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Vitiligo is a depigmented skin disease due to the destruction of melanocytes. Under oxidative stress, keratinocyte-derived chemokine C-X-C motif ligand 16 (CXCL16) plays a critical role in recruiting CD8+ T cells, which kill melanocytes. Autophagy serves as a protective cell survival mechanism and impairment of autophagy has been linked to increased secretion of the proinflammatory cytokines. However, the role of autophagy in the secretion of CXCL16 under oxidative stress has not been investigated. Herein, we initially found that autophagy was suppressed in both keratinocytes of vitiligo lesions and keratinocytes exposed to oxidative stress in vitro. Autophagy inhibition also promoted CXCL16 secretion. Furthermore, upregulated transient receptor potential cation channel subfamily M member 2 (TRPM2) functioned as an upstream oxidative stress sensor to inhibit autophagy. Moreover, TRPM2-mediated Ca2+ influx activated calpain to shear autophagy related 5 (Atg5) and Atg12-Atg5 conjugate formation was blocked to inhibit autophagy under oxidative stress. More importantly, Atg5 downregulation enhanced the binding of interferon regulatory factor 3 (IRF3) to the CXCL16 promoter region by activating Tank-binding kinase 1 (TBK1), thus promoting CXCL16 secretion. These findings suggested that TRPM2-restrained autophagy promotes CXCL16 secretion via the Atg5-TBK1-IRF3 signaling pathway under oxidative stress. Inhibition of TRPM2 may serve as a potential target for the treatment of vitiligo. © 2024 The Pathological Society of Great Britain and Ireland.
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Canais de Cátion TRPM , Vitiligo , Humanos , Vitiligo/metabolismo , Vitiligo/patologia , Canais de Cátion TRPM/genética , Canais de Cátion TRPM/metabolismo , Linfócitos T CD8-Positivos/patologia , Queratinócitos/patologia , Estresse Oxidativo , Autofagia , Quimiocina CXCL16/metabolismoRESUMO
Keratin 17 (K17) is a multifaceted cytoskeletal protein that is not commonly expressed in the epidermis under normal physiological conditions. However, in psoriasis, K17 is overexpressed in the suprabasal layer of the epidermis and plays an important role in the pathogenesis of the disease. In this review, we have summarized our findings and those reported in other studies concerning the pathogenic functions of K17, as well as the mechanisms underlying the increase in K17 expression in psoriasis. K17 exerts both pro-proliferative and pro-inflammatory effects on keratinocytes. Moreover, K17 peptides trigger autoreactive T cells and promote psoriasis-related cytokine production. In turn, these cytokines modulate the expression, stability, and protein-protein interactions of K17 through transcriptional and translational regulation and post-translational modification of K17 in keratinocytes. Thus, a K17/T-cell/cytokine autoimmune loop is implicated in the pathogenesis of psoriasis, which is supported by the fact that therapies targeting K17 have achieved good outcomes in psoriasis-like mouse models. Future perspectives of K17 in psoriasis have also been discussed to provide potential directions for further studies.
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Queratina-17 , Psoríase , Animais , Citocinas/metabolismo , Epiderme/metabolismo , Humanos , Queratina-17/genética , Queratina-17/metabolismo , Queratinócitos/patologia , Camundongos , Psoríase/genética , Psoríase/metabolismo , Psoríase/patologiaRESUMO
Chemoresistance is the primary reason for poor prognosis in patients with pancreatic cancer (PC). Recent studies have indicated that ferroptosis may improve chemoresistance, but the underlying mechanisms remain unclear. In this study, significant upregulation of heat shock protein 90α (Hsp90α) expression is detected in the peripheral blood and tissue samples of patients with chemoresistant PC. Further studies reveal that Hsp90α promotes the proliferation, migration, and invasion of a chemoresistant pancreatic cell line (Panc-1-gem) by suppressing ferroptosis. Hsp90α competitively binds to Kelch-like ECH-associated protein 1 (Keap1), liberating nuclear factor erythroid 2-related factor 2 (Nrf2) from Keap1 sequestration. Nrf2 subsequently translocates into the nucleus and activates the glutathione peroxidase 4 (GPX4) pathway, thereby suppressing ferroptosis. This process further worsens the chemoresistance of PC cells. This study provides valuable insight into potential molecular targets to overcome chemoresistance in PC. It sheds light on the intricate mechanisms linking Hsp90α and ferroptosis to chemoresistance in PC and provides a theoretical foundation for the development of novel therapeutic strategies.
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Waterborne acrylic coatings, the largest market share of predominant environmentally friendly coatings, face limitations in their extensive application due to their flammability. The flame-retardant properties of the coatings could be significantly enhanced by incorporate inorganic flame retardants. However, inorganic flame retardants tend to aggregate and unevenly disperse in waterborne acrylic coatings, causing a substantial decrease in flame retardancy. In this work, sodium silicate was utilized as a flame retardant, with urea and melamine serving as modifiers and synergistic agents. This combination resulted in the preparation of a sodium silicate/urea/melamine ternary synergistic waterborne acrylic flame-retardant coating. This coating was applied to the surface of poplar veneer to create flame-retardant poplar veneer. Subsequently, various instruments, including a scanning electron microscope (SEM), a limiting oxygen index meter (LOI), a thermogravimetric analyzer (TG), and a cone calorimeter (CONE), were employed to investigate the relevant properties and mechanisms of both the flame-retardant coating and poplar veneer. The results demonstrated that the sodium silicate/urea/melamine ternary synergistic flame retardant did not exhibit aggregation and could be uniformly dispersed in waterborne acrylic coatings. The physical and mechanical properties of the ternary synergistic flame-retardant poplar veneer coating were satisfactory. Melamine and urea, acting as modifiers, not only greatly enhanced the dispersibility of sodium silicate in waterborne acrylic coatings, but also assisted in the formation of a silicon-containing char layer through the generation of nitrogen, achieving ternary synergistic flame retardancy. In conclusion, this work explores a novel method to efficiently and uniformly disperse inorganic flame retardants in organic coatings. It significantly improves the dispersibility and uniformity of inorganic flame retardants in organic polymers, thereby substantially enhancing the flame-retardant performance of coatings. This work provides a theoretical basis for the research and application of new flame-retardant coatings in the field of chemistry and materials.
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The incompatibility between inorganic flame retardants and organic acrylic coatings represents a significant challenge that requires resolution. This work selected environmentally friendly organic aqueous acrylic coatings as the substrate, sodium silicate hydrate as the inorganic flame retardant, and melamine cyanurate (MCA) as the flame-retardant modifier and the flame-retardant co-modifier, with the objective of improving the dispersion and flame-retardant properties of sodium silicate hydrate in the aqueous acrylic coatings. Subsequently, the sodium silicate/MCA/waterborne acrylic acid flame-retardant coating was prepared. The flame-retardant treatment was then applied to poplar veneer in order to create a flame-retardant poplar veneer. The dispersion of the flame-retardant coating was characterized by scanning electron microscopy (SEM), energy-dispersive spectroscopy (EDX), and X-ray diffractometry (XRD). Furthermore, the flame-retardant properties of the flame-retardant poplar veneer were analyzed by thermogravimetry (TG), limiting oxygen index (LOI), and cone calorimeter. The results demonstrated that the MCA-modified sodium silicate flame retardant was well dispersed in aqueous acrylic coatings. The results of the flame-retardant properties of the poplar veneer indicated that the ignition time of the 9% flame retardant-treated poplar veneer was increased by 122.7%, the limiting oxygen index value was increased by 43.0%, and the peak heat release rate (pHRR), the peak total heat release rate (pTHR), and the peak mass loss rate were decreased by 19.9%, 10.8%, and 27.2%, respectively, in comparison to the non-flame retardant-treated poplar veneer. Furthermore, the residual char mass increased by 14.4%, and the residual char exhibited enhanced thickness, density, and regularity. The results demonstrated that MCA was an effective promoter of sodium silicate dispersion in acrylic coatings. Furthermore, the sodium silicate/MCA/waterborne acrylic flame-retardant coating significantly enhance the flame retardancy of wood, and its flame retardant mechanism was consistent with the synergistic silicone-nitrogen expansion flame-retardant mechanism. This work presents a novel approach to enhancing the dispersion of inorganic flame retardants in organic coatings, offering a valuable contribution to the advancement of research and application in the domains of innovative flame retardant coatings and flame retardant wood.
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BACKGROUND: The activation of CD8+ T cells and their trafficking to the skin through JAK-STAT signaling play a central role in the development of vitiligo. Thus, targeting this key disease pathway with innovative drugs is an effective strategy for treating vitiligo. Natural products isolated from medicinal herbs are a useful source of novel therapeutics. Demethylzeylasteral (T-96), extracted from Tripterygium wilfordii Hook F, possesses immunosuppressive and anti-inflammatory properties. METHODS: The efficacy of T-96 was tested in our mouse model of vitiligo, and the numbers of CD8+ T cells infiltration and melanocytes remaining in the epidermis were quantified using whole-mount tail staining. Immune regulation of T-96 in CD8+ T cells was evaluated using flow cytometry. Pull-down assay, mass spectrum analysis, molecular docking, knockdown and overexpression approaches were utilized to identify the target proteins of T-96 in CD8+ T cells and keratinocytes. RESULTS: Here, we found that T-96 reduced CD8+ T cell infiltration in the epidermis using whole-mount tail staining and alleviated the extent of depigmentation to a comparable degree of tofacitinib (Tofa) in our vitiligo mouse model. In vitro, T-96 decreased the proliferation, CD69 membrane expression, and IFN-γ, granzyme B, (GzmB), and perforin (PRF) levels in CD8+ T cells isolated from patients with vitiligo. Pull-down assays combined with mass spectrum analysis and molecular docking showed that T-96 interacted with JAK3 in CD8+ T cell lysates. Furthermore, T-96 reduced JAK3 and STAT5 phosphorylation following IL-2 treatment. T-96 could not further reduce IFN-γ, GzmB and PRF expression following JAK3 knockdown or inhibit increased immune effectors expression upon JAK3 overexpression. Additionally, T-96 interacted with JAK2 in IFN-γ-stimulated keratinocytes, inhibiting the activation of JAK2, decreasing the total and phosphorylated protein levels of STAT1, and reducing the production and secretion of CXCL9 and CXCL10. T-96 did not significantly inhibit STAT1 and CXCL9/10 expression following JAK2 knockdown, nor did it suppress upregulated STAT1-CXCL9/10 signaling upon JAK2 overexpression. Finally, T-96 reduced the membrane expression of CXCR3, and the culture supernatants pretreated with T-96 under IFN-γ stressed keratinocytes markedly blocked the migration of CXCR3+CD8+ T cells, similarly to Tofa in vitro. CONCLUSION: Our findings demonstrated that T-96 might have positive therapeutic responses to vitiligo by pharmacologically inhibiting the effector functions and skin trafficking of CD8+ T cells through JAK-STAT signaling.
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Vitiligo , Animais , Camundongos , Vitiligo/tratamento farmacológico , Vitiligo/metabolismo , Linfócitos T CD8-Positivos , Simulação de Acoplamento Molecular , Pele/metabolismoRESUMO
We design a graded-index ring-core fiber with a GeO2-doped silica ring core and SiO2 cladding. This fiber structure can inhibit the effect of spin-orbit coupling to mitigate the power transfer among different modes and eventually enhance the orbital angular momentum (OAM) mode purity. By changing the high-index ring core from the step-index to parabolic graded-index profile, the purity of the OAM1,1 mode can be improved from 86.48% to 94.43%, up by 7.95%. The proposed fiber features a flexible structure, which can meet different requirements for mode order, effective mode area, etc. Simulation results illustrate that the parabolic-index ring-core fiber is promising in enhancing the OAM mode purity, which could potentially reduce the channel crosstalk in mode-division-multiplexed optical communication systems.
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Efficient methods for synthesizing 1,2-aryl(alkenyl) heteroatomic cores, encompassing heteroatoms such as nitrogen, oxygen, sulfur, and halogens, are of significant importance in medicinal chemistry and pharmaceutical research. In this study, we present a mild, versatile and practical photoredox/iron dual catalytic system that enables access to highly privileged 1,2-aryl(alkenyl) heteroatomic pharmacophores with exceptional efficiency and site selectivity. Our approach exhibits an extensive scope, allowing for the direct utilization of a wide range of commodity or commercially available (hetero)arenes as well as activated and unactivated alkenes with diverse functional groups, drug scaffolds, and natural product motifs as substrates. By merging iron catalysis with the photoredox cycle, a vast array of alkene 1,2-aryl(alkenyl) functionalization products that incorporate a neighboring azido, amino, halo, thiocyano and nitrooxy group were secured. The scalability and ability to rapid synthesize numerous bioactive small molecules from readily available starting materials highlight the utility of this protocol.
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Noncoding RNAs have been verified to regulate the infiltration of macrophages to accelerate tumor biological progression, however the regulation of macrophages by circular RNAs in hepatocellular carcinoma (HCC) remains unresolved. Using high-throughput RNA sequencing, we demonstrated that hsa_circ_0003410 was clearly upregulated in HCC. 5-Ethynyl-2'-deoxyuridine and transwell assays showed that hsa_circ_0003410 facilitated the proliferation and migration of HCC cells in vitro. We knocked down the expression of hsa_circ_0003410 in HepG2 cells and performed next-generation sequencing to determine possible target genes of hsa_circ_0003410. Kyoto Encyclopedia of Genes and Genomes analysis revealed that different genes were mainly enriched in immune-related pathways. Mechanistically, we identified CCL5 as the target gene of hsa_circ_0003410. RNA-FISH showed the co-expression of hsa_circ_0003410 and CCL5. Western blot and ELISA also verified that hsa_circ_0003410 could upregulate the expression of CCL5 protein. Flow cytometry and immunofluorescence assays indicated that CCL5 activated and recruited M2 macrophages and increased the ratio of M2/M1 macrophages to promote the progression of HCC. Animal experiments in vitro also confirmed our results. Taken together, our experiments revealed that noncoding RNAs play a critical role in the HCC microenvironment and can be considered as markers for the diagnosis and prognosis of HCC.
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Carcinoma Hepatocelular/genética , Quimiocina CCL5/genética , Neoplasias Hepáticas/genética , MicroRNAs/genética , RNA Circular/genética , Macrófagos Associados a Tumor/imunologia , Animais , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Quimiocina CCL5/imunologia , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Camundongos , Microambiente Tumoral/imunologiaRESUMO
HINTERGRUND UND ZIELE: Ziel dieser Studie war die Untersuchung des Zusammenhangs zwischen Vitiligo und dem metabolischen Syndrom (MetS) sowie dessen relevanten Komponenten. MATERIAL UND METHODEN: Die Datenbanken PubMed, Web of Science, Cochrane Library und Embase wurden von deren Beginn bis zum 30. März 2021 nach relevanten Studien durchsucht. Querschnitts- und Fall-Kontroll-Studien, die entweder die Prävalenz oder die Odds-Ratio [OR] des MetS oder seiner Komponenten bei Vitiligo-Patienten berichteten, wurden eingeschlossen. Die Daten wurden entsprechend der Heterogenität entweder mit einem Zufallseffektmodell oder einem Modell mit festen Effekten gepoolt. ERGEBNISSE: Es wurden 30 Studien mit insgesamt 28.325 Vitiligo-Patienten eingeschlossen. Signifikante Zusammenhänge wurden zwischen Vitiligo und Diabetes mellitus (gepoolte OR, 3,30; 95 %-Konfidenzintervall [KI], 2,10-5,17) sowie zwischen Vitiligo und Adipositas (gepoolte OR, 2,08; 95 %-KI, 1,40-3,11) ermittelt. Die Gesamtprävalenz der Hypertonie bei Patienten mit Vitiligo betrug 19,0 % (95 %-KI, 2,0 %-36,0 %). SCHLUSSFOLGERUNGEN: Unserer Ergebnisse lassen auf einen Zusammenhang zwischen Vitiligo und Diabetes mellitus sowie Hypertonie schließen. Dermatologen wird empfohlen diese Zusammenhänge zu berücksichtigen, um potenzielle Begleiterkrankungen bei Vitiligo-Patienten zeitnah zu identifizieren. Zudem wird Vitiligo-Patienten empfohlen, Parameter wie BMI, Blutzuckerspiegel und Blutdruck zu überwachen und bei auffälligen Veränderungen dieser Parameter unverzüglich einen Spezialisten zu konsultieren.
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BACKGROUND AND OBJECTIVES: This study aimed to investigate the association of vitiligo with metabolic syndrome (MetS) and its relevant components. MATERIAL AND METHODS: We searched PubMed, Web of Science, Cochrane Library and Embase databases from inception to March 30, 2021, for relevant studies. Cross-sectional and case-control studies that reported either the prevalence or odds ratio [OR] of MetS or its components in vitiligo patients were included. Data were pooled using either random-effects model or fixed-effects model according to the heterogeneity. RESULTS: Thirty studies with a total of 28,325 vitiligo patients were included. Significant associations were found between vitiligo and diabetes mellitus (pooled OR, 3.30; 95 % confidence interval [CI], 2.10-5.17) and between vitiligo and obesity (pooled OR, 2.08; 95 % CI, 1.40-3.11). The overall prevalence of hypertension in the patients with vitiligo was 19.0 % (95 % CI, 2.0 %-36.0 %). CONCLUSIONS: Our findings suggest the association of vitiligo with diabetes mellitus, obesity, and hypertension. It is recommended for dermatologists to take these associations into account so as to identify potential comorbidities promptly in vitiligo patients. Additionally, vitiligo patients are advised to monitor the indexes including BMI, blood glucose, and blood pressure levels and the consultation with specialists is necessary upon abnormal changes of these indexes.
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Diabetes Mellitus , Hipertensão , Síndrome Metabólica , Vitiligo , Estudos Transversais , Humanos , Síndrome Metabólica/epidemiologia , Obesidade/epidemiologia , Vitiligo/epidemiologiaRESUMO
Herein, we report the structures of chiral-at-cage carborane derivatives bearing carbazole chromophores that emit circularly polarized luminescence (CPL) and aggregation-induced electrochemiluminescence (AIECL). By adjusting the substituent positions on the carborane derivatives, two chiral luminescent molecules, Cb1 and Cb2, with different properties were obtained. The photoluminescence dissymmetry factors |gPL | of both (R/S)-Cb1 and (R/S)-Cb2 enantiomers in neat films were as high as 6.24×10-3 and 7.38×10-3 , respectively. Cb1 showed a deep blue emission peak at 434â nm in n-pentane. Interestingly, distinct fluorescence and CPL spectra were observed in solvents of different polarities due to the twisted intramolecular charge transfer effect, suggesting its potential use in solvent recognition. Meanwhile, Cb2 exhibited good AIECL property, excellent ECL stability and could be used for determining dopamine concentrations, suggesting its potential applications in biology and diagnosis.
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Luminescência , Medições Luminescentes , EstereoisomerismoRESUMO
In this paper, we propose and design a multi-orbital-angular-momentum multi-ring air-core fiber, which has seven high-index rings with each ring supporting 62 radially fundamental OAM modes across C and L bands (from 1530 nm to 1625 nm), i.e. 434 OAM modes in total. The designed fiber features >4×10-4 intra-ring modal indices difference for OAM modes with the same topological charge l in a ring across the C and L bands. Moreover, it can keep <-52 dB crosstalk between the OAM modes in the adjacent rings at 1550 nm, and <-24 dB crosstalk across C and L bands after 100-km fiber propagation. This kind of seven-air-core-ring fiber would be a robust candidate for transmitting efficient OAM modes and boosting the capacity of optical fiber communications systems.
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Recombinant human interferon-α1b (IFN-α1b) is the first genetic engineered drug of China and is approved for cancer treatment by Chinese Food and Drug Administration. Although recombinant IFN-α1b is biologically and therapeutically active, its long-term efficacy against advanced melanoma is unknown. Ninety patients who were diagnosed with stage IV melanoma and received recombinant IFN-α1b therapy in our department were included in this study. The safety and efficacy of IFN-α1b were analyzed. IFN-α1b was overall well tolerated, with only 7.8% of the patients showing grade 3 toxicity and none with grade 4 toxicity or treatment-related death. The most common adverse effect was fever (78.9%). Furthermore, increasing the drug dosage showed no increase in the incidence of adverse events. The median overall survival (mOS) of the cohort was 14.1 months (95% confidence interval, 11.3-16.9 months). There was no significant difference of the mOS between samples of various primary sites. In the 42 patients who had not received prior adjuvant interferon therapy, the objective response rate, disease control rate and clinical benefit rate were 7.1, 28.5 and 21.4%, respectively. Our findings suggest that systemic IFN-α1b treatment is a relatively safe therapy and could prolong the survival of patients with unresectable metastatic melanoma.
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Interferon-alfa/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Feminino , Humanos , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Estudos Retrospectivos , Neoplasias Cutâneas/patologia , Análise de Sobrevida , Adulto JovemRESUMO
BACKGROUND: Keratinocytes can function as innate immune cells under oxidative stress and aggravate the cutaneous T-cell response that undermines melanocytes in the setting of vitiligo. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a regulator of innate immunity that exists in keratinocytes. However, the role of the NLRP3 inflammasome in the pathogenesis of vitiligo has not been investigated. OBJECTIVE: We sought to explicate the contribution of the activated NLRP3 inflammasome in keratinocytes to the autoimmune response in patients with vitiligo. METHODS: Perilesional and serum samples from patients with vitiligo were collected to examine the status of the NLRP3 inflammasome in the setting of vitiligo. Cultured keratinocytes were treated with H2O2 to investigate the mechanism for NLRP3 inflammasome activation under oxidative stress. Peripheral blood T cells were extracted from patients with vitiligo to explore the influence of the NLRP3 inflammasome on the T-cell response in patients with vitiligo. RESULTS: Expressions of NLRP3 and downstream cytokine IL-1ß were consistently increased in perilesional keratinocytes of patients with vitiligo. Notably, serum IL-1ß levels were increased in patients with vitiligo, correlated with disease activity and severity, and decreased after effective therapy. Furthermore, oxidative stress promoted NLRP3 inflammasome activation in keratinocytes through transient receptor potential cation channel subfamily M member 2 (TRPM2), a redox-sensitive cation channel, which was dependent on TRPM2-mediated calcium influx. More importantly, blocking TRPM2-induced NLRP3 inflammasome activation in keratinocytes impaired chemotaxis for CD8+ T cells and inhibited the production of cytokines in T cells in patients with vitiligo. CONCLUSION: Oxidative stress-induced NLRP3 inflammasome activation in keratinocytes promotes the cutaneous T-cell response, which could be targeted for the treatment of vitiligo.
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Inflamassomos/imunologia , Queratinócitos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Pele/imunologia , Linfócitos T/imunologia , Vitiligo/imunologia , Humanos , Estresse Oxidativo/imunologiaRESUMO
The difunctionalization of alkenes involving a trifluoromethylthio group (SCF3) for the conversion of versatile and readily available olefins into structurally more complex molecules has been successfully studied. However, the disproportionate dithiolation of alkenes is unknown. Herein, a transition-metal-free protocol is presented for the vicinal trifluoromethylthio-thiolation of unactivated alkenes via a radical process under mild conditions with a broad substrate scope and excellent tolerance.
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In this Letter, we proposed a super sensitive optic-fiber curvature sensor with ultra-low temperature crosstalk based on Vernier effect and achieved it experimentally. This sensor composes a pair of parallelized 2CFMIs (2-core-fiber Michelson interferometers) in similar lengths, both of which are involved sensing, but there is a rotation angle between their cross-sections. When the rotation angle approaches 180°, the magnification factor for curvature sensitivity is doubled compared with conventional Vernier effect, while for temperature it is always 1. Therefore, advanced curvature sensitivity and abated temperature crosstalk can be realized simultaneously when demodulating Vernier envelops. The experiment results indicate that the curvature sensitivity of this sensor reached 214.533nm/m-1, and temperature crosstalk was as low as 0.000276m-1/∘C. The fabrication process is extremely flexible and repeatable, and the magnification factor of Vernier effect could be controlled conveniently.
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Vitiligo is a depigmentation disorder that develops as a result of the progressive disappearance of epidermal melanocytes. The elevated level of amino acid metabolite homocysteine (Hcy) has been identified as circulating marker of oxidative stress and known as a risk factor for vitiligo. However, the mechanism underlying Hcy-regulated melanocytic destruction is currently unknown. The present study aims to elucidate the effect of Hcy on melanocytic destruction and its involvement in the pathogenesis of vitiligo. Our results showed that Hcy level was significantly elevated in the serum of progressive vitiligo patients. Notably, Hcy induced cell apoptosis in melanocytes via activating reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress protein kinase RNA-like ER kinase (PERK)-eukaryotic translation initiation factor 2α (eIF2α)-C/EBP homologous protein (CHOP) pathway. More importantly, folic acid, functioning in the transformation of Hcy, could lower the intracellular Hcy level and further reverse the apoptotic effect of Hcy on melanocytes. Additionally, Hcy disrupted melanogenesis whereas folic acid supplementation could reverse the melanogenesis defect induced by Hcy in melanocytes. Taken together, Hcy is highly increased in vitiligo patients at progressive stage, and our in vitro studies revealed that folic acid could protect melanocytes from Hcy-induced apoptosis and melanin synthesis inhibition, indicating folic acid as a potential benefit agent for patients with progressive vitiligo.
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Apoptose , Fator de Iniciação 2 em Eucariotos/metabolismo , Homocisteína/metabolismo , Melanócitos/metabolismo , Melanócitos/patologia , Fator de Transcrição CHOP/metabolismo , Vitiligo/metabolismo , eIF-2 Quinase/metabolismo , Adulto , Apoptose/efeitos dos fármacos , Estudos de Casos e Controles , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Ácido Fólico/farmacologia , Homocisteína/sangue , Humanos , Masculino , Melaninas/biossíntese , Melanócitos/efeitos dos fármacos , Modelos Biológicos , Transdução de Sinais/efeitos dos fármacos , Vitiligo/sangueRESUMO
A robust, novel, to the best of our knowledge, fiber Mach-Zehnder interferometer strain sensor is designed and experimentally implemented. The sensor consists of two concave-lens-like long-period fiber gratings and is engraved by the high frequency ${{\rm CO}_2}$CO2 laser. The concave-lens-like grids can excite higher-order cladding modes to interfere with the fundamental mode, which increases the light-material contact. The excellent interference spectra are obtained and analyzed theoretically. The experimental results show that the strain sensitivity of the sensor can reach 0.011 dB/µ$\unicode{x03B5}$ε in the range of 0-2160 µ$\unicode{x03B5}$ε. The resolution of the sensor is up to 0.91 µ$\unicode{x03B5}$ε. Moreover, the temperature crosstalk can be self-compensated by monitoring a pair of split interfering dips. These outstanding characteristics make it very suitable as a candidate for strain measurement.
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Redox-active esters (RAEs) as active radical precursors have been extensively studied for C-B bond formations. However, the analogous transformations of stabilized radicals from the corresponding acid precursors remain challenging owing to the strong preference towards single-electron oxidation to the stable carbocations. This work describes a general strategy for rapid access to various aliphatic and aromatic boronic esters by mild photoinduced decarboxylative borylation. Both aryl and alkyl radicals could be generated from the leaving group-assisted N-hydroxybenzimidoyl chloride esters, even α-CF3 substituted substrates could be activated for further elaboration.