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Interleukin-6 (IL-6) is a cytokine generated by healthy constituents of the skin, but is also up-regulated by a wide range of skin lesions and inflammatory conditions to trigger cytopathy of skin cells. TRIM27 was identified to contribute to the functional effects of IL-6 on skin cells. However, the underlying mechanism was not clear. Lentivirus infection was used for gene overexpression or silencing. RT-PCR and Western blot were used to respectively assess mRNA and protein levels. Cell viability was assessed by CCK-8 assay. Extracellular flux analysis was used to assess the levels of oxygen consumption rate and extracellular acidification rate. Mouse back skin was treated with imiquimod to produce psoriasis-like inflammation in vivo. Histological assessment and immunohistochemistry staining were respectively applied to analyse lesioned mouse and human skin samples. IL-6-induced increased viability, glycolysis and inflammation in keratinocytes was inhibited both by a chemical methylation inhibitor and by METTL14 knockdown. Further investigation found that METTL14 induces m6A methylation of TRIM27, which is recognized by a m6A reader, IGF2BP2. Elevation of TRIM27 level and activation of IL-6/STAT3 signalling pathway were found in an in vivo psoriasis-like inflammation model, whereas inhibition m6A methylation strongly alleviated the inflammation. Finally, METTL14, TRIM27, STAT3, p-STAT3 and IL-6 expressions were all found to be increased in clinical skin samples of psoriatic patients. Our results unravelled METTL14/TRIM27/IGF2BP2 signalling axis in keratinocyte cytopathy, which plays a critical role in facilitating the activation of IL-6/STAT3 signalling pathway. Our findings should provide inspirations for the design of new therapeutics for skin inflammatory diseases including psoriasis.
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Adenina , Interleucina-6 , Metiltransferases , Psoríase , Animais , Humanos , Camundongos , Adenina/análogos & derivados , Proteínas de Ligação a DNA , Glicólise , Células HaCaT , Inflamação/patologia , Interleucina-6/farmacologia , Queratinócitos/patologia , Proteínas Nucleares , Psoríase/patologia , Proteínas de Ligação a RNA , Fatores de Transcrição , Proteínas com Motivo TripartidoRESUMO
Psoriasis is a skin disease that is inflammatory and persistent, causing a high rate of recurrence, poor quality of life, and significant socioeconomic burden. Its main pathological manifestations are abnormal activation and infiltration of T cells and excessive proliferation of keratinocytes (KCs). The great majority of patients with psoriasis will relapse after remission. It usually lasts a lifetime and necessitates long-term treatment strategies. During periods of activity and remission, one of the main cell types in psoriasis is memory T cells, which include tissue-resident memory T (TRM) cells, central memory T (TCM) cells, and effector memory T (TEM) cells. They work by releasing inflammatory factors, cytotoxic particles, or altering cell subpopulations, leading to increased inflammation or recurrence. This review summarizes the role of memory T cells in the pathology and treatment of psoriasis, with a view to potential novel therapies and therapeutic targets.
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Atopic dermatitis (AD) is a prevalent chronic inflammatory skin disease that carries a significant global economic burden. Elevated levels of reactive oxygen species (ROS) have been recognized as contributing to AD exacerbation, making them a potential therapeutic target for AD treatment. Here, we introduce a dual-site biomimetic copper/zinc metal-organic framework (Cu/Zn-MOF) featuring four types of enzyme-like activities for AD treatment via suppressing the Fcγ receptor (FcγR)-mediated phagocytosis signal by mimicking the bimetallic sites of natural copper-zinc superoxide dismutase (CuZn-SOD). Interestingly, the neighboring Cu and Zn sites in both Cu/Zn-MOF and CuZn-SOD are at similar distances of â¼5.98 and â¼6.3 Å from each other, respectively, and additionally, both Cu and Zn sites are coordinated to nitrogen atoms in both structures, and the coordinating ligands to Cu and Zn are both imidazole rings. Cu/Zn-MOF exhibits remarkable SOD-like activity as well as its glutathione peroxidase (GPx)-, thiol peroxidase (TPx)-, and ascorbate peroxidase (APx)-like activities to continuously consume ROS and mitigate oxidative stress in keratinocytes. Animal experiments show that Cu/Zn-MOF outperforms halcinonide solution (a potent steroid medication) in terms of preventing mechanical injuries, reducing cutaneous water loss, and inhibiting inflammatory responses while presenting favorable biosafety. Mechanistically, Cu/Zn-MOF functions through an FcγR-mediated phagocytosis signal pathway, decreasing the continuous accumulation of ROS in AD and ultimately suppressing disease progression. These findings will provide an effective paradigm for AD therapy and contribute to the development of two-site bionics (TSB).
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Dermatite Atópica , Estruturas Metalorgânicas , Humanos , Animais , Superóxido Dismutase/metabolismo , Cobre , Receptores de IgG , Zinco/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Biomimética , Glutationa Peroxidase/metabolismoRESUMO
BACKGROUND: Diabetic ulcers (DUs) are characterized by chronic inflammation and delayed re-epithelialization, with a high incidence and weighty economic burden. The primary therapeutic strategies for refractory wounds include surgery, non-invasive wound therapy, and drugs, while the optimum regimen remains controversial. Sirtuin-6 (SIRT6) is a histone deacetylase and a key epigenetic factor that exerts anti-inflammatory and pro-proliferatory effects in wound healing. However, the exact function of SIRT6 in DUs remains unclear. METHODS: We generated tamoxifen-inducible SIRT6 knockout mice by crossing SIRT6flox/flox homozygous mice with UBC-creERT2+ transgenic mice. Systemic SIRT6 null mice, under either normal or diabetic conditions, were utilized to assess the effects of SIRT6 in DUs treatment. Gene and protein expressions of SIRT6 and inflammatory cytokines were measured by Western blotting and RT-qPCR. Histopathological examination confirmed the altered re-epithelialization (PCNA), inflammation (NF-κB p50 and F4/80), and angiogenesis (CD31) markers during DUs restoration. RESULTS: Knockout of SIRT6 inhibited the healing ability of DUs, presenting attenuated re-epithelialization (PCNA), exacerbated inflammation responses (NF-κB p50, F4/80, Il-1ß, Tnf-α, Il-6, Il-10, and Il-4), and hyperplasia vascular (CD31) compared with control mice. CONCLUSIONS: SIRT6 could boost impaired wound healing through improving epidermal proliferation, inflammation, and angiogenesis. Our study highlighted the therapeutic potential of the SIRT6 agonist for DUs treatment.
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Camundongos Knockout , Sirtuínas , Cicatrização , Animais , Cicatrização/genética , Sirtuínas/genética , Sirtuínas/metabolismo , Sirtuínas/deficiência , Camundongos , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Citocinas/metabolismo , Camundongos Endogâmicos C57BL , Inflamação/genética , Inflamação/patologia , Inflamação/metabolismo , MasculinoRESUMO
Psoriasis is a chronic immune-mediated recurrent skin disease causing systemic damage. Increased angiogenesis has been reported to participate in the progression of psoriasis. However, angiogenesis-related genes (ARGs) in psoriasis have not been systematically elucidated. Therefore, we aim to identify potential biomarkers and subtypes using two algorithms. Transcriptome sequencing data of patients with psoriasis were obtained, in which differentially expressed genes were assessed by principal component analysis (PCA). A diagnostic model was developed using random forest algorithm (ntree=400) and validated by ROC curves. Subsequently, we performed consensus clustering to calculate angiogenesis-associated molecular subtypes of psoriasis. Additionally, a correlation analysis was conducted between ARGs and immune cell infiltration. Finally, validation of potential ARG genes was performed by qRT-PCR. We identified 29 differentially expressed ARGs, including 13 increased and 16 decreased. Ten ARGs, CXCL8, ANG, EGF, HTATIP2, ANGPTL4, TNFSF12, RHOB, PML, FOXO4, and EMCN were subsequently sifted by the diagnostic model based on a random forest algorithm. Analysis of the ROC curve (area under the curve [AUC] = 1.0) indicated high diagnostic performance in internal validation. The correlation analysis suggested that CXCL8 has a high positive correlation with neutrophil (R =0.8, P<0.0001) and interleukins pathway (R=0.79, P<0.0001). Furtherer, two ARG-mediated subtypes were obtained, indicating potential heterogeneity. Finally, the qRT-PCR demonstrated that the mRNA expression levels of CXCL8 and ANGPTL4 were elevated in psoriasis patients, with a reduced expression of EMCN observed. The current paper indicated potential ARG-related biomarkers of psoriasis, including CXCL8, ANGPTL4, and EMCN, with two molecular subtypes.
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Macrophages play a pivotal role in the healing of diabetic ulcers. The sustained elevation of glucose levels damages the insulin signaling pathway in macrophages, leading to dysfunctional macrophages that struggle to transition from pro-inflammatory (M1) to reparative (M2) states. Therefore, modulating macrophage inflammatory responses via the insulin pathway holds promise for diabetic ulcer treatment. Additionally, the presence of biofilm impedes drug penetration, and the resulting immunosuppressive microenvironment exacerbates the persistent infiltration of pro-inflammatory M1 macrophages. Therefore, we designed an array of dissolvable microneedle (denoted as NPF@MN) loaded with self-assembled nanoparticles that could deliver NPF nanoparticles, acid-sensitive NPF-releasing Protocatechualdehyde (PA) with hypoglycemic and insulin-like effects, regulating macrophage polarization to an anti-inflammatory M2 phenotype. Additionally, this study extensively examined the mechanism by which NPF@MN accelerates the healing of diabetic ulcers through the activation of the insulin signaling pathway. Through RNA-seq and GSEA analysis, we identified a reduction in the expression of pathway-related factors such as IR, IRS-1, IRS-2, and SHC. Our work presents an innovative therapeutic approach targeting the insulin pathway in diabetic ulcers and underscores its translational potential for clinical management.
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Biofilmes , Insulina , Macrófagos , Agulhas , Transdução de Sinais , Cicatrização , Animais , Cicatrização/efeitos dos fármacos , Insulina/metabolismo , Camundongos , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Masculino , Anti-Inflamatórios/farmacologia , Diabetes Mellitus Experimental , Nanopartículas/química , Células RAW 264.7 , Camundongos Endogâmicos C57BLRESUMO
Diabetic ulcers (DUs) are characterised by a high incidence and disability rate. However, its pathogenesis remains elusive. Thus, a deep understanding of the underlying mechanisms for the pathogenesis of DUs has vital implications. The weighted gene co-expression network analysis was performed on the main data from the Gene Expression Omnibus database. Gene Ontology (GO) terms, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were adopted to analyse the potential biological function of the most relevant module. Furthermore, we utilised CytoHubba and protein-protein interaction network to identify the hub genes. Finally, the hub genes were validated by animal experiments in diabetic ulcer mice models. The expression of genes from the turquoise module was found to be strongly related to DUs. GO terms, KEGG analysis showed that biological functions are closely related to immune response. The hub genes included IFI35, IFIT2, MX2, OASL, RSAD2, and XAF1, which were higher in wounds of DUs mice than that in normal lesions. Additionally, we also demonstrated that the expression of hub genes was correlated with the immune response using immune checkpoint, immune cell infiltration, and immune scores. These data suggests that IFI35, IFIT2, MX2, OASL, RSAD2, and XAF1 are crucial for DUs.
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Diabetes Mellitus , Úlcera , Animais , Camundongos , Biomarcadores , Biologia Computacional , Bases de Dados FactuaisRESUMO
Diabetes mellitus (DM) can lead to diabetic ulcers (DUs), which are the most severe complications. Due to the need for more accurate patient classifications and diagnostic models, treatment and management strategies for DU patients still need improvement. The difficulty of diabetic wound healing is caused closely related to biological metabolism and immune chemotaxis reaction dysfunction. Therefore, the purpose of our study is to identify metabolic biomarkers in patients with DU and construct a molecular subtype-specific prognostic model that is highly accurate and robust. RNA-sequencing data for DU samples were obtained from the Gene Expression Omnibus (GEO) database. DU patients and normal individuals were compared regarding the expression of metabolism-related genes (MRGs). Then, a novel diagnostic model based on MRGs was constructed with the random forest algorithm, and classification performance was evaluated utilizing receiver operating characteristic (ROC) analysis. The biological functions of MRGs-based subtypes were investigated using consensus clustering analysis. A principal component analysis (PCA) was conducted to determine whether MRGs could distinguish between subtypes. We also examined the correlation between MRGs and immune infiltration. Lastly, qRT-PCR was utilized to validate the expression of the hub MRGs with clinical validations and animal experimentations. Firstly, 8 metabolism-related hub genes were obtained by random forest algorithm, which could distinguish the DUs from normal samples validated by the ROC curves. Secondly, DU samples could be consensus clustered into three molecular classifications by MRGs, verified by PCA analysis. Thirdly, associations between MRGs and immune infiltration were confirmed, with LYN and Type 1 helper cell significantly positively correlated; RHOH and TGF-ß family remarkably negatively correlated. Finally, clinical validations and animal experiments of DU skin tissue samples showed that the expressions of metabolic hub genes in the DU groups were considerably upregulated, including GLDC, GALNT6, RHOH, XDH, MMP12, KLK6, LYN, and CFB. The current study proposed an auxiliary MRGs-based DUs model while proposing MRGs-based molecular clustering and confirmed the association with immune infiltration, facilitating the diagnosis and management of DU patients and designing individualized treatment plans.
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Diabetes Mellitus , Úlcera , Animais , Humanos , Biomarcadores , Consenso , Bases de Dados FactuaisRESUMO
The northern high latitude (NHL, 40°N to 90°N) is where the second peak region of gross primary productivity (GPP) other than the tropics. The summer NHL GPP is about 80% of the tropical peak, but both regions are still highly uncertain (Norton et al. 2019, https://doi.org/10.5194/bg-16-3069-2019). Carbonyl sulfide (OCS) provides an important proxy for photosynthetic carbon uptake. Here we optimize the OCS plant uptake fluxes across the NHL by fitting atmospheric concentration simulation with the GEOS-CHEM global transport model to the aircraft profiles acquired over Alaska during NASA's Carbon in Arctic Reservoirs Vulnerability Experiment (2012-2015). We use the empirical biome-specific linear relationship between OCS plant uptake flux and GPP to derive the six plant uptake OCS fluxes from different GPP data. Such GPP-based fluxes are used to drive the concentration simulations. We evaluate the simulations against the independent observations at two ground sites of Alaska. The optimized OCS fluxes suggest the NHL plant uptake OCS flux of -247 Gg S year-1, about 25% stronger than the ensemble mean of the six GPP-based OCS fluxes. GPP-based OCS fluxes systematically underestimate the peak growing season across the NHL, while a subset of models predict early start of season in Alaska, consistent with previous studies of net ecosystem exchange. The OCS optimized GPP of 34 PgC yr-1 for NHL is also about 25% more than the ensembles mean from six GPP data. Further work is needed to fully understand the environmental and biotic drivers and quantify their rate of photosynthetic carbon uptake in Arctic ecosystems.
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Diabetic wounds are a protracted complication of diabetes mainly characterised by chronic inflammation, obstruction of epithelialization, damaged blood vessels and collagen production (maturation), as well as neuropathy. As a non-coding RNA (ncRNA) that lack coding potential, long non-coding RNAs (lncRNAs) have recently been reported to play a salient role in diabetic wound healing. Here, this review summarises the roles of lncRNAs in the pathology and treatments of diabetic wounds, providing references for its potential clinical diagnostic criteria or therapeutic targets in the future.
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Diabetes Mellitus , RNA Longo não Codificante , Colágeno , Humanos , RNA Longo não Codificante/genética , Reepitelização , Cicatrização/genéticaRESUMO
Psoriasis is a chronic inflammatory skin disease characterized by excessive proliferation of keratinocytes (KCs). Onset of psoriasis is related to genetic, immune and environmental factors. The environment can interact with the genome through epigenetic modifications, including DNA methylation, and this modification is involved in the pathogenesis of psoriasis. In addition to a skin disease, psoriasis is also considered a systemic disease. We reviewed the current literature of psoriatic DNA methylation for studies from several aspects on the DNA methylation distribution patterns in different tissues/cells, single-nucleotide polymorphisms, and candidate disease genes and identified target genes regulated by DNA methylation that have been directly/indirectly validated. This review contributes to a comprehensive understanding of the important a role that DNA methylation plays in psoriasis from a holistic perspective and will promote the implementation of DNA methylation in diagnostic and therapeutic strategies for psoriatic patients.
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Metilação de DNA , Epigênese Genética , Polimorfismo de Nucleotídeo Único , Psoríase/genética , Linfócitos T CD4-Positivos/fisiologia , Estudo de Associação Genômica Ampla , Humanos , Leucócitos Mononucleares/fisiologia , Psoríase/patologiaRESUMO
BACKGROUND: Cyr61 is considered a novel proinflammatory factor. Gouty arthritis (GA) is a self-limited inflammatory reaction caused by monosodium urate (MSU) crystals. In this study, we assessed the role of Cyr61 in the inflammatory process of GA. METHODS: We investigated the expression of Cyr61 in MSU-induced rat gout models and MSU-stimulated rat fibroblast-like synovial (FLS) cells. After inhibiting the expression of Cyr61, levels of IL-1ß, TNF-α, and IL-6 were detected by ELISA, qPCR, western blot, and immunohistochemical methods. We probed the downstream NF-κB signaling pathway using the NF-κB inhibitor PDTC, and levels of NF-κB and p-NF-κB were detected by western blot and qPCR. RESULTS: Our results demonstrate that Cyr61 plays a potent role in the formation of local inflammation in vitro and in vivo. Cyr61 was highly expressed in synovial tissues of gout models, and the expression of Cyr61 protein was also significantly increased in MSU-stimulated FLS cells. Cyr61 promoted MSU-induced acute inflammation via the NF-κB signaling pathway. CONCLUSIONS: Our study has revealed that Cyr61 is an important regulatory factor for the initiation of inflammation in GA. The high expression of Cyr61 protein can induce synovial cells to produce many inflammatory cytokines, such as IL-1ß, TNF-α, and IL-6, partly in an NF-κB-dependent manner. Thus, inhibition of Cyr61 could be a new target and strategy for the prevention and treatment of GA.
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Artrite Gotosa/imunologia , Artrite Gotosa/metabolismo , Proteína Rica em Cisteína 61/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Animais , Artrite Gotosa/genética , Western Blotting , Proteína Rica em Cisteína 61/genética , Citocinas/metabolismo , Imunofluorescência , Imuno-Histoquímica , Técnicas In Vitro , Inflamação/induzido quimicamente , Inflamação/genética , Masculino , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Ácido Úrico/toxicidadeRESUMO
Glycosides from the roots of Tripterygium wilfordii Hook. f. are used for the treatment of oral lichen planus (OLP), a chronic inflammatory disease affecting the oral mucosa. To investigate the effectiveness and safety of Tripterygium glycosides (TGs) for OLP treatment, we conducted a systematic review of 18 randomized controlled trials, comprising 1,339 participants, from international and Chinese databases. We evaluated outcomes of TGs alone or in combination with conventional treatments. In combination with topical glucocorticoids (TGCs), including triamcinolone acetonide and prednisone, the total effectiveness rate (risk ratio [RR], 1.17; 95% confidence interval [CI], 1.09-1.25; p < .00001), symptom score reducing index (mean difference [MD], -2.44; 95% CI, -3.12 to -1.77; p < .0001), and visual analog scale score (MD, -1.61; 95% CI, -2.22 to -1.00; p < .0001) were significantly improved. Patients treated with TGs combined with TGCs experienced lower recurrence rates (RR, 0.37; 95% CI, 0.18-0.76; p = 0.007). The occurrence of adverse events was not significantly different between the TGs groups and controls. The combination of TG and TGCs improved clinical efficacy and reduced recurrence without increasing the risk of adverse events. A high-quality multicenter clinical study is needed to corroborate these findings.
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Líquen Plano Bucal/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Tripterygium/química , Adulto , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Glicosídeos/isolamento & purificação , Glicosídeos/uso terapêutico , Humanos , Líquen Plano Bucal/epidemiologia , Masculino , Pessoa de Meia-Idade , Fitoterapia , Raízes de Plantas/química , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Recidiva , Resultado do TratamentoRESUMO
BACKGROUND: This study was performed to assess the efficacy and feasibility of definitive chemoradiotherapy consisting of weekly doses of combined paclitaxel and carboplatin concurrent with radiation therapy, followed by 2 cycles of consolidation chemotherapy for advanced esophageal carcinoma. METHODS: Eligibility criteria included local, advanced, newly diagnosed and postoperative local regional lymph node metastasis; Eastern Cooperative Oncology Group (ECOG) score ≤ 2; and adequate organ function. Patients received concurrent chemoradiation therapy consisting of radiotherapy (50.4 Gy/28 Fx or 61.2 Gy/34 Fx) and concurrent paclitaxel (50 mg/m2) and carboplatin (area under the curve, AUC = 2) on days 1, 8, 15, 22 and 29. The two-cycle consolidation chemotherapy protocol was paclitaxel (175 mg/m2) plus carboplatin (AUC = 5) administered on days 57 and 85, after concurrent chemoradiotherapy. RESULTS: Between August 2013 and February 2015, 65 patients with oesophageal carcinoma were enrolled in the study; 34 (52.3%) were newly diagnosed and 31 (47.6%) had postoperative local regional lymph node metastasis. The median overall survival time was 21.7 months (95% confidence interval [CI] 16.7-26.6), and the median progression-free survival time was 12.1 months (95% CI 9.0-15.3). A total of 96.9% (63/65) and 67.6% (44/65) patients completed ≥5 cycles and all 7 cycles of chemotherapy, respectively. A total of 93.8% (61/65) patients completed radiation therapy. The 1- and 2-year overall survival rates were 73.7 and 42.0%, respectively. The 1- and 2-year progression-free survival rates were 50.6 and 31.1%, respectively. Grade 3-4 toxicity during chemoradiotherapy included neutropenia (24.5%), thrombocytopenia (4.6%), fatigue (1.5%), anaemia (1.5%), radiation dermatitis (1.5%), pneumonitis (1.5%), oesophagitis (4.6%) and vomiting (1.5%). CONCLUSIONS: In patients with locally advanced oesophageal cancer, the combination of weekly doses of paclitaxel and carboplatin was well tolerated and produced comparable results. A three-arm randomised phase III trial (NCT02459457) comparing paclitaxel in combination with cisplatin, carboplatin or 5-fluorouracil with concurrent radiotherapy is on-going at our hospital.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia/métodos , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/radioterapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Quimiorradioterapia/efeitos adversos , Cisplatino/uso terapêutico , Quimioterapia de Consolidação , Intervalo Livre de Doença , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Feminino , Humanos , Leucopenia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Resultado do TratamentoRESUMO
BACKGROUND: Sheng-ji Hua-yu(SJHY) formula is one of the most useful Traditional Chinese medicine (TCM) in the treatment of the delayed diabetic wound. However, elucidating the related molecular biological mechanism of how the SJHY Formula affects excessive inflammation in the process of re-epithelialization of diabetic wound healing is a task urgently needed to be fulfilled. The objectives of this study is to evaluate the effect of antagonisic expression of pro-/anti-inflammatory factors on transforming growth factor-ß(TGF-ß) superfamily (activin and follistatin) in the process of re-epithelialization of diabetic wound healing in vivo, and to characterize the involvement of the activin/follistatin protein expression regulation, phospho-Smad (pSmad2), and Nuclear factor kappa B p50 (NF-kB) p50 in the diabetic wound healing effects of SJHY formula. METHODS: SJHY Formula was prepared by pharmaceutical preparation room of Yueyang Hospital of Integrated Traditional Chinese and Western Medicine. Diabetic wound healing activity was evaluated by circular excision wound models. Wound healing activity was examined by macroscopic evaluation. Activin/follistatin expression regulation, protein expression of pSmad2 and NF-kB p50 in skin tissue of wounds were analyzed by Real Time PCR, Western blot, immunohistochemistry and hematoxylin and eosin (H&E) staining. RESULTS: Macroscopic evaluation analysis showed that wound healing of diabetic mice was delayed, and SJHY Formula accelerated wound healing time of diabetic mice. Real Time PCR analysis showed higher mRNA expression of activin/follistatin in diabetic delayed wound versus the wound in normal mice. Western Blot immunoassay analysis showed reduction of activin/follistatin proteins levels by SJHY Formula treatment 15 days after injury. Immunohistochemistry investigated the reduction of pSmad2 and NF-kB p50 nuclear staining in the epidermis of diabetic SJHY versus diabetic control mice on day 15 after wounding. H&E staining revealed that SJHY Formula accelerated re-epithelialization of diabetic wound healing. CONCLUSION: The present study found that diabetic delayed wound healing time is closely related to the high expression level of activin/follistatin, which leads to excessive inflammation in the process of re-epithelization. SJHY Formula accelerates re-epithelialization and healing time of diabetic wounds through decreasing the high expression of activin/follistatin.
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Ativinas/metabolismo , Diabetes Mellitus Experimental/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Folistatina/metabolismo , Reepitelização/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/complicações , Medicamentos de Ervas Chinesas/uso terapêutico , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Úlcera/tratamento farmacológicoRESUMO
Autophagy is required for the long-term maintenance of Ag-specific memory B cells. However, whether autophagy is also important for the initial formation of memory B cells remains unclear. In this study, we show that newly generated memory B cells do not display active autophagy but are capable of forming Ab-secreting cells after rechallenge with Ags. Increases in autophagy took place over time after the initial formation of memory B cells. The expression of transcription factors involved in autophagy, but not changes in epigenetic regulation by DNA methylation, was required for autophagy gene expression and the development of active autophagy in memory B cells. This indicates that autophagy is not critical for the initial generation of memory B cells but is required for their long-term persistence. Our results suggest that promoting autophagy to improve Ab-dependent immunological memory is more effective during memory B cell maintenance stage.
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Autofagia/imunologia , Linfócitos B/imunologia , Imunização/métodos , Memória Imunológica/imunologia , Transferência Adotiva , Animais , Autofagia/genética , Proteína 7 Relacionada à Autofagia , Linfócitos B/metabolismo , Linfócitos B/transplante , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Células Cultivadas , Feminino , Citometria de Fluxo , Expressão Gênica/imunologia , Haptenos , Hemocianinas/imunologia , Imuno-Histoquímica , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/deficiência , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/transplante , Fatores de Tempo , Fatores de Transcrição/genética , Fatores de Transcrição/imunologiaRESUMO
PURPOSE: The safety and efficacy of using simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) for patients with esophageal squamous cell carcinoma were evaluated in a single-institution phase II setting. METHODS AND MATERIALS: Between June 2007 and October 2009, 45 patients underwent concurrent chemoradiotherapy (n = 27) or radiotherapy alone (n = 18). Two planning target volumes (PTV) were defined for the SIB: PTVC and PTVG, with prescribed doses of 50.4 Gy to the PTVC (1.8 Gy/fraction) and 63 Gy to the PTVG (2.25 Gy/fraction), both given in 28 fractions. RESULTS: At a median follow-up interval of 20.3 months, the 3-year overall survival (OS) and progression-free survival (PFS) rates were 42.2 and 40.7 %, respectively. The median overall survival time was 21 months; locoregional control rates were 83.3 % at 1 year and 67.5 % at 3 years. According to CTCAE (version 3.0) criteria, none of the patients developed grade 4-5 toxicity. The most common grade 2 and 3 radiation-related toxicity was radiation esophagitis, occurring in 64 % of all patients (but only 13 % as grade 3). No patient developed grade > 2 pulmonary complications. CONCLUSION: SIB-IMRT is a feasible therapeutic approach for esophageal carcinoma patients and provides encouraging locoregional control with a low toxicity profile. Further investigations should focus on dose escalation and optimization of the combination with systemic therapies.
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Carcinoma de Células Escamosas/radioterapia , Neoplasias Esofágicas/radioterapia , Esofagite/etiologia , Recidiva Local de Neoplasia/prevenção & controle , Lesões por Radiação/etiologia , Radioterapia Conformacional/métodos , Adulto , Idoso , Carcinoma de Células Escamosas/complicações , Carcinoma de Células Escamosas/diagnóstico , Quimiorradioterapia Adjuvante/efeitos adversos , Quimiorradioterapia Adjuvante/métodos , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Fracionamento da Dose de Radiação , Neoplasias Esofágicas/complicações , Neoplasias Esofágicas/diagnóstico , Esofagite/diagnóstico , Esofagite/prevenção & controle , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Lesões por Radiação/diagnóstico , Lesões por Radiação/prevenção & controle , Radioterapia Conformacional/efeitos adversos , Fatores de Risco , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: We investigated nimotuzumab (h-R3), a humanized monoclonal antibody against epidermal growth factor receptor, when combined with irradiation or chemoradiation for squamous cell carcinoma (SCC) of the esophagus. The aim of this study was to evaluate its safety and efficacy. METHODS: We retrospectively analyzed 66 patients with esophageal SCC treated with a combination of h-R3 and radiation or chemoradiation between December 2008 and September 2011 at Fudan University Shanghai Cancer Center. Fifty-two of the 66 patients received h-R3 combined with chemoradiation and 14 received h-R3 plus radiation. The median total irradiation dose was 61 Gy given by conventional fractionation. The h-R3 weekly dosage was 100 mg (6/66), 200 mg (54/66), or 400 mg (6/66) given concurrently during the irradiation period. RESULTS: Patients tolerated the treatment well. Grade 3-4 adverse events and toxicities occurred in 50 % of the patients. h-R3-related toxicities manifested as Grade 1 skin rash in 1 case and Grade 2 infusion-related reaction in 2 cases. The median overall survival (OS) and progression-free survival (PFS) were 26.0 months and 16.7 months, respectively. OS, PFS and locoregional control (LC) at 2 years were 54, 37 and 80 %, respectively. CONCLUSIONS: h-R3 in combination with irradiation or chemoradiation was safe and tolerable, and yielded encouraging OS, PFS and LC.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia , Neoplasias Esofágicas/terapia , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Quimiorradioterapia/efeitos adversos , Intervalo Livre de Doença , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Carga TumoralRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Volatile oil is widely used in traditional Chinese medicine owing to its unique hydrophobic and lipophilic properties and rapid skin absorption. Artemisia annua L. (A.annua) essential oil (AAEO), a volatile oil extracted from A. annua, exhibits anti-inflammatory properties. However, few studies have investigated its effects on skin inflammation. AIM OF THE STUDY: To investigate and elucidate the mechanisms of action of AAEO in the treatment of atopic dermatitis (AD). MATERIALS AND METHODS: Network pharmacology was used to predict the targets and pathways of AAEO for the treatment of AD. The AD mouse model was established by topical application of 2,4-dintrochlorobenzene (DNCB), AAEO, and the positive control drug hydrocortisone butyrate cream (HBC). We evaluated the symptoms of AD, SCORAD scores, histological analysis, and serum IgE and TNF-α levels in mice. Immunofluorescence, western blotting, and qPCR were used to investigate the signaling pathways. RESULTS: Network pharmacology analysis indicated that AAEO may exert its effects via the MAPK/NF-κB signaling pathway. Animal experiments demonstrated that topical application of AAEO and HBC significantly ameliorated skin lesions, reduced dermatitis score, and decreased spleen weight compared to DNCB treatment. AAEO reduced skin epidermal thickness and mast cell infiltration. DNCB markedly reduced the protein levels of filaggrin (FLG) and loricrin (LOR), whereas AAEO reversed these changes. Notably, the 5% concentration of AAEO demonstrated substantial improvement in skin barrier function. Compared to the DNCB group, the levels of FLG and LOR remained almost unchanged following HBC treatment. DNCB markedly elevated IgE and TNF-α levels, which were reversed by AAEO and HBC treatment. Among the inflammatory cytokines, DNCB increased mRNA expression of TNF-α, IL-1ß, and IL-6, however, it reduced IL-10, with AAEO and HBC reversing these changes to various degrees. Additionally, DNCB-induced ERK, JNK, and P38 phosphorylation, associated with the upregulation of phosphorylation of NF-κB, whereas, AAEO and HBC exhibited potent inhibition of the MAPK/NF-κB signaling pathway. CONCLUSIONS: This study systematically demonstrated the possible therapeutic effects and mechanisms of AAEO in AD via network pharmacological analysis and experimental confirmation. These results revealed that topical application of AAEO can suppress skin inflammation and restore skin barrier function. These findings provide the potential application of AAEO in synthesizing external preparations for both pharmacological and cosmetic industries.
Assuntos
Artemisia annua , Dermatite Atópica , Dinitroclorobenzeno , Proteínas Filagrinas , Camundongos Endogâmicos BALB C , Óleos Voláteis , Animais , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/patologia , Óleos Voláteis/farmacologia , Óleos Voláteis/administração & dosagem , Óleos Voláteis/química , Camundongos , Artemisia annua/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/administração & dosagem , NF-kappa B/metabolismo , Pele/efeitos dos fármacos , Pele/patologia , Pele/metabolismo , Modelos Animais de Doenças , Masculino , Administração Cutânea , Imunoglobulina E/sangue , Administração Tópica , Transdução de Sinais/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genéticaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Atopic dermatitis (AD) is a prevalent chronic inflammatory skin disorder that poses a significant global health challenge. There is a lack of safe and effective medications to treat AD. Astragalus membranaceous is a traditional Chinese medicine widely used in clinical treatment of skin diseases. Calycosin (CA), derived from the root of Astragalus membranaceous, exhibits dual attributes of anti-inflammatory and antioxidant properties, suggesting its promise for addressing cutaneous inflammation. Nonetheless, the precise mechanisms underlying CA's therapeutic actions in AD remain elusive. AIM OF THE STUDY: This study aimed to evaluate the efficacy and safety of CA in treating AD while also delving into the mechanistic underpinnings of CA's action in AD. MATERIALS AND METHODS: The cell viability and anti-inflammatory impacts of CA in vitro were first gauged using CCK-8 and RT-qPCR. The potential mechanisms of CA were then probed using modular pharmacology. Flow cytometry was employed to ascertain the differentiation of Treg and Th17 cells derived from naïve T cells, as well as the proportions and mean fluorescence intensity (MFI) of human iTreg cells. The expressions of IL-10 and TGF-ß1 were measured and Treg suppression assay was performed. The in vivo therapeutic efficacy of topical CA application was assessed using a calcipotriol (MC903)-induced AD mouse model. The expression metrics of inflammatory cytokines, IL-17A, FOXP3, and RORγt were authenticated via immunohistochemistry, RT-qPCR, Western blot, and ELISA. RESULTS: CA exhibited a favorable safety profile and reduced the mRNA expressions of Th2 inflammatory cytokines in HaCaT cells. Modular pharmacology analysis pinpointed Th17 differentiation as the pivotal mechanism behind CA's therapeutic effect on AD. In vitro, CA fostered the differentiation of naïve T cells into Tregs while inhibiting their differentiation into Th17 cells. Furthermore, CA augmented the proliferation of human iTregs. In vivo, CA alleviated skin manifestations and decreased the levels of inflammatory mediators (IL-4, IL-5, IL-13, TSLP, and NF-κB related cytokines) in AD-like mouse models. Simultaneously, it regulated Treg/Th17 balance through suppressing IL-17A and RORγt expressions and bolstering FOXP3 expression. CONCLUSIONS: The study provides insights into the mechanistic pathways through which CA exerts its anti-inflammatory effects, particularly through promoting Treg cell differentiation and inhibiting Th17 cell differentiation. Furthermore, CA emerges as an alternative or adjunctive treatment strategy for managing AD.