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Recent studies have illustrated that psoriatic lesions are innervated by dense sensory nerve fibers. Psoriatic plaques appeared to improve after central or peripheral nerve injury. Therefore, the nervous system may play a vital role in psoriasis. We aimed to clarify the expression of nerve fibers in psoriasis and their relationship with immune cells and keratinocytes, and to explore the effect of skin nerve impairment. Our results illustrated that nerve fibers in psoriatic lesions increased and were closely innervated around immune cells and keratinocytes. RNA-seq analysis showed that peripheral sensory nerve-related genes were disrupted in psoriasis. In spinal cord hemi-section mice, sensory impairment improved psoriasiform dermatitis and inhibited the abnormal proliferation of keratinocytes. Botulinum toxin A alleviated psoriasiform dermatitis by inhibiting the secretion of calcitonin gene-related peptide. Collectively, cutaneous nerve fibers participate in the progression of psoriasis by linking epidermal keratinocytes and immunocytes. Neurological intervention may be a new treatment strategy for psoriasis.
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Dermatite , Psoríase , Animais , Dermatite/metabolismo , Dermatite/patologia , Epiderme/metabolismo , Queratinócitos/metabolismo , Camundongos , Fibras Nervosas/metabolismo , Psoríase/patologiaRESUMO
Secukinumab is a recombinant, fully human monoclonal anti-IL-17A antibody approved to treat moderate-to-severe psoriasis and psoriatic arthritis. Its effectiveness and safety have been confirmed, but a gradual increase in the secukinumab dosing interval has not been investigated. To assess the feasibility, efficacy, and safety of gradually increasing the secukinumab dosing interval; the interval duration was determined by changes in the Psoriasis Area and Severity Index scores. Patients with moderate-to-severe plaque psoriasis received secukinumab 300 mg subcutaneously at baseline and weeks 0, 1, 2, and 3. At week 4, the improvement from baseline PASI guided the next injection time until week 36. In total, 83 patients were recruited. PASI 75 was achieved by 80%, 96%, and 95% of patients at weeks 4, 12, and 36, respectively. PASI 90 was achieved by 54%, 95%, and 84% of patients at weeks 4, 12, and 36, respectively. PASI 100 was achieved by 28%, 89%, and 68% of patients at weeks 4, 12, and 36, respectively. The average PASI score (1.05 ± 1.83) was significantly lower at week 36 than at baseline. Most patients reached PASI 75 at week 36 in our modified study. This study may provide information for future biotherapies.
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Anticorpos Monoclonais , Psoríase , Humanos , Estudos Prospectivos , Anticorpos Monoclonais/efeitos adversos , Índice de Gravidade de Doença , Resultado do Tratamento , Método Duplo-Cego , Psoríase/diagnóstico , Psoríase/tratamento farmacológicoAssuntos
Anticorpos Monoclonais Humanizados , Psoríase , Células Th2 , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Psoríase/tratamento farmacológico , Psoríase/imunologia , Células Th2/imunologia , Células Th2/metabolismo , Resultado do Tratamento , Inflamação/tratamento farmacológico , Feminino , MasculinoRESUMO
Aim To explore a more effective surgical procedure, the outcomes of closed manipulative reduction (CMR) combined with minimally invasive plate osteosynthesis (MIPO) and conventional open reduction and internal fixation (ORIF) for treating proximal humeral fractures were compared. Material and methods In a retrospective study of patients operated for humerus shaft fractures from April 2008 to July 2011, the outcomes of 33 patients treated with CMR/MIPO were compared with the outcomes of 42 patients treated with ORIF. The fractures were classified, and the incision length, blood transfusion, operating time, as well as the VAS (Visual Analog Scale) pain scores were analyzed. The neck-shaft angles of the proximal humerus were detected, and the postoperative function of the shoulder was evaluated. Results The mean values of incision length, blood transfusion, and VAS pain scores at the 1st and 3rd day after CMR/MIPO and operation time were lower than that of ORIF. The postoperative radiographs verified good position of all screws and satisfactory bone fracture reduction in both groups. Meanwhile, in the ORIF group, nonunion (three cases) and humeral head necrosis (four cases) were detected. Conclusions The MR/MIPO technique showed smaller incisions, easier operation, less blood transfusion and more effective recovery of shoulder joint function for treating proximal humeral fractures than ORIF.
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Placas Ósseas , Fixação Interna de Fraturas/métodos , Fraturas do Úmero/cirurgia , Manipulação Ortopédica/métodos , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Atividades Cotidianas , Adulto , Idoso , Idoso de 80 Anos ou mais , Transfusão de Sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Dor/epidemiologia , Complicações Pós-Operatórias/epidemiologia , Recuperação de Função Fisiológica , Estudos Retrospectivos , Adulto JovemRESUMO
OBJECTIVE: This study presents a multichannel patient-specific seizure detection method based on the empirical mode decomposition (EMD) and support vector machine (SVM) classifier. MATERIALS AND METHODS: The EMD is used to extract features from intracranial electroencephalography (EEG). A machine-learning algorithm is used as a classifier to discriminate between seizure and nonseizure intracranial EEG epochs. A postprocessing algorithm is proposed to reject artifacts and increase the robustness of the method. The proposed method was evaluated using 463 hours of intracranial EEG recordings from 17 patients with a total of 51 seizures in the Freiburg EEG database. RESULTS: The proposed method had better performance than most of the existing seizure detection systems, including an average sensitivity of 92%, false detection rate (FDR) of 0.17/hour, and time delay (TD) of 12 sec. Moreover, the FDR could be further reduced by a TD extension. CONCLUSIONS: Given its high sensitivity and low FDR, the proposed patient-specific seizure detection method can greatly assist clinical staff with automatically marking seizures in long-term EEG or detecting seizure onset online with high performance. Early and accurate seizure detection using this method may serve as a practical tool for planning epilepsy interventions.
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Algoritmos , Processamento Eletrônico de Dados , Convulsões/diagnóstico , Convulsões/fisiopatologia , Eletroencefalografia , Feminino , Humanos , Masculino , Máquina de Vetores de Suporte , Fatores de TempoRESUMO
Background: Patients with psoriasis may experience an exacerbation in symptoms following COVID-19 infection. After abandoning 'zero COVID' strategies, China experienced a surge of Omicron infections. Objectives: We aimed to investigate psoriasis exacerbation in psoriatic patients with COVID-19, following treatment with three different biologics, adalimumab, secukinumab, and ixekizumab. Methods: We performed a prospective study (n = 209) at our hospital between November 01, 2022, and February 15, 2023. We defined â³ PASI as post-COVID-19 PASI minus pre-COVID-19 PASI. Two endpoints were set in this study. â³ PASI >0 was defined as exacerbation of psoriasis after infection. â³ PASI >3 was defined as a severe exacerbation of psoriasis symptoms after infection. In addition, serum OAS1, OAS2, and OAS3 were also assessed. Results: Results showed that the severity of psoriasis can worsen after COVID-19 infection, and a smaller proportion of patients taking biologics developed worsening psoriasis compared to those not using biologics; however, only the patients taking ixekizumab demonstrated a statistically significant difference (p < 0.05), while those taking adalimumab or secukinumab didn't. What's more, the use of biological agents suppressed the serum OAS2 and OAS3 at low levels and elevated the serum OAS1 level in patients with psoriasis. Conclusions: This study provided new insights into the protective role of biological agents in patients with psoriasis who were infected with COVID-19, and we proposed that psoriatic patients treated with biologics should continue with the treatment during the COVID-19 pandemic.
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Neuropathic pain (NP) is usually treated with analgesics and symptomatic therapy with poor efficacy and numerous side effects, highlighting the urgent need for effective treatment strategies. Recent studies have reported an important role for peroxisome proliferator-activated receptor alpha (PPARα) in regulating metabolism as well as inflammatory responses. Through pain behavioral assessment, we found that activation of PPARα prevented chronic constriction injury (CCI)-induced mechanical allodynia and thermal hyperalgesia. In addition, PPARα ameliorated inflammatory cell infiltration at the injury site and decreased microglial activation, NOD-like receptor protein 3 (NLRP3) inflammasome production, and spinal dendritic spine density, as well as improved serum and spinal cord metabolic levels in mice. Administration of PPARα antagonists eliminates the analgesic effect of PPARα agonists. PPARα relieves NP by inhibiting neuroinflammation and functional synaptic plasticity as well as modulating metabolic mechanisms, suggesting that PPARα may be a potential molecular target for NP alleviation. However, the effects of PPARα on neuroinflammation and synaptic plasticity should be further explored.
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Camundongos Endogâmicos C57BL , Neuralgia , PPAR alfa , Medula Espinal , Animais , PPAR alfa/metabolismo , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Masculino , Camundongos , Medula Espinal/metabolismo , Medula Espinal/efeitos dos fármacos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Metabolômica , Microglia/efeitos dos fármacos , Microglia/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/metabolismo , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/patologia , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacosRESUMO
BACKGROUND: Existing evidence suggests that the composition of the gut microbiota is associated with neuropathic pain (NP), but the mechanistic link is elusive. Peroxisome proliferator-activated receptor α (PPARα) has been shown to be a pharmacological target for the treatment of metabolic disorders, and its expression is also involved in inflammatory regulation. The aim of this study was to investigate the important modulatory effects of PPARα on gut microbiota and spinal cord metabolites in mice subjected to chronic constriction injury. METHODS: We analyzed fecal microbiota and spinal cord metabolic alterations in mice from the sham, CCI, GW7647 (PPARα agonist) and GW6471 (PPARα antagonist) groups by 16â¯S rRNA amplicon sequencing and untargeted metabolomics analysis. On this basis, the intestinal microbiota and metabolites that were significantly altered between treatment groups were analyzed in a combined multiomics analysis. We also investigated the effect of PPARα on the polarization fractionation of spinal microglia. RESULTS: PPARα agonist significantly reduce paw withdrawal threshold and paw withdrawal thermal latency, while PPARα antagonist significantly increase paw withdrawal threshold and paw withdrawal thermal latency. 16â¯S rRNA gene sequencing showed that intraperitoneal injection of GW7647 or GW6471 significantly altered the abundance, homogeneity and composition of the gut microbiome. Analysis of the spinal cord metabolome showed that the levels of spinal cord metabolites were shifted after exposure to GW7647 or GW6471. Alterations in the composition of gut microbiota were significantly associated with the abundance of various spinal cord metabolites. The abundance of Licheniformes showed a significant positive correlation with nicotinamide, benzimidazole, eicosanoids, and pyridine abundance. Immunofluorescence results showed that intraperitoneal injection of GW7647 or GW6471 altered microglial activation and polarization levels. CONCLUSION: Our study shows that PPARα can promote M2-type microglia polarization, as well as alter gut microbiota and metabolites in CCI mice. This study enhances our understanding of the mechanism of PPARα in the treatment of neuropathic pain.
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Microbioma Gastrointestinal , Metabolômica , Neuralgia , PPAR alfa , RNA Ribossômico 16S , Medula Espinal , Animais , Masculino , Camundongos , Fezes/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Microglia/efeitos dos fármacos , Neuralgia/metabolismo , Neuralgia/tratamento farmacológico , Neuralgia/microbiologia , Oxazóis , PPAR alfa/metabolismo , RNA Ribossômico 16S/genética , Medula Espinal/metabolismo , Medula Espinal/efeitos dos fármacos , Tirosina/análogos & derivadosRESUMO
Psoriasis is characterized by excessive keratinocyte proliferation and immunocyte infiltration, but the underlying pathogenesis remains unclear. Aminoacyl-tRNA synthetases are universally expressed enzymes that catalyze the first step of protein synthesis. Glycyl-tRNA synthetase (GARS) is a member of the aminoacyl-tRNA synthetase family. In addition to its canonical function, we found that GARS was overexpressed in the serum and skin lesions of patients with psoriasis. Moreover, GARS was highly expressed in human skin keratinocytes, and GARS knockdown in keratinocytes suppressed cell proliferation and promoted apoptosis through NF-κB/MAPK signaling pathway. Moreover, intradermal injection of recombinant GARS protein caused skin thickening, angiogenesis, and IFN/TNF-driven skin inflammation. Intriguingly, the reported functional receptor for GARS, cadherin 6 (CDH6), was specifically expressed in vascular endothelial cells, and we found that keratinocyte-derived GARS promotes inflammation and angiogenesis of vascular endothelial cells through CDH6. In addition, intradermal injection of GARS aggravated the phenotype and angiogenesis in imiquimod-induced psoriasiform dermatitis models, whereas the psoriatic phenotype and angiogenesis were relieved after knockdown of GARS by adeno-associated virus. Taken together, the results of this study identify the critical role of GARS in the pathogenesis of psoriasis and suggest that blocking GARS may be a therapeutic approach for alleviating psoriasis.
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Dermatite , Glicina-tRNA Ligase , Psoríase , Humanos , Angiogênese , Dermatite/patologia , Células Endoteliais/patologia , Glicina-tRNA Ligase/genética , Glicina-tRNA Ligase/metabolismo , Inflamação/patologia , Queratinócitos/metabolismo , Psoríase/patologia , Pele/patologiaRESUMO
The function and survival of melanocytes is regulated by an elaborate network of paracrine factors synthesized mainly by epidermal keratinocytes (KCs). KCs and melanocytes respond to UV exposure by eliciting a tanning response. However, how KCs and melanocytes interact in the absence of UV exposure is unknown. In this study, we demonstrate that after SPRY1 knockout in epidermal KCs, melanocyte stem cells in the hair follicle exit the niche without depleting the pool of these cells. We also found that melanocyte stem cells migrate to the epidermis in a p53/stem cell factor/C-KIT-dependent manner induced by a tanning-like response resulting from SPRY1 loss in epidermal KCs. Once there, these cells differentiate into functional melanocytes. These findings provide an example in which the migration of melanocyte stem cells to the epidermis is due to loss of SPRY1 in epidermal KCs and show the potential for developing therapies for skin pigmentation disorders by manipulating melanocyte stem cells.
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Atopic dermatitis (AD) is one of the most common inflammatory skin diseases with complex pathogenesis involving epidermal barrier dysfunction, skin microbiome abnormalities and type-2-skewed immune dysregulation. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that plays critical roles in various biological processes. However, the role of STAT3 in epidermal keratinocytes in AD remains unclear. In this study, we generated an epidermal keratinocyte-specific Stat3-deficient mouse strain (termed Stat3 cKO mice). After topical 2,4-dinitrochlorobenzene (DNCB) treatment, Stat3 cKO mice developed worsened AD-like skin inflammation with increased Ki67+ cells, decreased filaggrin and loricrin expression, and downregulated S100A9 and LL37. The dominant microbial population in Stat3 cKO mice changed from Ralstonia to Staphylococcus. DNCB-treated Stat3 cKO mice displayed more infiltrating type-2 inflammatory cells, including mast cells, eosinophils, and CD4+T cells, accompanied by increased skin IL-4 and serum IgE levels. Moreover, thymic stromal lymphopoietin (TSLP), mainly produced by keratinocytes, was highly expressed in the ear skin of Stat3 cKO mice and chemoattracted more TSLPR+ cells. TSLP blockade significantly alleviated DNCB-induced AD-like skin inflammation in Stat3 cKO mice. Thus, epidermal keratinocyte-specific STAT3 deficiency can aggravate AD-like skin inflammation in mice, possibly through TSLP dysregulation.
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Dermatite Atópica , Animais , Camundongos , Citocinas/metabolismo , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/genética , Dinitroclorobenzeno , Inflamação/metabolismo , Queratinócitos , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Linfopoietina do Estroma do Timo , Regulação para CimaRESUMO
OBJECTIVE: To detect the cytokines levels in serums of patients with trichloroethylene-induced hypersensitivity dermatitis and explore the effect biomarkers associated with this disease. METHODS: Twenty-two patients with TCE-induced hypersensitivity dermatitis, twenty-two healthy TCE-exposed workers from the same workshops with patients and twenty-two comparable unexposed controls were recruited in this study. Eight cytokines in serums from all subjects were detected using Liquid Suspended Biochip; the correlation among the eight cytokines including interleukin (IL)-1ß (IL-1ß), IL-5, IL-8, IL-10, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), macrophage chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1ß (MIP-1ß) and the correlation between IL-5 and eosinophil count were analyzed. RESULTS: The medians of levels of IL-1ß, IFN-γ, IL-5, IL-10, MCP-1, MIP-1ß, IL-8 among patients were 0.15, 80.13, 2.95, 6.45, 83.83, 1057.90, 440.22 pg/ml, respectively, which were higher than those among the TCE-exposed workers (0.09, 16.93, 0.11, 0.07, 28.75, 241.07, 28.26 pg/ml, respectively, all P values < 0.01) and unexposed controls (0.09, 3.14, 0.11, 0.07, 25.27, 209.64, 207.34 pg/ml, respectively, all P values < 0.01). The median of level of TNF-α among the patients was 13.26 pg/ml, which was significantly higher than that among TCE-exposed workers (4.87 pg/ml, P < 0.01) but not among unexposed controls; the median of level of IL-5 among the TCE-exposed workers was 0.11 pg/ml, which was significantly higher than that among the unexposed controls (0.11 pg/ml, P < 0.01). The median of levels of IL-8 among the unexposed controls was 207.34 pg/ml, which was significantly higher than that among the TCE-exposed workers (28.26 pg/ml, P < 0.01). In case group, except for correlation of TNF-α and IFN-γ, TNF-α and IL-5, the significant positive correlations were found among any two cytokines (r(IL-1ß,IFN-γ) = 0.500, r(IL-1ß,TNF-α) = 0.348, r(IL-1ß,MCP-1) = 0.537, r(IL-1ß,MIP-1ß) = 0.477, r(IL-1ß,IL-8) = 0.466, r(IL-1ß,IL-5) = 0.610, r(IL-1ß,IL-10) = 0.626, r(IFN-γ,MCP-1) = 0.460, r(IFN-γ,MIP-1ß) = 0.491, r(IFN-γ,IL-8) = 0.322, r(IFN-γ,IL-5) = 0.532, r(IFN-γ,IL-10) = 0.511, r(TNF-α,MCP-1) = 0.325, r(TNF-α,MIP-1ß) = 0.283, r(TNF-α,IL-8) = 0.430, r(TNF-α,IL-10) = 0.271, r(MCP-1,MIP-1ß) = 0.659, r(MCP-1,IL-8) = 0.526, r(MCP-1,IL-5) = 0.504, r(MCP-1,IL-10) = 0.614, r(MIP-1ß,IL-8) = 0.601, r(MIP-1ß,IL-5) = 0.451, r(MIP-1ß,IL-10) = 0.579, r(IL-8,IL-5) = 0.255, r(IL-8,IL-10) = 0.403, r(IL-5,IL-10) = 0.798, all P values < 0.05). The median of level of IL-5 among the patients with high eosinophils counts was 8.92 pg/ml, which was significantly higher than that among the patients with low eosinophils counts (1.04 pg/ml, P < 0.05). CONCLUSION: The abnormal production of IL-1ß, IFN-γ, TNF-α, IL-8, MCP-1, MIP-1ß, IL-5 and IL-10 was related with the pathogenesis of hypersensitivity dermatitis induced by TCE. These cytokines could be used as referential indexes in the early health surveillance and clinic disease treatment.
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Dermatite Ocupacional/sangue , Dermatite Ocupacional/etiologia , Tricloroetileno/efeitos adversos , Adolescente , Adulto , Quimiocina CCL2/sangue , Quimiocina CCL4/sangue , Feminino , Humanos , Hipersensibilidade/sangue , Interferon gama/sangue , Interleucinas/sangue , Masculino , Fator de Necrose Tumoral alfa/sangue , Adulto JovemRESUMO
OBJECTIVE: To evaluate the chromium (Cr) levels in blood and urine among general population in China between 2009 and 2010, and thereby to analyze its prevalent features. METHODS: From year 2009 to 2010, a total of 11 983 subjects of general population aged between 6 and 60 year-old were recruited from 24 districts in 8 provinces in eastern, central and western China mainland, by cluster random sampling method. The information about their living environment and health status were collected by questionnaire, and 11 983 blood samples and 11 853 urine samples were also collected. Inductively coupled plasma mass spectrometry (ICP-MS) was applied to test the Cr level both in blood and urine; and the Cr distribution in blood and urine among groups of population in different ages, genders and districts, were then analyzed. RESULTS: Among general population in China, the geometric mean (GM) of Cr concentration in blood was 1.19 µg/L, with median at 1.74 µg /L and 95% percentile at 5.59 µg/L. The Cr concentration in blood among males and females were separately 1.18 µg/L and 1.20 µg/L(P > 0.05); while its GM in the groups of population aged 6 - 12, 12 - 16, 16 - 20, 20 - 30, 30 - 45 and 45 - 60 years old were 1.00, 1.22, 1.01, 1.40, 1.27 and 1.30 µg/L (P < 0.01), respectively; and the figures in populations from eastern, central and western China were 1.00, 1.70 and 1.98 µg/L (P < 0.01), respectively. Among general population, the GM of Cr concentration in urine was 0.53 µg/L, with median was lower than 0.42 µg/L and 95% percentile at 3.53 µg/L. The Cr concentration in urine among males and females were separately 0.52 µg/L and 0.53 µg/L (P > 0.05);while its GM in the groups of population aged 6 - 12, 12 - 16, 16 - 20, 20 - 30, 30 - 45 and 45 - 60 years old were 0.56, 0.60, 0.52, 0.50, 0.52 and 0.46 µg/L (P < 0.01), respectively;and the figures in populations from eastern, central and western China were 0.58, < 0.42 and 0.60 µg/L (P < 0.01), respectively. CONCLUSION: The study reported the Cr levels in blood and urine among general population in China, and thereby provided basic data evidence for the following Cr biological monitoring studies in near future.
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Cromo/sangue , Cromo/urina , Vigilância da População , Adolescente , Adulto , Criança , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
OBJECTIVE: To establish an animal model of lung injury in SD rats using intratracheal instillation of unknown polymer and to provide the base for exploring the molecular mechanism of lung tissue injury induced by occupational exposure. METHODS: One hundred forty SD rats were randomly divided into seven groups, including the control group 1 which was exposed to normal solution, the control group 2 which was not exposed to any one and five treatment groups which were exposed to 1 ml unknown polymer (0.5 ml for each lung) at the doses of 40, 30, 20, 10 and 5 mg/ml, respectively by intratracheal instillation. The rats were sacrificed on the 1st, 3rd, 7th, 10th, 14th, 21th and 28th day after exposure, then the lung tissues were examined pathologically and the blood bio-chemical analysis was conducted. RESULTS: The results of blood biochemical analysis indicated that ALT and AST levels in rats exposed to 30 and 40 mg/ml unknown polymer were significantly higher than those in control groups. Intratracheal instillation of unknown polymer can causes PLF in experimental animals on the 14th days after exposure. The results of pathological examination exhibited that the lung tissue injury in rats exposed to unknown polymer for 14 days or more was found and the dose-effect relationship was observed. CONCLUSION: An animal model of lung injury in SD rats induced by unknown polymer with intratracheal instillation was established successfully. The results of pathological examination showed that the types of rat lung injury were similar to the clinical lung injury after exposure to unknown polymer, which provided a base for studying the mechanism of lung injury caused by occupational exposure to unknown polymer.
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Modelos Animais de Doenças , Lesão Pulmonar/induzido quimicamente , Polímeros/toxicidade , Animais , Feminino , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Background: Treatment for pediatric psoriasis is challenging because of the lack of real-world evidence, especially for biological therapies. Objectives: This study evaluated the efficacy and safety of biologics in children with psoriasis based on real-world evidence. Methods: Pediatric psoriasis patients aged <18 years who were treated with biologics in our hospital (2020-2022) were prospectively analyzed. Patients treated with adalimumab, secukinumab, or ixekizumab were followed up for at least 16 weeks, and 22 of 38 patients completed the 52-week observation period. Dermatologist raters were blinded to ensure the reliability of the PASI, BSA, and PGA score assessments. PASI 75 or PGA 0/1 at week 12 represented an efficient indicator. Results: Thirty-eight patients (20 males and 18 females; median age, 12.6 ± 4.1 years) were enrolled, and none were lost to follow-up. All participants were diagnosed with psoriasis, including plaque psoriasis (n = 36), nail psoriasis (n = 1), and pustular psoriasis (n = 1). Within 12 weeks, all patients achieved scores above PASI 75 and PGA 0/1. The average time to reach PASI 75 was 4.3 ± 2.0, 3.2 ± 1.8, and 2.4 ± 0.4 weeks in patients using adalimumab, secukinumab, and ixekizumab, respectively, and, 27.2% (3/11), 86.4% (19/22), and 75.0% (3/4) of these patients achieved PASI 100 at week 12, respectively. Moreover, 18 of 20 patients with plaque psoriasis maintained ≥PASI 75 after 52 weeks. The most commonly reported adverse effect was upper respiratory tract infection, and no severe adverse effects were reported. Conclusions: Our real-world data demonstrated the safety and effectiveness of adalimumab, secukinumab, and ixekizumab in children with psoriasis.
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Psoriasis is a systemic immuneâmediated inflammatory disease characterized by hyperproliferation and abnormal differentiation of epidermal keratinocytes. Recent studies have identified IL-17 and IL-23 as key drivers of psoriasis pathogenesis, but the underlying molecular mechanisms remain unclear. The 2'-5'-oligoadenylate synthetases (OASs), namely, OAS1, OAS2, OAS3, and OASL, are a family of IFN-induced enzymes with multiple antiviral activities, but their role in psoriasis is unknown. In this study, we identified the overexpression of OAS1, OAS2, and OAS3 in human lesional psoriatic skin and serum and found that their expression was downregulated by biologics. Moreover, OASs were highly expressed in epidermal keratinocytes, epidermal dendritic cells, epidermal CD3+ T cells, dermal antigen-presenting cells, and dermal T cells from the psoriatic epidermis and dermis, as determined by flow cytometry. In addition, OASs were upregulated by poly(I:C), poly(dA:dT), and IFN-1s but downregulated by Jak inhibitors in normal human epidermal keratinocytes. Furthermore, silencing of OASs inhibited the phosphorylation of Jak1 and signal transducer and activator of transcription 1. Knockdown of OASs suppressed keratinocyte proliferation by inhibiting cell cycle progression. Thus, OASs may be therapeutic biomarkers in psoriasis.
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2',5'-Oligoadenilato Sintetase/metabolismo , Produtos Biológicos , Psoríase , Antivirais , Biomarcadores/metabolismo , Ciclo Celular , Proliferação de Células , Epiderme/metabolismo , Humanos , Interleucina-17/metabolismo , Interleucina-23/metabolismo , Janus Quinase 1 , Queratinócitos/metabolismo , Ligases/metabolismo , Fosforilação , Psoríase/patologia , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismoRESUMO
OBJECTIVE: To study the effects of trichloroethylene (TCE) to lymphocyte subsets among exposed workers, and explore the early immunological effect biomarkers for prevention of hypersensitivity dermatitis induced by TCE. METHODS: Twenty-eight patients with TCE-induced hypersensitivity dermatitis, 56 healthy TCE-exposed workers from the same workshops with patients, and 28 comparable unexposed controls were recruited in this study. The total lymphocyte count and the major lymphocyte subsets including T cell, CD4(+) T cell, CD8(+) T cell, B cell, NK cell in peripheral blood were measured by Flow Cytometer analysis and Standard blood count analysis. RESULTS: The total lymphocyte count and T cell, CD4(+) T cell, CD8(+) T cell among patients (median at 2810.00, 1846.17, 831.87, 904.05 cell counts/µl blood) were significantly increased compared with TCE-exposed workers (median at 2101.00, 1218.59, 643.87, 482.81 cell counts/µl blood, Z = -3.19, -4.96, -3.22, -4.99, P < 0.001) and unexposed controls (median at 1900.00, 1223.60, 558.60, 325.80 cell counts/µl blood, Z = -3.30, -4.46, -3.45, -5.03, P < 0.001), the NK cell and CD3(+)CD4(+)/CD3(+)CD8(+) ratio among patients (median at 255.50 cell counts/µl blood and 1.11) were significantly decreased compared with the unexposed controls (median at 642.60 cell counts/µl blood and 1.96, Z = -3.56 and -3.11, P < 0.01). Meanwhile, for the exposed workers, the CD8(+) T cell (median at 482.81 cell counts/µl blood) was significantly increased and the NK cell and CD3(+)CD4(+)/CD3(+)CD8(+) ratio (median at 318.76 cell counts/µl blood and 1.27) were significantly decreased compared with unexposed controls (median at 325.80 and 642.60 cell counts/µl blood and 1.96, Z = -2.63, -3.52, -2.29, P < 0.05). CONCLUSION: Occupational exposure to TCE could affect the lymphocyte subsets, especially T cell and NK cell. The total lymphocyte count, T cell and CD4(+) T cell might be effect biomarkers for subjects with hypersensitivity dermatitis among TCE-exposed workers.
Assuntos
Dermatite Ocupacional/imunologia , Toxidermias/imunologia , Subpopulações de Linfócitos , Tricloroetileno/efeitos adversos , Adolescente , Adulto , Dermatite Ocupacional/sangue , Toxidermias/sangue , Toxidermias/etiologia , Feminino , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
OBJECTIVE: To explore effects of acrylamide on synaptic plasticity of rat neuron and its mechanisms. METHODS: 24 Wistar rats were divided into control and test groups randomly, 12 rats in each group. The ratio of male and female in each group was 1:1. Acrylamide (30 mg/kg) was administered to rats by intraperitoneal injection in test group and normal saline (5 g/kg) was given to rats in control group. The neurobehavioral and pathologic changes of heart, liver, spleen, lung and kidney were observed. Changes of parameters in synapse were recorded by electron microscope. As an important target of synapse, change of Synapsin I was measured by immunohistochemical method. RESULTS: Compared with the control group (male: 1.00 ± 0.00; female: 1.00 ± 0.00), the gait score was increased significantly in ACR treated group (male: 2.50 ± 0.55, t = -7.24, P < 0.01; female: 3.17 ± 0.41, t = -12.19, P < 0.01). No obvious pathological changes of heart, liver, spleen, lung and kidney were found in all rats. Compared with the control group (male: (0.41 ± 0.09) µm; female: (0.40 ± 0.06) µm), the length of active zone of synapse was decreased significantly in ACR treated group (male: (0.15 ± 0.05) µm, t = 6.59, P < 0.05; female: (0.14 ± 0.07) µm, t = 7.26, P < 0.05). The width and postsynaptic density of synapse in ACR treated group had no significant difference with control group. The location of Synapsin I of control group and ACR treated group was both in gray matter of spinal dorsal horn. Compared with the control group (male: 195.40 ± 12.30; female: 195.19 ± 6.71), the concentration of Synapsin I was decreased significantly in ACR treated group (male: 60.90 ± 29.19, t = 10.40, P < 0.05; female: 67.56 ± 20.23, t = 15.65, P < 0.05). CONCLUSION: Neuronal synaptic plasticity was found in damage of nervous system induced by acrylamide in rats, which might be associated with the expression of Synapsin I.
Assuntos
Acrilamida/toxicidade , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Animais , Feminino , Masculino , Ratos , Ratos WistarRESUMO
OBJECTIVE: To elucidate the mechanism of carcinogenesis induced by coke oven emissions by investigating the cell genetic damage index and the methylation of O6-methylguanine-DNA methyltransferase (MGMT). METHODS: The human bronchial epithelial cell 16HBE was treated by 1 µmol/L B(a)P for 48 h, and then was exposed continuously to either 1 dimethyl sulfoxide (DMSO) or organic extracts of coke oven emission (OE-COE) for five days at the concentrations of 0, 2.5, 5.0, 10.0 and 20.0 µg/ml. The methylation-specific PCR (MSP-PCR), RT-PCR and immunoblotting were applied to detect the methylation status, changes of mRNA and protein of MGMT, respectively. Single cell gel electrophoresis was used to detect DNA damage induced by OE-COE. RESULTS: Compared with the control group (DMSO), there was a significant hypermethylation in all study groups, along with the suppression of mRNA and protein in a dose-dependent manner, and the gradation ratio of them was 1.0, 0.96, 0.96, 0.85, 0.32 and 1.0, 1.0, 1.1, 0.41, 0.52, separately. There was a significant DNA damage with a dose-effect relationship in all study groups (F = 41.22, P < 0.05), and the comet Olive tail moment was (2.98 ± 1.43), (4.76 ± 1.79), (10.09 ± 1.75), (11.38 ± 1.77), (11.67 ± 1.88). The further study found that the index of DNA damage was negatively correlated to the expression of MGMT mRNA and its protein. CONCLUSION: The DNA damage induced by COE might be associated with the suppression of MGMT caused by its hypermethylation.