and knock-down of HO-1 in A375 cell lines, especially knockout HO-1 using CRISPR-Cas9, verified HO-1 regulate cell proliferation in vivo and in vitro. Finally, Western blot analysis and qRT-PCR were performed to investigate the mechanisms by which HO-1 mediates cell cycle by B-RAF-ERK1/2 signaling. RESULTS: First, histology and Co-IP show that HO-1 interacts with B-Raf directly in melanoma tissue. Further study illustrated that HO-1 overexpression promotes melanoma cell proliferation while HO-1 reduction represses melanoma cell proliferation because of HO-1 affects cell cycle. Mechanistic studies revealed that HO-1 was associated with a marked activation of B-RAF-ERK1/2 signaling and led to CDK2/cyclin E activation, thereby promoting melanoma proliferation. CONCLUSIONS: Our result reveals a previously unknown mechanism that the HO-1-B-RAF-ERK axis plays an important role in melanoma cell proliferation. Therapeutic target on HO-1 could be a novel method for treating melanoma.


Assuntos
Heme Oxigenase-1/metabolismo , Sistema de Sinalização das MAP Quinases , Melanoma/metabolismo , Melanoma/patologia , Proteínas Proto-Oncogênicas B-raf/metabolismo , Animais , Sequência de Bases , Ciclo Celular , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Camundongos Nus , Fosforilação , Ligação Proteica
14.
Anticancer Drugs ; 30(1): 56-64, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30198914

RESUMO

The vitamin A derivative 9-cis-retinoic acid (9-cis-RA) has been used for the treatment and prevention of cutaneous T-cell lymphoma (CTCL). However, the precise mechanism by which 9-cis-RA treatment ameliorates CTCL remains elusive. Our research shows that 9-cis-RA inhibits proliferation and induces apoptosis in CTCL cells in a dose-dependent and time-dependent manner. 9-Cis-RA also induced G0/G1 cell cycle arrest by downregulation of cyclin D1. We confirmed that 9-cis-RA significantly decreased phosphorylation of JAK1, STAT3, and STAT5 and downregulated Bcl-xL and cyclin D1, indicating that 9-cis-RA inhibited the activation of JAK/STAT signaling. Meanwhile, 9-cis-RA also activated classical RA-mediated transcription by retinoic acid receptors (RAR) and/or retinoid X receptors (RXR) in a CTCL cell line. Thus, 9-cis-RA may be effective for chemotherapy and may prevent human CTCL by inhibiting proliferation and inducing apoptosis by inhibition of the JAK/STAT pathway and activation of the RAR/RXR pathway.


Assuntos
Alitretinoína/farmacologia , Linfoma Cutâneo de Células T/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Janus Quinases/antagonistas & inibidores , Janus Quinases/biossíntese , Janus Quinases/genética , Janus Quinases/metabolismo , Linfoma Cutâneo de Células T/genética , Linfoma Cutâneo de Células T/metabolismo , Linfoma Cutâneo de Células T/patologia , Nitrilas , Pirazóis/farmacologia , Pirimidinas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores do Ácido Retinoico/biossíntese , Receptores do Ácido Retinoico/genética , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Fatores de Transcrição STAT/antagonistas & inibidores , Fatores de Transcrição STAT/biossíntese , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/metabolismo , Neoplasias Cutâneas/patologia
15.
Cell Commun Signal ; 16(1): 58, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-30219085

RESUMO

BACKGROUND: The extensive involvement of microRNA (miRNA) in the pathophysiology of psoriasis is well documented. However, in order for this information to be useful in therapeutic manipulation of miRNA levels, it is essential that detailed functional mechanisms are elucidated. This study aimed to explore the effects of IL-6 targeting by let-7b and ERK1/2 mediated signaling on keratinocyte differentiation in psoriasis. METHODS: Following imiquimod cream (IMQ) application to let-7bTG (keratinocyte-specific let-7b overexpression mouse) and control mice for 7 days, we analyzed erythema, scaling and thickening of skin. A dual luciferase reporter assay and bioinformatics was carried out to detect target gene of let-7b. Additionally, the differentiation markers were measured. Immunohistochemistry analyses demonstrate a relationship of let-7b with IL-6 and ERK signaling. RESULTS: we found let-7bTG inhibits acanthosis and reduces the disease severity by treatment with IMQ compared to wild-type mice. Further study illustrated that let-7b promotes differentiation of keratinocytes in vivo and in vitro. Using bioinformatics and reporter gene assays, we found that IL-6 is a target gene of let-7b. In psoriasis, high expression levels of IL-6 lead to increased acivation of p-ERK1/2. High levels of let-7bTG transgene expression suppresses IL-6 expression and leads to increased keratinocyte differentiation. Moreover, let-7b acts as an upstream negative regulator of the ERK signaling pathway in keratinocytes of psoriasis. CONCLUSIONS: Our result reveals a previously unknown mechanism for regulation of IL-6 levels during psoriasis by let-7b and highlights a critical role for the ERK1/2 signaling pathway in epidermal differentiation during psoriasis. TRIAL REGISTRATION: The ethical approval for this study was from the Affiliated Hospital of Medical University of Anhui _ Fast_ PJ2017-11-14.


Assuntos
Diferenciação Celular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Interleucina-6/genética , Queratinócitos/patologia , Sistema de Sinalização das MAP Quinases/genética , MicroRNAs/genética , Psoríase/genética , Psoríase/patologia , Regiões 3' não Traduzidas/genética , Animais , Linhagem Celular , Feminino , Humanos , Masculino , Camundongos , Fosforilação/genética
16.
Free Radic Res ; 52(11-12): 1359-1370, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30693837

RESUMO

Ultraviolet A (UVA) irradiation is a potential environmental stressor, which contributes to inflammation, photoaging, and carcinogenesis. UVA causes endoplasmic reticulum stress, hence phosphorylates the α subunit of eIF2. Meanwhile, UVA also induces expression of haem oxygenase-1 (HO-1) and nuclear factor erythroid-derived two related factor 2 (Nrf2) in human skin cells. In mouse JB6 cell, we found high dose UVA could change cell morphology, cause cell viability loss. UVA irradiation activated phosphorylation of eIF2α and Nrf2-HO-1 pathway in a dose-dependent manner. Besides, modulation of eIF2α phosphorylation status could alter expression pattern of Nrf2-HO-1 signalling. Salubrinal, a selective inhibitor of eIF2α dephosphorylation, increased the S phase in cell cycle of JB6 cells after UVA irradiation, suggesting phosphorylation status of eIF2α may affect cellular homeostasis under UVA irradiation. The study directed to further acknowledge about the relationship of UVA-induced eIF2α phosphorylation and Nrf2-HO-1 pathway, which may play a role in phototherapy and photo protection.


Assuntos
Células Epidérmicas/metabolismo , Células Epidérmicas/efeitos da radiação , Fator de Iniciação 2 em Eucariotos/química , Fator de Iniciação 2 em Eucariotos/metabolismo , Heme Oxigenase-1/biossíntese , Raios Ultravioleta , Animais , Sobrevivência Celular , Células Cultivadas , Perfilação da Expressão Gênica , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Camundongos , Fosforilação , Reação em Cadeia da Polimerase , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo
17.
Med Sci Monit Basic Res ; 23: 352-361, 2017 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-29104283

RESUMO

BACKGROUND Hailey-Hailey disease (HHD) is a rare autosomal dominant skin condition. The ATP2C1 gene was identified as the defective gene in HHD. To date, 166 pathogenic mutations in ATP2C1 have been observed worldwide. The aim of this study was to identify variations in HHD and summarize the features of the mutations identified in China. MATERIAL AND METHODS We examined 2 familial and 2 sporadic cases of HHD. Genomic DNA polymerase chain reaction and direct sequencing of the ATP2C1 were performed from HHD patients, unaffected family members, and 200 healthy individuals. We also searched the published literature for data about the ATP2C1 gene using PubMed and the Chinese Biological Medicine Database. RESULTS We detected 3 heterozygous mutations, including 2 novel frameshift mutations (c.819insA (273LfsX) and c.1264insTAGATGG (421LfsX)) and 1 recurrent nonsense mutation (c.115C>T (R39X)). To the best of our knowledge, 90 different mutations (including our current results) have been reported in China, all of which occurred in the Chinese Han population. CONCLUSIONS Our data may add to the existing list of ATP2C1 mutations and provide new insight into genetic variants of HHD in China.


Assuntos
ATPases Transportadoras de Cálcio/genética , ATPases Transportadoras de Cálcio/metabolismo , Pênfigo Familiar Benigno/genética , Adulto , China , Bases de Dados Genéticas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , Pele/patologia
18.
Mol Med Rep ; 16(6): 8448-8454, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28983594

RESUMO

The present study aimed to investigate the key roles and possible regulatory mechanism of microRNA (miR)­24­1­5p in regulating the autophagy, and apoptosis of malignant melanoma cells. The expression levels of miR­24­1­5p in malignant melanoma tissues were determined. Human melanoma A375 cells were transfected with miR­24­1­5p mimic and control. The effects of miR­24­1­5p overexpression on regulating the expressions of autophagy­related proteins [microtubule­associated protein 1A/1B­light chain 3 (LC3)­II, LC3­I and Beclin­1] and apoptosis­related proteins [apoptosis regulator Bcl­2 (Bcl­2) and (BCL2 like 1) Bcl­xL] were investigated. The percentage of apoptotic cells in different transfected cells was detected. In addition, luciferase reporter assays were performed to confirm whether ubiquitin D (UBD) was a target of miR­24­1­5p. The effects of UBD silencing on autophagy and apoptosis were also investigated. The expression levels of janus kinase (JNK), phosphorylated (P)­JNK, Jun proto­oncogene AP­1 transcription factor subunit (c­Jun) and p­c­Jun were determined following the overexpression of miR­24­1­5p, and UBD. In comparison with adjacent normal tissues, miR­24­1­5p was significantly downregulated in malignant melanoma tissues. Overexpression of miR­24­1­5p significantly increased the levels of LC3­II/I ratio and Beclin­1 expression, and decreased the expression levels of Bcl­2 and Bcl­xL. Flow cytometry also showed that miR­24­1­5p overexpression promoted cell apoptosis. Moreover, UBD was confirmed as a direct target of miR­24­1­5p. Silencing of UBD promoted melanoma cell autophagy and apoptosis via regulating the expression levels of related proteins. Besides, the levels of the p­JNK/JNK and p­c­Jun/Jun ratios were significantly increased following miR­24­1­5p overexpression, which were reversed following co­overexpression of miR­24­1­5p, and UBD. Overexpression of miR­24­1­5p may target UBD, and subsequently promote the autophagy and apoptosis of malignant melanoma cells through activation of the JNK signaling pathway.


Assuntos
Apoptose/genética , Autofagia/genética , Melanoma/genética , MicroRNAs/genética , Interferência de RNA , Neoplasias Cutâneas/genética , Ubiquitinas/genética , Linhagem Celular Tumoral , Inativação Gênica , Humanos , Sistema de Sinalização das MAP Quinases
20.
Curr Top Med Chem ; 16(5): 529-36, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26268331

RESUMO

BACKGROUND: There is no curative treatment for Alzheimer's disease (AD). Ginseng is widely used in the treatment of AD in Asian countries. OBJECTIVE: To evaluate the effectiveness and safety of ginseng for AD. METHODS: We searched seven main databases for randomized clinical trials (RCTs) on ginseng for AD from their inception to December 2014. The Cochrane risk of bias tool was used to assess the methodological quality. We used RevMan 5.2 to synthesize the results. RESULTS: Four RCTs involving 259 participants were identified for this systematic review. The methodological quality of included studies was not promising. All comparisons were made between combined treatment (ginseng plus conventional treatment) versus conventional treatment. The results of meta-analyses and several individual studies showed that the effectiveness of combined treatment was inconsistent as measured by MMSE, ADAS-cog, ADAS-noncog, and CDR. No studies reported the outcomes of quality of life (QoL). The current data did not report serious adverse events. CONCLUSION: This review showed that the effects of ginseng on AD were still inconclusive. The main limitations of the available studies were small sample sizes, poor methodological qualities and no placebo controls. Larger, well-designed studies are needed to test the effect of ginseng on AD in the future.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Panax/química , Extratos Vegetais/uso terapêutico , Animais , Humanos , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Ensaios Clínicos Controlados Aleatórios como Assunto
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