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BACKGROUND: We aim to report the latest pooled analyses to evaluate the additive efficacy and safety of probiotics in the treatment of ulcerative colitis (UC). METHODS: We systematically searched the relevant literature investigating the efficacy and/or safety of probiotics in patients with UC from PubMed, Embase and Web of Science up to January 2023. Two researchers independently screened the literature, extracted data, and evaluated the quality of the included studies according to the inclusion and exclusion criteria. Any discrepancies throughout these processes were solved by consensus. All statistical analyses were performed by Review Manager version 5.4 and Stata version 15.0. RESULTS: A total of 13 articles were included in the pooled analyses, and the studies were all randomized controlled trials with a total of 930 patients. There were no significant differences between the probiotics and placebo groups concerning demographic and baseline characteristics. For patients with active UC, the probiotic group boosted the remission rate by 87% compared to the placebo group, but failed to reach a statistical difference (OR: 1.87; 95% CI 0.98, 3.57; P = 0.06, I2 = 67%); furthermore, there were no statistical differences in maintenance of clinical remission, clinical response, change in UCDAI scores, or mucosal healing outcomes in the probiotic group compared to the placebo group. For patients in clinical remission, the clinical relapse rates were significantly lower in the probiotic group than in the placebo group (OR: 0.34; 95% CI 0.14, 0.79; P = 0.01). Moreover, this study did not observe a significant difference between the two groups for general adverse events rate (OR: 1.98; 95% CI 0.69, 5.68; P = 0.20). CONCLUSION: Probiotic-assisted therapy may be effective in inhibiting UC recurrence in patients in clinical remission without increasing the risk of treatment-related adverse events; furthermore, probiotics may increase the rate of clinical remission in patients with active UC. However, caution is needed when interpreting the clinical efficacy of probiotics in improving the clinical outcome of patients with active UC.
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Colite Ulcerativa , Probióticos , Humanos , Colite Ulcerativa/dietoterapia , Colite Ulcerativa/tratamento farmacológico , Probióticos/administração & dosagem , Probióticos/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
Although the patient's survival time in various cancers has significantly increased in recent decades, the overall 5-year survival rate of pancreatic ductal adenocarcinoma (PDAC) has remained virtually unchanged due to rapid progression and metastasis. While N-acetyltransferase 10 (NAT10) has been identified as a regulator of mRNA acetylation in many malignancies, its role in PDAC remains unclear. Here, we found that NAT10 mRNA and protein levels were upregulated in PDAC tissues. Increased NAT10 protein expression was significantly correlated with poor prognosis in PDAC patients. Through our experiments, we demonstrated that NAT10 acted as an oncogene to promote PDAC tumorigenesis and metastasis in vitro and in vivo. Mechanistically, NAT10 exerts its oncogenic effects by promoting mRNA stability of receptor tyrosine kinase AXL in an ac4C-dependent manner leading to increased AXL expression and further promoting PDAC cell proliferation and metastasis. Together, our findings highlight the critical of NAT10 in PDAC progression and reveal a novel epigenetic mechanism by which modified mRNA acetylation promotes PDAC metastasis.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/metabolismo , Proliferação de Células/genética , RNA Mensageiro/genética , Acetiltransferases N-Terminal , Neoplasias PancreáticasRESUMO
BACKGROUND: To evaluate the long-term efficacy of transoral incisionless fundoplication (TIF) with Medigus Ultrasonic Surgical Endostapler (MUSE) for gastroesophageal reflux disease (GERD). METHODS: A total of 16 patients with proton pump inhibitor-dependent gastroesophageal reflux disease had undergone TIF by MUSE in Shanghai General Hospital ï¼Shanghai, Chinaï¼from March 2017 to December 2018. Patients were followed up at 6 months, and the GERD-health-related quality of life (GERD-HRQL) questionnaire score, the GERD questionnaire (GERD-Q) score, high-resolution esophageal manometry (HREM) and 24 h esophageal pH parameters, the Hill grade of the gastroesophageal flap valve (GEFV) and daily Proton pump inhibitor (PPI) consumption before and after procedure were compared. Patients also were followed up at 3 years and 5 years using a structured questionnaire via phone which evaluated symptoms of reflux, dose of PPI medication and side effects. RESULTS: Follow-up data were collected from 13 patients, ranging from 38 to 63 months, 53 months on average. 10/13 patients reported symptomatic improvement and daily PPI consumption was stopped or halved in 11/13. After procedure, the mean scores of GERD-HRQL and GERD-Q were significantly increased. The mean DeMeester score, the mean acid exposure time percentage and the mean number of acid reflux episodes were significantly lower. The mean rest pressure at lower esophageal sphincter (LES) had no significant difference. CONCLUSION: TIF by MUSE has significant efficacy in the treatment of PPI-dependent GERD, which can improve symptoms and life quality of patients, and reduce the acid exposure time for long-term. Chictr.org.cn. TRIAL REGISTRATION: ChiCTR2000034350.
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Fundoplicatura , Refluxo Gastroesofágico , Humanos , Fundoplicatura/efeitos adversos , Fundoplicatura/métodos , Alprostadil/uso terapêutico , Qualidade de Vida , Inibidores da Bomba de Prótons/uso terapêutico , Ultrassom , Resultado do Tratamento , China , Refluxo Gastroesofágico/diagnósticoRESUMO
BACKGROUND: N6-methyladenosine (m6A) is the most abundant reversible methylation modification of eukaryotic mRNA, and it plays vital roles in tumourigenesis. This study aimed to explore the role of the m6A demethylase ALKBH5 in pancreatic cancer (PC). METHODS: The expression of ALKBH5 and its clinicopathological impact were evaluated in PC cohorts. The effects of ALKBH5 on the biological characteristics of PC cells were investigated on the basis of gain-of-function and loss-of-function analyses. Subcutaneous and orthotopic models further uncovered the role of ALKBH5 in tumour growth. mRNA and m6A sequencing and assays of m6A methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR) were performed to identify the targeted effect of ALKBH5 on PER1. P53-binding sites in the ALKBH5 promoter were investigated by ChIP and luciferase assays to reveal the interplay between ALKBH5 and PER1-activated ATM-CHK2-P53/CDC25C signalling. RESULTS: ALKBH5 loss characterized the occurrence and poor clinicopathological manifestations in patients with PC. Overexpression of ALKBH5 reduced tumoural proliferative, migrative, invasive activities in vitro and ameliorated tumour growth in vivo, whereas ALKBH5 knockdown facilitated PC progression. Mechanistically, ALKBH5 posttranscriptionally activated PER1 by m6A demethylation in an m6A-YTHDF2-dependent manner. PER1 upregulation led to the reactivation of ATM-CHK2-P53/CDC25C signalling, which inhibited cell growth. P53-induced activation of ALKBH5 transcription acted as a feedback loop regulating the m6A modifications in PC. CONCLUSION: ALKBH5 serves as a PC suppressor by regulating the posttranscriptional activation of PER1 through m6A abolishment, which may highlight a demethylation-based approach for PC diagnosis and therapy.
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Adenosina/análogos & derivados , Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Pancreáticas/patologia , Proteínas Circadianas Period/genética , Proteínas de Ligação a RNA/metabolismo , Ativação Transcricional , Adenosina/química , Homólogo AlkB 5 da RNA Desmetilase/genética , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Movimento Celular , Proliferação de Células , Feminino , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Proteínas Circadianas Period/metabolismo , Prognóstico , Processamento Pós-Transcricional do RNA , Proteínas de Ligação a RNA/genética , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Rosacea is a chronic inflammatory cutaneous disease which mainly affects central face, leading to cosmetic disfigurement and compromised social psychology in billions of rosacea patients. Though the exact etiology of rosacea remains elusive, accumulating evidence has highlighted the dysfunction of innate immunity and inflammation in rosacea pathogenesis. Disintegrin Metalloprotease ADAM-like Decysin-1 (ADAMDEC1) is an orphan ADAM-like metalloprotease which is believed to be closely related to inflammation. Here for the first time, we reported that Adamdec1 expression was significantly increased in the skin lesions of rosacea patients and LL37-induced rosacea-like mouse models. Immunofluorescence analysis revealed co-localization of ADAMDEC1 and macrophages in patient and mouse biopsies. In cellular experiment, the expression of ADAMDEC1 was prominently elevated in M1 but not M2 macrophages. Knocking down of ADAMDEC1 significantly blunted M1 polarization in macrophages induced from human monocytes and THP-1â¯cell lines. Furthermore, silencing of Adamdec1 in LL-37-induced mouse model also suppressed the expression of M1 signature genes such as IL-6, iNOS and TNF-α, resulting in attenuated rosacea-like phenotype and inflammation. Taken together, our results demonstrate that ADAMDEC1 plays a pro-inflammatory role in rosacea via modulating the M1 polarization of macrophages.
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Proteínas ADAM/metabolismo , Inflamação/metabolismo , Macrófagos/metabolismo , Rosácea/metabolismo , Pele/metabolismo , Adulto , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
DCZ3301, a novel aryl-guanidino compound, was previously found to have potent anti-tumor activity in myeloma and B-cell lymphoma. In the present study, we investigated the effects of DCZ3301 on T-cell leukemia/lymphoma cells both in vitro and in vivo via cell proliferation, cell cycle analysis, apoptosis assay, mitochondrial membrane potential (MMP) assay, western blot analysis and tumor xenograft models. We found that DCZ3301 inhibited the viability of T-cell leukemia/lymphoma cells in a dose- and time-dependent manner. DCZ3301-induced G2/M cell cycle arrest, associated with downregulation of CDK1, cyclin B1, and cdc25C. DCZ3301 also induced cell apoptosis by decreasing MMP in T-cell leukemia/lymphoma cells, but had no significant pro-apoptotic effect on normal peripheral blood mononuclear cells (PBMCs). In addition, DCZ3301-induced apoptosis may be mediated by the caspase-dependent pathway and suppressing the phosphoinositide 3-kinase (PI3K)/AKT pathway. Finally, we showed that DCZ3301 treatment effectively inhibited tumor growth, with no significant side effects, in xenograft mouse models. In conclusion, these results suggest that DCZ3301 may be regarded as a new therapeutic strategy for T-cell leukemia/lymphoma patients.
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Amidas/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Leucemia de Células T/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piridinas/farmacologia , Amidas/química , Antineoplásicos/química , Linhagem Celular Tumoral , Humanos , Células Jurkat , Leucemia de Células T/metabolismo , Leucemia de Células T/patologia , Linfoma de Células T/metabolismo , Linfoma de Células T/patologia , Estrutura Molecular , Piridinas/química , Transdução de Sinais/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Mantle cell lymphoma (MCL) is an aggressive and mostly incurable B-cell malignancy with frequent relapses after an initial response to standard chemotherapy. Therefore, novel therapies are urgently required to improve MCL clinical outcomes. In this study, MCL cell lines were treated with pterostilbene (PTE), a non-toxic natural phenolic compound primarily found in blueberries. The antitumor activity of PTE was examined by using the Cell Counting Kit-8, apoptosis assays, cell cycle analysis, JC-1 mitochondrial membrane potential assay, western blot analysis, and tumor xenograft models. PTE treatment induced a dose-dependent inhibition of cell proliferation, including the induction of cell apoptosis and cell cycle arrest at the G0/G1 phase. Moreover, the PI3K/Akt/mTOR pathway was downregulated after PTE treatment, which might account for the anti-MCL effects of PTE. Synergistic cytotoxicity was also observed, both in MCL cells and in xenograft mouse models, when PTE was administered in combination with bortezomib (BTZ). The antitumor effects of PTE shown in our study provide an innovative option for MCL patients with poor responses to standardized therapy. It is noteworthy that the treatment combining PTE with BTZ warrants clinical investigation, which may offer an alternative and effective MCL treatment in the future.
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Linfoma de Célula do Manto/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estilbenos/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Progressão da Doença , Feminino , Humanos , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Camundongos Endogâmicos NOD , Camundongos SCID , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
MCT-1 (multiple copies in T-cell lymphoma-1), a novel oncogene, was originally identified in T-cell lymphoma. A recent study has demonstrated that MCT-1 is highly expressed in 85% of diffuse large B-cell lymphomas (DLBCL). PKC (protein kinase C) plays an essential role in signal transduction for multiple biologically active substances for activating cellular functions and proliferation. In this study, we found that the mRNA and protein expression levels of MCT-1 were visibly decreased after knocking down PKC by siRNA in SUDHL-4 and OCI-LY8 DLBCL cell lines. A selective PKC inhibitor, sotrastaurin, effectively inhibited cell proliferation and induced cell apoptosis in a dose- and time-dependent manner. Meanwhile, we also observed that the cell cycle was arrested in the G1 phase in sotrastaurin-treated cells. In addition, MCT-1 was down-regulated in the sotrastaurin treatment group in vivo. Furthermore, we demonstrated that the PKC inhibitor sotrastaurin induced cell apoptosis and cell cycle arrest in DLBCL cells potentially through regulating the expression of MCT-1. Our data suggest that targeting PKC may be a potential therapeutic approach for lymphomas and related malignancies that exhibit high levels of MCT-1 protein.
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Proteínas de Ciclo Celular/metabolismo , Regulação da Expressão Gênica , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Proteínas Oncogênicas/metabolismo , Proteína Quinase C/antagonistas & inibidores , Pirróis/farmacologia , Quinazolinas/farmacologia , Animais , Apoptose , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Relação Dose-Resposta a Droga , Feminino , Inativação Gênica , Humanos , Linfoma/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Transdução de SinaisRESUMO
Multiple myeloma (MM) is the second most frequent malignant hematological disease. Dihydrocelastrol (DHCE) is synthesized by hydrogenated celastrol, a treterpene isolated from Chinese medicinal plant Tripterygium regelii. In this study, we first reported the anti-tumor activity of DHCE on MM cells. We found that DHCE could inhibit cell proliferation and promote apoptosis through caspase-dependent way in vitro. In addition, DHCE could inactivate the expression of interleukin (IL)-6 and downregulate the phosphorylation of extracellular regulated protein kinases (ERK1/2) and the signal transducer and activator of transcription 3 (STAT3) in MM. It also retained its activity against MM cell lines in the presence of IL-6. Furthermore, treatment of MM cells with DHCE resulted in an accumulation of cells in G0/G1 phase of the cell cycle. Notably, DHCE reduced the expression of cyclin D1 and cyclin-dependent kinases 4 and 6 in MM cell lines. Additionally, its efficacy toward the MM cell lines could be enhanced in combination with the histone deacetylase inhibitor panobinostat (LBH589), which implied the possibility of the combination treatment of DHCE and LBH589 as a potential therapeutic strategy in MM. In addition, treatment of NCI-H929 tumor-bearing nude mice with DHCE (10 mg/kg/d, i.p., 1-14 days) resulted in 73% inhibition of the tumor growth in vivo. Taken together, the results of our present study indicated that DHCE could inhibit cellular proliferation and induce cell apoptosis in myeloma cells mediated through different mechanisms, possibly through inhibiting the IL-6/STAT3 and ERK1/2 pathways. And it may provide a new therapeutic option for MM patients.
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Apoptose/efeitos dos fármacos , Interleucina-6/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Fator de Transcrição STAT3/metabolismo , Triterpenos/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Nus , Mieloma Múltiplo/patologia , Triterpenos Pentacíclicos , Resultado do TratamentoRESUMO
Inflammation triggered by necrotic acinar cells contributes to the pathophysiology of acute pancreatitis (AP), but its precise mechanism remains unclear. Recent studies have shown that Cyclophilin A (CypA) released from necrotic cells is involved in the pathogenesis of several inflammatory diseases. We therefore investigated the role of CypA in experimental AP induced by administration of sodium taurocholate (STC). CypA was markedly upregulated and widely expressed in disrupted acinar cells, infiltrated inflammatory cells, and tubular complexes. In vitro, it was released from damaged acinar cells by cholecystokinin (CCK) induction. rCypA (recombinant CypA) aggravated CCK-induced acinar cell necrosis, promoted nuclear factor (NF)-κB p65 activation, and increased cytokine production. In conclusion, CypA promotes pancreatic damage by upregulating expression of inflammatory cytokines of acinar cells via the NF-κB pathway.
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Ciclofilina A/metabolismo , NF-kappa B/metabolismo , Pâncreas/metabolismo , Pancreatite/metabolismo , Células Acinares/efeitos dos fármacos , Células Acinares/metabolismo , Células Acinares/patologia , Animais , Morte Celular/efeitos dos fármacos , Colecistocinina/toxicidade , Ciclofilina A/genética , Ciclofilina A/toxicidade , Citocinas/genética , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Masculino , Pâncreas/patologia , Pancreatite/genética , Pancreatite/patologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Regulação para CimaRESUMO
Aging represents a multifaceted process culminating in the deterioration of biological functions. Despite the introduction of numerous anti-aging strategies, their therapeutic outcomes have often been less than optimal. Consequently, discovering new targets to mitigate aging effects is of critical importance. We applied Mendelian randomization (MR) to identify potential pharmacological targets against aging, drawing upon summary statistics from both the Decode and FinnGen cohorts, with further validation in an additional cohort. To address potential reverse causality, bidirectional MR analysis with Steiger filtering was utilized. Additionally, Bayesian co-localization and phenotype scanning were implemented to investigate previous associations between genetic variants and traits. Summary-data-based Mendelian randomization (SMR) analysis was conducted to assess the impact of genetic variants on aging via their effects on protein expression. Additionally, mediation analysis was orchestrated to uncover potential intermediaries in these associations. Finally, we probed the systemic implications of drug-target protein expression across diverse indications by MR-PheWas analysis. Utilizing a Bonferroni-corrected threshold, our MR examination identified 10 protein-aging associations. Within this cohort of proteins, MST1, LCT, GMPR2, PSMB4, ECM1, EFEMP1, and ISLR2 appear to exacerbate aging risks, while MAX, B3GNT8, and USP8 may exert protective influences. None of these proteins displayed reverse causality except EFEMP1. Bayesian co-localization inferred shared variants between aging and proteins such as B3GNT8 (rs11670143), ECM1 (rs61819393), and others listed. Mediator analysis pinpointed 1,5-anhydroglucitol as a partial intermediary in the influence LCT exhibits on telomere length. Circulating proteins play a pivotal role in influencing the aging process, making them promising candidates for therapeutic intervention. The implications of these proteins in aging warrant further investigation in future clinical research.
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Envelhecimento , Análise da Randomização Mendeliana , Humanos , Envelhecimento/genética , Teorema de BayesRESUMO
Background and study aims Symptomatic simple hepatic cysts require treatment, with several guidelines recommending laparoscopic deroofing. However, cysts located in the posterosuperior segments are considered poor candidates for this procedure. Gastrointestinal endoscopes are more flexible and able to reach less accessible areas than laparoscopes. This study aimed to evaluate the utility of endoscopic transgastric hepatic cyst deroofing (ETGHCD) for treatment of simple hepatic cysts. Patients and methods Seven patients with simple hepatic cysts were evaluated between June 2021 and October 2023. The success rate, procedure time, post-procedure length of hospital stays, complications, pathologic diagnosis, and efficacy were recorded. Results Eleven cysts in seven patients (5 men; mean age 65.5 (standard deviation [SD] 8.5) years) were successfully treated without any complications. The mean procedure time was 65.6 minutes (SD 17.2). Mean post-procedure hospitalization was 4.4 days (SD 1.0). The pathologic diagnosis of 11 cysts showed simple hepatic cysts. The size of the cysts was significantly decreased from 337.0 cm 3 (SD 528.8) to 5.2 cm 3 (SD 6.3) 1 month after ETGHCD. During the median 12.7-month follow-up in seven patients, the cysts showed a 99.6% reduction with no recurrence. Conclusions ETGHCD provided a feasible, safe, effective, and minimal invasive alternative approach for the treatment of simple hepatic cysts.
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Recent efforts have described the transcriptomic landscape of rosacea. However, little is known about its proteomic characteristics. In this study, the proteome and phosphoproteome of lesional skin, paired nonlesional skin, and healthy skin were analyzed by liquid chromatography coupled with tandem mass spectrometry. The molecular characteristics and potential pathogenic mechanism of rosacea were demonstrated by integrating the proteome, phosphoproteome, and previous transcriptome. The proteomic data revealed a significant upregulation of inflammation- and axon extension-related proteins in lesional skin and nonlesional skin versus in healthy skin, implying an inflammatory and nerve-hypersensitive microenvironment in rosacea skin. Of these, axon-related proteins (DPYSL2 and DBNL) were correlated with the Clinician's Erythema Assessment score, and neutrophil-related proteins (ELANE and S100A family) were correlated with the Investigator's Global Assessment score. Moreover, comorbidity-related proteins were differentially expressed in rosacea; of these, SNCA was positively correlated with Clinician's Erythema Assessment score, implying a potential correlation between rosacea and comorbidities. Subsequently, the integrated proteome and transcriptome demonstrated consistent immune disturbances at both the transcriptional and protein levels. The integrative analysis of the proteome and phosphoproteome revealed the key transcription factor network and kinase network that drive the dysregulation of immunity and vasculature in rosacea. In conclusion, our multiomics analysis enables more comprehensive insight into rosacea and offers an opportunity for, to our knowledge, previously unreported treatment strategies.
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Proteoma , Rosácea , Humanos , Multiômica , Proteômica , Rosácea/metabolismo , EritemaRESUMO
Psoriasis and rosacea are both chronic inflammatory skin disorders resulted from aberrant keratinocyte-immune cell crosstalk, but the common molecular foundations for these 2 conditions are poorly understood. In this study, we reveal that both patients with psoriasis and those with rosacea as well as their mouse models have significantly elevated expressions of SERPINB3/B4 (members of serine protease inhibitor) in the lesional skin. Skin inflammation in mice that resembles both psoriasis and rosacea is prevented by SERPINB3/B4 deficiency. Mechanistically, we demonstrate that SERPINB3/B4 positively induces NF-κB signaling activation, thereby stimulating disease-characteristic inflammatory chemokines and cytokines production in keratinocytes and promoting the chemotaxis of CD4+ T cells. Our results suggest that in keratinocytes, SERPINB3/B4 may be involved in the pathogenesis of both psoriasis and rosacea by stimulating NF-κB signaling, and they indicate a possible treatment overlap between these 2 diseases.
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BACKGROUND: Pancreatic fibrosis is a hallmark feature of chronic pancreatitis (CP), resulting in persistent damage to the pancreas. The sustained activation of pancreatic stellate cells (PSCs) plays a pivotal role in the progression of pancreatic fibrosis and is a major source of extracellular matrix (ECM) deposition during pancreatic injury. METHODS: Calpain is a calcium-independent lysosomal neutral cysteine endopeptidase and was found to be correlated to various fibrotic diseases. Studies have revealed that calpeptin, a calpain inhibitor, can improve the fibrosis process of multiple organs. This study investigated the effect of the calpain inhibitor, calpeptin, on fibrosis in experimental CP and activation of cultured PSCs in mice. CP was induced in mice by repeated injections of cerulein for four weeks in vivo, and the activation process of mouse PSCs was isolated and cultured in vitro. Then, the inhibitory effect of calpeptin on pancreatic fibrosis was confirmed based on the histological damage of CP, the expression of α-smooth muscle actin (α-SMA) and collagen-Iα1(Col1α1), and the decrease in mRNA levels of calpain-1 and calpain-2. RESULTS: In addition, it was revealed that calpeptin can inhibit the activation process of PSCs and induce significant PSCs apoptosis by downregulating the expression of calpain-1, calpain-2 and TGF-ß1, and the expression and phosphorylation of smad3 in vitro. CONCLUSION: These results suggest that the calpain inhibitor, calpeptin, plays a key role in the regulation of PSC activation by inhibiting the TGF-ß1/smad3 signaling pathway, which supports the potential of calpeptin as an inhibitor of pancreatic fibrosis in mice by interfering with calpain.
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[This corrects the article on p. 5507 in vol. 9, PMID: 29312502.].
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Rosacea is a common inflammatory skin disorder mediated by the dysregulation of both keratinocytes and T cells. Here, we report that aquaporin 3 (AQP3), a channel protein that mediates the transport of water/glycerol, was highly expressed in the epidermis and CD4+ T cells of both rosacea patients and experimental mice. Specifically, AQP3 deletion blocked the development of rosacea-like skin inflammation in model mice with LL37-induced rosacea-like disease. We also present mechanistic evidence showing that AQP3 was essential to the activation of NF-κB signaling and subsequent production of disease-characteristic chemokines in keratinocytes. Moreover, we show that AQP3 was upregulated during T cell differentiation and promotes helper T (Th) 17 differentiation possibly via the activation of STAT3 signaling. Our findings reveal that AQP3-mediated activation of NF-κB in keratinocytes and activation of STAT3 in CD4+ T cells acted synergistically and contributed to the inflammation in rosacea.
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Aquaporina 3 , Rosácea , Humanos , Animais , Camundongos , Aquaporina 3/genética , NF-kappa B/metabolismo , Queratinócitos/metabolismo , Pele/metabolismo , Rosácea/metabolismo , Inflamação/metabolismoRESUMO
Background: Antibiotics are considered the backbone of rosacea management, especially for controlling inflammatory papules and pustules. We aim to evaluate the efficacy and safety of varied prescriptions and doses of antibiotics in treating rosacea by network meta-analysis. Methods: In this study, we compared all available randomized controlled trials (RCTs) that have studied systemic and topical antibiotics and placebo in rosacea therapy. We searched databases such as the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PubMed, Web of Science, and LILACS for published and unpublished RCTs on ClinicalTrials.gov before April 2023. The primary outcome was the improvement of the Investigator's Global Assessment (IGA) scores, and the secondary outcomes consisted of the improvement of the Patient's Global Assessment (PaGA) scores, Clinician's Erythema Assessment (CEA) scores, and adverse events (AEs). We used Bayesian random effects models for multiple treatment comparisons. Results: We identified 1,703 results through these databases. Thirty-one randomized trials with 8,226 patients were included. The heterogeneity and inconsistency between the trials were low, with a low risk of bias of all trials. Oral doxycycline 40 mg, minocycline 100 mg, and minocycline 40 mg, as well as topical ivermectin and metronidazole 0.75%, were effective in treating papules and pustules, thereby decreasing IGA in rosacea. Among these, minocycline 100 mg ranked top in efficacy. As for improving the PaGA scores, topical ivermectin, metronidazole 1%, and systemic oxytetracycline were effective, of which oxytetracycline worked the best. Both doxycycline 40 mg and metronidazole 0.75% presented no therapeutic effect for erythema. Considering the safety of the agents, systemic application of azithromycin and doxycycline 100 mg significantly increase the risk of AEs. Conclusion: Our review suggests that a high dosage of systemic minocycline is the most effective in treating rosacea phenotypes with papules and pustules with a low risk of AEs. However, there were no sufficient evidence-based data in exploring the influence of antibiotics on erythema. The phenotype of rosacea should be taken into consideration along with benefit and safety when making prescriptions due to AEs. Clinical Trial Registration: NCT(2016): http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/962/CN-01506962/frame.html NCT(2017): http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/764/CN-01565764/frame.html.
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Background: In chronic kidney disease (CKD), cognitive impairment is a definite complication. However, the mechanisms of how CKD leads to cognitive impairment are not clearly known. Methods: Cerebral blood flow (CBF) information was collected from 37 patients with CKD (18 in stage 3; 19 in stage 4) and 31 healthy controls (HCs). For CKD patients, we also obtained laboratory results as well as neuropsychological tests. We conducted brain perfusion imaging studies using arterial spin labeling and calculated the relationship between regional CBF changes and various clinical indicators and neuropsychological tests. We also generated receiver operator characteristic (ROC) curves to explore whether CBF value changes in certain brain regions can be used to identify CKD. Results: Compared with HCs, CBF decreased in the right insula and increased in the left hippocampus in the CKD4 group; through partial correlation analysis, we found that CBF in the right insula was negatively correlated with the number connection test A (NCT-A) (r = −0.544, p = 0.024); CBF in the left hippocampus was positively correlated with blood urea nitrogen (r = 0.649, p = 0.005) and negatively correlated with serum calcium level (r = −0.646, p = 0.005). By comparing the ROC curve area, it demonstrated that altered CBF values in the right insula (AUC = 0.861, p < 0.01) and left hippocampus (AUC = 0.862, p < 0.01) have a good ability to identify CKD. Conclusions: Our study found that CBF alterations in the left hippocampus and the right insula brain of adult patients with stage 4 CKD were correlated with disease severity or laboratory indicators. These findings provide further insight into the relationship between altered cerebral perfusion and cognitive impairment in patients with non-end-stage CKD as well as, additional information the underlying neuropathophysiological mechanisms.
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Rosacea is a chronic inflammatory skin disease originated from damaged skin barrier and innate/adaptive immune dysregulation. Toll-like receptors (TLRs) sense injured skin and initiate downstream inflammatory and immune responses, whose role in rosacea is not fully understood. Here, via RNA-sequencing analysis, we found that the TLR signaling pathway is the top-ranked signaling pathway enriched in rosacea skin lesions, in which TLR7 is highlighted and positively correlated with the inflammation severity of disease. In LL37-induced rosacea-like mouse models, silencing TLR7 prevented the development of rosacea-like skin inflammation. Specifically, we demonstrated that overexpressing TLR7 in keratinocytes stimulates rapamycin-sensitive mTOR complex 1 (mTORC1) pathway via NFκB signaling. Ultimately, TLR7/NFκ B/mTORC1 axis promotes the production of cytokines and chemokines, leading to the migration of CD4+T cells, which are infiltrated in the lesional skin of rosacea. Our report reveals the crucial role of TLR7 in rosacea pathogenesis and indicatesa promising candidate for rosacea treatments.