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Cancer is one of the leading causes of death worldwide, and more effective ways of attacking cancer are being sought. Cancer immunotherapy is a new and effective therapeutic method after surgery, radiotherapy, chemotherapy, and targeted therapy. Cancer immunotherapy aims to kill tumor cells by stimulating or rebuilding the body's immune system, with specific efficiency and high safety. However, only few tumor patients respond to immunotherapy and due to the complex and variable characters of cancer immune escape, the behavior and regulatory mechanisms of immune cells need to be deeply explored from more dimensions. Epigenetic modifications, metabolic modulation, and cell-to-cell communication are key factors in immune cell adaptation and response to the complex tumor microenvironment. They collectively determine the state and function of immune cells through modulating gene expression, changing in energy and nutrient demands. In addition, immune cells engage in complex communication networks with other immune components, which are mediated by exosomes, cytokines, and chemokines, and are pivotal in shaping the tumor progression and therapeutic response. Understanding the interactions and combined effects of such multidimensions mechanisms in immune cell modulation is important for revealing the mechanisms of immunotherapy failure and developing new therapeutic targets and strategies.
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AIMS: The incidence and mortality of liver hepatocellular carcinoma (LIHC) were increasing year by year. The aim of this study was to investigate the comprehensive roles of lncRNA FAM99A and FAM99B in LIHC. MAIN METHODS: According to the data of TCGA and GTEx, the expression levels of FAM99A and FAM99B in LIHC were evaluated, and the overall survival (OS), disease-free survival (DFS), immune cell infiltration and tumor stage were analyzed. The subcellular localization of FAM99A and FAM99B in various cancer cell lines was predicted by lncATLAS database. In addition, we also used ENCORI, KEGG, LinkedOmics, Metascape and other databases. It was verified by in vivo and in vitro experiments. KEY FINDINGS: Compared with adjacent normal tissues, FAM99A and FAM99B were down-regulated in LIHC tissues, and significantly correlated with immune cell infiltration. With the progression of tumor stage and grade, the expression of FAM99A and FAM99B showed a decreasing trend, and the prognosis of patients were also poor. In addition, the biological functions, signaling pathways and protein interactions of FAM99A and FAM99B in LIHC were enriched to study the potential molecular mechanisms. The overlapping RNA binding proteins (RBP) of FAM99A and FAM99B mainly included CSTF2T, BCCIP, RBFOX2 and SF3B4. Finally, experiments showed that overexpression of FAM99A attenuated the proliferation, invasion, colony formation and tumor growth of LIHC cells. SIGNIFICANCE: Taken together, the above studies demonstrated that FAM99A and FAM99B had an inhibitory effect on the progression of LIHC, which might be promising diagnostic biomarkers and therapeutic targets for LIHC patients.
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Carcinoma Hepatocelular , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas , RNA Longo não Codificante , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Animais , Camundongos , Prognóstico , Masculino , Proliferação de Células/genética , Feminino , Linhagem Celular Tumoral , Camundongos Nus , Transdução de Sinais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Camundongos Endogâmicos BALB C , Pessoa de Meia-IdadeRESUMO
Insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3) is a critical m6A reader. It encodes proteins that contain several KH domains, which are important in RNA binding, RNA synthesis and metabolism. Lots of researches have studied the malignant potential of m6A readers in tumors. However, the biological functional analysis of IGF2BP3 in hepatocellular carcinoma (HCC) and pan-cancer is not comprehensive. In this study, we used a bioinformatics approach to comprehensively analyze the significance of IGF2BP3 in HCC through analyzing its expression, mutation, prognosis, protein-protein interaction (PPI) network, functional enrichment, and the correlation with ferroptosis, stemness as well as immune modulation in HCC. IGF2BP3 presented a negative correlation with the ferroptosis molecule NFE2L2, and a positive correlation with the ferroptosis molecule SLC1A5 as well as the immune checkpoint HAVCR2. In addition, we also analyzed IGF2BP3 expression, prognosis and immune modulation in pan-cancer, revealing the prognostic value of IGF2BP3 in a variety of tumors. Finally, we verified the biological functions of IGF2BP3 in HCC through various experiments. The data showed that IGF2BP3 may enhance the proliferation, colony formation and invasion capacities of HCC cells, and IGF2BP3 is mainly positively correlated with the expression level of stemness marker SOX2. In conclusion, IGF2BP3 had a potential to be a new perspective biomarker in forecasting the immune response, ferroptosis, stemness and prognosis of HCC or even pan-cancer.
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Objective: To investigate the clinical and molecular biological characteristics of patients with accelerated chronic lymphocytic leukemia (aCLL) . Methods: From January 2020 to October 2022, the data of 13 patients diagnosed with aCLL at The First Affiliated Hospital of Nanjing Medical University were retrospectively analyzed to explore the clinical and molecular biological characteristics of aCLL. Results: The median age of the patients was 54 (35-72) years. Prior to aCLL, five patients received no treatment for CLL/small lymphocytic lymphoma (SLL), while the other patients received treatment, predominantly with BTK inhibitors. The patients were diagnosed with aCLL through pathological confirmation upon disease progression. Six patients exhibited bulky disease (lesions with a maximum diameter ≥5 cm). Positron emission tomography (PET) -computed tomography (CT) images revealed metabolic heterogeneity, both between and within lesions, and the median maximum standardized uptake value (SUVmax) of the lesion with the most elevated metabolic activity was 6.96 (2.51-11.90). Patients with unmutated IGHV CLL accounted for 76.9% (10/13), and the most frequent genetic and molecular aberrations included +12 [3/7 (42.9% ) ], ATM mutation [6/12 (50% ) ], and NOTCH1 mutation [6/12 (50% ) ]. Twelve patients received subsequent treatment. The overall response rate was 91.7%, and the complete response rate was 58.3%. Five patients experienced disease progression, among which two patients developed Richter transformation. Patients with aCLL with KRAS mutation had worse progression-free survival (7.0 month vs 26.3 months, P=0.015) . Conclusion: Patients with aCLL exhibited a clinically aggressive course, often accompanied by unfavorable prognostic factors, including unmutated IGHV, +12, ATM mutation, and NOTCH1 mutation. Patients with CLL/SLL with clinical suspicion of disease progression, especially those with bulky disease and PET-CT SUVmax ≥5, should undergo biopsy at the site of highest metabolic uptake to establish a definitive pathological diagnosis.
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Humanos , Pessoa de Meia-Idade , Idoso , Leucemia Linfocítica Crônica de Células B/genética , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Estudos Retrospectivos , Biópsia , Progressão da DoençaRESUMO
Introduction: RALA is a member of the small GTPase Ras superfamily and has been shown to play a role in promoting cell proliferation and migration in most tumors, and increase the resistance of anticancer drugs such as imatinib and cisplatin. Although many literatures have studied the cancer-promoting mechanism of RALA, there is a lack of relevant pan-cancer analysis. Methods: This study systematically analyzed the differential expression and mutation of RALA in pan-cancer, including different tissues and cancer cell lines, and studied the prognosis and immune infiltration associated with RALA in various cancers. Next, based on the genes co-expressed with RALA in pan-cancer, we selected 241 genes with high correlation for enrichment analysis. In terms of pan-cancer, we also analyzed the protein-protein interaction pathway of RALA and the application of small molecule drug Guanosine-5'-Diphosphate. We screened hepatocellular cancer (HCC) to further study RALA. Results: The results indicated that RALA was highly expressed in most cancers. RALA was significantly correlated with the infiltration of B cells and macrophages, as well as the expression of immune checkpoint molecules such as CD274, CTLA4, HAVCR2 and LAG3, suggesting that RALA can be used as a kind of new pan-cancer immune marker. The main functions of 241 genes are mitosis and protein localization to nucleosome, which are related to cell cycle. For HCC, the results displayed that RALA was positively correlated with common intracellular signaling pathways such as angiogenesis and apoptosis. Discussion: In summary, RALA was closely related to the clinical prognosis and immune infiltration of various tumors, and RALA was expected to become a broad-spectrum molecular immune therapeutic target and prognostic marker for pan-cancer.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Prognóstico , Análise de Sistemas , Proteínas de Checkpoint Imunológico , Proteínas ral de Ligação ao GTPRESUMO
N6-methyladenosine (m6A) modification regulators are essential for the diagnosis and treatment of various cancers. However, the comprehensive analysis about roles of m6A "readers" in hepatocellular carcinoma (HCC) remains unclear. UALCAN, GEPIA2, HPA, Kaplan Meier plotter, cBioPortal, STRING WebGestalt, Metascape and TIMER 2.0 database and Cytoscape software were used to comprehensively analyze the bioinformatic data. We found that m6A "readers" were upregulated at the mRNA level and protein level in HCC patients. Highly expressed YTHDF1, IGF2BP3 and NKAP were positively correlated with advanced HCC stage and had a poor prognosis in OS and PFS. The gene alterations of m6A "readers" happened frequently, and YTHDF3 had the highest mutation rate. The function of m6A "readers" on HCC may be closely correlated with splicing related proteins (including HNRNP family, SNRP family, and SR family), metabolic process, protein binding and RNA splicing related signaling pathways. Moreover, although the correlation of YTHDF3 and CD8+ T cell infiltration, and the correlation of IGF2BP3 and infiltration of mast cells and CAF are negative, most m6A "readers" had a positive correlation with immune cells (including CD8+ T cell, CD4+ T cell, Tregs, B cell, neutrophil, monocyte, macrophage, myeloid dendritic cell, nature killer cell, mast cell, and CAF). Macrophages, CD4+ T cell, Treg, B cell, monocyte, and myeloid dendritic cell had a positively strong correlation (Rho>0.4) with most m6A "readers" (such as YTHDC1, YTHDC2, YTHDF1, IGF2BP3, HNRNPA2B1 and HNRNPC). In conclusion, by comprehensive analysis of m6A "readers", we found that they were involved in the prognosis of HCC, and m6A "readers" might regulate the development and progression of HCC by participating in some metabolism-related and RNA splicing-related signaling pathways as well as immune cell infiltration.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Adenosina/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Prognóstico , RNA Mensageiro/metabolismo , Proteínas RepressorasRESUMO
Hepatocellular carcinoma (HCC) is one of the most lethal tumors in China and worldwide, although first-line therapies for HCC, such as atezolizumab and bevacizumab, have been effective with good results, the researches on new therapies have attracted much attention. With the deepening research on tumor immunology, the role and operation mechanism of immune cells in the tumor microenvironment (TME) of HCC have been explained, such as programmed cell death protein 1 (PD-1) binding to ligand could cause T cell exhaustion and reduce IFN-γ T cell secretion, cytotoxic T lymphocyte 4 (CTLA-4) and CD28 mediate immunosuppression by competing for B7 protein and disrupting CD28 signal transduction pathway, which also lays the foundation for the development and application of more new immune checkpoint inhibitors (ICIs). The biological behavior of various immune checkpoints has been proved in HCC, such as PD-1, programmed cell death ligand 1 (PD-L1), CTLA-4 and so on, leading to a series of clinical trials. Currently, FDA approved nivolumab, pembrolizumab and nivolumab plus ipilimumab for the treatment of HCC. However, the treatment of ICI has the disadvantages of low response rate and many side effects, so the combination of ICIs and various other therapies (such as VEGF or VEGFR inhibition, neoadjuvant and adjuvant therapy, locoregional therapies) has been derived. Further studies on immune checkpoint mechanisms may reveal new therapeutic targets and new combination therapies in the future.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Antígeno B7-H1/metabolismo , Antígenos CD28/uso terapêutico , Antígeno CTLA-4/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Humanos , Imunoterapia/métodos , Ligantes , Neoplasias Hepáticas/tratamento farmacológico , Nivolumabe/efeitos adversos , Receptor de Morte Celular Programada 1/uso terapêutico , Microambiente TumoralRESUMO
Background: Due to the molecular heterogeneity of hepatocellular carcinoma (HCC), majority of patients respond poorly among various of therapy. This study is aimed at conducting a comprehensive analysis about roles of SOX family in HCC for obtaining more therapeutic targets and biomarkers which may bring new ideas for the treatment of HCC. Methods: UALCAN, Kaplan Meier plotter, cBioPortal, STRING, WebGestalt, Metascape, TIMER 2.0, DiseaseMeth, MethSurv, HPA, CCLE database, and Cytoscape software were used to comprehensively analyze the bioinformatic data. Results: SOX2, SOX4, SOX8, SOX10, SOX11, SOX12, SOX17, and SOX18 were significantly differentially expressed in HCC and normal tissues and were valuable for the grade and survival of HCC patients. In addition, the gene alterations of SOX family happened frequently, and SOX4 and SOX17 had the highest mutation rate. The function of SOX family on HCC may be closely correlated with the regulation of angiogenesis-related signaling pathways. Moreover, SOX4, SOX8, SOX11, SOX12, SOX17, and SOX18 were correlation with 8 types of immune cells (including CD8+ T cell, CD4+ T cell, B cell, Tregs, neutrophil, macrophage, myeloid DC, and NK cell), and we found that most types of immune cells had a positive correlation with SOX family. Notably, CD4+ T cell and macrophage were positively related with all these SOX family. NK cells were negatively related with most SOX family genes. DNA methylation levels in promoter area of SOX2, SOX4, and SOX10 were lower in HCC than normal tissues, while SOX8, SOX11, SOX17, and SOX18 had higher DNA methylation levels than normal tissues. Moreover, higher DNA methylation level of SOX12 and SOX18 demonstrated worse survival rates in patients with HCC. Conclusion: SOX family genes could predict the prognosis of HCC. In addition, the regulation of angiogenesis-related signaling pathways may participate in the development of HCC. DNA methylation level and immune microenvironment characteristics (especially CD4+ T cell and macrophage immune cell infiltration) could be a novel insight for predicting prognosis in HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/patologia , Metilação de DNA , Humanos , Neoplasias Hepáticas/patologia , Prognóstico , Fatores de Transcrição SOXC/genética , Fatores de Transcrição SOXC/metabolismo , Fatores de Transcrição SOXE/metabolismo , Fatores de Transcrição SOXF/genética , Fatores de Transcrição SOXF/metabolismo , Microambiente Tumoral/genéticaRESUMO
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. HCC has high rates of death and recurrence, as well as very low survival rates. N6-methyladenosine (m6A) is the most abundant modification in eukaryotic RNAs, and circRNAs are a class of circular noncoding RNAs that are generated by back-splicing and they modulate multiple functions in a variety of cellular processes. Although the carcinogenesis of HCC is complex, emerging evidence has indicated that m6A modification and circRNA play vital roles in HCC development and progression. However, the underlying mechanisms governing HCC, their cross-talk, and clinical implications have not been fully elucidated. Therefore, in this paper, we elucidated the biological functions and molecular mechanisms of m6A modification in the carcinogenesis of HCC by illustrating three different regulatory factors ("writer", "eraser", and "reader") of the m6A modification process. Additionally, we dissected the functional roles of circRNAs in various malignant behaviors of HCC, thereby contributing to HCC initiation, progression and relapse. Furthermore, we demonstrated the cross-talk and interplay between m6A modification and circRNA by revealing the effects of the collaboration of circRNA and m6A modification on HCC progression. Finally, we proposed the clinical potential and implications of m6A modifiers and circRNAs as diagnostic biomarkers and therapeutic targets for HCC diagnosis, treatment and prognosis evaluation.
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Adenosina/análogos & derivados , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , RNA Circular/genética , Adenosina/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Prognóstico , RNA Circular/metabolismoRESUMO
Cancer stemness, mainly consisting of chemo-resistance, radio-resistance, tumorigenesis, metastasis, tumor self-renewal, cancer metabolism reprogramming, and tumor immuno-microenvironment remodeling, play crucial roles in the cancer progression process and has become the hotspot of cancer research field in recent years. Nowadays, the exact molecular mechanisms of cancer stemness have not been fully understood. Extensive studies have recently implicated that non-coding RNA (ncRNA) plays vital roles in modulating cancer stemness. Notably, N6-methyladenosine (m6A) modification is of crucial importance for RNAs to exert their biological functions, including RNA splicing, stability, translation, degradation, and export. Emerging evidence has revealed that m6A modification can govern the expressions and functions of ncRNAs, consequently controlling cancer stemness properties. However, the interaction mechanisms between ncRNAs and m6A modification in cancer stemness modulation are rarely investigated. In this review, we elucidate the recent findings on the relationships of m6A modification, ncRNAs, and cancer stemness. We also focus on some key signaling pathways such as Wnt/ß-catenin signaling, MAPK signaling, Hippo signaling, and JAK/STAT3 signaling to illustrate the underlying interplay mechanisms between m6A modification and ncRNAs in cancer stemness. In particular, we briefly highlight the clinical potential of ncRNAs and m6A modifiers as promising biomarkers and therapeutic targets for indicating cancer stemness properties and improving the diagnostic precision for a wide variety of cancers.
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Adenosina/análogos & derivados , Neoplasias/genética , RNA não Traduzido/genética , Adenosina/metabolismo , Animais , Biomarcadores Tumorais , Humanos , Terapia de Alvo Molecular , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Transdução de SinaisRESUMO
OBJECTIVE: To evaluate the effect of scaling and root planing (SRP) on serum C-reactive protein (CRP) levels in patients with moderate to severe chronic periodontitis. METHODS: We searched the PubMed, Web of Science, EMBASE, Cochrane, CNKI, Wanfang, and VIP databases from the inception to July 8th, 2019. Two reviewers independently screened literature, extracted data, and evaluated the bias risk of included studies. Then, a meta-analysis was performed using RevMan 5.3 software. RESULTS: A total of 13 randomized controlled clinical trials and 12 prospective clinical trials were included. Meta-analysis showed that serum CRP levels decreased at 2 and 3 months after SRP (P<0.05), and no significant difference in serum CRP levels was found at 6 months (P=0.49). CONCLUSIONS: SRP can reduce serum CRP levels in systematically healthy patients with moderate to severe chronic periodontitis at 2 and 3 months after SRP.
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Periodontite Crônica , Proteína C-Reativa , Raspagem Dentária , Humanos , Estudos Prospectivos , Aplainamento RadicularRESUMO
For further the understanding of the adsorption mechanism of heavy metal ions on the surface of protein-inorganic hybrid nanoflowers, a novel protein-derived hybrid nanoflower was prepared to investigate the adsorption behavior and reveal the function of organic and inorganic parts on the surface of nanoflowers in the adsorption process in this study. Silk fibroin (SF)-derived and copper-based protein-inorganic hybrid nanoflowers of SF@Cu-NFs were prepared through self-assembly. The product was characterized and applied to adsorption of heavy metal ion of Pb(II). With Chinese peony flower-like morphology, the prepared SF@Cu-NFs showed ordered three-dimensional structure and exhibited excellent efficiency for Pb(II) removal. On one hand, the adsorption performance of SF@Cu-HNFs for Pb(II) removal was evaluated through systematical thermodynamic and adsorption kinetics investigation. The good fittings of Langmuir and pseudo-second-order models indicated the monolayer adsorption and high capacity of about 2000 mg g-1 of Pb(II) on SF@Cu-NFs. Meanwhile, the negative values of Δ r G m ( T ) θ and Δ r H m θ proved the spontaneous and exothermic process of Pb(II) adsorption. On the other hand, the adsorption mechanism of SF@Cu-HNFs for Pb(II) removal was revealed with respect to its individual organic and inorganic component. Organic SF protein was designated as responsible 'stamen' adsorption site for fast adsorption of Pb(II), which was originated from multiple coordinative interaction by numerous amide groups; inorganic Cu3(PO4)2 crystal was designated as responsible 'petal' adsorption site for slow adsorption of Pb(II), which was restricted from weak coordinative interaction by strong ion bond of Cu(II). With only about 10% weight content, SF protein was proven to play a key factor for SF@Cu-HNFs formation and have a significant effect on Pb(II) treatment. By fabricating SF@Cu-HNFs hybrid nanoflowers derived from SF protein, this work not only successfully provides insights on its adsorption performance and interaction mechanism for Pb(II) removal, but also provides a new idea for the preparation of adsorption materials for heavy metal ions in environmental sewage in the future.
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The adsorption of dye molecules is an important process for the photodegradation removal of dye pollutants. In this work, a semiconductor photocatalyst of Cr-doped ZnO nanorods (Cr-ZnO NRs) was synthesized, and its adsorption-photocatalysis synergy (APS) effect was investigated for anionic methyl orange (MO-) and cationic methylene blue (MB+). The detailed thermodynamic information (including adsorption maximum capacity qmax, adsorption equilibrium constant Kads and adsorption efficiency AE %) and dynamic information (including adsorption rate constant ka, degradation rate constant kd and degradation efficiency DE %) were obtained to evaluate the different reaction performances for MO- and MB+. With qmax(MB+) = 40.59 mg g-1 > qmax(MO-) = 15.95 mg g-1, ka(MB+) = 20.61 min-1 > ka(MO-) = 4.62 min-1, and AE(MB+) = 40% > AE(MO-) = 9%, Cr-ZnO NRs showed much superior adsorption performance for MB+ than MO-. With kd (MB+) = 0.0430 min-1 > kd (MO-) = 0.0014 min-1 and DE(MB+) = 98% > AE(MO-) = 20%, Cr-ZnO NRs also showed much superior photodegradation performance for MB+ than MO-. The APS mechanism of Cr-ZnO NRs is revealed to be multiple π-π interactions and stronger electrostatic attractions dominant for enhanced adsorption of MB+ and higher AE and more photocatalytic active species dominant for enhanced photodegradation of MB+. The APS was furthermore characterized and verified by zeta potential analysis, Fourier transform infrared investigation, and fluorescence imaging. The results indicate that Cr-ZnO NRs are promising adsorbent and photocatalyst candidates favorable for positive MB+ than negative MO-. Such an APS investigation can effectively help to improve the photodegradation treatment performance of photocatalysts for dye pollutant removal.
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Legionella pneumophila, an environmental bacterium that parasitizes protozoa, is the causative pathogen of Legionnaires' disease. L. pneumophila adopts a distinct biphasic life cycle that allows it to adapt to environmental conditions for survival, replication, and transmission. This cycle consists of a non-virulent replicative phase (RP) and a virulent transmissive phase (TP). Timely and fine-tuned expression of growth and virulence factors in a life cycle-dependent manner is crucial. Herein, we report evidence that CsrA, a key regulator of the switch between the RP and the TP, is dually regulated in a ClpP-dependent manner during the biphasic life cycle of L. pneumophila. First, we show that the protein level of CsrA is temporal during the life cycle and is degraded by ClpP during the TP. The ectopic expression of CsrA in a ΔclpP mutant, but not in the wild type, inhibits both the initiation of the RP in vitro and the invasiveness to Acanthamoeba castellanii, indicating that the ClpP-mediated proteolytic pathway regulates the CsrA protein level. We further show that the temporally expressed IHFB is the transcriptional inhibitor of csrA and is degraded via a ClpP-dependent manner during the RP. During the RP, the level of CsrA is increased by promoting the degradation of IHFB and reducing the degradation of the accumulated CsrA via a ClpP-dependent manner. During the TP, the level of CsrA is decreased by inhibiting the degradation of IHFB and promoting the degradation of the accumulated CsrA via a ClpP-dependent manner as well. In conclusion, our results show that the growth-stage-specific expression level of CsrA is dually regulated by ClpP-dependent proteolysis at both the transcription and protein levels during the biphasic life cycle of L. pneumophila.
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In the previous work, we have indicated that HMGB1, a pro-inflammatory cytokine, is closely associated with the pathogenesis of psoriasis. To further clarify the role of HMGB1 in the pathogenesis of psoriasis, we investigated the direct function of HMGB1 application and HMGB1 blockade in imiquimod (IMQ)-induced psoriatic mouse model in this study. Mice were treated with imiquimod (IMQ) to induce psoriasis-like inflammation, and consecutively injected with recombinant HMGB1 or phosphate-buffered saline (PBS) i.d. Abundant cytoplasmic expression of HMGB1 was observed in lesional skin from IMQ-treated skin. The injection of HMGB1 into the IMQ-treated skin further aggravated the psoriasis-like disease, enhanced the infiltration of CD3+ T cells, myeloperoxidase+ neutrophils and CD11c+ dendritic cells, increased the number of γδ T cells, and upregulated the mRNA expression of interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon (IFN)-γ and IL-17 compared with the PBS injection. Finally, by using anti-HMGB1 monoclonal antibody or HMGB1 inhibitor glycyrrhizin, we indicated that HMGB1 blockade reduced the number of γδ T cells, suppressed the mRNA expression of IL-6, TNF-α, IFN-γ and IL-17, and moderated clinical and histological evolvement in the IMQ-treated skin. Our data suggest that HMGB1 may act as a pro-inflammatory cytokine, and contribute to the development of IMQ-induced psoriasis-like inflammation. HMGB1 blockade may represent a new direction in the suppression of psoriasis.
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Anti-Inflamatórios/uso terapêutico , Ácido Glicirrízico/uso terapêutico , Proteína HMGB1/metabolismo , Psoríase/imunologia , Aminoquinolinas , Animais , Anti-Inflamatórios/farmacologia , Citocinas/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Ácido Glicirrízico/farmacologia , Imiquimode , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Psoríase/tratamento farmacológico , Psoríase/metabolismoRESUMO
OBJECTIVE: To evaluate the characteristics of enhancement of focal nodular hyperplasia (FNH) of the liver by analyzing the dynamic contrast-enhanced multislice computed tomography (MSCT) features and correlating them with pathological findings. PATIENTS AND METHODS: Nine males and 16 females with pathologically confirmed FNH and complete preoperative contrast-enhanced MSCT data were recruited for this study. The imaging features of FNH on the pre- and postcontrast MSCT were analyzed by two experienced radiologists by consensus. RESULTS: Pathology showed central scars and abnormal blood vessels in 17 and 21 of 25 lesions, respectively, while MSCT with multiphase enhancement showed central scars in eight of the 17 lesions (47.1%) and abnormal arteries or draining veins in 13 of the 21 lesions (61.9%). Furthermore, abnormal draining veins in five lesions were found to be diagnostic, which is another important finding. CONCLUSION: Multiphase scanning can provide the panorama of FNH lesions and reveal their enhancement patterns and pathological characteristics. Abnormal blood vessels within or around the lesion are demonstrated more often than central scar, and both should be observed for FNH diagnosis.
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Monoammonim glycyrrhizate (MAG) derived from licorice has been shown to have anti-inflammatory properties. Chemokines are vital inflammatory mediators that are involved with endothelial damage from leukocyte infiltrates in various inflammatory skin diseases. In this study, we investigated the anti-inflammatory effects and mechanisms of MAG on tumor necrosis factor-α (TNF-α) induced chemokine production in a human dermal microvascular endothelial cell line (HMEC-1). HMEC-1 cells were treated with TNF-α, with or without MAG. The results showed that MAG suppressed TNF-α-induced chemokine (including CXCL8, CX3CL1, and CXCL16) mRNA expression in HMEC-1 cells, in a dose-dependent manner, and reduced the secretion of these chemokines in culture supernatant. Moreover, endothelial activation in the presence of MAG blocked the chemotactic activities of TNF-α-stimulated HMEC-1 cell supernatant on the migration of primary neutrophils and primary monocytes. In addition, Western blot and immunofluorescence data revealed that MAG inhibited nuclear translocation of nuclear factor-κB p65 (NF-κB p65). It is the first report to demonstrate that MAG suppresses TNF-α-induced chemokine production in HMEC-1 cells, and that the mechanism may be inhibiting the translocation of NF-κB p65 into the nucleus to prevent the starting of inflammatory signaling pathway. Our results revealed that MAG is a potential anti-inflammatory agent capable of improving inflammatory skin diseases.
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Anti-Inflamatórios/farmacologia , Núcleo Celular/metabolismo , Quimiocinas/biossíntese , Ácido Glicirrízico/farmacologia , Fator de Transcrição RelA/metabolismo , Transporte Ativo do Núcleo Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quimiotaxia de Leucócito/efeitos dos fármacos , Endotélio Vascular/citologia , Humanos , Microvasos/citologia , Pele/irrigação sanguínea , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
High-mobility group box-1 (HMGB1) has been implicated as a pro-inflammatory cytokine in the pathogenesis of various inflammatory and autoimmune diseases. However, information about HMGB1 in Henoch-Schönlein purpura (HSP) is still unclear. Herein, we investigated the role of HMGB1 in patients with HSP and the pro-inflammatory effects of HMGB1 on human dermal microvascular endothelial cell line (HMEC-1). Serum HMGB1 levels in patients with HSP together with patients with allergic vasculitis (AV) and urticarial vasculitis (UV) were detected by enzyme-linked immunosorbent assay (ELISA). HMEC-1 cells were treated with HMGB1 at concentrations ranging from 4 ng/ml to 100 ng/ml. Serum HMGB1 levels were significantly increased in patients with HSP, AV and UV, when compared with those in control group. Moreover, abundant cytoplasmic expression of HMGB1 was observed in endothelial cells in lesional skin of HSP patients. Using membrane cytokine antibody array, we indicate that HMGB1 markedly induced TNF-α and IL-6 release in cultured supernatant. Furthermore, by real-time quantitative PCR and ELISA, the effects of HMGB1 on these cytokines production in HMEC-1 cells were established. Finally, Western blot data revealed that HMGB1 can induce phosphorylation of inhibitor of κB-α (IκBα) and the nuclear translocation of nuclear factor-κB (NF-κB) p65 in HMEC-1 cells. In conclusion, this study provides first observations on the association of HMGB1 with HSP. We suggest that HMGB1 may be an important mediator of endothelial inflammation through the induction of TNF-α and IL-6 production and may play a crucial role in the pathogenesis of HSP.
Assuntos
Proteína HMGB1/sangue , Proteína HMGB1/fisiologia , Vasculite por IgA/sangue , Vasculite por IgA/fisiopatologia , Adolescente , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Células Cultivadas , Criança , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Feminino , Proteína HMGB1/farmacologia , Humanos , Vasculite por IgA/etiologia , Interleucina-6/metabolismo , Masculino , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Urticária/sangue , Vasculite Leucocitoclástica Cutânea/sangue , Adulto JovemRESUMO
Henoch-Schönlein purpura (HSP) is a commonest systemic vasculitis (SV) in childhood characterized by an inflammatory reaction directed at vessels. Endothelial damage and perivascular leukocyte infiltrates are vital in the development of HSP. Vascular endothelial (VE)-cadherin is an endothelial cell-specific adhesion molecule, which plays critical roles in angiogenesis and endothelial integrity. Herein, we investigated the serum levels of soluble VE-cadherin (sVE-cadherin) in patients with HSP and other forms of SV. The serum levels of sVE-cadherin in 30 patients with HSP, together with patients with urticarial vasculitis, allergic vasculitis, Behcet disease, psoriasis vulgaris (PV) and atopic dermatitis (AD) and 26 health controls were measured by enzyme-linked immunosorbent assay. Serum levels of sVE-cadherin were significantly increased in patients with HSP in acute stage and patients with other forms of SV but not in patients with PV or AD. Moreover, Serum sVE-cadherin levels in HSP patients were correlated with the severity of this disease and serum concentrations of IgA anticardiolipin antibodies and vascular endothelial growth factor. Taken together, we show firstly that serum sVE-cadherin is abnormally increased in HSP patients. Increased serum levels of sVE-cadherin might be a novel biomarker for evaluating the severity of HSP and useful for identifying the presence of SV in inflammatory skin conditions.
Assuntos
Antígenos CD/sangue , Caderinas/sangue , Vasculite por IgA/sangue , Vasculite Sistêmica/sangue , Adolescente , Adulto , Anticorpos Anticardiolipina/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Criança , Diagnóstico Diferencial , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Vasculite por IgA/diagnóstico , Vasculite por IgA/imunologia , Imunoglobulina A/sangue , Masculino , Valor Preditivo dos Testes , Índice de Gravidade de Doença , Vasculite Sistêmica/diagnóstico , Vasculite Sistêmica/imunologia , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/sangue , Adulto JovemRESUMO
The number of papers published in American Journal of Pharmaceutical Education and Chinese Journal of Pharmaceutical Education from 2003 to 2013 was calculated .The knowledge maps of research hot spots and co-operation maps of research institutions in the two journals were plotted .The different research-oriented key points and the cooperative relationship between different research institutions in the two journals and the problems existed in domestic journals of pharmaceutical education were analyzed with certain suggestions put forward for the solution of the problems existed in domestic journals of pharmaceutical education .